A de novo approach to C-branched inositols: synthesis of a myo-inositol precursor for C-linked glycosyl phosphatidylinositols

Article abstract of DOI:10.1016/j.carres.2006.04.026

C-Linked glycosyl inositols are valuable structure-activity probes because of their greater hydrolytic stability and different conformational behavior compared with their parent O-glycosides. Simple C-branched inositols are synthetic precursors to these a

Full text of DOI:10.1016/j.carres.2006.04.026

Carbohydrate Research 341 (2006) 1322–1332
A de novo approach to C-branched inositols: synthesis of a
myo-inositol precursor for C-linked glycosyl phosphatidylinositols
Sunej Hans and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021, USA
The Graduate Center, CUNY, 365 5th Avenue, New York, NY 10016, USA
Received 17 February 2006; received in revised form 16 April 2006; accepted 18 April 2006
Available online 15 May 2006
Abstract—C-Linked glycosyl inositols are valuable structure-activity probes because of their greater hydrolytic stability and differ-
ent conformational behavior compared with their parent O-glycosides. Simple C-branched inositols are synthetic precursors to these
and other groups of inositol mimetics. Herein is described a de novo synthesis of C-branched inositols that contain a versatile eth-
enyl side chain for elaboration into more complex appendages. The approach centers on a stereoselective oxocarbenium ion–allylsilane
cyclization and provides C-branched inositols with different stereochemical motifs. The synthesis of C-ethenyl-di-O-isopropyl-
idene-myo-, neo-, epi-, and allo-inositols is discussed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: C-Branched inositol; Oxocarbenium ion; Allysilane
1. Introduction
OH
HO
OH
HO
OR6
OR6
R1O
HO
R1O
HO
OH
OH
O
O
5
3
1
Glycosylinositols are subunits of the glycosyl phos-
phatidylinositols (GPI)1 anchors that covalently link
certain proteins to the outer leaflet of eukaryotic cell
membranes, and related phosphatidyl inositol manno-
sides (PIM)2 structures in the cell wall of mycobacteria.
Both GPI and PIM contain a myo-inositol residue that
is connected at O6 via an a-glycoside linkage to mannose
(in PIM, cf 1) or glucosamine (in GPI, cf 2), which is
attached at the reducing end of a trimannan chain
(Fig. 1). The myo-inositol segment is also connected at
O1 to a phosphatidyldiacylglycerol residue. In GPIs,
the O2 position bears a fatty acid ester, whereas PIMs
are linked to a mannose or oligomannan at this position.
Both GPIs and PIMs may contain an additional fatty
acid ester at O4.
O
O
O
O
OR4
OR5
HO
H2N
O
O
P
P
O
O
OH
OH
OR2
OR3
OR2
OR3
1
2
R1 = Trimannan; R2, R3 = CH3(CH2)nCO
R4 = (Man)n; R5 = R3 = CH3(CH2)nCO
R6 = R3 = CH3(CH2)nCO/H
Figure 1. Generalized GPIs and PIMs.
likely controlled by lipid substitution and the conforma-
tion of this subunit.3 The formation of such lipid micro-
domains has been associated with signaling
mechanisms.4 Components of GPIs have also been sug-
gested as second messengers of insulin action.5 In para-
sites such as Trypanosoma brucei, the GPI anchoring
system provides a protective protein coating, which
undergoes antigenic variation and constitutes a defense
mechanism against the host immune response.1,6 The
The hydrophobic nature of the myo-inositol residue is
believed to facilitate lipid clustering and translocation in
the bilayer surface, and the specificity of aggregation is
*
Corresponding author. Tel.: +1 212 772 4356; fax: +1 212 772
5332; e-mail: dmootoo@hunter.cuny.edu
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.04.026

S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1323
PGO
PGO
PGO
MeOTf
O
O
X
PivO
O
O
PivO
O
O
O
X = PhS
O
O
O
7
O
8
O
OPG
3
C-myo
4
C-neo
OPG
OPG
O
PGO
OPG
O
MeOTf
X
O
O
PivO
O
O
PivO
O
O
X = PhS
O
TMSCH2
O
9
10
O
O
Scheme 1. Oxocarbenium ion cyclizations for C-branched inositols.
5
C-epi
6
C-allo
Figure 2. C-Branched inositols.
state leading to 8. By analogy, we envisaged that cycliza-
tion of a precursor such as 9 should lead to the C-
branched myo-inositol 10 with high stereoselectivity.
While the use of an allylsilane (in place of the isobutenyl
residue in 7), was expected to facilitate the trapping of
the oxocarbenium ion, the more complex substitution
in 9 compared with 7 led to concerns about both com-
peting side reactions and stereoselectivity. Indeed, preli-
minary investigations on the derivatives of 9 with benzyl
ether or ester protecting groups suggested that products
arising from attack on the intermediate oxocarbenium
ion by neighboring oxygen substituents were predomi-
nant. We argued that strategic positioning of cyclic
and ester protecting groups would limit these processes
because of unfavorable ring strain and electronic effects
in the cyclization reaction. Accordingly, substrate 22
was proposed as a suitable precursor to 3 (Schemes 2
and 3).
To evaluate the generality of the cyclization method-
ology, a divergent synthesis that led to 22 as well as dia-
stereomeric cyclization precursors was developed.
The synthesis started with commercially available 1,2-
O-isopropylidene-a-D-xylofuranose, which was con-
verted to the known 5-iodo derivative 11.16 Treatment
of 11 with 2 equiv of n-butyl lithium at low temperature
followed by quenching of the reaction with acetic anhy-
dride provided diacetate 12 as a mixture of acetal iso-
mers. Exposure of this mixture to boron trifluoride
etherate and thiophenol at low temperature led to
1-thio-1,2-O-isopropylidene acetal 13 as a single isomer,
which was presumed to have the trans stereochemistry
by analogy with the earlier investigation.15 Ester hydro-
lysis on 13 and treatment of the resulting alcohol under
Mitsunobu conditions provided nitrobenzoate 14.
Hydrolysis of 14 provided an allylic alcohol that was
diastereomeric to the substrate for the Mitsunobu reac-
tion, confirming that the reaction proceeded with inver-
sion of configuration. Ozonolysis of 14 provided the
aldehyde derivative, which was treated without purifica-
tion with an excess of vinylmagnesium bromide. This
two-step sequence provided a mixture of diastereomeric
diols 15 and 16 in a 3:1 ratio. The configuration at the
implication of GPIs and PIMs in a variety of disease
mechanisms has led to interest in several areas of GPI
biochemistry,1,2 including the design of inhibitors of
GPI biosynthesis,7,8 immunological studies on the speci-
ficity of GPI-membrane integration,9 and investigation
of glycosyl inositol analogues of putative insulin mim-
ics.10 C-Linked glycosyl inositols are potentially valu-
able mechanistic probes, because of their greater
hydrolytic stability and different conformational behav-
ior compared with their parent O-glycosides.11 In this
vein, we were interested in the 6-C-ethenyl-myo-inositol
analogue 3, a synthetic precursor to more complex C-
branched myo-inositols (Fig. 2). Herein, we describe
the synthesis of 3 and the diastereomeric analogues 4,
5, and 6.
Previous syntheses of C-branched cyclitols include the
modification of naturally occurring cyclitols,12 the de
novo formation of the cyclitol framework through cycli-
zation of acyclic precursors,13 or cycloaddition14 strate-
gies. A 6-C-branched myo-inositol related to 3, involving
an intramolecular silyl nitronate cycloaddition, has been
reported.13e We were interested in a de novo synthesis
because of the versatility of such an approach for pro-
viding different substitution patterns. In this context,
we have been developing an oxocarbenium ion–alkene
cyclization strategy for C-branched, oxygenated cyclo-
hexanes, and the synthesis of 3 provided an opportunity
to evaluate the scope of this methodology.15
2. Results and discussion
In the aforementioned study, it was observed that treat-
ment of thioacetal–alkene 7 with methyl triflate led to
one of the four possible diastereomeric cyclization prod-
ucts (Scheme 1). The favored isomer contained a cis-
fused O-isopropylidene and a vicinal isopropenyl substi-
tuent that was trans to the isopropylidene residue. The
stereoselectivity of this transformation was rationalized
in terms of the cyclic nature of the oxocarbenium ion inter-
mediate and conformational factors in the transition

1324
S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
I
OR
O
OR
X
PhS
O
e
f
O
OR
O
O
c, d
a
O
OR
O
+
O
PhS
O
AcO
PhS
O
HO
p-O2NC6H4CO2
11
O
14
12 X = OAc
13 X = SPh
b
15 R = H
17 R = (CH3)2C
16 R = H
18 R = (CH3)2C
f
g
g
O
O
O
HO
O
HO
HO
O
O
O
SPh
SPh
SPh
O
O
O
O
O
h, i
21
20
19
h, i
O
O
O
PivO
O
PivO
O
O
PivO
O
O
SPh
O
SPh
SPh
O
O
TMSCH2
TMSCH2
TMSCH2
O
23
22
24
Scheme 2. Synthesis of cyclization precursors. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 ꢁC, then Ac2O, pyridine, DMAP, 86%; (b) PhSH,
BF3ÆOEt2, CH2Cl2, ꢀ78!ꢀ40 ꢁC, 88%; (c) NaOCH3, CH3OH, 99%; (d) p-O2N–C6H4COOH, DIAD, THF, 98%; (e) (i) O3, CH3OH/CH2Cl2,
ꢀ78 ꢁC then Ph3P; (ii) CH2@CHMgBr, THF, 0 ꢁC, 15/16 (3:1), 60%; (f) DMP, CH2Cl2, CSA, 17 (87%), 18 (82%); (g) see (e), 19/20 (2:1), 66%; 21,
63% (h) TMSCH2CH@CH2, CH2Cl2, Grubbs II catalyst; (i) PivCl, CH2Cl2, pyridine, DMAP, 22/23 (68%), 24 (59%) two steps.
H
OR
H
H
O
H
RO
OR
O
H
OR'
RO
RO
5
R'O
RO
RO
OR
OR
OR
OR
O
3
b
5
OR
b
5
RO
RO
O
H
1
1
3
3
1
H
H
H
H
H
H
H
H
H
H
H
3 (41%)
R = (CH3)2C; R' = Piv
5 (74%)
R = (CH3)2C; R' = Piv
27 R = Ac
25 R = Ac
J2,3 = J3,4 = 3.3 Hz
J4,5 = 3.3; J5,6 = 10.5 Hz
J1,2 = 2.9; J1,6 = 11.2 Hz
J1,2 = 2.6 (2.2); J2,3 = 2. 6 (2.2) Hz
J3,4 = 10.3 (8.5); J4,5 = 10.3 (8.5) Hz
J1,6 = 10.3 (9.9); J5,6 = 10.3 (9.9) Hz
a
22
24
+
a
23
H
H
O
H
H
RO
RO
OR
O
H
RO
5
b
OR
O
3
b
3
RO
OR'
1
5
5
RO
OR
RO
O
RO
RO
OR
3
1
H
1
OR
OR'
RO
H
H
H
H
H
H
28 R = Ac
4 (19%)
R = (CH3)2C; R' = Piv
6 (22%)
R = (CH3)2C; R' = Piv
26 R = Ac
J1,2 = 3.2; J2,3 = 3.3Hz
J3,4 = 3.5; J4,5 = 5.0 Hz
J1,6 = 10.1; J5,6 = 3.5 Hz
J1,2 = 2.8; J2,3 = 2.8 Hz
J3,4 = 10.9; J4,5 = 3.1 Hz
J1,6 = 11.1; J5,6 = 2.6 Hz
Scheme 3. Cyclization reactions and stereochemical assignment of products. Average of mutual J values indicated. Calculated J values for idealized
chair are shown in parentheses. Double headed arrows indicate unambiguous NOE’s. Reagents and conditions: (a) CH3OTf, CH2Cl2, DTBMP; (b)
(i) DIBALH, THF, ꢀ78 ꢁC; (ii) CH3OH, HCl; (iii) Ac2O, pyridine, EtOAc.
newly formed carbinol center in 15 and 16 was assigned
by correlation with the subsequent cyclization products,
the structures of which were analyzed through 1H NMR
analysis (vide infra). The major isomer 15 corresponds
to the stereochemistry required for the myo-inositol tar-
get 3. Diols 15 and 16 were converted to their respective

S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1325
di-O-isopropylidene derivatives 17 and 18, which were
individually processed using an ozonolysis/Grignard
addition protocol that was similar to that used on alkene
14. This reaction sequence gave an approximately 2:1
mixture of allylic alcohols 19/20 from 17, and a single
product 21 from 18. Once again, the configuration at
the newly introduced stereogenic center in 19–21 relied
on the assignment of stereochemistry in the later cycliza-
tion products. Unseparated mixture 19/20 and 21 were
then individually subjected to olefin cross-metathesis
with allyltrimethylsilane.17 Treatment of the metathesis
product arising from 19/20 with pivaloyl chloride
provided an inseparable 2:1 mixture of isomers 22/23
NOE’s between H1, H3, and H5. Similar NOE’s were
observed for the di-O-isopropylidene precursor 3. In
addition to setting the configurations at the two stereo-
genic centers that were generated in the cyclization reac-
tion (C1 and C6), the structure for 3 (and 25) established
the configurations at C4 and C5 in the corresponding
cyclization precursor 22, that is, the new stereogenic cen-
ters that were formed in the two Grignard reactions
leading to 22. Based on the synthetic grounds, 22 and
23 differ only with respect to the configuration at C5,
and therefore the assignment of structure 22 established
the structure of 23. The epimeric relationship between 22
and 23 was independently confirmed by JH,H analysis on
26, the pentacetate derivative of the other cyclization
product (i.e., 4), from the mixture 22/23. Thus, for 26,
J4,5 = 3.1 and J5,6 = 2.6 Hz, which was in line with an
equatorial–axial relationship between H5, and both H4
and H6. Unambiguous NOE’s between H1 and H3,
and H4 and H6 in both 4 and 26 confirmed the neo con-
figuration. Using similar arguments, the cyclization
products 5 and 6 and their respective pentaacetates 27
and 28 were assigned as epi and allo, and the structure
of the corresponding precursor deduced as 24. Of note
is the observation that the coupling constant data for
25 and 26 were consistent with a predominant confor-
mation with a chair-like geometry, even though the pres-
ence of the 1,3-diaxial oxygen substituents might have
been expected to lead to significant distortion.
The stereochemistry of the cyclization reaction
appears to be controlled by conformational factors.
Thus, the high stereoselectivity observed for the reac-
tions of 22 and 23 is consistent with a clear preference
for chair-like transition states 29A and 30A, respectively,
over the other diastereomeric possibilities (Fig. 3). The
particular flip chair conformation in these structures is
determined by the 3,4-O-isopropylidene residue (in
which the oxygens of the cyclic acetal are in a trans die-
quatorial relationship in the forming six-membered
ring). The configuration at C1 is controlled by the pref-
erence for a 1,2-O-isopropylidene that is cis-fused (vs
trans-fused) in the resulting tricyclic framework. The
constraints imposed by the two cyclic acetal residues
are met in a pair of low energy transition states, 29A/
29A0 and 30A/30A0, corresponding to precursors 22
and 23, respectively. Of these 29A and 30A, in which
the C6 substituent adopts the pseudo-equatorial (vs
the pseudo-axial orientation in 29A0 and 30A0), in the
forming six-membered ring, are expected to be highly
favored, thereby leading to single cyclization products
from 22 and 23, respectively. Analysis of transition
states for the cyclization of 24 is complicated by the fact
that both O-isopropylidene rings in the diastereomeric
products 5 and 6 are cis-fused, and therefore a wider
range of low energy transition state conformations are
possible, compared to the cyclizations leading to 3 and
4. In addition, chair-like geometries would probably
1
in overall yield of 68% from 19/20. H NMR analysis
of this mixture suggested that the stereoselectivity of
the cross-metathesis was greater than 90% in favor of
the E-alkene. Similarly, the cross-metathesis-pivaloyl-
ation sequence on 21 led to 24 in 59% yield.
The cyclization reactions on unseparated mixture of
22/23 and 24 were promoted with methyl triflate in the
presence of 2,6-di-t-butyl-4-methylpyridine (DTBMP)
˚
and freshly activated 4 A molecular sieves in anhydrous
dichloromethane (Scheme 3). Under these conditions,
an approximately 2:1 mixture of 22/23 afforded 3
(41%) and 4 (19%). Stereochemical analysis of the prod-
ucts (vide infra) indicated that 3 was produced from 22,
and 4 from 23. In comparison, the reaction of 24 pro-
duced a mixture of 5 (74%) and 6 (22%). Thus, the reac-
tions of 22 and 23 were both highly stereoselective,
giving in each case a single diastereomer in which the
newly formed O-isopropylidene was cis-fused to the
cyclitol ring, and the adjacent isopropenyl substituent
was trans to the isopropylidene ring. The cyclization
of 24 was less selective giving a mixture of products
which also contained a cis-fused O-isopropylidene, but
differed with respect to the configuration at the ethenyl-
ated carbon.
The stereochemistry of 3–6 was assigned by consider-
ing the synthetic sequence leading to the cyclization
1
precursors in connection with H NMR analysis of the
cyclization products 3–6 and their pentaacetate deriva-
tives 25–28 (Scheme 3). Due to the uncertainty in pre-
dicting well-defined conformations for the di-O-
isopropylidene derivatives, structural assignments were
based on vicinal JH,H values and NOE’s in 25–28, and
corroborated with NOE’s for 3–6. Thus, the stereo-
chemistry at C2 and C3 in 3, 4, and 6 (cf. C3 and C4
in 5 due to different numbering) is set in the common
precursor 14. Di-O-isopropylidene 3, the major product
from the cyclization of a mixture of 22/23, was deter-
mined to have the myo configuration by comparison of
the experimental coupling constants for the derived pen-
taacetate 25, with those expected by application of the
Haasnoot–Altona equation18,19 to an idealized chair
conformation (Scheme 3). This assignment was con-
firmed by NOE’s between H4 and H6, and mutual

1326
S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
4. Experimental
TMSCH2 PivO
PivO
OR
OR
TMSCH2
O
O
O
O
RO
+
RO
+
O
O
4.1. General methods
29A'
29A
Unless otherwise stated, all reactions were carried out
under a nitrogen atmosphere in oven-dried glassware
using standard syringe and septa technique. Optical
rotations were recorded at room temperature using a
TMSCH2
OR
TMSCH2
OR
O
O
RO
+
RO
+
OPiv
30A
OPiv
Rudolph Autopol III polarimeter. H and 13C NMR
1
30A'
spectra were obtained on a Varian Unity Plus 500
(500 MHz) spectrometer. Chemical shifts are relative
to the deuterated solvent peak or the tetramethylsilane
(TMS) peak at (d 0.00) and are in parts per million
(ppm). Assignments for selected nuclei were determined
from 1H COSY experiments. High resolution mass spec-
trometry (HRMS) was performed on an Ultima Micro-
mass Q-Tof instrument at the Mass Spectrometry
Laboratory of the University of Illinois, Urbana-Cham-
paign. Thin layer chromatography (TLC) was done
on 0.25 mm thick precoated silica gel HF254 alumi-
num sheets. Chromatograms were observed under UV
(short and long wavelength) light, and/or were visual-
ized by heating plates that were dipped in a solution
of ammonium(VI) molybdate tetrahydrate (12.5 g) and
cerium (IV) sulfate tetrahydrate (5.0 g) in 10% aq sulfu-
ric acid (500 mL). Flash column chromatography (FCC)
was performed using Silica Gel 60 (230–400 mesh) and
employed a stepwise solvent polarity gradient, corre-
lated with TLC mobility.
R = (CH3)2C
PivO
O
O
O
O
5
5
PivO
OR
OR
OR
TMSCH2
OR
+
+
TMSCH2
TMSCH2
31A
31A'
O
O
O
O
TMSCH2
RO
RO
RO
RO OPiv
+
OPiv
+
32A'
32A
Figure 3. Transition state models for oxocarbenium ion cyclization.
be disfavored because of severe 1,3-diaxial interactions
between oxygen substituents of the two isopropylidene
rings. Assuming a half-chair like geometry, four low
energy pathways 31A/31A0 and 32A/32A0 corresponding
to pairs of ‘flip’ conformations may be considered for 5
and 6, respectively. Of these 31A and 32A, in which the
alkene substituent adopts a pseudo-equatorial position,
are expected to be favored (over 31A0 and 32A0). While
31A should be preferred over 32A, and as a result 5
should predominate over 6, the high degree of steric
congestion in both structures would be expected to have
a leveling effect on their relative energies, thereby lead-
ing to low product selectivity. The observed ratio of
5/6 (3:1) appears to be consistent with this argument.
4.2. 1,3-Di-O-acetyl-4,5-dideoxy-1,2-O-isopropylidene-4-
eno-L-threo-pentose (12)
To a solution of 11 (6.24 g, 20.8 mmol) in THF (100 mL)
was added n-BuLi (33 mL of a 2.5 M solution in THF,
83.2 mmol) dropwise at ꢀ78 ꢁC, under an atmosphere
of argon. The reaction was stirred at this temperature
for 1 h, then pyridine (6.73 mL, 83.2 mmol), acetic anhy-
dride (15.7 mL, 83.2 mmol) and DMAP (2.50 g,
20 mmol) were added. The mixture was warmed to
ꢀ40 ꢁC, stirred for an additional 1 h at this temperature,
then poured into ice-cold satd aq NaHCO3, and ex-
tracted with Et2O. The combined organic phase was
dried (Na2SO4), filtered, and evaporated in vacuo.
FCC of the residue afforded 12 as an approximately 1:1
mixture of diastereomers (4.60 g, 86%). A portion of this
mixture was subjected to further FCC for characteriza-
tion purposes. For the less polar component: Rf = 0.80
(20%, EtOAc/petroleum ether); [a]D ꢀ20.6 (c 2.5,
3. Conclusion
A novel oxocarbenium ion–allylsilane synthetic strategy
for the C-ethenyl inositols has been described. Notewor-
thy aspects of this methodology are the easy accessibility
of the 1-thio-1,2-O-isopropylidene-alkene precursor
from 1,2-O-isopropylidene-a-D-xylofuranose and the
stereoselectivity of the key oxocarbenium ion cycliza-
tions. The potential for obtaining diastereomeric precur-
sors from other common 1,2-O-isopropylidene sugars,
and the synthetic versatility of the 1-thio-1,2-O-iso-
propylidene–alkene building blocks suggest that
C-branched inositols with a variety of substitution
patterns, and other groups of highly oxygenated cyclo-
hexanes may be possible through this approach.
1
CHCl3); H NMR (CDCl3): d 1.41, 1.51 (each 3H, both
s, (CH3)2C), 2.09, 2.13 (each 3H, both s, CH3CO · 2),
4.23 (1H, dd, J = 3.4, 3.5 Hz, H-2), 5.31 (1H, d,
J = 10.6 Hz, H-5), 5.39 (1H, d, J = 17.2 Hz, H-50), 5.53
(1H, t, J = 7.6 Hz, H-3), 5.73 (1H, m, H-4), 6.20 (1H,
d, J = 3.4 Hz, H-1); 13C NMR (CDCl3): d 21.0, 21.1,
27.1, 30.5, 73.1, 82.8, 96.3, 113.7, 120.1, 131.9, 170.2,

S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1327
170.2; ESIMS m/z 281.1 [M+Na]+. For the more polar
component: Rf = 0.70 (20%, EtOAc/petroleum ether);
134.2, 136.8; ESIMS m/z calcd for C14H18O3NaS
[M+Na]+: 289.0874. Found: 289.0887. Diisopropylazo-
dicarboxylate (2.05 mL, 10.6 mmol) was added dropwise
at 0 ꢁC to a mixture of the product from the previous step
(1.88 g, 7.05 mmol), Ph3P (2.2 g, 8.46 mmol), and p-
nitrobenzoic acid (1.77 g, 10.6 mmol) in anhydrous tolu-
ene (30 mL). The reaction was maintained at this temper-
ature for 2 h, then quenched by the addition of satd aq
NaHCO3. The mixture was then extracted with Et2O
and the organic phase was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. FCC of
the residue gave 14 (2.81 g, 98%): Rf = 0.85 (15%,
1
[a]D ꢀ80.3 (c 4.0, CHCl3); H NMR (CDCl3): d 1.40,
1.51 (each 3H, both s, (CH3)2C), 2.80, 211 (each 3H, both
s, CH3CO · 2), 4.23 (1H, dd, J = 3.5 Hz, 10.6 Hz, H-2),
5.29 (1H, d, J = 10.6 Hz, H-5), 5.37 (1H, d, J = 17.3 Hz,
H-50), 5.54 (1H, t, J = 7.7 Hz, H-3), 5.70 (1H, m, H-4),
5.20 (1H, d, J = 3.5 Hz, H-1); 13C NMR (CDCl3): d
21.3, 21.4, 26.2, 28.3, 72.9, 80.1, 93.4, 113.0, 120.3,
131.9, 169.9, 170.0; ESIMS m/z 281.1 [M+Na]+.
4.3. 3-O-Acetyl-4,5-dideoxy-1,2-O-isopropylidene-4-eno-
L-threo-pentose-S-phenyl-monothiohemiacetal (13)
1
EtOAc/petroleum ether); [a]D +142 (c 0.6, CHCl3); H
NMR (CDCl3): d 1.34, 1.47 (each 3H, both s,
(CH3)2C), 4.26 (1H, q, J = 4.3 Hz, H-2), 5.35 (1H,
d, J = 10.6 Hz, H-5), 5.38 (1H, d, J = 6.3 Hz, H-1),
5.37–5.42 (1H, d, J = 17.2 Hz, H-50), 5.70 (1H, t,
J = 5.4 Hz, H-3), 5.95 (1H, m, H-4), 7.24 (3H, m, Ar–
H), 7.41 (2H, dd, J = 1.1, 1.5 Hz, Ar–H), 8.20 (2H, d,
J = 8.7 Hz, Ar–H), 8.24 (2H, d, J = 8.7 Hz, Ar–H); 13C
NMR (CDCl3): d 26.3, 27.5, 75.4, 82.2, 85.9, 112.6,
120.6, 123.8, 128.0, 129.3, 131.1, 131.4, 132.3, 135.5,
152.1, 164.1; ESIMS m/z calcd for C21H21NO6NaS
[M+Na]+: 438.0987. Found: 438.0996.
BF3ÆOEt2 (3.05 mL, 24.2 mmol) was slowly added at
ꢀ78 ꢁC, under argon, to a solution of 12 (4.17 g,
16.2 mmol) and thiophenol (4.15 mL, 40.4 mmol), in
anhydrous CH2Cl2 (70 mL). The mixture was warmed
to ꢀ40 ꢁC, and stirring was continued at this tempera-
ture for 1 h (or until the TLC indicated complete dis-
appearance of the starting material). The reaction
mixture was quenched by the addition of Et3N (3 mL),
then poured into 1 N aq NaOH and extracted with
Et2O. The organic phase was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. FCC of
the residue gave 13 (4.40 g, 88%): Rf = 0.7 (15%,
EtOAc/petroleum ether); [a]D +118.7 (c 1.2, CHCl3);
1H NMR (CDCl3): d 1.50, 1.57 (each 3H, both s,
(CH3)2C), 2.12 (3H, s, CH3CO), 4.25 (1H, t,
J = 5.6 Hz, H-2), 5.34 (1H, d, J = 6.5 Hz, H-1), 5.35
(1H, d, J = 10.8 Hz, H-5), 5.42 (1H, d, J = 17.6 Hz,
H-50), 5.49 (1H, t, J = 5.9 Hz, H-3), 5.79 (1H, m, H-
4), 7.34 (3H, m, Ar–H), 7.54 (2H, d, J = 7.1 Hz, Ar–
H); 13C NMR (CDCl3): d 21.6, 26.8, 27.8, 74.1, 82.2,
86.2, 112.9, 120.9, 128.2, 129.6, 132.5, 132.5, 134.6,
170.4; ESIMS m/z 331.1 [M+Na]+.
4.5. 5,6-Dideoxy-1,2-O-isopropylidene-5-eno-L-lyxo-
hexose-S-phenyl-monothiohemi-acetal (15) and 5,6-di-
deoxy-1,2-O-isopropylidene-5-eno-D-ribo-hexose-
S-phenyl-monothiohemiacetal (16)
Alkene 14 (2.71 g, 6.28 mmol) was dissolved in a 5/1
mixture of CH2Cl2/CH3OH (35 mL). The solution was
cooled to ꢀ78 ꢁC and treated with a stream of O3 in
O2 until TLC indicated the complete disappearance of
the starting material. The reaction was then purged with
nitrogen, and Ph3P (3.29 g, 12.5 mmol) was added. The
mixture was warmed to rt, stirred for 1 h at this temper-
ature, and concentrated under reduced pressure. The
crude material was dried under high vacuum and dis-
solved in anhydrous THF (30 mL). The resulting solu-
tion was added dropwise at 0 ꢁC to a mixture of
vinylmagnesium bromide (50 mL of a 1 M solution in
THF, 50.0 mmol) in THF (60 mL). The reaction was
stirred for 1 h at this temperature, then poured into satd
aq NH4Cl and extracted with Et2O. The organic phase
was washed with brine, dried (Na2SO4), and concen-
trated in vacuo. FCC of the residue afforded 15/16 as
a 3:1 mixture (0.90 g, 60%). Further FCC of the mixture
provided separate samples of 15 and 16. For 15:
Rf = 0.53 (40%, EtOAc/petroleum ether); [a]D +127.4
4.4. 4,5-Dideoxy-1,2-O-isopropylidene-3-O-p-nitro-
benzoyl-4-eno-D-erythro-pentose-S-phenyl-monothio-
hemiacetal (14)
NaOCH3 (100 mg, 1.85 mmol) was added to a solution of
13 (2.23 g, 7.24 mmol) in anhydrous CH3OH (20 mL).
The reaction was stirred at rt for 2 h and the pH was then
adjusted to 7 by addition of a solution of HCl in CH3OH.
The mixture was concentrated under reduced pressure
and the residue purified by FCC to give the derived alco-
hol (1.93 g, 99%): Rf = 0.50 (15%, EtOAc/petroleum
1
ether); [a]D +158 (c 0.9, CHCl3); H NMR (CDCl3): d
1.40, 1.43 (each 3H, both s, (CH3)2C), 2.19 (1H, br s,
OH), 3.96 (1H, dd, J = 4.0 Hz, H-2), 4.13 (1H, m, H-3),
5.18 (1H, dt, J = 1.2, 10.5 Hz, H-5), 5.31 (1H, dt,
J = 1.4, 17.2 Hz, H-50), 5.33 (1H, d, J = 6.6 Hz, H-1),
5.84 (1H, m, H-4), 7.20 (3H, m, Ar–H), 7.43 (2H, d,
J = 7.1 Hz, Ar–H); 13C NMR (CDCl3): d 26.2, 27.5,
71.9, 83.4, 85.8, 112.1, 117.4, 127.7, 128.5, 129.2, 131.8,
1
(c 0.9, CHCl3); H NMR (CDCl3): d 1.40, 1.47 (each
3H, both s, (CH3)2C), 2.40 (2H, br d, J = 7.7 Hz,
OH), 3.62 (1H, br d, J = 4.4, 8.8 Hz, H-3), 4.14 (1H, t,
J = 5.3 Hz, H-2), 4.25 (1H, br s, H-4), 5.24 (1H, dt,
J = 1.3, 10.6 Hz, H-6), 5.4 (1H, dt, J = 1.4, 17.3 Hz,
H-60), 5.51 (1H, d, J = 6.0 Hz, H-1), 5.90 (1H, m,

1328
S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
H-5), 7.22 (3H, m, Ar–H), 7.45 (2H, m, Ar–H); 13C
NMR (CDCl3): d 26.1, 27.7, 71.8, 74.1, 81.6, 86.0,
111.9, 118.0, 127.6, 129.2, 131.7, 134.7, 136.8; ESIMS
m/z calcd for C15H20O4NaS [M+Na]+: 319.0980.
Found: 319.1031. For 16: Rf = 0.30 (40%, EtOAc/petro-
leum ether); [a]D +392.5 (c 0.4, CHCl3); 1H NMR
(CDCl3): d 1.49, 1.55 (each 3H, both s, (CH3)2C), 2.29
(1H, d, J = 3.6 Hz, OH), 2.38 (1H, d, J = 4.4 Hz,
OH), 3.81 (1H, m, H-3), 4.23 (1H, t, J = 5.7 Hz, H-2),
4.30 (1H, m, H-4), 5.30 (1H, dt, J = 1.2, 10.5 Hz, H-
6), 5.40 (1H, dt, J = 1.3, 17.3 Hz, H-60), 5.65 (1H, d,
J = 5.9 Hz, H-1), 6.01 (1H, m, H-5), 7.30 (3H, m, Ar–
H), 7.51 (2H, d, J = 7.1 Hz, Ar–H); 13C NMR (CDCl3):
d 26.1, 27.7, 73.8, 74.0, 81.6, 85.8, 111.9, 118.3, 127.7,
129.2, 131.7, 134.3, 136.5; ESIMS m/z calcd for
C15H20O4NaS [M+Na]+: 319.0980. Found: 319.0982.
4.8. 6,7-Dideoxy-1,2,3,4-di-O-isopropylidene-6-eno-D-
gulo-heptose-S-phenyl-monothiohemiacetal (19) and 6,7-
dideoxy-1,2,3,4-di-O-isopropylidene-6-eno-L-manno-hep-
tose-S-phenyl-monothiohemiacetal (20)
Treatment of alkene 17 (0.592 g, 1.9 mmol) following
the ozonolysis-Grignard reaction sequence that was
described for the preparation of 15/16 provided 19/20
as an approximately 2/1 inseparable mixture of alcohols
(0.42 g, 66%): Rf = 0.55 (25%, EtOAc/petroleum ether):
1H NMR (CDCl3): d 1.40, 1.41, 1.43, 1.44, 1.47, 1.49,
1.57, 1.58, 1.60 (12H, all s, (CH3)2C · 2), 2.40 (0.5H,
br d, J = 8.3 Hz, OH), 2.59 (0.5H, br s, J = 3.6 Hz,
OH), 4.04 (1H, dd, J = 6.4, 11.5 Hz, H-3), 4.09 (1H,
dd, J = 6.8, 10.4 Hz, H-4), 4.16 (0.5H, t, J = 5.7 Hz,
H-2), 4.20 (0.5H, t, J = 5.6 Hz, H-2), 4.25 (1H, m, H-
5), 5.26 (0.5H, dt, J = 1.4, 10.6 Hz, H-7), 5.27 (0.5H,
dt, J = 1.4, 10.5 Hz, H-7), 5.40 (1H, dt, J = 1.5,
17.3 Hz, H-70), 5.61 (1H, dd, J = 3.7, 5.1 Hz, H-1),
5.97 (1H, m, H-6), 7.31 (3H, m, Ar–H), 7.65 (2H, m,
Ar–H); 13C NMR (CDCl3): d 26.4, 26.7, 27.2, 27.3,
27.4, 27.4, 27.7, 27.9, 29.8, 71.8, 73.2, 78.9, 81.7, 81.8,
82.1, 82.5, 86.4, 86.8, 110.4, 110.5, 112.4, 112.6, 116.9,
117.4, 127.6, 129.2, 131.7, 134.5, 136.4, 137.3; ESIMS
m/z calcd for C19H26O5NaS [M+Na]+: 389.1399.
Found: 389.1396.
4.6. 5,6-Dideoxy-1,2,3,4-di-O-isopropylidene-5-eno-L-
lyxo-hexose-S-phenyl-monothiohemiacetal (17)
A solution of diol 15 (0.599 g, 2.16 mmol), dimethoxypro-
pane (5.30 mL, 43.2 mmol) and camphorsulfonic acid
(0.05 g, 0.22 mmol) in anhydrous CH2Cl2 (20 mL) was
stirred at 0 ꢁC for 1 h. The reaction was then quenched
by the addition of satd aq NaHCO3 and extracted with
Et2O. The organic extract was dried (Na2SO4) and con-
centrated under reduced pressure. FCC of the residue
provided 17 (0.592 g, 87%): Rf = 0.70 (15%, EtOAc/
4.9. 6,7-Dideoxy-1,2,3,4-di-O-isopropylidene-6-eno-L-
talo-heptose-S-phenyl-monothiohemiacetal (21)
1
petroleum ether); [a]D ꢀ11.3 (c 0.2, CHCl3); H NMR
(CDCl3): d 1.34, 1.36, 1.39, 1.47 (each 3H, all s,
(CH3)2C · 2), 3.85 (1H, dd, J = 4.7, 8.1 Hz, H-3), 4.14
(1H, dd, J = 4.8, 5.6 Hz, H-2), 4.42 (1H, dd, J = 7.0,
7.9 Hz, H-4), 5.19 (1H, dt, J = 1.0, 10.4 Hz, H-6), 5.38
(1H, dt, J = 1.1, 17.2 Hz, H-60), 5.48 (1H, d, J = 5.7 Hz,
H-1), 5.81 (1H, m, H-5), 7.22 (5H, m, Ar–H), 7.45 (2H,
m, Ar–H); 13C NMR (CDCl3): d 26.5, 27.1, 27.3, 27.8,
79.5, 80.4, 81.3, 85.5, 110.1, 112.2, 119.0, 127.6, 129.2,
131.8, 134.5, 135.7; ESIMS m/z 359.1 [M+Na]+.
Treatment of alkene 18 (0.208 g, 0.66 mmol) following
the ozonolysis-Grignard reaction sequence that was de-
scribed for the preparation of 15/16 provided alcohol 21
(0.15 g, 63%): Rf = 0.76 (20%, EtOAc/petroleum ether);
[a]D +89 (c 1.0, CHCl3); 1H NMR (CDCl3): d 1.26,1.37,
1.45, 1.51 (each 3H, all s, (CH3)2C · 2), 2.47 (1H, d,
J = 6.9 Hz, OH), 4.02 (1H, dd, J = 6.1, 9.1 Hz, H-3),
4.10 (1H, dd, J = 4.0, 6.0 Hz, H-4), 4.48–4.50 (2H, m,
H-2, H-5), 5.15 (1H, dt, J = 1.6, 10.6 Hz, H-6), 5.36
(1H, dt, J = 1.6, 17.3 Hz, H-60), 5.53 (1H, d, J =
4.5 Hz, H-1), 5.96 (1H, m, H-6), 7.23 (3H, m, Ar–H),
7.46 (2H, d, J = 7.1 Hz, Ar–H); 13C NMR (CDCl3): d
25.2, 26.8, 27.6, 28.3, 69.6, 78.4, 79.6, 80.1, 88.3, 109.3,
112.8, 116.0, 127.4, 129.1, 131.6, 135.2, 137.9; ESIMS
m/z calcd for C19H26O5NaS [M+Na]+: 389.1399.
Found: 389.1385.
4.7. 5,6-Dideoxy-1,2,3,4-di-O-isopropylidene-5-eno-D-
ribo-hexose-S-phenyl-monothiohemiacetal (18)
Treatment of diol 16 (0.232 g, 0.84 mmol) following the
procedure that was described for 17 provided 18 (0.23 g,
82%): Rf = 0.60 (15%, EtOAc/petroleum ether); 1H
NMR (CDCl3): d 1.37, 1.45, 1.52, 1.58 (each 3H, all s,
(CH3)2C · 2), 4.09 (1H, dd, J = 6.0, 8.6 Hz, H-3), 4.17
(1H, dd, J = 4.2, 9.6 Hz, H-2), 4.72 (1H, t, J = 6.2 Hz,
H-4), 5.32 (1H, dt, J = 1.4, 10.5 Hz, H-6), 5.45 (1H,
dt, J = 1.5, 17.2 Hz, H-60), 5.66 (1H, d, J = 4.2 Hz, H-
1), 6.01 (1H, m, H-5), 7.30 (3H, m, Ar–H), 7.51 (2H,
d, J = 7.1 Hz, Ar–H); 13C NMR (CDCl3): d 25.7, 26.9,
28.0, 28.3, 78.7, 79.0, 80.1, 87.7, 109.4, 112.6, 118.4,
127.3, 129.1, 129.2, 131.5, 133.0, 135.3; ESIMS m/z
calcd for C18H24O4NaSSi [M+Na]+: 359.1293. Found:
359.1297.
4.10. 6,7,8-Trideoxy-1,2,3,4-di-O-isopropylidene-5-O-
pivaloyl-8-trimethylsilyl-6(E)-eno-D-gulo-octose-S-phen-
yl-monothiohemiacetal (22) and 1,2,3,4-di-O-isopropylid-
ene-5-O-pivaloyl-6,7,8-trideoxy-8-trimethylsilyl-6(E)-eno-
L-manno-octose-S-phenyl-monothiohemiacetal (23)
Grubbs’ catalyst second generation (39 mg, 0.05 mmol)
in CH2Cl2 (3 mL) was injected at rt into a degassed solu-
tion of a mixture of 19/20 (320 mg, 0.93 mmol) and

S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1329
allyltrimethylsilane (0.89 mL, 10.8 mmol) in CH2Cl2
(10 mL). After 2 h at this temperature, the reaction
was quenched by the addition of DMSO (1 mL), stirred
for an additional 5 h and concentrated in vacuo. The
residue was purified by FCC to afford an approximately
2:1 mixture of products (0.369 g, 95%): Rf = 0.82 (15%,
4.50 (1H, dd, J = 4.3, 8.6 Hz, H-2), 5.45 (1H, dd,
J = 6.3, 15.4 Hz, H-6), 5.62 (1H, d, J = 4.3, H-1), 5.79
(1H, m, H-7), 7.22–7.30 (3H, m, Ar–H), 7.51 (2H, m,
Ar–H); 13C NMR (CDCl3): d ꢀ1.62, 23.3, 25.4, 27.0,
27.7, 28.3, 69.9, 78.4, 79.9, 80.8, 88.3, 109.1, 112.8,
127.4, 128.0, 129.2, 129.9, 131.6, 135.4; ESIMS m/z
calcd for C23H36O5NaSSi [M+Na]+: 451.1974. Found:
451.1955. Treatment of a sample of the material from
the previous step (152 mg, 0.34 mmol) following the
pivaloylation procedure that was used for 22/23 pro-
vided 24 (141 mg, 65%); Rf = 0.84 (15%, EtOAc/petro-
1
EtOAc/petroleum ether); H NMR (CDCl3): d 0.0 (9H,
s, TMS), 1.37, 1.38, 1.39, 1.48, 1.53 (12H, all s,
(CH3)2C · 2), 1.39–1.50 (2H, m buried under singlets,
CH2-8), 2.25 (1H, br m, OH’s), 3.90–4.22 (4H, m, H-
2,3,4,5), 5.35 (1H, m, H-6), 5.55 (0.4H, d, J = 5.3 Hz,
H-1), 5.56 (0.6H, d, J = 5.5 Hz, H-1), 5.75 (1H, m, H-
7), 7.22–7.30 (3H, m, Ar–H), 7.50 (2H, m, Ar–H); 13C
NMR (CDCl3): d 1.68, 1.71, 23.2, 23.3, 26.5, 26.6,
27.2, 27.5, 27.8, 73.0, 73.8, 82.1, 82.3, 86.4, 110.2,
110.4, 112.3, 126.5, 127.1, 127.5, 127.6, 129.2, 131.5,
131.8, 132.0, 134.7; ESIMS m/z calcd for C23H36O5NaS-
Si [M+Na]+: 475.1950. Found: 475.1938. DMAP
(15 mg, 0.12 mmol), pyridine (0.34 mL, 4.2 mmol) and
pivaloyl chloride (0.44 mL, 3.6 mmol) were added to a
solution of the product from the previous step
(269 mg, 0.59 mmol), in dry CH2Cl2 (10 mL). The mix-
ture was stirred at rt for 12 h and then poured into
H2O and extracted with Et2O. The organic phase was
washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. FCC of the residue gave
an approximately 2:1 inseparable mixture of 22/23
(220 mg, 72%): Rf = 0.85 (15%, EtOAc/petroleum
ether); 1H NMR (CDCl3): d 0.0 (9H, s, TMS), 1.21
(9H, s, (CH3)3CCO), 1.39, 1.41, 1.43, 1.44, 1.48, 1.54,
1.56 (12H, all s, (CH3)2C · 2), 1.45–1.52 (2H, m buried
under singlets, CH2-8), 4.00 (0.65H, t, H-2), 4.04
(0.35H, dd, J = 5.5, 6.8 Hz, H-2), 4.19 (2H, m, H-3,4),
5.28–5.39 (2H, m, H-5,6), 5.57 (1H, d, J = 5.2 Hz, H-
1), 5.85 (1H, m, H-7), 7.29 (3H, m, Ar–H), 7.54 (2H,
m, Ar–H); 13C NMR (CDCl3): d ꢀ1.78, 23.4, 23.5,
26.3, 26.6, 27.4, 27.5, 27.6, 27.7, 27.9, 74.0, 74.9, 80.2,
80.8, 82.1, 82.3, 85.9, 86.2, 110.5, 110.6, 112.3, 112.4,
122.4, 123.0, 127.5, 127.6, 129.1, 131.7, 131.8, 134.4,
134.5, 135.1; ESIMS m/z calcd for C28H44O6NaSSi
[M+H]+: 559.2526. Found: 559.2528.
1
leum ether); H NMR (CDCl3): d 0.0 (9H, s, TMS),
1.24 (9H, s, (CH3)3CCO), 1.34, 1.44, 1.53, 1.57 (each
3H, all s, (CH3)2C · 2), 1.47–1.53 (2H, m, buried under
singlets, CH2-8), 4.03 (1H, dd, J = 6.0, 9.3 Hz, H-3),
4.21 (1H, dd, J = 3.1, 6.0 Hz, H-4), 4.26 (1H, dd,
J = 4.2, 9.3 Hz, H-2), 5.42 (1H, m, H-6), 5.55 (1H, dd,
J = 4.0, 7.5 Hz, H-5), 5.62 (1H, d, J = 4.2 Hz, H-1),
5.85 (1H, m, H-7), 7.27 (3H, m, Ar–H), 7.53 (2H, m,
Ar–H); 13C NMR (CDCl3): d 1.77, 23.3, 25.6, 26.9,
27.2, 27.4, 28.4, 39.1, 72.0, 78.2, 79.7, 79.8, 88.4, 109.4,
112.8, 124.1, 127.2, 129.1, 131.5, 132.9, 178.2; ESIMS
m/z 554.2 (M+NH4).
4.12. 6-Deoxy-6-C-ethenyl-1,2,3,4-di-O-isopropylidene-5-
O-pivaloyl-D-myo-inositol (3) and 6-deoxy-6-C-ethenyl-
1,2,3,4-di-O-isopropylidene-5-O-pivaloyl-D-neo-inositol
(4)
A mixture of 22/23 (316 mg, 0.61 mmol), 2,6-di-t-butyl-
4-methylpyridine (1.38 g, 6.70 mmol), and freshly acti-
˚
vated, powdered 4 A molecular sieves (700 mg) in anhy-
drous CH2Cl2 (4 mL), was stirred under an argon
atmosphere for 15 min at rt, then cooled to 0 ꢁC. Methyl
triflate (0.62 mL, 5.5 mmol) was introduced, and the
reaction warmed to rt and stirred for an additional
18 h, at which time Et3N (1 mL) was added. The mixture
was diluted with Et2O, washed with satd aq NaHCO3
and brine, dried (Na2SO4), filtered, and evaporated
zunder reduced pressure. FCC of the residue afforded
3 (79 mg, 41%) and 4 (37 mg, 19%). For 3: Rf = 0.22
(15%, EtOAc/petroleum ether); [a]D ꢀ27.5 (c 1.0,
1
4.11. 6,7,8-Trideoxy-1,2,3,4-di-O-isopropylidene-5-O-
pivaloyl-8-trimethylsilyl-6(E)-eno-L-talo-octose-S-phenyl-
monothiohemiacetal (24)
CHCl3); H NMR (C6D6): d 1.18 (3H, s, (CH3)2C), 1.2
(9H, s, (CH3)3CCO), 1.38, 1.41, 1.45 (each 3H, all s,
(CH3)2C), 2.61 (1H, dt, J = 7.3, 6.3 Hz, H-6), 3.37
(1H, dd, J = 3.1, 10.0 Hz, H-3), 3.80 (1H, dd, J = 5.4,
6.5 Hz, H-1), 4.27 (1H, dd, J = 3.1, 5.2 Hz, H-2), 4.48
(1H, t, J = 9.7 Hz, H-4), 5.50 (1H, br d, J = 10.6 Hz,
H-8), 5.12 (1H, br d, J = 17.1 Hz, H-80), 5.21 (1H, t,
J = 8.9 Hz, H-5), 5.70 (1H, ddd, J = 17.3, 10.3, 7.9 Hz,
H-7); 13C NMR (CDCl3): d 25.4, 26.9, 27.2, 27.3, 27.6,
38.9, 51.2, 72.4, 73.0, 74.6, 75.3, 78.8, 111.4, 111.6,
118.6, 135.9, 177.9; ESIMS m/z calcd for C19H31O6
[M+H]+: 355.21. Found 355.21. For 4: Rf = 0.39
(15%, EtOAc/petroleum ether); [a]D ꢀ6.7 (c 0.2,
Allylic alcohol 21 (63 mg, 0.18 mmol) was subjected to
the metathesis procedure that was used in the prepara-
tion of 22/23. FCC of the crude product afforded the
cross-metathesis product (0.074 g, 90%): Rf = 0.67
(10%, EtOAc/petroleum ether); [a]D +51.2 (c 0.7,
1
CHCl3); H NMR (CDCl3): d 0.0 (9H, s, TMS), 1.32,
1.44, 1.55, 1.57 (each 3H, all s, (CH3)2C · 2), 1.45–1.50
(2H, m buried under singlets, CH2-8), 2.40 (1H, br d,
J = 5.7, OH), 4.03 (1H, dd, J = 6.1, 8.6 Hz, H-3), 4.09
(1H, dd, J = 4.6, 5.9 Hz, H-4), 4.42–4.47 (1H, m, H-5),
1
CHCl3); H NMR (C6D6): d 1.15 (9H, s, (CH3)3CCO),

1330
S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1.23, 1.33, 1.36, 1.45 (each 3H, all s, (CH3)2C · 2), 2.27
(1H, m, H-6), 3.92 (1H, dd, J = 4.6, 8.4 Hz, H-1), 4.01
(1H, dd, J = 1.9, 10.1 Hz, H-4), 4.05 (1H, dd, J = 2.7,
10.1 Hz, H-3), 4.42 (1H, dd, J = 2.7, 4.5 Hz, H-2), 5.09
(1H, dt, J = 1.3, 10.6 Hz, H-8), 5.19 (1H, dt, J = 1.4,
17.4 Hz, H-80), 5.63 (1H, t, J = 2.5 Hz, H-5), 5.71 (1H,
ddd, J = 17.2, 10.6, 6.3 Hz, H-7); 13C NMR (C6D6): d
27.0, 27.5, 27.6, 28.0, 29.1, 39.6, 48.4, 69.4, 73.7, 74.3,
74.4, 79.0, 111.2, 111.9, 117.9, 136.0, 176.8; ESIMS
m/z calcd for C19H31O6 [M+H]+: 355.2121. Found:
355.2119.
appearance of two layers, then extracted with CH2Cl2.
The organic phase was washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced
pressure. The crude material was filtered through a plug
of silica gel, and the filtrate evaporated to dryness. The
residue was dissolved in CH3OH (2 mL) and concen-
trated HCl (0.05 mL) added to the solution. The mixture
was stirred for 6 h, then adjusted to pH 7 by addition of
a solution of NaOCH3 in CH3OH. The solvent was re-
moved in vacuo and pyridine (0.2 mL), EtOAc (2 mL),
Ac2O (0.28 mL, 3 mmol) and DMAP (6 mg, 0.05 mmol)
were added to the residue. The reaction mixture was stir-
red at rt for 12 h, then quenched with CH3OH (0.2 mL)
and concentrated under reduced pressure. The residue
was purified by FCC to afford 25 (40 mg, 86%):
Rf = 0.42 (30%, EtOAc/petroleum ether); [a]D +5.5 (c
4.13. 1-Deoxy-1-C-ethenyl-2,3,4,6-di-O-isopropylidene-6-
O-pivaloyl-D-epi-inositol (5) and 6-deoxy-6-C-ethenyl-1,2,
3,4-di-O-isopropylidene-5-O-pivaloyl-D-allo-inositol (6)
1
Allylsilane 24 (88 mg, 0.17 mmol) was subjected to the
procedure that was used for the preparation of 3 and 4.
FCC of the crude product afforded recovered 24
(10 mg), 5 (40 mg, 74% based on recovered 24) and 6
(12 mg, 22% based on recovered 24). For 5: Rf = 0.59
(15%, EtOAc/petroleum ether); [a]D ꢀ94.0 (c 2.2,
CHCl3); 1H NMR (C6D6): d 1.11 (3H, s, (CH3)2C),
1.18 (9H, s, (CH3)3CCO), 1.30 (3H, s, (CH3)2C), 1.63
(6H, s, (CH3)2C), 1.77 (1H, ddd, J = 3.8, 9.4, 12.7 Hz,
H-1), 3.81–3.86 (2H, m, H-2, H-4), 4.16 (1H, dd,
J = 3.6, 6.8 Hz, H-3), 4.24 (1H, t, J = 7.4 Hz, H-5),
4.98 (1H, dd, J = 2.1, 17.2 Hz, H-8), 5.02 (1H, dd,
J = 2.1, 10.2 Hz, H-80), 5.88 (1H, dd, J = 7.1, 12.4 Hz,
H-6), 6.08 (1H, ddd, J = 2,4, 9.9, 17.2 Hz, H-7); 13C
NMR (C6D6): d 24.7, 26.3, 26.8, 27.1, 27.8, 39.0, 48.4,
71.1, 74.5, 74.5, 76.8, 78.9, 109.7, 111.1, 118.4, 136.1,
177.2; ESIMS m/z calcd for C19H31O6 [M+H]+:
355.2121. Found: 355.2129. For 6: Rf = 0.63 (15%,
3.0, CHCl3); H NMR (C6D6): d 1.61, 1.65, 1.68, 1.72,
1.78 (each 3H, s, CH3CO), 2.93 (1H, dt, J = 11.2,
9.4 Hz, H-6), 4.94 (1H, dd, J = 2.6, 11.5 Hz, H-1), 4.99
(1H, dd, J = 1.5, 10.0 Hz, H-8), 5.06 (1H, dd, J = 1.0,
16.7 Hz, H-80), 5.12 (1H, t, J = 10.3 Hz, H-5), 5.19
(1H, dd, J = 2.8, 10.5 Hz, H-3), 5.52 (1H, ddd,
J = 2.3, 9.7, 17.1 Hz, H-7), 5.80 (1H, t, J = 10.1 Hz,
H-4), 5.87 (1H, t, J = 2.6 Hz, H-2); 13C NMR (C6D6):
d 20.5 (3C), 20.6, 20.7, 47.6, 69.0, 69.9, 70.0, 71.2,
71.4, 120.4, 135.1, 169.2, 169.5, 169.5, 170.0, 170.0;
ESIMS m/z calcd for C18H25O10 [M+H]+: 401.1448.
Found: 401.1443.
4.15. 1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-C-ethenyl-D-
neo-inositol (26)
Treatment of 4 (37 mg, 0.10 mmol) following the identi-
cal three-step procedure that was used for 25 provided
26 (38 mg, 90%): Rf = 0.45 (30%, EtOAc/petroleum
1
EtOAc/petroleum ether) [a]D +32.1 (c 1.0, CHCl3); H
1
NMR (CDCl3): d 1.18 (9H, s, (CH3)3CCO), 1.34, 1.41,
1.52, 1.57 (each 3H, s, (CH3)2C · 2), 2.95 (1H, ddd,
J = 1.5, 6.3, 7.7 Hz, H-6), 4.13 (1H, dd, J = 2.1, 6.9 Hz,
H-4), 4.33 (1H, t, J = 7.4 Hz, H-1), 4.38 (1H, dd,
J = 3.9, 7.2 Hz, H-2), 4.55 (1H, dd, J = 3.9, 6.9 Hz, H-
3), 4.99 (1H, br s, H-5), 5.20 (1H, d, J = 10.5 Hz, H-8),
5.25 (1H, d, J = 16.3 Hz, H-80), 5.83 (1H, ddd, J = 6.4,
10.5, 17.1 Hz, H-7); 13C NMR (CDCl3): d 24.3, 25.5,
26.6, 26.8, 27.3, 39.1, 41.2, 73.3 (2C), 73.4, 74.8, 75.2,
109.8, 110.1, 117.3, 136.8, 177.1; ESIMS m/z calcd for
C19H31O6 [M+H]+: 355.2121. Found: 355.2117.
ether); [a]D ꢀ6.7 (c 0.2, CHCl3); H NMR (C6D6): d
1.54, 1.60, 1.63, 1.72, 1.74 (each 3H, all s, CH3CO),
3.13 (1H, ddd, J = 2.6, 8.0, 11.1 Hz, H-6), 4.89 (1H, d,
J = 17.3 Hz, H-8), 4.9 (1H, d, J = 10.1 Hz, H-80), 5.62
(1H, ddd, J = 7.9, 10.6, 17.2 Hz, H-7), 5.6 (1H, dd,
J = 2.8, 11.7 Hz, H-1), 5.62 (1H, dd, J = 2.9, 10.9 Hz,
H-4), 5.72 (1H, dd, J = 2.9, 10.9 Hz, H-3), 5.79 (1H, t,
J = 2.8 Hz, H-5), 6.12 (1H, t, J = 2.8 Hz, H-2); 13C
NMR (CDCl3): d 20.8, 20.9 (3C), 21.0, 43.0, 67.9,
68.0, 69.6, 69.7, 70.3, 120.1, 132.7, 169.9, 170.0, 170.2
(2C), 170.5; ESIMS m/z calcd for C18H25O10 [M+H]+:
401.1448. Found: 401.1439.
4.14. 1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-C-ethenyl-D-
myo-inositol (25)
4.16. 2,3,4,5,6-Penta-O-acetyl-1-deoxy-1-C-ethenyl-D-
epi-inositol (27)
Compound 3 (37 mg, 0.1 mmol) was dissolved in
CH2Cl2 (2 mL), and DIBALH (0.16 mL, 0.14 mmol)
was added at ꢀ78 ꢁC. The reaction was warmed to rt,
stirred for an additional 3 h at this temperature, then
quenched by the addition of satd aq potassium sodium
tartrate tetrahydrate. The mixture was stirred until the
Treatment of 5 (74 mg, 0.20 mmol) following the identi-
cal three-step procedure that was used for 25 provided
27 (66 mg, 80%): Rf = 0.34 (30%, EtOAc/petroleum
1
ether); [a]D ꢀ8.84 (c 1.9, CHCl3); H NMR (C6D6): d
1.66, 1.68, 1.69 (each 3H, all s, CH3CO), 1.73 (6H, s,

S. Hans, D. R. Mootoo / Carbohydrate Research 341 (2006) 1322–1332
1331
S.; Saito, T.; Iwabuchi, K.; Hamaoka, T.; Inokuchi, J.;
Kosugi, A. J. Biol. Chem. 2003, 278, 5192–51927; (b)
Denny, P. W.; Field, M. C.; Smith, D. F. FEBS Lett. 2001,
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J. Cell. Biol. 1999, 146, 313–320; (d) Ilangumaran, S.;
Arni, S.; van Echten-Deckert, G.; Borisch, B.; Hoessli, D.
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CH3CO), 1.93 (1H, ddd, J = 2.9, 8.5, 11.2 Hz, H-1), 4.84
(1H, t, J = 3.34 Hz, H-5), 4.92 (1H, d, J = 17.2 Hz, H-
8), 4.97 (1H, d, J = 10.3 Hz, H-80), 5.06 (1H, dd,
J = 3.3, 10.3 Hz, H-3), 5.48 (1H, br t, J = 3.3 Hz, H-
6), 5.68 (1H, ddd, J = 8.4, 10.3, 17.3 Hz, H-7), 5.8
(1H, t, J = 10.7 Hz, H-2), 5.84 (1H, br t, J = 3.3 Hz,
H-4); 13C NMR (C6D6): d 20.5, 20.6, 20.7, 20.8, 46.6,
68.2, 68.9, 70.1, 71.2, 71.8, 119.9, 133.6, 169.3, 169.7,
169.8, 169.9, 170.1; ESI HRMS calcd for C18H25O10
[M+H]+: 401.1448. Found: 401.1439.
5. (a) Field, M. C. Glycobiology 1997, 7, 161–168; (b) Larner,
J.; Romero, G.; Kennington, A. S.; Lilley, K.; Kilgour, E.;
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290–294.
4.17. 1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-C-ethenyl-D-
allo-inositol (28)
6. Vickerman, K.; Luckins, A. G. Nature 1969, 224, 1125–
1127.
Treatment of 6 (19 mg, 0.05 mmol) following the identi-
cal three-step procedure that was used for 25 provided
28 (18 mg, 86%): Rf = 0.32 (30%, EtOAc/petroleum
ether); [a]D +1.9 (c 1.2, CHCl3); 1H NMR (3% v/v
CDCl3/C6D6): d 1.58, 1.73, 1.74, 1.74, 1.79 (each 3H,
all s, CH3CO), 3.16 (1H, m, H-6), 5.03 (1H, dt,
J = 1.1, 10.5 Hz, H-8), 5.11 (1H, dt, J = 1.2, 17.3 Hz,
H-80), 5.38 (1H, t, J = 3.4 Hz, H-3), 5.41 (1H, dd,
J = 3.6, 5.0 Hz, H-5), 5.46–5.51 (2H, m, H-1, H-4),
5.60 (1H, ddd, J = 7.9, 10.5, 17.3 Hz, H-7), 5.69 (1H,
br t, J = 3.4 Hz, H-2); 13C NMR (3% v/v CDCl3/
C6D6): d 20.3, 20.6, 20.7 (2C), 20.8, 41.5, 67.9, 68.1
(2C), 69.2, 71.3, 120.0, 133.6, 169.2, 169.4, 169.6,
169.8, 170.0; ESIMS m/z calcd for C18H25O10
[M+H]+: 401.1448. Found: 401.1435.
7. Smith, T. K.; Crossman, A.; Brimacombe, J. S.; Ferguson,
M. A. EMBO J. 2004, 23, 4701–4708.
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Acknowledgments
This investigation was supported by Grant R01
GM57865 from the National Institutes of Health
(NIH). ‘Research Centers in Minority Institutions’
award RR-03037 from the National Center for Research
Resources of the NIH, which supports the infrastructure
and instrumentation of the Chemistry Department at
Hunter College, is also acknowledged.
Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-
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VCH: Weinheim, 2000; pp 495–530; (d) Jimenez-Barbero,
J.; Espinosa, J. F.; Asensio, J. L.; Canada, F. J. Adv.
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J.; Potter, B. V. L. Bioorg. Med. Chem. Lett. 1996, 6,
2197–2200; (b) Sun, H.; Reddy, G. B.; George, C.;
Meuillet, E. J.; Berggren, M.; Powis, G.; Kozikowski, A.
P. Tetrahedron Lett. 2002, 43, 2835–2838.
13. (a) Kan, T.; Nara, S.; Ozawa, T.; Shirahama, H.;
Matsuda, F. Angew. Chem., Int. Ed. 2000, 39, 355–357;
(b) Kan, T.; Hosokawa, S.; Nara, S.; Tamiya, H.;
Shirahama, H.; Matsuda, F. J. Org. Chem. 2004, 69,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2006.04.026.
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