Resolution of orthogonally protected myo-inositols with Novozym 435 providing an enantioconvergent pathway to Ac2PIM1

Article abstract of DOI:10.1021/jo5019188

Orthogonally protected chiral myo-inositol derivatives are important intermediates for higher order myo-inositol-containing compounds. Here, the use of the immobilized enzyme Novozym 435 to efficiently catalyze the acetylation of the 5R configured enantio

Full text of DOI:10.1021/jo5019188

Article
pubs.acs.org/joc
Resolution of Orthogonally Protected myo-Inositols with Novozym
435 Providing an Enantioconvergent Pathway to Ac2PIM1
Alastair M. M. Lee,† Gavin F. Painter,‡ Benjamin J. Compton,*,‡ and David S. Larsen*,†
†Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand
‡Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand
S
* Supporting Information
ABSTRACT: Orthogonally protected chiral myo-inositol
derivatives are important intermediates for higher order myo-
inositol-containing compounds. Here, the use of the
immobilized enzyme Novozym 435 to efficiently catalyze the
acetylation of the 5R configured enantiomer of racemic 1,2-O-
isopropylidene-myo-inositols possessing chemically and steri-
cally diverse protecting groups at O-3 and O-6 is described.
The resolutions were successful with allyl, benzyl, 4-bromo-, 4-
methoxy-, 4-nitro-, and 4-(3,4-dimethoxyphenyl)benzyl, prop-
yl, and propargyl protection at O-6 in combination with either
allyl or benzyl groups at O-3. Bulky protecting groups slow the rate of acetylation. No reaction was observed for 3,6-di-O-
triisopropylsilyl-1,2-O-isopropylidene-myo-inositol. The utility of this methodology was demonstrated by the first reported
synthesis of an Ac2PIM1 (9), which used both enantiomers of the resolved 3-O-allyl-6-O-benzyl-1,2-O-isopropylidene-myo-
inositol in a convergent synthesis.
that only one stereoisomer is useful and half of a valuable
intermediate is generally wasted. More recently, the use of
immobilized lipases that effect a kinetic resolution of racemic
myo-inositol derivatives have been reported. Simas et al.10,11
demonstrated the kinetic resolution of ( )-1,2-O-isopropyli-
dene-3,6-di-O-benzyl-myo-inositol (1) with ethyl acetate using
the immobilized enzyme Candida antarctica lipase B (Novozym
435), which gave acetate (−)-2 in 34% yield with an ee of 99%
(Scheme 1). The starting material was recovered enriched in
enantiomer (+)-1. The use of vinyl acetate as the acetylating
reagent increased the conversion to 49%.
INTRODUCTION
■
Phosphatidylinositol phosphates (PIPs),1 glycophosphatidyl-
inositols (GPIs),2 phosphatidylinositol mannosides (PIMs),
and lipomannans (LMs)3 are examples of synthetically
accessible classes of cell membrane anchors and signaling
molecules that have significant roles in various biological
processes. The structural complexity and diversity of these
inositol-containing (glyco-)phospholipids makes the isolation
of discrete compounds from cell wall extracts for biological
evaluation difficult. Chemical synthesis4 has provided a
solution, but there are still synthetic challenges that need to
be overcome to access these molecules. Many of the syntheses
that have been reported to date use various strategies that start
with the achiral cyclitol myo-inositol and involve a desymmet-
rization step to access an enantiomerically enriched or pure
intermediate. An enantiodivergent approach reported by Miller
et al.5 utilizes a peptide-catalyzed phosphorylation of meso-
configured inositols for the syntheses of 1D- and 3D-myo-
inositol phosphates. However, approaches that have proven to
be the most used are where the reactions of myo-inositol or
protected myo-inositols with chiral auxilaries such as L-
camphor,6 (R)- and (S)-mandelic acid,7 or L-menthyl
derivatives8 lead to diastereoisomers that can be separated by
either chromatography or crystallization. Subsequent removal
of the chiral auxiliary provides the homochiral inositol fit for
derivatization. For targets containing carbohydrate groups
glycosylation results in the formation of diastereoisomeric
mixtures that are generally separated by chromatography.9 The
latter has the advantage that the chiral derivatizing agent is also
a component of the target. Both approaches suffer from the fact
Scheme 1. Kinetic Resolution by Simas et al.10,11
Further to this work Simas et al.12 reported the kinetic
resolution of ( )-1,3,4-tri-O-benzyl-myo-inositol using Novo-
zym 435 and vinyl acetate. The conversion into (−)-5-O-acetyl-
1,3,6-tri-O-benzyl-L-myo-inositol was in 43% yield with an ee of
98%. In a similar fashion ( )-4,6-di-O-benzyl-myo-inositol was
successfully resolved using Lipozyme TL-IM.13
Received: August 18, 2014
© XXXX American Chemical Society
A
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a
Scheme 2. General Synthesis of Enzyme Substrates
a
Protecting groups R1 and R2 are given in Table 1.
Despite the success of such lipase-catalyzed resolutions, there
are relatively few examples where this methodology has been
used for the syntheses of lipidated inositols. The advantages of
a chemoenzymatic approach over a chemical resolution are that
the desymmetrization reaction is catalytic and applicable to
scale-up and the immobilized enzyme provides easily separable
single enantiomers of myo-inositol precursors efficiently and
economically. However, the immobilized lipase-catalyzed
kinetic resolution of racemic myo-inositol derivatives that
have a high degree of orthogonal protection, suitable for the
synthesis of complex molecules such as GPIs and PIMs, has yet
to be explored. Herein, we report our investigation into the
Novozym 435 catalyzed kinetic resolution of racemic 1,2-O-
isopropylidene-myo-inositols possessing different protecting
groups at the O-3 and O-6 positions to determine the scope
and limitations of this methodology. Furthermore, we then
demonstrate their use by the first total synthesis of
mycobacterial cell wall component Ac2PIM1.
presence of tetrabutylammonium iodide (TBAI) to give
( )-5d, while the p-nitrobenzyl (PNB) protecting group in
( )-5h was incorporated using a Ag2O-promoted alkylation
with 4-nitrobenzyl bromide in CH2Cl2. The 3,6-di-O-propyl
intermediate ( )-5i was prepared by catalytic hydrogenation of
( )-5a, and 3,6-di-O-triisopropylsilyl-1,2-O-isopropylidene-
myo-inositol (( )-5j) was synthesized by reaction of ( )-3
with triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) and
triethylamine. The more labile 4,5-trans-fused isopropylidene
group in intermediates ( )-5a−j was selectively hydrolyzed
with TFA in CH2Cl2 at 0 °C, affording substrates ( )-6a−j fit
for enzymatic resolution.
The kinetic resolutions of ( )-6a−j were carried out with
vinyl acetate, as both reactant and solvent, and Novozym 435 at
30 °C for 24 h. The results are shown in Table 1. The
Table 1. Desymmetrization of Substituted myo-Inositols with
Novozym 435
RESULTS AND DISCUSSION
■
A range of O-3 and O-6 protected 1,2-O-isopropylidene-myo-
inositols were synthesized from ( )-1,2:4,5-di-O-isopropyli-
dene-myo-inositol (( )-3), as shown in Scheme 2, to evaluate
whether steric or electronic factors influence the reactivity of
these molecules with the enzyme. The only examples utilizing
Novozym 435 for the kinetic resolution of myo-inositol
derivatives contain benzyl protection at O-4/O-6, adjacent to
the acylation site. We proposed to explore alternative groups
that include substituted aromatic, aliphatic, and sterically
demanding silyl groups which are orthogonal to those at O-
1/O-3 as well as the acetal protecting group. Also reported are
a propargyl and p-bromobenzyl (PBB) group which can be
further modified for the attachment of fluorescent probes or
biologically active cargo.
The synthesis started with selective alkylation at the less
hindered C-3 hydroxyl group of ( )-3,14 with sodium hydride
(NaH) and either allyl or benzyl bromide providing the allyl
and benzyl ethers ( )-4a and ( )-4b, respectively. A small
amount (10%) of the bis-allyl ether ( )-5a was recovered from
the former reaction. The reaction of ( )-4b with NaH and allyl
bromide gave ( )-5b in good yield. Protection of the C-6
hydroxyl group of 3-O-allyl-1,2:4,5-di-O-isopropylidene-myo-
inositol (( )-4a) gave the further six intermediates ( )-5c−h.
The aromatic protecting groups of benzyl ( )-5c, p-
methoxybenzyl (PMB) ( )-5e, p-(3,4-dimethoxyphenyl)benzyl
(DMPB) ( )-5f, and PBB ( )-5g were installed using NaH
and the requisite alkyl bromide. Installation of the propargyl
moiety was achieved with NaH and propargyl chloride in the
ee (%)
a
entry reactant
R1
All
R2
(−)-6 (+)-6 conversn (%)
1
( )-6a
( )-6b
( )-6c
( )-6d
( )-6e
( )-6f
( )-6g
( )-6h
( )-6i
( )-6j
All
All
Bn
>98
>98
>98
>98
>98
>98
98
>98
>98
>98
>98
98
49
50
50
50
49
24
44
44
50
0
2
Bn
All
All
All
All
All
All
Pr
3
4
propargyl
PMB
DMPB
PBB
5
6
42
7
86
8
PNB
>98
>98
N/A
86
9
Pr
>98
N/A
10
TIPS
TIPS
a
1
Based on the H NMR spectra (500 MHz, CDCl3).
conversions were determined by integration of relevant proton
signals in the 1H NMR spectra of the aforementioned reaction.
To assess the enantiomeric excess of each product, isolated
inositol acetates (−)-7 were converted into inositols (−)-6 and
analyzed by chiral HPLC using a charged aerosol detector
(CAD) (see Figure 1 for a representative example). Pleasingly,
Novozym 435 converted the di-O-allyl-protected substrate
( )-6a into the monoacetate (−)-7a in a 46% isolated yield
B
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rotation, [α]D20 = −1.5° (c 1.1, CHCl3) (lit.16 [α]D20 = −2.3° (c
1, CHCl3)).
The relative ease of this methodology in successfully
resolving myo-inositols prompted us to utilize it in the first
synthesis of the complex mycobacterial cell wall phospholipid,
Ac2PIM1 (9). McConville et al. and Besra et al.18 have found
that Ac1PIM1, which is acylated at O-6′ of the mannosyl
residue, is a biosynthetic precursor of the more abundant
Ac1PIM2s. Access to highly lipidated Ac2PIM1, which is further
acylated at O-3 of the inositol, might be useful to determine if
these molecules are part of the biosynthetic pathway to higher
order Ac2PIMs. A retrosynthetic analysis of Ac2PIM1 (9)
showed that it could be accessed via an enantioconvergent
synthesis from both components of the resolution of ( )-6c,
i.e. (−)-7c and (+)-6c, both of which were available in gram
quantities (Scheme 4). Routine manipulation of the protecting
groups of each would provide the enantiomeric inositols 10a,b,
which would serve as precursors to the key intermediate 11.
The choice of DMPB as a protecting group was made on the
basis that it is orthogonal to both benzyl and allyl groups and is
stable to reaction conditions required for mannosylation and
phosphatidylation.4b,15
Figure 1. Chiral HPLC analysis of the resolution of 6e using a (R,R)-
Whelk-O 1 column (5 μm; 100 Å, 4.6 × 250 mm) with a 94/6
hexane/2-propanol mixture (1.5 mL/min) as the mobile phase at 40
°C.
with an ee of >98% (entry 1). Unreacted (+)-6a was recovered
in 41% yield with >98% ee. The orthogonally protected benzyl
allyl ethers ( )-6b,c resulted in efficient kinetic resolutions,
with the corresponding acetates being isolated in high yields
and ee values (entries 2 and 3). Both electron-withdrawing and
-donating substituents on the 4-O-benzyl protecting group were
well tolerated (entries 5 and 8), with acetate (−)-7e being
isolated in 45% yield with 98% ee and recovered 6e isolated in
48% yield (ee > 98%). The resolution of inositols 6d,g,
containing groups that could be modified by either copper-
catalyzed azide−alkyne cycloaddition (CuAAC) or cross-
coupling reactions, gave high conversions to the monoacetates
7d,g with high ee’s (entries 4 and 7). Unfortunately, the ee of
6d was unable to be determined directly by chiral HPLC using
either a Regis (R,R)-Whelk-O 1 or Chiracel OD-H column.
Instead, both (−)-6d and (+)-6d were subjected to hydro-
genation conditions and analyzed as the corresponding propyl
ether derivatives. Unsaturation in the protecting group at O-6
was not essential, as resolution of di-O-propyl ether ( )-6i gave
(−)-7i and recovered (+)-6i in both high yield and high ee
(entry 9). The reaction of the bulkier DMPB-protected15
inositol ( )-6f was slow, culminating in the acetate 7f being
isolated in 18% yield (ee >98%). To further probe the extent of
steric constraint tolerated by the enzyme, inositol ( )-6j with
the bulky TIPS protecting groups at O-4 and O-6 was subjected
to the reaction conditions and unsurprisingly remained
unreactive with no evidence of acylation by 1H NMR
spectroscopy.
The forward synthesis of intermediate 11 from (−)-7c
started with removal of the acetate to give (−)-6c and then
benzylation to afford tri-O-benzyl ether 12 (Scheme 5). Acidic
hydrolysis of the isopropylidene group gave diol 13, which was
selectively protected at O-3 via a stannylene acetal to give the
protected inositol 14. Mannosylation with the orthogonally
protected mannosyl trichloroacetimidate donor 15 gave
pseudodisaccharide 16 in an excellent yield of 92%. Zemplen
́
deprotection of the O-2′ benzoate via 17 followed by
benzylation afforded 18 in 93% yield for the two steps. Acidic
methanolysis of the O-6′ silyl protecting group and acylation
with palmitic acid gave the O-6′ palmitate 20 in 71% yield over
the two steps. Deprotection of the DMPB ether was achieved
by treatment with TFA and cation scavenger 3,4-
(methylenedioxy)toluene15 to give alcohol 21 in good yield.
Esterification of the C-3 hydroxyl group with stearic acid gave
allyl-inositol 22, which upon treatment with a catalytic amount
of hydrogen-activated (1,5-cyclooctadiene)bis-
(methyldiphenylphosphine)iridium(I) hexafluorophosphate
followed by an oxymercuration protocol provided key
intermediate 11 in 18% overall yield for the 12 steps from
(−)-7c.
Replacing inositol (−)-6c with its enantiomer (+)-6c, which
was isolated in 49% yield (ee > 98%) from ( )-6c, in the
synthesis would produce a series of intermediates where the O-
1 and O-3 protecting groups are interchanged. Reversing the
order of removal of the DMPB and allyl protecting groups
should converge to give key intermediate 11, as shown in
Scheme 6. Inositol (+)-6c was benzylated, and the acetal
protecting group was hydrolyzed to give the diol ent-13.
Stannylene acetal mediated alkylation of O-1 with DMPBBr
provided ent-14 in moderate yield (71%) which, upon
glycosylation with either mannosyl donor 15 or 23,4b gave
pseudodisaccharide 24, both in good yield. Protecting group
manipulation followed by acylation afforded palmitate 27.
Deallylation, acylation, and hydrolysis of the DMPB ether, all
under the same conditions used in Scheme 5, gave
pseudodisaccharide 11. Spectroscopic and optical data of 11
were consistent with those from those for the preparation from
(−)-7c. The overall yield for the 11-step sequence from (+)-6c
was 24%.
To unequivocally prove that we had correctly identified the
absolute stereochemistry of inositols (−)-7a−i, we embarked
on a synthesis that converted (+)-6c into the known inositol 8
(Scheme 3). Removal of the isopropylidene group of (+)-6c
followed by global benzylation gave inositol (−)-8. The 1H and
13C NMR spectra of the key intermediate 8 matched those
reported by Aneja et al.16 and Elie et al.,17 as did the specific
Scheme 3. Synthesis of Known Intermediate 8
C
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Scheme 4. Retrosynthetic Analysis of Ac2PIM1 (9)
a
Scheme 5. Synthesis of Common Intermediate 11 from Acetylated Inositol (−)-7c
a
Reagents and conditions: (a) IRA-400 (OH−), MeOH, room temperature, 94%; (b) NaH, BnBr, DMF, room temperature, 97%; (c) TFA, MeOH,
n
CH2Cl2, room temperature. 93%; (d) Bu2SnO, toluene, reflux; (e) CsF, 4-(3,4-dimethoxyphenyl)benzyl bromide (DMPBBr), DMF, 50 °C, 69%;
(f) TMSOTf, 15, toluene, −78 °C, 92%; (g) NaOMe, MeOH, room temperature, 98%; (h) NaH, BnBr, DMF, room temperature, 94%; (i) AcCl,
CH2Cl2, MeOH, room temperature, 89%; (j) C15H31COOH, DMAP, DCC, CH2Cl2, room temperature, 80%; (k) TFA, 3,4-(methylenedioxy)-
toluene, CH2Cl2, room temperature, 83%; (l) C17H35COOH, DMAP, DCC, CH2Cl2, room temperature. 83%; (m) (COD)(MePPh2)IrPF6, H2,
THF, room temperature; (n) HgO, HgCl2, acetone, H2O, 100 °C, 71%.
Phosphatidylation of 11 was achieved using H-phosphonate
304b,c and gave, after oxidation with iodine in pyridine, the
protected PIM 31 in 87% yield (Scheme 7). After the
triethylammoniun cation was exchanged for sodium, global
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a
Scheme 6. Synthesis of Common Intermediate 11 from Inositol (+)-6c
a
n
Reagents and conditions: (a) NaH, BnBr, DMF, room temperature, 99%; (b) TFA, MeOH, CH2Cl2, room temperature, 81%; (c) Bu2SnO,
toluene, relux, (d) CsF, DMPBBr, DMF; 50 °C, 71%; (e) either TMSOTf, 15, toluene, 0 °C, 72%, or TBSOTf, 23, toluene, −78 °C, 88%; (f)
NaOMe, MeOH, room temperature, 81%; (g) NaH, BnBr, DMF, room temperature, 96%; (h) AcCl, CH2Cl2, MeOH, room temperature, 99%; (i)
C15H31COOH DMAP, DCC, CH2Cl2, room temperature, 99%; (j) (COD)(MePPh2)IrPF6, H2, THF, room temperature; (k) HgO, HgCl2, acetone,
H2O, 100 °C, 92%; (l) C17H35COOH, DMAP, DCC, CH2Cl2, room temperature; 93%; (m) TFA, 3,4-(methylenedioxy)toluene, CH2Cl2, room
temperature, 76%.
Scheme 7. Synthesis of Ac2PIM1 (9) from Common
Intermediate 11
However, bulky protecting groups slow the rate of acetylation.
No reaction was observed for substrate ( )-6j, possessing
triisopropylsilyl ethers at O-3 and O-6. The utility of this
methodology was demonstrated by the first reported synthesis
of an Ac2PIM1, which used both components of the resolution
in a synthesis which converged at pseudodisaccharide 11.
Manipulation of the protecting groups of (−)-7c and (+)-6c,
from the resolution of ( )-6c, gave orthogonally protected
inositol 14 and ent-14, both of which were transformed into the
key intermediate, pseudodisaccharide 11. Phosphatidylation
and global hydrogenolysis of the benzyl groups afforded
Ac2PIM1 (9).
a
a
Reagents and conditions: (a) 30, py, PivCl, room temperature; (b) I2,
py, H2O, TEAB; room temperature. 87%; (c) DOWEX 50WX8-200
(Na+), CHCl3, MeOH, room temperature; (d) Pd/C, H2, CH2Cl2,
MeOH, room temperature. 98%.
EXPERIMENTAL SECTION
■
General Experimental Considerations. Anhydrous solvents
were sourced commercially and used without further treatment unless
stated otherwise. Flash column chromatography was performed on
silica cartridges (40 μm) or silica gel (40−63 μm). All flash
chromatography solvents were AR grade. Petroleum ether used was
either bp 40−60 or 60−80 °C range. All compounds were isolated
after silica gel column chromatography, and fractions collected were
one spot by thin-layer chromatography (TLC). TLC was performed
on aluminum sheets coated with 60 F254 silica and were visualized
under an UV lamp and/or with Hanessian’s stain with subsequent
charring. Specific optical rotations were measured at ambient
temperature, unless otherwise stated, using a polarimeter with a cell
of path length 1.0 dm at the wavelength and concentration (g/100
hydrogenolysis of the benzyl protecting groups gave the target
compound (16:0,18:0)(19:0,16:0)PIM1 as its sodium salt 9 in
98% yield.
In conclusion, we have shown that the Novozym 435
efficiently catalyzes the acetylation of racemic 1,2-O-isopropy-
lidene-myo-inositols bearing a range of protecting groups at O-3
and O-6, resulting in the formation of readily separable
compounds. In general, the conversions are high, as are the ee
values of the resolved products. Alkyl, alkenyl, alkynyl, and
aromatic groups with either electron-withdrawing or -donating
groups at O-3 are tolerated as substrates by the enzyme.
1
mL) and in the solvent indicated. H NMR spectra were obtained at
E
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500 MHz and were referenced to tetramethylsilane at 0 ppm (internal
standard) or to the residual solvent peak (CHCl3 7.26 ppm, CHD2OD
3.31 ppm). 13C NMR spectra were recorded at 126 MHz and
referenced to tetramethylsilane at 0 ppm (internal standard) or to the
deuterated solvent peak (CDCl3 77.0 ppm, CD3OD 49.0 ppm).
CDCl3−CD3OD solvent mixtures were always referenced to the
methanol peak. 31P NMR spectra were recorded at 202 MHz with
H3PO4 (δ 0.0 ppm) as the external reference. High-resolution
electrospray ionization (ESI) mass spectra were recorded on Q-TOF
mass spectrometers. Analytical chiral HPLC data were obtained with a
charged aerosol detector (CAD) using a (R,R)-Whelk-O 1 column (5
μm; 100 Å, 4.6 × 250 mm) eluted with a 94/6 hexane/2-propanol
mixture (1.5 mL/min) at 40 °C, except for compound ( )-6f, which
was eluted with a 70/30 hexane/2-propanol mixture. Melting points
were determined using a automatic melting point apparatus and are
uncorrected. Infrared spectra (IR) were recorded on FT-IR
spectrometers (with a diamond attenuated total reflectance (ATR)
top plate). The error on the quoted values for microanalyses is 0.3%.
hydride (60% in oil, 33 mg, 1.4 mmol mmol) were added with stirring
to a solution of benzyl ether ( )-4b (195 mg, 0.56 mmol) in dry DMF
(5 mL) at 0 °C under nitrogen. The reaction mixture was stirred
overnight at room temperature. The reaction mixture was quenched
with water, diluted with EtOAc, and washed with water and then brine.
The organic phase was dried and evaporated. The residue was purified
by column chromatography (PE to EtOAc/PE 1/4) to give the title
compound ( )-5b (135 mg, 62%) as a white solid: νmax (cm−1) 2984,
1
2933, 745, 697; H NMR (500 MHz, CDCl3) δ 7.46−7.27 (5H, m),
5.93 (1H, ddt, J = 17.1, 10.4, 5.8 Hz), 5.31 (1H, dq, J = 17.2, 1.7 Hz),
5.20−5.14 (1H, m), 4.92−4.76 (2H, m), 4.33−4.29 (1H, m), 4.26
(2H, dt, J = 5.7, 1.4 Hz), 4.07−3.98 (2H, m), 3.74 (1H, dd, J = 10.2,
4.3 Hz), 3.65 (1H, dd, J = 10.7, 6.3 Hz), 3.29 (1H, dd, J = 10.7, 9.5
Hz), 1.54 (3H, s), 1.48 (3H, s), 1.44 (3H, s), 1.33 ppm (1H, s); 13C
NMR (126 MHz, CDCl3) δ137.97, 134.81, 128.39, 128.32, 127.84,
117.25, 112.11, 109.92, 81.36, 80.15, 78.62, 77.07, 76.80, 74.47, 71.89,
71.23, 28.07, 27.04, 27.02, 25.90 ppm; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C22H30O6Na 413.1940, found 413.1940.
(
)-1-O-Allyl-2,3:5,6-di-O-isopropylidene-myo-inositol
(
)-1-O-Allyl-4-O-benzyl-2,3:5,6-di-O-isopropylidene-myo-
(( )-4a). Allyl bromide (1.0 mL, 12 mmol) and then sodium hydride
(60% in oil, 0.7 g, 29 mmol) were added to a solution of diol 3 (2.486
g, 8.40 mmol) in dry THF (150 mL) at 0 °C under nitrogen. The
reaction mixture was heated for 6 h under reflux. The reaction mixture
was quenched with water, extracted into EtOAc, and washed with
water and then brine, and the organic phase was dried and evaporated.
The crude product was purified using column chromatography
(EtOAc/PE, 1/2 to 2/1) to give the title compound ( )-4a19
(1.721 g, 68%) and ( )-1,4-di-O-allyl-2,3:5,6-di-O-isopropylidene-
myo-inositol ( )-5a19 (0.277 g, 10%), both as white solids.
inositol (( )-5c). Using the procedure for the preparation of ( )-5b,
the reaction of allyl ether ( )-4a (1.858 g, 6.18 mmol), sodium
hydride (60% in oil, 0.37 g, 15.5 mmol), and benzyl bromide (1.1 mL,
9.28 mmol) gave after purification by column chromatography
(EtOAc/PE, 1/2) the title compound ( )-5c (2.366 g, 98%) as a
white solid: mp 121−122 °C (lit.20 mp 122−123 °C); νmax (cm−1)
2986, 1216, 868, 738, 695; 1H NMR (500 MHz, CDCl3) δ 7.39−7.37
(2H, m), 7.34−7.29 (2H, m), 7.26−7.22 (1H, m), 5.96 (1H, dddd, J =
22.7, 10.3, 6.5, 5.5 Hz), 5.29 (1H, ddd, J = 17.2, 3.0, 1.6 Hz), 5.20 (1H,
ddd, J = 10.3, 3.0, 1.3 Hz), 4.81 (2H, m), 4.47−4.41 (1H, m), 4.33−
4.28 (1H, m), 4.24−4.19 (1H, m), 4.12 (1H, dd, J = 6.5, 5.0 Hz),
3.98−3.90 (1H, m), 3.78 (1H, dd, J = 10.2, 4.2 Hz), 3.66 (1H, dd, J =
10.6, 6.6 Hz), 3.37 (1H, dd, J = 10.6, 9.4 Hz), 1.44 (3H, s), 1.43 (3H,
s), 1.37 (3H, s), 1.34 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
138.46, 134.91, 128.41, 128.19, 127.69, 118.34, 112.34, 110.22, 81.39,
80.18, 79.07, 77.15, 76.60, 74.96, 72.26, 71.37, 28.14, 27.27, 27.21,
26.18 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C22H30O6
413.1921, found m/z 413.1914. Anal. Calcd for C22H30O6: C, 67.67;
H, 7.74. Found: C, 67.85: H 7.81.
Data for ( )-4a: νmax (cm−1) 3509, 2982, 1644, 1213, 1003, 867;
1H NMR (500 MHz, CDCl3) δ 5.96 (1H, dddd, J = 17.1, 10.4, 6.6, 5.5
Hz), 5.30 (1H, ddd, J = 17.2, 3.1, 1.5 Hz), 5.22 (1H, ddd, J = 10.3, 3.0,
1.2 Hz), 4.46 (1H, t, J = 4.6 Hz), 4.31 (1H, ddt, J = 12.9, 5.5, 1.4 Hz),
4.22 (1H, ddt, J = 12.9, 6.6, 1.2 Hz), 4.00 (1H, dd, J = 6.5, 4.8 Hz),
3.96 (1H, dd, J = 9.5 Hz), 3.88 (1H, ddd, J = 10.6, 6.7, 2.8 Hz), 3.82
(1H, dd, J = 10.1, 4.2 Hz), 3.29 (1H, dd, J = 10.7, 9.3 Hz), 2.42 (1H, d,
J = 2.9 Hz), 1.53 (3H, s), 1.45 (3H, s), 1.43 (3H, s), 1.37 ppm (3H, s);
13C NMR (126 MHz, CDCl3) δ 134.81, 118.45, 112.70, 110.51, 81.92,
78.51, 77.32, 76.54, 75.02, 74.78, 71.41, 28.45, 27.18, 27.12, 26.14
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H24O6Na
323.1471, found 323.1465. Anal. Calcd for C15H24O6: C, 59.98; H,
8.05. Found: C, 60.11; H, 8.17.
(
)-1-O-Allyl-2,3;5,6-di-O-isopropylidene-4-O-propargyl-
myo-inositol (( )-5d). Using the procedure for the preparation of
( )-5b, the reaction of allyl ether ( )-4a (155 mg, 0.52 mmol),
sodium hydride (60% in oil, 40 mg, 1.7 mmol), propargyl chloride
(70% in toluene, 115 μL, 104 mmol), and tetra-n-butylammonium
iodide (10 mg, 0.03 mmol) in DMF (5 mL) gave after purification of
the crude product by column chromatography (PE to EtOAc/PE, 1/
4) the title compound ( )-5d (163 mg, 93%) as a white solid: νmax
1
Data for ( )-5a: H NMR (500 MHz, CDCl3) δ 6.04−5.88 (2H,
m), 5.34 (1H, dq, J = 3.4, 1.6 Hz), 5.30 (1H, dq, J = 3.5, 1.7 Hz),
5.24−5.17 (2H, m), 4.48−4.45 (1H, m), 4.35−4.21 (4H, m), 4.09
(1H, dd, J = 6.5, 5.2 Hz), 4.00−3.95 (1H, m), 3.79 (1H, dd, J = 10.2,
4.3 Hz), 3.66 (1H, dd, J = 10.6, 6.5 Hz), 3.33 (1H, dd, J = 10.4, 9.5
Hz), 1.54 (3H, s), 1.45 (3H, s), 1.43 (3H, s), 1.38 ppm (3H, s); 13C
NMR (126 MHz, CDCl3) δ 134.80, 134.71, 118.06, 117.28, 112.09,
109.97, 81.42, 80.18, 78.60, 76.86, 76.47, 74.82, 71.27, 71.16, 28.07,
27.02, 26.96, 25.92 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C18H28O6Na 363.1778, found 363.1779.
(cm−1) 3245, 2984, 2935; H NMR (500 MHz, CDCl3) δ 6.01−5.93
1
(1H, m), 5.32 (1H, dq, J = 17.3, 1.7 Hz), 5.24−5.21 (1H, m), 4.48−
4.45 (1H, m), 4.45−4.43 (2H, m), 4.36−4.21 (2H, m), 4.08 (1H, ddd,
J = 6.5, 5.0, 1.7 Hz), 4.00 (1H, td, J = 9.8, 1.9 Hz), 3.85 (1H, ddd, J =
10.7, 6.6, 1.9 Hz), 3.80 (1H, ddd, J = 10.2, 4.2, 1.7 Hz), 3.35−3.30
(1H, m), 2.43 (1H, td, J = 2.4, 1.1 Hz), 1.58 (3H, s), 1.46 (11H, s),
1.43 (11H, s), 1.38 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
134.67, 118.11, 112.35, 110.14, 80.79, 79.74, 79.39, 78.20, 77.02,
76.52, 74.73, 74.62, 71.19, 57.64, 28.03, 26.98, 26.92, 25.93 ppm;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H26O6Na 361.1627,
found 361.1618.
(
)-1-O-Benzyl-2,3:5,6-di-O-isopropylidene-myo-inositol
(( )-4b). Using the procedure for the synthesis of ( )-4a, the reaction
of benzyl bromide (0.460 mL, 3.88 mmol), sodium hydride (60% in
oil, 0.184 g, 7.68 mmol), and ( )-3 (1.000 g, 3.84 mmol) in dry THF
(50 mL) gave after purification by column chromatography (EtOAc/
PE, 1/2 to 2/1) the title compound ( )-4b19 (0.915 g, 68%) as a
white solid: 1H NMR (500 MHz, CDCl3) δ 7.46−7.27 (5H, m), 4.90
(1H, d, J = 12.6 Hz), 4.79 (1H, d, J = 12.6 Hz), 4.32 (1H, t, J = 4.4
Hz), 4.11−3.99 (1H, m), 3.97−3.84 (2H, m), 3.79 (1H, dd, J = 10.2,
4.2 Hz), 3.26 (1H, dd, J = 10.4, 9.4 Hz), 2.38 (1H, d, J = 2.8 Hz), 1.55
(3H, s), 1.49 (3H, s), 1.46 (3H, s), 1.34 ppm (3H, s); 13C NMR (126
MHz, CDCl3) δ 137.87, 128.42, 128.34, 127.90, 112.50, 110.23, 81.68,
78.36, 77.31, 76.68, 74.58, 74.47, 71.90, 28.23, 26.98, 26.95, 25.89
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26O6Na
373.1627, found 373.1617.
(
)-1-O-Allyl-2,3:5,6-di-O-isopropylidene-4-O-p-methoxy-
benzyl-myo-inositol (( )-5e). Using the procedure for the
preparation of ( )-5b, the reaction of allyl ether ( )-4a (145 mg,
0.48 mmol), sodium hydride (60% in oil, 29 mg, 1.2 mmol), and p-
methoxybenzyl bromide (80 μL, 0.59 mmol) in DMF (5 mL) gave
after purification of the crude product by column chromatography
(EtOAc/CH2Cl2, 1/1) the title compound ( )-5e (199 mg, 98%) as a
white solid: νmax (cm−1) 2986, 2934, 1614, 1513, 868; H NMR (500
1
MHz, CDCl3) δ 7.33−7.28 (2H, m), 6.87−6.82 (2H, m), 5.95 (1H,
dddd, J = 17.0, 10.3, 6.5, 5.5 Hz), 5.29 (1H. dq, J = 17.2, 1.6 Hz),
5.22−5.17 (1H, m), 4.73 (2H, s), 4.43 (1H, dd, J = 5.0, 4.2 Hz), 4.30
(1H, ddt, J= 13.0, 5.5, 1.4 Hz), 4.21 (1H, ddt, J = 13.0, 6.5, 1.3 Hz),
4.10 (1H, dd, J = 6.5, 5.0 Hz), 3.93 (1H, dd, J = 10.2, 9.4 Hz), 3.79−
Typical Procedure for the Alkylation of ( )-4a and ( )-4b:
( )-4-O-Allyl-1-O-benzyl-2,3;5,6-di-O-isopropylidene-myo-ino-
sitol (( )-5b). Allyl bromide (48 μL, 0.56 mmol) and then sodium
F
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.75 (4H, m), 3.64 (1H, dd, J = 10.6, 6.5 Hz), 3.35 (1H, dd, J = 10.6,
9.4 Hz), 1.44 (3H, s), 1.42 (3H, s), 1.38 (3H, s), 1.34 ppm (3H, s);
13C NMR (126 MHz, CDCl3) δ 159.36, 134.91, 130.57, 129.85,
118.32, 113.84, 112.30, 110.15, 81.43, 79.84, 79.07, 77.14, 76.58,
74.97, 71.95, 71.36, 55.51, 28.16, 27.27, 27.22, 26.18 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C23H32O7Na 443.2040, found
443.2021.
HRMS (ESI-TOF) m/z [M +Na]+ calcd for C22H29NO8Na 458.1791,
found 458.1783.
( )-2,3;5,6-Di-O-isopropylidene-1,4-di-O-propyl-myo-inosi-
tol (( )-5i). A mixture of diallyl ether ( )-5a (281 mg, 0.83 mmol)
and Pearlman’s catalyst (6 mg) was dissolved in CH2Cl2 (5 mL) and
stirred under an atmosphere of hydrogen at room temperature
overnight. The reaction mixture was then filtered through Celite, and
the solvents were evaporated. The crude product was purified by
column chromatography (PE to EtOAa/PE, 1/1) to give the title
compound ( )-5i (183 mg, 64%) as a white solid: νmax (cm−1) 2956,
( )-1-O-Allyl-4-O-(4-(3,4-dimethoxyphenyl)benzyl)-2,3:5,6-
di-O-isopropylidene-myo-inositol (( )-5f). Using the procedure
for the preparation of ( )-5b, the reaction of allyl ether ( )-4a (200
mg, 0.67 mmol), sodium hydride (60% in oil, 40 mg, 1.7 mmol), and
4-(3,4-dimethoxyphenyl)benzyl bromide (281 mg, 0.92 mmol) in
DMF (5 mL) gave after purification of the crude product by column
chromatography (PE to EtOAc/PE 1/4) the title compound ( )-5f
(290 mg, 87%) as a white solid: νmax (cm−1) 2928, 1505, 1217, 862;
1H NMR (500 MHz, CDCl3) δ 7.54−7.50 (2H, m), 7.47−7.43 (2H,
m), 7.13 (1H, dd, J = 8.2, 1.9 Hz), 7.10 (1H, d, J = 1.9 Hz), 6.94 (1H,
d, J = 8.2 Hz), 5.98 (1H, dddd, J = 17.1, 10.4, 6.5, 5.4 Hz), 5.32 (1H,
dq, J = 17.3, 1.6 Hz), 5.22 (1H, dq, J = 10.4, 1.4 Hz), 4.86 (2H, s),
4.49−4.43 (1H, m), 4.33 (1H, ddt, J = 13.0, 5.4, 1.4 Hz), 4.24 (1H,
ddt, J = 12.9, 6.6, 1.3 Hz), 4.15 (1H, dd, J = 6.6, 5.0 Hz), 4.00−3.94
(4H, m), 3.93−3.91 (3H, m), 3.81 (1H, dd, J = 10.2, 4.3 Hz), 3.71
(1H, dd, J = 10.4, 6.6 Hz), 3.40 (1H, dd, J = 10.4, 9.5 Hz), 1.48 (3H,
s), 1.46 (3H, s), 1.42 (3H, s), 1.37 ppm (3H, s); 13C NMR (126 MHz,
CDCl3) δ 149.23, 148.68, 140.31, 136.94, 134.72, 134.15, 128.45,
126.69, 119.38, 118.06, 112.13, 111.61, 110.55, 109.98, 81.23, 80.11,
78.89, 76.97, 76.43, 74.82, 71.84, 71.16, 56.03, 55.99, 27.97, 27.06,
27.01, 25.96 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C30H38O8Na 549.2464, found 549.2464.
1
2906, 1460, 1372; H NMR (500 MHz, CDCl3) δ 4.48 (1H, dd, J =
5.0, 4.2 Hz), 4.05 (1H, dd, J = 6.4, 5.0 Hz,), 3.95 (1H, dd, J = 10.1, 9.4
Hz), 3.76−3.64 (4H, m), 3.63−3.52 (2H, m), 3.30 (1H, dd, J = 10.6,
9.4 Hz), 1.66 (4 H, dq, J = 22.3, 7.2 Hz), 1.55 (3 H, s), 1.45 (3H, s),
1.43 (3H, s), 1.37 (3 H, s), 0.92 ppm (6H, td, J = 7.4, 3.0 Hz); 13C
NMR (126 MHz, CDCl3) δ 112.10, 110.00, 81.78, 81.52, 78.97, 76.92,
76.50, 76.49, 72.78, 72.33, 28.38, 27.30, 27.22, 26.13, 23.36, 23.17,
10.62, 10.57 ppm; HRMS (ESI-TOF) m/z [M +Na]+ calcd for
C18H32O6Na 367.2097, found 367.2091.
(
)-2,3;5,6-Di-O-isopropylidene-1,4-di-O-triisopropylsilyl-
myo-inositol (( )-5j). Triisopropylsilyl triflate was added to a
solution of diol ( )-3 (201 mg, 0.77 mmol) and Et3N (0.65 mL, 4.7
mmol) in CH2Cl2 (5 mL) at 0 °C under Ar over powdered 4 Å
molecular sieves. The reaction mixture was stirred overnight at room
temperature and then quenched with solid sodium bicarbonate. The
reaction mixture was filtered through Celite and the filtrate washed
with sodium bicarbonate, extracted into CH2Cl2, and washed with
brine. The organic layer was dried and evaporated and the residue
purified by column chromatography (PE to EtOAc/PE, 1/99) to give
the title compound ( )-5j (220 mg, 50%) as a white solid: νmax
(cm−1) 2986, 2939, 2867, 1463, 1377; 1H NMR (500 MHz, CDCl3) δ
4.30 (1H, t, J = 4.4 Hz), 4.09 (1H, dd, J = 10.0, 4.3 Hz), 3.99−3.91
(2H, m), 3.87 (1H, t, J = 9.7 Hz), 3.24−3.16 (1H, t, J = 9.7 Hz), 1.50
(3H,), 1.37 (3H, s), 1.35 (3H, s), 1.32 (3H, s), 1.18−1.02 ppm (42,
m); 13C NMR (126 MHz, CDCl3) δ 110.85, 109.14, 83.21, 79.47,
79.01, 77.08, 75.82, 70.68, 28.26, 26.85, 26.83, 25.77, 17.96,17.85,
17.83, 12.44, 12.38 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C30H60O6Si2Na 595.3826, found 595.3820.
(
)-1-O-Allyl-4-O-p-bromobenzyl-2,3:5,6-di-O-isopropyli-
dene-myo-inositol (( )-5g). Using the procedure for the prepara-
tion of ( )-5b, the reaction of allyl ether ( )-4a (200 mg, 0.67
mmol), sodium hydride (60% in oil, 40 mg, 1.7 mmol), and p-
bromobenzyl bromide (200 mg, 0.80 mmol) in DMF (5 mL) gave
after purification of the crude product by column chromatography
(EtOAc/CH2Cl2, 1:1) the title compound ( )-5g (310 mg, 99%):
1
νmax (cm−1) 2990, 2934, 867; H NMR (500 MHz, CDCl3) δ 7.49−
7.44 (2H, m), 7.31−7.27 (2H, m), 5.98 (1H, dddd, J = 17.0, 10.3, 6.5,
5.5 Hz), 5.33 (1H, dq, J = 17.2, 1.6 Hz), 5.26−5.22 (1H, m), 4.78 (2H,
s), 4.49−4.45 (1H, m), 4.34 (1H, ddt, J = 12.9, 5.5, 1.4 Hz), 4.25 (1H,
ddt, J = 13.0, 6.5, 1.2 Hz), 4.13 (1H, dd, J = 6.5, 5.0 Hz), 3.96 (1H, dd,
J = 10.1, 9.4 Hz), 3.81 (1H, dd, J = 10.2, 4.2 Hz), 3.65 (1H, dd, J =
10.6, 6.5 Hz), 3.38 (1H, dd, J = 10.6, 9.3 Hz), 1.47 (3H, s), 1.45 (3H,
s), 1.43 (3H, s), 1.38 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
137.56, 134.87, 131.51, 129.72, 121.53, 118.39, 112.41, 110.25, 81.33,
80.50, 78.93, 77.12, 76.62, 74.89, 71.47, 71.40, 28.21, 27.27, 27.20,
26.14 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C22H29BrO6Na 491.1040, found 491.1052. Anal. Calcd for
C22H29BrO6: C, 56.30; H, 6.23; Br, 17.02. Found: C, 56.39; H, 6.23;
Br, 16.87.
Typical Procedure for the Selective Hydrolysis of ( )-5:
( )-1,4-Di-O-allyl-2,3-O-isopropylidene-myo-inositol (( )-6a).
Water (0.015 mL, 0.83 mmol) and trifluoroacetic acid (TFA) (0.10
mL, 1.3 mmol) were added with stirring to a solution of ( )-5a (0.216
g, 0.635 mmol) in dry CH2Cl2 (10 mL) at 0 °C under Ar. After 90
min, the reaction mixture was diluted with EtOAc, washed with
sodium bicarbonate then brine. The organic layer was dried, the
solvents evaporated, and the residue was purified by column
chromatography (EtOAc/PE, 1:1) to give the title compound
( )-6a19 (0.149 g, 78%) as a white solid: 1H NMR (500 MHz,
CDCl3) δ 6.03−5.89 (2H, m), 5.35−5.28 (2H, m), 5.25−5.17 (2H,
m), 4.48−4.36 (2H, m), 4.32−4.16 (3H, m), 4.08 (1H, dd, J = 6.9, 5.3
Hz), 3.90 (1H, td, J = 9.4, 1.9 Hz), 3.54−3.44 (2H, m), 3.40−3.33
(1H, m), 2.86−2.81 (2H, m), 1.54 (3H, s), 1.38 ppm (3H, s); 13C
NMR (126 MHz, CDCl3) δ 134.81, 134.67, 118.11, 117.42, 110.03,
81.76, 79.31, 76.97, 73.94, 73.03, 72.38, 71.71, 71.49, 28.06, 25.98
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H24O6Na
323.1465, found 323.1455.
( )-4-O-Allyl-1-O-benzyl-2,3-O-isopropylidene-myo-inositol
(( )-6b). Using the procedure described for the preparation of
( )-6a, treatment of ( )-5b (126 mg, 0.32 mmol) in dry CH2Cl2 (5
mL) with water (45 μL, 2.5 mmol) and TFA (45 μL, 0.58 mmol) gave
after column chromatography (EtOAc/PE, 1:1) the title compound
( )-6b (93 mg, 82%) as a white solid: νmax (cm−1) 3411, 2986, 2926,
1646, 1117, 741, 696; 1H NMR (500 MHz, CDCl3) δ 7.44−7.27 (5H,
m), 5.99−5.85 (1H, m), 5.33−5.23 (1H, m), 5.23−5.13 (1H, m),
4.81−4.73 (2H, m), 4.43−4.34 (1H, m), 4.30 (1H, dd, J = 5.0, 3.8
Hz), 4.22−4.16 (1H, m), 4.02 (1H, dd, J = 6.9, 5.0 Hz), 3.94 (1H, td, J
= 9.5, 1.6 Hz), 3.52 (1H, dd, J = 9.6, 3.9 Hz), 3.46 (1H, dd, J = 9.5, 6.9
Hz), 3.33 (1H, td, J = 9.5, 2.0 Hz), 2.64 (1H, d, J = 1.9 Hz), 2.61 (1H,
d, J = 1.9 Hz), 1.54 (3H, s), 1.33 ppm (3H, s); 13C NMR (126 MHz,
CDCl3) δ 137.85, 134.79, 128.56, 128.14, 128.08, 117.40, 109.96,
(
)-1-O-Allyl-2,3:5,6-di-O-isopropylidene-4-O-p-nitroben-
zyl-myo-inositol (( )-5h). A mixture of p-nitrobenzyl bromide (140
mg, 0.65 mmol), silver oxide (140 mg, 0.60 mmol), and allyl ether
( )-4a (116 mg, 0.37 mmol) in dry CH2Cl2 (5 mL) was stirred in the
dark at room temperature overnight. The reaction mixture was cooled,
quenched with MeOH, and filtered through Celite, which was then
washed with CH2Cl2. The solvents were evaporated, and the residue
was purified by column chromatography (PE to EtOAc/PE, 1/5) to
give the title compound ( )-5h (132 mg, 79%) as a white solid: νmax
(cm−1) 2990, 2885, 1606, 1515, 1350, 849; 1H NMR (500 MHz,
CDCl3) δ 8.19 (2H, d, J = 8.7 Hz), 7.57 (2H, dt, J = 8.8, 0.8 Hz), 5.98
(1H, dddd, J = 17.0, 10.3, 6.5, 5.5 Hz), 5.32 (1H, dq, J = 17.2, 1.6 Hz),
5.23 (1H, dq, J = 10.3, 1.2 Hz), 4.95−4.91 (2H, m), 4.48 (1H, dd, J =
5.0, 4.2 Hz), 4.33 (1H, ddt, J = 12.9, 5.5, 1.4 Hz), 4.24 (1H, ddt, J =
12.9, 6.5, 1.2 Hz), 4.15 (1H, dd, J = 6.5, 5.0 Hz), 3.97 (1H, dd, J =
10.2, 9.3 Hz), 3.82 (1H, dd, J = 10.1, 4.1 Hz), 3.66 (1H, dd, J = 10.6,
6.5 Hz), 3.40 (1H, dd, J = 10.6, 9.3 Hz), 1.46 (3H, s), 1.45 (6H, s),
1.38 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 147.34, 146.12,
134.62, 127.82, 123.45, 118.17, 112.34, 110.14, 81.21, 81.04, 78.63,
76.94, 76.48, 74.66, 71.23, 70.86, 28.08, 27.06, 26.97, 25.88 ppm;
G
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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81.75, 79.30, 77.11, 74.01, 72.96, 72.66, 72.34, 71.60, 28.08, 25.93
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26O6Na
373.1627, found 373.1631.
ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 149.26, 148.77, 140.69,
136.77, 134.67, 133.98, 128.56, 126.93, 119.43, 118.15, 111.62, 110.57,
110.15, 82.12, 79.40, 77.02, 73.98, 73.17, 71.74, 71.50, 56.04, 56.01,
28.09, 26.03 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C27H34O8Na 509.2151, found 509.2145.
( )-1-O-Allyl-4-O-benzyl-2,3-O-isopropylidene-myo-inositol
(( )-6c). Using the procedure described for the preparation of ( )-6a,
treatment of ( )-5c (2.204 g, 5.64 mmol) in dry CH2Cl2 (30 mL)
with water (0.100 mL, 5.6 mmol) and TFA (0.870 mL, 11.29 mmol)
gave after column chromatography (EtOAc/PE, 1/2 to 2/1) the title
compound ( )-6c (1.879 g, 95%) as a white solid: νmax (cm−1) 3405,
2996, 1063, 735, 695; 1H NMR (500 MHz, CDCl3) δ 7.39−7.22 (5H,
m), 5.96 (1H, dddd, J = 17.2, 10.3, 6.0 Hz), 5.31 (1H, dq, J = 17.2, 1.5
Hz), 5.22 (1H, dq, J = 2.8, 1.2 Hz), 4.93 (1H, d, J = 11.5 Hz), 4.67
(1H, d, J = 11.5 Hz), 4.44 (1H, dd, J = 5.1, 4.0 Hz), 4.31−4.17 (2H,
m), 4.15 (1H, dd, J = 6.9, 3.6 Hz), 3.89 (1H, td, J = 9.5, 1.7 Hz), 3.56−
3.48 (2H, m), 3.40 (1H, td, J = 9.5, 2.0 Hz), 2.63 (2H, dd, J = 8.2, 1.9
Hz), 1.49 (3H, s), 1.37 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
138.35, 134.85, 128.67, 128.27, 128.07, 118.42, 110.33, 82.27, 79.55,
77.15, 74.16, 73.62, 73.29, 71.95, 71.66, 28.27, 26.24 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C19H26O6Na 373.1627, found
373.1609. Anal. Calcd for C19H26O6: C, 65.13; H, 7.48. Found: C,
65.30; H, 7.63.
( )-1-O-Allyl-2,3-O-isopropylidene-4-O-propargyl-myo-ino-
sitol (( )-6d). Using the procedure described for the preparation of
( )-6a, treatment of ( )-5d (134 mg, 0.40 mmol) in dry CH2Cl2 (5
mL) with water (65 μL, 3.6 mmol) and TFA (65 μL, 0.84 mmol) gave
after column chromatography (EtOAc/PE, 1/1) the title compound
( )-6i (96 mg, 81%) as a white solid: νmax (cm−1) 3476, 3309, 2980,
2906, 1098; 1H NMR (500 MHz, CDCl3) δ 6.02−5.93 (1H, m), 5.33
(1H, dq, J = 17.2, 1.5 Hz), 5.24 (1H, dq, J = 10.4, 1.3 Hz), 4.55−4.44
(2H, m), 4.45−4.42 (1H, m), 4.31−4.19 (2H, m), 4.07 (1H, dd, J =
7.3, 5.0 Hz), 3.93 (1H, td, J = 9.5, 1.9 Hz), 3.67 (1H, dd, J = 9.8, 7.3
Hz), 3.50 (1H, dd, J = 9.8, 4.1 Hz), 3.37 (1H, td, J = 9.6, 1.9 Hz), 2.68
(1H, d, J = 1.6 Hz), 2.64 (1H, d, J = 1.9 Hz), 2.47 (1H, t, J = 2.4 Hz),
1.58 (3H, s), 1.38 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
134.64, 118.16, 110.21, 81.01, 79.84, 78.99, 76.85, 74.88, 73.97, 72.66,
71.75, 71.55, 58.52, 28.09, 26.04 ppm; HRMS(ESI-TOF) m/z [M +
Na]+ calcd forC15H22O6Na 321.1314, found 321.1308.
(
)-1-O-Allyl-4-O-p-bromobenzyl-5,6-O-isopropylidene-
myo-inositol (( )-6g). Using the procedure described for the
preparation of ( )-6a, treatment of ( )-5g (311 mg, 0.66 mmol) in
dry CH2Cl2 (5 mL) with water (100 μL, 5.6 mmol) and TFA (100 μL,
1.3 mmol) gave after column chromatography (EtOAc/PE, 1/1) the
title compound ( )-6g (270 mg, 95%) as a white solid: νmax (cm−1)
1
3386, 2976, 2922, 1102, 802; H NMR (500 MHz, CDCl3) δ7.47−
7.42 (2H, m), 7.26−7.21 (2H, m), 5.95 (1H, ddt, J = 17.3, 10.3, 6.0
Hz), 5.30 (1H, dq, J = 17.2, 1.5 Hz), 5.22 (1H, dq, J = 10.3, 1.3 Hz),
4.86 (1H, d, J = 11.8 Hz), 4.65 (1H, d, J = 11.9 Hz), 4.43 (1H, dd, J =
5.1, 3.9 Hz), 4.26 (1H, ddt, J = 12.8, 6.0, 1.3 Hz), 4.18 (1H, ddt, J =
12.8, 6.0, 1.3 Hz), 4.11 (1H, dd, J = 6.9, 5.1 Hz), 3.87 (1H, td, J = 9.5,
1.9 Hz), 3.53−3.46 (2H, m), 3.39 (1H, td, J = 9.5, 2.0 Hz), 2.72 (1H,
d, J = 1.9 Hz), 2.69 (1H, d, J = 2.0 Hz), 1.46 (3H, s), 1.36 ppm (3H,
s); 13C NMR (126 MHz, CDCl3) δ 137.42, 134.77, 131.70, 129.86,
121.85, 118.46, 110.35, 82.38, 79.46, 77.11, 74.06, 73.33, 72.77, 71.90,
71.61, 28.27, 26.22 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C19H2579BrO6Na 451.0727, found 451.0729. Anal. Calcd for
C19H25BrO6: C, 53.16; H, 5.87; Br, 18.61. Found: C, 53.27; H, 5.88;
Br, 18.74.
( )-1-O-Allyl-2,3-O-isopropylidene-4-O-p-nitrobenzyl-myo-
inositol (( )-6h). Using the procedure described for the preparation
of ( )-6a, treatment of ( )-5h (124 mg, 0.28 mmol) in dry CH2Cl2
(5 mL) with water (44 μL, 3.1 mmol) and TFA (55 μL, 0.57 mmol)
gave after column chromatography (EtOAc/PE, 1/1) the title
compound ( )-6h (113 mg, 85%) as a white solid: νmax (cm−1)
1
3408, 2993, 2925, 1603, 1519, 1343, 1091, 842; H NMR (500 MHz,
CDCl3) δ 8.24−8.15 (2H, m), 7.59−7.52 (2H, m), 5.98 (1H, ddt, J =
17.2, 10.3, 6.0 Hz), 5.33 (1H, dq, J = 17.2, 1.5 Hz), 5.25 (1H, dq, J =
10.3, 1.3 Hz), 5.02 (1H, d, J = 13.2 Hz), 4.88 (1H, d, J = 13.2 Hz),
4.47 (1H, dd, J = 5.1, 3.9 Hz), 4.29 (1H, ddt, J = 12.8, 6.0, 1.3 Hz),
4.20 (1H, ddt, J = 12.7, 6.0, 1.3 Hz), 4.15 (1H, dd, J = 6.9, 5.1 Hz),
3.89 (1H, td, J = 9.5, 1.9 Hz), 3.58−3.49 (2H, m), 3.47 (1H, td, J =
9.6, 1.9 Hz), 2.73 (1H, d, J = 1.9 Hz), 2.71 (1H, d, J = 2.0 Hz), 1.48
(3H, s), 1.39 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 147.42,
145.97, 134.50, 128.01, 123.56, 118.31, 110.26, 82.85, 79.16, 76.92,
73.76, 73.26, 72.12, 71.64, 71.42, 28.12, 26.02 ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H25NO8Na 418.1478, found
418.1477.
(
)-1-O-Allyl-2,3-O-isopropylidene-4-O-p-methoxybenzyl-
myo-inositol (( )-6e). Using the procedure described for the
preparation of ( )-6a, treatment of ( )-5e (237 mg, 0.56 mmol) in
dry CH2Cl2 (5 mL) with water (85 μL, 4.7 mmol) and TFA (85 μL,
1.1 mmol) gave after column chromatography (EtOAc/PE, 1/1) the
title compound ( )-6d (203 mg, 95%) as a white solid: νmax (cm−1)
3397, 2980, 2923, 1612, 1513, 1100, 867; 1H NMR (500 MHz,
CDCl3) δ 7.31−7.25 (2H, m), 6.89−6.83 (2H, m), 5.96 (1H, ddt, J =
17.3, 10.3, 6.0 Hz), 5.30 (1H, dq, J = 17.2, 1.5 Hz), 5.21 (1H, dq, J =
10.3, 1.3 Hz), 4.86 (1H, d, J = 11.1 Hz), 4.59 (1H, d, J = 11.1 Hz),
4.42 (1H, dd, J = 5.1, 4.0 Hz), 4.26 (1H, ddt, J = 12.8, 6.1, 1.3 Hz),
4.19 (1H, ddt, J = 12.8, 6.0, 1.4 Hz), 4.12 (1H, dd, J = 7.0, 5.1 Hz),
3.91−3.83 (1H, m), 3.78 (3H, s), 3.55−3.44 (2H, m), 3.41−3.32 (1H,
m), 2.70 (1H, d, J = 1.5 Hz), 2.67−2.63 (1H, m), 1.49 (3H, s), 1.37
ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 159.57, 134.85, 130.47,
129.91, 118.37, 114.08, 110.28, 81.97, 79.60, 77.15, 74.16, 73.29,
73.23, 71.95, 71.66, 55.50, 28.29, 26.23 ppm; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C20H28O7Na 403.1727, found 403.1723.
(
)-2,3-O-Isopropylidene-1,4-di-O-propyl-myo-inositol
(( )-6i). Using the procedure described for the preparation of ( )-6a,
treatment of ( )-5i (120 mg, 0.35 mmol) in dry CH2Cl2 (5 mL) with
water (50 μL, 2.8 mmol) and TFA (50 μL, 0.67 mmol) gave after
column chromatography (EtOAc/PE, 1/1) the title compound ( )-6i
(82 mg, 77%) as a white solid: νmax (cm−1) 3413, 2959, 2924, 1462,
1366, 1104; 1H NMR (500 MHz, CDCl3) δ 4.43 (1H, dd, J = 5.1, 3.9
Hz), 4.04 (1H, dd, J = 6.6, 5.2 Hz), 3.86 (1H, td, J = 9.2, 1.7 Hz), 3.81
(1H, dt, J = 9.3, 6.8 Hz), 3.69 (1H, ddd, J = 9.3, 7.1, 6.3 Hz), 3.58−
3.53 (1H, m), 3.50 (1H, dt, J = 9.3, 7.0 Hz), 3.41−3.36 (2H, m), 3.34
(1H, td, J = 9.1, 1.9 Hz), 2.68 (1H, 2d, J = 1.9 Hz), 2.67 (1H, d, J = 1.7
Hz), 1.70−1.56 (4H, m), 1.53 (3H, s), 1.35 (3H, s), 0.92 ppm (6H, 2
× t, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ = 110.14, 82.82,
79.57, 78.34, 73.85, 73.77, 73.38, 72.59, 71.60, 28.30, 26.19, 23.53,
23.28, 10.72, 10.62 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H28O6Na 327.1784, found 327.1781.
(
)-1-O-Allyl-4-O-(4-(3,4-dimethoxyphenyl)benzyl)-2,3-O-
isopropylidene-myo-inositol (( )-6f). Using the procedure
described for the preparation of ( )-6a, treatment of ( )-5f (271
mg, 0.51 mmol) in dry CH2Cl2 (5 mL) with water (60 μL, 3.3 mmol)
and TFA (60 μL, 0.77 mmol) gave after column chromatography
(EtOAc/PE, 1:1) the title compound ( )-6f (250 mg, 80%) as a white
( )-2,3-O-Isopropylidene-1,4-di-O-triisopropylsilyl-myo-ino-
sitol (( )-6j). Using the procedure described for the preparation of
( )-6a, treatment of ( )-5j (224 mg, 0.39 mmol) in dry CH2Cl2 (5
mL) with water (45 μL, 2.5 mmol) and TFA (45 μL, 0.58 mmol) gave
after column chromatography (EtOAc/PE, 1/4) the title compound
( )-6j (208 mg, 83%) as a white solid: νmax (cm−1) 2986, 2941, 2867,
1
solid: νmax (cm−1) 3379, 2918, 1506, 1247, 1064, 866; H NMR (500
MHz, CDCl3) δ 7.58−7.50 (2H, m), 7.46−7.38 (2H, d, J = 8.5 Hz),
7.14 (1H, dd, J = 8.4, 2.0 Hz), 7.10 (1H, d, J = 2.2 Hz), 6.94 (1H, d, J
= 8.5 Hz), 5.98 (1H, ddt, J = 17.2, 10.3, 6.0 Hz), 5.33 (1H, dq, J =
17.3, 1.5 Hz), 5.25−5.22 (1H, m), 4.98 (1H, d, J = 11.3 Hz), 4.73 (1H,
d, J = 11.7 Hz), 4.47 (1H, dd, J = 5.0, 4.1 Hz), 4.33−4.25 (1H, m),
4.25−4.19 (1H, m), 4.18 (1H, dd J = 6.9, 5.0 Hz) 3.95−3.89 (7H, m),
3.58 (1H, dd, J = 9.5, 6.9 Hz), 3.52 (1H, dd, J = 9.6, 3.9 Hz), 3.43 (1H,
td, J = 9.5, 1.9 Hz), 2.66 (2H, 2 × d, J = 1.9 Hz), 1.52 (3H, s), 1.40
1
1464, 1372, 1113; H NMR (500 MHz, CDCl3) δ 4.36 (1H, dd, J =
5.9, 3.7 Hz), 4.10 (1H, t, J = 5.7 Hz), 4.00 (1H, dd, J = 9.4, 3.8 Hz),
3.93 (1H, dd, J = 6.9, 5.6 Hz), 3.85 (1H, ddd, J = 9.5, 7.9, 1.8 Hz), 3.45
(1H, ddd, J = 7.8, 6.9, 4.4 Hz), 2.48−2.46 (2H, m), 1.49 (3H, s), 1.32
H
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3H, s), 1.22−1.03 ppm (42H, m); 13C NMR (126 MHz, CDCl3) δ
109.52, 79.60, 76.32, 76.25, 76.07, 73.27, 71.53, 27.38, 24.99, 18.10,
18.08, 18.06, 17.99, 12.59, 12.42 ppm; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C27H56O6Si2Na 555.3513, found 555.3513.
127.92, 127.86, 118.41, 110.32, 79.14, 78.68, 75.62, 75.62, 73.59,
73.06, 72.10, 70.48, 27.49, 25.53, 21.29 ppm; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C21H28O7Na 415.1733, found 415.1729. Anal.
Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C, 64.48; H, 7.27.
28
Data for (+)-6c: [α]D = +16.4° (c 1.06, CHCl3); HRMS (ESI-
Typical Procedure for the Novozym 435 Catalyzed
Resolution of ( )-5: (−)-5-O-Acetyl-1,4-di-O-allyl-2,3-O-isopro-
pylidene-1D-myo-inositol ((−)-7a) and (+)-3,6-di-O-allyl-1,2-O-
isopropylidene-1D-myo-inositol ((+)-6a). A mixture of ( )-6a (80
mg, 0.27 mmol) and Novozym 435 beads (40 mg) in freshly distilled
vinyl acetate (5 mL) under Ar in a sealed flask at 30 °C was gently
stirred for 24 h. The mixture was filtered and the beads washed with
EtOAc. The solvents were removed from the combined filtrate and the
residue purified by column chromatography (EtOAc/PE, 1/2 to 2/1)
to give the title compounds (−)-7a (42 mg, 46%) and (+)-6a (33 mg,
41%) both as white solids.
TOF) m/z [M + Na]+ calcd for C19H26O6Na 373.1627, found
373.1621. All other spectroscopic data were consistent with those for
( )-6c.
(−)-5-O-Acetyl-1-O-allyl-2,3-O-isopropylidene-4-O-proparg-
yl-1D-myo-inositol ((−)-7d) and (+)-3-O-Allyl-1,2-O-isopropyli-
dene-6-O-propargyl-1D-myo-inositol ((+)-6d). Using the proce-
dure for the resolution of ( )-6a, treatment of ( )-6d (80 mg, 0.27
mmol) with Novozym 435 beads (40 mg) in freshly distilled vinyl
acetate (5 mL) gave after purification by column chromatography
(EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7d (44 mg, 48%)
and (+)-6d (39 mg, 48%) as white solids.
Data for (−)-7a: [α]D18 = −5.1° (c 0.94, CHCl3); νmax (cm−1) 3526,
18
Data for (−)-7d: [α]D = −6.7° (c 1.02, CHCl3); νmax (cm−1)
1
2991, 2929, 1722, 1648, 1107; H NMR (500 MHz, CDCl3) δ 6.00−
1
3464, 3266, 2990, 2914, 1749, 1102; H NMR (500 MHz, CDCl3) δ
5.91 (1H, m), 5.90−5.82 (1H, m), 5.34−5.29 (1H, m), 5.28−5.21
(2H, m), 5.16 (1H, dq, J = 10.4, 1.5 Hz), 4.82 (1H, t, J = 8.0 Hz), 4.49
(1H, dd, J = 6.0, 3.8 Hz), 4.30−4.14 (5H, m), 3.99 (1H, ddd, J = 9.1,
8.2, 2.2 Hz), 3.65 (1H, dd, J = 7.9, 6.0 Hz), 3.61 (1H, dd, J = 9.1, 3.5
Hz), 2.64 (1H, d, J = 2.2 Hz), 2.12 (3H, s), 1.54 (3H, s), 1.37 ppm
(3H, s); 13C NMR (126 MHz, CDCl3) δ 170.91, 134.63, 134.51,
118.08, 116.93, 110.02, 78.77, 78.30, 76.78, 75.54, 73.38, 72.05, 71.87,
70.36, 27.27, 25.27, 21.06 ppm; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C17H26O7Na 365.1576, found 365.1568.
5.95 (1H, ddt, J = 17.2, 10.3, 6.0 Hz), 5.35−5.29 (1H, m), 5.25−
5.21(1H, m), 4.79 (1H, t, J = 8.4 Hz), 4.48 (1H, dd, J = 5.8, 3.6 Hz),
4.39 (2H, d, J = 2.2 Hz), 4.24−4.31 (1H, m), 4.23−4.15 (2H, m),
4.04−3.98 (1H, m), 3.86 (1H, dd, J = 8.5, 6.3 Hz), 3.59 (1H, dd, J =
9.1, 3.8 Hz), 2.60 (1H, d, J = 2.2 Hz), 2.43−2.40 (1H, m), 2.14 (3H,
s), 1.57 (3H, s), 1.37 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
170.99, 134.46, 118.12, 110.21, 79.67, 78.33, 78.28, 76.77, 74.97,
74.42, 73.44, 71.91, 70.36, 58.29, 27.35, 25.39, 21.11 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H24O7Na 363.1420, found
363.1418.
19
Data for (+)-6a: [α]D = +16.0° (c 1.04, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C15H24O6Na 323.1465, found
323.1472. All other spectroscopic data were consistent with those for
( )-6a.
20
Data for (+)-6d: [α]D = +38.2° (c 1.14, CHCl3); HRMS(ESI-
TOF) m/z [M + Na]+ Calcd forC15H22O6Na 321.1314, found
321.1308. All other spectroscopic data were consistent with those for
( )-6d.
(−)-5-O-Acetyl-4-O-allyl-1-O-benzyl-2,3-O-isopropylidene-
1D-myo-inositol ((−)-7b) and (+)-4-O-Allyl-1-O-benzyl-2,3-O-
isopropylidene-1D-myo-inositol ((+)-6b). Using the procedure for
the resolution of ( )-6a, treatment of ( )-6b (93 mg, 0.27 mmol)
with Novozym 435 beads (40 mg) in freshly distilled vinyl acetate (5
mL) gave after purification by column chromatography (EtOAc/PE,
1/2 to 2/1) the title compounds (−)-7b (41 mg, 40%) and (+)-6b (35
mg, 38%), both as white solids.
(−)-5-O-Acetyl-1-O-Allyl-2,3-O-isopropylidene-4-O-p-me-
thoxybenzyl-1D-myo-inositol ((−)-7e) and (+)-3-O-Allyl-1,2-O-
isopropylidene-6-O-p-methoxybenzyl-1D-myo-inositol
((+)-6e). Using the procedure for the resolution of ( )-6a, treatment
of ( )-6e (99 mg, 0.26 mmol) with Novozym 435 beads (50 mg) in
freshly distilled vinyl acetate (5 mL) gave after purification by column
chromatography (EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7e
(50 mg, 45%) and (+)-6e (48 mg, 48%) as white solids.
19
Data for (−)-7b: [α]D = −4.9° (c 1.21, CHCl3); νmax (cm−1)
1
3524, 2982, 2931, 1725, 1646, 1118, 740, 696; H NMR (500 MHz,
Data for (−)-7e: [α]D17 = −7.7° (c 0.99, CHCl3); νmax (cm−1) 3521,
CDCl3) δ 7.40−7.27 (5H, m), 5.89−5.80 (1H, m), 5.26−5.20 (1H,
m), 5.18−5.12 (1H, m), 4.82−4.77 (2H, m), 4.74−4.69 (1H, m), 4.38
(1H, dd, J = 6.0, 3.8 Hz), 4.28−4.22 (1H, m), 4.18−4.12 (2H, m),
4.05−3.99 (1H, m), 3.68−3.62 (2H, m), 2.63 (1H, d, J = 2.5 Hz), 2.11
(3H, s), 1.53 (3H, s), 1.34 ppm (3H, s); 13C NMR (126 MHz,
CDCl3) δ 170.91, 137.78, 134.66, 128.55, 128.05, 128.03, 116.88,
109.97, 78.84, 78.36, 77.03, 75.44, 73.44, 72.78, 72.06, 70.51, 27.36,
25.30, 21.06 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C21H28O7Na 415.1733, found 415.1725.
1
2891, 1723, 1615, 1110, 862; H NMR (500 MHz, CDCl3) δ 7.25−
7.20 (2H, m), 6.90−6.81 (2H, m), 5.95 (1H, ddt, J = 17.2, 10.3, 5.9
Hz), 5.31 (1H, dq, J = 17.2, 1.5 Hz), 5.22 (1H, dq, J = 10.4, 1.3 Hz),
4.88 (1H, t, J = 7.9 Hz), 4.72 (1H, d, J = 11.6 Hz), 4.64 (1H, d, J =
11.6 Hz), 4.49 (1H, dd, J = 6.1, 3.6 Hz), 4.33−4.21 (2H, m), 4.21−
4.12 (1H, m), 3.99 (1H, t, J = 8.6 Hz), 3.80 (3H, s), 3.69 (1H, dd, J =
7.8, 5.8 Hz), 3.63 (1H, dd, J = 9.2, 3.6 Hz), 2.59 (1H, d, J = 2.4 Hz),
2.09 (3H, s), 1.50 (3H, s), 1.37 ppm (3H, s); 13C NMR (126 MHz,
CDCl3) δ 170.92, 159.27, 134.51, 130.21, 129.38, 118.10, 113.74,
110.07, 78.47, 78.45, 76.77, 75.61, 73.38, 72.47, 71.87, 70.32, 55.29,
27.25, 25.27, 21.10 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C22H30O8Na 445.1838, found 445.1835.
20
Data for (+)-6b: [α]D = +9.9° (c 1.13, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H26O6Na 373.1627, found
373.1623. All other spectroscopic data were consistent with those for
racemic ( )-6b.
20
Data for (+)-6e: [α]D = +16.1° (c 1.27, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C20H28O7Na 403.1727, found
403.1730. All other spectroscopic data were consistent with those for
( )-6e.
(−)-5-O-Acetyl-1-O-allyl-4-O-benzyl-2,3-O-isopropylidene-
1D-myo-inositol ((−)-7c) and (+)-3-O-Allyl-6-O-benzyl-1,2-O-
isopropylidene-1D-myo-inositol ((+)-6c). Using the procedure
for the resolution of ( )-6a, treatment of ( )-6c (1.937 g, 5.53
mmol) with Novozym 435 beads (0.999 g) in freshly distilled vinyl
acetate (25 mL) gave after purification by column chromatography
(EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7c (1.063 g, 49%)
and (+)-6c (0.949 g, 49%), both as white solids.
(−)-5-O-Acetyl-1-O-Allyl-4-O-(4-(3,4-dimethoxyphenyl)-
benzyl)-2,3-O-isopropylidene-1D-myo-inositol ((−)-7f) and
(+)-3-O-allyl-6-O-(4-(3,4-dimethoxyphenyl)benzyl)-1,2-O-iso-
propylidene-1D-myo-inositol ((+)-6f). Using the procedure for the
resolution of ( )-6a, treatment of ( )-6f (116 mg, 0.24 mmol) with
Novozym 435 beads (60 mg) in freshly distilled vinyl acetate (3 mL)
and EtOAc (2 mL) gave after purification by column chromatography
(EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7f (23 mg, 18%)
and (+)-6f (72 mg, 62%) as white solids.
Data for (−)-7c: [α]D20 = −9.4° (c 1.09, CHCl3); νmax (cm−1) 3522,
2983, 1718, 1023, 729, 696; 1H NMR (500 MHz, CDCl3) δ 7.35−7.22
(5H, m), 5.99−5.87 (1H, m), 5.29 (1H, ddd, J = 17.2, 2.5, 1.5 Hz),
5.21 (1H, ddd, J = 10.3, 2.5, 1.2 Hz), 4.88 (1H, t, J = 8.1 Hz), 4.78
(1H, d, J = 12.0 Hz), 4.69 (1H, d, J = 12.0 Hz), 4.48 (1H, dd, J = 6.0,
3.6 Hz), 4.30−4.21 (2H, m), 4.16 (1H, ddt, J = 12.8, 5.9, 1.2 Hz), 3.97
(1H, t, J = 8.7 Hz), 3.69 (1H, dd, J = 8.0, 5.9 Hz), 3.61 (1H, dd, J =
9.2, 3.6 Hz), 2.58 (1H, s), 2.07 (1H, s), 1.48 (3H, s), 1.35 ppm (3H,
s); 13C NMR (126 MHz, CDCl3) δ 171.17, 138.30, 134.67, 128.50,
Data for (−)-7f: [α]D19 = −4.5° (c 0.99, CHCl3); νmax (cm−1) 2499,
1
2987, 2936, 1739, 1504, 1247, 1247, 1143, 867; H NMR (500 MHz,
CDCl3) δ 7.55−7.49 (2H, m), 7.41−7.33 (2H, d, J = 8.2 Hz), 7.17−
7.07 (2H, m), 6.94 (1H, d, J = 8.2 Hz), 6.01−5.88 (1H, m), 5.31 (1H,
dq, J = 17.1, 1.6 Hz), 5.23 (1H, dq, J = 10.4, 1.3 Hz), 4.91 (1H, t, J =
I
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8.0 Hz), 4.83 (1H, d, J = 12.0 Hz), 4.75 (1H, d, J = 12.0 Hz), 4.51
(1H, dd, J = 6.0, 3.5 Hz), 4.33−4.25 (2H, m), 4.18 (1H, ddt, J = 12.8,
6.0, 1.3 Hz), 4.01 (1H, t, J = 8.5 Hz), 3.95 (3H, s), 3.92 (3H, s), 3.75
(1H, dd, J = 7.9, 6.0 Hz), 3.65 (1H, dd, J = 9.1, 3.8 Hz), 2.62 (1H, s),
2.11 (3H, s), 1.52 (3H, s), 1.38 (3H, s); 13C NMR (126 MHz, CDCl3)
δ 170.95, 149.24, 148.73, 140.47, 136.72, 134.49, 133.96, 128.17,
126.76, 119.38, 118.13, 111.60, 110.52, 110.12, 78.97, 78.47, 76.77,
75.53, 73.41, 72.60, 71.87, 70.33, 56.01, 55.99, 27.28, 25.30, 21.09
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C29H36O9Na
551.2257, found 551.2261.
2/1) the title compounds (−)-7i (41 mg, 44%) and (+)-6i (38 mg,
37%) as white solids.
Data for (−)-7i: [α]D19 = −3.9° (c 1.07, CHCl3); νmax (cm−1) 3481,
1
2962, 2937, 1739, 1458, 1374, 1075; H NMR (500 MHz, CDCl3) δ
4.81 (1H, t, J = 8.1 Hz), 4.48 (1H, dd, J = 5.9, 3.6 Hz), 4.17 (1H, t, J =
6.0 Hz), 3.96 (1H, ddd, J = 9.3, 8.2, 2.0 Hz), 3.76−3.64 (2H, m),
3.59−3.41 (4H, m), 2.55 (1H, d, J = 2.1 Hz), 2.10 (3H, s), 1.71−1.58
(2H, m), 1.58−1.47 (5H, m), 1.35 (3H, s), 0.90 ppm (6H, 2xt, J = 7.4
Hz); 13C NMR (126 MHz, CDCl3) δ 171.01, 110.19, 80.11, 78.65,
78.05, 75.65, 73.68, 73.28, 72.72, 70.34, 27.61, 25.56, 23.42, 23.27,
21.29, 10.73, 10.64 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H30O7Na 369.1889, found 369.1881.
Data for (+)-6f: [α]D20 = +4.7° (c 1.33, CHCl3); HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C27H34O8Na 509.2151, found 509.2160. All
other spectroscopic data were consistent with those for ( )-6f.
20
Data for (+)-6i: [α]D = +14.7° (c 0.95, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C15H28O6Na 327.1784, found
327.1777. All other spectroscopic data were consistent with those for
( )-6i.
(
)-5-O-Acetyl-1-O-allyl-4-O-p-bromobenzyl-2,3-O-isopro-
pylidene-1D-myo-inositol ((−)-7g) and (+)-3-O-Allyl-6-O-p-bro-
mobenzyl-1,2-O-isopropylidene-1D-myo-inositol ((+)-6g).
Using the procedure for the resolution of ( )-6a, treatment of
( )-6g (111 mg, 0.26 mmol) with Novozym 435 beads (55 mg) in
freshly distilled vinyl acetate (5 mL) gave after purification by column
chromatography (EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7g
(50 mg, 41%) and (+)-6g (55 mg, 49%) as white solids.
Typical Procedure for the Deacetylation of (−)-7: (−)-1,4-Di-
O-allyl-2,3-O-isopropylidene-1D-myo-inositol ((−)-6a). Method
A. A solution of sodium methoxide in MeOH (5.4 M, 20 μL, 0.11
mmol) was added to a stirred solution of (−)-7a (42 mg, 0.13 mmol)
in a 1:4 mixture of CH2Cl2 and methanol (5 mL) and the reaction was
stirred overnight at room temperature. The reaction mixture was
quenched with water and diluted with in EtOAc. The organic layer was
washed with water then brine, dried and the solvent removed to give
title compound (−)-6a (29 mg, 79%) as a white solid: [α]D21 = −12.7°
(c 0.75, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H24O6Na 323.1465, found 323.1470. All other spectroscopic data
were consistent with those for ( )-6a.
Data for (−)-7g: [α]D19 = −5.8° (c 1.04, CHCl3); νmax (cm−1) 3528,
1
2980, 2893, 1723, 1110, 801; H NMR (500 MHz, CDCl3) δ 7.48−
7.43 (2H, m), 7.22−7.16 (2H, m), 5.95 (1H, ddt, J = 17.2, 10.4, 5.9
Hz), 5.30 (1H, dq, J = 17.2, 1.5 Hz), 5.23 (1H, dq, J = 10.4, 1.3 Hz),
4.87 (1H, t, J = 8.1 Hz), 4.75 (1H, d, J = 12.3 Hz), 4.66 (1H, d, J =
12.3 Hz), 4.49 (1H, dd, J = 6.1, 3.6 Hz), 4.32−4.21 (2H, m), 4.17 (1H,
ddt, J = 12.8, 6.0, 1.3 Hz), 3.99 (1H, ddd, J = 9.0, 8.1, 2.4 Hz), 3.69
(1H, dd, J = 8.2, 6.0 Hz), 3.62 (1H, dd, J = 9.0, 3.6 Hz), 2.57 (1H, d, J
= 2.4 Hz), 2.09 (3H, s), 1.50 (3H, s), 1.37 ppm (3H, s); 13C NMR
(126 MHz, CDCl3) δ 170.93, 137.19, 134.45, 131.42, 129.29, 121.51,
118.16, 110.18, 79.14, 78.46, 76.76, 75.44, 73.41, 72.05, 71.90, 70.36,
27.30, 25.32, 21.06 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C21H2779BrO7Na 493.0838, found 493.0829.
(−)-4-O-Allyl-1-O-benzyl-2,3-O-isopropylidene-1D-myo-ino-
sitol ((−)-6b). Using method A, (−)-7b (41 mg, 0.11 mmol) gave the
22
title compound (−)-6b (32 mg, 87%) as a white solid: [α]D
=
−10.3° (c 0.79, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C19H26O6Na 373.1627, found 373.1621. All other spectroscopic data
were consistent with those for ( )-6d.
(−)-1-O-Allyl-4-O-benzyl-2,3-O-isopropylidene-1D-myo-ino-
sitol ((−)-6c). Method B. IRA-400 (OH−) ion-exchange resin (∼300
mg) was added to a stirred solution of (−)-7c (1.117 g, 2.85 mmol) in
methanol (20 mL). The solution was stirred overnight then filtered
and the solvent removed to give the title compound (−)-6c (0.935 g,
94%) as a white solid: [α]D20 = −13.3° (c 1.01, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H26O6Na 373.1627, found
373.1621. All other spectroscopic data were consistent with those for
( )-6c.
20
Data for (+)-6g: [α]D = +6.7° (c 1.40, CHCl3); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C19H2579BrO6Na 451.0727, found
451.0728. All other spectroscopic data were consistent with those for
( )-6g.
(−)-5-O-Acetyl-1-O-Allyl-2,3-O-isopropylidene-4-O-p-nitro-
benzyl-1D-myo-inositol ((−)-7h) and (+)-3-O-Allyl-1,2-O-isopro-
pylidene-6-O-p-nitrobenzyl-1D-myo-inositol ((+)-6h). Using the
procedure for the resolution of ( )-6a, treatment of ( )-6h (95 mg,
0.24 mmol) with Novozym 435 beads (45 mg) in freshly distilled vinyl
acetate (5 mL) gave after purification by column chromatography
(EtOAc/PE, 1/2 to 2/1) the title compounds (−)-7h (38 mg, 36%)
and (+)-6h (38 mg, 40%) as white solids.
(−)-1-O-Allyl-2,3-O-isopropylidene-4-O-propargyl-1D-myo-
inositol ((−)-6d). Using method A, (−)-7i (42 mg, 0.13 mmol) gave
22
the title compound (−)-6d (35 mg, 95%) as a white solid: [α]D
=
−39.0° (c 0.41, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H22O6Na 321.1314, found 321.1306. All other spectroscopic data
were consistent with those for ( )-6d.
18
Data for (−)-7h: [α]D = −8.2° (c 1.32, CHCl3); νmax (cm−1)
1
3510, 2913, 1720, 1603, 1512, 1348, 1108, 840; H NMR (500 MHz,
CDCl3) δ 8.19 (2H, d, J = 8.7 Hz), 7.48 (2H, dd, J = 8.1, 0.8 Hz), 5.95
(1H, ddt, J = 17.2, 10.3, 5.9 Hz), 5.31 (1H, dq, J = 17.3, 1.6 Hz), 5.23
(1H, dq, J = 10.3, 1.3 Hz), 4.94 (1H, d, J = 13.4 Hz), 4.89 (1H, t, J =
8.4 Hz), 4.80 (1H, d, J = 13.4 Hz), 4.51 (1H, dd, J = 6.0, 3.6 Hz),
4.31−4.24 (2H, m), 4.18 (1H, ddt, J = 12.8, 6.0, 1.3 Hz), 4.00 (1H, td,
J = 8.5, 2.3 Hz), 3.74 (1H, dd, J = 8.6, 6.2 Hz), 3.63 (1H, dd, J = 8.8,
3.6 Hz), 2.61 (1H, d, J = 2.4 Hz), 2.11 (3H, s), 1.51 (3H, s), 1.38 ppm
(3H, s); 13C NMR (126 MHz, CDCl3) δ 170.92, 147.41, 145.80,
134.41, 127.63, 123.54, 118.18, 110.30, 80.03, 78.44, 76.78, 75.29,
73.49, 71.94, 71.65, 70.45, 27.41, 25.39, 21.05 ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C21H27NO9Na 460.1584, found
460.1577.
(−)-1-O-Allyl-2,3-O-isopropylidene-4-O-p-methoxybenzyl-
1D-myo-inositol ((−)-6e). Using method A, (−)-7e (42 mg, 0.10
mmol) gave the title compound (−)-6e (36 mg, 87%) as a white solid:
[α]D22 = −18.9° (c 1.01, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+
calcd for C20H28O7Na 403.1727, found 403.1737. All other
spectroscopic data were consistent with those for ( )-6e.
(−)-1-O-Allyl-4-O-(4-(3,4-dimethoxyphenyl)benzyl)-2,3-O-
isopropylidene-1D-myo-inositol ((−)-6f). Using method A, (−)-7f
(23 mg, 0.044 mmol) gave the title compound (−)-6f (14 mg, 66%) as
a white solid: [α]D20 = −5.7° (c 1.48, CHCl3); HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C27H34O8Na 509.2151, found 509.2154. All other
spectroscopic data were consistent with those for ( )-6f.
20
Data for (+)-6h: [α]D = +0.8° (c 1.26, CHCl3); HRMS (ESI-
(−)-1-O-Allyl-4-O-p-bromobenzyl-5,6-O-isopropylidene-1D-
TOF) m/z [M + Na]+ calcd for C19H25NO8Na 418.1478, found
418.1477. All other spectroscopic data were consistent with those for
( )-6h.
myo-inositol ((−)-6g). Using method A, (−)-7g (50 mg, 0.11 mmol)
20
gave the title compound (−)-6g (45 mg, 98%) as a white solid: [α]D
= −7.6° (c 0.84, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C19H2579BrO6Na 451.0727, found 451.0736. All other spectroscopic
data were consistent with those for ( )-6g.
(−)-5-O-Acetyl-2,3-O-isopropylidene-1,4-di-O-propyl-1D-
myo-inositol ((−)-7i) and (+)-1,2-O-isopropylidene-3,6-di-O-
propyl-1D-myo-inositol ((+)-6i). Using the procedure for the
resolution of ( )-6a, treatment of ( )-6i (81 mg, 0.27 mmol) with
Novozym 435 beads (40 mg) in freshly distilled vinyl acetate (5 mL)
gave after purification by column chromatography (EtOAc/PE, 1/2 to
(−)-1-O-Allyl-2,3-O-isopropylidene-4-O-p-nitrobenzyl-1D-
myo-inositol ((−)-6h). Using method A, (−)-7h (38 mg, 0.11 mmol)
22
gave the title compound (−)-6h (32 mg, 93%) as a white solid: [α]D
= −0.7° (c 0.94, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
J
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C19H25NO8Na 418.1478, found 418.1479. All other spectroscopic data
were consistent with those for ( )-6h.
17.2, 1.7 Hz), 5.17 (1H, dt, J = 10.5, 1.5 Hz), 4.94−4.77 (6H, m),
4.78−4.74 (2H, m), 4.25 (1H, q, J = 2.3 Hz), 4.18 (2H, dq, J = 5.7, 1.4
Hz), 4.03−3.89 (8H, m), 3.49−3.40 (2H, m), 3.30 (1H, ddd, J = 9.6,
2.7, 1.5 Hz), 2.47 ppm (1H, s); 13C NMR (126 MHz, CDCl3) δ
149.20, 148.73, 140.67, 138.76, 138.73, 138.70, 136.54, 134.69, 133.80,
128.37, 128.36, 128.09, 128.04, 127.83, 127.61, 127.59, 127.55, 126.92,
119.37, 117.46, 111.53, 110.41, 83.13, 81.23, 81.19, 79.89, 79.63,
76.00, 75.97, 75.95, 72.50, 71.94, 67.73, 56.01, 55.98 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C45H48O8Na 739.3247, found
739.3249.
(−)-2,3-O-Isopropylidene-1,4-di-O-propyl-1D-myo-inositol
((−)-6i). Using method A, (−)-7b (44 mg, 0.13 mmol) gave the title
21
compound (−)-6i (28 mg, 72%) as a white solid: [α]D = −14.3° (c
0.71, CHCl3). HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C15H28O6Na 327.1784, found 327.1780. All other spectroscopic data
were consistent with those for ( )-6i.
(+)-1-O-Allyl-4,5,6-tri-O-benzyl-2,3-O-isopropylidene-1D-
myo-inositol (12). Benzyl bromide (1.30 mL, 10.96 mmol) and then
sodium hydride (60% in oil, 0.38 g, 9.4 mmol) were added with
stirring to a solution of diol (−)-6c (1.097 g, 3.13 mmol) in dry DMF
(50 mL) at 0 °C under Ar. The reaction mixture was stirred overnight
at room temperature and then carefully quenched with water. The
mixture was diluted with EtOAc, washed with water and then brine,
and dried. After removal of the solvent the residue was purified by
column chromatography (EtOAc/PE, 1/6 to 1/5) to give the title
compound (+)-12 (1.607 g, 97%) as a colorless oil: [α]D20 = +33.1° (c
0.87, CHCl3); νmax (cm−1) 2987, 2889, 736, 697; 1H NMR (500 MHz,
CDCl3) δ 7.40−7.22 (15H, m), 5.96 (1H, ddt, J = 17.2, 10.4, 5.8 Hz),
5.29 (1H, dq, J = 17.3, 1.6 Hz), 5.19 (1H, dq, J = 10.3, 1.3 Hz), 4.90−
4.71 (6H, m), 4.41 (1H, d, J = 5.6, 3.8 Hz), 4.30−4.20 (2H, m), 4.17
(1H, dd, J = 6.8, 5.6 Hz), 3.90 (1H, t, J = 8.6 Hz), 3.79 (1H, dd, J =
9.3, 6.8 Hz), 3.65 (1H, dd, J = 8.7, 3.8 Hz), 3.44 (1H, dd, J = 9.3, 8.4
Hz), 1.51 (3H, s), 1.39 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ
138.58, 138.56, 138.52, 134.92, 128.30, 128.26, 128.21, 127.97, 127.92,
127.58, 127.52, 127.49, 117.51, 109.85, 82.47, 82.19, 80.78, 79.09,
77.03, 75.20, 75.19, 74.59, 73.84, 72.49, 27.65, 25.80 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C33H38O6Na 553.2566, found
553.2565.
(+)-1-O-Allyl-4,5,6-tri-O-benzyl-1D-myo-inositol (13). TFA
(1.38 mL, 17.9 mmol) and then methanol (0.73 mL, 17.9 mmol)
were added to (+)-12 (1.580 g, 2.98 mmol) in CH2Cl2 (15 mL), and
the mixture was stirred overnight at room temperature. The reaction
mixture was diluted with EtOAc, washed with sodium bicarbonate and
then brine, and dried and the solvent removed. The residue was
purified by column chromatography (EtOAc/PE, 1/1) to give the title
compound (+)-13 (1.325 g, 93%) as a white solid: [α]D20 = +26.4° (c
0.96, CHCl3); νmax (cm−1) 3435, 3031, 2886, 1130, 732, 697; 1H
NMR (500 MHz, CDCl3) δ 7.37−7.21 (15H, m), 5.93 (1H, ddt, J =
17.3, 10.4, 5.7 Hz), 5.30 (1H, dq, J = 17.2, 1.6 Hz), 5.19 (1H, dq, J =
10.4, 1.3 Hz), 4.98−4.72 (6H, m), 4.22−4.14 (3H, m), 3.92 (1H, t, J =
9.4 Hz), 3.82 (1H, t, J = 9.5 Hz), 3.53−3.43 (2H, m), 3.36 (1H, dd, J =
9.5, 2.8 Hz), 2.58−2.57 (1H, m), 2.49 ppm (1H, d, 4.6 Hz); 13C NMR
(126 MHz, CDCl3) δ 138.67, 138.58, 138.54, 134.56, 128.56, 128.37,
128.03, 127.96, 127.85, 127.79, 127.61, 127.59, 117.59, 83.20, 81.62,
81.35, 79.85, 75.93, 75.68, 75.61, 71.79, 69.34 ppm; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C30H34O6Na 513.2253, found
513.2253.
2-O-Benzoyl-3,4-di-O-benzyl-6-O-tert-butyldimethylsilyl-α-
D-mannopyranosyl Trichloroacetimidate (15). A solution of 3,4-
di-O-benzyl-2-O-benzoyl-6-O-tert-butyldimethylsilyl-D-mannopyranose
(0.160 g, 0.276 mmol) in dry CH2Cl2 (2 mL) was cooled to 0 °C
under nitrogen. Trichloroacetonitrile (0.270 mL, 2.76 mmol) and a
catalytic amount of sodium hydride were added. After the mixture was
stirred for 30 min, the solvent was removed under reduced pressure to
give 154b in quantitative yield as a yellow oil: H NMR (500 MHz,
1
CDCl3) δ 8.66 (1H, s), 8.15−8.12 (2H), 7.62−7.58 (1H), 7.49−7.45
(2H), 7.36−7.23 (10H, m), 6.39 (1H, d, J = 2.0 Hz), 5.73 (1H, dd, J =
2.1, 3.2 Hz), 4.92 (1H, d, J = 10.6 Hz), 4.81 (1H, d, J = 11.4 Hz), 4.69
(1H, d, J = 10.6 Hz), 4.62 (1H, d, J = 11.4 Hz), 4.23 (1H, t, J = 9.6
Hz), 4.14 (1H, dd, J = 3.3, 9.7 Hz), 4.03 (1H, dd, J = 2.9, 11.3 Hz),
3.92−3.86 (2H, m), 0.95 (s, 9H), 0.11 (s, 3H), 0.10 ppm (s, 3H).
1-O-Allyl-2-O-(2′-O-benzoyl-3′,4′-di-O-benzyl-6′-O-tert-bu-
tyldimethylsilyl-α-D-mannopyranosyl)-4,5,6-tri-O-benzyl-3-O-
(4-(3,4-dimethoxyphenyl)benzyl)-1D-myo-inositol (16). Trime-
thylsilyl triflate (TMSOTf; 4 μL, 0.02 mmol) was added to a mixture
of alcohol (−)-14 (162 mg, 0.226 mmol), TCA donor 15 (200 mg,
0.277 mmol), and powdered 4 Å molecular sieves in dry toluene (5
mL) at 0 °C. After it was stirred for 40 min at that temperature, the
reaction mixture was quenched with Et3N, filtered through Celite, and
evaporated to dryness. The residue was purified by column
chromatography (EtOAc/toluene 1/9, then EtOAc/PE 1/4 to 1/3)
20
to give the title compound 16 (265 mg, 92%) as a colorless oil: [α]D
= +18.1° (c 2.08, CHCl3); νmax (cm−1) 2929, 2856, 1725, 737, 698; 1H
NMR (500 MHz, CDCl3) δ 8.12 (2H, dd, J = 8.4, 1.4 Hz), 7.60−7.04
(34H, m), 6.94 (1H, d, J = 8.3 Hz), 5.86 (1H, ddt, J = 17.3, 10.5, 5.3
Hz), 5.74 (1H, dd, J = 2.7, 1.9 Hz), 5.32 (1H, d, J = 1.9 Hz), 5.25 (1H,
dq, J = 17.3, 1.7 Hz), 5.07 (1H, dq, J = 10.5, 1.4 Hz), 4.94−4.74 (9H,
m), 4.68−4.57 (3H, m), 4.37 (1H, t, J = 2.4 Hz), 4.19−4.04 (5H, m),
3.99−3.83 (8H, m), 3.71 (1H, dd, J = 11.4, 2.3 Hz), 3.54−3.41 (2H,
m), 3.35 (1H, dd, J = 9.9, 2.6 Hz), 3.30 (1H, dd, J = 9.7, 2.2 Hz), 0.91
(9H, s), 0.03 (3H, s), −0.01 ppm (3H, s); 13C NMR (126 MHz,
CDCl3) δ 165.66, 149.41, 148.91, 140.40, 139.28, 138.98, 138.93,
138.33, 137.03, 134.70, 134.14, 133.14, 130.48, 130.22, 128.57, 128.53,
128.50, 128.43, 128.32, 128.17, 127.99, 127.80, 127.74, 127.61, 126.94,
119.61, 116.98, 111.77, 110.69, 99.26 (1JCH = 172.4 Hz), 83.62, 81.61,
81.40, 80.73, 79.39, 78.02, 76.31, 76.10, 76.02, 75.15, 74.18, 72.77,
72.50, 72.33, 71.91, 71.86, 69.45, 62.00, 56.25, 56.17, 26.22, 18.55,
−4.96, −5.19 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C78H88O14SiNa 1299.5841, found 1299.5831.
(−)-1-O-Allyl-4,5,6-O-benzyl-3-O-(4-(3,4-dimethoxyphenyl)-
benzyl)-1D-myo-inositol (14). Diol (+)-13 (1.300 g, 2.65 mmol)
and dibutyltin oxide (0.788 g, 3.17 mmol) were coevaporated from
toluene, dried under high vacuum, and then redissolved in toluene (25
mL). The reaction mixture was heated at reflux in a Dean−Stark
apparatus for 1 h until a clear, yellow solution formed. Once the
solution was cooled, the solvent was removed under reduced pressure.
Cesium fluoride (0.650 g, 4.28 mmol) and 4-(3,4-dimethoxyphenyl)-
benzyl bromide (0.895 g, 2.91 mmol) were added to the residue,
which was coevaporated from toluene and dried under high vacuum.
Dry DMF (20 mL) was added, and the reaction mixture was heated
overnight at 55 °C. The reaction mixture was cooled to room
temperature and diluted with ether. The mixture was washed with
water, and the organic layers were washed with brine, dried, and
evaporated. The residue was purified by column chromatography
(EtOAc/PE, 1/6 to 1/4) to give the title compound (−)-14 (1.312 g,
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(3′,4′-di-O-benzyl-6′-O-tert-
butyldimethylsilyl-α-D-mannopyranosyl)-3-O-(4-(3,4-
dimethoxyphenyl)benzyl)-1D-myo-inositol (17). A solution of
sodium methoxide in methanol, formed from the reaction of sodium
(10 mg, 0.4 mmol) and MeOH (2 mL), was added to a suspension of
16 (50 mg, 0.039 mmol) in CH2Cl2/MeOH (1/9, 5 mL). The
reaction mixture was stirred for 36 h at room temperature, quenched
with water, diluted with EtOAc, washed with water and then brine and
the organic phase dried. The solvent was removed and the residue
purified by column chromatography (EtOAc/PE 1/5) to give the title
compound 17 (39 mg, 98%) as a colorless oil: [α]D20 = +54.5° (c 0.91,
1
CHCl3); νmax (cm−1) 3476, 2927, 2855, 1129, 737, 398; H NMR
(500 MHz, CDCl3) δ 7.55−7.17 (30H, m), 7.11−7.03 (1H, m), 6.94
(1H, J = 8.3 Hz), 5.90 (1H, ddt, J = 17.3, 10.7, 5.5 Hz), 5.31 (1H, d, J
= 1.7 Hz), 5.27 (1H, dq, J = 17.2, 1.6 Hz), 5.16 (1H, dq, J = 10.4, 1.4
Hz), 4.92 (1H, d, J = 10.8 Hz), 4.88−4.68 (9H, m), 4.63 (dd, J = 11.4,
2.2 Hz), 4.38 (t, J = 2.4 Hz), 4.20−4.10 (2H, m), 4.07 (2H, m), 3.95−
3.78 (10H, m), 3.64 (1H, dd, J = 11.5, 3.4 Hz), 3.52 (1H, dd, J = 11.4,
23
69%) as a white solid: [α]D = −1.5° (c 1.10, CHCl3); νmax (cm−1)
3437, 3029, 2904, 1131, 730, 694; 1H NMR (500 MHz, CDCl3) δ 7.51
(dt, J = 8.2, 1.8 Hz), 7.43−7.37 (2H, m), 7.35−7.22 (15H, m), 7.13
(1H, dt, J = 8.3, 1.9 Hz), 7.08 (1H, t, J = 1.9 Hz), 6.94 (1H, dd, J = 8.4,
1.5 Hz), 5.93 (1H, ddtd, J = 17.7, 10.3, 5.7, 1.6 Hz), 5.28 (1H, dt, J =
K
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.6 Hz), 3.44 (1H, t, J = 9.3 Hz), 3.33 (1H, dd, J = 9.9, 2.5 Hz), 3.27
(1H, dd, J = 9.8, 2.1 Hz), 2.31 (1H, s), 0.85 (9H, s), 0.01 (3H, s),
−0.02 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 149.20, 148.68,
140.18, 138.95, 138.75, 138.69, 138.08, 136.79, 134.59, 133.96, 128.54,
128.40, 128.34, 128.29, 128.22, 128.11, 128.04, 127.87, 127.83, 127.66,
127.60, 127.50, 126.71, 119.39, 117.12, 111.56, 110.48, 99.91, 83.46,
81.53, 81.20, 80.82, 79.56, 79.26, 76.16, 75.86, 75.72, 74.91, 74.05,
72.17, 72.12, 71.92, 71.84, 71.49, 68.76, 62.17, 56.03, 55.96, 25.99,
18.35, −5.09, −5.36 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C71H84O13SiNa 1195.5579, found 1195.5562.
(78 mg, 0.30 mmol), dimethylaminopyridine (DMAP; 4 mg, 0.03
mmol), and dicyclohexylcarbodiimide (DCC; 0.052 g, 0.25 mmol)
were added to a solution of the above compound (67 mg, 0.058
mmol) in dry CH2Cl2 (5 mL). The reaction mixture was stirred
overnight at room temperature and the solvent evaporated. The
residue was purified by column chromatography (EtOAc/PE, 1/9 to
1/2) to give the title compound 20 (65 mg, 80%) as a colorless oil:
30
[α]D = +28.0° (c 0.97, CHCl3); νmax (cm−1) 2922, 2852, 1731, 736,
1
697; H NMR (500 MHz, CDCl3) δ 7.57−6.86 (37H, m), 5.87 (1H,
ddt, J = 17.3, 10.4, 5.7 Hz), 5.39 (1H, d, J = 1.7 Hz), 5.25 (1H, dq, J =
17.2, 1.6 Hz), 5.14 (1H, dq, J = 10.4, 1.3 Hz), 4.95−4.48 (14H, m),
4.32 (1H, t, J = 2.4 Hz), 4.25−4.08 (4H, m), 4.06 (1H, d, J = 11.1, 2.0
Hz), 3.98 (1H, t, J = 9.7 Hz), 3.94 (3H, s), 3.92 (3H, s), 3.86 (1H, dd,
J = 9.6, 3.2 Hz), 3.78−3.73 (2H, m), 3.67 (1H, t, J = 9.5 Hz), 3.39
(1H, t, J = 9.3 Hz), 3.31 (1H, dd, J = 9.9, 2.6 Hz), 3.23 (1H, dd, J =
9.8, 2.2 Hz), 2.25 (2H, t, J = 7.6 Hz), 1.73−1.38 (2H, m), 1.38−1.09
(24H, m), 0.86 ppm (3H, t, J = 6.9 Hz); 13C NMR (126 MHz,
CDCl3) δ 173.85, 149.37, 148.81, 140.65, 138.86, 138.84, 138.82,
138.65, 138.46, 138.37, 136.65, 134.72, 134.22, 128.66, 128.64, 128.63,
128.61, 128.60, 128.57, 128.55, 128.45, 128.35, 128.33, 128.28, 128.22,
128.20, 128.03, 127.91, 127.88, 127.86, 127.83, 127.75, 127.14, 119.61,
117.73, 111.66, 110.76, 98.40, 83.54, 81.56, 81.32, 81.05, 79.22, 78.81,
76.38, 76.05, 75.93, 75.48, 74.59, 74.21, 72.62, 72.50, 72.33, 72.21,
72.03, 70.21, 63.33, 56.22, 56.17, 34.44, 32.14, 29.92, 29.90, 29.88,
29.85, 29.72, 29.58, 29.51, 29.43, 25.11, 22.91, 14.34 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C88H106O14Na 1409.7480, found
1409.7484.
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-
tert-butyldimethylsilyl-α-D-mannopyranosyl)-3-O-(4-(3,4-
dimethoxyphenyl)benzyl)-1D-myo-inositol (18). Benzyl bromide
(0.014 mL, 0.114 mmol) and then sodium hydride (60% in oil, 6 mg,
0.2 mmol) were added to a solution of 17 (76 mg, 0.076 mmol) in dry
DMF (5 mL) at 0 °C. The reaction mixture was stirred overnight at
room temperature and then quenched with water and diluted with
EtOAc. The mixture was washed with water and then brine, and the
organic phase was dried. The solvent was removed, and the residue
was purified by column chromatography (EtOAc/PE, 1/4) to give the
20
title compound 18 (71 mg, 94%) as an oil: [α]D = +36.5° (c 1.24,
1
CHCl3); νmax (cm−1) 2927, 2856, 737, 698; H NMR (500 MHz,
CDCl3) δ 7.53−7.13 (34H, m), 7.09 (1H, dd, J = 8.3, 2.1 Hz), 7.05
(1H, d, J = 2.1 Hz), 6.93 (1H, d, J = 8.3 Hz), 5.88 (1H, ddt, J = 17.2,
10.3, 5.6 Hz), 5.36 (1H, d, J = 1.7 Hz), 5.26 (1H, dq, J = 17.2, 1.6 Hz),
5.14 (1H, dq, J = 10.4, 1.4 Hz), 4.95−4.71 (8H, m), 4.67−4.56 (6H,
m), 4.37 (1H, t, J = 2.4 Hz), 4.12 (2H, dt, J = 5.7, 1.4 Hz), 4.07 (1H, t,
J = 9.7 Hz), 4.00 (1H, ddd, J = 9.9, 3.5, 1.6 Hz), 3.93 (3H, s), 3.92
(3H, s), 3.88 (1H, dd, J = 9.6, 3.2 Hz), 3.78 (1H, t, J = 9.5 Hz), 3.73
(1H, dd, J = 3.3, 1.7 Hz), 3.72−3.67 (2H, m), 3.54 (1H, dd, J = 11.5,
1.6 Hz), 3.40 (1H, t, J = 9.3 Hz), 3.31 (1H, dd, J = 9.9, 2.6 Hz), 3.23
(1H, dd, J = 9.8, 2.1 Hz), 0.86 (9H, s), 0.02 (3H, s), −0.01 (3H, s);
13C NMR (126 MHz, CDCl3) δ 149.35, 148.82, 140.33, 139.40,
138.95, 138.93, 138.91, 138.80, 138.70, 137.04, 134.81, 134.17, 128.60,
128.58, 128.55, 128.46, 128.46, 128.38, 128.31, 128.27, 128.21, 128.12,
128.10, 127.88, 127.84, 127.72, 127.71, 127.60, 126.91, 119.57, 117.57,
111.69, 110.61, 98.19, 83.58, 81.60, 81.33, 81.28, 79.37, 79.29, 77.43,
76.35, 76.07, 75.95, 75.16, 74.98, 74.71, 72.90, 72.35, 72.21, 72.02,
71.33, 62.53, 56.23, 56.15, 26.21, 18.59, −5.06, −5.30 ppm; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C78H90O13SiNa 1285.6048,
found 1285.6030.
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-α-D-
mannopyranosyl)-3-O-(4-(3,4-dimethoxyphenyl)benzyl)-1D-
myo-inositol (19). Acetyl chloride (96 μL, 1.3 mmol) was added to a
solution of 18 (85 mg, 0.067 mmol) in CH2Cl2/MeOH (3/7, 10 mL)
and stirred at room temperature for 45 min. The reaction mixture was
diluted with CH2Cl2 and washed with water and then brine. The
organic phase was dried and evaporated, and the residue was purified
by column chromatography (EtOAc/PE, 1/2 to 1/1) to give title
compound 19 (69 mg, 89%) as a colorless oil: [α]D20 = +43.2° (c 1.05,
CHCl3); νmax (cm−1) 3489, 3030, 2924, 739, 698; 1H NMR (500
MHz, CDCl3) δ 7.53−7.20 (34H, m), 7.15 (1H, dd, J = 8.2, 2.1 Hz),
7.11 (1H, d, J = 2.1 Hz), 6.98 (1H, d, J = 8.3 Hz), 5.95 (1H, ddt, J =
17.3, 10.4, 5.6 Hz), 5.40 (1H, d, J = 1.7 Hz), 5.33 (1H, dq, J = 17.2, 1.6
Hz), 5.22 (1H, dq, J = 10.4, 1.4 Hz), 5.04−4.59 (14H, m), 4.35 (1H, t,
J = 2.4 Hz), 4.22−4.10 (3H, m), 4.06 (1H, t, J = 9.6 Hz), 3.97 (3H, s),
3.96 (3H, s), 3.94 (1H, dd, J = 9.4, 3.1 Hz), 3.87−3.80 (2H, m), 3.73
(1H, t, J = 9.5 Hz), 3.66 (2H, t, J = 2.9 Hz), 3.46 (1H, t, J = 9.3 Hz),
3.37 (1H, dd, J = 9.9, 2.6 Hz), 3.29 (1H, dd, J = 9.8, 2.1 Hz), 1.88 ppm
(1H, s); 13C NMR (126 MHz, CDCl3) δ 149.34, 148.82, 140.44,
138.84, 138.81, 138.56, 138.37, 136.77, 134.72, 134.04, 128.62, 128.59,
128.58, 128.54, 128.53, 128.49, 128.30, 128.25, 128.19, 128.11, 127.96,
127.95, 127.87, 127.85, 127.83, 127.80, 127.71, 126.93, 119.54, 117.62,
111.68, 110.58, 98.78, 83.51, 81.54, 81.27, 81.06, 79.28, 79.00, 76.35,
76.02, 75.90, 75.32, 74.86, 74.60, 72.42, 72.40, 72.32, 72.26, 72.24,
62.31, 56.19, 56.14 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C72H76O13Na 1171.5184, found 1171.5177.
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-
palmitoyl-α-D-mannopyranosyl)-1D-myo-inositol (21). TFA
(0.80 mL, 10.4 mmol) was added to a solution of 20 (0.065 g,
0.047 mmol) and 3,4-(methylenedioxy)toluene (0.064 g, 0.47 mmol)
in dry CH2Cl2 (3.5 mL), and the reaction mixture was stirred at room
temperature for 3 h. Water was added to the mixture, which was then
extracted into CH2Cl2. The organic phase was washed with sodium
bicarbonate and brine, dried, and evaporated. The residue was purified
by column chromatography (EtOAc/PE, 1/4) to give the title
compound 21 (45 mg, 83%) as a colorless oil: [α]D30 = +0.4° (c 0.60,
1
CHCl3); νmax (cm−1) 2922, 2952, 1734, 734, 697; H NMR (500
MHz, CDCl3) δ 7.44−7.15 (30H, m), 5.88 (1H, ddt, J = 17.3, 10.5, 5.7
Hz), 5.31−5.25 (1H, m), 5.23 (1H, d, J = 1.8 Hz), 5.17 (1H, dq, J =
10.4, 1.4 Hz), 4.97−4.64 (9H, m), 4.62−4.53 (3H, m), 4.33 (1H, dd, J
= 11.9, 4.7 Hz), 4.25 (1H, dd, J = 11.9, 2.1 Hz), 4.16 (1H, t, J = 2.5
Hz), 4.11 (2H, dt, J = 5.6, 1.4 Hz), 4.06 (1H, ddd, J = 9.9, 4.7, 2.0 Hz),
3.93 (1H, t, J = 9.5 Hz), 3.84−3.75 (2H, m), 3.70 (1H, t, J = 9.5 Hz),
3.55 (1H, t, J = 9.5 Hz), 3.46−3.36 (2H, m), 3.31 (1H, dd, J = 9.7, 2.3
Hz), 2.35−2.29 (2H, m), 2.08 (1H, d, J = 4.1 Hz), 1.66−1.53 (2H, m),
1.34−1.19 (24H, m), 0.88 ppm (3H, t, J = 6.9 Hz); 13C NMR (126
MHz, CDCl3) δ 173.99, 138.79, 138.69, 138.55, 138.41, 138.33,
134.72, 128.94, 128.68, 128.66, 128.65, 128.62, 128.50, 128.35, 128.33,
128.23, 128.21, 128.18, 128.01, 127.96, 127.95, 127.92, 127.90, 117.70,
99.04, 83.62, 82.02, 81.25, 80.62, 79.27, 76.18, 76.11, 75.77, 75.57,
75.48, 74.73, 74.36, 72.30, 72.19, 72.15, 70.91, 70.54, 63.53, 34.45,
32.15, 29.92, 29.91, 29.89, 29.88, 29.85, 29.73, 29.59, 29.53, 29.43,
25.12, 22.92, 14.35 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C73H92O12Na 1183.6481, found 1183.6479.
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-
palmitoyl-α-D-mannopyranosyl)-3-O-stearoyl-1D-myo-inositol
(22). Stearic acid (19 mg, 0.067 mmol), DMAP (3 mg, 0.02 mmol),
and DCC (5 mg, 0.02 mmol) were added to a solution of 21 (12 mg,
0.010 mmol) in dry CH2Cl2 (5 mL). The reaction mixture was stirred
overnight at room temperature. The reaction mixture was filtered
through a plug of basic alumina and eluted with CH2Cl2. The crude
residue was purified by column chromatography (PE to EtOAc/PE 1/
9) to give the title compound 22 (13 mg, 83%) as a colorless oil:
31
[α]D = +19.8° (c 0.62, CHCl3); νmax (cm−1) 2921, 2852, 1737, 733,
697; 1H NMR (500 MHz, CDCl3) δ 7.47−7.12 (30 H, m), 5.88 (1H,
ddt, J = 17.3, 10.4, 5.7 Hz), 5.35 (1H, d, J = 1.7 Hz), 5.28 (1H, dq, J =
17.2, 1.6 Hz), 5.17 (1H, dq, J = 10.4, 1.3 Hz), 4.97 (1H, d, J = 10.7
Hz), 4.88−4.54 (13H, m), 4.41 (1H, dd, J = 11.7, 3.8 Hz), 4.23 (1H, t,
J = 2.4 Hz), 4.16 (1H, dd, J = 11.8, 1.6 Hz), 4.14−4.09 (2H, m), 4.01−
1-O-Allyl-4,5,6-tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-
p a l m i t o y l - α - D - m a n n o p y r a n o s y l ) - 3 - O - ( 4 - ( 3 , 4 -
dimethoxyphenyl)benzyl)-1D-myo-inositol (20). Palmitic acid
L
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.92 (2H, m), 3.84 (1H, dd, J = 8.9, 3.0 Hz), 3.79 (1H, dd, J = 3.1, 1.8
Hz), 3.75 (1H, dd, J = 10.4, 9.2 Hz), 3.68 (1H, t, J = 9.5 Hz), 3.48
(1H, t, J = 9.3 Hz), 3.40 (1H, dd, J = 9.7, 2.1 Hz), 2.35−2.28 (2H, m),
2.20−2.01 (2H, m), 1.68−1.44 (4H, m), 1.39−1.12 (52H, m), 0.88
ppm (6H, t, J = 6.8 Hz); 13C NMR (126 MHz, CDCl3) δ 173.88,
173.19, 138.73, 138.59, 138.53, 138.50, 138.31, 138.26, 134.45, 128.71,
128.66, 128.64, 128.62, 128.58, 128.51, 128.38, 128.32, 128.29, 128.22,
128.18, 128.01, 127.98, 127.96, 127.92, 127.78, 118.04, 98.12, 83.51,
81.46, 80.75, 79.28, 79.11, 76.43, 76.14, 75.60, 75.58, 74.58, 73.95,
72.94, 72.39, 72.17, 72.05, 71.74, 70.51, 63.33, 34.39, 34.33, 32.15,
29.96, 29.95, 29.93, 29.91, 29.89, 29.87, 29.75, 29.69, 29.59, 29.58,
29.56, 29.45, 29.39, 25.13, 24.93, 22.92, 14.35 ppm; HRMS (ESI-
TOF) m/z calcd for C91H126O13Na [M + Na]+ 1449.9091, found
1449.9089.
C30H34O6Na 513.2253, found 513.2230. All other spectroscopic data
were consistent with those for 13.
(+)-3-O-Allyl-4,5,6-O-benzyl-1-O-(4-(3,4-dimethoxyphenyl)-
benzyl)-1D-myo-inositol (ent-14). Diol ent-13 (0.680 g, 1.39 mmol)
and dibutyltin oxide (0.416 g, 1.67 mmol) were coevaporated from
toluene, dried under high vacuum, and then redissolved in toluene (25
mL). The reaction mixture was refluxed in a Dean−Stark apparatus for
1 h until a clear, yellow solution formed. Once the solution was cooled,
the solvent was removed under reduced pressure. Cesium fluoride
(0.316 g, 2.08 mmol) and 4-(3,4-dimethoxyphenyl)benzyl bromide
(0.468 g, 1.525 mmol) were added to the residue which was
coevaporated from toluene and dried under high vacuum. The mixture
was dissolved in dry DMF (20 mL) and heated overnight at 50 °C.
The reaction mixture was cooled to room temperature and then
diluted with ether and washed with water. The combined organic
layers were washed with brine, dried, and evaporated. The residue was
4,5,6-Tri-O-benzyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-palmitoyl-
α-D-mannopyranosyl)-3-O-stearoyl-1D-myo-inositol (11). (1,5-
Cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluoro-
phosphate (4 mg, 0.005 mmol) was added to a stirred solution of
22 (16 mg, 0.011 mmol), in dry THF (2 mL) at room temperature
under an atmosphere of Ar. The atmosphere was replaced with
hydrogen for ca. 1 min and then replaced by Ar, the red solution
changing to yellow. The reaction mixture was stirred for 2 h, the
solvent removed, and the residue dissolved in acetone/water (9/1, 10
mL). To the solution were added mercuric oxide (50 mg, 0.023 mmol)
and mercuric chloride (60 mg, 0.022 mmol), and this mixture was then
heated to 100 °C for 3 h. Once it was cooled to room temperature, the
reaction mixture was filtered through Celite and washed with CH2Cl2
and the solvent from the filtrate evaporated. The residue was dissolved
in CH2Cl2, the solution washed with aqueous potassium iodide (5%)
and dried, and the solvent evaporated. The residue was purified by
column chromatography (PE to EtOAc/PE 1/4) to give the title
compound 11 (11 mg, 71%) as a colorless oil: [α]D20 = +10.1° (c 1.07,
purified by column chromatography (EtOAc/PE, 1/6 to 1/4) to give
27
the title compound ent-14 (702 mg, 71%) as a white solid: [α]D
=
+1.3° (c 1.06, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C45H48O8Na 739.3247, found m/z 739.3265. All other spectroscopic
data were consistent with those for 14.
3-O-Allyl-2-O-(2′-O-benzoyl-3′,4′-di-O-benzyl-6′-O-tert-bu-
tyldimethylsilyl-α-D-mannopyranosyl)-4,5,6-tri-O-benzyl-1-O-
(4-(3,4-dimethoxyphenyl)benzyl)-1D-myo-inositol (24). (a)
TMSOTf (4 μL, 0.02 mmol) was added to a mixture of the alcohol
ent-14 (61 mg, 0.085 mmol), TCA donor 15 (0.08 g, 0.111 mmol),
and powdered 4 Å molecular sieves in dry toluene (3 mL) at 0 °C.
After it was stirred for 40 min at that temperature, the reaction mixture
was quenched with Et3N, filtered through Celite, and evaporated to
dryness. The residue was purified by column chromatography
(EtOAc/toluene 1/9, then EtOAc/PE 1/4) to give the title compound
28
24 (61 mg, 72%) as a colorless oil: [α]D = +4.4° (c 2.15, CHCl3);
νmax (cm−1) 2928, 2855, 1723, 738, 697; 1H NMR (500 MHz, CDCl3)
δ 8.08 (2H, dt, J = 8.3, 1.2 Hz), 7.56−7.47 (1H, m), 7.42−7.10 (30H,
m), 6.97−6.92 (2H, m), 6.88 (1H, d, J = 7.9 Hz), 5.84 (1H, ddtd, J =
16.9, 10.6, 5.3, 1.0 Hz), 5.76−5.71 (1H, m), 5.41−5.36 (1H, m), 5.25
(1H, dt, J = 17.2, 1.4 Hz), 5.11 (1H, dt, J = 10.6, 1.4 Hz), 4.95−4.56
(14H, m), 4.35 (1H, t, J = 2.5 Hz), 4.20−3.86 (13H, m), 3.82−3.74
(2H, m), 3.44 (1H, td, J = 9.3, 1.1 Hz), 3.40 (1H, ddd, J = 9.9, 2.3, 1.1
Hz), 3.22 (1H, ddd, J = 10.0, 2.8, 1.1 Hz), 0.95 (9H, s), 0.10 (3H, s),
0.08 ppm (3H, s); 13C NMR (126 MHz, CDCl3) δ 165.58, 149.28,
148.78, 140.36, 139.18, 138.91, 138.84, 138.27, 136.71, 134.91, 134.05,
133.02, 130.37, 130.14, 128.53, 128.49, 128.45, 128.39, 128.32, 128.26,
128.12, 128.02, 127.98, 127.75, 127.70, 127.60, 126.90, 119.49, 116.78,
111.66, 110.62, 99.08 (1JCH = 171.9 Hz), 83.53, 81.57, 81.27, 81.08,
79.11, 78.02, 76.26, 76.06, 75.92, 75.21, 74.20, 72.66, 72.47, 72.27,
71.87, 71.69, 69.47, 62.30, 56.16, 56.09, 26.19, 18.57, −4.94, −5.15
ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C78H88O14SiNa
1299.5836, found 1299.5811.
1
CHCl3); νmax (cm−1) 3506, 2921, 2853, 1739, 735, 697; H NMR
(500 MHz, CDCl3) δ 7.43−7.14 (30H, m), 5.29 (1H, d, J = 1.8 Hz),
4.99−4.73 (5H, m), 4.69−4.53 (8H, m), 4.43−4.36 (1H, m), 4.21−
4.13 (2H, m), 3.95 (2H, m), 3.85 (1H, dt, J = 6.9, 3.0 Hz), 3.77 (1H,
ddd, J = 10.4, 6.6, 2.6 Hz), 3.68 (1H, dd, J = 3.1, 1.8 Hz), 3.57 (1H, dt,
J = 6.7, 2.3 Hz), 3.54−3.49 (2H, m), 2.32−2.25 (2H, m), 2.22−2.03
(3H, m), 1.65−1.45 (6H, m), 1.30−1.13 (52H, m), 0.88 ppm (6H, t, J
= 6.8 Hz); 13C NMR (126 MHz, CDCl3) δ 173.66, 172.85, 138.33,
138.28, 138.24, 138.22, 138.18, 128.76, 128.52, 128.49, 128.42, 128.39,
128.21, 128.14, 128.07, 128.00, 127.89, 127.87, 127.80, 127.61, 127.58,
127.48, 98.37, 83.59, 80.97, 79.83, 78.88, 75.92, 75.44, 75.36, 74.64,
74.51, 74.37, 72.17, 71.98, 71.95, 71.68, 70.34, 63.08, 34.18, 34.15,
31.94, 29.71, 29.69, 29.68, 29.65, 29.63, 29.51, 29.44, 29.35, 29.33,
29.30, 29.22, 29.16, 24.91, 24.72, 22.70, 14.11 ppm; HRMS (ESI-
TOF): calcd for C88H122O13Na [M + Na]+ m/z 1409.8783, Found m/
z 1409.8773.
(−)-3-O-Allyl-4,5,6-tri-O-benzyl-1,2-O-isopropylidene-1D-
myo-inositol (ent-12). Benzyl bromide (0.58 mL, 4.8 mmol) and
then sodium hydride (60% in oil, 0.16 g, 6.5 mmol) were added with
stirring to a solution of diol (+)-6c (0.565 g, 1.612 mmol) in dry DMF
(20 mL) at 0 °C. The reaction mixture was stirred overnight at room
temperature. The reaction mixture was quenched with water, diluted
with EtOAc, and washed with water and then brine. The organic phase
was dried, the solvent removed, and the residue purified by column
chromatography (EtOAc/PE, 1/4) to give the title compound ent-12
(b) A solution of (+)-14 (476 mg, 0.664 mmol), phosphate donor
234b (669 mg, 0.868 mmol), and 4 Å molecular sieves, dried from
toluene, under Ar were dissolved in dry toluene (15 mL), and this
mixture was cooled to −78 °C before the dropwise addition of
TBSOTf (0.20 mL, 0.87 mmol). After 1 h Et3N (0.20 mL) was added.
The solution was then warmed to room temperature and filtered
through Celite, and the solvents were removed to give a yellow oil.
The residue was purified by column chromatography (PE to EtOAc/
PE, 1/5) to give the title compound 24 (747 mg, 88%) as a colorless
oil.
3-O-Allyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-tert-butyldimethyl-
silyl-α-D-mannopyranosyl)-4,5,6-tri-O-benzyl-1-O-(4-(3,4-
dimethoxyphenyl)benzyl)-1D-myo-inositol (25). A solution of
sodium methoxide, prepared from the reaction of sodium (31 mg, 1.6
mmol) and MeOH (2 mL), was added to 24 (173 mg, 0.135 mmol)
suspended in CH2Cl2/MeOH (1/9, 5 mL) and the mixture was stirred
overnight at room temperature. The reaction mixture was quenched
with water, diluted with EtOAc, and washed with water and then brine,
and the organic phase was dried and evaporated. The crude product
was purified by column chromatography (EtOAc/PE, 1/3) to give the
intermediate 3-O-allyl-2-O-(3′,4′-di-O-benzyl-6′-O-tert-butyldimethyl-
20
(0.847 g, 99%) as a colorless oil: [α]D = −36.3° (c 1.11, CHCl3);
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C33H38O6Na 553.2566,
found m/z 553.2563. All other spectroscopic data were consistent with
those for 12.
(−)-3-O-Allyl-4,5,6-tri-O-benzyl-1D-myo-inositol (ent-13).
TFA (120 μL, 1.6 mmol) and then methanol (80 μL, 1.9 mmol)
were added to ent-12 (133 mg, 0.251 mmol) in CH2Cl2 (15 mL), and
the mixture was stirred overnight at room temperature. The mixture
was diluted with EtOAc, washed with sodium bicarbonate and then
brine, and dried. The solvents were removed, and the residue was
purified by column chromatography (EtOAc/PE, 1/1) to give the title
20
compound ent-13 (99 mg, 81%) as a white solid: [α]D = −26.3° (c
1.29, CHCl3); HRMS (ESI-TOF) m/z [M + Na]+ calcd for
M
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
silyl-α-D-mannopyranosyl)-4,5,6-tri-O-benzyl-1-O-(4-(3,4-
dimethoxyphenyl)benzyl)-1D-myo-inositol (110 mg, 81%) as a color-
TOF) m/z [M + Na]+ calcd for C72H76O13Na 1171.5184, found
1171.5186.
33
less oil: [α]D = +14.6° (c 1.84, CHCl3); νmax (cm−1) 3489, 2927,
3-O-Allyl-2-O-(2′,3′,4′-tri-O-benzyl-6′-O-palmitoyl-α-D-man-
n o p y r a n o s y l ) - 4 , 5 , 6 - t r i - O - b e n z y l - 1 - O - ( 4 - ( 3 , 4 -
dimethoxyphenyl)benzyl)-1D-myo-inositol (27). Palmitic acid
(300 mg, 1.2 mmol), DMAP (12 mg, 0.10 mmol), and DCC (190
mg, 0.90 mmol) were added to a solution of 26 (551 mg, 0.479 mmol)
in CH2Cl2. The reaction mixture was stirred overnight at room
temperature and then filtered through a plug of basic alumina and
eluted with five column volumes of CH2Cl2. The residue was purified
using column chromatography (PE to EtOAc/PE, 1/4) to give the title
1
2855, 738, 698; H NMR (500 MHz, CDCl3) δ 7.53−7.48 (2H, m),
7.40−7.20 (27H, m), 7.13 (1H, dd, J = 8.3, 2.1 Hz), 7.09 (1H, d, J =
2.1 Hz), 6.94 (1H, d, J = 8.3 Hz), 5.86 (1H, ddt, J = 17.4, 10.6, 5.4
Hz), 5.41 (1H, d, J = 1.6 Hz), 5.25 (1H, dq, J = 17.3, 1.7 Hz), 5.11
(1H, dq, J = 10.5, 1.5 Hz), 4.90−4.64 (14H, m), 4.38 (1H, t, J = 2.4
Hz), 4.18 (ddt, J = 12.9, 5.4, 1.5 Hz), 4.12−4.05 (2H, m), 4.02 (1H,
ddt, J = 12.8, 5.4, 1.6 Hz), 3.95−3.76 (13H, m), 3.44 (1H, t, J = 9.3
Hz), 3.39 (1H, dd, J = 9.8, 2.1 Hz), 3.21 (1H, dd, J = 9.9, 2.6 Hz), 2.33
(1H, s), 0.91 (9H, s), 0.10 (3H, s), 0.08 ppm (3H, s); 13C NMR (126
MHz, CDCl3) δ 149.37, 148.86, 140.71, 139.11, 138.96, 138.94,
138.86, 138.26, 136.70, 134.93, 134.08, 128.73, 128.62, 128.55, 128.54,
128.53, 128.50, 128.35, 128.28, 128.27, 128.22, 128.09, 128.07, 127.88,
127.78, 127.76, 127.09, 119.55, 116.91, 111.71, 110.60, 99.78, 83.63,
81.72, 81.36, 81.30, 79.83, 79.19, 76.40, 76.10, 75.92, 75.15, 74.34,
72.79, 72.42, 72.11, 71.72, 70.86, 69.02, 62.76, 56.21, 56.16, 26.23,
18.64, −4.81, −5.08 ppm.
20
compound 27 (660 mg, 99%) as an oil: [α]D = +1.7° (c 1.79,
1
CHCl3); νmax (cm−1) 2925, 2854, 1735, 740, 698; H NMR (500
MHz, CDCl3) δ 7.45−7.38 (2H, m), 7.38−7.10 (32H, m), 7.03 (1H,
dd, J = 8.3, 2.1 Hz), 6.98 (1H, d, J = 2.1 Hz), 6.90 (1H, d, J = 8.3 Hz),
5.86 (1H, ddt, J = 17.4, 10.6, 5.4 Hz), 5.38 (1H, d, J = 1.7 Hz), 5.26
(1H, dq, J = 17.3, 1.7 Hz), 5.14 (1H, dq, J = 10.5, 1.5 Hz), 4.95−4.47
(13H, m), 4.45−4.38 (2H, m), 4.33 (1H, t, J = 2.4 Hz), 4.29−4.21
(2H, m), 4.17 (1H, ddt, J = 12.9, 5.4, 1.5 Hz), 4.03 (1H, ddt, J = 12.9,
5.4, 1.6 Hz), 3.98 (1H, t, J = 9.8 Hz), 3.91 (3H, s), 3.89 (3H, s), 3.84
(1H, dd, J = 9.6, 3.1 Hz), 3.76−3.65 (3H, m), 3.41 (1H, t, J = 9.3 Hz),
3.38 (1H, dd, J = 9.8, 2.2 Hz), 3.23 (1H, dd, J = 9.9, 2.6 Hz), 2.31 (2H,
td, J = 7.4, 2.1 Hz), 1.67−1.55 (2H,m), 1.32−1.16 (24H,m), 0.90−
0.83 ppm (3H, m); 13C NMR (126 MHz, CDCl3) δ 173.82, 149.14,
148.71, 140.70, 138.67, 138.63, 138.60, 138.45, 138.26, 138.18, 136.27,
134.62, 128.46, 128.42, 128.39, 128.37, 128.35, 128.20, 128.16, 128.10,
128.01, 127.96, 127.89, 127.80, 127.70, 127.66, 127.65, 127.63, 127.59,
127.38, 126.84, 119.34, 117.03, 111.45, 110.33, 98.29, 83.31, 81.35,
80.98, 80.96, 79.07, 78.66, 76.16, 75.79, 75.73, 75.26, 74.42, 74.38,
73.17, 72.26, 72.02, 71.76, 71.43, 69.89, 63.38, 55.99, 55.93, 34.28,
31.92, 29.69, 29.68, 29.66, 29.65, 29.62, 29.50, 29.35, 29.30, 29.24,
24.93, 22.69, 14.12 ppm; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C88H106O14Na 1409.7480, found 1409.7466;
Benzyl bromide (105 μL, 0.884 mmol), and sodium hydride (60
mg, 1.5 mmol) were added to a solution of the above intemediate
(0.689 g, 0.587 mmol) in dry DMF (10 mL) at 0 °C. The reaction
mixture was stirred over 72 h at room temperature and then quenched
with water, diluted with EtOAc, and washed with water then brine, and
the organic phase was dried and evaporated. The crude product was
purified using column chromatography (EtOAc/PE, 1/4) to give the
28
title compound 25 (709 mg, 96%) as an oil: [α]D = +0.9° (c 1.21,
1
CHCl3); νmax (cm−1) 2926, 2855, 735, 697; H NMR (500 MHz,
CDCl3) δ 7.47−7.41 (2H, m), 7.39−7.11 (27H, m, 7.06 (1H, dd, J =
8.3, 2.1 Hz), 7.01 (1H, d, J = 2.1 Hz), 6.92 (1H, d, J = 8.3 Hz), 5.87
(1H, ddt, J = 17.2, 10.6, 5.4 Hz), 5.43 (1H, d, J = 1.6 Hz), 5.26 (1H,
dq, J = 17.3, 1.6 Hz), 5.12 (1H, dq, J = 10.5, 1.4 Hz), 4.96−4.54 (12H,
m), 4.49−4.37 (3H, m), 4.19 (1H, ddt, J = 12.9, 5.3, 1.5 Hz), 4.10−
3.97 (3H, m), 3.97−3.83 (8H, m), 3.82−3.69 (3H, m), 3.67 (1H, dd, J
= 3.2, 1.7 Hz), 3.42 (1H, t, J = 9.3 Hz), 3.38 (1H, dd, J = 9.8, 2.1 Hz),
3.22 (1H, dd, J = 9.9, 2.6 Hz), 0.92 (9H, s), 0.11 (3H, s), 0.09 ppm
(3H, s); 13C NMR (126 MHz, CDCl3) δ 149.36, 148.93, 140.91,
139.38, 139.00, 138.96, 138.90, 138.82, 138.58, 136.58, 135.01, 133.88,
128.85, 128.62, 128.55, 128.48, 128.40, 128.27, 128.24, 128.19, 128.17,
127.97, 127.85, 127.75, 127.69, 127.64, 127.46, 127.08, 119.58, 116.90,
111.69, 110.57, 97.91, 83.56, 81.60, 81.58, 81.29, 79.41, 79.09, 76.36,
76.07, 75.94, 75.21, 74.98, 74.84, 73.09, 72.87, 72.39, 71.85, 71.49,
70.59, 62.91, 56.22, 56.15, 26.24, 18.67, −4.98, −5.22 ppm; HRMS
(ESI-TOF) m/z [M +Na]+ calcd for C78H90O13SiNa 1285.6048, found
1285.6041.
3-O-Allyl-2-O-(2′,3′,4′-tri-O-benzyl-α-D-mannopyranosyl)-
4,5,6-tri-O-benzyl-1-O-(4-(3,4-dimethoxyphenyl)benzyl)-1D-
myo-inositol (26). Acetyl chloride (0.80 mL, 11 mmol) was added to
a solution of 25 (701 mg, 0.555 mmol) in CH2Cl2/MeOH (3/7, 10
mL), and the mixture was stirred at room temperature for 40 min. The
reaction mixture was diluted with CH2Cl2 and washed with water and
then brine, and the organic phase was dried and evaporated. The
residue was purified using column chromatography (EtOAc/PE, 2/3)
to give the title compound 26 (709 mg, 99%) as an oil: [α]D219 = +2.8°
(c 1.26, CHCl3); νmax (cm−1) 3504, 2922, 2871, 737, 698; H NMR
(500 MHz, CDCl3) δ 7.45−7.39 (2H, m), 7.36−7.05 (32H, m), 7.02
(1H, dd, J = 8.3, 2.1 Hz), 6.96 (1H, d, J = 2.1 Hz), 6.87 (1H, d, J = 8.3
Hz), 5.81 (1H, ddt, J = 17.3, 10.7, 5.4 Hz), 5.31 (1H, d, J = 1.7 Hz),
5.20 (1H, dq, J = 17.3, 1.7 Hz), 5.08 (1H, dq, J = 10.5, 1.4 Hz), 4.92−
4.39 (14H, m), 4.24 (1H, t, J = 2.4 Hz), 4.12 (1H, ddt, J = 12.9, 5.5,
1.5 Hz), 4.04 (1H, dt, J = 9.9, 3.3 Hz), 4.01−3.91 (2H, m), 3.89 (3H,
s), 3.88 (3H, s), 3.81 (1H, dd, J = 9.5, 3.1 Hz), 3.74 (2H, d, J = 3.3
Hz), 3.71−3.63 (3H, m), 3.41−3.31 (2H, m), 3.17 (1H, dd, J = 9.9,
2.6 Hz), 1.60 ppm (1H, s); 13C NMR (126 MHz, CDCl3) δ 149.37,
148.95, 140.99, 138.90, 138.83, 138.80, 138.58, 138.32, 136.52, 134.90,
133.79, 128.72, 128.64, 128.62, 128.61, 128.60, 128.56, 128.39, 128.35,
128.23, 128.11, 127.91, 127.88, 127.87, 127.80, 127.79, 127.70, 127.11,
119.56, 117.17, 111.70, 110.55, 98.78, 83.53, 81.59, 81.27, 81.23,
79.34, 78.93, 76.38, 76.03, 75.93, 75.38, 75.01, 74.87, 73.41, 72.41,
72.40, 72.33, 72.17, 71.75, 62.63, 56.21, 56.15 ppm; HRMS (ESI-
2-O-(2′,3′,4′-Tri-O-benzyl-6′-O-palmitoyl-α-D-mannopyrano-
syl)-4,5,6-tri-O-benzyl-1-O-(4-(3,4-dimethoxyphenyl)benzyl)-
1 D - m y o - i n o s i t o l ( 2 8 ) . ( 1 , 5 - C y c l o o c t a d i e n e ) b i s -
(methyldiphenylphosphine)iridium(I) hexafluorophosphate (36 mg,
0.04 mmol) was added to a stirred solution of 27 (610 mg, 0.440
mmol), in dry THF (20 mL) at room temperature under an
atmosphere of Ar. The atmosphere was replaced with H2 for ca. 1 min,
followed by a gentle stream of Ar. The reaction mixture was stirred for
3 h, the solvent was removed, and the residue was dissolved in
acetone/water (9/1, 20 mL). To the solution were added mercuric
oxide (220 mg, 1.0 mmol) and mercuric chloride (250 mg, 0.9 mmol),
and this mixture was then heated to 100 °C for 4 h. Once it was cooled
to room temperature, the reaction mixture was filtered through Celite,
the pad was washed with CH2Cl2, and the solvent from the filtrate was
evaporated. The residue was dissolved in CH2Cl2, this solution was
washed with aqueous potassium iodide (5%) and dried, and the
solvent was evaporated. The residue was purified by column
chromatography (PE to EtOAc/PE, 1/2) to give the title compound
28 (557 mg, 92%) as a pale yellow oil: [α]D20 = +4.3° (c 1.09, CHCl3);
1
νmax (cm−1) 3560, 2924, 2854, 1734, 736, 698; H NMR (500 MHz,
CDCl3) δ 7.46−7.40 (2H, m), 7.38−7.15 (32H, m), 7.05 (1H, dd, J =
8.3, 2.1 Hz), 7.01 (1H, d, J = 2.1 Hz), 6.92 (1H, d, J = 8.3 Hz), 5.25
(1H, d, J = 1.6 Hz), 4.96−4.80 (6H, m), 4.73−4.44 (8H, m), 4.35−
4.24 (2H, m), 4.23 (1H, t, J = 2.5 Hz), 4.05 (1H, ddd, J = 9.9, 4.7, 2.3
Hz), 3.92 (3H, s), 3.90 (3H, m), 3.89 (1H, d, J = 1.4 Hz), 3.81−3.74
(3H, m), 3.57 (1H, t, J = 9.5 Hz), 3.49−3.40 (3H, m), 2.30 (2H, dd, J
= 8.4, 6.9 Hz), 2.09 (1H, d, J = 4.4 Hz), 1.63−1.54 (2H, m), 1.32−
1.18 (24H, m), 0.88 ppm (3H, t, J = 6.9 Hz); 13C NMR (126 MHz,
CDCl3) δ 173.73, 149.22, 148.78, 140.74, 138.66, 138.49, 138.36,
138.26, 138.20, 136.29, 133.66, 128.72, 128.44, 128.39, 128.27, 128.17,
128.11, 128.01, 127.95, 127.85, 127.83, 127.78, 127.74, 127.70, 127.67,
127.48, 126.90, 119.39, 111.55, 110.45, 99.05, 83.52, 81.91, 81.16,
80.56, 79.09, 75.98, 75.82, 75.36, 75.21, 74.66, 74.59, 72.911, 72.121,
71.961, 70.82, 70.49, 63.34, 56.02, 55.96, 34.25, 31.93, 29.70, 29.64,
29.51, 29.36, 29.32, 29.22, 24.92, 22.69, 14.11 ppm; HRMS (ESI-
TOF) [M + Na]+ m/z calcd for C85H102O14Na 1369.7167, found
1369.7177.
N
dx.doi.org/10.1021/jo5019188 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-O-(2′,3′,4′-Tri-O-benzyl-6′-O-palmitoyl-α-D-mannopyrano-
syl)-4,5,6-tri-O-benzyl-1-O-(4-(3,4-dimethoxyphenyl)benzyl)-3-
O-stearoyl-1D-myo-inositol (29). Stearic acid (220 mg, 0.77 mmol),
DCC (160 mg, 0.78 mmol), and DMAP (13 mg, 0.11 mmol) were
added to a solution of 28 (524 mg, 0.389 mmol) in anhydrous
CH2Cl2. The reaction mixture was stirred at room temperature for 60
h. The reaction mixture was filtered through a plug of basic alumina
which was eluted with five column volumes of CH2Cl2. The solvent
was removed from the combined filtrate, and the residue was purified
by column chromatography (PE to EtOAc/PE, 1/4) to give the title
compound 29 (582 mg, 93%) as a colorless oil: [α]D20 = +8.2° (c 2.12,
CHCl3); νmax (cm−1) 2923, 2853, 1738, 736, 697; 1H NMR (500
MHz, CDCl3) δ 7.44 (2H, d, J = 8.2 Hz), 7.38−7.15 (32H, m), 7.05
(1H, dd, J = 8.3, 2.1 Hz), 7.01 (1H, d, J = 2.1 Hz), 6.92 (1H, d, J = 8.3
Hz), 5.39 (1H, d, J = 1.8 Hz), 4.96 (1H, d, J = 10.7 Hz), 4.92−4.74
(6H, m), 4.71−4.53 (6H, m), 4.51−4.37 (3H, m), 4.35 (1H, t, J = 2.4
Hz), 4.20 (1H, dd, J = 11.8, 1.4 Hz), 3.98−3.88 (8H, m), 3.87−3.84
(1H, m), 3.79 (1H, dd, J = 10.4, 9.2 Hz), 3.77−3.72 (m), 3.57−3.50
(2H, m), 2.35−2.26 (2H, m), 2.22−2.02 (2H, m), 1.65−1.55 (2H, m),
1.54−1.44 (2H, m), 1.34−1.11 (52H, m), 0.88 ppm (6H, td, J = 6.9,
2.3 Hz); 13C NMR (126 MHz, CDCl3) δ 173.62, 173.01, 149.21,
148.78, 140.82, 138.59, 138.37, 138.32, 138.15, 138.09, 136.01, 133.67,
128.60, 128.48, 128.45, 128.42, 128.38, 128.16, 128.13, 128.11, 127.95,
127.85, 127.77, 127.73, 127.70, 127.57, 127.48, 126.91, 119.40, 111.54,
110.47, 97.97, 83.41, 81.33, 80.84, 79.16, 78.93, 76.22, 75.86, 75.38,
75.34, 74.43, 74.13, 73.08, 72.51, 71.90, 71.81, 71.65, 70.44, 63.15,
56.01, 55.96, 34.20, 34.14, 31.94, 29.74, 29.72, 29.54, 29.48, 29.37,
29.25, 29.20, 24.94, 24.72, 22.69, 14.11 ppm; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C103H136O15Na 1635.9777, found 1635.9768.
2-O-(2′,3′,4′-Tri-O-benzyl-6′-O-palmitoyl-α-D-mannopyrano-
syl)-4,5,6-tri-O-benzyl-3-O-stearoyl-1D-myo-inositol (11). TFA
(0.80 mL, 10 mmol) was added to a solution of 29 (582 mg, 0.361
mmol) and the scavenger 3,4-(methylenedioxy)toluene (250 mg, 1.8
mmol) in CH2Cl2 (3.2 mL), and the reaction mixture was stirred
overnight at room temperature. The reaction mixture was washed with
sodium bicarbonate and then brine, and the organic phase was dried
and evaporated. The residue was purified by column chromatography
(EtOAc/toluene, toluene to 1/19) to give the title compound 11 (381
mg, 76%) as a colorless oil. All spectroscopic data were consistent with
those for 11 synthesized from (−)-7c.
Triethylammonium 2-O-(2′,3′,4′-Tri-O-benzyl-6′-O-palmito-
yl-α-D-mannopyranosyl)-4,5,6-tri-O-benzyl-3-O-stearoyl-1-O-
(1-O-(R)-tuberculostearoyl-2-O-palmitoyl-sn-glycero-3-phos-
phoryl)-1D-myo-inositol (31). H-Phosphonate 304b,c (26 mg, 0.034
mmol) and 29 (25 mg, 0.018 mmol) were coevaporated from pyridine
and then dried under high vacuum. The residue was dissolved in dry,
distilled pyridine (4 mL) at room temperature under Ar. Freshly
distilled pivaloyl chloride (25 μL, 0.20 mmol) was added in one
portion, and the reaction mixture was stirred overnight at room
temperature. A freshly prepared solution of iodine (42 mg, 0.17 mmol)
in pyridine/water (9/1, 10 mL) was added, and the mixture was stirred
for a further 1 h. The solution was diluted with chloroform, stirred for
15 min, and then washed with sodium thiosulfate solution (10%). The
organic phase was washed with a triethylammonium bicarbonate
(TEAB) buffer (1 M, pH 7.5) and then dried and evaporated. The
residue was purified by silica gel column chromatography (CH2Cl2/
MeOH/Et3N 96/3/1) to give the title compound 31 (34 mg, 87%) as
a pale yellow oil: [α]D20 = +15.4° (c 0.59, CHCl3); νmax (cm−1) 2923,
2854, 1740, 736, 698; 1H NMR (500 MHz, CDCl3) δ 7.50 (2H, d, J =
7.4 Hz), 7.39 (2H, d, J = 7.4 Hz), 7.34−7.13 (26H, m), 5.49 (1H, s),
5.09 (1H, dq, J = 8.9, 5.1 Hz), 4.97 (1H, d, J = 10.7 Hz), 4.90 (1H, d, J
= 11.1 Hz), 4.85−4.72 (8H, m), 4.65−4.53 (3H, m), 4.51−4.45 (2H,
m), 4.34 (1H, dd, J = 11.9, 3.5 Hz), 4.27−4.20 (1H, m), 4.17 (2H, m),
4.04−3.90 (5H, m), 3.88−3.84 (1H, m), 3.81 (1H, dd, J = 9.5, 3.1
Hz), 3.75−3.65 (2H, m), 3.51 (1H, t, J = 9.2 Hz), 2.91 (6H, d, J = 7.3
Hz), 2.29−1.96 (8H, m), 1.52 (8H, m), 1.40−1.01 (43H, m), 0.91−
0.81 ppm (15H, m); 13C NMR (126 MHz, CDCl3) δ 173.63, 173.15,
172.87, 172.63, 138.47, 138.41, 138.36, 138.10, 128.45, 128.37, 128.34,
128.31, 128.21, 128.18, 128.06, 128.02, 127.84, 127.74, 127.67, 127.58,
127.54, 127.48, 98.27, 82.96, 80.18, 78.94, 78.48, 77.02, 76.14, 75.48,
75.35, 75.24, 74.23, 73.43, 71.45, 71.32, 70.46, 70.03, 64.48, 62.95,
62.27, 45.51, 37.16, 34.17, 34.09, 34.01, 32.81, 31.94, 30.06, 29.73,
29.58, 29.50, 29.37, 29.29, 29.20, 27.13, 24.93, 24.85, 24.78, 22.70,
19.71, 14.12, 8.43 ppm; 31P NMR (202 MHz, CDCl3) δ −1.54 ppm;
HRMS (ESI-TOF) m/z [M − Et3N]− calcd for C126H194O20P
2058.3901, found 2058.3894.
Sodium 2-O-(6′-O-Palmitoyl-α-D-mannopyranosyl)-3-O-
stearoyl-1-O-(1-O-(R)-tuberculostearoyl-2-O-palmitoyl-sn-glyc-
ero-3-phosphoryl)-1D-myo-inositol (9; Ac2PIM1). A solution of
triethylammonium salt 31 (22 mg, 0.010 mmol) in CHCl3/MeOH (1/
1, 10 mL) was stirred in the presence of DOWEX 50WX8-200 (Na+)
resin for 3 h. The resin was filtered off and the solvent evaporated. The
residue was dissolved in CH2Cl2/MeOH (2/3, 5 mL), Pd(OH)2/C
(10% w/w, 10 mg) was added, and the reaction mixture was stirred
under an atmosphere of hydrogen for 2 h at room temperature. The
reaction mixture was filtered through Celite and washed with CHCl3/
MeOH/water (70/40/6), and the solvents were evaporated. The
residue was purified on C-18 reversed-phase silica (MeOH to MeOH/
CHCl3) to give the title compound 9 (15 mg, 98%) as a white solid:
[α]D20 = +22.7° (c 0.41, CHCl3/MeOH 70/40); 1H NMR (500 MHz,
CDCl3/CD3OD/D2O 70/40/6) δ 5.22−5.27 (1H, m), 5.11 (1H, d, J
= 1.6 Hz), 4.77 (1H, dd, J = 10.6, 2.7 Hz), 4.45 (1H, dd, J = 12.0, 3.0
Hz), 4.40 (1H, dd, J = 12.3, 4.8 Hz), 4.27 (1H, t, J = 2.4 Hz), 4.24
(1H, dd, J = 12.4, 2.4 Hz), 4.18 (1H, dd, J = 12.0, 7.2 Hz), 3.94−4.10
(5H, m), 3.73−3.83 (3H), 3.63−3.71 (1H, m), 3.34 (1H, m), 2.28−
2.47 (8H, m), 1.55−1.68 (8H, m), 1.18−1.41 (43H, m), 0.82−0.94
ppm (15H, m): 13C NMR (126 MHz, CDCl3/CD3OD/D2O 70/40/
6) δ 175.05, 174.52, 174.15, 174.13, 102.20, 77.14, 76.89, 74.94, 72.77,
72.27, 71.12, 71.00, 70.93, 70.79, 70.73, 70.37, 67.62, 64.19, 63.11,
37.47, 37.44, 34.51, 34.44, 34.41, 34.28, 33.11, 32.25, 30.37, 30.35,
30.06, 30.04, 29.99, 29.97, 29.94, 29.91, 29.86, 29.77, 29.72, 29.67,
29.60, 29.54, 29.49, 27.44, 27.40, 25.27, 25.21, 25.15, 22.14, 22.97,
19.90, 14.21 ppm; 31P NMR (202 MHz, CDCl3/MeOD/D2O 70/40/
6) δ 0.04 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C84H159O20PNa 1542.1060, found 1542.1049; HRMS (ESI-TOF) m/z
[M − Na]− calcd for C84H158O20P 1518.1084, found 1518.1071.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra for all novel
compounds and chromatograms from the chiral HPLC analyses
of compounds 6a−i. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for B.J.C.: benjamin.compton@vuw.ac.nz.
*E-mail for D.S.L.: david.larsen@otago.ac.nz.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the IRL Charitable Trust and the University of Otago
for financial assistance for A.M.M.L.
■
REFERENCES
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