标准吧

wap.biaozhun8.com

羟基保护油漆盐雾试验测定标准

REVIEW
J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4005
Protecting groups
Krzysztof Jarowicki and Philip Kocienski
Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ
Covering: 1997
Previous review: Contemp. Org. Synth., 1997, 4, 454
1Introduction
2Hydroxy protecting groups
2.1Esters
2.2Silyl ethers
2.3Alkyl ethers
2.4Alkoxyalkyl ethers
3Thiol protecting groups
4Diol protecting groups
5Carboxy protecting groups
6Phosphate protecting groups
7Carbonyl protecting groups
8Amino protecting groups
9Miscellaneous protecting groups
10Reviews
11References
1Introduction
The following review covers new developments in protecting
group methodology which appeared in 1997. As with our previ-
ous annual review, our coverage is a personal selection of
methods which we deemed interesting or useful. Many of the
references were selected through a Science Citation Index
search based on the root words block, protect and cleavage;
however, casual reading unearthed many facets of protecting
group chemistry which are beyond the pale of a typical key-
word search. Inevitably our casual reading omits whole areas in
which we lack expertise and so we cannot claim comprehensive
coverage of the literature. The review is organised according to
the functional groups protected with emphasis being placed on
deprotection conditions. A separate annual review on combin-
atorial chemistry appeared earlier this year which incorporates
the related subject of solid phase linker chemistry.
2Hydroxy protecting groups
2.1Esters
Attempts to use standard basic reagents to cleave the O-acetyl
groups in aminosugar derivative 1 (e.g. MeONa in MeOH; NH3
in MeOH; K2CO3 in MeOH–H2O) also affected the  N-Troc
(2,2,2-trichloroethoxycarbonyl) group (Scheme 1).
1
 The goal
was finally achieved with a MeOH–CH2Cl2 solution of a mix-
ture of guanidine and guanidine nitrate (4)  [obtained by the
reaction of guanidine nitrate (3) with 0.2 equivalents of sodium
methoxide]. Both  S- and  O-glycosides are stable under the
reaction conditions as are some standard protecting groups
like NPhth (N-phthalimido), benzylidene and isopropyl-
idene acetals, BnO, and Ph2But
SiO but tetrachlorophthalimido,
N-Fmoc, and  O-Troc protecting groups are attacked by the
guanidine–guanidine nitrate reagent.
In the closing stages of an impressive synthesis of the marine
antitumour agent altohyrtin C (7, Scheme 2), Evans and co-
workers
2
 exploited the higher base lability of methoxyacetates
to achieve a selective deprotection in the presence of two
secondary acetate functions in intermediate 5.
The penultimate step in a recent synthesis of the antitumour
macrolides cryptophycin 1 (11) required a mild method for the
introduction of the epoxide ring in the side chain3
 (Scheme 3).
Scheme 1
O
SEt RO
NH
OBn
OCCl3
O
RO
H2N
H2N
NH2  NO3
3 (5 mmol)
4
1
2
94%
G/GHNO3
MeONa (1 mmol)
(in MeOH, 1 ml, 1 M)
MeOH-CH2Cl2
(50 ml, 9:1), rt 4 (6 ml)
rt, 15 min
0.1 mmol scale
G = guanidine
R = Ac
R = H
Scheme 2
82%
5
6
O
O
O
O
O
OAc
O
O
TBSO OTES
OMe
AcO
H
TESO
OMeH
OTBS
OTES
OR
R = COCH2OMe
R = H
NH3, MeOH
O
O
O
O
O
OAc
O
O
HO O
OMe
HO
H
HO
OMeH
OTBS
OH
HOO
6 steps
74006 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Scheme 3
OOHN
O
OH
Ph
OH
O
O
HNO
Cl
OMe
OOHN
O
O
O
HNO
Cl
OMe
Ph
O
O MeO
N3
OOHN
O
O
O
HNO
Cl
OMe
Cl
O
Ph
O
N3
OOHN
O
Ph
O
O
HNO
Cl
OMe
O
N3(CH2)3C(OMe)3
Me3SiCl
63%
–Me3SiOMe
(a) Ph3P, H2O (63%)
(b) K2CO3, Me2C=O (98%)
8 9
10 11
A variant of a direct method for the conversion of diols to
epoxides developed by Sharpless
4
 was cleverly adapted to the
case at hand. Thus diol  8 was treated with the 4-azido-1,1,1-
trimethoxybutane in the presence of chlorotrimethylsilane
to give the cyclic orthoester  9 which decomposed under the
reaction conditions with loss of Me3SiOMe to give the chloro-
hydrin ester  10 (inversion). Selective reduction of the azide
under Staudinger conditions produced an intermediate amino
ester which underwent intramolecular lactamisation to release
a hydroxy group. In the last step, the resultant chlorohydrin
was converted to the cryptophycin 1 (11) on treatment with
base.
The Hasan group5
 tested o-nitrobenzyloxycarbonyl (NBOC)
and related groups as photolabile protectors of nucleoside
5-hydroxy groups (Scheme 4). Generally the rates of photo-
removal of 2-(o-nitrophenyl)ethoxycarbonyl (NPEOC) deriv-
atives (12,  n = 1) were faster than the corresponding NBOC-
protected compounds (12,  n = 0). Also substitution at the
α-carbon had an enhancing effect. The most reactive com-
pound had a methyl group and ethyl chain (t1/2 = 0.66 min) and
the order of reactivity of  12 was found to be: R = Me,
n = 1>R = o-nitrophenyl, n = 1>R = o-nitrophenyl, n = 0.
Unden and co-workers reported that the 2,4-dimethylpentan-
Scheme 4
O
HO
N
NH
O
O
O (CH2)nO
O
R NO2
O
HO
N
NH
O
O HO
12
13
hν (365 nm, 200 W Hg lamp)
MeOH-H2O (1:1)
3-yloxycarbonyl (Doc) group can be used for protecting the
hydroxy group of tyrosine.
6
 The protection is achieved in the
reaction of tyrosine derivative 14 with 2,4-dimethylpentan-3-yl
chloroformate and ethyldiisopropylamine (Scheme 5). The Doc
group is 1000-fold more stable towards nucleophilic piperidine
than the commonly used 2-bromobenzyloxycarbonyl (2-BrCbz)
group and it is completely cleaved by hydrogen fluoride. How-
ever the 2-BrCbz group is superior in terms of acid stability (the
loss of protection after 20 min in 50% trifluoroacetic acid–
CH2Cl2 is 0.01% for 2-BrCbz group and 0.04% for Doc group).
2.2Silyl ethers
In the final steps of an elegant synthesis of dynemicin A (19,
Scheme 6), Myers and co-workers
7
 needed to deprotect the
hydroquinone in Diels–Alder adduct  18 before cleavage of
the sensitive bicyclic acetal followed by in situ oxidation to the
anthraquinone in the target. This required the use of an iso-
benzofuran (16) with highly labile protecting groups for which
the trimethylsilyl ether was ideally suited. Thus, brief treatment
of Diels–Alder adduct  18 with excess activated manganese
dioxide and triethylamine trihydrofluoride (1:1 molar ratio,
ca. 70 equiv.) led to cleavage of the three trimethylsilyl ethers
together with the triisopropylsilyl ester and the resultant
product oxidised in situ to afford dynemicin A (19) in 53% yield.
N-Silylpyridinium triflates are powerful silylating agents
which have been used in the preparation of enol silanes and for
the silylation of carboxylic acids.
8
 Olah and Klumpp report a
new method for their preparation as well as their use in the
silylation of alcohols
9
 (Scheme 7). The salts  21a–c were pre-
pared by reaction of an allylsilane 20 with triflic acid followed
Scheme 5
15
OH
COOBn
NHBoc
Pr
i
2CHOC(O)Cl
EtNPr
i
2
MeCN
Pd/H2
(a)
(b)
O
COOH
NHBoc
O
O
14J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4007
by addition of pyridine. They were obtained in nearly quanti-
tative yield as crystalline solids which were stable indefinitely
at room temperature in an inert atmosphere. However, the
reagents are more conveniently prepared  in situ and used
immediately as silylation reagents. No aqueous workup is
required to isolate the silyl ethers: the product mixture is simply
diluted with pentane to complete the precipitation of the pyrid-
inium triflate. Filtration of the product through a plug of silica
gel returns the pure silyl ether.
Phosphonium salt  24 (formed in the reaction of 2,4,4,6-
tetrabromocyclohexa-2,5-dienone  23 with triphenylphosphine,
Scheme 8) has been reported recently to transform primary and
secondary alcohols and THP ethers into the corresponding
bromides.
10
 It can also directly convert
11
 silyl ethers (e.g.  25)
into bromides. The reagent 24 is not isolated but is immediately
treated with the corresponding silyl ether. The reaction works
well with trimethylsilyl (TMS), triethylsilyl (TES) and  tert-
butyldimethylsilyl (TBS) ethers but is very slow with  tert-
Scheme 6
HN
H
CO2H
OMe
OH
OH
O
OOH
O
O
TMSO
TMSO
OTMS
N
H
CO2Si(Pr
i
)3
OMe
TMSO
TMSOO
O
O
O
TMS
N
H
CO2Si(Pr
i
)3
OMe
O
O
16 17
18
19
THF, –20 → 55 °C, 5 min
+
75%
MnO2, Et3N•3HF
THF, 23 °C, 9 min 53%
Scheme 7
SiR3
CF3SO3H (1 equiv.)
CH2Cl2, 0 °C, 2 h
pyridine (1 equiv.)
rt, 2 h
(a)
(b)
N
SiR3
CF3SO3

21a R = Me
21b R = Ph
21c R = Pr
i
O
TMSO
TMSO
TMSO
TMSO
OTMS
glucose
70%
20
22
butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS) ethers.
This allows the selective bromination of 25 to give 26 in 75%
yield.
Maiti and Roy12
 reported a selective method for deprotection
of primary allylic, benzylic, homoallylic and aryl TBS ethers
using aqueous DMSO at 90 C (Scheme 9). All other TBS-
protected groups as well as THP ethers, methylenedioxy ethers,
benzyl ethers, methyl ethers and aldehyde functionalities
remain unaffected. Also a benzyl TBS ether can be selectively
deprotected in the presence of an aryl TBS ether.
Full details of Fraser-Reid’s synthesis of the bacterial nodu-
lation factor  30 NodRf-III (C18:2, MeFuc) have been pub-
lished.
13
 The  final step of the synthesis required removal of
three TBS ethers, one of which was protecting the anomeric
position in  29 (Scheme 10). Anomeric deprotections using
TBAF are complicated by Lobry de Bruyn–Alberda van
Eckenstein rearrangements and other base catalysed degrad-
ations and mildly acidic methods (e.g. PPTS in MeOH at 55 C)
were fruitless even after extended reaction times. However buff-
ering the TBAF with AcOH gave the desired target 30 in 83%
yield. The problems associated with the basicity of fluoride are
underscored by another recent example taken from Boger’s syn-
thesis of the vancomycin CD and DE ring systems.
14
 Attempted
removal of the TBS group from 31 was accompanied by retro-
aldolisation of the resultant β-hydroxyphenylalanine subunit to
give 33 in 61% yield. Here again, buffering the reaction mixture
with AcOH suppressed the unwanted side reaction and gave the
desired deprotected product 32 in 60% yield.
Full details of the use of a non-ionic superbase 34 (Scheme
11) as a catalyst for the silylation of alcohols using  tert-
butyldimethylsilyl chloride or  tert-butyldiphenylsilyl chloride
has been reported.
15
 The reactions are carried out in acetonitrile
at 24–40 C though DMF at 24–80 C may be needed for
hindered systems. The catalyst, which is commercially available
from Strem, is compatible with aldehydes, ketones, esters,
nitriles and skipped dienes. The catalyst is expensive but it can
be easily recycled. The catalytic effect of 34 was attributed to
the formation of a transannular stabilised loose ion pair 35.
A new synthesis of protected phenolic ethers has been
reported16
 in which Ni(cyclooctadiene)2 and 1,1-bis(diphenyl-
phosphino)ferrocene mediates the reaction of electron deficient
aryl halides (e.g. 36a,b) with sodium tert-butyldimethylsiloxide
(Scheme 12). The reaction fails with the corresponding tri-
methylsilyl, triethylsilyl and triphenylsilyl derivatives. tert-Butyl
ethers of phenols can also be prepared using sodium  tert-
butoxide.
Scheme 8
25 R = OTES
26 R = Br
75%
23
24
Br
BrBr
O
Br
O–
 
+PPh3Br
BrBr
Br
PPh3 (1.5 mmol)
MeCN (3 ml)
CaCO3 (0.9 mmol)
0 °C
R
OTBDPS
1.5 mmol
24, THF (1 ml), rt, 6 h
(0.5 mmol scale)
Scheme 9
OMe
RO
27 R = TBS
28 R = H
82%
DMSO (10 ml)
H2O (2 ml), 90 °C, 8 h
OTBS4008 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Triphenylsilyl ethers are the poor relations of the silyl ether
family of protecting groups but their easy cleavage in the pres-
ence of TBS ethers offered a welcome degree of orthogonality
which Danishefsky et al. exploited in syntheses of the epothil-
ones (Scheme 13).
17
 The triphenylsilyl group is introduced via
the chloride in DMF using imidazole as base.
The Brook group used the tris(trimethylsilyl)silyl (sisyl)
group as a new photolabile protecting group for alcohols.
18
 The
Scheme 10
O O O O O
O
O
OH
OH
OMe
OR HO
NHAc NHAc
OR OR
HO
HO HO
NH
O
MeO2CN
H
H
N
NHBoc
O
O
RO
OMe
OOH NO2
Br
OMe
MeO2CN
H
H
N
NHBoc
O
O
OMe
OOH
Br
OMe
OHC
NO2
83%
29
30
TBAF, AcOH
MeOH-THF, rt
R = TBS
R = H
60%
31
32
TBAF (5 equiv.)
AcOH (6 equiv.)
MeOH-THF, rt
R = TBS
R = H
TBAF
THF, rt, 2 h 61%
33
Scheme 11
P
N
N
N
N Me Me
Me
Si
P N
N
N
N Me Me
Me
R
R
35 (R = Me, Ph)
Cl

δ+
34
δ+
Scheme 12
Br
R
OTBS
R
R = CHO (98%)
R = CN (96%)
Ni(COD)2 (15 mol%)
But
Me2SiONa
PhMe, 95 °C, 2 h
36a,b
37a
37b
sisyl ethers are prepared by treatment of a primary or second-
ary alcohol with tris(trimethylsilyl)silyl chloride (derived in one
step from commercial (Me3Si)3SiH and carbon tetrachloride)
and dimethylaminopyridine (DMAP) (Scheme 14). Tertiary
and hindered secondary alcohols fail to give the corresponding
ether presumably due to steric interactions. Sisyl ethers are
stable to a variety of synthetic protocols like organometallic re-
agents (MeMgBr, Ph3P CH2), oxidation (Jones reagent), acidic
conditions (PTSA; 0.2 M HCl) and some fluoride reagents (KF
and 18-crown-6; CsF). However, they are unstable in the pres-
ence of butyllithium, LiAlH4 (giving a mixture of products)
and tetrabutylammonium  fluoride. The deprotection can be
cleanly performed by photolysis using a medium pressure
mercury lamp (a Hanovia lamp and a Pyrex immersion well).
2.3Alkyl ethers
The nucleophilic cleavage of aryl alkyl ethers by alkanethiol-
ates
19
 or trimethylsilanethiolate20
 typically requires an excess
of the reagent at high temperature. A recent improvement in
the procedure21
 (Scheme 15) allows the use of only one equiv-
alent of thiophenol in 1-methyl-2-pyrrolidone (NMP) using a
catalytic amount (2–5 mol%) of potassium carbonate as the
base. The reactions are complete in 10–30 min at 190 C. A
noteworthy feature of the procedure is the preservation of
aromatic nitro and chloro substituents which are displaced with
stoichiometric thiolates. Moreover,  α,β-unsaturated carbonyl
compounds do not undergo Michael addition of thiolate under
these conditions.
Hwu and co-workers reported sodium bis(trimethylsilyl)-
amide  [NaN(SiMe3)2] and lithium diisopropylamide (LDA) as
efficient agents for demethylation and debenzylation of alkyl
ethers of phenol.
22
 However, the deprotection requires quite
Scheme 13
92%
38
39
OO
OTBS
OH
OR
S
N
H
R = SiPh3
R = H
HF•pyr
pyr, THF, rt
Scheme 14
79%
87%
H
RO
40 R = H
41 R = Si(SiMe3)3
40 R = H
(Me3Si)3SiCl (1.2 mmol)
DMAP (1.2 mmol)
CH2Cl2 (1.2 M solution)
rt, overnight, 1 mmol scale
hν (medium pressure mercury lamp)
MeOH–CH2Cl2 (0.01 M solution)
10 °C, 30 min,
H
H
H
H
Scheme 15
OMe
R
OH
R
PhSH (1.0 equiv.)
K2CO3 (2-5 mol%)
NMP, 190 °C, 10-30 min
68% (R = NO2)
83% (R = COCH=CHPh(E))J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4009
harsh conditions (heating at 185 C for 12 h) which might cause
decomposition of more sensitive molecules. In the case of
dimethoxybenzenes (e.g.  42) the selective mono-O-demethyl-
ation can be achieved (Scheme 16). LDA—but not sodium
bis(trimethylsilyl)amide—can also selectively deprotect a
benzyl ether such as 43 in the presence of a methoxy group.
Alkali metals in liquid ammonia are well known reagents
for deprotecting benzyl ethers.
23
 It is not then surprising that
lithium naphthalenide (prepared from lithium and 1.33 equiv-
alents of naphthalene) also proved successful in this transform-
ation (Scheme 17).
24
 The reagent seems rather harsh; however,
a wide range of functionalities survive the reaction conditions
like alcohols, carbon–carbon double bonds, benzene rings, and
THP, silyl and methoxymethyl ethers. A ketone group can also
be present but its prior conversion to an enolate is necessary.
A similar transformation, but with a catalytic amount of
naphthalene, has been reported by Yus and co-workers.
25
Although allyl ethers are also cleaved by the procedure, the
selective deprotection of benzyl groups is possible (Scheme 18).
Dimethylphenylsilyloxy (but not diphenyl-tert-butylsilyloxy)
groups can also be removed by this methodology.
The  final step in a synthesis of the serine/threonine phos-
phatase inhibitor okadaic acid26
 (49) required the reductive
cleavage of three benzyl ethers in the precursor 48 (Scheme 19).
Previous experience had shown that over-reduction occurs
readily upon debenzylation using lithium in liquid ammonia
containing ethanol.
27
 However, over-reduction was avoided
using lithium 4,4-di-tert-butylbiphenylide (LiDBB).
28
Scheme 16
OMe
OMe
OH
OMe
OBn
OMe
42 43
NaN(SiMe3)2
(2.5 equiv.)
DMEU (0.5 ml)
185 °C, 12 h
96% (0.95 mmol)
LDA (2.5 equiv.)
DMEU (0.5 ml)
185 °C, 12 h
87% (0.55 mmol)
DMEU = 1,3-dimethylimidazolidin-2-one
Scheme 17
44 R = Bn
45 R = H
94%
OH
H
OR
Lithium naphthalenide (6 equiv.)
THF, –25 °C, 80 min
Scheme 18
46 R = Bn
47 R = H
97%
OR Li (powder, 14 mmol)
naphthalene (0.08 mmol)
THF (7 ml)
–78 → –10 °C, 5 h
(1 mmol scale)
Scheme 19
O
O
HO
O
OR
O
O
OO
O
H
H
H
OR
H
OR
H
H
HO
48
49
70% LiDBB, THF, –78 °C
R = Bn
R = H
Discodermolide is a polyhydroxylated lactone exhibiting
potent microtubule stabilising activity similar to that of taxol.
In a recent synthesis of ()-discodermolide, Myles and co-
workers
29
 selectively cleaved the terminal benzyl ether in inter-
mediate  50 (Scheme 20) using Raney nickel and hydrogen in
ethanol. Reductive cleavage of the terminal  p-methoxy-
benzyl PMB ether was minimised under these conditions
and the trisubstituted alkene survived unscathed. Several
steps later, difficulty was encountered removing the MOM
ether from intermediate  52. After extensive experimentation,
the recalcitrant MOM ether was cleaved in 60% yield with 1
equiv. of chlorocatecholborane and 0.5 equiv. of water in
dichloromethane.
Hirota and co-workers
30
 reported that Pd/C catalysed
hydrogenolysis of PMB protected phenols can be selectively
inhibited by pyridine. This allows the selective removal of other
groups like benzyl and Cbz, as well as reduction of alkenes and
nitro groups in the presence of a PMB group (Scheme 21).
Staurosporine, the first member of the glycosylated indolo-
carbazoles to reveal potent protein kinase C activity, has been
investigated for its potential for the treatment of cancer,
Alzheimer’s disease, and other neurodegenerative disorders.
Wood  et al. have published31
 full details of their efficient
and general route to staurosporine and other members of
this family of compounds including ()-K252a, ()-RK286c,
()-MLR-52 and ()-TAN-1030a. The  final step in the
synthesis of ()-TAN-1030a (57, Scheme 22), cleavage of an
O-benzyl bond from an oxime, was accomplished with a large
excess of iodotrimethylsilane, albeit in poor yield (24%).
Scheme 20
OOMOM
OPMB
OTIPS RO
TIPS
OOR
OTIPS
TIPS
I
71%
50
51
R = Bn
R = H
Ra/Ni, H2, EtOH
60%
52
53
R = MOM
R = H
chlorocatecholborane (1 equiv.)
H2O (0.5 equiv.), CH2Cl2
5 steps
Scheme 21
N
H
COOMe
O
OR
BocHN
OPMB
54
55
R = Bn
R = H
H2, 5% Pd/C (10%, w/w)
MeOH-dioxane (1:1) or DMF (20 ml)
Pyridine (0.5 mmol), rt, 24 h
96 % (1 mmol scale)4010 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Iodine is a weak Lewis acid which promotes the peracetyl-
ation of unprotected sugars. However, acetylation of O-benzyl
protected derivatives may be accompanied by cleavage of the
benzyl protecting group. Thus treatment of the glucosamine
derivative 58 with iodine (100 mg g1
 sugar) in acetic anhydride
resulted in acetylation of the hydroxy group at C4 together
with selective cleavage of the primary O-benzyl group and its
replacement by acetate to give the 4,6-di-O-acetyl derivative 59
in >95% yield (Scheme 23).
32
The  O-benzylation of alcohols with benzyl trichloro-
acetimidate is usually accomplished using triflic acid as a
catalyst. However, in a concise synthesis of the cellular mes-
senger  -α-phosphitidyl--myo-inositol 3,4-bisphosphate,
33
trityl cation promoted benzylation of the C5 and C6 hydroxy
functions was used instead (Scheme 24).
34
Magnesium bromide–dimethyl sulfide is a mild reagent for
deprotecting p-methoxybenzyl (PMB) ethers to the correspond-
ing alcohols.
35
 The method is specially suitable for molecules
containing a 1,3-diene moiety (e.g.  62, Scheme 25) because
other PMB-deprotecting reagents (DDQ, CAN) are unsuccess-
ful in these cases. However, some isomerisation of the diene is
observed. Other protective groups like TBS, benzyl, benzoyl
and acetonide also remain intact. On the other hand the
MgBr2OEt2–SMe2 system fails when the PMB group is accom-
panied by a methoxymethyl (MOM) or benzyloxymethyl
(BOM) protecting group.
A p-methoxybenzyl (PMB) group can also be removed from
alcohols and phenols using a catalytic amount of AlCl3 or
SnCl22H2O in the presence of EtSH at room temperature.
36
Under these mild conditions other protecting groups such as
methyl, benzyl and TBDPS ethers,  p-nitrobenzoyl esters, iso-
propylidene acetals and glycosydic moieties (Scheme 26)
remain unchanged. EtSH, by trapping PMB cations, is essential
to obtain the product free from impurities.
Scheme 22
56
57
N N
H
N O
O
N
MeO
RO
Me3SiI (0.3 ml)
CDCl3 (3 ml), rt, 48 h
24% (0.02 mmol scale)
R = Bn
R = H
Scheme 23
O HO
OBn
BnO
NPhth
OEt
O AcO
OAc
BnO
NPhth
OEt
I2, Ac2O
rt, 24 h
>95%
58 59
Scheme 24
O
O
OR (BnO)2OPO
OR
(BnO)2OPO
>73%
60
61
PhCH2O—C(=NH)CCl3
Ph3CBF4 (5 mol%)
Et2O, 24 °C, 32 h
R = H
R = Bn
4-Azido-3-chlorobenzyl (Cl-Azb) ethers are prepared by alkyl-
ation of hydroxy groups with 4-azido-3-chlorobenzyl bromide,
available in two steps from commercial 2-chloro-4-methyl-
aniline.
37
 Cl-Azb ethers are more stable than the parent
4-azidobenzyl (Azb) ether. Cl-Azb ethers were inert towards
DDQ but were cleaved smoothly after conversion to the corre-
sponding iminophosphorane (Scheme 27).
6-O-Trityl monosaccharides are central to a strategy for the
synthesis of oligosaccharides based on thioglycoside activation.
Thus the trityl group in thioglycoside  69 (Scheme 28) was
robust enough to withstand the arming of the thioglycoside
acceptor using N-iodosuccinimide (NIS) in the presence of a
catalytic amount of triflic acid followed by reaction with the
donor 70 to give the disaccharide 71 in 62% yield.
38
 The pre-
ponderance of the α-anomer was attributed to the steric effect
of the trityl group. In a subsequent step, the trityl ether in 71
was cleaved and the freed hydroxy group acted as a donor when
the thioglycoside 72 was armed with NIS in the presence of one
equivalent of TMSOTf, whereupon the trisaccharide  73 was
formed in 70% yield, again with modest α-selectivity.
4-Dimethylamino-N-triphenylmethylpyridinium chloride
(75, Scheme 29) is a stable isolable salt which can be used for a
clean triphenylmethylation of a primary alcohol over a second-
Scheme 25
64%
62 R = PMB, Z/E = 12.6/1
63 R = H, Z/E = 8.4/1
      (8% recovery of 62)
O
O
RO
MgBr2•OEt2 (3 equiv.)
Me2S (10 equiv.)
CH2Cl2, rt, 20 h
Scheme 26
64 R = PMB
65 R = H
80% O
O O
OBn
OR
BnO
SnCl4•2H2O (0.3 equiv.)
EtSH (4 equiv.), rt, 3 h
H
Scheme 27
O
BnO
BnO
BnO
OMe
OH
O
BnO
BnO
BnO
OMe
O
N3
Cl
O
BnO
BnO
BnO
OMe
O
N
Cl
NaH, DMF
ArCH2Br
PPh3, THF
rt, 1 h
DDQ, H2O, AcOH (95%)
DDQ, silica gel, rt, 1.5 h (90%)
94%
66
67
68
PPh3J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4011
ary one.
39
 Recently Hernandez and co-workers published in
Organic Syntheses
40
 a detailed large scale procedure for this
reagent, slightly modifying their original method.
41
In order to protect the hydroxy function of serine and threo-
nine, temporary protection of α-amino and α-carboxy groups is
necessary. Recently a new methodology has been developed42
in which boron trifluoride–diethyl ether is used for the simul-
taneous protection of these two groups as a 2,2-difluoro-1,3,2-
oxazaborolidin-5-one derivative (e.g. 77, Scheme 30). Reaction
of 77 with isobutylene in acidic conditions afforded selectively
protected derivative  78. In similar fashion benzyl trichloro-
acetimidate converts  77 into the corresponding  O-benzyl
derivative.
Diborane generated in situ by reaction of NaBH4 with iodine
in THF at 0 C accomplishes the deprotection of allyl ethers
under mild conditions (Scheme 31).
43
 Both aryl and alkyl allyl
Scheme 28
O
OTr
BnO
BnO
BnO
O
OBn
HO
BnO
BnO
SEt
OMe
O
OTr
BnO
BnO
BnO O
OBn
BnO
BnOOMe
O
O BnO
BnO
BnO O
OBn
BnO
BnOOMe
O
O
OBn
BnO
BnO
BnO
SEt
O
OBn
BnO
BnO
BnOO
69
70
71 (62%)
72
73
NIS
TfOH (cat.)
α:β = 6:1
NIS, TMSOTf (1 equiv.)
CH2Cl2-Et2O (1:1)
rt, 15 min
70%
α:β = 3:1
Scheme 29
74
75
N
NMe2
N
NMe2
CPh3
Ph3CCl (0.1 mmol)
CH2Cl2 (200 ml)
20-25 °C, 3 h
96% (0.1 mol scale)
Cl

Scheme 30
dioxane (30 ml)
rt, 15 min
H3PO4 (0.4 ml)
rt, 15 min
isobutylene (20 ml)
–20 °C→rt, 2-2.5 h
(10 mmol scale)
(a)
(b)
(c)
HOOLi
O
NH2
BF3•OEt2 (6 ml)
THF (15 ml)
rt, 6 h; 40-45 °C, 2 h
100% (10 mmol scale)
HO
H2N B
F2
O
O
But
OOH
O
NH2
76
77 78
ethers are cleaved without detriment to cyano, ester, nitro,
acetonide and tetrahydropyranyl groups.
Miura and co-workers
44
 reported a new method for the
etherification of phenols by using allyl alcohols and catalytic
amounts of palladium() acetate and titanium() isopropoxide
(Scheme 32). The reaction is quite general; however, it fails
in the case of 3,5-dimethoxyphenol because of the exclusive
formation of a C-allylated product.
Benzyltriethylammonium tetrathiomolybdate deprotects
propargyl ethers and esters in acetonitrile at room temperature
(Scheme 33).
45
 Allyl ethers, nitro compounds, aldehydes and
ketones are not affected though alkyl halides are converted to
sulfides, and azides and thiocyanates are reduced.
Electroreductive cleavage of propargylic aryl ethers and
esters to the corresponding phenols and carboxylic acids
occurs in good yield (77–99%) using Ni
II
–bipyridine complex
as catalyst.
46
 Ester, cyano and, most interestingly, aryl ketone
functionalities (Scheme 34) are stable under the reaction condi-
tions. However, in the case of o-bromo and o-iodo derivatives,
the halogen is quantitatively replaced with hydrogen, whereas
an o-chloro atom is only partially reduced (20%).
2.4Alkoxyalkyl ethers
Methoxymethyl (MOM) protecting groups are quite robust and
their removal is often incompatible with many functional
groups. A further complication is the formation of formal
derivatives on deprotection of MOM-protected 1,3-diols. Never-
theless, Ghosh and Liu47
 were able to remove two MOM groups
protecting a 1,3-diol in the  final step of their synthesis of
the streptogramin antibiotic madumycin II (84, Scheme
Scheme 31
O
O O
OR
MeO
OR
87%
79
80
R = allyl
R = H
NaBH4, I2
THF, 0 °C, 30 min
Scheme 32
O
O
OH
O
O
O
CH2=CHCH2OH (4 mmol)
Pd(OAc)2 (0.01 mmol)
PPh3 (0.04 mmol)
Ti(OPr
i
)4 (0.25 mmol)
MS (4Å, 200 mg)
PhH (5 ml), 50 °C, 4-20 h
67% (1 mmol scale)
Scheme 33
O
OMe
CHO
OH
OMe
CHO
[PhCH2NEt3]2MoS4 (1 equiv.)
MeCN, 36 h, rt
87%
Scheme 34
O
O
Bu4NBF4 (10–3 M)
Ni(bipy)3(BF4)2 (0.3 mmol)
DMF (40 ml), E = 5-10 V, 60 mA
90% (3 mmol scale)
O
OH
81 824012 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
35). The successful method employed tetrabutylammonium
bromide (2 equiv.) and an excess of dichlorodimethylsilane in
dichloromethane at 0 C for 6 h.
The final step in a synthesis of the Annonaceous acetogenin
()-4-deoxygigantecin48
 entailed the cleavage of two MOM
ether groups using BF3OEt2 in the presence of SMe2 (Scheme
36).
49
During a synthesis of the diterpene epoxydictymene, the
Paquette group found that easy elimination took place during
the cleavage of the MOM ether in intermediate  87 (Scheme
37).
50
 When 1 equiv. of bromocatecholborane in dichloro-
methane was used, the desired cleavage took place to give the
requisite alcohol  88  in quantitative yield. However, when less
than 1 equiv. was used, the dimeric species 89 was generated.
Synthetic analogues of natural oligonucleotides have
attracted interest for their promising applications in antisense
chemotherapy.
51
 In a synthesis of the thymidine acyclonucleo-
side analogue 93 (Scheme 38), the MOM group in 90, normally
used as a hydroxy protecting group was converted to the ethyl-
thiomethyl ether intermediate  92 which was then used as a
functional group to append thymine.
Scheme 35
47%
83
84
HNO
O
O
H
N
ON
O
ROOR
Bu4NBr (2 equiv.), Me2SiCl2 (excess)
CH2Cl2, 4Å  MS, 0 °C, 6 h
R = MOM
R = H
Scheme 36
O
O
O
C12H25
ROOR HH
HHO
HO
57%
85
86
R = MOM
R = H
BF3•OEt2
SMe2
Scheme 37
100%
88
87
H
H
RO
H
H
O
H
H
O
R = H
R = MOM
bromocatecholborane (1 equiv.)
CH2Cl2, –78 °C
bromocatecholborane (< 1 equiv.)
CH2Cl2, –78 °C
89
Macrosphelide A (96) strongly inhibits adhesion of human
leukaemia HL-60 cells to human umbilical vein endothelial
cells by inhibiting the binding of sialyl Lewis x to E-selectin.
It is also orally active against lung metastasis of B16/BL6
melanoma in mice and it appears to be a lipoxygenase inhibitor
as well. The closing steps in a recent synthesis of macrosphelide
A required the stepwise release first of a hydroxy and carboxy
function as a prelude to macrolactonisation and then two
hydroxy groups protected as their (2-methoxyethoxy)methyl
(MEM) ethers—all this without detriment to the three lactone
functions.
52
 The  first deprotection was accomplished with a
mixture of trifluoroacetic acid (TFA, 5 parts) and thioanisole
(1 part) in dichloromethane (5 parts) (Scheme 39). The  final
deprotection of the 2 MEM groups (95→96) was accomplished
in good yield with trifluoroacetic acid in dichloromethane
(1:1).
A concise synthesis of zaragozic acid53
—an inhibitor of
squalene synthase—required the deprotection of a MEM ether
in the presence of two dioxolane rings. This was accomplished
(Scheme 40) using iodotrimethylsilane generated  in situ by
reaction of chlorotrimethylsilane and sodium iodide.
54
In 1993 a Cambridge group showed that BCl3SMe2 select-
ively cleaved benzyl ethers in the presence of acetate and  tert-
butyldiphenylsilyl groups.
55
 On the other hand trityl ethers are
rapidly cleaved in the presence of benzyl ethers. The same
group56
 applied the method twice in a synthesis of the marine
oxocin derivative laurencin as shown in Scheme 41. Early on the
benzyloxymethyl (BOM) ether 97 was cleaved in good yield and
the resultant hydroxy group converted to silyl ether 98 and later
Scheme 38
91
92 93
O OMe
H
MeO2C
FmocHN
O
N
NH
H
MeO2C
FmocHN
O Br
H
MeO2C
FmocHN
O SEt
H
MeO2C
FmocHN
O
O
Me2BBr (3.5 equiv.)
EtNPr
i
2 (0.1 equiv.)
CH2Cl2, –78 °C, 20 min
EtSH (3 equiv.)
EtNPr
i
2 (2.0 equiv.)
CH2Cl2, –78 °C, 3 h
60%
N
N
OTMS
OTMS
I2 (1.0 equiv.)
THF, rt, 48 h
58%
(5.0 equiv.)
90
Scheme 39
95 R = MEM
96 R = H
90%
O
O
OTBS
CO2But
O
OMEM
MEMO
O
TFA-CH2Cl2 (1:1)
O
O
O
O
OR
RO
O
O
(a) TFA-thioanisole-CH2Cl2 (5:1:5) (64%)
(b) 2,4,6-trichlorobenzoyl chloride, NEt3, DMAP (91%)
94J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4013
the  p-methoxybenzyl ether  99 was cleaved selectively in the
presence of the sensitive enyne.
Mycobactins are a family of siderophores produced by myco-
bacteria to promote growth via iron uptake processes. Hu and
Miller
57
 reported a synthesis of mycobactin S (102, Scheme 42)
which was a potent growth inhibitor of Mycobacterium tubercu-
losis. The use of a 2-(trimethylsilyl)ethoxymethyl (SEM) group
to protect the hydroxamic acid residue in the  Nα
-Cbz-Nε
-
hydroxy-Nε
-palmitoyl--lysine fragment 101 was crucial in the
construction of the ester linkage. Both the SEM and  tert-
butyldiphenylsilyl (TBDPS) groups were cleaved in the  final
step using trifluoroacetic acid.
A mild method for the deprotection of SEM ethers was dis-
covered by Marshall and Chen58
 during their synthesis of the
cytotoxic acetogenins aciminocin and asiminecin (104). In the
example shown (Scheme 43), the three SEM ethers were simul-
taneously cleaved from 103 by heating with pyridinium tosylate
(PPTS) in ethanol to give asiminecin (104) in 80% yield.
Mioskowski and co-workers
59
 described the direct conver-
sion of THP-protected alcohols into the corresponding chlor-
ides using dichlorophosgeniminium chloride 106 (Scheme 44).
The corresponding bromides can also be obtained if the reac-
tion is carried out in the presence of 2 equivalents of tetrabutyl-
Scheme 40
O O
O
O OH
MeO2C
EtO2C
HO OMEM
O O
O
O OH
MeO2C
EtO2C
HO OH
Me3SiCl, NaI
MeCN, 0 °C, 1 h
88%
Scheme 41
O
O OSiPh2But
RO
O
OAc
RO
SiMe3
97
98
75% (a) BCl3•SMe2 (2 equiv.), CH2Cl2, rt, 1 min
(b) TMSCl, NEt3, THF
R = BOM
R = SiMe3
99
100
75% BCl3•SMe2 (5 equiv.), CH2Cl2, rt, 5 min
(19.9 mmol scale)
R = PMB
R = H
(4.4 mmol scale)
Scheme 42
H
N
ON
H
N
O
OH O
OO
N
O
OR2
N
OR1
CH3(CH2)14
O
68%
101
102
R1 = SEM, R2 = TBDPS
R1 = R2 = H
CF3CO2H-CH2Cl2 (1:1)
rt, 1 h
ammonium bromide. The reaction works well with primary
alcohols. With secondary alcohols the formation of elimination
by-product is observed (which is the main product in the case of
tertiary alcohols).
Solvent free tetrahydropyranylation of alcohols and phenols
over HSZ zeolites as reusable catalysts has been reported by an
Italian group.
60
Selective protection of the hydroperoxy function in  108
(Scheme 45) using 2-methoxypropene enabled subsequent oxid-
ation of the remaining allylic alcohol function.
61
 The product
109 was converted to the marine cyclic peroxide plakorin.
Acetal derivatives prepared from N-substituted 4-methoxy-
1,2,5,6-tetrahydropyridine (e.g.  111) have been used by the
Reese group62,63
 for the protection of the 2-hydroxy function
in an automated solid phase synthesis of oligoribonucleotides.
The drawback of this methodology was the five steps required
to make 111 (and related compounds). Recently the same group
reported a much shorter procedure consisting of only two steps
(Scheme 46).
64
3Thiol protecting groups
Hypusine (Hpu) is an unusual amino acid uniquely found in
eLF-5A, a protein which serves as an initiation factor in all
growing eukaryotic cells and which plays a critical role in
the replication of human immunodeficiency virus-1 (HIV-1).
Bergeron and co-workers
65
 synthesised the hypusine-containing
Scheme 43
80%
103
104
OO
O
H
OR
H
n-C5H11
OR
OR
H O H
(  )11 (  )3
R = SEM
R = H
PPTS (13.3 equiv.)
EtOH, ∆, 16 h
Scheme 44
R
Me
N
Me
Cl
Cl
105 R = OTHP
107 R = Cl
78%
106 106 (1.05 equiv.)
CH2Cl2, 0 °C
Cl

Scheme 45
H33C16
OH
O
OTIPS
H33C16
O
OTIPS
O
O
OMe
HO
(a)
(b)
MeC(OMe)=CH2, PPTS
PDC
67% overall (2 steps)
108 109
Scheme 46
O
Cl Cl
N
Ar
OMe
ArNH2 (0.20 mol)
TsOH·H2O (0.22 mol)
MeOH (200 ml), ∆, 2h
HC(OMe)3 (0.6 mol)
∆, 1 h
Et3N (0.33 mol)
EtNPr
i
2 (0.48 mol)
BF3•OEt2 (0.40 mol)
CH2Cl2 (300 ml), 0 °C, 3 h
83% (0.22 mol scale)
(a)
(b)
(c)
(d)
Ar = o-fluorophenyl
110
1114014 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
pentapeptide  113 found in eIF-5A capped at its  N-terminus
with -cysteine (i.e. Cys-Thr-Gly-Hpu-His-Gly, Scheme 47) as
a means of covalently linking this peptidic hapten to a carrier
protein for ultimate use in raising antibodies specific to
hypusine-containing epitopes. The Cbz group used to protect
the cysteine thiol group was robust enough to survive aqueous
sodium carbonate in DMF and typical peptide coupling condi-
tions; however, in the  final step, it was cleaved together with
seven other acid-labile protecting groups, using neat refluxing
trifluoroacetic acid containing phenol as a scavenger.
S-9H-Xanthen-9-yl (Xan) and 2-methoxy-9H-xanthen-9-yl
(2-Moxan) are new S-protecting groups for cysteine which are
compatible with the base-labile  Nα
-fluoren-9-ylmethoxycarb-
onyl (Nα
-Fmoc) group currently used in solid phase peptide
synthesis.
66
 Both groups are introduced onto sulfhydryl func-
tions by  S-alkylation reactions involving the corresponding
xanthydrols 114a,b under acid catalysis (Scheme 48). Selective
removal of S-Xan or S-2-Moxan groups is best accomplished
with TFA–CH2Cl2–Et3SiH (1:98.5:0.5) at room temperature.
Alternatively, oxidative deprotection of S-Xan or S-2-Moxan
groups with iodine (10–20 equiv.) or thallium() tris(trifluoro-
acetate) (1–3 equiv.) provides the corresponding disulfides. Both
groups are more labile towards acidolysis and more readily
oxidised than S-acetamidomethyl (Acm), S-trityl and S-2,4,6-
trimethoxybenzyl (Tmob) protecting groups.
4Diol protecting groups
A detailed large scale  Organic Syntheses procedure has
appeared for the selective MOM-protection of 1,3-diols  via
regioselective cleavage of methylene acetals (Scheme 49)
67
 first
communicated in 1995.
68
Despite the relatively harsh conditions required for their
removal (2 M HCl in acetone, 50 C), methylene acetals are
occasionally used in synthesis. An Italian group69
 has added
POCl3 and SOCl2 in DMSO to the list of reagents which con-
vert diols to methylene acetals. Whilst  syn-1,2- and -1,3-diols
give the corresponding 1,3-dioxolane and 1,3-dioxane deriv-
atives respectively,  anti-1,2-diols or  syn-1,2-diols in sterically
crowded environments give the corresponding 1,3,5-trioxepane
derivatives as illustrated in Scheme 50. The method does not
work well with simple monohydric alcohols.
A new protecting group strategy for diols allows easy trans-
Scheme 47
112
113
N
H
H
N
N
H
H
N
N
H
OBut
CbzHN
O
O
O
O
O
O
OBut
H
CbzN
OTHP
NHCbz
CbzS
N
N–Boc
N
H
H
N
N
H
H
N
N
H
OH H2N
O
O
O
O
O
O
OH
H
HN
OH
NH2
HS
N
NH
phenol (50 µmol)
CF3COOH (5 ml), ∆, 90 min
24%
7.2 µmol scale
Hpu
formation of a group stable in acidic conditions into another
stable in basic conditions.
70
 The sequence, exemplified in
Scheme 51, begins with the formation of thiocarbonate 121 by
reaction of diol 120 with 1,1-thiocarbonyldiimidazole (TCDI).
The thiocarbonate moiety in 121 is stable under acidic condi-
tions as illustrated by selective hydrolysis of the isopropylidene
moiety to give 123 in quantitative yield, but the thiocarbonate
reverts to the starting diol 120 by basic hydrolysis. Easy trans-
formation of thiocarbonate  121 into methylene acetal  122 in
one step by radical desulfurisation with triphenyltin hydride in
the presence of AIBN gives a protecting group which is highly
stable in alkaline medium while it is labile towards acid.
Tricolorin A is an unusual tetrasaccharide macrolactone
isolated from Ipomoea tricolor, a plant used in Mexican tradi-
tional agriculture as a weed controller. Two syntheses of tri-
Scheme 48
O
OH
R
O
S
R
NH2
CO2H
O
S
R
NHFmoc
CO2H
L-cysteine
TFA-DME (1:50)
25 °C, 30 min
Fmoc-L-cysteine
TFA (1 equiv.)
CH2Cl2, rt, 30 min
115a R = H
115b R = OMe
Fmoc–OSu
NEt3, MeCN-H2O, rt, 3 h
114a R = H
114b R = OMe
116a R = H
116b R = OMe
114a115a
116a
81%
90%
88% 114b115b
116b
83%
83%
97%
Su = Succinimide
Scheme 49
AcOO OO Cl
AcCl (0.352 mmol)
ZnCl2 (0.5 mmol)
Et2O (200 ml)
rt, 3 h
HOOO
Me
K2CO3 (0.253 mol)
MeOH (100 ml)
H2O (50 ml)
rt, 2 h
89-92%
(0.1 mmol scale)
117
118 119
AcOOOMe
MeOH (1.11 mol)
EtNPr
i
2 (0.350 mol)
Et2O (60 ml)
0 °C→rt, 1 h
77-91%
(0.294 mol scale)
Scheme 50
O
HO
OH
HO
OMe
OH
O
O
OMe
O
O
O
O
POCl3, DMSO
65 °C, 2 h
85%J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4015
colorin A have been reported recently by the groups of Hui
71
and Heathcock.
72
 The closing stages of the Hui synthesis
entailed the simultaneous deprotection of a benzylidene acetal
and an isopropylidene acetal (Scheme 52) using DDQ in reflux-
ing aqueous acetonitrile. The last step, hydrogenolysis of the
three benzyl ether functions in 124 gave tricolorin A (125).
Benzylidene acetals can be cleaved to hydroxy esters using
2,2-bipyridinium chlorochromate (BPCC) and  m-chloro-
perbenzoic acid (MCPBA).
73
 The selectivity of the cleavage
favours the product having primary ester and secondary alcohol
functionality, as shown in Scheme 53. O-Allyl and O-benzyl
groups do not tolerate the reaction conditions, presumably
because they undergo competitive oxidation.
The base-induced intramolecular heteroconjugate addition
of the hemiacetal  127 (Scheme 54) derived from reaction
of alcohol  126 with benzaldehyde was used to generate the
benzylidene-protected 1,3-diol derivative 128 in 83% yield.
74
Scheme 51
120 121 122
123
OH HO
OO
O O
S
OO
O O
OO
O O
S
OH HO
TCDI (2 mmol)
MeCN
rt, 2-3 days
90%
(1 mmol scale)
Ph3SnH (2 mmol)
AIBN (10 mg)
PhMe (25 ml)
∆, 2-4 h, 91%
(1 mmol scale)
Amberlite 15(H+)
MeOH, rt, 30 min 100%
Scheme 52
O
O
O
O
O
O
O
O Ph
O
O
O
O
O
O
H
O
O
BnO BnO
BnO O
O
O
O
O
O
O
O
HO
HO
O
O
O
O
HO
OH
H
O
O
HO HO
HO O
O
(a) DDQ (3 equiv.)
       MeCN-H2O (9:1), ∆, 4 h
(b) H2, Pd/C, EtOH
70%
124
125
The oxidative cyclisation of mono-PMB ethers of 1,3-diols
to afford the corresponding p-methoxyphenyl acetals was first
reported by Yonemitsu and co-workers in 1982.
75
 Myles and co-
workers
76
 have shown that oxidative cyclisation can be used to
differentiate the end groups in 1,3,5-triol systems having pseudo
C2-symmetry as shown in Scheme 55.
Ferric chloride (either anhydrous or hexahydrate) absorbed
on silica gel is known to promote the cleavage of acetals.
77,78
 Sen
and co-workers have recently reported79
 that the reaction is
faster when non-absorbed FeCl36H2O in dichloromethane is
used. Depending on the number of equivalents, the selective
deprotection of either one or both acetal groups can be
achieved (Scheme 56). In both cases, the TBS ether remains
intact.
Ley has used the butane-2,3-diacetal protecting group in an
expedient synthesis of several rare 6-deoxy sugars starting from
cheap galactose and mannose.
80
 The general procedure is illus-
trated in Scheme 57 by the synthesis of methyl-α--rhamno-
pyranoside (135, unnatural rhamnose configuration). Selective
protection of the two equatorial hydroxy functions in methyl-α-
-mannopyranoside (132) occurred in a single step by treat-
ment with butane-2,3-dione and trimethyl orthoformate in the
presence of catalytic camphorsulfonic acid. Alternatively, the
requisite protection can be accomplished using BF3OEt2 as
the catalyst. The final deprotection to give 135 was effected by
hydrolysis using trifluoroacetic acid containing 10% water.
A detailed procedure for the large scale preparation of
1,1,2,2-tetramethoxycyclohexane  137 and its use in the pro-
tection of methyl α--mannopyranoside 138 has been described
in Organic Syntheses (Scheme 58).
81
 The paper summarised the
results obtained when 137 was used for the selective protection
of the  trans-hydroxy groups in a range of sugars. Further
experimental details of the methodology82,83
 and its application
in oligosaccharide assembly84,85
 have also been published.
The simultaneous and selective protection of the two
equatorial hydroxy groups in methyl dihydroquinate (140,
Scheme 59) as the butane-2,3-diacetal was a key strategic
feature in a synthesis of inhibitors of 3-dehydroquinate syn-
thase.
86
 Later in the synthesis, deprotection of intermediate 142
required three steps: (a) hydrolysis of the TMS ether and the
butane-2,3-diacetal with trifluoroacetic acid; (b) cleavage of
Scheme 53
OOMe
OMe O
O
Ph
OMe
H
H
OOMe
OMe HO
OMe
MCPBA (5 equiv.)
BPCC (2 equiv.)
CH2Cl2 (5 ml)
rt, 36 h, 70%
(0.64 mmol scale)
O Ph
O
BPCC = 2,2'-bipyridinium chlorochromate
MCPBA = m-chloroperbenzoic acid
Scheme 54
N
OMe
TrOOHO
Me
(a) KOBut
, THF, 0 °C
(b) PhCHO, 0 °C
N
OMe
TrOOO
Me
Ph
OK
N
OMe
TrOOO
Me
Ph
O
126
127
1284016 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
the isopropyl phosphonate with TMSBr; and (c) hydrolysis of
the methyl ester with aqueous NaOH.
5Carboxy protecting groups
Radiosumin is isolated from the freshwater blue-green alga
Plectonema radiosum. It is a highly potent inhibitor of trypsin
and a moderately active inhibitor of plasmin and thrombin.
In the last step of their synthesis of radiosumin (Scheme 60),
Shioiri and co-workers
87
 required an ester hydrolysis (144→
145) which did not epimerise the two amino acid residues. The
d, esired transformation was accomplished under neutral condi-
tions through the agency of bis(tri-n-butyltin) oxide.
88
Scheme 55
O
OH
OH
OMe
CO2Et
CO2Et
O
OH
O
HO
HO
OMe
CO2Et
CO2Et
O
O
OH
HO
HO
OMe
O
OH
O
OMe
O
O
OH
OMe
CO2Et
CO2Et
O
OH
OH
HO
HO
OMe
DDQ, 4Å MS
CH2Cl2, –30 °C
91%
+
82:18
DDQ, 4Å MS
CH2Cl2, –30 °C
93%
+
99:1
Scheme 56
129
130
131
O
O O
OTBS
H
O
O
O
OH HO
OTBS
H
HO
OH
O
O O
OTBS
H
HO
OH
FeCl3•6H2O (3.5 equiv.)
CH2Cl2, rt, 10 min
77%
FeCl3•6H2O (0.1 equiv.)
CH2Cl2, rt, 10 min
70% (by GLC)
The classical method for the preparation of tert-butyl esters
is the reaction of an acid with isobutylene in the presence of an
acidic catalyst.
23
 Wright and co-workers
89
 reported a modified
Scheme 57
O
OH
OH
HO
HO
OMe
O
OH
OH
OMe
OO
OMe
OMe
butane-2,3-dione
cat. CSA, HC(OMe)3
MeOH, ∆ (95%)
or butane-2,3-dione
cat. BF3•OEt2, HC(OMe)3
MeOH, rt (99%)
O
OH
OMe
OO
OMe
OMe
(a) I2, PPh3, imidazole, PhMe (85%)
(b) H2, Pd/C, Et2NH, MeOH (86%)
132 133
134 135
O
OH
HO
HO
OMe
TFA-H2O (9:1)
Scheme 58
136
137
138
139
OMe
OMe
OMe
OMe
O HO
HO
HO
OH
OMe
O
HO
OH
OMe
OO
MeO
MeO
137 (0.29 mol)
HC(OMe)3 (0.15 mol)
MeOH (300 ml)
CSA (0.015 mol)
∆, 16 h, 41-46%
(0.15 mmol scale)
O
O
CH(OMe)3 (1.46 mol)
H2SO4 (conc., ~32 drops)
MeOH (100 ml), ∆, 5 h
73% (0.4 mol scale)
Scheme 59
OH
OH
HO
CO2Me HO
HO
CO2Me HO
O
O
OMe
OMe
CO2Me TMSO
O
O
OMe
OMe
2,2,3,3-tetramethoxybutane
(MeO)3CH, MeOH, CSA, ∆
87%
P
O
Pr
i
O
Pr
i
O
CO2H HO
OH
OH
P
O
HO
HO
140
141
142 143
(a) TFA, H2O (20:1)
(b) TMSBr, NEt3, CH2Cl2
(c) 0.2 M NaOH
(d) Dowex 50 (H+)
>58% overall
Scheme 60
H
N
N
H
N
H
O
CO2R O
O
NH2
144  R = Me
145  R = H
(Bu3Sn)2O, PhH
26% (44% conversion)J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4017
procedure in which, instead of isobutylene,  tert-butyl alcohol
is used in the presence of a heterogeneous acid catalyst—
concentrated sulfuric acid dispersed on powdered anhydrous
magnesium sulfate. No internal pressure is developed during
the reaction and the method is successful for various aromatic,
aliphatic, olefinic, heteroaromatic and protected amino acids
(Scheme 61). Also primary and secondary alcohols can be con-
verted into the corresponding tert-butyl ethers using essentially
the same procedure (with the exception of alcohols particularly
prone to carbonium ion formation,  e.g. 4-methoxybenzyl
alcohol).
2-(Trimethylsilyl)ethoxymethyl (SEM) esters are usually
cleaved with HF in acetonitrile or with fluoride ion—conditions
which are incompatible with acid sensitive TBS ethers and Boc
groups or  fluoride sensitive Fmoc groups. Joullié and co-
workers
90
 have explored the virtues of SEM esters for the
protection of the C-terminus of peptides and found that many
of the previous incompatibilities can be reconciled by using
magnesium bromide–diethyl ether for the deprotection.
91
Protecting groups typically encountered in peptide chemistry
including Boc, Cbz, Fmoc and Troc carbamates are retained.
The procedure is illustrated by the efficient and selective
deprotection of the didemnin tetrapeptide  146 shown in
Scheme 62.
Damavaricin D (153), a biosynthetic precursor and degrad-
ation product of streptovaricin D, inhibits RNA-directed DNA
polymerase. Roush et al. recently accomplished a synthesis of
damavaricin D which is a salutary lesson in the frustrations
attending model studies.
92
 Success in the synthesis was very
dependent upon a carefully wrought protecting group strategy
which had been thoroughly evaluated in closely related models.
However, the preliminary studies were largely useless in the real
system. For our present purposes we will join the synthesis
at intermediate  148 (Scheme 63) and consider the selective
manipulation of the  five ester functions leading to the  final
product. Cleavage of the 2-(trimethylsilyl)ethyl ester with
TBAF followed by a Curtius rearrangement on the resultant
carboxylic acid returned an isocyanate intermediate which was
trapped with 2-(trimethylsilyl)ethanol to give the 2-(trimethyl-
silyl)ethyl carbamate 149. Selective reduction of the (Z)-enoate
of  149 required careful control of the reaction conditions in
order to avoid competing reduction on the two acetate esters.
Treatment of 149 with 5 equiv. of DIBAL-H in THF at 100 to
78 C for 1.5 h provided the (Z)-enal (14%), the correspond-
ing allylic alcohol (33%) and recovered  149 (49%). After
Scheme 61
OH
NHCbz
O
OBut
NHCbz
O
H2SO4 conc. (10 mmol)
MgSO4 anh. (40 mmol)
But
OH (50 mmol)
CH2Cl2, 25 °C, 18 h
87% (10 mmol scale)
Scheme 62
OMe
N
O
O
NHBoc
O
OR
Me
O
N
O
NHCbz
100%
146
147
R = CH2OCH2CH2SiMe3
R = H
MgBr2•OEt2 (3 equiv.)
CH2Cl2, –20 °C → rt
recycling  149, the enal and allylic alcohol functions were
obtained in 16 and 62% yields respectively. Conversion of the
allylic alcohol to the enal by Swern oxidation followed by a
Horner–Wadsworth–Emmons reaction then gave the dienoate
ester  150. Simultaneous deprotection of the nascent 2-(tri-
methylsilyl)ethyl ester and the 2-(trimethylsilyl)ethoxycarbonyl
group with tris(dimethylamino)sulfonium difluorotrimethyl-
silicate (TASF) returned an amino acid which macrolactamised
on treatment with N-methyl-2-chloropyridinium iodide to give
macrolactam  151 in 76% yield for the two steps. Selective
hydrolysis of the MOM group adjacent to the naphthalene
amide occurred together with the acetonide to yield a triol 152
from which the allyl ether and allyl ester functions were
removed by treatment with catalytic (Ph3P)4Pd and Bu3SnH in
toluene containing HOAc.
93
 Next, the two acetate functions
were hydrolysed with LiOH and the carboxylic acid esterified
with trimethylsilyldiazomethane. To complete the synthesis, the
remaining two MOM groups were hydrolysed with aqueous
TFA and the resultant diol oxidised in air to give damavaricin D
(153).
A Pfizer process development group showed that sulfinic
acids or the corresponding salts, in the presence of a catalytic
amount of Pd(PPh3)4, efficiently cleave the C–O bond of allyl
esters and ethers as well as the C–N bond of N-allyl amines in
dichloromethane or methanolic THF at room temperature.
94
The reaction works equally well with but-2-enyl, cinnamyl,
2-chloroprop-2-enyl and 2-methylprop-2-enyl esters. Most of
the 19 examples reported used toluene-p-sulfinic acid or its
sodium salt, but other sulfinates worked equally well such as
sodium thiophene-2-sulfinate, sodium 4-chloro-3-nitrobenzene-
sulfinate, sodium  tert-butylsulfinate, monosodium  p-sulfino-
benzoate and sodium formaldehyde sulfoxylate (Rongalit). To
demonstrate the power of the method, various allylic esters
(154a–e, Scheme 64) of the highly sensitive penem system were
removed efficiently with sodium toluene-p-sulfinate, whereas
other allyl scavengers such as carboxylic acids, morpholine,
dimedone and N,N-dimethylbarbituric acid led to poor results.
A major problem in the synthesis of serine or threonine
phosphopeptides is the selective removal of N- or C-terminal
protecting groups without causing  β-elimination of the
phosphate moiety—a transformation that occurs at pH>8.
Sebastian and Waldmann showed that heptyl esters were
enzyme-labile carboxy protecting groups that could be cleaved
under conditions mild enough to preserve phosphate residues.
95
A synthesis of phosphopentapeptide  158 representing a con-
sensus sequence of the Raf-1 kinase (Scheme 65) illustrates
the value of both the enzyme deprotection technique as well
as the use of Pd0
-catalysed deprotection of allyl phosphates,
carbamates and carboxylates.
The carbamoylmethyl (CAM) group developed by Mar-
tinez96
 was employed as a carboxy protecting group in the
construction of the Cys-Thr-Gly fragment  160 of the eIF-5A
hapten65
 (vide supra). The synthesis began with  N-Boc-Gly-
CAM ester from which the tripeptide 159 was constructed using
standard methodology. The CAM ester was removed with
sodium carbonate in aqueous DMF to give the desired frag-
ment  160 in 77% yield (Scheme 66). Note the survival of the
S-Cbz function under these conditions.
The Givens group97
 have reported the use of the p-hydroxy-
phenacyl group as a new photoactivated protecting group for
carboxy functions. Irradiation of buffered solutions of the ester
161 at room temperature led to rapid release of γ-aminobutyric
acid (162) with the concomitant formation of p-hydroxyphenyl-
acetic acid (164, Scheme 67).
The 3,5-dimethoxybenzoin (DMB) system can photo-
release a variety of functional groups with  ca. 350 nm irradi-
ation. A recent study98
 of the mechanism of the reaction using
nanosecond laser flash photolysis led to the suggestion that the
primary step in the photorelease is a charge transfer interaction
of the electron-rich dimethoxybenzene ring with the electron-4018 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Scheme 63
O H
N
O
MOMO
OMOM
OOAcOAcO
MOM
O
O
OO
O
SiMe3
CO2Me
O
O
O O
MOMO
OMOM
OOAcOAcO
MOM
O
SiMe3
OO
CO2Me
O H
N
O
MOMO
OMOM
OOAcOAcO
MOM
O
O
OO
O
SiMe3
OO
O H
N
O
MOMO
OMOM
O
MOM
OO
O
OAc OAcO
O
O H
N
O
HO
OMOM
O
MOM
OHO
HO
OAc OAcO
O
O H
N
OH
HO
O
O
OHO
HO
OH OHO
OMe
TBAF, DMF
Ph2PON3, NEt3,
Me3SiCH2CH2OH, THF
        66% (2 steps)
(a)
(b)
(a) DIBAL-H (5 equiv.), THF, –100 → –78 °C, 1.5 h
(b) Swern oxidation (67% 2 steps)
(c) (EtO)2POC(Me)CO2CH2CH2SiMe3, LiCl, DBU (86%)
149
TASF, DMF
N-methyl-2-chloropyridinium iodide
NEt3, CH2Cl2
               76% (2 steps)
(a)
(b)
SiMe3
(Ph3P)4Pd, Bu3SnH, HOAc
LiOH, THF–MeOH–H2O (2:2:1)
Me3SiCHN2   (50%, 3 steps)
TFA-H2O (9:1), then O2 (70%)
1 M HCl–THF (7:9), 23 °C, 14 h (54%)
148
150 151
152 153
(a)
(b)
(c)
(d)
deficient oxygen of the n,π* singlet excited acetophenone, to
form an intramolecular exciplex 166 which can return to 165 or
react to give cation 167 (Scheme 68). This mechanism accounts
for the high efficiency of the substitution pattern of the
methoxy groups as well as the absence of solvent-substitution
or radical-derived products in 3,5-dimethoxybenzoin photo-
chemistry.
During a synthesis of the challenging cyclodepsipeptide
Scheme 64
N
S
S
OH
H
O
O
OR
CH2C(Cl)=CH2
CH2C(CH3)=CH2
CH2CH=CHCH3
CH2CH=CHPh
CH2CH=CH2
S
O–
Pd(PPh3)4 (5 mol%)
TolSO2Na (1.0 equiv.)
THF–MeOH, rt
N
S
S
OH
H
O
O
OH
S
O–
97%
94%
91%
94%
87%
Time (min) RYield
105
130
35
30
25
H H
a
b
c
d
e
154
antibiotic enopeptin B, Schmidt and co-workers
99
 required an
acid labile protecting group that could be removed in the pres-
ence of a  tert-butyl ester and a sensitive pentenedioyl system.
The task was accomplished using a tert-butyldiphenylsilyl ester
which was removed from the fragment 169 using aqueous HF in
acetonitrile–THF (Scheme 69).
An alternative synthesis of Corey’s OBO group has been
reported by Charette and Chua100
 (Scheme 70). Imino and
iminium triflates derived from secondary and tertiary amides
respectively, react with 2,2-bis(hydroxymethyl)propan-1-ol in
the presence of pyridine to give the orthoester. Primary amides
cannot be used as substrates because they dehydrate to the
nitrile under the reaction conditions.
A new method for the protection of polyfunctionalised carb-
oxylic acids involves a zirconocene-catalysed epoxy ester–ortho
ester rearrangement.
101
 A synthesis of a  γ-hydroxyleucine
derivative  174 illustrates the method (Scheme 71). The epoxy
ester  172 prepared from (2S)-2-(benzyloxycarbonylamino)-
succinic acid 4-methyl ester 171 was treated with zirconocene
dichloride in the presence of silver() perchlorate to give the
2,7,8-trioxabicyclo[3.2.1]octane (ABO) derivative  173 in 99%
yield. Reaction of the remaining ester function with excess
methylmagnesium bromide followed by hydrolysis gave the
target molecule  174. The ABO ortho ester derivatives of a
number of amino acids were prepared in 90–100% yield by thisJ. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4019
Scheme 65
H2N
H
N
N
H
H
N
N
O
O
OH
O
O
OH
OH
O CO2H
P
OH
OH O
N
H
H
N
N
H
H
N
N
O
O
OH
O
O
OH
OH
O
P
OAll
OAll O
O
AllO
O
OAll
N
H
H
N
N
H
O
O
O
OH
O
O
OH
P
OAll
OAll O
O
AllO N
H
H
N
N
H
OH
O
O
OH
O
O
OH
P
OAll
OAll O
O
AllO
155 156
157 158
lipase from Aspergillus niger
0.2 M phosphate buffer/acetone (95:5)
pH 7, 37 °C
68%
H-Thr-Pro-OAll
EDC, HOBt, CH2Cl2
71%
(Ph3P)4Pd(0)
HCO2H, BuNH2
73%
procedure. A potentially useful feature of the new ABO protect-
ing group is its greater stability towards mild acid hydrolysis
than the 2,6,7-trioxabicyclo[2.2.2]octane (OBO) ortho ester.
102
Thus, OBO groups hydrolyse in 2 min with pyridinium tosylate
in aqueous methanol whereas the corresponding ABO group
requires 22 h.
A synthesis of  α-hydroxy-β-homoarginine derivative  177
(Scheme 72) was accomplished103
 by the addition of  [tris-
(methylthio)methyl]lithium104
 to the aldehyde 175 followed by
Hg2-catalysed methanolysis of the resultant orthothioester
176.
Scheme 66
N
H
H
N
O–CH2–CONH2
CbzHN
O
O
O
OBut
H
CbzS
N
H
H
N
OH
CbzHN
O
O
O
OBut
H
CbzS
159
160
(a) Na2CO3 (2.72 mmol)
      DMF-H2O (7:4, 22 ml), rt, 5 min
(b) add citric acid (0.5 M) to pH 6
77%
1.36 mmol scale
CAM
Scheme 67
OH
O
OO
NH3X
O
–OO
NH3X
OH
CO2H O
+
H2O hν
buffer
r.t.
161
162
163164
6Phosphate protecting groups
The (N-trifluoroacetylamino)butyl and (N-trifluoroacetyl-
amino)pentyl groups have been reported as alternatives to
Scheme 68
O
X
OMe
OMe
O
X
OMe
OMe
O
MeO
OMe
H
*
–HX
165
X = OCOR, OPO(OR)2
OCONHR, OCO2R
166
O
MeO
OMe
X–
167 168
Scheme 69
But
O
N
H
OR
O
O
O
85%
169
170
R = Si(But
)Ph2
R = H
HF, THF-H2O-MeCN
rt, 1 h
Scheme 70
Tf2O (1.3 equiv.)
pyr (3.0 equiv.)
CH2Cl2, –40 → 0 °C, 4 h
MeC(CH2OH)2CH2OH (1.5 equiv.)
EtOH, MeCN
ONEt2
OO O
(a)
(b)
88%4020 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
the traditional 2-cyanoethyl phosphate protecting group in
the solid phase synthesis of nucleosides.
105
 They can be
removed from oligonucleotides (e.g.  178) by treatment with
conc. aqueous ammonia at ambient temperature (Scheme 73).
Note that cleavage of 2-cyanoethyl phosphates is usually
carried out in non-nucleophilic basic conditions using DBU.
The deprotection kinetics, examined in the case of dimer 178,
showed that the initial rate-limiting cleavage of the N-trifluoro-
acetyl group was followed by a rapid cyclodeesterification of
the intermediate 179. Complete conversion occurred within 2 h
at 25 C producing phosphodiester 180 and innocuous pyrrol-
idine. By comparison, deprotection of a 2-cyanoethyl group
releases acrylonitrile which can form an addition by-product
with nucleobases.
The  C2-symmetric cyclic bis(phosphate)  184, a potent
inhibitor of oligonucleotide processing enzymes including
RNA integrase, was synthesised from 2-deoxy--ribose in 18%
overall yield.
106
 The synthesis required two orthogonal phos-
phate protecting groups (Scheme 74). In the closing stages of
the synthesis the diphenyl phosphate ester 181 was hydrogen-
olysed to generate the free acid, which promoted concomitant
cleavage of the TBS ether. Cyclisation of 182 was accomplished
with 2,4,6-triisopropylbenzenesulfonyl chloride (TPSCl) giving
183 in a 46% yield. Finally, reductive cleavage of the trichloro-
ethyl group with zinc–copper alloy returned the target in 96%
yield.
Recent studies on the  myo-inositol cycle have revealed a
family of pyrophosphoryl myo-inositol pentaphosphates (PP-
Scheme 71
CO2H
CO2Me
NHCbz
MeO2C
NHCbz
O
O
MeO2C
NHCbz
O
O
NHCbz
HO(CH2)2C(CH3)=CH2
DCC, DMAP, CH2Cl2
mcpba, CH2Cl2
O
O
O
O
(a)
(b)
171
172
Cp2ZrCl2 (10 mol%), AgClO4 (5 mol%)
CH2Cl2, 22 °C, 1 h
99%
(a) MeMgBr (excess)
(b) 1 M HCl
(c) LiOH, H2O-THF
       48% (3 steps)
173 174
55% (2 steps)
Scheme 72
HN
BocNNHBoc
CbzHN
O
HN
BocNNHBoc
CbzHN
C(SMe)3
OH
HN
BocNNHBoc
CbzHN
CO2Me
OH
175 176
177
(MeS)3CLi (ca. 52 mmol)
THF (182 ml), –65 °C, 5 h
54% (11.5 mmol scale)
HgCl2 (20.8 mmol)
HgO (7.82 mmol)
MeOH (118 ml), H2O (8.5 ml)
rt, 72 h
79% (6.2 mmol scale)
9:1
InsP5) and related bis-pyrophosphates which have an unusually
high metabolic turnover consistent with the speculation that
they act as phosphate donors for unidentified kinases. The
Falck group107
 have described a stereocontrolled synthesis of
5-PP--myo-InsP5 (191) outlined in Scheme 75 which illustrates
how a single phosphate residue in a hexakisphosphate deriv-
ative can be transformed selectively to a pyrophosphate. The
readily available  myo-inositol bis-disilanoxylidene  185 was
phosphorylated selectively at the less hindered equatorial C5
hydroxy group. Desilylation of  186 required carefully con-
trolled conditions as more basic or acidic reagents such as
TBAF, HF or TFA afforded a complex mixture. The desilyl-
ation was best achieved using HFpyridine complex where-
upon the desired pentaol  187 was produced in 68% yield.
Phosphorylation of the liberated hydroxy groups gave hexa-
kisphosphate 188. Then conversion of the C5 phosphate to the
corresponding pyrophosphate was initiated by specific cleavage
of the phosphate methyl ester using one equivalent of lithium
cyanide at room temperature. The resultant lithium salt  189
was coupled immediately with dibenzyl chlorophosphonate to
give the protected pyrophosphate derivative  190. Finally the
sequence was completed by hydrogenolysis of the benzyl phos-
Scheme 73
178
179
180
O Thy
O
ODMTr
P
O
OO(CH2)4NHCOCF3
O Thy
HO
O Thy
O
ODMTr
P
O
OO
O Thy
HO
NH2
O Thy
O
ODMTr
P
O
OO– NH4
O Thy
HO
H
N
NH3 aq. (conc.)
2 h, 25 °C
Thy = thymine
••
Scheme 74
181 182
183 184
O O
P
O
O
O
P
O
O OH
O Cl3CCH2O
O P
O
O
OTBS
O
Cl3CCH2O
H2, PtO2
EtOH, rt
96%
O
OPO(OPh)2
O P
O
O
OH
O
Cl3CCH2O
O
OPO(OH)2
O O
P
O
O
O
P
O
O OH
O HO
TPSCl, tetrazole
pyr, rt, 48 h
46%
Zn-Cu
DMF
50 °C
96%J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4021
Scheme 75
O Si
O
Si
O O Si
O
Si
O
OR
OH
OH
OH HO
HO
O
OH
P
OMe
OBn O
OPO(OBn)2
OPO(OBn)2 (BnO)2OPO
(BnO)2OPO
O
OPO(OBn)2
P
OMe
OBn O
OPO(OBn)2
OPO(OBn)2 (BnO)2OPO
(BnO)2OPO
O
OPO(OBn)2
P
OLi
OBn O
OPO(OBn)2
OPO(OBn)2 (BnO)2OPO
(BnO)2OPO
O
OPO(OBn)2
P
OBn
O O
OPO(ONa)2
OPO(ONa)2 (NaO)2OPO
(NaO)2OPO
O
OPO(ONa)2
P
ONa
O OP(ONa)2
O
P(OBn)2
O
R = H
R = PO(OMe)(OBn)
(a) Pr
i
2N–P(OMe)(OBn) (1 equiv.)
1H-tetrazole (2 equiv.), CH2Cl2, 0 °C, 3 h
(b) MCPBA, –78 °C, 15 min
185
186
92%
HF•pyr, THF (1:2.5), rt, 3 h
68%
(a) Pr
i
2N–P(OBn)2 (1 equiv.)
1H-tetrazole (2 equiv.)
CH2Cl2, 0 → 23 °C, 3 h
(b) MCPBA, –78 °C, 15 min
78%
LiCN (1 equiv.)
DMF, rt, 12 h
187188
(BnO)2POCl
 NEt3, CH2Cl2
 0 → 23 °C, 2 h
56% (2 steps)
Pd, H2 (50 psi)
NaHCO3
But
OH-H2O (6:1)
70%
189 190 191
Scheme 76
192
193
O
O
O
O
RO
OR
O
O
PACLev–O
O–PACLev RO
RO
OH
OH
PACLev–O
O–PACLev (FmO)2P(O)O
(FmO)2P(O)O
O
OH
PACLev–O
O–PACLev (FmO)2P(O)O
(FmO)2P(O)O
P
O
OMe
O
O2CC17H33
O2CC17H33
O
OH
HO
OH –HO2P(O)O
–HO2P(O)O
P
O
O–
O
O2CC17H33
O2CC17H33
PACLev–OH
DCC, DMAP 100%
TFA, MeOH, CH2Cl2
95%
(FmO)2PNPr
i
2, 1H-tetrazole
followed by MCPBA 93%
80% aq. HOAc, ∆
79%
pyr•HBr3
2,6-lutidine
90%
(a) NaI, acetone, ∆ (84%)
(b) Et3N, MeCN-EtCN (3:1), ∆ (86%)
(c) NH2NH2, pyr, HOAc (100%)
(d) But
OK (100%)
194
195
R = H
R = (FmO)2P(O)
R = H
R = PACLev
O2CC17H33
O2CC17H33
OP(OMe)2
196
197 198
3K+
CO2H
O
O
O
CH2 C17H33 = Fm = PACLev =
phate esters in the presence of sodium hydrogen carbonate to
give the target  191. A similar sequence was used to prepare
2-PP--myo-InsP5.
A recent synthesis of a -1,2-di-O-oleoyl-sn-glyceryl phos-
phate analogue of phosphatidylinositol 4,5-bisphosphate  198
(Scheme 76) incorporated  fluoren-9-ylmethyl (Fm) esters as
protecting groups for phosphate.
108
 The synthesis began with
the protection of the 3,6-dihydroxy functions in the inositol
derivative  192 as their 2-[2-(levulinoyloxy)ethyl]benzoyl
(PACLev) esters.
109
 Phosphorylation of the 4,5-diol functions
with difluorenylmethyl phosphoramidite gave the  fluoren-9-
ylmethyl diester 195 after oxidation of the phosphite intermedi-
ate with m-chloroperoxybenzoic acid. Subsequent regioselective
phosphorylation of the 1-hydroxy function in diol 196 gave the
triphosphate  197 which completed the assembly of the com-
ponents of the target. The deprotection regime began with the
1-phosphate group (NaI) followed by the  fluorenylmethyl
phosphates at the 4- and 5-positions using triethylamine. The
first Fm group in each phosphate was removed at room tem-
perature and the mixture then heated to remove the second Fm
group. Finally, the PAVLev esters were removed by reaction with
hydrazine in pyridine and acetic acid and the resultant hydroxy-
ethylbenzoates were treated with KOBut
 to afford the  final
product 198.4022 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Photoactivated protective groups play an important role in
the study of biochemical mechanisms, allowing the rapid
and efficient release of bioactive compounds in the tested
environment. Recently Park and Givens
110
 demonstrated that
p-hydroxyphenacyl groups can be used to trigger the photo-
release of adenosine 5-triphosphate (ATP, 200) from the pro-
tected nucleotide 199 when irradiated at wavelengths between
300–350 nm (Scheme 77).  p-Hydroxyphenacyl phototrigger
compares favourably with other photoactivated protecting
groups (e.g. desyl) because it has no chiral centres and has a
better aqueous buffer solubility. Also, the by-product of the
photolysis—p-hydroxyphenylacetic acid  201—does not com-
pete for the incident radiation in the 300–400 nm region, which
improves the yield of the photolysis.
7Carbonyl protecting groups
Lipshutz and co-workers
111
 devised a new carbonyl protecting
group which involves the formation of ‘cyclo-SEM’ derivatives
(e.g.  204, Scheme 78) in the reaction with 2-trimethylsilyl-
propane-1,3-diol (202). The deprotection is achieved with
lithium tetrafluoroborate in THF which also allows the select-
ive unmasking of one carbonyl group in  204 (only 2–3%
of the corresponding diketone is observed). The choice of
solvent can affect the selectivity of the deprotection;  e.g. in
MeCN the cyclo-SEM group as well as standard 1,3-dioxane
and 1,3-dioxolane derivatives are removed.
Scheme 77
POPOPO
OO
OO
O
O
N
N N
N
NH2
O
OH OH
O
HO
O
POPOPO
OO
OO
O
O
N
N N
N
NH2
O
OH OH
O
OH
HO
O
199
200
201
NH4 NH4 NH4
NH4 NH4 NH4
hν (300 nm irradiation)
TRIS buffer (5 ml, 0.05 M, pH 7.3)
(0.125 mmol scale)
TRIS = tris(hydroxymethyl)aminomethane
Scheme 78
O O
O
H
O O
H
O
O
Me3Si
202 (5.4 equiv.)
4Å MS, CSA (0.25 equiv.)
CH2Cl2, rt, 12 h
85%
HOOH
SiMe3
202
CSA = camphorsulfonic acid
LiBF4 (0.5 M in THF)
66 °C, 3 h
>80%
203 204
Lee and Cheng112
 reported that acetals and ketals can be
deprotected to the corresponding carbonyl compounds using a
catalytic amount of carbon tetrabromide in acetonitrile–water
mixture under either ultrasound or thermal (reflux) conditions
(Scheme 79). Ultrasound conditions are milder;  e.g. acetals
containing strong electronegative substituents (like  p-nitro-
benzaldehyde derivatives) remain intact.
A method for the cleavage of acetals and ketals to the corre-
sponding carbonyl compounds using lithium chloride and
water in DMSO at elevated temperatures (90–130 C) has been
described.
113
 The method is limited to systems which give
α,β-unsaturated aldehydes and ketones. Diaryl and saturated
compounds remain intact allowing selective deprotection, as
illustrated in Scheme 80.
Ferric chloride hexahydrate in dichloromethane is a mild
reagent for deprotecting acetals (Scheme 81) and the method is
compatible with some acid sensitive groups.
79
 For example, 205
was inert to olefin isomerisation under the conditions even after
long reaction times.
1,3-Dioxolanes are cleaved114
 in good yield using 1.5 equiv-
alents of CeCl3–7H2O in acetonitrile at room temperature. The
deprotection can be hastened by adding a catalytic amount of
sodium iodide and/or by heating to reflux. It is not possible to
ascertain from the 13 examples cited whether these new condi-
tions offer tangible benefits over the traditional aqueous acidic
conditions.
One step conversion of acetals to esters can be achieved with
hydrogen peroxide and hydrochloric acid in alcohols (Scheme
82).
115
 The reaction works well with saturated compounds but
with α,β-unsaturated acetals the yield is low due to competitive
addition of HCl to the olefin.
Scheme 79
CBr4 (0.2 mmol)
MeCN (1 ml), H2O (2 ml)
ultrasound
(Crest 575-D, 39 kHz)
~40 °C, 2 h
81% (1 mmol scale)
O
O
O
O
O
H
Scheme 80
O O
O
O
H
O
O
O LiCl (10 mmol)
H2O (2 ml)
DMSO (15 ml)
90 °C, 6 h
91% (2 mmol scale)
Scheme 81
205 206
OEt
O
FeCl3•6H2O (2.8 equiv.)
CH2Cl2, ∆, 20 min
77%
O
O
OEt
O
O
Scheme 82
HCl (12 M, 0.25 ml, 3 mmol)
H2O2 (34% in H2O, 3.0 mmol)
MeOH (4 ml)
0 °C, 30 min → 40 °C, 3 h
96% (2 mmol scale)
C9H19
MeOOMe
C9H19
OOMeJ. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4023
Acetalisation of  α,β-unsaturated carbonyl compounds is
often difficult with conventional acid catalysts. In 1992 Otera
and co-workers
116
 reported that distannoxanes (e.g.  209,
Scheme 83) are extremely active catalysts for acetalisation. The
reaction proceeds under almost neutral conditions and thus is
recommended for sensitive compounds like enones and enals.
Recently Malacria and co-workers
117
 successfully used 209 for
the protection of unsaturated aldehyde 208.
The classical ketalisation of the Wieland–Miescher ketone
211 (ethylene glycol, benzene, PTSA, reflux) (Scheme 84) is
capricious. It results in moderate yields of 212 due to the form-
ation of the corresponding bisketal and also because of the
presence of unreacted  211 in the reaction mixture. However,
selective ketalisation of 211 can be achieved in high yield using
ethylene glycol as solvent and a stoichiometric amount of
PTSA.
118
Solvent free acetalisation of aldehydes and ketones under
microwave irradiation has been described by Hamelin and co-
workers.
119
 Methyl or ethyl orthoformates, ethylene glycol or
2,2-dimethyl-1,3-dioxolane can be used as reagents and PTSA
or montmorillonite clay KSF as a catalyst (Scheme 85).
A new synthesis of dioxolanes from oxiranes and carbonyl
compounds has been reported120
 which is catalysed by methyl-
rhenium trioxide. The stereochemistry of the starting oxirane is
retained in the  final product owing to two inversions in the
sequence depicted in Scheme 86. Aldehydes and cyclic ketones
give good yields but acyclic ketones such as pentan-3-one and
cyclic conjugated enones such as cyclohexenone give poor to
modest yields. In some cases the bis(alkoxy)rhenium() com-
plexes 214 could be detected. Ketene acetals and oxazolidines
Scheme 83
O
OEt
O
H
SnOSnOH
Sn O Sn HO
NCS
Bu
Bu Bu
Bu
NCS
BuBu
Bu Bu
O
O
207
208
210
DIBAL-H, CH2Cl2
–78 → 0 °C
Swern oxidation
(a)
(b)
209, (HOCH2)2, PhH, ∆
83% (overall)
209
Scheme 84
O
O
O O
O
211 212
HOCH2CH2OH (730 ml)
PTSA (1 equiv.)
4Å MS, rt, 23 min
90% (146 mmol scale)
Scheme 85
H
O
O
O
O O
H
(3 equiv.)
KSF (10 mmol)
MW (120 °C, 15 min)
85% (10 mmol scale)
can also be formed from the analogous reaction of oxiranes
with ketenes and aldimines respectively.
Cyclic ketals of acetophenone can be prepared directly by the
reaction of aryl triflates, bromides or iodides (e.g. 216, Scheme
87) with hydroxyalkyl vinyl ethers (e.g. 217) in the presence of a
catalytic amount of palladium() acetate and 1,3-bis(diphenyl-
phosphino)propane (DPPP).
121
 The example illustrated in
Scheme 87 is especially noteworthy since the protected methyl
ketone was introduced in the presence of a reactive aldehyde
functionality.
Acetals are susceptible to oxidation by ozone and dioxolane
derivatives are especially reactive giving 2-hydroxyethyl esters at
a rate comparable with the oxidation of alkenes.
122
 Frigerio and
co-workers
123
 recently showed that dimethyldioxirane (DMD)
also effects the oxidation of dioxolanes in good yield. In the
single example illustrated in Scheme 88, the secondary alcohol
function is also oxidised to a ketone.
Deprotection of thioacetals using clay supported ammonium
nitrate124–126
 and zirconium sulfophenyl phosphonate127
 has
also been reported recently.
Yamamoto and co-workers
128
 reported a new protecting
group for aldehydes and ketones which is based on the reaction
of a carbonyl compound (e.g. 220, Scheme 89) with lithiocar-
borane (formed by treatment of o-carborane 219 with n-butyl-
lithium). The addition product  221, unlike acetals, is stable
under aqueous protic acid and Lewis acid conditions. The
adduct can be easily converted back into the corresponding
carbonyl compound under basic conditions using a catalytic
amount of KOH in aqueous THF. The practical application
of the methodology is illustrated in Scheme 89. Reduction of
the ester group in 221 by lithium aluminium hydride gave alco-
hol  222 which, after deprotection of the carbonyl function,
Scheme 86
O
Ph
Ph
MeReO3 (1 mol%)
CHCl3, rt, 2-5 days)
O
Re
O Ph
Ph
Me
O
O
O
O
Ph
Ph
213 (1.1 equiv.)
cyclopentanone (1 equiv.)
214
215 (87%)
Scheme 87
216
(217)
(10 mmol)
Pd(OAc)2 (0.15 mmol)
DPPP (0.30 mmol)
Et3N (7.5 mmol)
DMF (15 ml), 80 °C, 24 h
76% (5.0 mmol scale)
218
OHCOTf
OHC
O O
O
OH
Scheme 88
OH OH
O
O
HO O
O
O
DMD / acetone
rt
100%
OH4024 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
yielded hydroxy aldehyde 223. Chemoselective protection of an
aldehyde in the presence of a ketone can also be accomplished
using o-carboranyltributylstannane 224 and a catalytic amount
of Pd2dba3CHCl3.
8Amino protecting groups
A key element in Fraser-Reid’s synthesis of nodulation factor
NodRf-III (C18:1, MeFuc) was the use of a tetrachloro-
phthaloyl (TCP) group to provide  N-differentiation of the
linear glucosamine backbone.
13
 Thus installation of the (Z)-
octadec-11-enoyl group on the terminal glucosamine began by
selective deprotection of the TCP group in tetrasaccharide 225
(Scheme 90) using only 5 equivalents of ethylenediamine. After
amide bond formation and esterification of any deprotected
acetates, the two remaining phthalimide (Phth) groups were
removed by heating  226 in EtOH at 90 C for 34 h with 500
equivalents of ethylenediamine.
In the course of studies concerning the development of
orthogonal protecting group schemes for glycopeptide syn-
thesis, the selectivity between the reduction of N-dithiasuccinyl
Scheme 89
CHO MeO2C
B10H10
OH
MeO2C
B10H10
OH
B10H10
(a)
(b)
BuLi (5 mmol)
–78 °C, 30 min
220 (5.5 mmol)
–78 °C, 1 h then rt
95% (5 mmol scale)
LiAlH4
THF, ∆
CHO
KOH (0.15 equiv.)
THF-H2O (100:1)
rt, 2 days
77% HO HO
219 221
222
220
223
B10H10
SnBu3
224
95%
Scheme 90
O O O O O
O
O
OBz
OBz
OMe
OTBS HO
PhthN PhthN
OTBS OTBS
AcO
AcO AcO
N OO
Cl Cl
ClCl
O O O O O
O
O
OBz
OBz
OMe
OTBS AcO
PhthN PhthN
OTBS OTBS
AcO
AcO AcO
NH
O
ethylenediamine (5 equiv.)
MeCN-THF (3:1), 60 °C
2-chloro-N-methylpyridinium iodide (2.5 equiv.)
MeCN, NEt3, (Z)-octadec-11-enoic acid, 40 °C
Ac2O, NEt3, CH2Cl2, rt
(a)
(b)
(c)
25% (3 steps)
225
226
(N-Dts) and azido functionalities has been investigated.
129
 By
use of propane-1,3-dithiol (PDT) in the presence of diiso-
propylethylamine (DIPEA), it is possible to reduce selectively
the N-Dts group of 227 (Scheme 91) without affecting the azido
group. On the other hand, the more reactive dithiothreitol
(DTT)–DIPEA reduced both groups affording 229 in 96% yield
after acetylation.
During their synthesis of disaccharide  234 bearing an eth-
anolamine phosphate group (PEA), van Boom and co-
workers
130
 reported the first example of immobilised penicillin-
G acylase mediated deblocking of an N-phenylacyl-protected
PEA moiety. The introduction of the protected phosphate
group was achieved in the reaction of disaccharide  230
(Scheme 92) with phosphoramidite  232. Oxidation of the
intermediate phosphite triester with  tert-butyl hydroperoxide
and triethylamine was accompanied by the simultaneous de-
protection of the 2-cyanoethyl group. The resulting protected
phosphodiester 231 was subjected to hydrogenation (to cleave
the Cbz and benzyl groups) followed by treatment with
immobilised penicillin-G acylase (Seperase G) to remove the
N-phenylacetyl group from the PEA moiety.
A similar application of penicillin-G acylase for the de-
protection of  N-phenylacetyl-protected nucleobases in oligo-
nucleotides has been reported by the Waldmann group.
131
The use of a picolinoyl group as an electrochemically remov-
able protecting group for amines in peptide synthesis has been
reported.
132
 The protection step is carried out by treating an
amino acid ester or peptide (e.g.  235, Scheme 93) with pipe-
colinic acid (Pic-OH), 1-hydroxybenzotriazole (HOBT),
N-methylmorpholine (NMM) and 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride (EDC). The picolinoyl
protecting group is then removed from the tripeptide  237 by
electrolysis at  E = 1300 mV  vs. saturated calomel electrode
(SCE). The deprotection can be performed selectively in the
presence of tosyl, benzyloxycarbonyl,  O-benzyl,  tert-butoxy-
carbonyl and O-tert-butyl groups. However, two groups turned
out to be incompatible: trichloroethoxycarbonyl (Troc) (prob-
ably because of competitive cleavage of the C–Cl bond) and
fluoren-9-ylmethoxycarbonyl (solubility problems).
The pent-4-enoyl group133
 has been used for protection of an
α-amino function during the synthesis of aminoacylated trans-
fer RNA’s (Scheme 94).
134
 The protection step is carried out by
treating the methyl ester of (S)-valine  239 with pent-4-enoic
anhydride. The product 240 was then attached to a nucleotide
to give  241. Deblocking was then effected by treatment with
iodine.
Stannic chloride in ethyl acetate is a new reagent for the
deprotection of bis-Boc substituted guanidines
135
 (e.g.  243,
Scheme 95). The reagent is milder than the trifluoroacetic acid
typically used and gives good yields of the corresponding solid
guanidinium chlorides  244 whereas trifluoroacetate salts are
difficult to crystallise.
During a synthesis of the serine protease inhibitor cyclo-
theonamide B, a Dutch group103
 found that under many acidic
conditions, the  O-(tert-butyl)tyrosine in the dipeptide  245
Scheme 91
O AcO
AcO
OAc
SS
N OO
N3
O AcO
AcO
OAc
NHAc
N3
O AcO
AcO
OAc
NHAc
NHAc
PDT, EtNPr
i
2 , CH2Cl2
Ac2O-pyr (1:2)
94%
DTT, EtNPr
i
2, CH2Cl2
Ac2O-pyr (1:2)
96%
(a)
(b)
(a)
(b)
227
228
229J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4025
(Scheme 96) cleaved more rapidly than the  N-Boc group.
Fortunately, using the conditions of Ohfune and co-
workers,
136,137
 the  N-Boc group could be cleaved selectively
using TMSOTf followed by aqueous workup. The extreme
sensitivity of an O-(tert-butyl)tyrosine derivative towards careful
treatment with HCl in ethyl acetate (1 M, 500 mol%) was also
recently established in a study aimed at selective cleavage of
N-Boc groups in the presence of other acid-labile protecting
groups such as  tert-butyl esters, aliphatic  tert-butyl ethers,
S-Boc groups and S-trityl ethers.
138
During the early stages of Myers’ synthesis of dynemicin
A,
7
 deprotection of the Boc group in  247 (Scheme 97) was
required in order to effect internal amidation for the prepar-
ation of the quinolone 248. Initial experiments confirmed that
the enol ether function in 247 was too labile to the acidic condi-
tions usually associated with Boc deprotection (e.g. trifluoro-
acetic acid in dichloromethane). However, by heating 247 in the
weakly acidic 4-chlorophenol (180 C, 30 min) the Boc group
was cleaved while preserving the enol ether function to give the
quinolone 248 in 84% yield. 4-Chlorophenol was the optimal
solvent for the deprotection/amidation since aprotic solvents
such as diphenyl ether gave very slow reaction and phenol itself
was slower and gave a messy reaction with by-products derived
from reaction with the phenol.
The azinomycins are antitumour antibiotics isolated from
the culture broth of strain  Streptomyces griseofuscus S42227.
During a study directed towards the synthesis of the aziridine
core of the azinomycins, Coleman and Carpenter
139
 had
encountered difficulties in removing the benzyloxycarbonyl
(Cbz) group from the aziridine 249 (Scheme 98). For example,
hydrogenolysis using various palladium catalysts  [Pd–C, Pd-
(OH)2, Pd black, Pd–Al2O3] was incompatible with the bromo-
Scheme 92
233 R = NHC(O)Bn
234 R = NH3
+
84%
(0.14 mmol scale)
230  R = H
231  R =
O
O
O
OBn
BnO
ONHCbz
OBn
OBn
OBn
H
OBn
H
BnO
RO
OBn
O
O
O
OH
HO
ONH2
OH
OH
H
H
HO
O
OH P
O
O O
R
OH
OH
O
P
O
CN
N
HN
Ph
O
O
PO(CH2)2NHC(O)Bn
O– Et3HN+
(a) 232 (1.5 equiv.)
1H-tetrazole (1.9 equiv.)
CH2Cl2–MeCN (2:1), rt, 45 min
(b) But
OOH, Et3N, 0 °C, 16h
232
H2 (35 psi), Pd(OH)2 (10%, 0.3 g)
Pr
i
OH–H2O–AcOH (3:1:1), 20 ml
rt, 16 h, 61% (0.12 mmol scale)
Separase G (150 U g–1, 18 g mmol
–1)
H2O (5 ml), NaOH (0.01 M), pH = 7.5
rt, 16 h (0.036 mmol scale)
93%
Scheme 93
(a) Basic hydrolysis
(b) Peptide coupling
H2SO4, NaHSO4 (pH 2)
MeOH, 25 °C
E = –1300 mV vs. SCE
N
H
NH
O
N
H
O
H
NCO2Bn
Ph
N
O
84%
(0.6 mmol scale)
N
H
NH2
O
N
H
O
H
NCO2Bn
Ph
237
238
N
H
NH2
O
OMe
N
H
NH
O
OMe
N
O
Pic-OH (2 mmol), HOBT (2 mmol)
NMM (2 mmol), EDC (2.2 mmol)
CH2Cl2 (90 ml), 0 °C, 2 h; 20 °C, 2 h
235
236
Scheme 94
241 R = C(O)(CH2)2CH=CH2
242 R = H
H2N
OMe
O
H
N
OMe
O
O
O
N
N N
N
NH2
O
O
N
N
NH2
O
P O
O
O
O
P
O
OO
OH
I2, THF-H2O, 25 °C, 5 min
239
240
O
RHN
O
(H2C=CH(CH2)2CO)2O,
Et3N, 0 °C, 2 h
3 steps
73%
Scheme 95
243 244
HN
HNBoc
NBoc
SnCl4 (4 equiv.)
AcOEt, rt, 3 h
88% NHCOCF3
HN
NH2•HCl
NH
NHCOCF34026 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
alkene. Success was eventually achieved using the conditions of
Birkofer:
140
 PdCl2, Et3SiH, NEt3, 25 C.
Peptide nucleic acid (PNA) analogues of DNA have attracted
interest as potential regulators of gene expression owing to
their ability to invade duplex DNA, thereby forming PNA:
DNA heteroduplexes. During a synthesis of the requisite
α-amino acids harbouring the four DNA bases in the side
chain, difficulty was encountered protecting the  N6
-amino
group of the adenine in compound 252 as its Cbz derivative.
141
Treatment with benzyl chloroformate under all the usual con-
ditions did not give clean or efficient acylation. However,
when 1-(benzyloxycarbonyl)-3-ethylimidazolium tetrafluoro-
borate (253, Rapoport’s reagent
142
) was used instead, the
desired acylation was both clean and efficient (Scheme 99).
The  p-nitrobenzyloxycarbonyl (PNZ)  N-protecting group
has been reported as a participating group in the stereoselective
formation of 2-amino-β-glucosides (Scheme 100).
143
 The pro-
tection was carried out in the reaction of glucosamine hydro-
chloride 255 with sodium methoxide in methanol followed by
p-nitrobenzyl chloroformate (PNZ-Cl) and triethylamine. Sub-
Scheme 96
O
H
N
HN
O
NHR
OBut
100%
245
246
TMSOTf (8 mmol)
2,6-lutidine (10 mmol)
CH2Cl2 (4 ml), rt, 95 min
2 mmol scale
R = Boc
R = H
OOAll
Scheme 97
MeO2C
OMe
MeO
NHBoc
OMe
OMe
HN
O
247 248
4-ClPhOH
180 °C
30 min
84%
Scheme 98
249 R = Cbz
250 R = H
57%
N
Br
MeO2CHNCO2Me
AcO
TBSO
R
MeO2CHNCO2Me
Et3SiH (23 equiv.), PdCl2 (1.0 equiv.)
NEt3 (2.0 equiv.), 25 °C, 2 h
DABCO
CDCl3
50 °C, 1 h
(41% overall)
N AcO
TBSO
251
Scheme 99
N
N N
N
NH2
BocHNCO2Me
N N CO2Bn Et
+
BF4

N
N N
N
NHCbz
BocHNCO2Me
252 254
253 (6 equiv.)
CH2Cl2, rt, 12 h
82%
sequent acetylation gave the protected amino-sugar 256 in 81%
overall yield. The trichloroacetamide 257 was formed by regio-
selective deacetylation with benzylamine followed by treatment
with Cl3CCN in the presence of potassium carbonate. Glyco-
sidation of  258 with the glycosyl donor  257 was carried out
using boron trifluoride–diethyl ether as a promoter to give the
disaccharide  259 in 91% yield. This result indicates that the
combination of the PNZ moiety with anomeric trichloro-
acetimidate activation achieves  β-glycosidation in high yield
with high stereoselectivity. Finally the PNZ group was removed
by hydrogenolysis along with O-benzyl ethers to give  260 in
76% yield. Alternatively the PNZ group can be deprotected
selectively by sodium dithionite under neutral conditions where
benzyl ethers and carboxylate esters remain intact. Since
O-acetyl groups can be removed by treatment with MeONa–
MeOH in the presence of the PNZ group, this makes the PNZ
group effectively an orthogonal protecting group in oligo-
saccharide synthesis.
A German group144
 has introduced the  [(2-{[5-(dimethyl-
amino)-1-naphthyl]sulfonyl}ethoxy)carbonyl] group (Dnseoc)
for protection of amino function in nucleobases during oligo-
nucleotide synthesis (Scheme 101). The nucleoside (e.g.  261)
could be protected directly in the reaction with Dnseoc-Cl
(263) and N-methyl-1H-imidazole. However a better result was
obtained when the two hydroxy groups were temporarily trans-
formed into TMS ethers followed by reaction with  263 and
desilylation. The crude product 262 was then treated with 4,4-
Scheme 100
O AcO
OAc
AcO
HN
O
O BnO
BnO
BnO
PNZ
OMe
O HO
OH
HO
NH2•HCl
O AcO
OAc
AcO
HN
PNZ
OH OAc
O AcO
OAc
AcO
HN
PNZ OCCl3
NH
HO
O BnO
BnO
BnO OMe
O HO
OH
HO
H2N
O
O HO
HO
HOOMe
NO2
OCl
O
255
256
257
258
259
260
(a) BnNH2 (1.1 equiv)
THF, 16 h
(b) CCl3CN (10 equiv.)
K2CO3, CH2Cl2, 7 h
75% (overall)
(a)
(b)
(c)
MeONa (1 equiv.)
MeOH, 10 min,
PNZ-Cl (1 equiv.)
Et3N (1 equiv.)
0 → 20 °C
Ac2O, pyr, 16 h
78% (overall)
(a)
(b)
257 (0.375 mmol)
4 Å MS (250 mg), CH2Cl2 (0.75 ml)
–30 °C, 10 min
BF3•Et2O (0.125 mmol)
CH2Cl2 (0.75 ml), <0 °C, 2 h
91% (0.25 mmol scale)
MeONa, MeOH, 2.5 h
93%
H2, 10% Pd/C
MeOH, 76%
PNZ-Cl
(a)
 
(b)J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4027
dimethoxytrityl chloride to afford protected nucleoside 264 in
81% overall yield from 261. Deprotection of the nucleobase was
achieved by reaction with excess 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU). Kinetic experiments showed that the rate of
deprotection was much faster than the previously used  [2-(4-
nitrophenyl)ethoxy]carbonyl (Npeoc) group. In most cases
complete deprotection occurred within 30 min.
FR 900482 isolated from the fermentation broth of Strepto-
myces sandaensis  shows promising anti-tumour activity owing
Scheme 101
O
HO
N
N
NHR
O HO
O
HO
N
N
NHR
O (MeO)2TrO
NMe2
SO2
OC(O)Cl
(a)
(b)
(c)
Me3SiCl (21.4 mmol)
pyr (15 ml), rt, 2 h
263 (4.2 mmol)
rt, 2.5 h
H2O (30 ml), rt, 30 min
261 R = H
262 R = Dnseoc
(MeO)2TrCl (5.67 mmol)
pyr (20 ml), rt, 2 h
(MeO)2TrCl (1.89 mmol), rt, 30 min
81% (overall, 3.8 mmol scale)
264 R = Dnseoc
265 R = H
DBU (20 equiv)
MeCN (1 ml)
rt, half-life = 27 s
(0.01 mmol scale)
(a)
(b)
263 (Dnseoc-Cl)
to its ability to cross-link DNA. In studies directed towards the
synthesis of FR 900482, Rollins and Williams
145
 were unable to
deprotect the TBS ether in intermediate  266 (Scheme 102)
without prior deprotection of the adjacent aziridine. Simul-
taneous N-deprotection and reduction of the ester function was
accomplished in 61% yield using DIBAL-H without compet-
ing reduction of the 6-nitroveratryloxycarbonyl (Nvoc) group.
Cleavage of the TBS ether with TBAF followed by restoration
of the methoxycarbonyl group using  N-(methoxycarbonyl-
oxy)succinimide gave 269 in 89% yield for the two steps. After
Des, s–Martin oxidation to the keto aldehyde  270, the Nvoc
group was removed photochemically to give the target mitosene
derivative 271 in 38% yield.
Carpino et al. have invented a new base-sensitive amino pro-
tecting group which is more labile than the ubiquitous Fmoc
group.
146
 The 1,1-dioxobenzo[b]thiophene-2-methoxycarbonyl
(Bsmoc) group is introduced via its chloroformate or N-hydroxy-
succinimide derivative and it is stable to peptide coupling in
solution or solid phase using acyl fluorides or in situ activation
via ammonium or phosphonium salts. The Bsmoc group is
stable towards tertiary amines (pyridine, diisopropylethyl-
amine) for 24 h but deblocking occurs (via nucleophilic addition
followed by β-elimination) within 3–5 min using piperidine or
tris(2-aminoethyl)amine (TAEA). In Fmoc chemistry the
deblocking event generates dibenzofulvene which is sub-
sequently scavenged—an event which may not be very efficient
on solid phases. However, a particular advantage of the Bsmoc
group is that the deblocking and scavenging reactions are iden-
tical as illustrated in Scheme 103. The intermediate 273 decays
over 8–10 min to give the final stable deblocking product 274.
A synthesis of Bsmoc-(Leu)3-OFm illustrates the selective
deblocking of the  N-Bsmoc in the presence of a  fluoren-9-
ylmethyl (Fm) ester. Thus, treatment of Bsmoc-Leu-OFm
with 2% TAEA in dichloromethane followed by coupling with
Scheme 102
N
OTBS
NCO2Me
H
H
OMOM
MeO2C
O
O
O2N
O
O
N
OTBS
NH
H
H
OMOM
O
O
O2N
O
O
OH
N
OH
NH
H
H
OMOM
O
O
O2N
O
O
OH
N
OH
NCO2Me
H
H
OMOM
O
O
O2N
O
O
OH
N
O
NCO2Me
H
H
OMOM
O
O
O2N
O
O
O
N
OH
NHCO2Me
OMOM
O
N
O
O
O–CO2Me
266 267 268
269 270
271
DIBAL-H
CH2Cl2, –78 °C
61%
TBAF
THF, 0 °C → rt
pyr, rt
89% from 267
Dess-Martin
83%
350 nm
MeCN-H2O, rt
38%4028 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Bsmoc-Leu-F and subsequent repetition of the procedure pro-
duced the target tripeptide. However, selective cleavage of the
fluoren-9-ylmethyl ester could be accomplished using 10%
N-methylcyclohexylamine or diisopropylamine in dichloro-
methane.
Magnesium in anhydrous methanol has been reported as a
reagent for the removal of arylsulfonyl groups from  N-aryl-
sulfonylcarbamates and N-acylsulfonamides
147
 (Scheme 104).
The deprotection is carried out under ultrasonic conditions
and is compatible with other nitrogen protecting groups like
N-benzyl,  N-benzyloxycarbonyl (N-Cbz) and  N-tert-butoxy-
carbonyl (N-Boc). However an  N-2,2,2-trichloroethoxycarb-
onyl (N-Troc) group undergoes a known alkyl halide reduction
giving rise to the  N-2,2-dichloroethoxycarbonyl (N-Doc)
derivative. Furthermore, transesterification takes place when
the protected esters of amino acids are used.
The use of excess lithium powder and a catalytic amount
of naphthalene to cleave toluene-p-sulfonamides has been
reported.
25
 The procedure is chemoselective in so far as benzylic
derivative 277 affords the amine 278 without any cleavage of the
benzylic moiety (Scheme 105). Deprotection of the correspond-
ing mesyl (methanesulfonyl) derivatives fails but it works well
in the case of N,N-disubstituted sulfonamides. The removal of
tosyl, mesyl and benzyl groups from disubstituted carbox-
amides can also be achieved by the reported methodology.
Scheme 106 shows the synthesis of one of three scaffolds
used in a solution phase combinatorial search for poly-
azapyridinophanes with potent antibacterial activity.
148
 Alkyl-
ation of the bis-2-nitrobenzenesulfonyl-protected149
 derivative
279 with 2,6-di(bromomethyl)pyridine gave the macrocycle 280
Scheme 103
O2S
O
O
NH
Cl
O2S N
S
O2
N
Cl
NH2
piperidine (2 equiv.)
CHCl3, rt, 3–5 min
+
272
273
274
Scheme 104
N
R
N
Ph
O
Ph O
O
O
275 R = Ts
276 R = H
100%
Mg powder (10 equiv.)
MeOH
sonication
rt, 35 min
Scheme 105
NHR
81%
277 R = Ts
278 R = H
Li (powder, 14 mmol)
naphthalene (0.08 mmol)
THF (7 ml), –78 °C, 2 h
(1 mmol scale)
from which the arylsulfonyl groups were removed selectively
using benzenethiol in the presence of potassium carbonate.
4-Nitrobenzenesulfonamides, which are cleaved under similar
mild conditions, have been used to alkylate amino acids.
150
The 2- and 4-nitrophenylsulfonamide derivatives of amino
acids are useful substrates for mono-N-alkylation using only
caesium carbonate as the base (Scheme 107).
151
 The sulf-
onamide can then be easily cleaved in high yield by SNAr
reaction between the N-alkylated sulfonamide and potassium
phenylthiolate in acetonitrile to give the N-alkylated α-amino
esters without racemisation.
Hydrazine  282 harbouring three orthogonal protecting
groups has been prepared (two steps from H2N-NHCbz,
87%) and used for the stepwise synthesis of tetrasubstituted
hydrazine derivatives
152
 as illustrated in Scheme 108. Mitsu-
nobu alkylation of 282 gave 283 from which the 4-cyanophenyl-
sulfonyl group was removed by reduction and the resultant
product then alkylated under phase transfer conditions to give
284. Cleavage of the Boc group with dilute TFA allowed the
introduction of the third group, a benzoyl. Finally cleavage of
the Cbz group in refluxing neat TFA and acetylation returned
the tetrasubstituted hydrazine derivative  285 in 98% overall
yield.
A sequence for the glycosidation of glycals with concomitant
Scheme 106
N
N
O
SO2 NO2
O2S O2NNH HN
Boc
N
N
O
RN
Boc
NR
BrBr
97%
280 R = 2-nitrophenylsulfonyl
281 R = H
279
Cs2CO3, DMF, rt, 24 h
50%
(6.2 mmol scale)
PhSH, K2CO3
DMF, rt, 2 h
+
Scheme 107
NCO2Me
O2S
O2N
H
NCO2Me
O2S
O2N
NCO2Me
H
H2C=CH–(CH2)3Br
Cs2CO3 (1 equiv.)
DMF, 60 °C, 6 h
72%
K2CO3 (3.1 equiv.)
PhSH (1.1 equiv.)
MeCN, rt, 12 h
54%J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4029
acetamidation previously developed by Danishefsky et al.
153
 has
now been extended to a synthesis of a model glycopeptide in the
form of an asparagine-linked pentasaccharide154
 (Scheme 109).
We join the synthesis at the pentasaccharide stage when the
final iodoanthracenesulfonamidation is initiated using iodo-
nium bis(collidine) perchlorate to give the iodosulfonamide
Scheme 108
N
N
HCbz
O2SBoc
CN
N
N
Cbz
O2SBoc
CN
C6H4Cl
N
N
Cbz
MeBoc
C6H4Cl
N
N
Ac
MeCOPh
C6H4Cl
282
283
284 285 (98% overall)
4-ClC6H4CH2OH
Ph3P, DEAD
(a) Al(Hg), CO2, aq. Et2O
(b) MeI, K2CO3-NaOH, Bu4NHSO4
(a) TFA, CH2Cl2
(b) BzCl, pyr
(c) TFA, reflux
(d) Ac2O
derivative  287, which was then treated with tetrabutyl-
ammonium azide to give the glycosyl azide  289  via the
N-sulfonylaziridine intermediate  288. After acetylation of the
sulfonamide, the 9-anthrylsulfonyl group was removed under
very mild conditions using thiophenol in the presence of base.
Earlier in the same synthesis, benzenesulfonamide was used as
the nucleophilic partner in which case the phenylsulfonyl group
was removed using sodium naphthalenide.
Weinreb et al. have reported the use of the tert-butylsulfonyl
(Bus) group as a new protecting group for amines.
155
 The Bus
group is introduced (Scheme 110) by reaction of the amine with
tert-butylsulfinyl chloride followed by oxidation of the sulfin-
amide with dimethyldioxirane,  m-chloroperbenzoic acid, or
RuCl3 (cat.)/NaIO4. This two-step procedure is a consequence
of the instability of  tert-butylsulfonyl chloride; indeed,  tert-
butylsulfinyl chloride itself is also unstable though it can be
stored neat in a freezer indefinitely. The Bus group is stable
towards strong alkyllithium and Grignard reagents, 0.1 M HCl
in MeOH (20 C, 1 h), 0.1 M TFA in dichloromethane (20 C,
1 h), or pyrolysis at 180 C. However, Bus-protected secondary
amines can be cleaved with 0.1 M triflic acid in dichloro-
methane containing anisole as a cation scavenger at 0 C for 15–
30 min whilst primary amines are released more slowly at room
temperature. It is also possible to cleave Bus-protected second-
ary amines with neat TFA in anisole at room temperature over-
night whereas the corresponding primary sulfonamides are
unscathed under the same conditions.
Trimethylsilylethanesulfonyl chloride (SES-Cl) is a reagent
used to protect amines as their corresponding sulfonamides.
23
Scheme 109
O
OAc
O
O
PMB
O
OAc
O O
OBn
OO
O
O
OAc
BnO
BnO
BnO
BnO
BnO
BnO
BnO
NHAc
BnO
OBn
O
OBn
I
HN
O
BnO
O
OBn
O
BnO
SO2
O
OBn
O
BnO N3
NH
SO2
O
OBn
O
BnO N3
NHAc
N
SO2
O
OBn
O
BnO N3
NAc
SO2
I(coll)2ClO4, AnthrSO2NH2
4Å MS, THF, 0 °C, 3 h
Bu4NN3
THF, rt, 30 min
286
287
Ac2O
NEt3
86%
PhSH
288 289 (67% overall) 290
291
Pr
i
2NEt
60%4030 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Recently an improved large scale preparation of this reagent
has been published in Organic Syntheses (Scheme 111).
81
 In the
first step sodium bisulfite was added to trimethylvinylsilane
(295)  in the presence of a catalytic amount of  tert-butyl per-
benzoate. The resulting crude sodium sulfonate  296 was then
treated with thionyl chloride and a catalytic amount of DMF
to afford the corresponding sulfonyl chloride  297 in 53–66%
overall yield.
Neat acetic acid at 50–80 C cleaved the aminal protecting
group in 298 (Scheme 112) selectively without harm to the acid
labile N-Boc group.
156
 Lactonisation of the open chain inter-
mediate  299 occurred under these conditions whereas most
other methods produced mixtures of the desired lactone
300 together with varying amounts of the hydroxy ester  299.
Lactone 300 was used in a synthesis of deoxy aminohexoses.
During model studies directed towards the synthesis of the
marine antitumour agent mycalamide, Hoffmann and co-
workers
157
 discovered a reduction reaction which accompanied
the deprotection of an N-SEM [2-(trimethylsilyl)ethoxymethyl]
Scheme 110
NH
NH2
NSO2But
NHSO2But
NH
NHSO2But
But
SOCl, NEt3
CH2Cl2, 0 °C
MCPBA, CH2Cl2
rt, 45 min
293292
294
TfOH (0.1 M), anisole
CH2Cl2, rt, 2.5 h
67%
(a)
(b)
72%
TfOH (0.1 M)
anisole
CH2Cl2, 0 °C
25 min
86%
Scheme 111
Me3Si Me3Si
SO2R
295
296 (R = ONa)
297 (R = Cl)
SOCl2 (1.10 mol), DMF (5.2 mmol)
0 °C, 20 min → 20 °C, overnight
53-66%
overall
PhCO3But
 (3.6 mmol)
NaHSO3 (347 mmol)
MeOH (70 ml), H2O (70 ml)
50 °C, 48 h
(181 mmol scale)
Scheme 112
N
O
CO2Me
Boc
O
O
NHBoc
CO2Me HN
HO
Boc
298 299
300
AcOH
50-80 °C
68%
amide derivative  301 (Scheme 113). Treatment of  301 with
TBAF in DMPU at 45 C returned the α-hydroxy amide 302 in
excellent yield as a 3:1 mixture of diastereoisomers. Whilst the
nature of the reducing agent is unknown, the authors specu-
late that it must have been triggered by a reagent of the type
N-CH2-O- or F-CH2-O- derived from cleavage of the SEM
group. The reduction was a welcome and useful surprise since
the nascent hydroxy group is present in the natural product.
The SEM group can also be used for the regioselective
protection of the N1
 position of uracil allowing the selective
alkylation of the nitrogen at the 3-position.
158
Protection of the imidazole nucleus of histidine derivatives
(e.g. 303, R = H, Scheme 114) during peptide synthesis is highly
recommended to avoid racemisation at the α-carbon of the cor-
responding acid-activated species. Guibé and co-workers
159
reported that the allyl group at the Nπ
 position could be used
for this purpose. The regioselective protection of the imidazole
nucleus was achieved in two steps starting from Nτ
-trityl deriv-
ative 303 by (a) reaction with the excess of allyl bromide and
(b) removal of the trityl group from the resulting ammonium
salt with silver acetate in acetic acid. Basic hydrolysis of  304
(aqueous 1 M NaOH–methanol) followed by DCC mediated
peptide coupling of the corresponding acid occurred with good
(97%) conservation of enantiomeric purity. Selective removal
of the allyl group was then achieved by treatment with a catalytic
amount of tetrakis(triphenylphosphine)palladium(0) either in
the presence of N,N-dimethylbarbituric acid or PhSiH3 and
acetic acid.
During their synthesis of a potential inhibitor of glucosyl-
ceramide synthase Rayner and co-workers
160
 encountered dif-
ficulties in deprotecting the amino group in intermediate  307
(Scheme 115). Under conditions previously successful for this
transformation—(Ph3P)3RhCl–MeCN–H2O—only very low
yields of the desired product 308 were obtained. The problem
was  finally overcome by modifying the previously published
procedure of Picq and co-workers
161
 (Pd/C, MeSO3H and
water) to afford 308 in 82% yield.
In the closing stages of a recent synthesis of narciclasine,
Rigby and Mateo162
 encountered difficulties removing the
PMB group protecting the amide nitrogen in intermediate 309
(Scheme 116). The usual oxidative methods were to no avail but
an old desperate method of Williams
163
 eventually succeeded.
Scheme 113
O
O
N
O
O
H
MeO
O
SiMe3
O
OH
N
H
O
O
H
MeO
TBAF•3H2O
DMPU, 45 °C
87%
301302
Scheme 114
N
N
BocHNCO2Me
R
N
N
BocHNCO2Me
303 (R = Tr)
304
(a)
(b)
CH2=CHCH2Br
(20 mmol)
MeCN (50 ml)
40 °C, 72 h
90% (4 mmol scale)
AcOAg/AcOH
52%
NDMBA
Pd(PPh3)4 (cat)
CH2Cl2, ∆, 3 h
π
τ
303 (R = H)
Tr = triphenylmethyl
NDMBA = N,N ′-dimethylbarbituric acidJ. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4031
Thus treatment of the diol 309 with excess BuLi in THF whilst
bubbling oxygen through the solution cleaved the PMB group
and the natural product  310 was obtained by acid hydrolysis
of the acetonide. The yield was low but no doubt welcome
nevertheless.
The fumiquinazolines are moderately cytotoxic metabolites
isolated from fungi isolated from fish. In the synthesis of fumi-
quinazoline G (Scheme 117), He and Snider
164
 used a 2,4-
dimethoxybenzyl group (DMB) to protect an amide nitrogen in
two important steps: the cyclisation of 311 to 312 and acylation
step (b) in the conversion of 312 to 313. Note that the DMB
group is inert to the hydrogenation conditions. The DMB group
was finally removed with CAN prior to closure of the quinazol-
ine ring, which completes the skeleton of the target.
After Raphael  et al.
165
 had encountered problems in the
cleavage of an  N-benzyl group protecting the indole pyrrol-
idone ring system Wood et al.
166
 elected to use the acid labile
2,4-dimethoxybenzyl group which was successfully cleaved in
the  final step of their synthesis of the indolocarbazole ()-
K252a (Scheme 118) using trifluoroacetic acid (TFA). In the
absence of the thioanisole scavenger, an appreciable amount of
317 was formed.
The di(p-anisyl)methyl group is a useful protector for
the amino function during a synthesis of arylglycines  via a
Mannich reaction between an aldimine of glyoxylic acid and
an arylboronic acid (Scheme 119).
167
 The di(p-anisyl)methyl
protector is easily removed with hot 70% aqueous acetic acid.
Orienticin C is a member of the vancomycin family of anti-
biotics used for the treatment of methicillin resistant Staphylo-
coccus aureus infections. The Evans synthesis
168
 of orienticin C
exploited the 4,4-dimethoxydiphenylmethyl (Ddm) protecting
group for the asparagine unit; because it survived the synthesis
intact until the  final step (shown in Scheme 120), it helped
minimise epimerisation during peptide coupling, and it sup-
pressed the vexatious aspartate–isoaspartate rearrangement.
169
Scheme 115
N
O
N
OH
NH2
OH
TsO
O
OC13H27
OC13H27
OC13H27 OC13H27
N
O
N
O
305
307
308
(allyl)2NH
KI, DMF
2 steps
306
Pd/C (0.11 g)
MeSO3H (1.6 mmol)
H2O (10 ml), ∆, 12 h
82% (0.8 mmol scale)
81%
Scheme 116
O
O N
O
O
OHO
H
OH
PNB
O
O NH
OH
OH
OHO
H
OH
(a) BuLi, THF, O2
(b) TsOH
ca. 37%
309
310
The Ddm group, together with the Boc group, were removed
by treatment of 318 with trifluoroacetic acid to give the desired
product. In this preliminary communication the yield of the
final three steps is not specified.
The trityl group is well established for the  N-protection
of amino acids and other primary amine derivatives but the
more labile methoxy-substituted trityl derivatives have received
scant attention. Golding  et al. recently reported the use
of 4,4-dimethoxytrityl tetrafluoroborate (DMTBF4
) and
4,4,4-trimethoxytrityl tetrafluoroborate (TMTBF4
) as use-
ful reagents for the protection of primary and some secondary
Scheme 117
HN
HN
H
DMB
O
O
O
N
H
O
F3C
HN
N
H
DMB
O
N
H
O
F3C
O
N
N
H
DMB
O
N
H
O
F3C
O
O N3
N
N
H
H
O
N
H
O
F3C
N
O
CF3CO2H
PhMe, ∆
89%
(a) H2, Pd/C
(b) o-N3C6H4COCl
100%
(a) CAN (67%)
(b) Bu3P (63%)
311 312
313 314
Scheme 118
N N O
MeO2C OH
N O
MeOOMe
N N O
MeO2C OH
N
H
O
N N O
MeO2C OH
H
N O
OMe
OMe
TFA (1.4 ml)
CH2Cl2 (1.4 ml)
thioanisole (50 equiv.)
83%
315
316 [(–)-K252a]
3174032 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
amines.
170
 The latter reagent is stable indefinitely in air. Pro-
tected amines are obtained either by reaction of DMTBF4
 or
TMTBF4
 with the amine or by alkylating DMT- or TMT-
amine (available from DMTBF4
 and TMTBF4
 by treat-
ment with ammonia). Alkylation of DMT- or TMT-amines
stops after monoalkylation. The DMT and TMT amines are far
more stable than their corresponding ethers and require rela-
tively strongly acidic conditions even for the TMT group. For
example, DMT amines are cleaved with 2 M HCl in THF (1:1)
at room temperature whereas the TMT derivatives are cleaved
with 0.05–0.5 M HCl under similar conditions.
Bristol-Myers Squibb have developed a technique for target-
Scheme 119
HNCO2H
CH(C6H4OMe)2
S
B(OH)2
S
H2NCO2H
S
(p-MeOC6H4)2CH–NH2
+
HO2C–CHO•H2O
+
PhMe
r.t., 22 h
HOAc-H2O (7:3)
80 °C, 40 min
80% (2 steps)
Scheme 120
O O
OH
N
H
O
O
H
N
O
OH
N
H
OH
HO
NH
O
HO2C
O
N
H
OH
NMe
O
H
H
HN
O
HO
R2
R1
318
319
R1 = Boc, R2 = CH(C6H4OMe)2
R1 = R2 = H
TFA, SMe2
CH2Cl2, rt
ing anti-cancer pro-drugs using monoclonal antibodies that are
specifically internalised by the tumour cells.
171
 The pro-drugs
are then released by cathepsin B cleavage of a maleimido-
caproyl Phe-Lys linker attached through a self-immolative
p-aminobenzyloxycarbonyl spacer. One of the synthetic chal-
lenges in the synthesis of the pro-drug is its sensitivity to
common deprotection regimes used for amino groups such as
TFA in dichloromethane (Boc), hydrogenation (Cbz), Pd
(allyloxycarbonyl, Alloc) and secondary amines (Fmoc). A par-
ticularly vexing problem was the protection of the terminal
amino group of lysine. The problem was solved by using a
monomethoxytrityl (MMT) group which was introduced as
shown in Scheme 121. Lys(MMT) (323) was prepared from
Fmoc-Lys (320) by a one-pot tritylation procedure in which
both the amino and carboxy groups are temporarily silylated
with TMSCl followed by removal of the Fmoc group with
diethylamine. The Lys(MMT) (323) was then incorporated into
pro-drugs harbouring doxorubicin, taxol and mitomycin C as
the warheads. In the case of the doxorubicin pro-drug 324, the
MMT group was cleaved from the lysine using dichloroacetic
acid in the presence of anisole at room temperature. Under
these conditions the lysine was protonated, thereby preventing
addition of the amino group to the maleimide residue leading
to the formation of polymeric products.
The 9-phenylfluoren-9-yl (Pf) protecting group offers steric
protection to functional groups in its periphery. A Spanish
group172
 has shown that the certain chiral N-(9-phenylfluoren-
9-yl)-α-amido esters react with organolithium reagents to give
the corresponding enantiomerically pure ketones in good yield.
For example, the imidazolidinone  327 (Scheme 122) reacted
with chloromethyllithium to give ketone  328 in quantitative
yield. The protecting group was later removed from intermedi-
ate  329 by acidolysis to give  330, a core structure of the
streptothricin antibiotics.
The  [22] cycloaddition of ketenes generated from acid
chlorides and a tertiary organic base with imines (the
Staudinger reaction) is an important reaction in the commercial
synthesis of the azetidin-2-one ring system. Unfortunately, the
reaction has hitherto been limited mostly to imines prepared
from non-enolisable aldehydes. Palomo and co-workers
173
 have
shown that  N-[bis(trimethylsilyl)methyl]imines of enolisable
Scheme 121
HNCO2H
NH2
HNCO2TMS
NHTMS
HNCO2TMS
NH
OMe
H2NCO2H
NH
OMe
N
H
H
N
N
H O
O
O
O
R
OO
OH
OO
O
OH
OH
OMe
O
O
N
H
H
HO
O
OH
Fmoc Fmoc
Fmoc
N
324
325
326
57%
57%
(a) TMSCl, CH2Cl2, ∆, 1 h
(b) EtN(Pr
i
)2, 0 °C → rt
MMT-Cl
rt, 18 h
91%
321
322323
7 steps
R = NHMMT
R = NH3
+ Cl2CHCO2

R =
NH3
+ Cl

Cl2CHCO2H, anisole
CH2Cl2, rt, 1 h
AG® 2-X8 resin (Cl
–)
MeOH
320
Et2NH
DMF, rt, 1 h
100%J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4033
aldehydes (e.g. 334, Scheme 123) are stable and isolable reagents
which undergo easy and efficient  [22] cycloaddition with
homochiral aminoketene  332. The mild deprotection of the
bis(trimethylsilyl)methyl and phenyloxazolidinone  N-protect-
ing groups was accomplished with cerium() ammonium
nitrate (CAN) and hydrogen/Pd(OH)2 respectively. Alter-
natively, the latter protecting group can be cleaved with lithium
in liquid ammonia.
The bromine atoms in 1-protected 2,4,5-tribromoimidazole
can be sequentially replaced through selective Br→Li (or
MgBr) exchange strategies. However, application of this
strategy to the synthesis of polyfunctionalised imidazoles has
Scheme 122
N N
MeO2CCO2Me
Bn
O
Ph
N N
CO2Me
Bn
O
Cl
O
N N Bn
O
Pf
NH
HOO
H H
NH N Bn
O
NH
HOO
H H
Pf
ClCH2Li
 (2 equiv.)
THF
–78 °C, 75 min
100%
TFA
CH2Cl2
84%
327 328
329 330
Scheme 123
NSiMe3
SiMe3
H3C
OCl
N
Ph
O
O
H2NSiMe3
SiMe3

N
Ph
O
O
H
O
O
N
Ph
O
O
NSiMe3
CH3
SiMe3
H H
O
BocHN
NSiMe3
CH3
SiMe3
H H
O
BocHN
NH
CH3
H H
O
BocHN
NH
CH3
O
H H
CH3CHO, 4Å MS
CH2Cl2, rt
90% (E:Z = 94:6)
NEt3, 4Å MS, CHCl3
0 °C → ∆, 12 h
70%
cis:trans = 4:1
H2 (60 psi)
Pd(OH)2
(Boc)2O, EtOAc, rt
79%
CAN (4 equiv.)
MeOH, 60 °C, 3 h
78% (2 steps)
331
332
333
334
335
336
337 338
been hampered by lack of a suitable N-protecting group. For
example, previous attempts to convert various 1-protected
2,4,5-tribromoimidazoles to the thieno[2,3-d ]imidazole  342
(Scheme 124) failed owing to the instability of the product to
the acidic or basic conditions required for  N-deprotection.
Hartley and Iddon174
 have shown that the vinyl group survives
the three halogen metal exchange reactions used to convert
1-vinyl-2,4,5-tribromoimidazole (340) to the thienoimidazole
341. Oxidative cleavage of the vinyl group in 341 using ozone in
methanol (dimethyl sulfide workup) or potassium permangan-
ate in refluxing acetone gave the desired parent thieno[2,3-d ]-
imidazole 342 in excellent yield.
A French group175
 have shown that N,N-dibenzylformamid-
ine derivatives serve as useful protecting groups for the protec-
tion of the primary amino function of guanine and adenine
groups in nucleotide synthesis. The N,N-dibenzylformamidine
derivatives are prepared (Scheme 125) by reaction of the pri-
mary amino function with dibenzylformamide dimethyl acetal
prepared  in situ by reaction of dimethylformamide dimethyl
acetal with dibenzylamine (3 equiv.) in refluxing acetonitrile for
20 h. N,N-Dibenzylformamidines are cleaved by hydrogenolysis
using Pd(OH)2 (0.5–5.0 equiv.) in But
OH–H2O (1:1) at 70 psi.
The process research group176
 at Schering-Plough have
devised an asymmetric synthesis of the broad spectrum anti-
biotic florfenicol (348, Scheme 126) which made good strategic
use of a (dichloromethyl)oxazoline group as a protecting group
which is eventually incorporated in the final product after trans-
formation to a dichloroacetamide. Treatment of the homo-
chiral epoxy alcohol 343 with sodium hydride followed by zinc
chloride gave a zinc alkoxide, which reacted with dichloro-
acetonitrile to introduce the (dichloromethyl)oxazoline moiety.
The zinc chloride was added to suppress the Payne rearrange-
ment. After conversion of the hydroxy function in  344 to its
ethanesulfonate, the oxazoline was hydrolysed to the dichloro-
acetamide derivative  345. Intramolecular displacement of the
ethanesulfonate group (inversion) regenerated the oxazoline
ring which protected the hydroxy and amino functions during
the conversion of the free hydroxy group in 346 to the fluoro
derivative 347. Finally, hydrolysis of the oxazoline ring at pH
5.0 gave the crystalline florfenicol (348).
Scheme 124
N
N
Br
Br
Br
H
N
N
Br
Br
Br
N
N S
N
N
H
S
339 340
341 342
(a)
(b)
BrCH2CH2Br, NEt3, ∆
10% aq. NaOH, ∆
6 steps
KMnO4
acetone, ∆
99%
80%
Scheme 125
N
N N
N
NH2
O
O
O
OH
N
N N
N
N
O
O
O
OH
NBn2
Bn2N-CH(OMe)2 (2.5 equiv.)
MeCN, rt (87%)
Pd(OH)2/C, H2 (70 psi)
But
OH-H2O (1:1), rt (99%)4034 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
Primary amines can be protected as their 2,5-bis[(triiso-
propylsilyl)oxy]pyrrole (Bipsop) derivatives.
177
 The two step
protection sequence is shown in Scheme 127. In the first step the
amine (e.g.  349) is transformed into the corresponding imide
350 by reaction with succinic anhydride followed by cyclodehy-
dration of the intermediate amide acid with acetyl chloride. In
the second step the imide  350 is treated with triisopropylsilyl
triflate (TIPSOTf) in the presence of triethylamine to give the
desired pyrrole derivative  351. The bis[(triisopropylsilyl)oxy]-
pyrrole ring is stable to strong bases such as organolithium
reagents (78 to 20 C), heating at temperatures up to 150 C,
and chromatography on neutral alumina. Removal of the
Bipsop protecting group can be accomplished under mild con-
ditions by sequential reaction first with dilute acid followed by
refluxing the intermediate succinimide with hydrazine in
ethanol.
The first total synthesis of haliclamine A (357, Scheme 128)
was achieved by stepwise inter- and intra-molecular N-alkyl-
ations of 3-alkylpyridine derivatives.
178
 To avoid polymerisation
or intramolecular N-alkylation of 353 during coupling of 352
and 353, the nucleophilic nitrogen in 352 was protected as its
N-oxide. Mesylation of the alcohol function in 354 resulted in
expedient deoxygenation of the N-oxide whence macrocyclis-
ation of intermediate  355 gave the bispyridinium salt  356.
Reduction with sodium borohydride completed the synthesis.
9Miscellaneous protecting groups
Roberts and co-workers
179
 were looking for a protecting group
for arenesulfonic acids which, on the one hand, would be
compatible with a wide range of standard organic synthesis
methodologies, but on the other hand, could be removed under
Scheme 126
SO2Me
H
OH
H
O
SO2Me
H
OH
N
O Cl
Cl
H
SO2Me
H
EtSO2O
H
OH
N
H
O
Cl
Cl
SO2Me
N
O
H
H
OH
Cl
Cl
SO2Me
N
O
H
H
F
Cl
Cl
SO2Me
F
HN
HO
O
ClCl
343 344
345 346
347 348
(a)
(b)
(c)
NaH, THF, 5 °C, 30 min
add ZnCl2 (1.0 equiv.)
add Cl2CHCN (1.2 equiv.)
55 °C, 16 h
65% (128 mmol scale)
(a) EtSO2Cl, pyr, NEt3, 5 °C
(b) pH 2.0 (3.0 M H2SO4)
pH 12.0 (50% NaOH)
50% overall from 344
CF3CHFCF2NEt2
CH2Cl2, 100 °C, 3 h
Pr
i
OH-H2O
KOAc, ∆, 3 h
ca 90%
relatively mild conditions. It turned out that neopentyl (2,2-
dimethylpropyl) esters (e.g.  359, Scheme 129) served this
purpose well, withstanding such reagents as  tert-butyllithium,
vinylmagnesium bromide, CrO3, NBS/benzoyl peroxide, H2/
RaNi, DIBAL-H, NaI, HONH2, NaH, aq. HBr or NaOH.
Deprotection could be easy accomplished by heating the ester
with excess tetramethylammonium chloride in DMF.
Sulfate monoesters in carbohydrates can be protected as their
trifluoroethyl ester.
180
 The protected sulfates were prepared by
treatment of the carbohydrate (e.g. 361, Scheme 130) with sul-
fur trioxide–pyridine complex followed by reaction of the crude
monosulfate with trifluorodiazoethane. The resulting 2,2,2-
trifluoroethyl ester  362 was stable to sodium methoxide in
methanol, which allowed selective acetate methanolysis to give
363. The removal of the sulfate protecting group was achieved
with potassium tert-butoxide in tert-butyl alcohol. Apart from
sodium methoxide, 2,2,2-trifluoroethyl sulfates were also stable
to tetrabutylammonium fluoride, trifluoroacetic acid in ethanol
and catalytic hydrogenation, but not to dilute sulfuric acid (the
entire sulfate moiety was cleaved).
10Reviews
‘Recent developments in solid-phase organic synthesis’, R.
Brown, J. Chem. Soc., Perkin Trans. 1, 1998, 3293.
‘Solid Phase Synthesis’, R. Brown, Contemp. Org. Synth., 1997,
4, 216.
‘Protecting Groups’, K. Jarowicki and P. Kocienski, Contemp.
Org. Synth., 1997, 4, 454.
‘Allylic protecting groups and their use in a complete environ-
ment. 1. Allylic protection of alcohols’, F. Guibé,  Tetra-
hedron, 1997, 53, 13509.
‘Enzymatic Synthesis of Peptide Conjugates: Tools for the
Study of Biological Signal Transduction’, T. Kappies and
H. Waldmann, Liebigs Ann., 1997, 803.
‘Recent Advances in N-Protection for Amino Sugar Synthesis’,
J. Debenham, R. Rodebaugh and B. Fraser-Reid,  Liebigs
Ann., 1997, 791.
‘Esterifications, Transesterifications, and Deesterifications
Mediated by Organotin Oxides, Hydroxides, and Alkoxides’,
O. A. Mascaretti and R. L. E. Furlan, Aldrichim. Acta, 1997,
3, 55.
A new and practical removal of allyl and allyloxy-carbonyl
groups promoted by water-soluble Pd(0) catalysts, S. Lemaire-
Audoire, M. Savignac, J. P. Genet and J. M. Bernard, in Roots
of Organic Development, ed. J. R. Desmurs and S. Ratton,
1996, Elsevier, Amsterdam, p. 416.
Scheme 127
NH2
Br
O
O
O
N
Br
O O
N
Br
OTIPS TIPSO
349
350
351
(a)
(b)
4.1 mmol
PhH, ∆, 1-2 h
AcCl (11 ml), ∆, 1 h
92% (3.9 mmol scale)
TIPSOTf (4.27 mmol)
Et3N (6.21 mmol)
CH2Cl2 (8 ml), rt, 2 h
90% (1.94 mmol scale)
HCl (0.5 M, 1.09 mmol)
THF (7 ml), rt, 10 min
N2H4•H2O (2.74 mmol)
EtOH, ∆, 20 h
82% (0.55 mmol scale)
(a)
(b)J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4035
Protecting groups in oligosaccharide synthesis, T. B. Grindley, in
Modern Methods in Carbohydrate Synthesis, ed. S. H. Khan
and R. A. O’Neill, 1996, Harwood, Chur, p. 225.
Synthesis of isopropylidene, benzylidene, and related acetals,
P. Calinaud and J. Gelas, in Preparative Carbohydrate Chem-
istry, ed. S. Hanessian, 1997, Marcel Dekker, New York, p. 3.
Dialkyl dithioacetals of sugars, D. Horton and P. Norris, in
Preparative Carbohydrate Chemistry, ed. S. Hanessian, 1997,
Marcel Dekker, New York, p. 35.
Regioselective cleavage of O-benzylidene acetals to benzyl ethers,
P. J. Garegg, in Preparative Carbohydrate Chemistry, ed. S.
Hanessian, 1997, Marcel Dekker, New York, p. 53.
Selective O-substitution and oxidation using stannylene acetals
and stannyl ethers, S. David, in  Preparative Carbohydrate
Chemistry, ed. S. Hanessian, 1997, Marcel Dekker, New
York, p. 69.
O- and N-glycopeptides: Synthesis of selectively deprotected
building blocks, H. Kunz, in  Preparative Carbohydrate
Chemistry, ed. S. Hanessian, 1997, Marcel Dekker, New
York, p. 265.
Scheme 128
N
OMs
O–
N
N
N
N
N
N
O–
HO
N
HO
N
N
MsO
352
353
354
355
356
I

I

KI, MeCN, ∆, 4 d 67%
MsCl, NEt3, CH2Cl2, 0 °C, 1 h 64%
KI, MeCN, ∆, 2 d 41%
NaBH4, MeOH-H2O (3:2)
0 °C → rt, 12 h 65%
357
+
11References
1U. Ellervik and G. Magnusson, Tetrahedron Lett., 1997, 38, 1627.
2D. A. Evans, B. W. Trotter, B. Cote, P. J. Coleman, L. C. Dias and
A. N. Tyler, Angew. Chem., Int. Ed. Engl., 1997, 36, 2744.
3K. M. Gardinier and J. W. Leahy, J. Org. Chem., 1997, 62, 7098.
4H. C. Kolb and K. B. Sharpless, Tetrahedron, 1992, 48, 10515.
5A. Hasan, K. P. Stengele, H. Giegrich, P. Cornwell, K. R. Isham,
R. A. Sachleben, W. Pfleiderer and R. S. Foote, Tetrahedron, 1997,
53, 4247.
6K. Rosenthal, A. Karlstrom and A. Unden, Tetrahedron Lett., 1997,
38, 1075.
7A. G. Myers, N. J. Tom, M. E. Fraley, S. B. Cohen and D. J. Madar,
J. Am. Chem. Soc., 1997, 119, 6072.
8E. Anders, A. Stankowiak and R. Riemer, Synthesis, 1987, 931.
9G. A. Olah and D. A. Klumpp, Synthesis, 1997, 744.
10A. Tanaka and T. Oritani, Tetrahedron Lett., 1997, 38, 1955.
11A. Tanaka and T. Oritani, Tetrahedron Lett., 1997, 38, 7223.
12G. Maiti and S. C. Roy, Tetrahedron Lett., 1997, 38, 495.
13J. S. Debenham, R. Rodebaugh and B. Fraser-Reid, J. Org. Chem.,
1997, 62, 4591.
14D. L. Boger, R. M. Borzilleri, S. Nukui and R. T. Beresis, J. Org.
Chem., 1997, 62, 4721.
15B. A. D’Sa, D. McLeod and J. G. Verkade, J. Org. Chem., 1997, 62,
5057.
16G. Mann and J. F. Hartwig, J. Org. Chem., 1997, 62, 5413.
17D. F. Meng, P. Bertinato, A. Balog, D. S. Su, T. Kamenecka, E. J.
Sorensen and S. J. Danishefsky,  J. Am. Chem. Soc., 1997,  119,
10073.
18M. A. Brook, C. Gottardo, S. Balduzzi and M. Mohamed,
Tetrahedron Lett., 1997, 38, 6997.
19G. I. Feutrill and R. N. Mirrington, Tetrahedron Lett., 1970, 1327.
20M.-J. Shiao, L.-L. Lai, W.-S. Ku, P.-Y. Lin and J. R. Hwu, J. Org.
Chem., 1993, 58, 4742.
21M. K. Nayak and A. K. Chakraborti, Tetrahedron Lett., 1997, 38,
8749.
22J. R. Hwu, F. F. Wong, J. J. Huang and S. C. Tsay, J. Org. Chem.,
1997, 62, 4097.
23P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart,
1994.
24H. J. Liu, J. Yip and K. S. Shia, Tetrahedron Lett., 1997, 38, 2253.
25E. Alonso, D. J. Ramon and M. Yus,  Tetrahedron, 1997,  53,
14355.
26C. J. Forsyth, S. F. Sabes and R. A. Urbanek, J. Am. Chem. Soc.,
1997, 119, 8381.
Scheme 129
SO2Cl
Br
SO2OR
Br
HO
100%
359 R = CH2C(Me)3
360 R = H
Me4NCl (4-5 equiv.)
DMF,160 °C, 16 h
pyr
95%
358
Scheme 130
O
OR
AcO
AcO
OAc
OAc
O
OR
HO
HO
OH
OH
(a)
(b)
SO3•pyr (1-5 equiv.)
MeCN, 80 °C, 1-2 h
CF3CHN2 (~10 equiv.)
MeCN, 5 min
361 (R = H)
362 (R = SO2OCH2CF3)
But
OK (5 equiv.)
But
OH, ∆, 1-2 h
MeONa, MeOH
2 h, 66%
93% (overall)
88%
363 (R = SO2OCH2CF3)
364 (R = SO2O–K+)4036 J. Chem. Soc., Perkin Trans. 1, 1998,  4005–4037
27Y. Ichikawa, M. Isobe and T. Goto, Agric. Biol. Chem., 1988, 52,
975.
28P. K. Freeman and L. L. Hutchinson, J. Org. Chem., 1980, 45, 1924.
29S. S. Harries, G. Yang, M. A. Strawn and D. C. Myles,  J. Org.
Chem., 1997, 62, 6098.
30H. Sajiki, H. Kuno and K. Hirota,  Tetrahedron Lett., 1997,  38,
399.
31J. L. Wood, B. M. Stoltz, S. N. Goodman and K. Onwneme, J. Am.
Chem. Soc., 1997, 119, 9652.
32K. P. R. Kartha and R. A. Field, Tetrahedron, 1997, 53, 11753.
33K. K. Reddy, J. Rizo and J. R. Falck, Tetrahedron Lett., 1997, 38,
4729.
34N. Nakajima, K. Horita, R. Abe and O. Yonemitsu, Tetrahedron
Lett., 1988, 29, 4139.
35T. Onoda, R. Shirai and S. Iwasaki,  Tetrahedron Lett., 1997,  38,
1443.
36A. Bouzide and G. Sauvé, Synlett, 1997, 1153.
37K. Egusa, K. Fukase and S. Kusumoto, Synlett, 1997, 675.
38G. J. Boons, S. Bowers and D. M. Coe, Tetrahedron Lett., 1997, 38,
3773.
39T. W. Greene and P. G. M. Wuts,  Protective Groups in Organic
Synthesis, Wiley, New York, 1991.
40A. V. Bhatia, S. K. Chaudhary and O. Hernandez, Org. Synth., 1997,
75, 184.
41O. Hernandez, S. K. Chaudhary, R. H. Cox and J. Porter,
Tetrahedron Lett., 1981, 22, 1491.
42J. D. Wang, Y. Okada, W. Li, T. Yokoi and J. T. Zhu, J. Chem. Soc.,
Perkin Trans. 1, 1997, 621.
43R. M. Thomas, G. H. Mohan and D. S. Iyengar, Tetrahedron Lett.,
1997, 38, 4721.
44T. Satoh, M. Ikeda, M. Miura and M. Nomura, J. Org. Chem., 1997,
62, 4877.
45V. M. Swamy, P. Ilankumaran and S. Chandrasekaran,  Synlett,
1997, 513.
46S. Olivero and E. Dunach, Tetrahedron Lett., 1997, 38, 6193.
47A. K. Ghosh and W. M. Liu, J. Org. Chem., 1997, 62, 7908.
48H. Makabe, A. Tanaka and T. Oritani, Tetrahedron Lett., 1997, 38,
4247.
49H. Naito, E. Kawahara, K. Maruta, M. Maeda and S. Sasaki,
J. Org. Chem., 1995, 60, 4419.
50L. A. Paquette, L. Q. Sun, D. Friedrich and P. B. Savage,  J. Am.
Chem. Soc., 1997, 119, 8438.
51Y. S. Tsantrizos, J. F. Lunetta, M. Boyd, L. D. Fader and M. C.
Wilson, J. Org. Chem., 1997, 62, 5451.
52T. Sunazuka, T. Hirose, Y. Harigaya, S. Takamatsu, M. Hayashi,
K. Komiyama, S. Omura, P. A. Sprengeler and A. B. Smith, J. Am.
Chem. Soc., 1997, 119, 10247.
53H. Sato, S. Nakamura, N. Watanabe and S. Hashimoto,  Synlett,
1997, 451.
54J. H. Rigby and J. Z. Wilson, Tetrahedron Lett., 1984, 25, 1429.
55M. S. Congreve, E. C. Davison, M. A. M. Fuhry, A. B. Holmes,
A. N. Payne, R. A. Robinson and S. E. Ward, Synlett, 1993, 663.
56J. W. Burton, J. S. Clark, S. Derrer, T. C. Stork, J. G. Bendall and
A. B. Holmes, J. Am. Chem. Soc., 1997, 119, 7483.
57J. D. Hu and M. J. Miller, J. Am. Chem. Soc., 1997, 119, 3462.
58J. A. Marshall and M. Z. Chen, J. Org. Chem., 1997, 62, 5996.
59T. Schlama, V. Gouverneur and C. Mioskowski, Tetrahedron Lett.,
1997, 38, 3517.
60R. Ballini, F. Bigi, S. Carloni, R. Maggi and G. Sartori, Tetrahedron
Lett., 1997, 38, 4169.
61P. H. Dussault and K. R. Woller,  J. Am. Chem. Soc., 1997,  119,
3824.
62C. B. Reese, H. T. Serafinowska and G. Zappia, Tetrahedron Lett.,
1986, 27, 2291.
63C. B. Reese and E. A. Thompson, J. Chem. Soc., Perkin Trans. 1,
1988, 2881.
64M. Faja, C. B. Reese, Q. L. Song and P. Z. Zhang, J. Chem. Soc.,
Perkin Trans. 1, 1997, 191.
65R. J. Bergeron, C. Ludin, R. Muller, R. E. Smith and O. Phanstiel,
J. Org. Chem., 1997, 62, 3285.
66Y. X. Han and G. Barany, J. Org. Chem., 1997, 62, 3841.
67W. F. Bailey, M. W. Carson and L. M. J. Zarcone, Org. Synth., 1997,
75, 177.
68W. F. Bailey, L. M. J. Zarcone and A. D. Rivera, J. Org. Chem., 1995,
60, 2532.
69M. Guiso, C. Procaccio, M. R. Fizzano and F. Piccioni, Tetrahedron
Lett., 1997, 38, 4291.
70F. De Angelis, M. Marzi, P. Minetti, D. Misiti and S. Muck, J. Org.
Chem., 1997, 62, 4159.
71S. F. Lu, Q. Q. Oyang, Z. W. Guo, B. Yu and Y. Z. Hui,  J. Org.
Chem., 1997, 62, 8400.
72D. P. Larson and C. H. Heathcock, J. Org. Chem., 1997, 62, 8406.
73F. A. Luzzio and R. A. Bobb, Tetrahedron Lett., 1997, 38, 1733.
74D. A. Evans, P. J. Coleman and L. C. Dias, Angew. Chem., Int. Ed.
Engl., 1997, 36, 2738.
75Y. Oikawa, T. Yoshioka and O. Yonemitsu, Tetrahedron Lett., 1982,
23, 889.
76J. N. Shepherd, J. Na and D. C. Myles, J. Org. Chem., 1997, 62,
4558.
77A. Fadel, R. Yefsah and J. Salaün, Synthesis, 1987, 37.
78K. S. Kim, Y. H. Song, B. H. Lee and C. S. Hahn, J. Org. Chem.,
1986, 51, 404.
79S. E. Sen, S. L. Roach, J. K. Boggs, G. J. Ewing and J. Magrath,
J. Org. Chem., 1997, 62, 6684.
80S. V. Ley, D. R. Owen and K. E. Wesson, J. Chem. Soc., Perkin
Trans. 1, 1997, 2805.
81S. V. Ley, H. M. I. Osborn, H. W. M. Priepke and S. L. Warriner,
Org. Synth., 1997, 75, 170.
82A. Hense, S. V. Ley, H. M. I. Osborn, D. R. Owen, J. F. Poisson,
S. L. Warriner and K. E. Wesson, J. Chem. Soc., Perkin Trans. 1,
1997, 2023.
83P. Grice, S. V. Ley, J. Pietruszka, H. W. M. Priepke and S. L.
Warriner, J. Chem. Soc., Perkin Trans. 1, 1997, 351.
84P. Grice, S. V. Ley, J. Pietruszka, H. M. I. Osborn, H. W. M.
Priepke and S. L. Warriner, Chem. Eur. J., 1997, 3, 431.
85M. K. Cheung, N. L. Douglas, B. Hinzen, S. V. Ley and
X. Pannecoucke, Synlett, 1997, 257.
86J. L. Montchamp and J. W. Frost, J. Am. Chem. Soc., 1997, 119,
7645.
87H. Noguchi, T. Aoyama and T. Shioiri, Tetrahedron Lett., 1997, 38,
2883.
88C. J. Salomon, E. G. Mata and O. A. Mascaretti, J. Chem. Soc.,
Perkin Trans. 1, 1996, 995.
89S. W. Wright, D. L. Hageman, A. S. Wright and L. D. McClure,
Tetrahedron Lett., 1997, 38, 7345.
90W. C. Chen, M. D. Vera and M. M. Joullié, Tetrahedron Lett., 1997,
38, 4025.
91S. Kim, Y. H. Park and I. S. Kee, Tetrahedron Lett., 1991, 32, 3099.
92W. R. Roush, D. S. Coffey and D. J. Madar, J. Am. Chem. Soc.,
1997, 119, 11331.
93P. Four and F. Guibé, Tetrahedron Lett., 1982, 23, 1825.
94M. Honda, H. Morita and I. Nagakura, J. Org. Chem., 1997, 62,
8932.
95D. Sebastian and H. Waldmann, Tetrahedron Lett., 1997, 38, 2927.
96J. Martinez, J. Laur and B. Castro, Tetrahedron, 1985, 41, 739.
97R. S. Givens, A. Jung, C. H. Park, J. Weber and W. Bartlett, J. Am.
Chem. Soc., 1997, 119, 8369.
98Y. J. Shi, J. E. T. Corrie and P. Wan, J. Org. Chem., 1997, 62, 8278.
99U. Schmidt, K. Neumann, A. Schumacher and S. Weinbrenner,
Angew. Chem., Int. Ed. Engl., 1997, 36, 1110.
100A. B. Charette and P. Chua, Tetrahedron Lett., 1997, 38, 8499.
101P. Wipf, W. J. Xu, H. Kim and H. Takahashi, Tetrahedron, 1997, 53,
16575.
102E. J. Corey and N. Raju, Tetrahedron Lett., 1983, 24, 5571.
103H. M. M. Bastiaana, J. L. van der Baan and H. C. J. Ottenheijm,
J. Org. Chem., 1997, 62, 3880.
104D. Seebach, Angew. Chem., Int. Ed. Engl., 1967, 6, 442.
105A. Wilk, K. Srinivasachar and S. L. Beaucage, J. Org. Chem., 1997,
62, 6712.
106H. K. Chenault and R. F. Mandes, Tetrahedron, 1997, 53, 11033.
107K. M. Reddy, K. K. Reddy and J. R. Falck,  Tetrahedron Lett.,
1997, 38, 4951.
108Y. Watanabe, T. Nakamura and H. Mitsumoto, Tetrahedron Lett.,
1997, 38, 7407.
109Y. Watanabe, M. Ishimaru and S. Ozaki, Chem. Lett., 1994, 2163.
110C. H. Park and R. S. Givens, J. Am. Chem. Soc., 1997, 119, 2453.
111B. H. Lipshutz, P. Mollard, C. Lindsley and V. Chang, Tetrahedron
Lett., 1997, 38, 1873.
112A. S. Y. Lee and C. L. Cheng, Tetrahedron, 1997, 53, 14255.
113P. K. Mandal, P. Dutta and S. C. Roy, Tetrahedron Lett., 1997, 38,
7271.
114E. Marcantoni and F. Nobili, J. Org. Chem., 1997, 62, 4183.
115T. Takeda, H. Watanabe and T. Kitahara, Synlett, 1997, 1149.
116J. Otera, N. Dan-oh and H. Nozaki, Tetrahedron, 1992, 48, 1449.
117M. R. Elliott, A. L. Dhimane and M. Malacria, J. Am. Chem. Soc.,
1997, 119, 3427.
118P. Ciceri and F. W. J. Demnitz, Tetrahedron Lett., 1997, 38, 389.
119B. Perio, M. J. Dozias, P. Jacquault and J. Hamelin, Tetrahedron
Lett., 1997, 38, 7867.
120Z. L. Zhu and J. H. Espenson, Organometallics, 1997, 16, 3658.
121M. Larhed and A. Hallberg, J. Org. Chem., 1997, 62, 7858.
122P. Deslongchamps, C. Moreau, D. Fréhel and R. Chênevert, Can.
J. Chem., 1975, 53, 1204.
123M. Frigerio, M. Santagostino and S. Sputore, Synlett, 1997, 833.J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4037
124R. S. Varma and R. K. Saini, Tetrahedron Lett., 1997, 38, 2623.
125M. Hirano, K. Ukawa, S. Yakabe, J. H. Clark and T. Morimoto,
Synthesis, 1997, 858.
126H. M. Meshram, G. S. Reddy and J. S. Yadav, Tetrahedron Lett.,
1997, 38, 8891.
127M. Curini, M. C. Marcotullio, E. Pisani, O. Rosati and U.
Costantino, Synlett, 1997, 769.
128H. Nakamura, K. Aoyagi and Y. Yamamoto, J. Org. Chem., 1997,
62, 780.
129E. Meinjohanns, M. Meldal, T. Jensen, O. Werdelin, L. Galli-
Stampino, S. Mouritsen and K. Bock,  J. Chem. Soc.,  Perkin
Trans. 1, 1997, 871.
130N. C. R. van Straten, H. I. Duynstee, E. de Vroom, G. A. van der
Marel and J. H. van Boom, Liebigs Ann., 1997, 1215.
131H. Waldmann and A. Reidel, Angew. Chem., Int. Ed. Engl., 1997,
36, 647.
132N. Auzeil, G. Dutruc-Rosset and M. Largeron, Tetrahedron Lett.,
1997, 38, 2283.
133R. Madsen, C. Roberts and B. Fraser-Reid, J. Org. Chem., 1995,
60, 7920.
134M. Lodder, S. Golovine and S. M. Hecht, J. Org. Chem., 1997, 62,
778.
135H. Miel and S. Rault, Tetrahedron Lett., 1997, 38, 7865.
136M. Sakaitani and Y. Ohfune, Tetrahedron Lett., 1985, 26, 5543.
137M. Sakaitani and Y. Ohfune, J. Org. Chem., 1990, 55, 870.
138F. S. Gibson, S. C. Bergmeier and H. Rapoport,  J. Org. Chem.,
1994, 59, 3216.
139R. S. Coleman and A. J. Carpenter,  Tetrahedron, 1997,  53,
16313.
140L. Birkofer, E. Bierwirth and A. Ritter, Chem. Ber., 1961, 94, 821.
141N. M. Howarth and L. P. G. Wakelin,  J. Org. Chem., 1997,  62,
5441.
142B. E. Watkins and H. Rapoport, J. Org. Chem., 1982, 47, 4471.
143X. P. Qian and O. Hindsgaul, Chem. Commun., 1997, 1059.
144T. Wagner and W. Pfleiderer, Helv. Chim. Acta, 1997, 80, 200.
145S. B. Rollins and R. M. Williams,  Tetrahedron Lett., 1997,  38,
4033.
146L. A. Carpino, M. Philbin, M. Ismail, G. A. Truran, E. M. E.
Mansour, S. Iguchi, D. Ionescu, A. El-Faham, C. Riemer,
R. Warrass and M. S. Weiss, J. Am. Chem. Soc., 1997, 119, 9915.
147B. Nyasse, L. Grehn and U. Ragnarsson, Chem. Commun., 1997,
1017.
148H. Y. An, L. L. Cummins, R. H. Griffey, R. Bharadwaj, B. D.
Haly, A. S. Fraser, L. Wilson-Lingardo, L. M. Risen, J. R. Wyatt
and P. D. Cook, J. Am. Chem. Soc., 1997, 119, 3696.
149T. Fukuyama, C. K. Jow and M. Cheung, Tetrahedron Lett., 1995,
36, 6373.
150U. Bhatt, N. Mohamed, G. Just and E. Roberts, Tetrahedron Lett.,
1997, 38, 3679.
151W. R. Bowman and D. R. Coghlan, Tetrahedron, 1997, 53, 15787.
152L. Grehn, H. Lönn and U. Ragnarsson, Chem. Commun., 1997,
1381.
153S. J. Danishefsky and M. T. Bilodeau, Angew. Chem., Int. Ed. Engl.,
1996, 35, 1380.
154S. J. Danishefsky, S. Hu, P. F. Cirillo, M. Eckhardt and P. H.
Seeberger, Chem. Eur. J., 1997, 3, 1617.
155P. Sun, S. M. Weinreb and M. Y. Shang, J. Org. Chem., 1997, 62,
8604.
156A. M. P. Koskinen and L. A. Otsomaa,  Tetrahedron, 1997,  53,
6473.
157R. W. Hoffmann, S. Breitfelder and A. Schlapbach, Helv. Chim.
Acta, 1996, 79, 346.
158L. Arias, A. Guzman, S. Jaime-Figueroa, F. J. Lopez, D. J.
Morgans, F. Padilla, A. Perez-Medrano, C. Quintero, M. Romero
and L. Sandoval, Synlett, 1997, 1233.
159A. M. Kimbonguila, S. Boucida, F. Guibé and A. Loffet,
Tetrahedron, 1997, 53, 12525.
160Q. Y. Liu, A. P. Marchington, N. Boden and C. M. Rayner,
J. Chem. Soc., Perkin Trans. 1, 1997, 511.
161D. Picq, M. Cottin, D. Anker and H. Pacheco, Tetrahedron Lett.,1983, 24, 1399.
162J. H. Rigby and M. E. Mateo, J. Am. Chem. Soc., 1997, 119, 12655.
163R. M. Williams and E. Kwast, Tetrahedron Lett., 1989, 30, 451.
164F. He and B. B. Snider, Synlett, 1997, 483.
165I. Hughes, W. P. Nolan and R. A. Raphael, J. Chem. Soc., Perkin
Trans. 1, 1990, 2475.
166J. L. Wood, B. M. Stoltz, H. J. Dietrich, D. A. Pflum and D. T.
Petsch, J. Am. Chem. Soc., 1997, 119, 9641.
167N. A. Petasis, A. Goodman and I. A. Zavialov, Tetrahedron, 1997,
53, 16463.
168D. A. Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C. J.
Dinsmore, D. A. Evrard, K. M. DeVries, J. A. Ellman, S. D.
Rychnovsky and J. Lacour, J. Am. Chem. Soc., 1997, 119, 3419.
169J. L. Radkiewicz, H. Zipse, S. Clarke and K. N. Houk,  J. Am.
Chem. Soc., 1996, 118, 9148.
170A. P. Henderson, J. Riseborough, C. Bleasdale, W. Clegg, M. R. J.
Elsegood and B. T. Golding, J. Chem. Soc., Perkin Trans. 1, 1997,
3407.
171G. M. Dubowchik and S. Radia, Tetrahedron Lett., 1997, 38, 5257.
172E. Fernandez-Megia, J. M. Iglesias-Pintos and F. J. Sardina, J. Org.
Chem., 1997, 62, 4770.
173C. Palomo, J. M. Aizpurua, M. Legido, A. Mielgo and R. Galarza,
Chem. Eur. J., 1997, 3, 1432.
174D. J. Hartley and B. Iddon, Tetrahedron Lett., 1997, 38, 4647.
175S. Vincent, S. Mons, L. Lebeau and C. Mioskowski, Tetrahedron
Lett., 1997, 38, 7527.
176G. Z. Wu, D. P. Schumacher, W. Tormos, J. E. Clark and B. L.
Murphy, J. Org. Chem., 1997, 62, 2996.
177S. F. Martin and C. Limberakis, Tetrahedron Lett., 1997, 38, 2617.
178Y. Morimoto and C. Yokoe, Tetrahedron Lett., 1997, 38, 8981.
179J. C. Roberts, H. Gao, A. Gopalsamy, A. Kongsjahju and R. J.
Patch, Tetrahedron Lett., 1997, 38, 355.
180A. D. Proud, J. C. Prodger and S. L. Flitsch, Tetrahedron Lett.,
1997, 38, 7243.
Review 8/03688H

3130

下载说明:
1.请先分享,再下载
2.直接单击下载地址,不要使用"目标另存为"
3.压缩文件请先解压
4.PDF文件,请用PDF专用软件打开查看
5.如果资料不能下载,请联系本站

相关标准

  • 羟基保护油漆盐雾试验测定标准
  • 最新标准

  • 英国标准bs1199
  • 声屏障图纸
  • 钢筋进场验收记录表
  • GBT 20801.1-2006 压力管道规范 工业管道 第1部分:总则
  • GBT 20801.5-2006 压力管道规范 工业管道 第5部分:检验与试验
  • GBT 5458-2012 液氮生物容器
  • HG20613-2009钢制管法兰用紧固件(PN系列) (1)
  • 2SC2351
  • GB-T 9286-1998 色漆和清漆 漆膜的划格试验-1
  • 灭火系统规范-GB 50084
  • 热门标准

  • GB50210-2001 建筑装饰装修工程质量验收规范
  • GB/T1804-2000 一般公差线性尺寸的未注公差
  • 砖砌化粪池国标图集
  • GB/T2828.1-2012
  • GB2760-2011 食品安全国标食品添加剂使用标准
  • GB/T12706-2008 标准解读
  • HG/T20615-2009钢制管法兰 Class系列
  • GB 4706.1-2005 家用和类似部分的安全 第一部分:通用要求.pdf
  • 标准螺纹螺距对照表
  • JGJ 18-2012 钢筋焊接及验收规程
  • 羟基保护油漆盐雾试验测定标准
  • 本站所有信息来源于互联网,用于学习参考使用,版权归原作者所有!