Synthesis of serine-linked phosphatidylinositol mannosides (PIMs)

Article abstract of DOI:10.1002/ejoc.200400009

The 6-O-allyl group of inositol mannoside (D)-6 was used for the generation of O-linked serine residues via a sequence of dihydroxylation, selective 3″-O-protection, introduction of the 2″-amino group, deprotection, and oxidation of the 3″-position. Attachment of the phosphatidyl residue to 1-O of the inositol moiety and complete deprotection furnished target molecules (D)-1 and (D)-2. Alternatively, instead of introduction of a 6-O-allyl group, 2″,3″-dihydroxy propanylation of the 6-O-position of the inositol moiety using a silyl-protected cyclic sulfate of glycerol was possible. Thus, target molecule (L)-3 was obtained. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400009

FULL PAPER
Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
Andreas Stadelmaier,[a] Moritz B. Biskup,[a] and Richard R. Schmidt*[a]
Keywords: Phosphatidylinositol / Phosphatidylinositol mannoside / Serine attachment / Synthesis / Structural assignment
The 6-O-allyl group of inositol mannoside (
the generation of O-linked serine residues via a sequence
of dihydroxylation, selective 3ЈЈ-O-protection, introduction of
D
)-6 was used for
duction of a 6-O-allyl group, 2ЈЈ,3ЈЈ-dihydroxy propanylation
of the 6-O-position of the inositol moiety using a silyl-pro-
tected cyclic sulfate of glycerol was possible. Thus, target
the 2ЈЈ-amino group, deprotection, and oxidation of the 3ЈЈ- molecule (
position. Attachment of the phosphatidyl residue to 1-O of
L)-3 was obtained.
the inositol moiety and complete deprotection furnished tar-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
get molecules (
D)-1 and (
D)-2. Alternatively, instead of intro-
Introduction
In mycobacterial infections, the lipoglycans localize to
caveolae/lipid rafts of host membranes, which serve as sig-
nal transduction platforms, thus eliciting a biological re-
sponse. Such responses involve induced expression and se-
cretion of TNF-α and IL-6, and inhibition of T-cell pro-
liferative responses.[7] LAMs have also been shown to in-
hibit expression of IL-2, IL-5 and GM-CSF genes in
human T-cells, as well as inhibiting the IFN-γ-mediated ac-
tivation of macrophages.
Arabinogalactan-peptidoglycan (AGP) and lipido-
arabinomannan (LAM) complexes are important constitu-
ents of mycobacterial cell walls. The LAM complexes are
composed of phosphatidylinositol dimannosides (PIM2)
carrying further mannans (Ǟ lipomannan, LM) or arabino-
mannan moieties (Ǟ lipidoarabinomannan, LAM)
(Scheme 1).[1Ϫ4] Phophatidylinositols that are α-mannopyr-
anosylated at O-2 (Ǟ PIM), or at O-2 and O-6 (Ǟ PIM2),
are the precursors for the biosynthesis of LAMs.[5,6] The
extension of the α-(1Ǟ2)-linked mannopyranosyl residue
with further α-(1Ǟ2)- and α-(1Ǟ6)-linked mannopyranosyl
residues leads to LMs, and by the further addition of arabi-
nofuranosyl residues, LAMs are obtained.
As the PIM substructure of LAMs is able to inhibit
LAM-insertion into caveolae, the PIM substructure may
contain the necessary structural characteristics to target ca-
veolae. As the chain-extension at the 6-O-position of the
PIM, giving LMs, does not seem to be necessary for tar-
geting of the caveolae, it should be possible to synthesize
conjugates of PIM that would deliver the coupled partner
to the caveolae, and subsequently into the cell. Therefore, a
serine residue attached to the 6-O-position of the inositol
was chosen as a docking moiety for the coupling of partner
molecules. This serine attachment was selected in accord-
ance with the structure of naturally occurring GPI-anchors,
which carry a glucosamine-residue at the 6-O-position of
the inositol. Hence, we initiated a programme of investi-
gation into the synthesis of PIMs and their structural vari-
ants. Methods to allow the required regioselective access to
the 1-O-, 2-O- and 6-O-positions of ()- and ()-myo-inosi-
tol have been developed and reported.[8Ϫ10]
In this paper, the introduction of serine residues onto the
6-O-position of the inositol moiety of phosphatidyl-()-in-
ositol-mannoside and its pseudo-enantiomer, phosphatidyl-
()-inositol-mannoside, is reported. Several approaches to
introduce optically active residues at the 6-O-position were
investigated; these included nucleophilic opening of β-lac-
tones and aziridines, nucleophilic substitution at activated
glycerol species, and dihydroxylation of 6-O-allyl com-
pounds. In the case of the ()-inositol compounds, the in-
Scheme 1. Structure of PIMs, LM, LAM
[a]
Fachbereich Chemie, Universität Konstanz,
Fach M 725, 78457 Konstanz, Germany
Fax: (internat.) ϩ 49-(0)7531-88-3135
E-mail: richard.schmidt@uni-konstanz.de
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DOI: 10.1002/ejoc.200400009
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Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
FULL PAPER
Scheme 2. Structure of target compounds ()-1, ()-2 and ()-3
troduction of the naturally and unnaturally configured ser- introduce a serine residue at the free hydroxyl group at the
ine residues was accomplished. Dihydroxylation of a 6-O- 6-O-position of the inositol moiety.
allyl functionality, and subsequent refunctionalization to
Several possibilities for the introduction of serine to free
give the amino acid, gave the target compounds ()-1 and hydroxyl groups have been reported.[11] In this case, the
()-2. The corresponding introduction of a serine residue ring-opening addition of ()-8 to β-lactone 9, as described
into the pseudo-enantiomeric ()-inositol compound was by Vederas,[12Ϫ15] and the ring-opening of aziridine 10 by
accomplished enantioselectively by coupling to an enanti- nucleophilic attack of alcohols[16] were investigated. In ne-
omerically pure glycerol derivative and subsequent refunc- ither case could the desired serine-containing compound be
tionalization. These reactions yielded target compound ()- isolated. Next, the formation of an ether bond via nucleo-
3. In our synthesis, the efficient resolution of diastereomeric philic attack of the deprotonated alcohol ()-8 at activated
precursors of ()-1 and ()-2, and the enantioselective prep- O-isopropylidene-glycerol derivatives, as described by
aration of ()-3 (Scheme 2), allowed access to PIM-like Hajdu,[17] were tested. The reaction of ()-8 with compound
structures, which may be conjugated via standard peptide 11a or 11b in DMF in the presence of sodium hydride did
bond formation methods.
not yield the desired derivatives (Scheme 4).
Results and Discussion
In the synthesis of ()-1, ()-2 and ()-3, the diastereoiso-
meric pseudodisaccharides ()-4 and ()-5 were used as
known precursors.[9,10] Benzylation of ()-4 and ()-5 with
benzyl bromide in DMF, using sodium hydride as a base,
afforded the fully protected compounds ()-6 and ()-7 in
high yields (Scheme 3). Removal of the O-allyl group in
compound ()-7 with Wilkinson’s catalyst and DBU in
ethanol gave the free alcohol ()-8. We had then planned to
Scheme 4. Investigated serine precursors
As an alternative to the introduction of C3-synthons to
the partially deprotected ()-8, functionalization of the 6-
O-allyl group in compounds ()-6 and ()-7 by dihydroxyl-
ation would also lead to the type of compounds that are
accessible by direct addition of glycerol derivatives. How-
ever, the creation of the secondary alcohol at the C-2ЈЈ-cen-
tre would presumably give a 1:1 mixture of diastereoiso-
mers, and their subsequent separation would be required.
To avoid this problem, reaction conditions must be chosen
that would give diastereoselective dihydroxylation of the al-
lyl group. But in both cases, the configuration of the newly
formed stereogenic centre must be determined and as-
signed.
The dihydroxylation of allyl compound ()-6 with N-
methylmorpholine N-oxide and catalytic amounts of os-
mium tetroxide[18Ϫ20] afforded the expected 1:1 mixture of
the diastereoisomeric diols 12 in 97% yield. Selective protec-
tion of the primary hydroxyl group at the C-3ЈЈ-atom with
the tert-butyldiphenylsilyl group under standard conditions
gave a mixture of the diastereoisomeric alcohols 13h,l in
Scheme 3. Reagents and conditions: (a) BnBr, NaH, DMF, room
temp., 86%; (b) BnBr, NaH, DMF, room temp., 98%; (c) 1.
(PPh3)3RhCl, DBU, EtOH, 90 °C, 2. 1  HCl/acetone, 1:9, 90%
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A. Stadelmaier, M. Biskup, R. R. Schmidt
FULL PAPER
excellent yield. At this stage, the diastereoisomers, 13h and group at C-2ЈЈ with mesyl chloride in dichloromethane/pyri-
13l, could be separated by column chromatography on silica dine. From 13l and 13h, the corresponding mesylates 15 and
gel (Scheme 5).
16 were formed in yields of 98% and 93%, respectively. In
a second step, the mesyl groups are replaced by azides with
inversion of configuration in an SN2 reaction. Azides 17
and 18 were obtained from the mesylates in yields of 93%
and 84% by treatment with sodium azide in DMF at elev-
ated temperatures. The next step in the construction of the
amino acid is the oxidation of the C-3ЈЈ-carbon from an
alcohol to a carboxylic acid. To accomplish this conversion,
the primary alcohol was deprotected by treating the silyl-
protected compounds with TBAF in tetrahydrofuran,[23] af-
fording alcohols 19 and 20 in excellent yields. Conversion
of the primary alcohols into the benzyl esters 21 and 22
was achieved by oxidation with sodium hypochlorite in the
presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
in acetone, and immediate protection of the newly formed
carboxylic acid with a benzyl group under standard con-
ditions,[24] in yields of 77% and 81%, respectively, over two
steps. Under these reaction conditions, the MPM protecting
group at the 1-O-position is stable, and no racemization at
C-2ЈЈ was observed. Mild oxidative cleavage of the MPM
group with ceric()ammonium nitrate (CAN) furnished the
1-O unprotected compounds 23 and 24 in good yields
(Scheme 6).
Scheme 5. Reagents and conditions: (a) OsO4, acetone/H2O, NMO,
room temp., 97%; (b) TBDPSCl, imidazole, CH2Cl2, 0 °C, 3 h,
quant.; (c) MTPA-Cl, pyridine, room temp., 24 h, ഠ 90%
For the full structural assignment of 13l and 13h, assign-
ment of the configuration of the newly created stereogenic
centre at the C-2ЈЈ was necessary. In this case, the nuclear
magnetic resonance (NMR) method employing (α-meth-
oxy-α-trifluoromethyl-phenyl acetate) esters (MTPA-esters)
according to Dale and Mosher was employed.[21,22] After
enriching the mixture of compounds 13h ؉13l to a ratio
of 4:1, the (S)-(Ϫ)-MTPA- and (R)-(ϩ)-MTPA-esters were
formed by reaction with the corresponding MTPA-chloride
in pyridine. From these reactions, the mixtures of dia-
stereoisomers (S)-14h,l and (R)-14h,l, respectively, were ob-
tained. In the HMQC spectra, (R)-14h showed a low-field
shift of the 1ЈЈ-protons, and (S)-14h had a low-field shift of
the 3ЈЈ-protons, thus leading to an assignment of the (S)-
configuration at C-2ЈЈ of 13h. As expected, (R)-14l exhib-
ited a low-field shift for the 3ЈЈ-protons, whereas (S)-14l
showed a low-field shift for the 1ЈЈ-protons, thus supporting
an assignment of the (R)-configuration at C-2ЈЈ in 13l.
To convert the fully characterized pseudo-enantiomeric
compounds 13l and 13h into the target compounds 1 and
2, the functionalized propanyl residues have to be trans-
formed into serine residues, and finally, phosphatidylglycer-
Scheme 6. Reagents and conditions: (a) MsCl, pyr/CH2Cl2, room
temp., 3.5 h, ഠ95%; (b) NaN3, DMF, 90 °C, 24 h, ഠ 90%; (c)
TBAF, THF, 3.5 h, ഠ95%; (d) 1. NaOCl, TEMPO, KBr, acetone,
0 °C, 2. BnBr, CsF, DMF, room temp., 2 h, ഠ 80%; (e) CAN,
CH3CN/toluene/H2O, 2 h, ഠ 80%
Diacylglycerol-containing phosphitamide 27 could be
olipid moieties have to be introduced at C-1 of the inositol successfully linked to 23 and 24 in the presence of catalytic
moieties. The conversion of the propanyl residue begins by amounts of tetrazole. Subsequent oxidation of the phos-
converting the free secondary alcohol into an azido group, phite to the phosphate with tert-butyl hydroperoxide led,
which will ultimately be transformed into the serine’s amino due to generation of a stereogenic centre at the phosphorus
group. This conversion can be achieved in a stereospecific atom, to mixtures of the fully benzyl-protected diastereoiso-
fashion in two steps. The first is the introduction of a mesyl meric target compounds 25a,b and 26a,b in yields of 68%
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Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
FULL PAPER
Scheme 7. Reagents and conditions: (a) 1. tetrazole, CH2Cl2, room temp., 2. tBuOOH, about 75%; (b) Pd(OH)2/C, H2, CH2Cl2/MeOH/
H2O, room temp., about 70%
and 73%, respectively. The hydrogenolytic removal of the stage. Selectively protecting the primary hydroxyl groups in
nine O-benzyl groups was successfully carried out using the the mixture of diols ()-28h,l with tert-butyldiphenylsilyl
more reactive Pearlman’s catalyst [Pd(OH)2 on carbon] in a chloride and imidazole in dichloromethane gave a mixture
7.5:7.5:1 mixture of dichloromethane/ methanol/ water. The of the alcohols 29h,l. The ratio of 29h,l, as determined by
use of Pearlman’s catalyst[25] ensured the reduction of the NMR spectroscopy, was only 1.8:1. Unfortunately, it was
azido group at C-2ЈЈ into an amino group, thus liberating not possible to separate the compounds by column chroma-
the final compounds 1 and 2 from their protected precur- tography, so this route was abandoned at this stage and
sors in one step (Scheme 7). The structures of ()-1 and ()- alternatives were considered (Scheme 8).
2 are fully supported by NMR and MS data.
The addition of ()-8 to glycerol derivatives with defined
Starting from fully protected ()-7, the route described stereochemistry was selected for further investigation, this
to gain access to compounds ()-1 and ()-2 should also time not using O-isopropylidene derivatives, but cyclic sul-
lead to the corresponding compounds of the ()-myo-inosi- fates. Ring-opening reactions of cyclic 1,2-sulfates go via
tol series. Use of the osmium-catalysed Sharpless asymmet- an SN2 mechanism under basic conditions, and have been
ric dihydroxylation reaction[26] means that the lengthy sep- reported to be quite regioselective; the attack usually occurs
aration of diastereoisomers would be avoided. Upon treat- at the sterically least hindered position.[27,28] The depro-
ing 6-O-allyl compound ()-7 with AD-mix β in a mixture tonated alcohol ()-8 should attack the cyclic 1,2-sulfate 30
of acetone and water, a mixture of diastereoisomers ()- at the primary position, thus preserving the configuration
28h,l was obtained in 71% yield, and was inseparable at this at the central carbon atom. The sodium hydride mediated
coupling of inositol derivative ()-8 with the cyclic sulfate
30 in DMF gave the sodium salt 31, from which the desired
Scheme 8. Reagents and conditions: (a) AD-mix β, acetone/H2O,
Scheme 9. Reagents and conditions: (a) NaH, DMF, room temp.,
room temp., 71%; (b) TBDPSCl, imidazole, CH2Cl2, 0 °C, 1 h, 97% 24 h; (b) Hϩ, dioxane, room temp., 25Ϫ51% in 2 steps
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Scheme 10. Reagents and conditions: (a) MsCl, pyr/CH2Cl2, room temp., 3.5 h, quant.; (b) NaN3, DMF, 90 °C, 24 h, 88%; (c) TBAF,
THF, 92%; (d) 1. NaOCl, TEMPO, KBr, acetone, 0 °C, 2. BnBr, CsF, DMF, room temp., 2 h, 92%; (e) CAN, CH3CN/toluene/H2O, 2 h,
83%; (f) 1. tetrazole, CH2Cl2, room temp., 2. tBuOOH, 71%; (g) Pd(OH)2/C, H2, CH2Cl2/MeOH/H2O, room temp., 85%
coupling product (R)-29 was liberated by treatment with offers new ways of probing the lateral composition of lipid
acid.[29] Thus, in two steps, (R)-29 was obtained in yields of membranes and membrane transfer processes.[30]
25Ϫ51%, and this compound may be used as a precursor
for the preparation of ()-3 (Scheme 9). The NMR spectra
of isolated (R)-29 are identical to those of one compound
in the mixture of 29, and this also allows assignment of the
Experimental Section
configuration at C-2ЈЈ in these compounds.
The synthesis of the ()-myo-inositol derivative 3 from
compound (R)-29 follows the route described above
General Methods: Solvents were purified by distillation and dried
by normal procedures, except for distilled CH2Cl2, which was
passed through a column of commercially available neutral alumina
for compounds of the ()-myo-inositol series. Activation (ICN Alumina N, activity grade super I) as an alternative drying
procedure. Boiling range of the petroleum ether: 35Ϫ70 °C. Thin
layer chromatography (TLC) was performed on E. Merck Silica
Gel 60 F254 plates (0.2 mm). The plates were visualized by immer-
sion in mostain [200 mL 10% H2SO4, 10 g (NH4)6Mo7O24·4H2O,
200 mg Ce(SO4)2] or ninhydrin solution (1% in EtOH) or 10%
H2SO4 or KMnO4 solution (1% in water, 1% NaHCO3), followed
by heating (165 °C). High performance thin layer chromatography
(HPTLC) was performed on E. Merck HPTLC-glass plates, Silica
Gel 60. Preparative flash chromatography was carried out on Baker
Silica Gel 60 (30Ϫ60 mm) at a pressure of 0.02Ϫ0.04 MPa.
FABMS was recorded on a modified Finnigan MAT 312/AMD
5000. 1H NMR, 13C NMR and 31P spectra were recorded on a
Bruker AC 250 Cryospec and a Bruker DRX 600 instrument. Pro-
ton chemical shifts are reported in ppm relative to Me4Si as internal
standard. Assignments of protons and carbons were carried out
with the aid of 600 MHz spectra: COSY, HMQC, ROESY, TOCSY.
(Ǟ 32), azide introduction (Ǟ 33), removal of the O-silyl
protecting group (Ǟ 34), oxidation with subsequent ester
formation (Ǟ 35) and oxidative cleavage of the p-meth-
oxybenzyl ether gave alcohol 36, which was coupled with
the benzyl protected phosphitamide 27. Oxidation to the
phosphate gave a diastereomeric mixture of the fully protec-
ted compounds 37a,b. Using Pearlman’s catalyst, the target
molecule ()-3 was liberated. The structure of compound
()-3 is supported by NMR and MS data (Scheme 10).
Conclusion
This work describes synthetic routes to the serine-con-
taining PIM compounds ()-1, ()-2 and ()-3. The possible
conjugation of markers and biologically active compounds Measurements of optical rotations were performed on
a
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Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
PerkinϪElmer polarimeter 241 MC (1 dm cell) at 20 °C. Melting nitrile-water, 3:2) [M Ϫ Hϩ]Ϫ: calcd. m/z ϭ 1003.2; found m/z ϭ
FULL PAPER
points: Gallenkamp metal block; not corrected. MALDI-MS were
obtained on a Kratos Analytical Kompact Maldi 2 instrument with
2,5-dihydroxybenzoic acid (DHB) as matrix (positive mode) or
2Ј,4Ј,6Ј-trihydroxyacetophenone (THAP) and 6-aza-2-thiothymine
(ATT) (negative mode).
1002.3. C46H86NO20P·2.5H2O (1049.2): calcd. C 52.66, H 8.74, N
1.33; found C 52.79, H 8.94, N 1.03.
6-O-[(2S)-2-Amino-2-hydroxycarbonylethyl]-2-O-α-
pyranosyl- -myo-inosit-1-yl-[(2R)-2,3-bis(myristoyloxy)propyl]phos-
phate [( )-3]: A mixture of the diastereomeric compounds 37a,b
D-manno-
L
L
(180 mg, 0.09 mmol) and Pearlman’s catalyst (3 mg, 0.2 equiv.) in
CH2Cl2/methanol/water (7.5:7.5:1, 3 mL) was degassed under re-
duced pressure and saturated, with H2 several times. The suspen-
sion was stirred at room temp. overnight, filtered through Celite
and washed with CH2Cl2/methanol/water (7.5:7.5:1, 2 mL), and the
filtrate was diluted with water. After lyophilization, the title com-
pound ()-3 (83 mg, 85%) was obtained as a white powder. 1H
NMR (600 MHz, [D6]DMSO): δ ϭ 0.78Ϫ0.90 (t, 6 H, Me),
6-O-[(2S)-2-Amino-2-hydroxycarbonylethyl]-2-O-α-
pyranosyl- -myo-inosit-1-yl-[(2R)-2,3-bis(myristoyloxy)propyl]phos-
phate [( )-1]: Compound ()-1 was synthesized following the pro-
cedure described for compound ()-2. Compound 25a,b (250 mg,
0.14 mmol) gave ()-1 (96 mg, 68%) as a colourless powder. 1H
NMR (600 MHz, [D6]DMSO): δ ϭ 0.76Ϫ0.90 (t, 6 H, Me),
D-manno-
D
D
1.07Ϫ1.35 (s, 40 H, CH2-chain), 1.42Ϫ1.55 (m,
4
H,
COCH2CH2R), 2.18Ϫ2.35 (m, 4 H, COCH2CH2R), 3.11 (m, 1 H,
5a-H), 3.19 (m, 1 H, 3a-H), 3.34 (m, 2 H, 6a-H, 4a-H), 3.48 (m, 2
H, 6b-H, 4b-H), 3.49 (m, 1 H, 3b-H), 3.56 (m, 1 H, 6b-H), 3.66
(m, 1 H, 2b-H), 3.86 (m, 3 H, 1Ј-H, 5b-H), 3.92 (m, 1 H, 1ЈЈ-H),
3.93 (m, 1 H, 2ЈЈ-H), 3.94 (m, 1 H, 2a-H), 3.98 (m, 1 H, 1a-H),
4.09 (m, 1 H, 3Ј-H), 4.19 (m, 1 H, 1ЈЈ-H), 4.28 (m, 1 H, 3Ј-H), 4.97
(d, 1 H, J Ͻ 1 Hz, 1b-H), 5.11 (m, 1 H, 2Ј-H), 8.67 (br. s, 2 H,
NH2) ppm. 13C NMR (150.9 MHz, [D6]DMSO): δ ϭ 13.88 (2 C,
Me), 22.04/28.43Ϫ29.04/31.25 (20 C, CH2-chain) 24.36/24.43 (2 C,
COCH2CH2R), 33.36/33.51 (2 C, COCH2CH2R), 52.45 (1 C, C-
2ЈЈ), 60.71 (1 C, C-6b), 62.07 (1 C, C-3Ј), 63.10 (1 C, C-1Ј), 66.44
(1 C, C-4b), 69.51 (1 C, C-1ЈЈ), 69.83 (1 C, C-3a), 69.86 (1 C, C-
2Ј), 70.28 (1 C, C-2b), 70.64 (1 C,C-3b), 72.36 (1 C, C-4a), 72.49
(1 C, C-5b), 74.62 (1 C, C-1a), 74.71 (1 C, C-5a), 76.92 (1 C, C-
2a), 81.66 (1 C, C-6a), 100.14 (1 C, C-1b), 168.97 (1 C, COOH),
172.35/172.54 (2 C, COR) ppm. 31P NMR (242.9 MHz,
[D6]DMSO): δ ϭ 0.847 (s, 1 P) ppm. MALDI-MS (negative mode,
matrix THAP, acetonitrile/water, 3:2 ) [M Ϫ Hϩ]Ϫ: calcd. m/z ϭ
1003.2; found m/z ϭ 1002.7. C46H86NO20P·3.5H2O (1067.2): calcd.
C 51.77, H 8.78, N 1.31; found C 51.74, H 9.00, N 0.98.
1.08Ϫ1.35 (s, 40 H, CH2-chain), 1.40Ϫ1.56 (m,
4
H,
COCH2CH2R), 2.18Ϫ2.33 (m, 4 H, COCH2CH2R), 3.12 (m, 1 H,
5a-H), 3.23 (m, 1 H, 3a-H), 3.24 (m, 1 H, 6b-H), 3.27 (m, 1 H, 4b-
H), 3.30 (m, 1 H, 6a-H), 3.38 (m, 1 H, 4a-H), 3.47 (m, 1 H, 3b-H),
3.65 (m, 1 H, 2b-H), 3.66 (m, 1 H, 1ЈЈ-H), 3.69 (m, 1 H, 6b-H),
3.78 (m, 1 H, 2ЈЈ-H), 3.8 (m, 1 H, 1Ј-H), 3.81 (m, 1 H, 5b-H), 3.93
(m, 1 H, 1Ј-H), 3.94 (m, 1 H, 2a-H), 3.99 (m, 1 H, 1a-H), 4.06 (m,
1 H, 3Ј-H), 4.26 (m, 1 H, 1ЈЈ-H), 4.29 (m, 1 H, 3Ј-H), 5.02 (m, 1
H, 1b-H), 5.10 (m, 1 H, 2Ј-H), 8.65Ϫ8.9 (br. s, 2 H, NH2) ppm.
13C NMR (150.9 MHz, [D6]DMSO, selection): δ ϭ 52.8 (1 C, C-
2ЈЈ), 61.6 (1 C, C-3Ј), 62.0 (1 C, C-6b), 62.3 (1 C, C-1Ј), 68.0 (1 C,
C-4b), 68.9 (1 C, C-1ЈЈ), 69.9 (1 C, C-2b), 70.0 (1 C, C-2Ј), 70.3 (1
C, C-3b), 71.3 (1 C, C-3a), 72.2 (2 C, C-1a, C-5b), 72.5 (1 C, C-
4a), 74.2 (1 C, C-5a), 76.3 (1 C, C-2a), 81.2 (1 C, C-6a), 100.2 (1
C, C-1b) ppm. 31P NMR (242.9 MHz, [D6]DMSO): δ ϭ 0.023 (s,
1 P) ppm. MALDI-MS (negative mode, matrix ATT, H2O) [M Ϫ
Hϩ]Ϫ: calcd. m/z ϭ 1003.1; found. m/z ϭ 1001.8. MALDI-MS
(positive mode, matrix DHB, H2O) [M ϩ Na]ϩ: calcd. m/z ϭ
1027.2; found m/z ϭ 1027.5; [(MϪNaϩ)ϩNa]ϩ: calcd. m/z ϭ
1050.16; found m/z ϭ 1049.4; [(MϪNaϩ)ϩK]ϩ: calcd. m/z ϭ
1066.16; found m/z ϭ 1065.3. C46H86NO20P·1.5H2O (1031.2):
calcd. C 53.58, H 8.70, N 1.36; found C 53.61, H 8.71, N 0.80.
6-O-[(2R)-2-Amino-2-hydroxycarbonylethyl]-2-O-α-
pyranosyl- -myo-inosit-1-yl-[(2R)-2,3-bis(myristoyloxy)propyl]phos-
phate [( )-2]: A mixture of the diastereomeric compounds 26a,b
D-manno-
D
D
6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-(3,4,6-tri-
(250 mg, 0.14 mmol) and Pearlman’s catalyst (4 mg, 0.2 equiv.) in
CH2Cl2/methanol/water (7.5:7.5:1, 3 mL) was degassed under re-
duced pressure, and saturated with H2 several times. The suspen-
sion was stirred at room temp. overnight, filtered through Celite
and washed with CH2Cl2/methanol/water (7.5:7.5:1, 2 mL), and the
filtrate was diluted with water. After lyophilization, the title com-
pound ()-2 (102 mg, 73%) was obtained as a white powder. 1H
O-benzyl-α-
D-mannopyranosyl)-(1Ǟ2)-D-myo-inositol [(D)-4]: Com-
pound ()-4 was prepared as previously reported.[10]
6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-(2,4,6-tri-
O-benzyl-α- -mannopyranosyl)-(1Ǟ2)- -myo-inositol [( )-5]: Com-
pound ()-5 was prepared as previously reported.[10]
D
L
L
NMR (600 MHz, [D6]DMSO): δ ϭ 0.78Ϫ0.90 (t, 6 H, Me), 6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-
1.05Ϫ1.35 (s, 40 H, CH2-chain), 1.40Ϫ1.56 (m, H, tetra-O-benzyl-α- -mannopyranosyl)-(1Ǟ2)- -myo-inositol [( )-6]:
4
D
D
D
COCH2CH2R), 2.18Ϫ2.33 (m, 4 H, COCH2CH2R), 3.14 (m, 1 H,
A solution of compound ()-4 (14 g, 13.42 mmol) in dry DMF
5a-H), 3.19 (m, 1 H, 3a-H), 3.34 (m, 1 H, 4a-H), 3.35 (m, 1 H, 6a-
(150 mL), was treated with benzyl bromide (2.87 mL, 24.16 mmol),
H), 3.47 (m, 2 H, 6b-H, 4b-H), 3.49 (m, 1 H, 3b-H), 3.57 (m, 1 H, then NaH (580 mg, 24.16 mmol) was added. The reaction mixture
6b-H), 3.66 (m, 1 H, 2b-H), 3.74 (m, 1 H, 1ЈЈ-H), 3.83 (m, 2 H, 1Ј- was stirred at room temp. for 3 h, then concentrated under reduced
H), 3.86 (m, 1 H, 5b-H), 3.95 (m, 1 H, 2a-H), 3.97 (m, 1 H, 2ЈЈ- pressure. The residue was diluted with EtOAc and washed with
H), 4.02 (m, 1 H, 1a-H), 4.09 (m, 1 H, 3Ј-H), 4.27 (m, 2 H, 1Ј-H, water and brine. The organic phase was dried (MgSO4) and concen-
3Ј-H), 4.98 (d, 1 H, J Ͻ 1 Hz, 1b-H), 5.10 (m, 1 H, 2Ј-H), 8.65Ϫ8.9
trated under reduced pressure. The residue was purified by flash
(br. s, 2 H, NH2) ppm. 13C NMR (150.9 MHz, [D6]DMSO): δ ϭ chromatography (petroleum ether/EtOAc, 5:1) to yield compound
13.88 (2 C, Me), 22.05/28.42Ϫ29.04/31.26 (20C, CH2-chain) 24.36/
24.44 (2 C, COCH2CH2R), 33.37/33.53 (2 C, COCH2CH2R), 52.72
()-6 (13.1 g, 86%) as a colourless syrup. TLC (petroleum ether/
EtOAc, 2:1): Rf ϭ 0.74. [α]D ϭ ϩ12.8 (c ϭ 1, CHCl3). H NMR
1
(1 C, C-2ЈЈ), 60.74 (1 C, C-6b), 61.99 (1 C, C-3Ј), 62.85 (1 C, C- (250 MHz, CDCl3): δ ϭ 3.22Ϫ3.41 (m, 4 H), 3.48Ϫ3.65 (m, 2 H),
1Ј), 66.55 (1 C, C-4b), 69.48 (1 C, C-1ЈЈ), 69.87 (2 C, C-2Ј, C-3a), 3.71 (s, 3 H, OMe), 3.65Ϫ3.87 (m, 2 H), 3.99Ϫ4.17 (m, 2 H),
70.25 (1 C, C-2b), 70.59 (1 C, C-3b), 72.27 (1 C, C-4a), 72.61 (1 C,
C-5b), 74.53 (1 C, C-1a), 74.67 (1 C, C-5a), 76.93 (1 C, C-2a), 81.93
4.2Ϫ4.69, 4.7Ϫ4.92 (m, 20 H, CH2CHϭCH2, CH2ϪPh, a-H, b-H),
5.12Ϫ5.36 (m, 2 H, CH2CHϭCH2), 5.42 (s, 1 H, 1b-H), 5.91Ϫ6.10
(1 C, C-6a), 100.0 (1 C, C-1b), 168.78 (1 C, COOH), 172.25/172.51 (m, 1 H, CH2CHϭCH2), 6.76Ϫ6.86 (m, 2 H, HPMB), 7.07Ϫ7.40
(2 C, COR) ppm. 31P NMR (242.9 MHz, [D6]DMSO): δ ϭ 0.909 (m, 37 H, ArH) ppm. C72H76O12 (1133.4): calcd. C 76.30, H 6.76;
(s, 1 P) ppm. MALDI-MS (negative mode, matrix THAP, aceto-
www.eurjoc.org
found C 76.09, H 6.77.
Eur. J. Org. Chem. 2004, 3292Ϫ3303
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3297

A. Stadelmaier, M. Biskup, R. R. Schmidt
FULL PAPER
6-O-Allyl-3,4,5,-tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6- action mixture was stirred at 0 °C for 3 h. NH4Cl solution was
tetra-O-benzyl-α- -mannopyranosyl)-(1Ǟ2)- -myo-inositol [( )-7]: added and the two layers were separated. The organic phase was
Compound ()-7 was synthesized following the procedure described washed with water, dried (MgSO4) and concentrated under reduced
D
L
L
for compound ()-6. Compound ()-5 (15.9 g, 15.24 mmol) gave pressure. The residue was purified by flash chromatography (petro-
()-7 (17 g, 98%) as a colourless syrup. [α]D ϭ ϩ20.1 (c ϭ 1, leum ether/EtOAc, 4:1). The mixture of diastereomeric alcohols
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 3.21 (dd, J ϭ 9.8, J ϭ
2.5 Hz, 1 H, a-H), 3.29Ϫ3.45 (m, 3 H), 3.51Ϫ3.87 (m, 5 H), 3.77
(s, 3 H, OMe), 4.0Ϫ4.19 (m, 2 H), 4.20Ϫ4.91 (m, 19 H, CH2ϪPh,
CH2CHϭCH2, 2a-H), 5.12 (dd, Jgem. ϭ 10.4, Jvic. ϭ 1.7 Hz, 1 H,
CH2CHϭCH2), 5.25 (dd, Jgem. ϭ 17.2, Jvic. ϭ 1.7 Hz, 1 H,
CH2CHϭCH2), 5.42 (d, J ϭ 1.2 Hz, 1 H, 1b-H), 5.88Ϫ6.04 (m, 1
H, CH2CHϭCH2), 6.75Ϫ6.84 (m, 2 H, HPMB), 7.07Ϫ7.40 (m, 37
H, ArH) ppm. C72H76O12 (1133.4): calcd. C 76.30, H 6.76; found
C 76.10, H 6.57.
13h,l was obtained quantitatively.
3,4,5-Tri-O-benzyl-6-O-[(2R)-2-hydroxy-3-(tert-butyldiphenylsilyl-
oxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D
-mannopyranosyl)-
O-[(2S)-2-hydroxy-3-(tert-butyldiphenylsilyloxy)propyl]-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α- -mannopyranosyl)-
-myo-inositol (13h): Separation of the mixture of diastereomers
D-myo-inositol (13l) and 3,4,5-Tri-O-benzyl-6-
D
D
13h,l into the pure alcohols 13l and 13h was possible by repetitive
chromatography (6:1 petroleum ether/EtOAc) on silica gel columns.
13l: HPTLC (toluene/EtOAc, 10:1): Rf ϭ 0.40. [α]D ϭ ϩ8.1 (c ϭ
1, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 1.05 (s, 9 H, tBu),
3.2Ϫ3.29 (m, 2 H, 1a-H, 3a-H), 3.3Ϫ3.45 (m, 2 H, 5a-H, 6b-H),
3.51Ϫ3.77 (m, 9 H, OMe, 3ЈЈ-H, 6b-H, 6a-H, 4a-H, 2b-H),
3.79Ϫ3.86 (m, 2 H, 1ЈЈ-H, 3b-H), 3.9 (m, 1 H, 2ЈЈ-H), 3.96 (dd,
Jvic. ϭ 2.9, Jgem. ϭ 10.8 Hz, 1 H, 1ЈЈ-H), 4.0Ϫ4.12 (m, 2 H, 4b-H,
5b-H), 4.3Ϫ4.5, 4.51Ϫ4.61, 4.69Ϫ4.78, 4.8Ϫ4.91 (m, 17 H,
CH2ϪPh, 2a-H), 5.35 (d, 1 H, 1b-H), 6.72Ϫ6.74 (m, 2 H, HPMB),
7.06Ϫ7.43, 7.60Ϫ7.70 (m, 47 H, ArH) ppm. C88H96O14Si (1405.8):
calcd. C 75.20, H 6.90; found C 74.95, H 6.90. 13h: HPTLC (tolu-
ene/EtOAc, 10:1): Rf ϭ 0.45. [α]D ϭ ϩ10.8 (c ϭ 1, CHCl3). 1H
3,4,5-Tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-
benzyl-α-D-mannopyranosyl)-(1Ǟ2)-L-myo-inositol [(L)-8]: DBU
(0.12 mL, 0.80 mmol) and (Ph3P)3RhCl (0.91 g, 1.02 mmol) were
added to a solution of ()-7 (7.74 g, 6.83 mmol) in dry EtOH
(150 mL), and the mixture was refluxed at 90 °C. After 1.5 h for
isomerization, the reaction mixture was concentrated under re-
duced pressure, and the residue was redissolved in 1  HCl/acetone
(1:9) and refluxed at 70 °C for 20 min. The solution was neutralized
with NEt3, diluted with EtOAc and washed with water. After dry-
ing (MgSO4), the organic phase was concentrated and purified by
flash chromatography on silica gel (petroleum ether/EtOAc, 4:1),
to afford ()-8 (6.7 g, 90%). TLC (petroleum ether/EtOAc, 2:1):
Rf ϭ 0.61. [α]D ϭ ϩ28.3 (c ϭ 1, CHCl3), 1H NMR (250 MHz,
CDCl3): δ ϭ 2.40 (d, J ϭ 1.8 Hz, 1 H, OH), 3.01 (dd, J ϭ 2.4, J ϭ
10.0 Hz, 1 H, a-H), 3.32 (dd, 1 H, J ϭ 9.2 Hz, a-H), 3.34Ϫ3.40 (m,
1 H, a-H), 3.45Ϫ3.52 (m, 1 H, 6b-H), 3.57Ϫ3.76 (m, 3 H), 3.80 (s,
3 H, OMe), 3.81Ϫ3.93 (m, 2 H) 4.02 (dd, 1 H, J ϭ 9.4 Hz),
4.10Ϫ4.19 (m, 1 H, 5b-H), 4.38Ϫ4.91 (m, 17 H, CH2ϪPh, 2a-H),
5.40 (d, J1,2 ϭ 1.5 Hz, 1 H, 1b-H), 6.79Ϫ6.86 (m, 2 H, HPMB),
7.10Ϫ7.40 (m, 37 H, ArH) ppm. C69H72O12 (1093.3): calcd. C
75.80, H 6.64; found C 75.51, H 6.56.
NMR (600 MHz, CDCl3): δ ϭ 1.05 (s, 9 H, tBu), 3.21 (dd, J1,2
ϭ
1.2, J1,6 ϭ 9.8 Hz, 1 H, 1a-H), 3.25 (dd, J3,4 ϭ 9.9, J3,2 ϭ 2.0 Hz,
1 H, 3a-H), 3.32 (dd, J5,6 ϭ J5,4 ϭ 9.3 Hz, 1 H, 5a-H), 3.35Ϫ3.39
(m, 1 H, 6b-H), 3.54 (dd, Jvic. ϭ 3.7, Jgem. ϭ 12.1 Hz, 1 H, 6b-H),
3.75Ϫ3.68 (m, 6 H, OMe, 3ЈЈ-H, 6a-H), 3.69Ϫ3.75 (m, 2 H, 2b-H,
4a-H), 3.78Ϫ3.82 (m, 2 H, 3b-H, 2ЈЈ-H), 3.87Ϫ3.94 (m, 2 H, 1ЈЈ-
H), 4.04 (dd, J4,5 ϭ J4,3 ϭ 9.7 Hz, 1 H, 4b-H), 4.07Ϫ4.13 (m, 1 H,
5b-H), 4.33Ϫ4.61, 4.70Ϫ4.80, 4.81Ϫ4.85 (m, 17 H, CH2ϪPh, 2a-
H), 5.35 (d, 1 H, 1b-H), 6.65Ϫ6.67 (m, 2 H, HPMB), 7.03Ϫ7.43,
7.59Ϫ7.69 (m, 47 H, ArH) ppm. C88H96O14Si (1405.8): calcd. C
75.20, H 6.90; found C 75.32, H 6.89.
3,4,5-Tri-O-benzyl-6-O-[(2R/2S)-2,3-dihydroxypropyl]-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-
3,4,5-Tri-O-benzyl-6-O-[3-(tert-butyldiphenylsilyloxy-2-(R)-α-
methoxy-α-trifluoromethyl-phenylacetoxy)-(R,S)propyl]-1-O-(4-
D-myo-inositol (12): Osmium tetroxide (100 mg, 0.39 mmol) and N-
methylmorpholine N-oxide (3.3 g, 24.42 mmol) were added to a
solution of alkene ()-6 (14 g, 12.35 mmol) in acetone/water (8:1).
The solution was stirred at room temp. for 14 h, then saturated
sodium hydrogen sulfite solution (170 mL) was added, and stirring
was continued for a further 30 min. The solution was separated
from the resultant precipitate, the filtrate was diluted with EtOAc
(400 mL) and the phases were separated. The organic phase was
dried (MgSO4) and concentrated. Flash chromatography (petro-
leum ether/EtOAc, 1:1Ǟ1:2) of the residue gave a 1:1 mixture of
diastereomeric diols 12 (14 g, 97%) as a colourless syrup. TLC
(petroleum ether/EtOAc, 2:1): Rf ϭ 0.11. [α]D ϭ ϩ11.8 (c ϭ 1,
CDCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.53 (s, 2 H, OH),
1.89Ϫ1.99 (m, 2 H, OH), 3.18Ϫ3.89 (m, 34 H, OMe, OMe),
3.99Ϫ4.16 (m, 4 H), 4.3Ϫ4.63, 4.68Ϫ4.80, 4.81Ϫ4.95 (m, 34 H,
CH2ϪPh), 5.34 (d, 1 H, J Ͻ 1 Hz, 1b-H), 5.36 (d, J ϭ 1.5 Hz, 1
H, 1b-H), 6.72Ϫ6.83 (m, 4 H, HPMB), 7.09Ϫ7.39 (m, 74 H, ArH)
ppm. C72H78O16 (1167.4): calcd. C 74.08, H 6.74; found C 74.01,
H 6.88.
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-
(1Ǟ2)- -myo-inositol [(R)-14h,l]: (S)-(ϩ)-α-Methoxy-α-trifluoro-
D
methylphenylacetyl chloride (40 µL, 0.21 mmol) was added to a
solution of compounds 13h,l (4:1) (194 mg, 0.14 mmol) in dry pyri-
dine (2 mL). After stirring at room temp. for 24 h, the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in diethyl ether, and washed with water and brine. The
organic layer was dried (MgSO4) and concentrated. Purification
by flash chromatography (petroleum ether/EtOAc, 6:1 ) afforded a
mixture of compounds (R)-14h,l (205 mg, 91%) as a colourless
syrup. TLC (petroleum ether/EtOAc, 7:2): Rf ϭ 0.54. [α]D ϭ ϩ17
(c ϭ 1, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 0.98 (s, 9 H,
tBuh), 1.02 (s, 2.25 H, tBul), 2.77 (dd, 0.25 H, J1,6 ϭ 9.6 Hz, 1a-
Hl), 3.09 (dd, 1 H, J1,6 ϭ 9.7 Hz, 1a-Hh), 3.12Ϫ3.19 (m, 0.5 H, 3a-
Hl, 5a-Hl), 3.20Ϫ3.26 (m, 2 H, 3a-Hh, 5a-Hh), 3.33Ϫ3.41 (m, 1.5
H, 6a-Hl, 6b-Hl, 6b-Hh), 3.48 (dd, J6,1 ϭ J6,5 ϭ 9.4 Hz, 1 H, 6a-
Hh), 3.51Ϫ3.60 (m, 6 H, 6b-Hh, 6b-Hl, 1ЈЈ-Hl, OMeh, OMel, OMel),
3.61Ϫ3.84 (m, 10.25 H, OMeh, 3ЈЈ-Hh, 3ЈЈ-Hl, 1ЈЈ-Hh, 2b-Hh, 2b-
Hl, 3b-Hh, 3b-Hl, 4a-Hh, 4a-Hl), 3.90 (m, 0.25 H, 1ЈЈ-Hl), 4.0Ϫ4.19
(m, 3.5 H, 1ЈЈ-Hh, 4b-Hh, 5b-Hh,), 4.28 (m, 0.25 H, 2a-Hl), 4.31 (m,
1 H, 2a-Hh), 4.32Ϫ4.92 (m, 20 H, CH2-Ph), 5.31 (m, 0.25 H, 1b-
Hl), 5.35 (m, 1 H, 1b-Hh), 5.47Ϫ5.55 (m, 1.25 H, 2ЈЈ-Hl, 2ЈЈ-Hh),
6.6Ϫ6.7 (m, 2.5 H, HPMB h, HPMB l), 7.01Ϫ7.41, 7.51Ϫ7.66 (m, 65
H, ArH) ppm. MALDI-MS (positive mode, matrix DHB, THF)
3,4,5-Tri-O-benzyl-6-O-[(2R/2S)-2-hydroxy-3-(tert-butyldiphenyl-
silyloxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-
benzyl-α-D-mannopyranosyl)-D-myo-inositol (13h,l): A mixture of
diastereomeric diols 12 (12.87 g, 11.02 mmol) was dissolved in dry
CH2Cl2 (300 mL). Imidazole (2.25 g, 33.05 mmol) and tert-butyldi-
phenylsilyl chloride (7.1 mL, 27.74 mmol) were added, and the re-
3298
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3292Ϫ3303

Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
FULL PAPER
[M ϩ Na]ϩ: calcd. m/z ϭ 1645.0; found m/z ϭ 1641.9; [M ϩ K]ϩ:
calcd. m/z ϭ 1661.1; found m/z ϭ 1657.9. C98H103F3O16Si (1622.0):
calcd. C 72.57, H 6.40; found C 72.51, H 6.56.
(petroleum ether/EtOAc, 3:1) gave mesylate 18 (5.06 g, 93%) as a
colourless foam. TLC (petroleum ether/EtOAc, 3:1): Rf ϭ 0.33.
[α]D ϭ ϩ15.5 (c ϭ 1, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ
1
1.02 (s, 9 H, tBu), 2.92 (s, 3 H, OMs), 3.09Ϫ3.18 (m, 1 H, 1a-H),
3.19Ϫ3.30 (m, 2 H, 5a-H, 3a-H), 3.36 (m, 1 H, 6b-H), 3.46 (m, 1
H, 6a-H), 3.56 (m, 1 H, 6b-H), 3.66Ϫ3.94 (m, 9 H, OMe, 2b-H,
4a-H, 3ЈЈ-H, 3b-H, 1ЈЈ-H), 3.96Ϫ4.18 (m, 3 H, 1ЈЈ-H, 4b-H, 5b-H),
4.29Ϫ4.93 (m, 18 H, 2ЈЈ-H, CH2ϪPh, 2a-H), 5.35 (d, 1 H, J Ͻ
1 Hz, 1b-H), 6.68Ϫ6.76 (m, 2 H, HPMB), 7.10Ϫ7.47, 7.61Ϫ7.71 (m,
47 H, ArH) ppm. C89H98O14SSi (1483.9): calcd. C 72.00, H 6.66;
found C 72.04, H 6.50.
3,4,5-Tri-O-benzyl-6-O-[3-(tert-butyldiphenylsilyloxy)-(S)-α-
methoxy-α-trifluoromethylphenylacetoxy)-(R,S)propyl]-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-
(1Ǟ2)- -myo-inositol [(S)-14h,l]: (R)-(Ϫ)-α-Methoxy-α-trifluoro-
D
methylphenylacetyl chloride (50 µL, 0.27 mmol) was added to a
solution of compounds 13h,l (4:1) (248 mg, 0.18 mmol) in dry pyri-
dine (2.5 mL). After stirring at room temp. for 24 h, the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in diethyl ether, and washed with water and brine. The
6-O-[(2S)-2-Azido-3-(tert-butyldiphenylsilyloxy)propyl]-3,4,5-tri-O-
organic layer was dried (MgSO4) and concentrated. Purification benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-D-
by flash chromatography (petroleum ether/EtOAc, 6:1 ) afforded a
mixture of compounds (S)-14h,l (254 mg, 88%) as a colourless
syrup. TLC (petroleum ether/EtOAc, 7:2): Rf ϭ 0.54. [α]D ϭ Ϫ33
(c ϭ 1, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 0.98 (s, 2.25 H,
tBul), 1.0 (s, 9 H, tBuh), 2.92 (dd, J5,6 ϭ J5,4 ϭ 9.2 Hz, 1 H, 5a-
mannopyranosyl)-D-myo-inositol (17): Compound 17 was synthe-
sized following the procedure described for compound 18. Com-
pound 15 (4.12 g, 2.78 mmol) gave 17 (3.60 g, 93%) as a colourless
syrup. [α]D ϭ ϩ5.3 (c ϭ 0.54, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.02Ϫ1.12 (s, 9 H, tBu), 3.14Ϫ3.58 (m, 6 H), 3.6Ϫ3.85
Hh), 3.21Ϫ3.28 (m, 0.5 H, 5a-Hl, 3a-Hl,), 2.99 (dd, J1,2 ϭ 1.4, J1,6 ϭ (m, 8 H), 3.69 (s, 3 H, OMe), 4.0Ϫ4.14 (m, 2 H), 4.3Ϫ4.63,
9.7 Hz, 1 H 1a-Hh), 3.14 (dd, 1.25 H, J3,4 ϭ 9.8, J3,2 ϭ 2.2 Hz, 3a-
Hh,1a-Hl), 3.34 (dd, 2.25 H, J6,1 ϭ J6,5 ϭ 11.3 Hz, 6a-Hh, 6b-Hl,6b-
Hh), 3.49Ϫ3.90 (m, 17.5 H, 4a-Hh, 4a-Hl, 6a-Hl, 6b-Hl, 6b-Hh, 2b-
4.69Ϫ4.92 (m, 17 H, CH2ϪPh, 2a-H), 5.34 (d, 1 H, 1b-H),
6.68Ϫ6.73 (m, 2 H, HPMB), 7.07Ϫ7.46, 7.62Ϫ7.72 (m, 47 H, ArH)
ppm. MALDI-MS (positive mode, matrix DHB, THF) [M ϩ Na]ϩ:
Hl, 2b-Hh, OMeh, OMeh, OMel, OMel, 3ЈЈ-Hl, 1ЈЈ-Hl, 3b-Hl, 3b-Hh, calcd. m/z ϭ 1453.82; found m/z ϭ 1453.3. C88H95N3O13Si
3ЈЈ-Hh, 1ЈЈ-Hh), 4.0Ϫ4.12 (m, 2.75 H, J4,5 h ϭ J4,3 h ϭ 9.7 Hz, 1Ј- (1430.8): calcd. C 73.87, H 6.69, N 2.90; found C 73.96, H 6.97,
Hl, 4b-Hh, 5b-Hh, 4b-Hl, 5b-Hl), 4.22Ϫ4.48, 4.49Ϫ4.62, 4.63Ϫ4.89
(m, 21.25 H, CH2ϪPh, 2a-Hl, 2a-Hh), 5.32 (d, 1 H, JϽ1 Hz, 1b-
Hh), 5.36 (m, 1 H, 1b-Hl), 5.45Ϫ5.5 (m, 0.25 H, 2ЈЈ-Hl), 5.54 (m, 1
H, 2ЈЈ-Hh), 6.58Ϫ6.63 (m, 0.5 H, HPMB l), 6.65Ϫ6.71 (m, 2 H,
HPMB h), 7.0Ϫ7.42, 7.5Ϫ7.69 (m, 65 H, ArH) ppm. C98H103F3O16Si
(1622.0): calcd. C 72.57, H 6.40; found C 72.63, H 6.56.
N 2.60.
6-O-[(2R)-2-Azido-3-(tert-butyldiphenylsilyloxy)propyl]-3,4,5-tri-O-
benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
mannopyranosyl)- -myo-inositol (18): Sodium azide (3.33 g,
3.41 mmol) was added to a solution of mesylate 16 (5.06 g,
3.41 mmol) in dry DMF (150 mL). This suspension was stirred at
90 °C for 24 h. After letting the reaction mixture cool to room
temp., it was diluted with diethyl ether and washed with water. The
aqueous phase was extracted with diethyl ether (3 ϫ 200 mL). The
combined organic extracts were dried (MgSO4) and concentrated.
The residue was purified by flash chromatography (petroleum
D-
D
3,4,5-Tri-O-benzyl-6-O-[(2R)-3-(tert-butyldiphenylsilyloxy)-2-
(methylsulfonyloxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-
tetra-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (15): Com-
pound 15 was synthesized following the procedure described for
compound 16. Compound 13l (3.99 g, 2.84 mmol) gave 15 (4.15 g,
98%) as a colourless foam. [α]D ϭ ϩ11.5 (c ϭ 1, CHCl3). 1H NMR ether/EtOAc, 5:1) to yield 18 (4.1 g, 84%) as a colourless syrup.
(600 MHz, CDCl3): δ ϭ 1.04 (s, 9 H, tBu), 2.87 (s, 3 H, OMs), 3.13 TLC (petroleum ether/EtOAc, 5:1): Rf ϭ 0.24. [α]D ϭ ϩ18 (c ϭ 1,
(dd, J1,2 ϭ 1.5, J1,6 ϭ 8.9 Hz, 1 H, 1a-H), 3.19Ϫ3.26 (m, 2 H, 5a-
H, 3a-H), 3.37 (m, 1 H, 6b-H), 3.46 (dd, J6,5 ϭ J6,1 ϭ 9.4 Hz, 1 H, 3.14Ϫ3.58 (m, 6 H), 3.6Ϫ3.85 (m, 8 H), 3.69 (s, 3 H, OMe),
6a-H), 3.55 (m, 1 H, 6b-H), 3.63Ϫ3.74 (m, 5 H, OMe, 2b-H, 4a- 4.0Ϫ4.14 (m, 2 H), 4.3Ϫ4.63, 4.69Ϫ4.92 (m, 17 H, CH2ϪPh, 2a-
H), 3.77Ϫ3.85 (m, 4 H, 3ЈЈ-H, 1ЈЈ-H, 3b-H), 4.02Ϫ4.13 (m, 3 H, H), 5.34 (d, 1 H, 1b-H), 6.69Ϫ6.74 (m, 2 H, HPMB), 7.07Ϫ7.46,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.02Ϫ1.12 (s, 9 H, tBu),
1ЈЈ-H, 4b-H, 5b-H), 4.3Ϫ4.9, 4.52Ϫ4.66, 4.7Ϫ4.83, 4.83Ϫ4.90 (m,
18 H, 2ЈЈ, CH2ϪPh, 2a-H), 5.34 (d, 1 H, 1b-H), 6.68Ϫ6.75 (m,
2 H, HPMB), 7.05Ϫ7.45, 7.60Ϫ7.69 (m, 47 H, ArH). 13C NMR
(150.9 MHz, CDCl3): δ ϭ 19.17 [1 C, C(CH3)3], 26.78 [3 C,
C(CH3)3], 38.40 (1 C, SO2ϪCH3), 55.14 (1 C, OMe), 63.79 (1 C,
C-3ЈЈ), 68.95 (1 C, C-6b), 71.18 (1 C, C-2a), 71.85Ϫ75.83 (12 C,
CH2Ph, C-1ЈЈ, C-4b, C-5b, C-2b), 78.46 (1 C, C-3a), 79.04 (1 C, C-
3b), 80.11 (1 C, C-1a), 80.95 (1 C, C-4a), 82.05 (1 C, C-6a), 82.12
(1 C, C-2ЈЈ), 82.88 (1 C, C-5a), 98.38 (1 C, C-1b), 113.92 (2 C,
CPMB), 127.3Ϫ138.37 (57 C, Ph), 159.38 (1 C, COMe) ppm.
C89H98O14SSi (1483.9): calcd. C 72.00, H 6.66; found C 71.81, H
6.70.
7.62Ϫ7.72 (m, 47 H, ArH) ppm. C88H95N3O13Si (1430.8): calcd. C
73.87, H 6.69, N 2.90; found C 73.63, H 6.78, N 2.48.
6-O-[(2R)-2-Azido-3-hydroxypropyl]-3,4,5-tri-O-benzyl-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-
D-myo-inositol (19): Compound 19 was synthesized following the
procedure described for compound 20. Compound 17 (3.59 g,
2.51 mmol) gave 19 (2.80 g, 93%) as a colourless oil. [α]D ϭ ϩ19.2
(c ϭ 1, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 1.9 (s, 1 H,
OH), 3.23 (dd, J1,2 ϭ 1.4, J1,6 ϭ 9.7 Hz, 1 H, 1a-H), 3.26 (dd,
J3,4 ϭ 9.9, J3,2 ϭ 2.2 Hz, 1 H, 3a-H), 3.33 (dd, J5,6 ϭ J5,4 ϭ 9.2 Hz,
1 H, 5a-H), 3.36Ϫ3.41 (m, 1 H, 6b-H), 3.45 (dd, J6,1 ϭ J6,5
ϭ
9.5 Hz, 1 H, 6a-H), 3.52Ϫ3.58 (m, 2 H, 2ЈЈ-H, 6b-H), 3.59Ϫ3.77
(m, 7 H, OMe, 2b-H, 3ЈЈ-H, 4a-H), 3.80Ϫ3.88 (m, 3 H, 1ЈЈ-H, 3b-
H), 4.05 (dd, J4,5 ϭ J4,3 ϭ 9.8 Hz, 1 H, 4b-H), 4.13 (m, 1 H, 5b-
H), 4.34Ϫ4.41, 4.41Ϫ4.46, 4.71Ϫ4.78, 4.84Ϫ4.94 (m, 17 H,
CH2ϪPh, 2a-H), 5.37 (d, 1 H, 1b-H), 6.78Ϫ6.83 (m, 2 H, HPMB),
7.10Ϫ7.38 (m, 37 H, ArH) ppm. 13C NMR (150.9 MHz, CDCl3):
δ ϭ 55.21 (1 C, OMe), 62.58 (1 C, C-2ЈЈ), 62.77 (1 C, C-3ЈЈ), 68.94
(1 C, C-6b), 71.11 (1 C, C-2a), 71.82Ϫ75.93 (12 C, CH2Ph, C-1ЈЈ,
C-4b, C-5b, C-2b), 78.63 (1 C, C-3a), 79.16 (1 C, C-3b), 80.27 (1
C, C-1a), 81.08 (1 C, C-4a), 81.96 (1 C, C-6a), 83.08 (1 C, C-5a),
3,4,5-Tri-O-benzyl-6-O-[(2S)-3-(tert-butyldiphenylsilyloxy)-2-
(methylsulfonyloxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-
tetra-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (16): Com-
pound 13h (5.25 g, 3.74 mmol) was dissolved in pyridine/CH2Cl2
(1:1, 80 mL) and treated with methanesulfonyl chloride (0.87 mL,
11.20 mmol) at room temp. The reaction mixture was stirred for
3.5 h, diluted with CH2Cl2 and washed with sat. NaHCO3 solution
and water. The organic phase was dried (MgSO4) and concentrated
under reduced pressure. Purification by flash chromatography
Eur. J. Org. Chem. 2004, 3292Ϫ3303
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3299

A. Stadelmaier, M. Biskup, R. R. Schmidt
98.35 (1 C, C-1b), 113.96 (2 C, CPMB), 127.3Ϫ138.79 (45 C, Ph), 3.47 (dd, J6,1 ϭ J6,5 ϭ 9.4 Hz, 1 H, 6a-H), 3.54 (dd, Jgem. ϭ 10.7,
FULL PAPER
159.52 (1 C, COMe) ppm. C72H77N3O13 (1192.4): calcd. C 72.50, H
6.50, N 3.52; found C 72.42, H 6.26, N 3.28.
Jvic. ϭ 3.5 Hz, 1 H, 6b-H), 3.64 (m, 1 H, 2b-H), 3.69 (s, 3 H, OMe),
3.72 (dd, J4,5 ϭ J4,3 ϭ 9.5 Hz, 1 H, 4a-H), 3.81 (dd, J3,4 ϭ 9.4,
J3,2 ϭ 3.0 Hz, 1 H, 3b-H), 4.01 (dd, 1 H, Jvic. ϭ 5.4 Hz, 2ЈЈ-H),
4.05 (dd, J4,5 ϭ J4,3 ϭ 9.6 Hz, 1 H, 4b-H), 4.07Ϫ4.13 (m, 3 H, 1ЈЈ-
H, 5b-H), 4.29Ϫ4.39, 4.41Ϫ4.48, 4.51Ϫ4.62, 4.7Ϫ4.79, 4.82Ϫ4.92
(m, 17 H, CH2ϪPh, 2a-H), 5.12 (d, 1 H, Jgem. ϭ 12.2 Hz,
COOCH2ϪPh), 5.23 (d, 1 H, Jgem. ϭ 12.2 Hz, COOCH2ϪPh), 5.34
(d, 1 H, 1b-H), 6.72Ϫ6.8 (m, 2 H, HPMB), 7.10Ϫ7.40 (m, 42 H,
ArH) ppm. MALDI-MS (positive mode, matrix DHB, THF) [M
ϩ Na]ϩ: calcd. m/z ϭ 1319.5; found m/z ϭ 1318.3; [M ϩ K]ϩ:
calcd. m/z ϭ 1335.6; found m/z ϭ 1333.7. C79H81N3O14 (1296.5):
calcd. C 73.19, H 6.30, N 3.24; found C 73.03, H 6.28, N 2.73.
6-O-[(2S)-2-Azido-3-hydroxypropyl]-3,4,5-tri-O-benzyl-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-
D-myo-inositol (20): A solution of compound 18 (3.7 g, 2.59 mmol)
in THF (100 mL) at 0 °C was treated with tetrabutylammonium
fluoride solution (1  in THF, 0.9 mL). After removing the cooling
bath, the solution was stirred at room temp. for 3.5 h. The reaction
mixture was diluted with EtOAc, washed with NH4Cl solution and
water. The organic phase was dried (MgSO4) and concentrated un-
der reduced pressure. Chromatographic purification of the residue
with silica gel (petroleum ether/EtOAc, 3:1) gave 20 (2.93 g, 95%)
as a colourless oil. TLC (petroleum ether/EtOAc, 3:1): Rf ϭ 0.14.
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (23):
1
[α]D ϭ ϩ13.8 (c ϭ 1, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ
1.99 (dd, 1 H, J ϭ 7.1 Hz, OH), 3.20Ϫ3.90 (m, 17 H, OMe, 1a-H,
3a-H, 5a-H, 6b-H, 6a-H, 2ЈЈ-H, 3ЈЈ-H, 4a-H, 2b-H), 4.0Ϫ4.18 (m,
2 H, 4b-H, 5b-H), 4.32Ϫ4.66, 4.7Ϫ4.95 (m, 17 H, CH2ϪPh, 2a-
H), 5.38 (d, J ϭ 1.3 Hz, 1 H, 1b-H), 6.76Ϫ6.84 (m, 2 H, HPMB),
7.10Ϫ7.40 (m, 37 H, ArH) ppm. MALDI-MS (positive mode, ma-
trix DHB, THF) [M ϩ Na]ϩ: calcd. m/z ϭ 1215.4; found m/z ϭ
1214.0; [M ϩ K]ϩ: calcd. m/z ϭ 1231.5; found m/z ϭ 1230.0.
C72H77N3O13 (1192.4): calcd. C 72.52, H 6.51, N 3.52; found C
72.38, H 6.30, N 2.99.
Compound 23 was synthesized following the procedure described
for compound 24. Compound 21 (1.03 g, 0.79 mmol) gave 23
(757 mg, 81%) as a colourless syrup. [α]D ϭ ϩ15.8 (c ϭ 1, CHCl3).
1H NMR (250 MHz, CDCl3): δ ϭ 3.10 (d, J ϭ 1.5 Hz, 1 H, OH),
3.18Ϫ3.41 (m, 5 H), 3.58 (dd, 1 H, Jgem. ϭ 12.0 Hz, 6b-H),
3.65Ϫ3.77 (m, 3 H), 3.78Ϫ3.89 (m, 1 H), 4.02Ϫ4.13 (m, 3 H),
4.19Ϫ4.28 (m, 1 H), 4.29Ϫ4.95 (m, 15 H), 5.20 (d, J ϭ 9.2 Hz, 1
H, COOCH2ϪPh), 5.30 (d, J ϭ 10.4 Hz, 1 H, COOCH2ϪPh), 5.46
(d, J ϭ 1.6 Hz, 1 H, 1b-H), 7.12Ϫ7.43 (m, 40 H, ArH) ppm.
C71H73N3O13 (1176.4): calcd. C 72.49, H 6.26, N 3.57; found C
72.33, H 6.36, N 2.95.
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-1-
O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-manno-
pyranosyl)- -myo-inositol (21): Compound 21 was synthesized fol-
D
6-O-[(2R)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-D-myo-inositol (24):
lowing the procedure described for compound 22. Compound 19
(2.75 g, 2.31 mmol) gave 21 (2.30 g, 77%) as a colourless syrup.
A solution of compound 22 (1 g, 0.77 mmol) in acetonitrile/tolu-
ene/water (60:3:4, 40 mL) was cooled to 0 °C and treated with
Ce(NH4)2(NO3)6 (2.1 g, 3.83 mmol). After stirring for 1 h, the cool-
ing bath was removed and the solution was stirred for further
90 min at room temp. The reaction mixture was diluted with
EtOAc, washed with sat. NaHCO3 solution, dried (MgSO4) and
concentrated. Flash chromatography (petroleum ether/EtOAc, 4:1)
of the residue afforded the free alcohol 24 (0.77 g, 85%) as a colour-
1
[α]D ϭ ϩ20.5 (c ϭ 1, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ
3.20Ϫ3.39 (m, 4 H, 1a-H, 3a-H, 6b-H), 3.42Ϫ3.58 (m, 2 H, 6a-H,
6b-H), 3.61Ϫ3.67 (m, 1 H, 2b-H), 3.69 (s, 3 H, OMe), 3.70Ϫ3.84
(m, 2 H, 4a-H, 3b-H), 3.93Ϫ4.23 (m, 5 H, 2ЈЈ-H, 4b-H, 1ЈЈ-H, 5b-
H), 4.30Ϫ4.63, 4.69Ϫ4.92 (m, 17 H, CH2ϪPh, 2a-H), 5.02 (d, 1 H,
Jgem. ϭ 12.2 Hz, COOCH2ϪPh), 5.23 (d, 1 H, Jgem. ϭ 12.2 Hz,
COOCH2ϪPh), 5.34 (d, 1 H, J Ͻ 1 Hz, 1b-H), 6.73Ϫ6.81 (m, 2 H,
HPMB), 7.09Ϫ7.40 (m, 42 H, ArH) ppm. C79H81N3O14 (1296.5):
calcd. C 73.19, H 6.30, N 3.25; found C 73.12, H 6.42, N 2.80.
less syrup. TLC (petroleum ether/EtOAc, 2:1): Rf ϭ 0.51. [α]D
ϭ
1
ϩ43 (c ϭ 1, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 2.88 (d, 1
H, J Ͻ 1 Hz, OH), 3.18Ϫ3.40 (m, 5 H), 3.55 (dd, 1 H, Jgem.
11.4 Hz, 6b-H), 3.62Ϫ3.85 (m, 4 H), 3.93Ϫ4.01 (m, 1 H),
4.02Ϫ4.20 (m, H), 4.27Ϫ4.96 (m, 15 H), 5.28 (s, H,
ϭ
6-O-[(2R)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-1-
O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-manno-
3
2
pyranosyl)- -myo-inositol (22): NaHCO3 solution (5% w/v, 10 mL),
D
COOCH2ϪPh), 5.43 (d, 1 H, J Ͻ 1 Hz, 1b-H), 7.09Ϫ7.41 (m, 40
H, ArH)ppm. MALDI-MS (positive mode, matrix DHB, THF) [M
ϩ Na]ϩ: calcd. m/z ϭ 1199.37; found m/z ϭ 1198.9; [M ϩ K]ϩ:
calcd. m/z ϭ 1215.5; found m/z ϭ 1215.9. C71H73N3O13 (1176.4):
calcd. C 72.49, H 6.26, N 3.57; found C 72.32, H 6.38, N 3.00.
KBr (295 mg, 2.45 mmol) and TEMPO (427 mg, 1.67 mmol) were
added to a solution of compound 20 (2.9 g, 2.43 mmol) in acetone
(20 mL), and the reaction mixture was cooled to 0 °C. NaOCl solu-
tion (13% w/v, 5 mL) was added to this suspension over 5 min, and
stirring was continued for 10 min at 0 °C. The reaction mixture was
diluted with water and extracted with EtOAc (3 ϫ 50 mL). The
combined organic extracts were washed with sat. NaCl solution,
dried (MgSO4), concentrated under reduced pressure and dried for
1 h under reduced pressure; Rf (toluene/acetone, 1:1) ϭ 0.26. The
crude carboxylic acid was converted into the ester without further
purification. A solution of the crude acid in dry DMF (50 mL)
was treated with benzyl bromide (0.59 mL, 4.97 mmol) and CsF
(754 mg, 4.97 mmol) and stirred at room temp. for 3 h. The reac-
tion mixture was diluted with EtOAc, washed with NH4Cl solution
and brine, dried (MgSO4) and concentrated. Purification of the
residue by silica gel chromatography (petroleum ether/EtOAc, 4:1)
gave ester 22 (2.55 g, 81%) as a colourless syrup. TLC (petroleum
ether/EtOAc, 3:1): Rf ϭ 0.41. [α]D ϭ ϩ18.8 (c ϭ 1, CHCl3). 1H
NMR (600 MHz, CDCl3): δ ϭ 3.18 (dd, J1,2 ϭ 1.3, J1,6 ϭ 9.6 Hz,
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-D-myo-inosit-1-yl-
[benzyl]-[(2R)-2,3-bis(myristoyloxy)propyl]-phosphate (25a,b): Com-
pound 25a,b was synthesized following the procedure described for
compound 26a,b. Compound 23 (417 mg, 0.35 mmol) gave 25a,b
(490 mg, 75%) as a colourless syrup. [α]D ϭ ϩ7 (c ϭ 1, CHCl3). 1H
NMR (250 MHz, CDCl3): δ ϭ 0.8Ϫ0.95 (t, 6 H, Me), 1.14Ϫ1.39 (s,
40 H, CH2-chain), 1.46Ϫ1.56 (m, 4 H, COCH2CH2R), 2.15Ϫ2.35
(m, 4 H, COCH2CH2R), 3.20Ϫ3.38 (m, 3 H), 3.45Ϫ3.59 (m, 2 H),
3.65Ϫ3.85 (m, 3 H), 3.93Ϫ4.32 (m, 10 H), 4.40Ϫ4.92 (m, 15 H),
5.04Ϫ5.25 (m, 5 H, 2Ј, COOCH2ϪPh, POCH2Ph), 5.31 (d, 0.5 H,
J Ͻ 1 Hz, 1b-H), 5.34 (d, 0.5 H, J Ͻ 1 Hz, 1b-H), 7.10Ϫ7.41 (m,
45 H, ArH) ppm.
1 H, 1a-H), 3.23 (dd, J3,4 ϭ 9.9, J3,2 ϭ 2.1 Hz, 1 H, 3a-H), 3.32 6-O-[(2R)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
(dd, J5,6 ϭ J5,4 ϭ 9.2 Hz, 1 H, 5a-H), 3.34Ϫ3.38 (m, 1 H, 6b-H), O-(2,3,4,6-tetra-O-benzyl-α- -mannopyranosyl)- -myo-inosit-1-yl-
D
D
3300
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3292Ϫ3303

Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
FULL PAPER
benzyl-[(2R)-2,3-bis(myristoyloxy)propyl]phosphate (26a,b): A solu-
(370 mg, 0.32 mmol) in dry CH2Cl2 (10 mL). The reaction mixture
tion of alcohol 24 (600 mg, 0.51 mmol) in dry CH2Cl2 (20 mL) was was stirred at 0 °C for 1 h. NH4Cl solution was added, and after
treated with dry tetrazole (93 mg, 1.33 mmol) and stirred at room subsequent washing with water, the organic phase was dried
temp. in an inert atmosphere. The phosphoramidite 27 (765 mg,
1.02 mmol) was added to this solution, and after stirring for 2 h, the residue was purified by flash chromatography (petroleum ether/
tert-butyl hydroperoxide solution (4.7  in isooctane, 1 mL) was EtOAc, 4:1). This gave the mixture of diastereomeric compounds
added over 15 min. The reaction mixture was diluted with CH2Cl2, 29 (433 mg, 97%) as a colourless syrup. TLC (petroleum ether/
(MgSO4). The solvent was removed under reduced pressure, and
and sodium hydrogen sulfite solution (5% w/v in water) added.
After phase-separation, the organic phase was washed with brine,
dried (MgSO4) and concentrated. Purification of the residue by
flash chromatography (petroleum ether/EtOAc, 4:1 and toluene/
EtOAc, 2:1): Rf ϭ 0.72; HPTLC (petroleum ether/EtOAc, 10:1):
Rf ϭ 0.33. [α]D ϭ ϩ23.5 (c ϭ 1, CHCl3). 1H NMR (600 MHz,
CDCl3): δ ϭ 1.00, 1.01 (2s, 9 H, tBu), 3.09Ϫ3.20 (m, 1 H, 1a-H),
3.20Ϫ3.36 (m, 2 H, 3a-H, 5a-H), 3.45 (dd, 1 H, Jgem. ϭ 10.7 Hz,
EtOAc, 10:1) gave a mixture of the diastereomers 26a,b (732 mg, 6b-H), 3.52Ϫ3.76 (m, 9 H, OMe, 3ЈЈ-H, 6b-H, 6a-H, 4a-H, 2b-H),
78%) as a colourless syrup. TLC (petroleum ether/EtOAc, 4:1):
3.77Ϫ3.88 (m, 2.36 H, 2ЈЈ-H, 3b-H, 1ЈЈ-H), 3.88Ϫ3.92 (m, 1.28
H, 1ЈЈ-H), 3.95Ϫ4.09 (m, 2.36 H, 4b-H, 5b-H, 1ЈЈ-H), 4.32Ϫ4.65,
Rf ϭ 0.27. [α]D ϭ ϩ12.7 (c ϭ 1, CHCl3). 1H NMR (600 MHz,
CDCl3): δ ϭ 0.8Ϫ0.92 (t, 6 H, Me), 1.08Ϫ1.40 (s, 40 H, CH2- 4.70Ϫ4.88 (m, 17 H, CH2ϪPh, 2a-H), 5.40 (d, 1 H, 1b-H),
chain), 1.44Ϫ1.67 (m, 4 H, COCH2CH2R), 2.12Ϫ2.36 (m, 4 H, 6.66Ϫ6.73 (m, 0.72 H, PhPMB), 6.73Ϫ6.79 (m, 1.28 H, PhPMB),
COCH2CH2R), 3.21Ϫ3.38 (m, 3 H, 3a-H, 5a-H, 6b-H), 3.45Ϫ3.56 7.03Ϫ7.45, 7.56Ϫ7.68 (m, 47 H, ArH) ppm. C88H96O14Si·0.5H2O
(m, 2 H, 6a-H, 6b-H), 3.68Ϫ3.77 (m, 2 H, 4a-H, 2b-H), 3.82 (dd, (1414.8): calcd. C 74.71, H 6.91; found C 74.71, H 6.90.
J3,4 ϭ 9.4, J3,2 ϭ 2.5 Hz, 1 H, 3b-H), 3.88Ϫ4.35 (m, 10 H, 1Ј-H,
tert-Butyl-(2,2-dioxo-2λ6-[1,3,2]dioxathiolan-4-yl-methoxy)diphenyl-
3Ј-H, 1ЈЈ-H, 2ЈЈ-H, 4b-H, 1a-H, 5b-H), 4.40Ϫ4.92, (m, 15 H, 2a-H,
silane (30): The cyclic sulfate 30 was prepared from 1,2-O-isopro-
CH2ϪPh), 5.03Ϫ5.28 (m, 5 H, 2Ј-H, COOCH2ϪPh, POCH2Ph),
pylidene-sn-glycerol as described.[32Ϫ34]
5.32 (d, 0.5 H, J Ͻ 1 Hz, 1b-H), 5.34 (d, 0.5 H, J Ͻ 1 Hz, 1b-H),
7.03Ϫ7.42 (m, 45 H, ArH) ppm. 31P NMR (242.9 MHz, CDCl3):
5-Tri-O-benzyl-6-O-[(2R)-2-hydroxy-3-O-(tert-butyldiphenylsilyl-
δ ϭ 0.1 (s, 1 P), 0.402 (s, 1 P) ppm. MALDI-MS (positive mode,
matrix p-nitroaniline ϩ NaI, MeOH) [M ϩ Na]ϩ: calcd. m/z ϭ
1864.4; found m/z ϭ 1865.
oxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
-mannopyranosyl)- -myo-inositol [(R)-29]: Sodium hydride (4 mg,
D
L
0.17 mmol) was added to a solution of the alcohol ()-8 (40 mg,
0.037 mmol) and the sulfate 30 (143.6 mg, 0.37 mmol) in dry DMF
(2.5 mL), and the mixture was stirred under argon. The reaction
was monitored by TLC (EtOAc/MeOH, 18:1): Rf ϭ 0.30; (petro-
leum ether/EtOAc, 2:1): Rf ϭ 0. After stirring for 4 h at room
Diacylglycerophosphite (27): Compound 27 was prepared as re-
ported by Baeschlin et al.[31]
3,4,5-Tri-O-benzyl-6-O-[(2R/2S)-2,3-dihydroxypropyl]-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
L
D-mannopyranosyl)- temp., further sulfate 30 (70 mg, 0.18 mmol) and sodium hydride
-myo-inositol (28): AD-mixβ[26] (866 mg) was added to a solution
(10 mg, 0.42 mmol) were added. Stirring was continued for 20 h at
room temp., after which time the solvent was removed under re-
duced pressure. The residue was purified by column chromatogra-
phy on silica gel (EtOAc/MeOH, 18:1). The sodium salt 31 so-
obtained was immediately dissolved in dioxane (2 mL) and acidi-
fied with sulfuric acid (0.1 ). After stirring for 1 h at room temp.,
the reaction mixture was diluted with EtOAc, washed with aqueous
NaHCO3 solution and dried (MgSO4). After removal of the sol-
vent, the residue was purified by flash chromatography on silica gel
to afford the diol (R)-29 (26 mg, 51%) as a colourless syrup. TLC
of O-allyl compound ()-7 (0.7 g, 0.62 mmol) in acetone/water (3:1,
8 mL), and the solution was stirred at room temp. for 100 h. So-
dium sulfite (3 g) was added to the reaction mixture, and stirring
was continued for 1 h. The reaction mixture was diluted with
EtOAc and washed with water. After phase-separation, the aque-
ous phase was extracted one further time with EtOAc. The com-
bined organic extracts were dried (MgSO4) and concentrated under
reduced pressure. Purification of the residue by column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 2:1Ǟ1:2) gave the mix-
ture of diastereomers 28 (516 mg, 71%) as a colourless oil. TLC (petroleum ether/EtOAc, 2:1 ): Rf ϭ 0.72. [α]D ϭ ϩ24.5 (c ϭ 1,
(petroleum ether/EtOAc, 2:1 ): Rf ϭ 0.06. [α]D ϭ ϩ29.8 (c ϭ 1, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 1.00 (s, 9 H, tBu), 3.14
1
CHCl3). H NMR (600 MHz, CDCl3): δ ϭ 1.87Ϫ1.97 (br. s, 1 H,
(dd, J1,2 ϭ 2.2, J1,6 ϭ 7.8 Hz, 1 H, 1a-H), 3.23Ϫ3.29 (m, 1 H, 3a-
OH), 1.97Ϫ2.09 (br. s, 1 H, OH), 3.12Ϫ3.21 (m, 1 H, 1a-H), H), 3.31 (dd, J5,6 ϭ J5,4 ϭ 7.9 Hz, 1 H, 5a-H), 3.44 (dd, 1 H,
3.24Ϫ3.36 (m, 2 H, 5a-H, 3a-H), 3.38Ϫ3.93 (m, 14 H, 1Ј-H, 2Ј-H, gem. ϭ 10.2 Hz, 6b-H), 3.54Ϫ3.74 (m, 9 H, OMe, 3ЈЈ-H, 6b-H, 6a-
3Ј-H, 4a-H, 6a-H, 2b-H, 3b-H, 6b-H, OMe), 4.00Ϫ4.14Ϫ3.74 (m, H, 4a-H, 2b-H), 3.76Ϫ3.84 (m, 2 H, 2ЈЈ-H, 3b-H), 3.86Ϫ3.93 (m,
2 H, 4b-H, 5b-H), 4.34Ϫ4.96 (m, 17 H, CH2ϪPh, 2a-H), 5.42 (d, 2 H, 1ЈЈ-H), 4.0Ϫ4.09 (m, 2 H, 4b-H, 5b-H), 4.32Ϫ4.65, 4.70Ϫ4.88
J
J1,2 ϭ 1.2 Hz, 1 H, 1b-H), 6.76Ϫ6.86 (m, 2 H, PhPMB), 7.11Ϫ7.43 (m, 17 H, CH2ϪPh, 2a-H), 5.40 (d, 1 H, 1b-H), 6.66Ϫ6.73 (m, 2
(m, 37 H, Ph) ppm. 13C NMR (150.9 MHz, CDCl3): δ ϭ 55.23 (1 H, HPMB), 7.03Ϫ7.45, 7.56Ϫ7.68 (m, 47 H, ArH) ppm.
C, OMe), 63.57 (1 C, C-3Ј), 69.08 (1 C, C-6b), 71.0 (1 C, C-2a), C88H96O14Si·0.5H2O (1414.8): calcd. C 74.71, H 6.91; found C
71.1Ϫ76.0 (8 C, CH2Ph), 71.49 (1 C, C-2Ј), 71.79 (1 C, C-5b), 74.34
(1 C, C-2b), 74.6 (1.72 C, C-1Ј, C-4b), 75.4 (1.28 C, C-1Ј), 77.21 (1
C, C-1a), 78.95 (1 C, C-3b), 80.85 (1 C, C-3a), 81.12 (0.34 C, C-
6a), 81.33 (1 C, C-4a), 81.73 (0.64 C, C-6a), 83.36 (1 C, C-5a),
98.44 (1 C, C-1b), 113.85 (2 C, CPMB), 127.39Ϫ138.68 (45 C, Ph),
159.27 (1 C, COMe) ppm. C72H78O16·0.5H2O (1176.4): calcd. C
73.51, H 6.77; found C 73.56, H 6.74.
74.73, H 6.82.
3,4,5-Tri-O-benzyl-6-O-[(2R)-3-O-(tert-butyldiphenylsilyloxy-2-O-
methylsulfonyloxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-
tetra-O-benzyl-α-D-mannopyranosyl)-L-myo-inositol (32): Com-
pound 32 was synthesized following the procedure described for
compound 16. Compound (R)-29 (1.74 g, 1.24 mmol) gave 32
(1.77 g) quantitatively as a colourless syrup. [α]D ϭ ϩ18 (c ϭ 1,
3,4,5-Tri-O-benzyl-6-O-[(2R/2S)-2-hydroxy-3-O-(tert-butyldiphenyl- CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 0.99 (s, 9 H, tBu), 2.78
silyloxy)propyl]-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-
benzyl-α- -mannopyranosyl)- -myo-inositol (29): Imidazole (65 mg,
0.96 mmol) and tert-butyldiphenylsilyl chloride (100 µL,
0.35 mmol) were added to a solution of the diastereomers 28
(s, 3 H, OMs), 3.08 (dd, J1,2 ϭ 2.2, J1,6 ϭ 9.8 Hz, 1 H, 1a-H),
3.21Ϫ3.29 (m, 2 H, 5a-H, 3a-H), 3.46 (dd, 1 H, Jgem. ϭ 9.7, 6b-
H), 3.51 (dd, J6,5 ϭ J6,1 ϭ 12.5 Hz, 1 H, 6a-H), 3.61 (m, 1 H, 6b-
H), 3.66 (dd, J4,5 ϭ J4,3 ϭ 10.1 Hz, 1 H, 4a-H), 3.69 (m, 1 H, 2b-
D
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Eur. J. Org. Chem. 2004, 3292Ϫ3303
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3301

A. Stadelmaier, M. Biskup, R. R. Schmidt
FULL PAPER
H), 3.73 (s, 3 H, OMe), 3.75Ϫ3.84 (m, 3 H, 3ЈЈ-H, 3b-H), 4.70Ϫ4.90 (m, 17 H, CH2ϪPh, 2a-H), 4.99 (d, 1 H, Jgem.
3.89Ϫ3.95 (m, 1 H, 1ЈЈ-H), 4.0Ϫ4.13 (m, 3 H, 1ЈЈ-H, 4b-H, 5b-H), 12.2 Hz, COOCH2ϪPh), 5.20 (d, H, Jgem. 12.2 Hz,
4.29Ϫ4.89, (m, 18 H, 2ЈЈ-H, CH2ϪPh, 2a-H), 5.42 (d, 1 H, 1b-H), COOCH2ϪPh), 5.41 (d, J ϭ 1.4 Hz, 1 H, 1b-H), 6.76Ϫ6.83 (m, 2
ϭ
1
ϭ
6.69Ϫ6.77 (m, 2 H, HPMB), 7.03Ϫ7.41, 7.53Ϫ7.66 (m, 47 H, ArH) H, HPMB), 7.06Ϫ7.39 (m, 42 H, ArH) ppm. C79H81N3O14 (1296.5):
ppm. 13C NMR (150.9 MHz, CDCl3): δ ϭ 19.13 [1 C, C(CH3)3], calcd. C 73.19, H 6.30, N 3.24; found C 72.87, H 6.35, N 2.95.
27.74 [3 C, C(CH3)3], 38.42 (1 C, SO2ϪCH3), 55.20 (1 C, OMe),
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
63.68 (1 C, C-3ЈЈ), 69.08 (1 C, C-6b), 71.12 (1 C, C-2a), 71.72Ϫ77.3
O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-L-myo-inositol (36):
(13 C, CH2Ph, C-1ЈЈ, C-1a, C-4b, C-5b, C-2b), 79.15 (1 C, C-3b),
80.87 (1 C, C-3a), 81.26 (1 C, C-4a), 81.79 (1 C, C-6a), 82.44 (1 C,
C-2ЈЈ), 83.09 (1 C, C-5a), 98.24 (1 C, C-1b), 113.76 (2 C, CPMB),
127.41Ϫ138.74 (57 C, Ph), 159.12 (1 C, COMe) ppm. C89H98O14SSi
(1483.9): calcd. C 72.00, H 6.66; found C 71.38, H 6.69.
Compound 36 was synthesized following the procedure described
for compound 24. Compound 35 (1.10 g, 0.85 mmol) gave 36
(828 mg, 83%) as a colourless syrup. [α]D ϭ ϩ3.9 (c ϭ 1, CHCl3).
1H NMR (250 MHz, CDCl3): δ ϭ 2.83 (d, J ϭ 4.2 Hz, 1 H, OH),
3.38Ϫ3.45 (m, 4 H), 3.65Ϫ3.85 (m, 5 H), 3.89Ϫ4.00 (m, 2 H),
4.05Ϫ4.27 (m, 4 H), 4.42Ϫ4.70, 4.71Ϫ4.92 (m, 14 H, CH2ϪPh),
5.13 (d, 1 H, Jgem. ϭ 12.1 Hz, COOCH2ϪPh), 5.22 (d, 1 H, Jgem. ϭ
12.1 Hz, COOCH2ϪPh), 5.27 (d, J1,2 ϭ 1.5 Hz, 1 H, 1b-H),
7.11Ϫ7.40 (m, 40 H, ArH) ppm. C71H73N3O13 (1176.4): calcd. C
72.49, H 6.26, N 3.57; found C 72.32, H 6.27, N 3.15.
6-O-[(2S)-2-Azido-3-O-(tert-butyldiphenylsilyloxy)propyl]-3,4,5-tri-
O-benzyl-1-O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-
mannopyranosyl)- -myo-inositol (33): Compound 33 was synthe-
L
sized following the procedure described for compound 18. Com-
pound 32 (1.77 g, 1.19 mmol) gave 33 (1.50 g, 88%) as a colourless
syrup. [α]D ϭ ϩ12.7 (c ϭ 1, CHCl3). 1H NMR (600 MHz, CDCl3):
δ ϭ 1.02 (s, 9 H, tBu), 3.13 (dd, J1,2 ϭ 2.3, J1,6 ϭ 9.8 Hz, 1 H, 1a-
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-2-
O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-L-myo-inosit-1-yl-
H), 3.25Ϫ3.30 (m, 2 H, 5a-H, 3a-H), 3.36 (dd, 1 H, Jgem.
ϭ
[benzyl]-[(2R)-2,3-bis(myristoyloxy)propyl]-phosphate (37a,b): Com-
pound 37a,b was synthesized following the procedure described for
compound 26a,b. Compound 36 (1.10 g, 0.85 mmol) gave the mix-
ture of diastereomeric compounds 37a,b (456 mg, 71%) as a colour-
less syrup. [α]D ϭ ϩ7.6 (c ϭ 1, CHCl3). 1H NMR (600 MHz,
CDCl3): δ ϭ 0.78Ϫ0.93 (t, 6 H, Me), 1.03Ϫ1.37 (s, 40 H, CH2-
chain), 1.44Ϫ1.65 (m, 4 H, COCH2CH2R), 2.16Ϫ2.35 (m, 4 H,
COCH2CH2R), 3.30-.40 (m, 2 H, 3a-H, 5a-H), 3.53Ϫ3.87 (m, 6 H,
1ЈЈ-H, 6a-H, 4a-H, 3b-H, 2b-H), 3.90Ϫ4.00 (m, 3 H, 2ЈЈ-H, 5b-H,
6b-H,), 4.03Ϫ4.28 (m, 7 H, 1Ј-H, 3Ј-H, 6b-H, 1a-H, 4a-H),
4.34Ϫ4.90, (m, 15 H, 2a-H, CH2-Ph), 5.02Ϫ5.14, 5.16Ϫ5.28 (m, 5
H, 2Ј-H, COOCH2ϪPh, POCH2Ph), 5.30 (d, 0.5 H, J1,2 ϭ 1.5 Hz,
1b-H), 5.37 (d, 0.5 H, 1b-H), 7.02Ϫ7.44 (m, 45 H, ArH) ppm. 31P
NMR (242.9 MHz, CDCl3): δ ϭ Ϫ0.1407 (s, P), 0.0651 (s, P) ppm.
MALDI-MS (positive mode, matrix DHB, THF) [M ϩ Na]ϩ:
calcd. m/z ϭ 1864.4; found m/z ϭ 1863.8.
10.6 Hz, 6b-H), 3.46 (dd, J6,5 ϭ J6,1 ϭ 9.5 Hz, 1 H, 6a-H), 3.5Ϫ3.79
(m, 11 H, 6b-H, OMe, 1ЈЈ-H, 2ЈЈ-H, 3ЈЈ-H, 4a-H, 2b-H, 3b-H), 3.84
(m, 1 H, 1ЈЈ-H), 4.01Ϫ4.06 (m, 2 H, 4b-H, 5b-H), 4.29Ϫ4.66,
4.69Ϫ4.86 (m, 17 H, CH2ϪPh, 2a-H), 5.39 (d, 1 H, 1b-H),
6.68Ϫ6.76 (m, 2 H, HPMB), 7.06Ϫ7.41, 7.56Ϫ7.65 (m, 47 H, ArH)
ppm. 13C NMR (150.9 MHz, CDCl3): δ ϭ 19.09 [1 C, C(CH3)3],
26.69 [3 C, C(CH3)3], 55.19 (1 C, OMe), 63.65 (1 C, C-3ЈЈ), 64.57
(1 C, C-2ЈЈ), 68.86 (1 C, C-6b), 71.5Ϫ76.02 (13 C, CH2Ph, C-1ЈЈ,
C-2a, C-4b, C-5b, C-2b), 77.91 (1 C, C-1a), 79.19 (1 C, C-3b), 80.91
(1 C, C-3a), 81.24 (1 C, C-4a), 82.01 (1 C, C-6a), 83.18 (1 C, C-
5a), 98.35 (1 C, C-1b), 113.69 (2 C, CPMB), 127.37Ϫ138.81 (57 C,
Ph), 159.0 (1 C, COMe) ppm. C88H95N3O13Si (1430.8): calcd. C
73.87, H 6.69, N 2.90; found C 73.63, H 6.78, N 2.35.
6-O-[(2R)-2-Azido-3-hydroxypropyl]-3,4,5-tri-O-benzyl-1-O-(4-
methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-
L
-myo-inositol (34): Compound 34 was synthesized following the
procedure described for compound 20. Compound 33 (1.47 g,
1.03 mmol) gave 34 (1.23 g, 92%) as a colourless syrup. [α]D
ϭ
Acknowledgments
1
ϩ15.6 (c ϭ 1, CHCl3). H NMR (600 MHz, CDCl3): δ ϭ 2.15 (s,
1 H, OH), 3.17 (dd, J1,2 ϭ 1.9, J1,6 ϭ 9.9 Hz, 1 H, 1a-H), 3.26Ϫ3.36
(m, 2 H, 3a-H, 5a-H), 3.38Ϫ3.69 (m, 7 H, 3ЈЈ-H, 2ЈЈ-H, 6b-H, 4a-
H, 6a-H), 3.71 (m, 1 H, 2b-H), 3.75Ϫ3.83 (m, 4 H, OMe, 3b-H),
3.85Ϫ3.95 (m, 2 H, 1ЈЈ-H), 4.01Ϫ4.09 (m, 2 H, 4b-H, 5b-H),
4.32Ϫ4.71, 4.72Ϫ4.88 (m, 17 H, CH2ϪPh, 2a-H), 5.42 (d, 1 H, 1b-
H), 6.75Ϫ6.84 (m, 2 H, HPMB), 7.04Ϫ7.35 (m, 37 H, ArH) ppm.
13C NMR (150.9 MHz, CDCl3): δ ϭ 55.25 (1 C, OMe), 62.06 (1
C, C-3ЈЈ), 62.65 (1 C, C-2ЈЈ), 68.95 (1 C, C-6b), 71.09Ϫ76.0 (13 C,
CH2Ph, C-1ЈЈ, C-2a, C-4b, C-5b, C-2b), 77.46 (1 C, C-1a), 79.1 (1
C, C-3b), 80.80 (1 C, C-3a), 81.34 (1 C, C-4a), 81.73 (1 C, C-6a),
82.29 (1 C, C-5a), 98.45 (1 C, C-1b), 113.83 (2 C, CPMB),
This work was supported by the Deutsche Forschungsge-
meinschaft, the Rademacher Group Ltd., and the Fonds der
Chemischen Industrie. The authors thank Professor Thomas W.
Rademacher (University College London Medical School) for
fruitful discussions.
[1]
P. Draper in The Biology of Mycobacteria, vol. 2 (Eds.: C. Rat-
ledge, J. Stanford), Academic Press, London, 1986, 9Ϫ52.
[2]
P. J. Brennan, H. Nikaido, Annu. Rev. Biochem. 1991, 64,
887Ϫ888.
[3]
D. Chatterjee, K.-H. Khoo, Cell. Mol. Life Sci. 2001, 58,
2018Ϫ2042.
127.4Ϫ138.61 (45 C, Ph), 159.21 (1 C, COMe
)
ppm.
[4]
D. Chatterjee, K.-H. Khoo, Glycobiology 1998, 8, 113Ϫ120.
C72H77O13N3·0.5H2O (1201.4): calcd. C 71.98, H 6.54, N 3.50;
found C 71.96, H 6.38, N 2.97.
[5]
P. J. Brennan, C. E. Ballou, J. Biol. Chem. 1997, 242,
3046Ϫ3056.
[6]
G. S. Besra, C. B. Morehouse, C. M. Rittner, C. J. Waechter,
6-O-[(2S)-2-Azido-2-(benzyloxycarbonyl)ethyl]-3,4,5-tri-O-benzyl-1-
P. J. Brennan, J. Am. Soc., Biochem. Mol. Biol. 1997, 272,
O-(4-methoxybenzyl)-2-O-(2,3,4,6-tetra-O-benzyl-α-
D-manno-
18460Ϫ18466.
pyranosyl)- -myo-inositol (35): Compound 35 was synthesized fol-
L
[7]
S. Ilangumaran, S. Arni, M. Poincelet, J.-M. Theler, P. J. Bren-
lowing the procedure described for compound 22. Compound 34
(1.15 g, 0.96 mmol) gave 35 (1.15 g, 92%) as a colourless syrup.
nan, Nasir-du-Din, D. C. Hoessli, J. Immunol. 1995, 155,
1334Ϫ1342.
1
[α]D ϭ ϩ29.1 (c ϭ 1, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ
[8]
A. Stadelmaier, Diploma Thesis, University of Konstanz, Ger-
3.15 (dd, J1,2 ϭ 1.8, J1,6 ϭ 9.7 Hz, 1 H, 1a-H), 3.25Ϫ3.40 (m, 3
H), 3.55 (m, 2 H), 3.63Ϫ3.85 (m, 3 H), 3.76 (s, 3 H, OMe), 3.93
(dd, J ϭ 3.9, J ϭ 6.1 Hz, 1 H), 4.40Ϫ4.24 (m, 4 H), 4.30Ϫ4.69,
many 1999.
[9]
A. Stadelmaier, Ph. D. Dissertation, University of Konstanz,
Germany 2003.
3302
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3292Ϫ3303

Synthesis of Serine-Linked Phosphatidylinositol Mannosides (PIMs)
FULL PAPER
L. F. Fieser, M. Fieser, Reagents for Organic Synthesis, Wiley,
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