1-methyl 1′-cyclopropylmethyl (MCPM) as an anomeric protecting group

Article abstract of DOI:10.1016/j.tet.2011.05.133

A pragmatic approach for preparing glycoconjugates of complex oligosaccharides is to prepare the oligosaccharide as a building block with most of its protecting groups exchanged to protecting groups whose cleavage and other manipulations are highly compatible with the functional groups of complex aglycones. For such an approach the reducing end sugar of the building bloc must be protected with a cleavable protecting group during the oligosaccharide synthesis. We demonstrate that the acid labile 1-methyl 1′- cyclopropylmethyl (MCPM) can be effectively used for this purpose. A trisaccharide glycolipid and a disaccharide glycoamino acid are prepared. The absolute chirality of the MCPM in one key acceptor is determined by a combination of NMR NOE measurements, DFT molecular modeling and Noyori catalyst catalyzed asymmetric reduction.

Full text of DOI:10.1016/j.tet.2011.05.133

Tetrahedron 67 (2011) 5750e5761
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1-Methyl 10-cyclopropylmethyl (MCPM) as an anomeric protecting group
*
Siu Hong Yu, Dennis M. Whitfield
National Research Council, Institute for Biological Sciences, 100 Sussex Drive, Ottawa, ON, Canada K1A 0R6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2011
Received in revised form 30 May 2011
Accepted 31 May 2011
Available online 13 June 2011
A pragmatic approach for preparing glycoconjugates of complex oligosaccharides is to prepare the oli-
gosaccharide as a building block with most of its protecting groups exchanged to protecting groups
whose cleavage and other manipulations are highly compatible with the functional groups of complex
aglycones. For such an approach the reducing end sugar of the building bloc must be protected with
a cleavable protecting group during the oligosaccharide synthesis. We demonstrate that the acid labile 1-
methyl 10-cyclopropylmethyl (MCPM) can be effectively used for this purpose. A trisaccharide glycolipid
and a disaccharide glycoamino acid are prepared. The absolute chirality of the MCPM in one key acceptor
is determined by a combination of NMR NOE measurements, DFT molecular modeling and Noyori cat-
alyst catalyzed asymmetric reduction.
Keywords:
Protecting group
Glycolipid
Glycopeptide
Oligosaccharide
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
1. Introduction
at O-2 and subsequently converted into an anomeric leaving group
such as trichloroacetimidate, was needed.
In order to meet the increasing demand for oligosaccharides and
their related glycoconjugates it is often advantageous to prepare
oligosaccharide building blocks that can be subsequently converted
into oligosaccharide donors.1 Such donors can be reacted with an
array of aglycones. Since the aglycones in many glycoconjugates are
often expensive or sensitive to the reagents used in functional
group manipulations it is often practical to minimize functional
group transformations post glycosylation.2 Our research group is
involved in the preparation of various glycoconjugates including
glycolipids and glycopeptides. For example, we recently synthe-
For another synthetic project we wanted to make the di-
saccharide GlcNAc( 1/2)Man -linked to Serine in sufficient
quantities to be made into a glycopeptide that could be used to
study enzyme specificities. A few syntheses of similar building
blocks have been reported.6 Such glycopeptides are found in the
b
a
glycoprotein
a-dystroglycan and defects in the related glycosyl-
transferases are correlated with a variety of neuromuscular disease
states.7 Thus, we needed a temporary anomeric protecting group
that is stable to hydrogenation conditions. Although the 2-
trimethylsilylethanol group8 likely would work we reasoned that
the 1-methyl 10-cyclopropylmethyl (MCPM) protecting group that
was introduced by us could be an attractive alternative. It is an acid
sized a series of Man(
a
1/2)nMan(
a
1/O)Arch (n¼0e4) where
Arch is a glycerol derived diether lipid from the domain archaea
named archaeol. Immunological experiments showed that the tri-
saccharide and tetrasaccharides were the most active giving both
major histocompatibility complex type I and type II activation. The
initial studies were done by sequential glycosylations with donor
1,4 see Fig. 1. Thus, the relatively expensive archaeol lipid had to be
carried through multiple glycosylation, deprotection steps followed
by overall deprotection. We reasoned that synthesizing a tri-
saccharide donor with only O-acetyl groups could be more efficient
due to minimizing the steps with the lipid. Since this trisaccharide
is frequently found in cell surface oligosaccharides a number of
syntheses of similar oligosaccharide donors have been reported.5
Consequently, a mannose derivative that could be chain extended
BnO
BnO
BnO
OH
O
BnO
BnO
BnO
OAc
O
O
O
NH
2a( )
R
1
Cl3C
BnO
BnO
OH
O
BnO
BnO
OH
O
O
BnO
BnO
O
2a(S)
2b(R,S)
* Corresponding author. Tel.: þ1 613 993 5265; fax: þ1 613 952 9092; e-mail
address: dennis.whitfield@nrc-cnrc.gc.ca (D.M. Whitfield).
Fig. 1. Structures of donor 1 and target 2-OH glycosides 2a(R,S) and 2b(R,S).
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.133

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5751
cleavable protecting group orthogonal to many common protecting
2. Results and discussion
groups.9 As well, since it is an ether and relatively small it can be
considered an activating protecting group. Its use as an anomeric
protecting group was not tested in the previous study. Combining
these two synthetic objectives led to a desire to synthesize the
anomerically protected 2-OH free glycoside 2ab, see Fig. 1. The
expectation was that the anomeric MCPM group would allow both
for functional group transformations and activate the adjacent
hydroxyl for glycosylation due to its electron donating potential.9
In a previous study, the MCPM group was introduced as an
electrophile via trichloroacetimidate 3a, see Scheme 1.9 Mild Lewis
acids like silver triflate and boron trifluoride etherate were used as
activators. Attachment to the anomeric position by glycosylation
chemistry requires that alcohol 3b, which is the synthetic precursor
to 3a, act as a nucleophile. Previous reports from our group with an
electronically similar alcohol namely 4 had shown that glycosyla-
tion chemistry led to styrene 5 as the major by-product, see Scheme
2.10 We reasoned that styrene 5 was generated by elimination from
the corresponding resonance-stabilized carbenium ion derived
from 4. Since the MCPM is cleaved by Lewis acids or Bronstead acids
in the presence of nucleophiles, glycosylation with alcohol 3b was
previously deemed difficult and had never been explored. In ad-
dition, we have determined that the MCPM is stable to 5% TFA in
CH2Cl2 but partly labile to 7.5% and completely labile to 10% TFA,
which contrasts with methoxybenzyl protecting group, which is
labile to 5% TFA in CH2Cl2.9
To implement this strategy we reacted well known donor 1 with
the commercially available racemic alcohol 1-methyl 10-cyclo-
propylmethanol under standard glycosylation conditions with
triethylsilyl trifluoromethanesulfonate to yield an inseparable
a/
b
(85/15) of the (R/S)-MCPM glycosides 6a and 6b, respectively, see
Scheme 3. The yield was only 65% possibly reflecting the antici-
pated reactivity difficulties but still sufficient to continue the syn-
thesis. The acetates in 6a and 6b were readily removed under
Zemplen conditions to give the desired acceptor mixture 2ab. This
mixture could be glycosylated with donor 1 to 7ab, deacetylated to
8ab, glycosylated again with donor 1 to trisaccharide 9ab. All
transformations proceeded smoothly indicating the stability of the
anomeric MCPM group to glycosylation conditions. Since the
MCPM group is orthogonal to most hydrogenation conditions the
O-benzyl groups were removed at this stage by standard Pd cata-
lyzed hydrogenation. Subsequent acetylation led to peracetyl tri-
saccharides 10ab in 50% yield for two steps. Then the MCPM group
was cleaved with 10% TFA in CH2Cl2 to yield the
a
/
b
-hemiacetal
-tri-
11ab, which was readily transformed into known
a/b
chloracetimodyl donor 12ab.11
The lipid archaeol could then be glycosylated with the promoter
silver trifluormethanesulfonate (AgOTf)12 to give in 61% isolated
yield pure a-glycoside 13a after separation from traces of b-glyco-
side 13b by careful silica gel chromatography. After Zemplen
Established chemistry
Proposed chemistry
Cl3C
OH
NaH/CCl3CN
O
HN
(R,S)
(R,S)
3b
3a
O
O
(HO)4
Lewis acid
(PGO)4
Lewis acid
OR
X
O
O
(HO)3
MCPMO
(PGO)4
OR
OMCPM
Scheme 1. Switching of reactivity to introduce the MCPM group from the established electrophilic route to a nucleophilic route.
(R,S)
HO
(R,S)
HO
Lewis acid
OPEGM
OPEGM
4
4
(no reaction)
O
(PGO)4
X
(R,S)
HO
Lewis acid
OPEGM
OPEGM
4
5
Scheme 2. Glycosylation dependent elimination reaction of an alcohol (4) that can form a resonance-stabilized carbenium ion.

5752
S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
BnO
BnO
BnO
OR
HO
O
(R,S)
1
BnO
BnO
BnO
OR
O
3 Å m.s., TESOTf
BnO
BnO
BnO
O
3 Å m.s., TESOTf
O
1
CH2Cl2
0 °C, 1 h
CH2Cl2
0 °C, 1 h
OMCPM
OMCPM
NaOMe
6ab( , ), R = Ac, 65%
R S
NaOMe
7ab( , ), R = Ac, 63%
R S
2ab( , ), R = H, 96%
R S
8ab( , ), R = H, 98%
R S
RO
RO
RO
RO
RO
RO
OR
OAc
O
O
1
RO
RO
RO
RO
RO
RO
O
O
10% TFA
3 Å m.s., TESOTf
O
O
CH2Cl2
r.t., 2 h
CH2Cl2
0 °C, 1 h
then r.t., 30 min
RO
RO
RO
RO
RO
RO
O
O
O
O
X
OMCPM
9ab( , ), R = Bn, 78%
R S
11ab, R = Ac, X = OH
CCl3CN, DBU
12ab, R = Ac, X = TCI, 66%
1) Pd(OH)2/H2
2) Ac2O/Pyridine
10ab( , ), R = Ac, 64%
R S
archaeol, AgOTF
13a, R = Ac, X = Arch, 61%
NaOMe
Arch =
O
O
O
14, R = H, X = Arch, 98%
Scheme 3. Synthesis of trisaccharide glycolipid 14 via monosaccharide donor 1.
deacetylation 13a was turned into the previously synthesized 14 in
high purity after silica gel chromatography. Glycolipid 14 is being
used in ongoing immunological experiments.
In none of the steps above with the chiral MCPM protecting
group at the anomeric center was there any evidence for diaster-
eoselectivity for either (R)- or (S)-glycosides. In some case during
silica gel chromatography detailed TLC analysis of the separated
fractions suggested some slight polarity difference between di-
astereomers. Frequently, the chromatography fractions chosen for
concentration based on eliminating all non-product contaminants
led to enrichment in one isomer over the other but the ratio’s rarely
exceed 55/45. The absolute chirality of none of the isomers was
known. In one case during reaction optimization of the formation of
disaccharides 16ab, it proved possible to separate unreacted 2ab
into two samples with one predominantly as diastereomer 2a and
Similarly the mixture of alcohols 2a and 2b could be glycosy-
lated with known trichloroethoxycarbonyl (Troc) protected glu-
cosamine donor 1513 in an acceptable yield of 70% to give
b-linked
disaccharides 16ab, see Scheme 4. The Troc could be transformed
into the N-acetyl of the target by treatment with Zn powder in
acetic anhydride to yield 17ab in good yield.14 Subsequent hydro-
genation and acetylation led to peracetyl disaccharides 18ab.
For characterization purposes a small portion of disaccharides
18ab was deacetylated to 19ab. The main portion of 18ab had
the anomeric MCPM group cleaved by 10% TFA in CH2Cl2 to yield
the hemiacetal, which was readily transformed into the tri-
chloracetimidate donor 20. Thus, the MCPM allowed for an efficient
synthesis of this disaccharide donor 20.
the other as diastereomer 2a along with traces of the (R,S)-b-
mannosides 2b. This result emphasizes that there appears to be no
major reactivity difference but only slight polarity differences be-
tween the diastereomers. With these partially purified samples we
performed 1H NMR NOE analyses to see if any conformational
preferences existed which could in turn be used to assign the ab-
solute chirality, see Supplementary data for further NOE experi-
ments. As shown in Fig. 2a and b the NOE interactions between the
anomeric proton and the MCPM protons were markedly different
for the two diastereomers. In both isomers the expected strong NOE
interaction with Man H-2 is observed along with a strong NOE to
the MCPM ether methine. But, in one isomer (Fig. 2a) the pre-
dominant long range interactions are between Man H-1 and three
of the cyclopropyl protons whereas for the other isomer (Fig. 2b)
the predominant long range interaction is between Man H-1 and
Donor 20 could be reacted with commercially available fluo-
renylmethoxycarbonyl (Fmoc) N-protected and phenylacetyl
(PhAc) CO-protected serine derivative 21 to give
amino acid 22 in a good yield with no detectable
a
-linked glyco-
b
-isomer formed
in the presence of the promoter BF3$Et2O. The PhAc group was
cleaved by treatment with Zn powder in ethyl acetate in the
presence of a small amount of acetic acid to yield glycoamino acid
building block 23. For characterization a small amount of 23 had the
O-acetates selectively removed in the presence of the Fmoc pro-
tecting group using KCN in methanol to yield 24. Glycoamino acid
23 is being used to synthesize glycopeptides.

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5753
1) Zn, Ac2O
AcO
AcO
AcO
2) H2, Pd(OH)2
then
Ac2O, pyridine
O
2ab, 4 Å m.s.
NIS, TfOH
O
AcO
AcO
O
NTroc
BnO
BnO
BnO
AcO
SPh
NTroc
3) 10% TFA, CH2Cl2
4) CCl3CN, DBU
CH2Cl2
0 °C, 45 min
O
15
OMCPM
16ab, 75%
NHFmoc
O
HO
R1O
R1O
1O
R
O
Ph
R
O
1O
1O
R
O
21
O
R
1O
O
NHAc
O
R1
R
NR3
O
.
R2O
R2O
R
1O
O
BF3 OEt2
1O
O
4 Å m.s., CH2Cl2
0 °C, 2 h
R
2O
NHFmoc
CO2
22, R1 = Ac, R2 = CH2COPh, 72%
Zn, AcOH
23, R1 = Ac, R2 = H, 75%
KCN, MeOH
24, R1 = R2 = H, 80%
O
X
R2
17ab, R1 = Ac, R2 = Bn, R3 = HAc, X = OMCPM, 85%
18ab, R1 = R2 = Ac, R3 = HAc, X = OMCPM, 88%
NaOMe
19ab, R1 = R2 = OH, R3 = HAc, X = OMCPM, 95%
20, R1 = R2 = Ac, R3 = HAc, X = TCI, 88%
Scheme 4. Synthesis of glycoamino acid building block 23 via disaccharide 16ab.
the MCPM methyl. These results strongly suggest a conformational
difference between the two diastereomers.
Computational-based conformational analysis (see Supplemen-
tary data) was performed on the (R)- and (S)-(1-methyl cyclo-
Consequently, it was decided to investigate this torsion by Density
Functional Theory (DFT) calculations using a relatively large for this
size of molecule TZP basis set. Experimentation showed that a
relatively small rotation step size of 3ꢁ was necessary to avoid
discontinuities, which are still apparent in Fig. 3a and b but mini-
mized. The results shown in Fig. 3a and b indicate a remarkable
diastereoselective dependence with the (R)-isomer favoring Family
1 and the S-isomer favoring Family 2. Fig. 4a and b show molecular
models of the two minimum energy conformers for the two fam-
ilies of the (R)- and (S)-isomers. It is readily apparent that the cal-
culated minimum energy conformation for the (R)-isomer fits the
NOE data in Fig. 2a whereas the calculated conformation of the (S)-
isomer fits the data in Fig. 2b providing a plausible assignment of
the absolute stereochemistry.
propylmethyl) 3,4,6-tri-O-methyl-a-D-mannopyranosides 25(R)
and 25(S) (Figs. 3 and 4), which are analogues of (R,S)-2a where the
O-methyl simplifies the multiple minima problem created by the O-
benzyl groups.15 Initial computational studies used semi-empirical
calculations to exhaustively search the four most likely bonds to
exhibit conformational flexibility: phi (fH¼CH-1eC-1/O-1eCH),
xsi (
j
¼C-1eO-1/CHeCcp), omega (uH¼CHe5-Ce5/C-6eO-6)
and
c
1¼O-1eCH(CH3)/CHcpeCcpH2. This analysis revealed that
phi strongly favored the exo-anomeric position of approximately
ꢀ50ꢁ for both isomers and for most values of the remaining torsion
angles. Rotation about
c1 showed limited barriers such that all
To further corroborate the assignments we undertook a stereo-
selective synthesis of 1-methyl 10-cyclopropylmethanol by asym-
metric reduction of cyclopropylmethyl ketone. To this end
three rotamers were all populated for any combination of the three
other torsions. When feasible, due to lack of spectral overlap,
coupling constant analysis between the two methines shows
a similar value for all compounds determined to be near 9 Hz
suggesting a predominant but not exclusive population of the trans
isomer with respect to the methines torsion. The experimental
value for 2a(R) and 2a(S) is 8.2 Hz. Similarly omega showed the
‘normal’ preferences for values of ꢀ60ꢁ (gt) and 180ꢁ (gg) with
a slight preference for conformations near 180ꢁ for any combina-
the ketone was reduced using the Noyori catalyst ((R)-Ru(h6
-
mesitylene)-(R,R)-TsDPEN) with formic acid as the hydrogen
source.17 This gave an approximately 90/10 mixture of epimers, see
Supplementary data. To assign the major isomer the Mosher esters
derived from both commercially available chlorides were pre-
pared.18 The NMR parameters suggest an absolute stereochemistry
of (R) for the major isomer, see Supplementary data for details.19 A
previous report of Noyori hydrogenation of cyclopropylmethyl ke-
tone also led to predominant formation of the (R)-isomer but using
different experimental conditions.20 After purification of a small
amount of the alcohol from the reduction mixture the glycoside
mixture 6a and 6b was produced by reaction with donor 1. Purifi-
cation by preparative TLC followed by deacetylation and further
preparative TLC led to a small amount of slightly impure 2a(R).
Significant NMR resonances and NOE patterns after irradiation of
H-1 strongly corroborated the (R)-assignment from molecular
modeling by computation.
tion of the other three torsions. The torsion
j, however, essentially
sorted the conformers into two families, see Fig. 4. The
j
value for
Family 1 and 2 are about 60ꢁ and 180ꢁ, respectively. Based on
strictly steric arguments it has been suggested that glycosides with
chiral centers at the aglycone carbon of
a
-
D
-mannopyranosides
defined with
should have
j
equal to 180ꢁ for both isomers (with
j
the highest priority carbon replacing Ccp).16 In our case this torsion
likely depends on a combination of steric and hyper-conjugative
effects as well as sigma donation from the cyclopropyl ring. The
magnitude of the last effect being particularly difficult to predict.

5754
S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
Fig. 2. Partial 1H NMR (400 MHz) 1D difference NOE spectra. (a) Single isomer 2a (probably R) irradiated on Man H-1: note small NOE to CH3 and medium to cyclopropyl CH’s. (b)
The other single isomer 2a (probably S) irradiated on Man H-1: note large NOE to CH3 and very small to cyclopropyl CH’s. M-1, M-2, M-3 and M-5 refer to mannose H-1, H-2, H-3,
and H-5, respectively.
3. Conclusion
been successfully extended to temporary anomeric protection in
oligosaccharide synthesis.
As exemplified by the synthesis of trisaccharide donor 12ab and
disaccharide donor 20, the MCPM protecting group can be used as
a temporary anomeric protecting group. The MCPM group was
shown to be stable to hydrogenation and reduction with Zn metal,
which often used in carbohydrate protecting group manipulations
and can compromise the selection of anomeric protecting groups
such as allyl, benzyl, trichloroethyl and related derivatives. The
successful glycosylation at O-2 adjacent to the anomeric MCPM of
2ab also suggests that this protecting group is activating for gly-
cosylations. The absolute chirality of the MCPM group in key ac-
ceptor 2a was established by a combination of asymmetric
synthesis, 1H NMR NOE experiments and DFT calculations. These
computational studies also show that the conformational bias of
4. Experimental
4.1. Materials and general methods
The 1H NMR spectra were obtained on a Varian VXR-500
(500 MHz) or Varian-400 (400 MHz) with tetramethylsilane or
the residual signal of the solvent as the internal standard. The 13C
NMR spectra were recorded at Varian-400 (100 MHz). Optical ro-
tations were measured at 20 ꢁC in a 1 dm cell on a PerkineElmer
343 polarimeter with a Na/Hal lamp at 589 nm. Thin-layer chro-
matography was performed on precoated plates of silica gel (60-
F254, E. Merck, Darmstadt) and visualized with H2SO4/H2O (1:20
v/v) followed by heating. Unless otherwise stated, flash column
chromatography was performed on silica gel 60 (230e400 mesh,
the MCPM group about
j is different from that expected on solely
steric grounds. Thus, the use of the MCPM protecting group has

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5755
Fig. 3. Rotational profiles for rotation about
j for (a) 25(R) and (b) 25(S) based on DFT Calculations (ADF-TPZ basis set), see Supplementary data for computational details.
Fig. 4. Ball and stick representations of the two minima for each diastereomer of 25(R) and 25(S) based on DFT Calculations (ADF-TPZ basis set). The numbers written on the
structures are distances from Man H-1 in angstroms.

5756
S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
Merck). Medium pressure liquid chromatography (MPLC) was
performed in self packed glass silica columns with a flow rate of
8e10 mL/min delivered using high performance liquid chroma-
tography pumps. All solvents and reagents were purified and dried
by adding Rexyn 101(H) resin until acidic pH (w4). Water-aspirator
filtration with 1:1 MeOH/CH2Cl2 rinse followed by solvent removal
yielded alcohol 2ab (0.87 g, 96%). Compound 2a 1H NMR CDCl3:
d
7.43e7.22 (m, 30H, BnArH), 5.36 (d, J1,2¼<1, H-1(R)), 5.03 (d,
according to standard procedures. 3,4,6-Tri-O-benzyl-
b-
D-man-
J1,2¼<1, H-1(S)), 4.95e4.55 (m, 12H, BnCH2), 4.11 (br d, J2,3¼3.2, H-
2(R)), 4.03 (br d, J2,3¼3.2, H-2(S)), 3.99 (dd, J3,4¼9.4, H-3(S)), 3.97 (dd,
J3,4¼8.8, H-3(R)), 3.91 (dd, J4,5¼9.4, H-4(S)), 3.91 (dd, J4,5¼9.4, H-
nopyranose-1,2-(methylorthoacetate) was obtained from Toronto
Research Chemicals, Toronto, ON, Canada. Phenylacetyl, Fmoc-Ser
(21) was obtained from Sussex Research Laboratories, Ottawa,
ON, Canada.
0
4(R)), 4.01 (m, H-5(S)), 3.86 (dd, J5,6¼4.5, J6,6 ¼11.6, H-6(S)), 3.84 (m,
0
0
H-5(R)), 3.81 (br d, H-6(R)), 3.78 (dd, J5,6 ¼1.7, H-6 (S)), 3.73 (br d, H-
60(R)), 3.02 (dq, JCHeCHcp¼8.2, JCHeCH3¼6.2, MCPMeCH(R)), 3.13 (dq,
JCHeCHcp¼8.2, JCHeCH3¼6.2, MCPMeCH(S)), 2.55 (br d, 2H, OH),
1.29 (d, 3H, MCPMeCH3(R)), 1.26 (d, 3H, MCPMeCH3(S)), 0.94 (m,
1H, MCPMecpCH(S)), 0.82 (m, 1H, MCPMecpCH(R)), 0.59 (m, 1H,
MCPMecpCH2(R)), 0.52 (m, 2H, MCPMecpCH2(S)), 0.50 (m,
2H, MCPMecpCH2(R)), 0.41 (m, 1H, MCPMecpCH2(S)), 0.18 (m, 1H,
MCPMecpCH2(S)), 0.06 (m, 1H, MCPMecpCH2(R)); 13C NMR CDCl3:
4.1.1. 2-O-Acetyl-3,4,6-tri-O-benzyl-
a/
b-
D-mannopyranosyl
tri-
chloroacetimidate 1. 3,4,6-Tri-O-benzyl-
b-D
-mannopyranose-1,2-
(methylorthoacetate) (5.0 g, 9.87 mmol) was dissolved in 95%
acetic acid (15 mL) and stirred at room temperature for 1.5 h.
After solvent removal, co-evaporation with toluene (5ꢂ) and
further drying under high vacuum, the resulting crude was
redissolved in anhydrous CH2Cl2 (22 mL) and cooled to 0 ꢁC.
Trichloroacetonitrile (11.2 mL, 108.6 mmol) and CsCO3 (0.365 g,
1.08 mmol) were added sequentially. Stirring continued for 16 h
under an atmosphere of Ar with the temperature gradually rising
up to room temperature. Silica gel flash chromatography using
7.5:2:0.5 hexanes/EtOAc/CH2Cl2 as eluent yielded the desired
product 1 (5.42 g, 86%).
d
138.3 and 138.0 (BnArCipso), 128.4e127.4 (BnArCH), 96.7 (C-1(R)),
96.6 (C-1(S)), 80.32 and 80.27 (C-3(R,S)), 77.3 (MCPMeCH(S)), 76.3
(MCPMeCH(R)), 75.1 (BnCH2), 74.45 and 74.44 (C-4(R,S)), 73.34
and 73.28 (BnCH2), 71.82 and 71.80 (BnCH2), 70.98 and 70.93
(C-5(R,S)), 68.93 (C-6(R,S)), 68.8 (C-2(R)), 68.7 (C-2(S)), 21.2
(MCPMeCH3(S)), 18.9 (MCPMeCH3(R)), 17.0 (MCPMecpCH(R)), 15.5
(MCPMecpCH(S)), 4.4 (MCPMecpCH2(R)), 4.2 (MCPMecpCH2(S)),
2.2 (MCPMecpCH2(R)), 0.3 (MCPMecpCH2(S)). Compound 2b par-
4.1.2. (R,S)-Methyl cyclopropylmethyl 2-O-acetyl-3,4,6-tri-O-benzyl-
tial 1H NMR CDCl3:
d
4.95 and 4.52 (2ꢂbr s, 2H, J1,2¼<1, H-1(R,S)),
a/
b-
D-mannopyranoside 6ab. Trichloroacetimidate (1, 2.04 g,
4.16 and 4.03 (2ꢂbr dd, 2H, H-2(R,S)), 3.63 (m, 2H, H-3(R,S)), 3.45 (m,
2H, H-5(R,S)), 3.32 and 3.29 (2ꢂm, 2H, MCPMeCH(R,S)), 1.370 (d,
3.20 mmol) was dissolved in anhydrous CH2Cl2 (36 mL) followed
by the addition of 3 A molecular sieve (3.6 g) and racemic 1-
JCHeCH3¼6.2, MCPMeCH3(R or S)); partial 13C NMR CDCl3:
d 97.1 and
ꢀ
methyl 10-cyclopropylmethanol (0.625 mL, 6.40 mmol). The
resulting suspension was stirred at room temperature under an
atmosphere of Ar for 30 min. The mixture was then cooled to 0 ꢁC
96.3 (C-1(R,S)), 81.76 and 81.71 (C-3(R,S)), 78.9 and 77.7
(MCPMeCH(R,S)), 21.3 and 19.4 (MCPMeCH3(R,S)), 16.9 and 15.0
(MCPMecpCH(R,S)), 4.6 and 4.1 (MCPMecpCH2(R,S)), 2.3 and
0.4 (MCPMecpCH2(R,S)); HRMS obsd 541.2605, calcd C32H38O6Na1
(MþNa)þ 541.2566.
followed by the addition of TESOTf (80 mL, 0.35 mmol). Stirring
continued at 0 ꢁC for 1 h and the reaction was quenched with
diisopropylethylamine (DIPEA, 0.4 mL) followed by gravity filtra-
tion with filter paper and solvent removal. Silica gel flash chro-
matography using 7.5:1.5:1 hexanes/EtOAc/CH2Cl2 as eluent
4.1.4. (R,S)-Methyl cyclopropylmethyl-2-O-(2-O-acetyl-3,4,6-tri-O-
benzyl-a-D-mannopyranosyl)-3,4,6-tri-O-benzyl-a/b-D-mannopyr-
yielded the desired product 6ab (1.16 g, 65%,
a
/
b
about 85:15).
anoside 7ab. Alcohol (2ab, 0.87 g, 1.68 mmol) was dissolved in
anhydrous CH2Cl2 (17 mL) followed by the addition of 3 A mo-
Compound 6a 1H NMR CDCl3:
d
7.42e7.19 (m, 30H, BnArH), 5.45
ꢀ
and 5.40 (2ꢂdd, 2H, J2,3¼3.2, H-2(R,S)), 5.31 and 4.98 (2ꢂd, 2H,
J1,2¼1.8, H-1(R,S)), 5.02e4.51 (m, 12H, BnCH2), 4.11e3.69 (m, 10H,
H-3, H-4, H-5, H-6, H-60(R,S)), 3.17 and 3.10 (2ꢂdq, 2H,
JCHeCHcp¼8.2, JCHeCH3¼6.2), MCPMeCH(R,S), 2.203 and 2.192 (2ꢂs,
Ac CH3(R,S)), 1.287 and 1.268 (2ꢂd, 6H, MCPMeCH3(R,S)), 0.94 and
0.82 (2ꢂm, 2H, MCPMecpCH(R,S)), 0.66e0.36 (m, 6H,
MCPMecpCH2(R,S)), 0.17 and 0.10 (m, 2H, MCPMecpCH2(R,S)); 13C
lecular sieve (4.5 g). Trichloroacetimidate (1, 1.63 g, 2.56 mmol)
was added via cannulation with anhydrous CH2Cl2 (6 mL). The
resulting suspension was stirred at room temperature under an
atmosphere of Ar for 45 min. The mixture was then cooled to 0 ꢁC
followed by the dropwise addition of TESOTf (30.3
0.134 mmol). Stirring continued at 0 ꢁC for 1 h and the reaction
was quenched with DIPEA (120 L) followed by gravity filtration
mL,
m
NMR CDCl3:
d
170.44 and 170.43 (AcC]O(R,S)), 138.3, 138.2 and
with filter paper and solvent removal. Silica gel flash chroma-
138.1 (BnArCipso), 128.3e127.4 (BnArCH), 95.6 and 95.1 (C-1(R,S)),
78.3 (C-3(R,S)), 78.3 and 78.2 (MCPMeCH(R,S)), 76.6 (BnCH2),
75.1 (C-4(R,S)), 74.4 (BnCH2), 71.7 (BnCH2), 71.3 and 71.2 (C-5(R,S)),
69.4 and 69.1 (C-2(R,S)), 68.83 and 68.81 (C-6(R,S)), 21.11
(AcCH3), 21.07 and 19.19 (MCPMeCH3(R,S)), 16.95 and 15.35
(MCPMecpCH(R,S)), 4.53 and 4.35 (MCPMecpCH2(R,S)), 2.22 and
0.29 (MCPMecpCH2(R,S)). Compound 6b partial 1H NMR CDCl3:
tography using 7.5:1.5:1 hexanes/EtOAc/CH2Cl2 as eluent yielded
the desired product (7ab, 1.04 g, 63%). 1H NMR CDCl3:
d 7.39e7.16
(m, 60H, BnArH), 5.58 (m, 2H, H-2(R,S)II), 5.23 (d, 1H, J1,2¼1.5, H-
1(R)I), 5.13 and 5.12 (2ꢂd, 2H, J1,2¼1.28, H-1(R,S)II), 4.97 (s, 1H, H-
1(S)I), 4.88 and 4.86 (2ꢂd, 4H, J¼2.7, BnCH2), 4.71e4.41 (m, 20H,
BnCH2), 4.05e3.70 (m, 22H, H-2(R,S)I, H-3(R,S)I,II, H-4(R,S)I,II, H-
5(R,S)I,II
,
H-6(R,S)I,II
,
H-60(R,S)I,II), 3.11 (dq, 1H, JCHeCHcp¼7.8,
d
5.68 and 5.62 (2ꢂdd, 2H, J2,3¼2.6, H-2(R,S)), 5.02 and 4.63 (2ꢂd,
JCHeCH3¼6.3, MCPMeCH(R or S)), 3.00 (dq, 1H, JCHeCHcp¼8.2,
JCHeCH3¼6.1, MCPMeCH(R or S)), 2.143 and 2.140 (2ꢂs, 6H,
AcCH3(R,S)), 1.22 and 1.14 (2ꢂd, 6H, J¼6.3, MCPMeCH3(R,S)), 0.88
and 0.72 (2ꢂm, 2H, MCPMecpCH(R,S)), 0.52e0.32 (m, 6H,
2H, J1,2¼0.6, H-1(R,S)), 3.51 (m, 2H, H-5(R,S)), 3.32 and 3.29 (2ꢂm,
2H, MCPMeCH(R,S)), 2.245 (1ꢂs, Ac CH3(R or S)); partial 13C NMR
CDCl3:
d 170.66 and 170.64 (AcC]O(R,S)), 96.5 and 95.5 (C-1(R,S)),
80.7 and 80.5 (C-3(R,S)), 78.7 and 77.8 (MCPMeCH(R,S)), 68.6 and
68.5 (C-2(R,S)); HRMS obsd 583.2695 calcd C34H40O7Na1 (MþNa)þ
583.2672.
MCPMecpCH2(R,S)),
0.09
and
ꢀ0.01
(2ꢂm,
2H,
MCPMecpCH2(R,S)); 13C NMR CDCl3:
d
170.13 and 170.11 (AcC]
O(R,S)), 138.6e138.0 (BnArCipso), 128.3e127.3 (BnArCH), 99.6 (C-
1II), 96.5 and 96.4 (C-1(R,S)I), 79.84 and 79.80 (C-2(R,S)I), 78.2 (C-
3II), 77.6 and 76.6 (MCPMeCH(R,S)), 75.5 (C-3I), 75.2e75.0
(2ꢂBnCH2), 74.8, 74.4 and 74.3 (C-4(R,S)I,II), 73.4e73.2 (2ꢂBnCH2),
72.0e71.8 (2ꢂBnCH2, C-5(R,S)I,II), 69.3, 69.1 and 68.9 (C-6(R,S)I,II),
68.7 (C-2II), 21.2 (MCPMeCH3(R)), 21.14 and 21.12 (AcCH3(R,S)),
19.1 (MCPMeCH3(S)), 17.0 and 15.7 (MCPMecpCH(R,S)), 4.27, 4.18,
4.1.3. (R,S)-Methyl cyclopropylmethyl 3,4,6-tri-O-benzyl-a/b-D-man-
nopyranoside 2ab. Acetates 6ab (0.99 g, 1.76 mmol) were dissolved
in 1:2 MeOH/CH2Cl2 (30 mL) followed by the addition of 1 M
methanolic NaOMe (1.4 mL). The reaction was stirred at room
temperature under an atmosphere of Ar for 16 h and then quenched

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5757
2.28 and 0.46 (MCPMecpCH2(R,S)); HRMS obsd 1010.4990, calcd
C61H72NO12 (MþNH4)þ 1010.5054.
1.15 g, 0.807 mmol) was dissolved in EtOAc (80 mL) and hydroge-
nated at 50 psi. at room temperature in the presence of 20%
Pd(OH)2/C (2.2 g) for 48 h. The resulting mixture was filtered
through a bed of Celite with 1:1 MeOH/EtOAc rinse. After solvent
evaporation under reduced pressure, the crude deprotected in-
termediate was redissolved in anhydrous pyridine (10 mL) and
cooled to 0 ꢁC. Acetic anhydride (5 mL) was added through
a dropping funnel. Stirring continued for 16 h under an atmosphere
of Ar with the temperature gradually rising up to room tempera-
ture. After solvent removal and co-evaporation with toluene (4ꢂ),
the desired product (10ab, 0.51 g, 64% overall) was obtained from
silica gel flash chromatography using 1:2 hexanes/EtOAc as eluent.
4.1.5. (R,S)-Methyl cyclopropylmethyl-2-O-(3,4,6-tri-O-benzyl-
a-D-
mannopyranosyl)-3,4,6-tri-O-benzyl- -mannopyranoside
a/b-D
8ab. Acetates (7ab,1.04 g, 1.05 mmol) were dissolved in 1:2 MeOH/
CH2Cl2 (30 mL) followed by the addition of 1 M methanolic NaOMe
(1.4 mL). The reaction was stirred at room temperature under an
atmosphere of Ar for 16 h and then quenched by adding Rexyn
101(H) resin until acidic pH (w4). Water-aspirator filtration with
1:1 MeOH/CH2Cl2 rinse followed by solvent removal yielded alco-
hol (8ab, 0.98 g, 98%). 1H NMR CDCl3:
d 7.44e7.25 (m, 30H, BnArH),
5.31 (d, 1H, J1,2¼1.4, H-1I), 5.27 (s, 1H, H-1II), 4.92 and 4.89 (2ꢂd, 2H,
J¼6.5, BnCH2), 4.81e4.56 (m, 10H, BnCH2), 4.22 (s, 1H, H-2II), 4.13
(m,1H, H-2I), 4.05e3.75 (m,10H, H-3I,II, H-4I,II, H-5I,II, H-6I,II, H-60I,II),
3.16 (dq, 1H, JCHeCHcp¼7.8, JCHeCH3¼6.6, MCPMeCH), 2.51 (s, 1H,
OH), 1.27 (d, 3H, J¼6.4, MCPMeCH3), 0.77 (m, 1H, MCPMecpCH),
1H NMR CDCl3: 5.41e5.22 (m, 14H, H-2(R,S)III, H-3(R,S)I,II,III, H-
d
4(R,S)I,II,III), 5.24 (s, 1H, H-1(R)I), 5.12 and 5.10 (2ꢂd, 2H, J1,2¼1.8, H-
1(R,S)II), 4.97 (d, 1H, J1,2¼2.1, H-1(S)I), 4.95 (m, 2H, H-1(R,S)III),
4.23e3.92 (m, 20H, H-2(R,S)I,II
, , , H-
H-5(R,S)II,III H-6(R,S)I,II,III
60(R,S)I,II,III), 4.00 and 3.97 (2ꢂm, 2H, H-5(R,S)I), 3.14 (dq, 1H,
JCHeCHcp¼8.0, JCHeCH3¼6.6, MCPMeCH(R or S)), 3.03 (dq, 1H,
JCHeCHcp¼8.0, JCHeCH3¼6.6, MCPMeCH(R or S)), 2.14e2.00 (m, 60H,
AcCH3(R,S)), 1.28 and 1.24 (2ꢂd, 6H, J¼6.4, MCPMeCH3(R,S)), 0.94
and 0.81 (2ꢂm, 3H, MCPMecpCH(R,S)), 0.61e0.37 (m, 4H,
MCPMecpCH2(R,S)), 0.30 (m, 1H, MCPMecpCH2(R,S)), 0.14 and 0.06
0.57e0.37 (m, 3H, MCPMecpCH2), 0.04 (m, 1H, MCPMecpCH2); 13
C
NMR CDCl3: d 138.6e138.0 (BnArCipso), 128.4e127.3 (BnArCH), 101.0
(C-1II), 96.6 (C-1I), 80.0 and 79.9 (C-3I,II), 76.6 (MCPMeCH), 75.1 (C-
2I), 75.1e75.0 (2ꢂBnCH2 and C-4II), 74.3 (C-4I), 73.4 and 73.2
(2ꢂBnCH2), 72.2 and 72.1 (2ꢂBnCH2), 71.8 and 71.6 (C-5I,II), 69.4
and 69.0 (C-6I,II), 68.5 (C-2II), 21.2 (MCPMeCH3), 15.7
(MCPMecpCH), 4.14 and 0.47 (MCPMecpCH2(R,S)). HRMS obsd
973.4495, calcd C59H66O11Na (MþNa)þ 973.4502.
(2ꢂm, 2H, MCPMecpCH2(R,S)); 13C NMR CDCl3:
d 170.9e169.3
(AcC]O(R,S)), 99.65 and 99.56 (C-1(R,S)II), 99.36 and 99.33 (C-
1(R,S)III), 96.4 and 96.3 (C-1(R,S)I), 79.4 and 78.1 (MCPMeCH(R,S)),
77.2e76.7 (C-2 I,II), 70.5, 70.4, 69.7, and 69.6 (C-3(R,S)I,II,III), 69.4,
69.2, and 68.5 (C-5(R,S)I,II,III), 68.4 (C-2(R,S)III), 66.7, 66.6, 66.2, 66.1,
and 66.0 (C-4(R,S)I,II,III), 62.5, 62.3, and 62.0 (C-6(R,S)I,II,III), 21.2
(MCPMeCH3(R or S)), 20.8, 20.7, and 20.6 (AcCH3(R,S)), 19.5
(MCPMeCH3(R or S)), 17.0 and 15.8 (MCPMecpCH(R,S)), 4.44, 4.20,
2.46, and 0.71 (MCPMecpCH2(R,S)); HRMS obsd 993.3436, calcd
C43H61O26 (MþH)þ 993.3451.
4.1.6. (R,S)-Methyl cyclopropylmethyl-2-O-(2-O-acetyl-3,4,6-tri-O-
benzyl-
a
-
D
-mannopyranosyl)-2-O-(3,4,6-tri-O-benzyl-
-mannopyranoside
a
-
D
-man-
nopyranosyl)-3,4,6-tri-O-benzyl-a/b-D
9ab. To
a round-bottom flask containing alcohol (8ab, 0.98 g, 1.03 mmol)
ꢀ
and 3 A molecular sieve (3 g), trichloroacetimidate (1, 1.29 g,
2.02 mmol) was added via cannulation with anhydrous CH2Cl2
(4ꢂ4 mL). The resulting suspension was stirred at room tempera-
ture under an atmosphere of Ar for 30 min. The mixture was then
4.1.8. Trichloroacetimidoyl-2-O-(2,3,4,6-tetra-O-acetyl-
nopyranosyl)-2-O-(3,4,6-tri-O-acetyl- -mannopyranosyl)-3,4,6-
tri-O-acetyl- -mannopyranoside 12ab. Product (10ab, 0.51 g,
a-D-man-
cooled to 0 ꢁC followed by the dropwise addition of TESOTf (18.7
mL,
a-D
0.082 mmol). Stirring continued at 0 ꢁC for 1 h and an additional
30 min at room temperature. The reaction was quenched with
a/b-D
0.51 mmol) was dissolved in CH2Cl2 (11 mL) followed by the addi-
tion of trifluoroacetic acid (3 mL). The resulting solution was stirred
at room temperature for 2 h. Upon cooling to 0 ꢁC, saturated
aqueous NaHCO3 (50 mL) was added followed by the addition of
solid NaHCO3 until basic pH (w9). The mixture was diluted with
CH2Cl2 and the resulting layers were separated through a separa-
tory funnel. The organic phase was further washed with saturated
aqueous NaHCO3 (3ꢂ) and the combined aqueous phase was re-
extracted with CH2Cl2 (3ꢂ). The combined organic phase was
dried with anhydrous Na2SO4, filtered, concentrated, and dried
overnight under high vacuum. The crude intermediate 11ab was
then redissolved in anhydrous CH2Cl2 (14 mL) and cooled to 0 ꢁC.
Trichloroacetonitrile (0.6 mL, 5.98 mmol) and DBU (10 drops) were
added sequentially. Stirring continued under an atmosphere of Ar
for 1 h at 0 ꢁC and 1 h at room temperature followed by solvent
removal. Silica gel flash chromatography using basified (0.1% Et3N)
3.5:6.5 hexanes/EtOAc as eluent yielded the desired product (12ab,
DIPEA (80 mL) followed by gravity filtration with filter paper and
solvent removal. The desired product (9ab, 1.15 g, 78%) was
obtained from silica gel flash chromatography (7.5:1.5:1 hexanes/
EtOAc/CH2Cl2) followed by Sephadex LH-20 chromatography (4:3
CHCl3/MeOH). 1H NMR CDCl3:
d 7.42e7.21 (m, 90H, BnArH), 5.62 (m,
2H, H-2(R,S)III), 5.30 (s, 1H, H-1(R)I), 5.29 and 5.26 (2ꢂs, 2H, H-
1(R,S)II), 5.15 and 5.14 (2ꢂs, 2H, H-1(R,S)III), 5.06 (s, 1H, H-1(S)I), 4.93
and 4.88 (m, 6H, BnCH2), 4.78e4.36 (m, 30H, BnCH2), 4.19 (m, 2H, H-
2(R,S)II), 4.08e3.71 (m, 30H, H-2(R,S)I, H-3(R,S)I,II,III, H-4(R,S)I,II,III, H-
5(R,S)I,II,III, H-6(R,S)I,II,III, H-60(R,S)I,II), 3.60 and 3.58 (2ꢂd, 2H, J5,6 ¼3.4,
0
H-60(R,S)III), 3.15 (dq, 1H, JCHeCHcp¼7.8, JCHeCH3¼6.4, MCPMeCH(R or
S)), 3.03 (dq, 1H, JCHeCHcp¼7.8, JCHeCH3¼6.4, MCPMeCH(R or S)), 2.20
(s, 6H, AcCH3(R,S)), 1.26 and 1.18 (2ꢂd, 6H, J¼6.3, MCPMeCH3(R,S)),
0.94 and 0.77 (2ꢂm, 2H, MCPMecpCH(R,S)), 0.56e0.32 (m, 6H,
MCPMecpCH2(R,S)), 0.12 and 0.02 (2ꢂm, 2H, MCPMecpCH2(R,S));
13C NMR CDCl3:
d 170.1 (AcC]O(R,S)), 138.6e137.7 (BnArCipso),
128.4e127.3 (BnArCH), 100.6 and 100.5 (C-1(R,S)II), 99.3 (C-1III), 96.7
and 96.5 (C-1(R,S)I), 79.70 and 79.67 (C-3(R,S)III), 78.2 and 78.1 (C-
3(R,S)I,II), 77.6 and 76.7 (MCPMeCH(R,S)), 75.6 (C-2I), 75.3e74.7
(3ꢂBnCH2, C-2II and C-4I,II), 74.2 (C-4III), 73.3e73.2 (3ꢂBnCH2),
72.3e71.8 (3ꢂBnCH2 and C-5I,II,III), 69.5, 69.4, and 69.3 (C-6I,II,III), 68.7
(C-2III), 21.2 and 21.1 (MCPMeCH3(R or S), AcCH3(R,S)), 19.1
(MCPMeCH3(R or S)), 17.0 and 15.7 (MCPMecpCH(R,S)), 4.25, 4.10,
2.23, and 0.50 (MCPMecpCH2(R,S)); HRMS obsd 1442.6790, calcd
C88H100NO17 (MþNH4)þ 1442.6991.
363 mg, 66%). 1H NMR CDCl3:
d
8.74 (s,1H, NH), 6.41 (d,1H, J¼2.1, H-
1I), 5.41e5.24 (m, 7H, H-2III, H-3I,II,III, H-4I,II,III), 5.18 (d, 1H, J¼1.5, H-
1II), 4.95 (s, 1H, H-1III), 4.29 (m, 1H, H2I), 4.25e4.08 (m, 10H, H-2II,
H-5I,II,III, H-6I,II,III, H-60I,II,III), 2.14e1.99 (m, 30H, Ac-CH3); 13C NMR
CDCl3:
d
170.8e169.3 (AcC]O), 160.1 (C]N), 99.6 (C-1II), 99.3
(C-1III), 95.6 (C-1I), 90.5 (CCl3), 77.1 (C-2II), 74.3 (C-2I), 71.2 (C-
5I), 69.8 (C-3), 69.6e69.5 (C-3 and C-5II,III), 68.3 (C-3), 66.2 and 65.9
(C-4I,II,III), 65.5 (C-2III), 62.4, 62.0 and 61.6 (C-6I,II,III), 20.8e20.6
(AcCH3).
4.1.7. (R,S)-Methyl cyclopropylmethyl-2-O-(2,3,4,6-tetra-O-acetyl-
-mannopyranosyl)-2-O-(3,4,6-tri-O-acetyl- -mannopyranosyl)-
3,4,6-tri-O-acetyl- -mannopyranoside 10ab. Benzyl ether (9ab,
a
-
4.1.9. (2R)-2,3-Bis[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyloxy]
D
a
-
D
propan-1-yl-2-O-(2,3,4,6-tetra-O-acetyl-
a-D-mannopyranosyl)-2-O-
a/b
-D
(3,4,6-tri-O-acetyl- -mannopyranosyl)-3,4,6-tri-O-acetyl-a-D-
a
-
D

5758
S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
mannopyranoside 13a. (a) To a round-bottom flask containing
trichloroacetimidate (12ab, 363 mg, 0.34 mmol) and 3 A molecular
sieve (0.7 g), archaeol (130 mg, 0.20 mmol) was added via cannu-
lation with anhydrous CH2Cl2 (4ꢂ1.8 mL). The resulting suspension
was stirred at room temperature under an atmosphere of Ar for
30 min. The mixture was then cooled to 0 ꢁC followed by the
36:64 to yield a colorless oil (16ab, 75%): 1H NMR CDCl3:
d 7.41e7.21
(m, 30H, BnArH), 5.62 (br t, 2H, H-3II), 5.22 (br d, 2H, NHII), 5.16 (d,1H,
J1,2¼1.9, H-1(R)I),5.09(brd,2H, H-1II),4.98(t, 2H, J¼9.2,H-4II),4.88(br
ꢀ
d, 2H, JH,H¼8.6, TroceCHH), 4.83 (d, J1,2¼1.9, H-1(S)I), 4.77e4.48 (m,
II
0
14H, BnCH2, TroceCHH), 4.25 (dd, 2H, J5,6¼5.2, J6,6 ¼12.3, H-6 ), 4.15
0II
(m, 2H, H-2(R,S)I), 4.12 (dd, 2H, J5,6 ¼<1 H-6 ), 3.98e3.62 (m,12H, H-
0
dropwise addition of TESOTf (3.6
ued at 0 ꢁC for 1 h and an additional 30 min at room temperature.
The reaction was quenched with DIPEA (15 L) followed by gravity
filtration with filter paper and solvent removal. The desired gly-
mL, 0.016 mmol). Stirring contin-
3(R,S)I, H-4(R,S)I, H-5(R,S)I, H-6(R,S)I, H-60(R,S)I, H-5II), 3.25 (m, 2H, H-
2II), 3.11 (dq, JCHeCHcp¼8.2, JCHeCH3¼6.2, MCPMeCH(R)), 3.02 (dq,
JCHeCHcp¼8.2, JCHeCH3¼6.2, MCPMeCH(S)), 2.03, 2.022, 2.015, 2.0,1.99
(5s, 18H, Ac-CH3), 1.22 (d, 3H, MCPMeCH3(R)), 1.19 (d, 3H,
MCPMeCH3(S)), 0.87 (m, 1H, MCPMecpCH(S)), 0.76 (m, 1H,
MCPMecpCH(R)), 0.50 (m, 1H, MCPMecpCH2(R)), 0.45 (m, 4H,
MCPMecpCH2(R,S)), 0.30 (m, 1H, MCPMecpCH2(S)), 0.12 (m, 1H,
MCPMecpCH2(S)), 0.02 (m, 1H, MCPMecpCH2(R)); 13C NMR CDCl3:
m
a
coside (13a, 110 mg, 35%) was isolated from a series of gradient
silica gel MPLC (hexanes/EtOAc, 2:1/1:1/1:2).
(b) Alternative, scaled-up glycosidation with AgOTf:
To a round-bottom flask containing trichloroacetimidate (12ab,
1.05 g, 0.98 mmol), archaeol (0.38 g, 0.58 mmol) was added via
cannulation with anhydrous CH2Cl2 (3ꢂ7 mL). The resulting mix-
ture was then cooled to 0 ꢁC followed by the addition of AgOTf
(75 mg, 0.29 mmol). Stirring continued at 0 ꢁC under Ar for 2 h. The
reaction was then quenched by adding saturated NaHCO3 (15 mL)
and 10% Na2S2O3 (15 mL). The resulting mixture was stirred at room
temperature for 20 min followed by phase separation with a sepa-
ratory funnel. The aqueous phase was further extracted with CH2Cl2
(3ꢂ). The combined organic phase was dried with Na2SO4, filtered
d
170.59, 170.57, 170.1, 169.6 (Ac-C]O), 153.8 (TroceC]O), 138.5,
138.4, and 138.0 (BnArCipso), 128.4e127.4 (BnArCH), 98.1 (br, C-1II),
95.5 and 95.2 (C-1(R,S)I), 78.7 and 78.6 (C-3(R,S)I), 77.3
(MCPMeCH(S)), 76.5 (MCPMeCH(R)), 75.14 (TroceCH2), 74.9 (C-
4(R,S)I), 74.3e74.1 (C-2(R,S)I, BnCH2), 73.27 and 73.19 (BnCH2),
72.4e71.9 (C-5(R,S)I, C-5II, BnCH2), 70.7 (C-3II), 69.2 (C-6(R,S)I), 69.0
(C-4II), 62.4 and 62.3 (C-6II), 56.1 (C-2II), 21.2 (MCPMeCH3(S)), 20.68,
20.62, 20.60 (Ac-CH3), 19.1 (MCPMeCH3(R)), 17.0 (MCPMecpCH(R)),
15.6 (MCPMecpCH(S)), 4.34 and 4.33 (MCPMecpCH2(R,S)), 2.3
(MCPMecpCH2(R)), 0.5 (MCPMecpCH2(S)). Compound 16b partial 1H
and concentrated under reduced pressure. The desired
a-glycoside
(13a, 556 mg, 61%) was isolated from a series of gradient silica gel
NMR CDCl3:
d
4.83 (br s, 1H, J1,2¼<1, H-1(R or S)I), 3.58 (m, 2H, H-
MPLC (hexanes/EtOAc, 2:1 to 1:2). 1H NMR CDCl3:
d
5.41e5.25 (m,
3(R,S)I), 3.38 (2ꢂm, 2H, MCPMeCH(R,S)), 1.39 (d, JCHeCH3¼6.4,
MCPMeCH3(R or S)); MS obsd 997.3104 calcd C47H60Cl3N2O15
(MþNH4)þ 997.3059.
7H, H-2III, H-3I,II,III, H-4I,II,III), 5.10 (d, 1H, J1,2¼1.8, H-1I), 4.97 (d, 1H,
J1,2¼1.8, H-1II), 4.94 (d, 1H, J1,2 1.5, H-1III), 4.1 (m, 1H, H2I), 4.05 (m,
1H, H2II), 4.25e4.08 (m, 9H, H-5I,II,III, H-6I,II,III, H-60I,II,III), 2.151, 2.131,
2.123, 2.082, 2.067, 2.047, 2.036, 2.027, 2.011, 2.001 (10ꢂs, 30H,
4.1.12. (R,S)-Methyl cyclopropylmethyl [3,4,6-tri-O-acetyl-2-deoxy-
2-acetamido-b-D-glucopyranosyl]-(1/2)-3,4,6-tri-O-benzyl-a/b-D-
AcCH3); 13C NMR CDCl3:
d
170.9, 170.7, 170.4, 170.0(2), 169.8, 169.7,
169.45, 169.41, 169.3 (10ꢂAcC]O), 99.9 (C-1I), 99.4 (C-1III), 98.1 (C-
1II), 77.5 (C-2II), 77.4 (CH-gly), 76.8 (C-2I), 70.6 (C-2III), 70.2, 70.1
(OCH2, arch), 69.7, 69.6 (C-4), 69.5, 69.3 (C-5), 69.2 (CH2-gly), 68.5
(C-5), 68.4 (C-4), 68.1 (SugOCH2-gly), 66.3, 66.2, 66.1 (C-3I,II,III), 62.5,
62.2, and 61.9 (C-6I,II,III), 39.6, 37.5, 37.42, 37.38, 37.3, 37.1, 36.6 (CH2-
arch), 32.8, 30.0, 29.8, 28.0 (CH, arch), 24.8, 24.5, 24.4 (CH2, arch),
22.7, 22.6 (CH3, arch), 20.8e20.7 (AcCH3), 19.7, 19.6 (CH3, arch);
HRMS obsd 1576.9540, calcd C81H142O28N1 (MþNH4)þ 1576.9718.
mannopyranoside 17ab. Disaccharide (16ab, 400 mg, 0.41 mmol)
was dissolved at room temperature in acetic anhydride (5.0 mL)
and Zinc powder (500 mg) was added. After stirring for 6 h more
acetic anhydride (5.0 mL) and Zinc (500 mg) were added. After
stirring for 2 more hours the mixture was filtered by suction
through a bed of Celite and rinsed with ethyl acetate (about
150 mL). The solvent was evaporated and the residue co-
evaporated with toluene (2ꢂ about 100 mL). This residue was pu-
rified by flash chromatography eluting with ethyl acetate/hexanes
50:50 to 66.6:33.3 to yield a colorless oil (17ab, 296 mg, 85%): 1H
4.1.10. (2R)-2,3-Bis[(3R,7R,11R)-3,7,11,15-tetramethylhexadecyloxy]
propan-1-yl-2-O-(-
a
-
D
-mannopyranosyl)-2-O-(
a
-
D
-mannopyr-
NMR CDCl3:
d
7.39e7.21 (m, 30H, BnArH), 5.80 (2ꢂt, 2H, J2,3¼10.0,
anosyl)- -mannopyranoside 14. Acetate (13a,110 mg, 0.070 mmol)
a-D
H-3II), 5.39 (br t, 2H, NHII), 5.16 (d, 1H, J1,2¼1.0, H-1(R)I), 5.24 and
5.21 (2ꢂd, 2H, J1,2¼8.2, H-1II), 5.00 (t, 2H, J4,5¼9.4, H-4II), 4.94e4.44
(m, 12H, BnCH2), 4.82 (d, 1H, J1,2¼1.0, H-1(S)I), 4.28 (dd, 2H, J5,6¼5.3,
was dissolved in 1:2 MeOH/CH2Cl2 (24 mL) followed by the addition
of 1 M methanolic NaOMe (1.2 mL). The reaction was stirred at room
temperature under an atmosphere of Ar for 16 h and then quenched
by adding Rexyn 101(H) resin until acidic pH (w4). Water-aspirator
filtration with 1:1 MeOH/CH2Cl2 rinse followed by solvent removal
yielded known trimannoside (14, 79.2 mg, 98%).3
II
0II
I
I
0
J6,6 ¼12.6, H-6 ), 4.13 (m, 3H, H-6 , H-2(R) ), 4.07 (br d, H-2(S) ),
4.1e3.6 (m, 12H, H-3(R,S)I), H-4(R,S)I, H-5(R,S)I, H-6(R,S)I, H-60(R,S)I,
(H-5II), 3.21 (m, 2H, H-2II), 3.09 (dq, JCHeCHcp¼8.2, JCHeCH3¼6.4,
MCPMeCH(R)), 3.01 (dq, JCHeCHcp¼8.2, JCHeCH3¼6.4, MCPMeCH(S)),
2.05, 2.01, 2.00, 1.73 (4s, 24H, Ac-CH3), 1.21 (d, 3H, MCPMeCH3(R)),
1.20 (d, 3H, MCPMeCH3(S)), 0.88 (m, 1H, MCPMecpCH(S)), 0.75 (m,
1H, MCPMecpCH(R)), 0.62 (m, 1H, MCPMecpCH2(R)), 0.44 (m, 4H,
MCPMecpCH2(R,S)), 0.30 (m, 1H, MCPMecpCH2(S)), 0.11 (m, 1H,
MCPMecpCH2(S)), ꢀ0.01 (m, 1H, MCPMecpCH2(R)); 13C NMR
4.1.11. (R,S)-Methyl cyclopropylmethyl [3,4,6-tri-O-acetyl-2-deoxy-2-
(2,20,200-trichloroethoxycarbonylamino)-
b
-
D
-glucopyranosyl]-(1/2)-
16ab. Donor phenyl
3,4,6-tri-O-acetyl-2-deoxy-2-(2,20,200-trichloroethoxycarbonylamino)-
-1-thioglucopyranoside (15, 732 mg, 1.28 mmol)13 and acceptor
3,4,6-tri-O-benzyl-a/b-D-mannopyranoside
b-D
CDCl3: d 170.7, 170.1, 170.0, 169.7 (Ac-C]O), 138.5, 138.4 and 138.2
(2a, 442 mg, 0.85 mmol) were dissolved in dichloromethane (4 mL)
(BnArCipso), 128.4e127.5 (BnArCH), 97.5 (C-1II), 95.3 and 94.6 (C-
1(R,S)I), 78.5 and 78.4 (C-3(R,S)I), 78.2 (MCPMeCH(S)), 77.2
(MCPMeCH(R)), 75.26 and 75.21 (BnCH2), 74.54 and 74.53 (C-
4(R,S)I), 74.3 and 74.1 (C-2(R,S)I), 73.28 and 73.24 (BnCH2), 71.7 (m, C-
5(R,S)I, C-5II, BnCH2), 70.98 and 70.93 (C-3II), 69.34 (C-6(R,S)I), 69.29
(C-4II), 62.59 and 62.52 (C-6II), 56.59 and 56.52 (C-2II), 23.2
(AcNeCH3), 21.2 (MCPMeCH3(S)), 20.72, 20.69 (AcOeCH3),
19.4 (MCPMeCH3(R)),17.1 (MCPMecpCH(R)),15.5 (MCPMecpCH(S)),
4.6 and 4.4 (MCPMecpCH2(R,S)), 2.3 (MCPMecpCH2(R)), 0.5
ꢀ
along with powdered 4A molecular sieves (about 500 mg) and cooled
inanicesaltbathto0ꢁCunderanatmosphereofargon. Tothemixture
was added solid N-iodosuccinimide (383 mg, 1.7 mmol) followed by
trifluoromethanesulfonic acid (15
stirring for 45 min the reaction was quenched with DIPEA (about
100 L). The resulting mixture was filtered by gravity directly into
mL, 0.17 mmol) by syringe. After
m
a separatory funnel with rinsing with dichloromethane. The organic
layer was washed by a mixture of NaHCO3(aq) and NaS2O3(aq), which
was concentrated after drying with Na2SO4 and filtration. The residue
was purified by MPLC eluting with ethyl acetate/hexanes 25:75 to
(MCPMecpCH2(S)). Compound 17b partial 1H NMR CDCl3:
d 3.58 (m,
2H, H-3(R,S)I), 3.4 (2ꢂm, 2H, MCPMeCH(R,S)), 1.39 (d, JCHeCH3¼6.4,

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5759
MCPMeCH3(R or S)); HRMS obsd 870.3789 calcd C46H57N1O14Na1
(MþNa)þ 870.3777.
73.0, 72.9 74.53 (C-4(R,S)I), (C-5(R,S)I), 69.9 (C-3II), 69.7 (C-3(R,S)I),
67.3 (C-4II), 61.5 (C-6(R,S)I), 60.6 (C-6II), 55.43 and 55.38 (C-2II), 22.3
(AcNeCH3), 20.1 (MCPMeCH3(S)), 17.6 (MCPMeCH3(R)), 16.3
(MCPMecpCH(R)), 15.0 (MCPMecpCH(S)), 3.9 and 3.5 (MCPMe
cpCH2(R,S)), 1.9 and 0.0 (MCPMecpCH2(R,S)). Compound 19b par-
4.1.13. (R,S)-Methyl cyclopropylmethyl [3,4,6-tri-O-acetyl-2-deoxy-
2-acetamido-b-D-glucopyranosyl]-(1/2)-3,4,6-tri-O-acetyl-a/b-D-
mannopyranoside 18ab. Disaccharide (17ab, 1.38 g, 1.6 mmol) was
dissolved in ethyl acetate (45 mL) and hydrogenated in a Parr ap-
paratus at room temperature at 45 p.s.i of H2(g) in the presence of
Pearlman’s catalyst (10% Pd(OH)2 on carbon, 1 g) overnight. The
solids were removed by filtration by suction through a bed of Celite
followed by rinsing extensively with alternate aliquots of ethyl
acetate and methanol. The liquids were evaporated and the residue
was dissolved in pyridine (20 mL). After cooling in an ice bath acetic
anhydride (10 mL) was added. After stirring for 4 h the liquids were
removed by evaporation. The residue was purified by flash chro-
matography eluting with ethyl acetate/hexanes 65:35 to 80:20 to
tial 1H NMR D2O: 4.91 (br s, H-1(R)I), 4.89 (br s, H-1(S)I), 4.23 (br d,
d
1H, J2,3¼3.2, H-2(R)I), 4.19 (br d, J2,3¼3.0, H-2(S)I) 3.33 (2ꢂm, 2H,
MCPMeCH(R,S)); HRMS obsd 452.2728 calcd C19H33N1O11 (MþH)þ
452.2131.
4.1.15. 3,4,6-Tri-O-acetyl-2-deoxy-2-acetamido-
(1/2)-3,4,6-tri-O-acetyl- -mannopyranose and 3,4,6-tri-O-ace-
tyl-2-deoxy-2-acetamido- -glucopyranosyl-(1/2)-3,4,6-tri-O-
acetyl- -mannopyranosyl trichloroacetimidate 20. MCPM pro-
b-D-glucopyranosyl-
a-D
b-D
a-D
tected disaccharide (18ab, 0.99 g, 1.4 mmol) was dissolved at room
temperature under an atmosphere of argon in dichloromethane
(17 mL) and trifluoroacetic acid (3 mL) was added dropwise. After
stirring for 45 min the mixture was cooled in an ice bath diluted
with dichloromethane (about 40 mL) and cold NaHCO3(aq) (about
100 mL) followed by addition of solid NaHCO3 until effervescence
ceased. The mixture was transferred to a separatory funnel, sepa-
rated and the organic layer washed with NaHCO3(aq) (about
100 mL). After drying over Na2SO4, filtration, concentration the
residue was dried at high vacuum. Partial 1H NMR CDCl3: 5.75 (d,
1H, J2,NH¼7.9, NHII), 5.56 (dd, 1H, J2,3¼10.4, H-3II), 5.22 (t, 1H,
J4,5¼10.0, H-4I), 5.08 (dd, 1H, J3,4¼10.3, H-3I), 5.00 (d, 1H, J1,2¼8.2, H-
1II), 4.99 (t, 1H, J4,5¼9.1, H-4II), 4.70 (br s, 1H, J1,2¼1.8, H-1I), 4.25 (dd,
yield a viscous oil (18ab, 0.99 g, 88%): 1H NMR CDCl3:
d 5.59 (m, 4H,
J2,NH¼7.6, NHII, H-3II), 5.21 (m, 2H, J3,4¼10.0, H-3(R,S)I), 5.11 (br s,
1H, H-1(R)I), 5.09 (m, 2H, H-4II), 5.06 (d, 2H, J1,2¼8.6, H-1II), 4.99 (t,
2H, J4,5¼10.3, H-4(R,S)I), 4.76 (br s, 1H, H-1(S)I), 4.3e4.0 (m, 10H, H-
0II
6II, H-6 , H-2(R,S)I, H-6(R,S)I, H-60(R,S)I), 3.87 (m, 2H, H-5(R,S)I),
3.69 (m, 2H, H-5II), 3.43 (ddd, 2H, J2,3¼10.3, H-2II), 3.06 (dq,
JCHeCHcp¼8.8, JCHeCH3¼6.2, MCPMeCH(R)), 2.99 (dq, JCHeCHcp¼8.8,
JCHeCH3¼6.2, MCPMeCH(S)), 2.07 (s, 6H, Ac-CH3), 2.06 (s, 3H, Ac-
CH3), 2.04 (s, 3H, Ac-CH3), 2.033, 2.025, 2.01 2.00, 1.92 (5ꢂs, 15H,
Ac-CH3), 1.27 (d, 3H, MCPMeCH3(R)), 1.24 (d, 3H, MCPMeCH3(S)),
0.95 (m, 1H, MCPMecpCH(S)), 0.83 (m, 1H, MCPMecpCH(R)), 0.64
(m, 1H, MCPMecpCH2(R)), 0.45 (m, 4H, MCPMecpCH2(R,S)), 0.31
(m, 1H, MCPMecpCH2(S)), 0.13 (m, 1H, MCPMecpCH2(S)), 0.02 (m,
II
I
0
0
1H, J5,6¼5.3, J6,6 ¼12.3, H-6 ), 4.20 (dd, 1H, J5,6¼5.9, J6,6 ¼0 12.3, H-6 ),
4.15 (dd, 1H, J2,3¼3.5, H-2I), 4.05 (dd, 1H, J5,6 ¼2.4, H-6 ), 4.01 (dd,
I
0
1H, MCPMecpCH2(R)); 13C NMR CDCl3:
d
170.8e170.6, 170.4e170.3,
1H, J5,6 ¼2.1, H-6 ), 3.88 (ddd,1H, H-5 ), 3.69 (m,1H, H-5 ), 3.50 (m,
1H, H-2II), 2.078, 2.072, 2.034, 2.025 (4ꢂs,12H, AcOCH3), 2.01 (s, 6H,
AcOCH3), 1.93 (s, 3H, AcNCH3); HRMS obsd 636.2770 calcd
C26H38N1O17 (MþH)þ 636.2139. The residue was cooled in an ice
bath under an atmosphere of argon and dissolved in dichloro-
methane (13 mL) followed by addition of trichloroacetonitrile
II
I
II
0
0
169.7, 169.6 (Ac-C]O), 98.7 (C-1II), 95.5 and 94.8 (C-1(R,S)I), 79.1
(MCPMeCH(S)), 76.3 (MCPMeCH(R)), 75.15 and 73.05 (C-2(R,S)I),
71.8 (C-5II), 71.33 and 71.26 (C-3II), 70.3 (C-4II), 68.95 and 68.89 (C-
4(R,S)I), 68.5 and 68.4 C-5(R,S)I), 66.4 and 66.3 (C-3(R,S)I), 63.15 and
63.07(C-6(R,S)I), 62.1 (C-6II), 56.16 and 56.10 (C-2II), 23.3
(AcNeCH3), 21.1 (MCPMeCH3(S)), 20.78e20.66 (AcOeCH3), 19.4
(MCPMeCH3(R)), 17.0 (MCPMecpCH(R)), 15.3 (MCPMecpCH(S)),
4.73 and 4.47 (MCPMecpCH2(R,S), 2.4 (MCPMecpCH2(R)), 0.5
(MCPMecpCH2(S)). HRMS obsd 704.2819 calcd C31H46N1O17
(MþH)þ 704.2766; obsd 726.2681 calcd C31H45N1O17Na1 (MþNa)þ
726.2585.
(2.5 mL) and 1,8-diazobicyclo[5.4.0]undec-7-ene (about 80 mL). The
mixture was stirred for 1 h and then concentrated. The reside was
purified by flash chromatography eluting with ethyl acetate/hex-
anes 65:35 to 80:20 to yield a viscous oil (20, 0.99 g, 88%). Com-
pound 20 1H NMR CDCl3:
d
8.69 (s, 1H, NH), 6.17 (d, 1H, J1,2¼2.0,
H-1I), 5.68 (d, 1H, J2,NH¼7.9, NHII), 5.39 (m, 2H, H-3II, H-4I), 5.10 (dd,
1H, J3,4¼10.3, H-3I), 5.05 (t, 1H, J4,5¼10.0, H-4II), 4.89 (d, 1H, J1,2¼8.4,
H-1II), 4.41 (dd, 1H, J2,3¼3.5, H-2I), 4.27 (dd, 1H, J5,6¼5.1, J6,6 ¼12.1,
0
4.1.14. (R,S)-Methyl cyclopropylmethyl [2-deoxy-2-acetamido-
b-
D-
I
I
H-6II), 4.23 (dd, 1H, J5,6¼5.3, J6,6 ¼12.3, H-6 ), 4.12 (m, 2H, H-5 , H-
0
glucopyranosyl]-(1/2)- -mannopyranoside 19ab. A small
a/b-D
0
II
II
6 I), 4.03 (dd,1H, J5,6 ¼2.2, H-6 ), 3.79 (ddd, 1H, H-2 ), 3.70 (ddd, 1H,
0
amount of (18ab, 20 mg, 0.03 mmol) was dissolved in dry methanol
(5 mL) and 1 M NaOMe in MeOH (0.5 mL) was added and the
mixture stirred overnight at room temperature under an atmo-
sphere of Ar. The resulting solution was neutralized with Rexyn
101(H) resin, filtered and evaporated. The residue was purified by
reverse phase C-18 Sepak loading in water and eluting stepwise
with water, 5% v/v methanol/water, 10% methanol/water and 50%
methanol/water. The product eluted predominantly in 10% meth-
anol/water to yield a white powder (19ab, 13 mg, 95%). Compound
H-5II), 2.10, 2.07, 2.06, 2.04, 2.03, 2.01, 1.97 (7ꢂs, 21H, Ac-CH3); 13
C
NMR CDCl3: d 170.8,170.7,170.6,170.5,170.4,169.4,169.3 (Ac-C]O),
160.1 (C]N), 99.8 (C-1II), 95.1 (C-1I), 85.5 (CCl3), 72.7 (C-2I), 71.9 (C-
5II), 71.7 (C-3II), 71.4 (C-5I), 69.9 (C-3I), 68.4 (C-4II), 65.0 (C-4I), 62.1
(C-6I), 61.9 (C-6II), 55.0 (C-2II), 23.2 (AcNeCH3), 20.7 (m, AcOeCH3),
MS obsd 636.3 calcd C26H38N1O17 (M-TCIþH2O)þ 636.2.
4.1.16. N-(9-Fluorenylmethoxycarbonyl)-O-[3,4,6-tri-O-acetyl-2-
19a 1H NMR D2O:
d
5.21 (d, 1H, J1,2¼1.6, H-1(R)I), 4.95 (d, J1,2¼1.6, H-
deoxy-2-acetamido-
b
-
D
-glucopyranosyl]-(1/2)-3,4,6-tri-O-acetyl-
1(S)I), 4.56 (d, 2H, J1,2¼8.2, H-1II), 4.05 (dd, 1H, J2,3¼3.5, H-2(R)I),
4.02 (dd, J2,3¼3.5, H-2(S)I), 3.93e3.29 (m, 22H, H-60II, H-4II, H-3II, H-
6II, H-3(R,S)I, H-4(R,S)I, H-5(R,S)I, H-6(R,S)I, H-60(R,S)I, H-5II, H-2II),
3.27 (dq, JCHeCHcp¼8.5, JCHeCH3¼6.4, MCPMeCH(R)), 3.18 (dq,
JCHeCHcp¼8.8, JCHeCH3¼6.2, MCPMeCH(S)), 2.06, 2.04 (2s, 6H, Ac-
CH3), 1.29 (d, 3H, MCPMeCH3(R)), 1.26 (d, 3H, MCPMeCH3(S)), 0.96
(m, 1H, MCPMecpCH(S)), 0.87 (m, 1H, MCPMecpCH(R)), 0.62 (m,
1H, MCPMecpCH2(R)), 0.52 (m, 6H, MCPMecpCH2(R,S)), 0.34 (m,
1H, MCPMecpCH2(S)), 0.29 (m, 1H, MCPMecpCH2(S)), 0.13 (m, 1H,
a-D
-mannopyranosyl]-L
-serine phenylacyl ester 22. Disaccharide
donor (20, 0.315 g, 0.41 mmol), protected serine (21, 0.12 g,
ꢀ
0.27 mmol), and 4 A molecular sieves (about 400 mg) were dried
overnight at high vacuum. To this mixture was added CH2Cl2 (4 mL)
and the flask was cooled in an ice bath under an atmosphere of
argon. Subsequently boron trifluoride etherate (20
was added by syringe and after 1 h at the same T another aliquot
(10 L) was added. After further stirring for 1 h the reaction was
quenched with DIPEA (30 L) and after filtration and concentration
mL, 0.59 equiv)
m
m
MCPMecpCH2(R)); 13C NMR D2O:
d
174.7 (Ac-C]O), 99.9 and 99.7
the residue was purified by flash chromatography eluting with
hexanes/ethyl acetate:CH2Cl2 6:3:1 to yield a viscous oil (22,
(C-1II), 94.8 and 94.0 (C-1(R,S)I), 78.1 (MCPMeCH(S)), 78.0
(MCPMeCH(R)), 77.2 and 77.0 (C-2(R,S)I), 75.8 (C-5II), 73.3, 73.2,
207 mg, 72%). 1H NMR CDCl3:
d
7.95 (d, 2H, Jo,m¼7.3, FmoceCHo),

5760
S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
7.77 (d, 2H, Jo,m¼7.3, FmoceCHo), 7.65 (m, 3H, PhAc), 7.58 (t, 2H,
Jp,m¼7.3, FmoceCHm), 7.40 (t, 2H, Jp,m¼7.6, FmoceCHm), 7.33 (m,
d, 2H, FmoceCHH), 4.23 (m, 2H, FmoceCH, H-
a
S), 3.99, 3.92 (2ꢂbr
d, JH b 10.5, H-bb0S), 3.91 (br d, 1H, H-2I), 3.86 (dd, 1H, J5,6 2.0, J6,6
0
b
,H
2H, PhAc), 6.21 (d, 1H, J2,NH¼9.0, NHII), 5.95 (d, 1H, Ja ¼8.8, NHS),
12.0, H-6II), 3.77 (m, 1H, H-6I), 3.74 (m, 1H, H-4I), 3.69 (dd, 1H, J5,6
0
,NH
5.76 (d, 1H JH,H¼16.6, PhAceCHH), 5.26 (m, 4H, H-3II,H-1I, H-4I,
5.4, H-60II), 3.62 (m, 2H, H-60I, H-2II), 3.55 (m, 2H, H-5I, H-3I), 3.49
PhAceCHH), 5.09 (dd, 1H, J2,3¼3.7, J3,4¼9.6, H-3I), 5.03 (t, 1H,
(m, 1H, H-3II), 3.34 (m, 1H, H-4II), 3.31 (m, 1H, H-5II), 2.02 (s, 3H, Ac-
J4,5¼9.9, H-4II), 4.71 (m, 2H, J1,2¼8.6, H-1II, H-
a
S), 4.42 (m, 2H,
b
CH3); 13C NMR CD3OD: 174.7 (S-COOH, CO-NHII), 158.3
d
FmoceCH2), 4.22 (m, 6H, H-6II, H-2I, H-6I, H-60I, H-
S, FmoceCH),
(FmoceCO), 145.5, 142.7 (Fmocipso), 128.9 (Fmoco), 128.4 (Fmocm),
126.4 (Fmoco), 121.0 (Fmocm), 102.1 (C-1II), 99.5 (C-1I), 79.2 (C-2I),
78.0 (C-5II), 75.5 (C-3II), 75.2 (C-5I), 72.0 (C-4I), 71.6 (C-4II), 69.6 (S-
4.02 (m, 3H, H-2II, H-60II, H-b0S), 3.90 (m, 1H, H-5I), 3.54 (ddd, 1H,
II
0
J5,6¼2.2, J5,6 ¼4.9, H-5 ), 2.11, 2.07, 2.04 (3ꢂs, 9H, Ac-CH3), 2.03 (s,
6H, Ac-CH3), 1.98, 1.89 (2ꢂs, 6H, Ac-CH3); 13C NMR CDCl3:
d
193.7
b
a
), 69.1 (C-3I), 68.2 (FmocCH2), 63.4 (C-6I), 62.6 (C-6II), 57.3 (C-2II, S-
), 48.2 (FmocCH), 23.5 (AcNeCH3); HRMS obsd 693.2486 calcd
(PhAceCO), 170.9, 170.69, 170.65, 170.5, 169.8, 169.3 (Ac-C]O, S-
CO), 156.1 (FmoceCO), 143.7, 141.3 (Fmocipso), 134.7 (PhAcp), 133.7
(PhAcipso), 129.4 (Fmocm), 127.8 (Fmoco), 127.7 (Fmocm), 127.1
(PhAcm), 125.2 (PhAco), 120.0 (Fmoco), 100.3 (C-1II), 98.7 (C-1I), 74.6
(C-2I), 72.5 (C-3II), 71.7 (C-5II), 70.1 (C-3I), 69.3 (C-5I), 68.5 (C-4II),
C32H41N2O15 (MþH)þ 693.2506.
Acknowledgements
67.5 (S-
b
, FmocCH2), 66.8 (PhAceCH2), 65.9 (C-4I), 62.3 (C-6I), 61.9
), 47.1 (FmocCH), 23.0 (AcNeCH3), 20.74,
The authors greatly thank Prof. George A.O0Doherty for the kind
gift of the Noyori catalyst as well as helpful advice. They also thank
Sussex Research Laboratories for ongoing support. This work was
partly supported by a CIHR grant on innate immunity.
(C-6II), 54.2 (C-2II, S-
a
20.71, 20.65, 20.56 (AcO-CH3); HRMS obsd 1063.3550 calcd
C52H59N2O22 (MþH)þ 1063.3559.
4.1.17. N-(9-Fluorenylmethoxycarbonyl)-O-[3,4,6-tri-O-acetyl-2-
deoxy-2-acetamido-
b
-
D
-glucopyranosyl]-(1/2)-3,4,6-tri-O-acetyl-
Supplementary data
a-D
-mannopyranosyl]-L
-serine 23. Phenylacyl ester (22, 200 mg,
0.19 mmol) was dissolved in acetic acid (8 mL) and ethyl acetate
(2 mL). To this solution at room temperature under an atmosphere
of argon was added Zinc powder (1 g). After stirring for 15 min the
reaction was filtered through a bed of Celite and rinsed well with
ethyl acetate. The liquids were removed by evaporation followed by
co-evaporation with toluene. The residue was purified by flash
chromatography eluting with CH2Cl2 followed by ethyl acetate/
CH2Cl2 3:1, 10% v/v methanol/ethyl acetate and 20% v/v methanol/
ethyl acetate to yield a viscous oil (23, 133 mg, 75%). 1H NMR
Supplementary data for this article can be found in the online
version. It contains experimental procedures for the Mosher esters,
computational details and representative NMR spectra. Supple-
mentary data associated with this article can be found in online
version at doi:10.1016/j.tet.2011.05.133.
References and notes
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CDCl3þfive drops CD3OD:
d
7.71 (d, 2H, Jo,m¼7.1, FmoceCHo), 7.61
(d, 2H, Jo,m¼7.1, FmoceCHo), 7.35 (t, 2H, Jp,m¼7.3, FmoceCHm), 7.27
(t, 2H, Jp,m¼7.3, FmoceCHm), 6.29 (d, 1H, J2,NH¼7.4, NHII), 5.62 (br t,
1H, J2,3¼10.0, J3,4¼10.0, H-3II), 5.10 (dþt, 2H, J1,2¼8.1,
J3,4¼10.0 J4,5¼10.0, H-1II, H-4I), 5.01 (dd, 1H, J2,3¼3.4, J3,4¼10.0, H-
3I), 4.92 (t, 1H, J4,5¼10.5, H-4II), 4.71 (br s, 1H, H-1I), 4.38 (m, 1H,
FmoceCHH), 4.2e4.15 (m, 5H, FmoceCHH, H-6II, H-6I, H-aS
,
FmoceCH, H-2I), 4.0 (m, 3H, H-60I, H-60II, H- S), 3.89e3.85 (m, 2H,
b
H-5I, H-b0S), 3.76 (m, 1H, H-5II), 3.21 (br t, J2,3 10.0, H-2II), 2.03, 2.00,
1.982 (3ꢂs, 9H, Ac-CH3), 1.977 (s, 6H, Ac-CH3), 1.96, 1.90 (2ꢂs, 6H,
Ac-CH3); 13C NMR CDCl3:
d
175.7 (S-COOH), 173.2 (CO-NHII) 171.1,
171.0, 170.8, 170.6 (2), 169.8 (Ac-C]O), 156.0 (FmoceCO), 143.8,
141.1 (Fmocipso), 127.6 (Fmoco), 127.0 (Fmocm), 125.0 (Fmoco), 119.8
(Fmocm), 98.4 (C-1II), 98.1 (C-1I), 74.7 (C-2I), 71.3 (C-3II, C-5II), 70.8
6. (a) Jansson, A. M.; Meldal, M.; Bock, K. J. Chem. Soc., Perkin Trans. 1 1992,
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(C-4I), 68.9 (C-4II), 68.5 (C-5I), 68.2 (S-
b
), 66.9 (FmocCH2), 66.0 (C-
3I), 62.6 (C-6I), 61.9 (C-6II), 55.7 (C-2II, S-
a
), 47.1 (FmocCH), 22.3
(AcNeCH3), 20.51, 20.40 (AcOeCH3). MS obsd 967.4 calcd
C44H52N2O21Na (MþNa)þ 967.3.
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4.1.18. N-(9-Fluorenylmethoxycarbonyl)-O-[2-deoxy-2-acetamido-
b-
D
-glucopyranosyl]-(1/2)- -mannopyranosyl]- -serine 24. An ali-
a
-
D
L
quot of glycoamino acid (23, 76 mg, 0.08 mmol) was dissolved in
dry methanol (5 mL) under an atmosphere of argon at room tem-
perature. KCN21 (63 mg, 12 equiv) was added and the reaction
monitored by TLC using ethyl actetate/methanol/acetic acid 80:15:5
v/v/v as eluent. The reaction was quenched with a small amount of
Rexyn 101(H) resin, filtered and evaporated. The residue was pu-
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d
7.79 (d, 2H, Jo,m¼7.6, FmoceCHo), 7.69 (d, 2H, Jo,m¼7.3,
FmoceCHo), 7.39 (t, 2H, Jp,m¼7.3, FmoceCHm), 7.32 (t, 2H, Jp,m¼7.6,
FmoceCHm), 4.81 (br s, 1H, H-1I), 4.44 (d, 1H, J1,2 8.1, H-1II), 4.34 (br

S.H. Yu, D.M. Whitfield / Tetrahedron 67 (2011) 5750e5761
5761
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