Synthesis of phosphatidylinositol mannosides (PIMs)

Article abstract of DOI:10.1016/j.carres.2003.06.002

Two strategies towards the synthesis of phosphatidylinositol mannosides (PIMs) were elaborated which permit selective access to the O-1-, O-2-, and the O-6 position of the myo-inositol residue. Starting materials are 1,2:5,6- and 1,2:4,5-di-O-cyclohexylid

Full text of DOI:10.1016/j.carres.2003.06.002

Carbohydrate Research 338 (2003) 2557ꢃ2569
/
www.elsevier.com/locate/carres
Synthesis of phosphatidylinositol mannosides (PIMs)
Andreas Stadelmaier, Richard R. Schmidt*
Fachbereich Chemie, Universitat Konstanz, Fach M 725, D-78457 Konstanz, Germany
¨
Received 2 April 2003; received in revised form 26 May 2003; accepted 23 June 2003
Abstract
Two strategies towards the synthesis of phosphatidylinositol mannosides (PIMs) were elaborated which permit selective access to
the O-1-, O-2-, and the O-6 position of the myo-inositol residue. Starting materials are 1,2:5,6- and 1,2:4,5-di-O-cyclohexylidene-
DL-myo-inositol, respectively. In the latter case, the required assignment to the
enantiomer into known (ꢀ)-liriodentritol. The efficiency and potential versatility of the two approaches is exemplified in the
synthesis of PIMs ( )-1a and its pseudoenantiomer ( )-1b, both having myristoyl residues as part of the phosphatidyl moiety.
# 2003 Elsevier Ltd. All rights reserved.
D- or L-series is based on the transformation of one
/
D
L
Keywords: Phosphatidylinositol; Phosphatidylinositol mannoside; Synthesis; Glycosidation; Structural assignment
1. Introduction
IL-5, and GM-CSF genes in human T-cells and the
IFN-g-mediated activation of macrophages.
Important constituents of the mycobacterial cell wall are
arabinogalactan-peptidoglycan (AGP) and lipoarabino-
mannan (LAM) complexes. The LAM structure is
Because the PIM substructure of LAMs is able to
inhibit LAM insertion into caveolae, the PIM substruc-
tures may contain the necessary structural characteris-
tics to target to caveolae. Therefore, such compounds
have to be investigated if they are mimics of the
naturally occurring PIMs, thus inducing biological
responses normally attributed to the natural compound
if they act as biologically inert carriers delivering specific
pharmaceutically active compounds to caveolae. Hence,
we initiated a program to the synthesis of PIMs and
structural variants, thus requiring regioselective access
composed of
(PIM2) which carries a mannan (0
LAM) (Scheme 1).1
a
phosphatidylinositol dimannoside
/lipomannan, LM)
or an arabinomannan moiety (0
/
Precursors for the biosynthesis of LAMs are phospha-
tidylinositols (PIs) which are a-mannopyranosylated at
O-2 (0
extension of the a-(10
due with additional a-(10
/
PIM) or at O-2- and O-6 (0
/
PIM2).2 Chain
/
6)-linked mannopyranosyl resi-
/
6)- and a-(102)-linked
/
mannopyranosyl residues will lead to LMs and by
further adding arabinofuranosyl residues finally LAMs
are obtained.
In mycobacterial infections, the lipoglycans localize to
caveolae/lipid rafts of host membranes which serve as
signal transduction platforms, thus eliciting a profound
biological response. Such responses involve induced
expression and secretion of TNF-a and IL-6 and
inhibition of T-cell proliferative responses.1,3 LAMs
have also been shown to inhibit expression of IL-2,
to the O-1, O-2, and O-6 position of (
inositol.4,5
D
)- or (
L
)-myo-
In this paper, the synthesis of phosphatidyl-(
inositol mannoside with R6ꢁ
H (Scheme 1, ( )-1a)
and of its pseudoenantiomer ( )-1b with ( )-inositol
configuration (which is actually a diastereomer of ( )-
1a) is reported. Structural analogs of ( )-1a were
D)-
/
D
L
L
D
D
previously synthesized by routes which did not consider
eventual attachments to the O-6 position of the inositol
moiety.6 Also, the successful synthesis of PIM2 was
already reported starting from racemic inositol deriva-
tives.7 The resolution of unsymmetrically substituted
myo-inositol derivatives with the help of an a-linked
mannosyl residue at the O-2 position turned out to be
laborious. Therefore, in our synthesis, designed chiral
* Corresponding author. Tel.: ꢂ
/
49-7531-882538; fax: ꢂ49-
/
7531-883135.
E-mail address: richard.schmidt@uni-konstanz.de (R.R.
Schmidt).
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.06.002

2558
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
Scheme 1. Structure of PIMs, LM and LAM and of target
molecules ( )-1a and ( )-1b.
D
L
Scheme 2. Reagents and conditions: (a) Ref. 8; (b) All-Br,
Ag2O, DMF, 0 8C; KI (86%); see also Ref. 9.
auxiliaries for efficient resolution were employed. The
designed synthesis takes also into account future regio-
selective attachment of residues at the O-6 position of
the inositol moiety, thus permitting the synthesis of
PIM2, LMs, and LAMs and structural variants thereof.5
ment with potassium iodide; workup led to desired (
7.9
D
)-
Selective 4,5-O-cyclohexylidene group removal on
D)-7 under acid catalysis with pyridinium p-toluene-
(
sulfonate (PPTSA)ꢃ/p-toluenesulfonic acid (PTSA)
furnished 4,5-O unprotected (
on treatment with benzyl bromide in the presence of
D)-8 (Scheme 3), which
silver oxide afforded cleanly 4,5-di-O-benzyl protected
2. Results and discussion
derivative (
with camphorsulfonic acid (CSA) as catalyst in metha-
nol afforded 2,3-O unprotected ( )-10, which on treat-
D)-9. Following 2,3-O-decyclohexylidenation
Following a literature procedure,8 myo-inositol (Scheme
2) can be readily transformed into di-O-cyclohexylidene
D
ment with acetyl chloride in the presence of dimethyltin
dichloride10 in THF and potassium carbonate as base
derivatives 2ꢃ4 which are separated by crystallisation
(3) and by chromatography (2 and 4).
/
afforded a 7:3-mixture of desired monoacetylated (
and ( )-12. After chromatographic separation, reaction
of (
)-11 as acceptor with known 138a,9,11 as mannosyl
D)-11
Compound 2 has been frequently employed for the
synthesis of phosphatidylinositol derived compounds,
particularly glycosylphosphatidylinositol (GPI) an-
chors8,9 which require access to the O-1 and O-6
position of myo-inositol. Therefore, resolution of (DL)-
D
D
donor and tin(II) trifluoromethanesulfonate as catalyst
furnished, by applying the inverse procedure,12 a-linked
inositol mannoside (D)-14 in 95% yield. O-Deacetyla-
tion of (D)-14 with dimethylamine in ethanol gave (
2 with the help of (ꢀ
/
)-menthyloxycarbonyl derivatives
)-6 is well studied.8b,9 In order to take into
D)-15
(
L
)-5 and (
D
in 79% yield. Following O-benzylation with benzyl
bromide and sodium hydride as base in DMF at room
temperature furnished the hepta-O-benzyl derivative
account the desired selective access to the O-6 position
for later PIM related syntheses, O-6 allylation with allyl
bromide in the presence of silver oxide in DMF at 0 8C
was carried out, thus avoiding menthyloxycarbonyl
migration, which was observed under more drastic
conditions. Excess silver ions were removed by treat-
(D)-16 which is now accessible to selective modifications
at O-1 and/or O-6 position. Full structural assignment
could be based on NMR data. The a configuration of

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2559
Scheme 4. Reagents and conditions: (a) K2CO3, MeOH, 60 8C
(86%); (b) tetrazole, CH2Cl2; t-BuO2H; Me2NH, EtOH (78%);
(c) Pd(PPh3)4, Tol-SO2Na, HOAc, CH2Cl2, rt (58%); (d) Pd/C,
Scheme 3. Reagents and conditions: (a) 13:1 PPTSAꢃPTSA,
/
H2, 7.5:7.5:1 CH2Cl2ꢃ
/
MeOHꢃH2O (73%).
/
CH2Cl2, MeOH, 45 8C (68%); (b) BnBr, Ag2O, CH2Cl2, rt
(71%); (c) CSA, MeOH, 45 8C (89%); (d) AcCl, Me2SnCl2,
THF, rt, K2CO3 (65%, 7:3); (e) Sn(OTf)2, Et2O, rt (95%); (f)
HNMe2 in EtOH (79%); (g) BnBr, NaH, DMF, rt (85%).
assignment of this compound was based on NMR
(HMQC, DQF-COSY, SED-31P, ROESY) and MS
data.
the mannosyl residue was ascertained by the JC1b,H1b
coupling of 171.3 Hz.13
For the transformation of pseudodisaccharide (D)-16
into the phosphatidyl residue carrying target molecule,
the menthyloxycarbonyl group at O-1 was removed by
treatment with potassium carbonate in methanol at
Although the synthesis of (D)-1a from (DL)-2 is rather
straightforward, the ready availability of (DL)-3 by
crystallisation from the reaction mixture led us to design
an alternative procedure for the synthesis of pseudoe-
nantiomer (
able to the (
L
)-1b; this procedure should be also applic-
D
)-series of PIMs and LAMs. In the new
60 8C, thus affording O-1 unprotected (
D
)-17 (Scheme
procedure, the possible migration of the menthyloxy-
carbonyl or any other acyl group, thus requiring mild
silver oxide-supported introduction of allyl and benzyl
groups, should be avoided. The first steps followed a
procedure by Vacca and coworkers16: (DL)-3 was
selectively benzylated at the more reactive O-3 position
4). Reaction of (
D
)-17 with the known diacylglycerol
carrying phosphitamide 1814 in the presence of tetrazole
as catalyst and then oxidation with tert-butylhydroper-
oxide and base catalyzed removal of the cyanoethyl
group furnished the O-protected target molecule (D)-19
which was structurally assigned by the NMR and MS
data. O-Deallylation with palladium(0) as catalyst and
sodium p-toluene sulfinate as nucleophile15 in acetic
[0
residue was attached to the O-6 resulting in (
22, which could be simply separated by crystallisation
and flash chromatography on silica gel; thus ( )- and
)-22 were readily obtained in ꢀ99% enantiomeric
excess. Base catalyzed removal of the camphanoyl
residues furnished ( )- and ( )-23. Because the previous
/
(
DL)-21] (Scheme 5) and then the (ꢀ
/
)-camphanoyl
D
)- and ( )-
L
acidꢃ
)-20 in 58% yield. Hydrogenolytic O-debenzylation
with palladium on carbon as catalyst led to the desired
unprotected target molecule ( )-1a. Full structural
/dichloromethane at room temperature afforded
D
(
D
(
L
/
D
L
D

2560
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
Scheme 6. Reagents and conditions: (a) All-Br, NaH, DMF, 1
h, rt (qu); (b) 13:1 PPTSAꢃPTSA, CH2Cl2, MeOH, 40 8C
/
(78%); (c) BnBr, NaH, DMF, rt (84%); (d) CSA, 10:1 MeOH,
CH2Cl2 10:1, 24 h, rt (95%); (e) Bu2SnO, Tol, 3 h, refl.,
MPMCl, TBAI, 1.5 h, 110 8C (79%).
28] and then O-benzylation under standard conditions
afforded the tri-O-benzyl derivative (L)-29. CSA-cata-
lyzed cleavage of the 1,2-O-cyclohexylidene group in the
presence of methanol led to the 1,2-O-unprotected
derivative (L)-30, again in high yield. Regioselective O-
Scheme 5. Reagents and conditions: (a) Ref. 16; (b) Pd(OH)2/
C, H2, THF (98%); (c) MeI, NaH, DMF, rt (92%); (d) CSA,
CH2Cl2, MeOH, rt, 24 h (78%).
1 protection by treatment with dibutyltin oxide in
refluxing toluene and then with 4-methoxyphenylmethyl
(MPM) chloride in the presence of tetrabutylammonium
iodide (TBAI) furnished O-2 unprotected
which*compared with ( )-11*offers also the desired
regioselective access to the O-1, O-2, and O-6 position;
however, ( )-31 is much more reluctant to further
transformation than ( )-11.
Mannosylation of (
)-31 with 138a,9,11 as mannosyl
(L)-31
configurational assignment of these compounds was not
/
D
/
clear,16 the configuration of (
L
)-23 was ascertained by
transformation into known (ꢀ
)-liriodentritol (26).17
Hydrogenolytic O-debenzylation of ( )-23 with Pearl-
/
L
L
D
man’s catalyst in THF, thus avoiding partial O-decy-
clohexylidenation, gave 3,O-6 unprotected 24 in high
yield. O-Methylation with methyl iodide and sodium
hydride as base in DMF afforded di-O-methyl deriva-
tive 25, which on CSA-catalyzed O-decyclohexylidena-
tion furnished 26 in 78% yield.
L
donor in the presence of TMSOTf as catalyst in Et2O as
solvent at room temperature furnished the desired a-
linked pseudodisaccharide which on treatment with
methylamine in ethanol led to O-deacetylation, thus
furnishing (
configuration of the mannosyl residue was ascertained
L
)-32 in 71% yield (Scheme 7). The a
This compound was in all aspects identical with
natural (ꢀ
structural assignment of (
synthesis of ( )-1b could be based on (
of ( )-23 with allyl bromide in the presence of sodium
hydride as base in DMF afforded fully protected myo-
inositol derivative ( )-27 in high yield (Scheme 6).
Selective removal of the 4,5-O-cyclohexylidene group
with PPTSA/PTSA in the presence of methanol [0 )-
/
)-liriodentritol, thus leading to unequivocal
)- and ( )-23. Hence, the
)-23. Allylation
by the JC1b-H1b coupling of 173.3 Hz.13 Then O-6
L
D
deallylation of (
carried out because selective access to O-6 was not
required for the synthesis of ( )-1b. Thus, O-2b, O-6a
unprotected ( )-33 was obtained, which was subjected to
dibenzylation again under standard conditions to fur-
nish octa-O-benzyl ( )-34 in 86% yield. Mild oxidative
L)-32 under standard conditions was
L
L
L
L
L
L
/(
L
L

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2561
decisive intermediates, particularly those obtained
from 1,2:4,5-di-O-cyclohexylidene-myo-inositol, permit
any structural variation at O-1, O-2, and/or O-6
position, thus giving access to a wide variety of PIMs,
LMs, and LAMs.
3. Experimental
3.1. 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 (ICN Alumina N, activity grade super
I) as an alternative drying procedure. 13C Assignments
were based on heteronuclear multiple-quantum correla-
tion (HMQC). Boiling range of the petroleum ether: 35ꢃ
/
70 8C. Thin layer chromatography (TLC) was per-
formed on E. Merck Silica Gel 60 F254 plates (0.2
mm). The plates were visualized by immersion in
mostain [200 mL 10% H2SO4, 10 g (NH4)6Mo7O24×
/
4
H2O, 200 mg Ce(SO4)2] or ninhydrin soln 1% in EtOH)
or 10% H2SO4 or KMnO4 soln (1% in water, 1%
NaHCO3) followed by heating (165 8C). Preparative
flash chromatography was carried out on Baker Silica
Gel 60 (30ꢃ
/
60 mm) at a pressure of 0.02ꢃ0.04 MPa.
/
FABMS was recorded on a modified Finnigan MAT
1
312/AMD 5000. H, 13C NMR and 31P spectra were
recorded on a Bruker AC 250 Cryospec and a Bruker
DRX 600 instrument. Proton chemical shifts are re-
ported 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. Measurements of optical rotations
Scheme 7. Reagents and conditions: (a) TMSOTf, Et2O, rt;
H2NMe, EtOH (71%); (b) (Ph3P)3RhCl, DBU, EtOH, 90 8C;
HCl, Me2CO (87%); (c) BnBr, NaH, DMF, rt (86%); (d) CAN,
MeCN, Tol, H2O, 0 8C0
/
rt, 75 min (94%); (e) tetrazole,
CH2Cl2; t-BuO2H; Me2NH, EtOH (76%); (f) Pd/C, H2,
CH2Cl2, MeOH, H2O, rt (74%).
were performed on a PerkinꢃElmer polarimeter 241 MC
/
(1 dm cell). Melting points: Gallenkamp metal block;
not corrected. MALDIMS were obtained on a Kratos
Analytical Kompac Maldi 2 instrument with 2,5-dihy-
droxybenzoic acid as matrix (positive mode) or 6-aza-2-
thiothymin (ATT) (negative mode).
cleavage of the MPM group with ceric(IV)ammonium
nitrate (CAN) furnished O-1 unprotected (L)-35 in high
yield; transformation of (L)-34 into (L)-35 with DDQ as
oxidizing agent was accompanied by decomposition of
the starting material.5 Diacylglycerol containing phos-
phitamide 1814 could be successfully linked to (
L)-35 in
3.2. 6-O-Allyl-2,3-O-cyclohexylidene-1-O-(1R)-
menthyloxycarbonyl-D-myo-inositol [(D)-8]
the presence of tetrazole as catalyst; ensuing oxidation
with tert-butylhydroperoxide and then base-catalyzed
removal of the cyanoethyl group led to O-benzyl-
protected target molecule (L)-36 in 76% yield. Hydro-
genolytic removal of the eight O-benzyl groups could be
successfully carried out with palladium on carbon as
Bis-ketal (
mixture of dry 1:1 CH2Cl2ꢃ
up to 45 8C. To this soln was added 10 mL of a mixture
of 13:1 PPTSAꢃPTSA (0.86 m in dry DCM). The
reaction was followed by TLC. Stirring was maintained
for 1 h and 10 min before the reaction was quenched
with NEt3. The residue obtained upon evaporation was
D
)-79 (48.75 g, 0.1 mol) was dissolved in a
MeOH (600 mL) and heated
/
/
catalyst in a 7.5:7.5:1-mixture of dichloromethaneꢃ
methanolꢃwater providing pure ( )-1b in 74% yield.
)-1b is fully supported by the NMR
/
/
L
The structure of (
and MS data.
L
purified by flash chromatography (3:10
etherꢃEtOAc) to yield ( )-8 (28.3 g, 68%) as a colourless
foam; TLC (1:1 petroleum etherꢃEtOAc); Rf 0.47; [a]D
/1:1 petroleum
/
D
In conclusion, efficient syntheses of phosphatidylino-
sitol mannosides (PIMs) could be developed. The
/
1
ꢀ498 (c 1, CHCl3); mp 129.2 8C; H NMR (250 MHz,
/

2562
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
CDCl3): d 0.75ꢃ
1.79 (m, 14 H, 10 Hcyclohexylidene, HMnt), 1.9ꢃ
H, HMnt, 2 OH), 3.41 (dd, 1 H, J5,4 10.3, J5,6 8.6 Hz, H-
5), 3.71 (dd, 1 H, J6,5 J6,1 8.5 Hz, H-6), 3.79 (dd, 1 H,
J4,3 7.4, J4,5 10.3 Hz, H-4), 4.08 (dd, 1 H, J3,2 5.5, J3,4 7.3
Hz, H-3), 4.18ꢃ4.38 (m, 2 H, OCH2CHÄCH2), 4.5 (dd,
1 H, J2,1 4.1, J2,3 5.4 Hz, H-2), 4.56ꢃ4.63 (m, 1 H,
/
1.16 (3 d, m, 12 H, 3 Me, HMnt), 1.38ꢃ
/
H, CH2Ph), 4.7 (dd, 1 H, J1,2 2.7, J1,6 10.1 Hz, H-1),
5.08ꢃ5.28 (m, 2 H, CHÄCH2), 5.8ꢃ5.98 (m, 1 H, CH Ä
CH2), 7.21ꢃ7.39 (m, 10 H, Ph). MALDIMS [Mꢂ
Na]ꢂ:
Calcd 605.7, Found 605.4; [Mꢂ
K]ꢂ Calcd 621.8,
Found 621.4. Anal. Calcd for C34H46O8 (582.7): C,
70.08; H, 7.96. Found: C, 69.67; H, 7.99.
/2.12 (m, 4
/
/
/
/
/
/
ꢁ
/
/
/
/
/
H
Mnt), 4.92 (dd, 1 H, J1,2 4.1, J1,6 8.4 Hz, H-1), 5.19ꢃ
/
3.5. 3-O-Acetyl-6-O-allyl-4,5-di-O-benzyl-1-O-(1R)-
D)-11]
5.36 (m, 2 H, CHÄ
Anal. Calcd for C26H42O8 (482.61): C, 64.71; H, 8.77.
Found: C, 64.69; H, 8.60.
/
CH2), 5.85ꢃ
/
6.01 (m, 1 H, CH Ä/CH2).
menthyloxycarbonyl-D-myo-inositol [(
The diol (D)-10 (10.58 g, 18 mmol), dissolved in dry
THF (100 mL), was treated with anhyd K2CO3 (5.62 g,
2.24 equiv) and dimethyltin dichloride (4.39 g, 1.1 equiv)
and stirred for 0.5 h under AP. To this reaction mixture
was added acetyl chloride (1.56 mL, 1.2 equiv) and
stirred overnight. Then K2CO3 was filtered off and the
reaction mixture was concentrated under diminished
pressure. Silica gel column chromatography (15:1
3.3. 6-O-Allyl-4,5-di-O-benzyl-2,3-O-cyclohexylidene-1-
D)-9]
O-(1R)-menthyloxycarbonyl-D-myo-inositol [(
To a mixture of (D)-8 (30.89 g, 64 mmol), silver (I) oxide
(118 g, 8 equiv) and dry DCM (350 mL) was treated
BnBr (45.6 mL, 6 equiv, exothermic). After stirring for 3
h at room temperature (rt), the mixture was filtered over
celite and concentrated under diminished pressure. The
obtained residue was purified on silica gel (20:1 petro-
tolueneꢃ
solid; TLC (6:1 tolueneꢃ
(c 1, CHCl3); mp 144.5 8C. 1H NMR (600 MHz,
CDCl3): d 0.7ꢃ1.08 (3 d, m, 12 H, 3 Me, HMnt), 1.33ꢃ
1.63 (m, 4 H, HMnt), 1.8ꢃ1.9, 1.98ꢃ2.05 (m, 2 H, HMnt),
1.94 (s, 3 H, OAc), 3.48 (dd, 1 H, J5,6 J5,4 9.5 Hz, H-5),
3.82 (dd, 1 H, J6,1 J6,5 9.82 Hz, H-6), 3.93 (dd, 1 H,
J4,5 J4,3 9.82 Hz, H-4), 4.1ꢃ4.16, 4.23ꢃ4.27 (m, 2 H,
CH2CHÄCH2), 4.19 (dd, 1 H, J2,3 J2,1 2.6 Hz, H-2),
4.45ꢃ4.52 (m, 1 H, HMnt), 4.57ꢃ4.82 (4 d, dd, 5 H,
CH2Ph, J1,2 2.6, J1,6 10.2 Hz, H-1), 4.85 (dd, 1 H, J3,4
10.2, J3,2 2.8 Hz, H-3), 5.03ꢃ5.21 (m, 2 H, CHÄCH2),
5.8ꢃ5.9 (m, 1 H, CH ÄCH2), 7.14ꢃ7.3 (m, 10 H, Ph).
/EtOAc) afforded (
D)-11 (7.3 g, 65%) as a white
/EtOAc): Rf 0.56; [a]D
ꢀ
/
23.58
leum etherꢃ
colourless oil; TLC (6:1 petroleum etherꢃ
/
EtOAc) to give 29.8 g (71%) of (
EtOAc): Rf
31.98 (c 1, CHCl3); H NMR (250 MHz,
CDCl3): d 0.72ꢃ1.13 (3 d, m, 12 H, 3 Me, HMnt), 1.3ꢃ
1.75 (m, 14 H, 10 Hcyclohexylidene, HMnt), 1.9ꢃ2.12 (m, 2
H, HMnt), 3.45 (dd, 1 H, J5,6 9.5, J5,4 8.3 Hz, H-5), 3.79
(dd, 1 H, J6,5 9.5 Hz, H-6), 3.81 (dd, 1 H, H-4), 4.19ꢃ
4.23 (m, 3 H, CH2CHÄCH2, H-3), 4.44 (dd, 1 H, J2,1
3.8, J2,3 5.7 Hz, H-2), 4.48ꢃ4.6 (m, 1 H, HMnt), 4.78 (m,
2 H, CH2Ph), 4.8 (2 d, 2 H, CH2Ph), 4.95 (dd, 1 H, J1,2
3.8, J1,6 8.3 Hz, H-1), 5.1ꢃ5.3 (m, 2 H, CHÄCH2), 5.82ꢃ
5.9 (m, 1 H, CH ÄCH2), 7.2ꢃ7.4 (m, 10 H, Ph). Anal.
Calcd for C40H54O8 (662.86): C, 72.45; H, 8.21. Found:
C, 72.55; H, 8.21; MALDIMS: m/z 685.3 [Mꢂ
Na]ꢂ,
701.3 [Mꢂ
K]ꢂ.
D
)-9 as
/
/
/
/
/
1
0.7; [a]D
ꢀ
/
ꢁ
/
/
/
ꢁ
/
/
ꢁ
/
/
/
/
ꢁ
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Anal. Calcd for C36H48O9 (624.77): C, 69.21; H, 7.74.
Found: C, 69.16; H, 7.74.
/
/
/
3.6. 3-O-Acetyl-6-O-allyl-4,5-di-O-benzyl-O-1-(1R)-
menthyloxycarbonyl-2-O-(2-O-acetyl-3,4,6-tri-O-benzyl-
/
a- D-myo-inositol [(
D
-mannopyranosyl)-
D)-14]
3.4. 6-O-Allyl-4,5-di-O-benzyl-2,3-1-O-(1R)-
menthyloxycarbonyl- -myo-inositol [( )-10]
D
D
To a soln of acceptor (D)-11 (8.02 g, 18 mmol), in anhyd
ether (50 mL), was added under Ar Sn(OTf)2 (268 mg,
0.05 equiv). Then donor 138a,9,11 (16.35 g, 0.026 mol,
dissolved in 50 mL anhyd ether) was added drop-wise
over 5 min to the reaction mixture. Stirring was
maintained for 1 h, then the reaction was quenched
with triethylamine and the mixture concentrated. The
residue was purified by flash chromatography (24:1
For the cleavage of the ketal protecting group, com-
pound (D)-9 (16.74 g, 25 mmol) was dissolved in 10:1
MeOHꢃ/CH2Cl2 (220 mL). To this soln was added
camphor-10-sulfonic acid (0.75 g, 3.23 mmol) and the
reaction mixture was stirred for 8.5 h at 45 8C. Next, the
mixture was neutralized with Et3N, diluted with toluene
and concentrated under diminished pressure. The resi-
tolueneꢃ
colourless foam; TLC (12:1 tolueneꢃ
Et3N): Rf 0.57. [a]D
5.98 (c 1, CHCl3); 1H NMR
(250 MHz, CDCl3) d 0.7ꢃ1.11 (3 d, m, 12 H, 3 Me,
Mnt), 1.3ꢃ1.7 (m, 4 H, HMnt), 1.78 (s, 3 H, OAc), 1.81ꢃ
2.16 (m, 2 H, HMnt), 2.1 (s, 3 H, OAc), 3.5ꢃ3.6 (m, 2 H),
3.66ꢃ3.95 (m, 6 H), 4.17ꢃ4.37 (m, 3 H, OCH2CHÄ
CH2), 4.4ꢃ4.68 (m, 6 H), 4.7ꢃ4.9 (m, 7 H), 5.0ꢃ5.05
(d, 1 H, H-2b), 5.12ꢃ5.31 (m, 2 H, CHÄCH2), 5.45 (d, 1
H, H-1b), 5.8ꢃ5.99 (m, 1 H, CH ÄCH2), 7.1ꢃ7.4 (m, 25
/EtOAc) to give (
D)-14 (13.4 g, 95%) as a
due was purified on silica gel (6:1 petroleum etherꢃ
EtOAc) to give 13.1 g (89%) of product ( )-10 as a
colourless foam; TLC (2:1 petroleum etherꢃEtOAc): Rf
0.55; 1H NMR (250 MHz, CDCl3): d 0.72ꢃ
1.13 (3 d, m,
12 H, 3 Me, HMnt), 1.32ꢃ1.72 (m, 4 H, HMnt), 1.88ꢃ2.3
/
/acetone, 1%
D
ꢂ
/
/
/
/
H
/
/
/
/
/
(m, 4 H, HMnt, 2 OH), 3.49 (dd, 1 H, H-5), 3.55 (dd, 1 H,
J3,2 2.7, J3,4 9.6 Hz, H-3), 3.76 (dd, 1 H, H-6), 3.89 (dd, 1
/
/
/
/
/
/
H, H-4), 4.15ꢃ
2.6 Hz, H-2), 4.48ꢃ
/
4.35 (m, 3 H, CH2CHÄ
/
CH2, J2,3
ꢁ
/
J2,1
ꢁ
/
/
/
/
4.6 (m, 1 H, HMnt), 4.66ꢃ
/
4.97 (4 d, 4
/
/
/

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2563
H, Ph). MALDI-MS: 1122.2 [Mꢂ
for C65H78O15 (1099.32): C, 71.02; H, 7.15. Found: C,
71.07; H, 7.20.
/
Na]ꢂ. Anal. Calcd
Calcd for C75H86O13 (1195.5): C, 75.35; H, 7.25. Found:
C, 75.08; H, 7.49. MALDIMS: 1217.4 [Mꢂ
Na]ꢂ.
/
3.9. 6-OAllyl-3,4,5-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-
benzyl-a- -mannopyranosyl)- -myo-inositol [( )-17]
3.7. 6-O-Allyl-4,5-di-O-benzyl-1-O-(1R)-
menthyloxycarbonyl-2-O-(3,4,6-tri-O-benzyl-a-
mannopyranosyl)- -myo-inositol [( )-15]
D
D
D
D-
D
D
To a soln of (D)-16 (3.1 g, 2.6 mmol), in 10:1 anhyd
MeOHꢃEt2O (110 mL), was added K2CO3 (3 g, 21.7
/
Compound (
D
)-14 (13.4 g, 12 mmol) was dissolved in
mmol) and the mixture was stirred for 6 h at 60 8C.
After evaporation, the residue was purified by silica gel
100 mL of methylamine soln (33% in anhyd EtOH) and
stirred for 24 h at rt. The reaction mixture was
concentrated, diluted with toluene and evaporated.
Silica gel column chromatography of the residue (10:1
column chromatography (6:1 tolueneꢃ
/
EtOAc) to afford
)-17 (2 g, 86%) as a colourless oil. TLC (3:1 petroleum
(
D
1
etherꢃ
NMR (250 MHz, CDCl3) d 3.28ꢃ
3.6 (m, 1 H), 3.68ꢃ3.9 (m, 3 H), 3.98ꢃ
4.98 (m, 16 H), 5.1ꢃ5.29 (m, 2 H, CHÄ
H, H-1b), 5.79ꢃ5.96 (m, 1 H, CH ÄCH2), 7.11ꢃ
/
EtOAc): Rf 0.17; [a]D
ꢂ
/
35.18 (c 1, CHCl3); H
3.42 (m, 5 H), 3.52ꢃ
4.15 (m, H), 4.31ꢃ
CH2), 5.46 (d, 1
7.4 (m,
tolueneꢃ/EtOAc) afforded (
D
)-15 (9.8 g, 79%) as a
EtOAc):
3.78 (c 1, CHCl3); H NMR (250 MHz,
CDCl3): d 0.72ꢃ1.12 (3 d, m, 12 H, 3 Me, HMnt), 1.33ꢃ
1.72 (m, 4 H, HMnt), 1.8ꢃ2.2 (m, 4 H, HMnt, 2 OH), 3.4ꢃ
3.8 (m, 8 H), 4.01ꢃ4.12 (m, 2 H), 4.12ꢃ4.32 (m, 3 H,
OCH2CHÄCH2, H-2), 4.4ꢃ4.89 (m, 12 H), 4.96 (d, 1 H,
H-1b), 5.09ꢃ5.3 (m, 2 H, CHÄCH2), 5.81ꢃ5.99 (m, 1 H,
CH ÄCH2), 7.11ꢃ7.4 (m, 25 H, Ph). MALDIMS: 1037.4
[Mꢂ
Na]ꢂ, 1053.3 [MꢂK]ꢂ. Anal. Calcd for
C61H74O13 (1015.25×0.5 H2O): C, 71.53; H, 7.38. Found:
C, 71.63; H, 7.33.
/
/
colourless foam; TLC (3:1 petroleum etherꢃ
/
/
/
/
1
Rf 0.48; [a]D
ꢀ
/
/
/
/
/
/
/
/
/
/
35 H, Ph). MALDIMS: 1035.2 [Mꢂ
/
Na]ꢂ, 1051.2 [Mꢂ
/
/
/
K]ꢂ. Anal. Calcd for C64H68O11 (1013.24): C, 75.87; H,
6.77. Found: C, 75.96; H, 7.02.
/
/
/
/
/
/
/
3.10. 6-O-Allyl-3,4,5-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-
/
/
benzyl-a-
2,3-bis-(myristoyloxy)propyl]-phosphate [(
D
-mannopyranosyl)-
D
-myo-inosit-1-yl-[(2R)-
/
D)-19]
Tetrazole (360 mg, 2.6 equiv) and cyanethoxy-N,N-
diisopropylphosphoramidite (18)14 (2.82 g, 2 equiv) were
dried for 1 h under high diminished pressure. Com-
3.8. 6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(1R)-
menthyloxycarbonyl-2-O-(2,3,4,6-tetra-O-benzyl-a-D-
mannopyranosyl)-
D-myo-inositol [(
D)-16]
pound (D)-17 (2 g, 1.97 mmol, dissolved in 100 mL
anhyd CH2Cl2) was added to the mixture of tetrazole
and 18. Stirring was maintained at rt under Ar atmo-
sphere for 2 h. The two diastereomers (3:1 petroleum
To a soln of (D)-15 (9.8 g, 9.65 mmol), in anhyd DMF
(100 mL), was added BnBr (5.73 mL, 5 equiv). After
cooling to 0 8C, NaH was added portion-wise (579 mg,
2.5 equiv). The reaction mixture was allowed to reach rt
and after 2.5 h stirring the mixture was quenched with
etherꢃEtOAc, Rf 0.50 and 0.56) were then treated with
/
tert-butylhydroperoxide (4.7 m in isooctane, 7.85 mL).
After 1 h, the reaction mixture was concentrated to 10
mL, treated with dimethylamine soln (36 mL, 33% in
anhyd EtOH) and stirred for 1 h. Then the reaction
mixture was again concentrated to 10 mL, diluted with
CH2Cl2, a satd NaHCO3-soln was added, and the two
layers were separated. The organic layer was washed
with brine, dried (Na2SO4) and concentrated. The
1:3 CH3COOHꢃ
under diminished pressure. The residue was purified on
silica gel (10:1 petroleum etherꢃEtOAc) to give 9.75 g
(85%) of ( )-16 as a colourless oil. TLC (3:1 petroleum
etherꢃEtOAc): Rf 0.73. [a]D
NMR (600 MHz, CDCl3): d 0.61ꢃ
Me, HMnt), 1.25ꢃ1.64 (m, 4 H, HMnt), 1.8ꢃ
2.08 (m, 2 H, HMnt), 3.16ꢃ3.19, 3.36ꢃ3.42 (m, H, H-6b),
3.28ꢃ3.37 (m, 2 H, H-5a, H-3a), 3.52 (dd, 1 H, H-6a),
3.63 (dd, 1 H, H-4a), 3.64ꢃ3.73 (m, 2 H, H-2b, H-3b),
3.9ꢃ4.05 (m, 2 H, H-4b, H-5b), 4.08ꢃ4.2 (m, 2 H,
CH2CHÄCH2), 4.2ꢃ4.26, 4.33ꢃ4.4, 4.45ꢃ4.54, 4.66ꢃ
4.85 (m, 15 H, CH2Ph, HMnt), 4.32 (dd, 1 H, H-2a),
4.6 (dd, 1 H, H-1a), 4.97ꢃ5.04, 5.1ꢃ5.2 (m, 2 H, CHÄ
CH2), 5.27 (d, 1 H, H-1b), 5.79ꢃ5.9 (m, 1 H, CH ÄCH2),
6.98ꢃ
7.48 (m, 35 H, Ph); 13C NMR (150.9 MHz,
CDCl3): d 68.3 (C-6b), 70.1ꢃ75.6 (CH2Ph), 71.7 (C-
4b), 72.9 (C-2b), 73.5 (C-2a), 74.4 (C-5b), 74.5
(OCH2CHÄCH2), 77.1 (C-1a), 78.5 (C-3a), 78.7 (C-
3b), 79.0 (C-6a), 79.1 (C-Mnt), 80.9 (C-4a), 83.1 (C-5a),
98.2 (C-1b), 117.0 (CHÄCH2), 134.8 (CHÄCH2). Anal.
/EtOAc and the mixture concentrated
/
D
1
/
ꢀ
/
1.88 (c 1, CHCl3); H
1.08 (3 d, m, 12 H, 3
1.9, 2.02ꢃ
/
/
/
/
residue was purified by flash chromatography (9:10
1:10 tolueneꢃacetone) to afford ( )-19 (2.6 g, 78%) as
a slightly yellow oil; TLC (10:1 CHCl3ꢃMeOH): Rf
0.34; 31P NMR (242.9 MHz, 1:1 CD3ODꢃ
CDCl3): d ꢀ
3.97 (s, 1P); H NMR (600 MHz, 1:1 CDCl3ꢃCD3OD):
d 0.8ꢃ0.95 (t, 6 H, Me), 1.04ꢃ1.4 (m, 40 H, CH2-chain),
1.4ꢃ1.7 (m, 4 H, COCH2ÃCH2ÃR), 2.18ꢃ2.3 (m, 4 H,
COCH2ÃCH2ÃR), 3.1 (m, H-6b), 3.29ꢃ3.43 (m, 3 H, H-
6b, H-5a, H-3a), 3.59 (dd, 1 H, H-6a), 3.72 (dd, 1 H, H-
4a), 3.79 (dd, 1 H, H-2b), 3.82 (dd, 1 H, H-3b), 4.0ꢃ4.18
(m, 7 H, H-4b, H-5b, H-1a, H-1?, H-3?), 4.25ꢃ4.4 (m, 2
H, OCH2CHÄCH2), 4.2ꢃ4.25, 4.4ꢃ4.9 (m, 14 H,
CH2Ph), 4.58 (dd, 1 H, H-2a), 5.13ꢃ5.32 (m, 3 H,
CHÄCH2, H-2?), 5.61 (d, 1 H, H-1b), 5.9ꢃ6.1 (m, H,
CH ÄCH2), 7.1ꢃ
7.52 (m, 35 H, Ph); 13C NMR (1:1 150.9
/
/
/
/
D
/
/
/
/
/
1
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/

2564
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
MHz, CDCl3ꢃ
(C-6b), 70.6 (C-2?), 71.2ꢃ
73.7 (C-2b), 73.8 (C-2a), 74.5 (C-4b), 74.8 (OCH2CHÄ
CH2), 77.0 (C-1a), 78.5 (C-3b), 79.0 (C-3a), 80.3 (C-6a),
81.1 (C-4a), 83.2 (C-5a), 98.0 (C-1b). C95H127O18P
/
CD3OD): d 62.8 (C-3?), 64.2 (C-1?), 68.4
25.1 (2 C, COCH2CH2R), 34.0 (2 C, COCH2CH2R),
45.9 (3 C, CH2CH3NEt3), 61.6 (C-6b), 63.1 (C-1,3), 63.6
(C-1,3), 68.2 (C-6a), 71.0 (C-2?), 71.1 (C-2b), 71.2 (C-
3a), 71.4 (C-3b), 73.0 (C-4b), 73.3 (C-5b), 76.1 (C-5a),
72.2 (C-1a), 77.9 (C-2a), 100.7 (C-1b); MALDIMS:
/
76.8 (CH2Ph), 71.7 (C-5b),
/
(1587.09). MALDIMS: 1587.6 [Mꢀ
/
H]ꢀ.
Calcd (Mꢀ
H)ꢀ: m/z 915.7, Found m/z 914.9.
/
3.11. 3,4,5-Tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-a-
-mannopyranosyl)- -myo-inosit-1-yl-[(2R)-2,3-
bis[(myristoyloxy)-propyl]phosphate [( )-20]
3.13. 3-O-Benzyl-1,2:4,5-di-O-cyclohexylidene-6-O-
camphanoyl- -myo-inositol [( )-22]
D
D
L
L
D
Compound (D)-22 was synthesized following a proce-
dure of Vacca and coworkers.16a Separation procedure:
The mother liquors were evaporated and flash chroma-
To a soln of (
D
)-19 (310 mg, 0.2 mmol), in CH2Cl2 (2
mL), was added under Ar atmosphere Pd(PPh3)4 (22
mg, 0.1 equiv), p-toluenesulfinic acid sodium salt (40.6
mg, 1.2 equiv) and AcOH (26.1 mL, 2.4 equiv). The
tography (8:1 petroleum etherꢃ
crude ( )-22 which was dissolved in CH2Cl2, treated
with 100 g silica gel and evaporated to dryness. Column
chromatography (¥ 7 cm, lꢁ40 cm) yielded pure ( )-22
(8.6 g) as a colourless solid. TLC (3:1 petroleum etherꢃ
/EtOAc) yielded 11 g of
L
reaction mixture was followed by TLC (4:1 CHCl3ꢃ
/
MeOH, Rf 0.730
reaction was completed. The mixture was concentrated
under diminished pressure and purified by silica gel
/0.69). After 2 h stirring at rt, the
/
L
/
EtOAc): Rf 0.44.
column chromatography (48:1 CHCl30
MeOH) to yield ( )-20 (180 mg, 58%) as a colourless
oil; TLC (4:1 CHCl3ꢃ
MHz, 1:1 CDCl3ꢃCD3OD): d 0.82ꢃ
1.17ꢃ1.4 (m, 40 H, CH2), 1.45ꢃ1.65 (m, 4 H, COCH2Ã
CH2ÃR), 2.2ꢃ2.3 (m, 4 H, COCH2ÃCH2ÃR), 3.15ꢃ3.25
(m, 1 H), 3.3ꢃ3.5 (m, 3 H), 3.73ꢃ4.3 (m, 11 H), 4.39ꢃ
4.98 (m, 16 H), 5.22ꢃ5.35 (m, 1 H, H-2?), 5.53 (d, 1 H,
H-1b), 7.1ꢃ7.5 (m, 35 H, Ph).
/
CHCl3ꢃ
/
D
3.14. 3-O-Benzyl-1,2:4,5-di-O-cyclohexylidene-6-O-
camphanoyl-
1
/
MeOH); Rf 0.69; H NMR (250
0.95 (t, 6 H, Me),
D-myo-inositol [(
D)-22]
/
/
/
/
/
TLC (3:1 petroleum etherꢃ/EtOAc): Rf 0.37.
/
/
/
/
/
/
/
/
3.15. 1,2:4,5-Di-O-cyclohexylidene-
L
-myo-inositol [(L)-
/
24]
/
A mixture of (L)-23 (950 mg, 2.21 mmol), anhyd THF
3.12. Triethylammonium [2-O-(a-
myo-inosit-1-yl]-[(2R)-2,3-bis(myristoyloxy)propyl]-
phosphate [( )-1a]
D
-mannopyranosyl)-
D-
(25 mL) and Pearlman’s catalyst (10 mol%) was
degassed under diminished pressure and saturated with
H2 three times. The suspension was stirred at rt for 2 h,
then neutralized with Et3N, filtered over celite, washed
D
A stirred mixture of (
D
)-20 (170 mg, 0.1 mmol, 7.5:7.5:1
with THF and concentrated. Compound (
98%) was obtained as a white solid; TLC (1:1 petroleum
etherꢃEtOAc): Rf 0.32; mp 190 8C; [a]D 17.38 (c 0.75,
CHCl3); H NMR (250 MHz, CDCl3): d 1.25ꢃ1.86 (m,
20 H, Hcyclohexylidene), 3.39ꢃ2.7 (2 s, 2 H, OH), 3.32 (dd,
1 H, J 10.7, J 9.3 Hz, H-5), 3.72ꢃ3.93 (m, 2 H), 3.95ꢃ
4.12 (m, 2 H), 4.49 (dd, 1 H, J2,3 J2,1 4.8 Hz, H-2).
0.25 H2O (344.9): C, 62.68;
L)-24 (736 mg,
CH2Cl2ꢃMeOHꢃwater 3 mL) and Pd/C (0.2 equiv) was
/
/
degassed under diminished pressure and saturated with
H2 (H2-filled balloon) three times. The suspension was
stirred at rt overnight, filtered over celite, washed with
/
ꢂ
/
1
/
/
7.5:7.5:1 CH2Cl2ꢃ
with some Et2N. The solvents were removed under
diminished pressure by lyophilization to afford ( )-1a
(82 mg, 73%) as a white powder; TLC (65:35:8 CHCl3ꢃ
MeOHꢃ
0.2% CaCl2): Rf 0.26; 31P NMR (242.9 MHz,
Me2SO-d6): d ꢀ
1.31 (s, 1 P); 1H NMR (600 MHz,
Me2SO-d6): d 0.75ꢃ0.91 (t, 6 H, Me), 1.05ꢃ1.37 (m, 49
H, CH2-chain, MeEt3N), 1.39ꢃ1.57 (m, H,
COCH2CH2R), 2.17ꢃ2.35 (m, 4 H, COCH2CH2R),
2.93 (dd, 1 H, H-5a), 3.08 (m, 6 H, HN(CH2ÃCH3)3),
/
MeOHꢃ
/water (2 mL) and treated
/
/
ꢁ
/
D
Anal. Calcd for C18H28O6×
/
/
H, 8.33. Found: C, 62.76; H, 8.35.
/
/
3.16. 2,3:5,6-Di-O-cyclohexylidene-1,4-di-O-methyl-
myo-inositol (25)
D-
/
/
/
4
/
To a soln of compound 24 (440 mg, 1.29 mmol), in dry
DMF (5 mL), were added ICH3 (200 mL, 3.2 mmol) and
NaH (116 mg, 4.8 mmol). After 3 h stirring at rt, the
reaction mixture was diluted with satd aq NH4Cl-soln
and CH2Cl2. The organic layer was washed with water
/
3.18 (dd, 1 H, H-3a), 3.32 (dd, 1 H, H-4a), 3.47 (m, 2 H,
H-6a, H-6b), 3.48 (dd, H, H-4b), 3.51 (dd, 1 H, H-3b),
3.54 (m, 1 H, H-6b), 3.64 (dd, 1 H, H-2b), 3.72 (dd, 1 H,
H-1a), 3.77 (m, 1 H, H-1,3), 3.84 (ddd, 1 H, H-5b), 3.89
(m, 1 H, H-1,3), 4.00 (dd, 1 H, H-2a), 4.1 (m, 1 H, H-
1,3), 4.31 (m, 1 H, H-1,3), 5.02 (d, 1 H, H-1b), 5.09 (m, 1
H, H-2?). 13C NMR (150.9 MHz, Me2SO-d6): d 9.3 (3C,
MeEt3N), 14.8 (2C, Me), 22.9, 29.8, 32.5 (20 C, (CH2)n)
(ꢄ
purified by column chromatography (2:1 petroleum
etherꢃEtOAc) to afford 25 (438 mg, 92%) as a white
solid. TLC (1:1 petroleum etherꢃEtOAc): Rf 0.76; mp
/2), dried (MgSO4) and concentrated. The residue was
/
/
1
118 8C; [a]D
ꢂ88 (c 1, CHCl3); H NMR (600 MHz,
/

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2565
CDCl3): d 1.25ꢃ
dene), 3.31 (dd, 1 H, J5,6ꢁ
J4,5 10.6, J4,3 6.4 Hz, H-4), 3.58 (s, 3 H, OMe), 3.60 (s, 3
H, OMe), 3.62 (dd, 1 H, J1,2 4.2, J1,6 10.1 Hz, H-1), 3.96
/
1.5, 1.51ꢃ
/
1.82 ( m, 20 H, Hcyclohexyli-
5.14ꢃ
(m, 1 H, CH2CH Ä
Anal. Calcd for C28H38O6 (470.6): C, 71.46; H, 8.14.
Found: C, 71.43; H, 8.14.
/
5.21, 5.3ꢃ
/
5.35 (m, 2 H, CH2CHÄ
/
CH2), 5.90ꢃ
/
5.99
/J5,4 9.8 Hz, H-5), 3.47 (dd, 1 H,
/
CH2), 7.24ꢃ7.44 (m, 5 H, ArH).
/
(dd, 1 H, J6,1
J3,2 5.6 Hz, H-3), 4.52 (dd, 1 H, J2,3
ꢁ
/
J6,5 9.8 Hz, H-6), 4.06 (dd, 1 H, J3,4
ꢁ
/
ꢁ
/
J2,1 4.6 Hz, H-2).
Anal. Calcd for C20H32O6 (368.5): C, 65.19; H, 8.75.
Found: C, 65.16; H, 8.75.
3.19. 6-O-Allyl-3-O-benzyl-1,2-O-cyclohexylidene-
myo-inositol [( )-28]
L-
L
3.17. 1,4-Di-O-methyl-
Liriodentritol (26)
D
-myo-inositol/(ꢀ)-
/
Bis-ketal (
dry CH2Cl2ꢃ
To this soln was added 0.3 mL of a mixture of 13:1
PPTSAꢃPTSA (0.86 m) in dry DCM. The reaction was
followed by TLC (1:1 petroleum etherꢃEtOAc, Rf 0.2).
Stirring was maintained for 1 h 10 before the reaction
was quenched with Et3N. The residue obtained upon
evaporation was purified by flash chromatography (1:1
L
)-27 (12 g, 25.5 mmol) was dissolved in 1:1
/
MeOH (200 mL) and heated up to 40 8C.
To a soln of 25 (160 mg, 0.41 mmol) in 1:1 MeOHꢃ
/
/
CH2Cl2 (2 mL), was added camphor-10-sulfonic acid (15
mg, 0.065 mmol) at rt and the soln was stirred for 24 h.
The white precipitate, which was formed, was filtered,
washed with CH2Cl2 and dried under high diminished
pressure. Compound 26 was obtained in 78% yield (67
/
petroleum etherꢃ
EtOAcꢃMeOH) to yield (
solid; mp 138 8C; [a]D 18.18 (c 1, CHCl3); H NMR
(250 MHz, CDCl3): d 1.3ꢃ1.8 (m, 10 H, Hcyclohexylidene),
2.73 (s, 2 H, OH), 3.33 (dd, 1 H, J5,6 J5,4 9.7 Hz, H-5),
3.46 (dd, 1 H, J4,5 9.7, J4,3 7.0 Hz, H-4), 3.52 (dd, 1 H,
J1,2 4.1, J1,6 9.7 Hz, H-1), 3.94 (dd, 1 H, J6,1 J6,5 9.4
Hz, H-6), 4.01 (dd, 1 H, J3,4 7.0, J3,2 5.0 Hz, H-3), 4.18ꢃ
4.21, 4.39ꢃ4.42 (m, 2 H, CH2CHÄCH2), 4.31 (dd, 1 H,
J2,3 J2,1 4.7 Hz, H-2), 4.73ꢃ4.79 (m, 2 H, CH2ÃPh),
5.17ꢃ5.20, 5.27ꢃ5.30 (m, 2 H, CH2CHÄCH2), 5.91ꢃ
5.98 (m, 1 H, CH2CH ÄCH2), 7.25ꢃ7.44 (m, 5 H,
/EtOAc, dissolved in a minimum of
mg); TLC (5:1 CHCl3ꢃ
[a]D 258 (c 1.5, water); [a]D
NMR (600 MHz, Me2SO-d6): d 2.78 (dd, 1 H, J1,2 2.5,
J1,6 9.6 Hz, H-1), 3.0 (ddd, 1 H, J5,6 J5,4 9.1, J5-OH 4.7
Hz, H-5), 3.08 (dd, 1 H, J4,5 J4,3 9.4 Hz, H-4), 3.18
/
MeOH): Rf 0.07; mp 226 8C.
/
L
)-28 (7.8 g, 78%) as a white
1
ꢀ
/
ꢀ258 (c 2, water); H
/
1
ꢀ
/
/
ꢁ
/
ꢁ
/
ꢁ
/
(ddd, 1 H, J3,4 9.4, J3,2 2.7, J3-OH 6.4 Hz, H-3), 3.28 (s 3
H, Ome at O-1), 3.43 (s, 3 H, OMe at O-4), 3.43 (ddd, 1
H, J6,1 9.6, J6,5 9.1, JO-6H 4.9 Hz, H-6), 3.88 (ddd, 1 H,
J2,3 2.72, J2,1 2.5, JO-6H 4.0 Hz, H-2), 4.54 (d, 1 H, J 6.7
Hz, OH-3), 4.56 (d, 1 H, J 4.0 Hz, OH-2), 4.58 (d, 1 H, J
4.9 Hz, OH-6), 4.65 (d, 1 H, J 4.7 Hz, OH-5); 13C NMR
(150.9 MHz, Me2SO-d6): d 56.59 (OMeC-1), 56.68
(OMeC-4), 68.53 (C-2), 71.08 (C-3), 71.93 (C-6), 74.67
(C-5), 81.39 (C-1), 83.10 (C-4). Anal. Calcd for C8H16O6
(208.2): C, 46.14; H, 7.75. Found: C, 46.00; H, 7.71.
ꢁ
/
/
/
/
ꢁ
/
/
/
/
/
/
/
/
/
ArH). Anal. Calcd for C22H30O6 (390.5): C, 67.67; H,
7.74. Found: C, 67.48; H, 7.61.
3.18. 6-O-Allyl-3-O-benzyl-1,2:4,5-di-O-
)-27]
3.20. 6-O-Allyl-3,4,5-tri-O-benzyl-1,2-O-
L)-29]
cyclohexylidene-
L
-myo-inositol [(
L
cyclohexylidene-
L
-myo-inositol [(
A soln of (L)-23 (23 g, 54 mmol), in dry DMF (580 mL),
To a soln of (L)-28 (14.43 g, 37 mmol), in dry DMF (430
was treated with allyl bromide (5.9 mL, 75.43 mmol),
then NaH (2.3 g, 0.90 mmol) was added. The reaction
mixture was stirred at rt for 45 min, quenched with
MeOH and concentrated under diminished pressure.
The residue was diluted with EtOAc, washed with water
and brine. The organic layer was dried with MgSO4 and
concentrated under diminished pressure. The resulting
syrup was applied to a short column of silica gel which
mL), was added BnBr (11 mL, 92.6 mmol). NaH (2.7 g,
113 mmol) was slowly added to the soln and after
stirring for 4 h at rt, the reaction mixture was treated
with MeOH. After usual workup (EtOAcꢃwater) the
/
organic layer was dried (MgSO4) and concentrated
under diminished pressure. Flash chromatography
(10:1 petroleum etherꢃ
colourless syrup; TLC (8:1 petroleum etherꢃ
/
EtOAc) gave (
L
)-29 (84%) as a
EtOAc): Rf
43.18 (c 1, CHCl3); H NMR (250 MHz,
CDCl3): d 1.3ꢃ1.88 (m, 10 H, Hcyclohexylidene), 3.35 (dd, 1
H, J 8.6, J 9.8 Hz, Hinositol), 3.63ꢃ3.75 (m, 2 H,
inositol), 3.91 (dd, 1 H, J 8.6 Hz, Hinositol), 4.0 (dd, 1
H, J 5.5, J 7.1 Hz, Hinositol), 4.2ꢃ4.31, 4.32ꢃ4.43 (m, 2
H, H-2, CH2CHÄCH2), 4.70ꢃ4.89 (m, 6 H, CH2ÃPh),
5.12ꢃ5.36 (m, 2 H, CH2CHÄCH2), 5.89ꢃ6.08 (m, 1 H,
CH2CH ÄCH2), 7.20ꢃ7.47 (m, 15 H, ArH). Anal. Calcd
/
1
was eluted with 9:10
give ( )-27 (25.1 g, quant.) as a white solid; TLC (3:1
petroleum etherꢃEtOAc): Rf 0.67; mp 90.2 8C; [a]D
41.78 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): d 1.3ꢃ
1.85 (m, 20 H, Hcyclohexylidene), 3.27 (dd, 1 H, J5,6 J5,4
/
3:1 petroleum etherꢃ/EtOAc to
0.35; [a]D
ꢂ
/
L
/
/
ꢂ
/
/
/
H
ꢁ
/
/
/
10 Hz, H-5), 3.63 (dd, 1 H, J6,1 6.5, J6,5 10.6 Hz, H-6),
3.73 (dd, 1 H, J3,4 10.3, J3,2 4.1 Hz, H-3), 4.00 (dd, 1 H,
/
/
/
/
/
/
J1,2 5.0, J1,6 6.8 Hz, H-1), 4.03 (dd, 1 H, J4,5
Hz, H-4), 4.25ꢃ4.31 (m, 2 H, CH2CHÄCH2), 4.33 (dd, 1
H, J2,3 J2,1 4.4 Hz, H-2), 4.80ꢃ4.91 (m, 2 H, CH2ÃPh),
ꢁ
/
J4,3 9.7
/
/
/
/
for C36H42O6 (570.7): C, 75.76; H, 7.42. Found: C,
ꢁ
/
/
/
75.78; H, 7.40.

2566
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
3.21. 6-O-Allyl-3,4,5-tri-O-benzyl-
30]
L
-myo-inositol [(
L
)-
3.23. 6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(4-
methoxybenzyl)-2-O-(2,4,6-tri-O-benzyl-a-
D-
mannopyranosyl)-(10
/
2)-
L
-myo-inositol [(
L)-32]
For cleavage of the ketal, compound (
L)-29 (20.8 g, 25
A mixture of imidate 138a,9,11 (20 g, 31.4 mmol), and
acceptor (L)-31 (11.6 g, 19 mmol) was dissolved in anhyd
ether (220 mL, ultrasound). Trimethylsilyl triflate (0.52
mL) was added and the mixture was stirred for 10 s,
then quenched with triethylamine, diluted with toluene
and concentrated. The residue was purified by flash
chromatography (5:10
give the crude product. TLC: (2:1 petroleum etherꢃ
EtOAc, 1% Et3N), Rf 0.72. Without further purifica-
tion, the crude product was dissolved in 200 mL 33%
methylamine soln in anhyd EtOH and stirred for 6 h at
rt. The reaction mixture was concentrated, diluted with
toluene and evaporated. Silica gel column chromato-
mmol) was dissolved in 10:1 MeOHꢃCH2Cl2 (330 mL).
/
To this soln was added camphor-10-sulfonic acid
(1.1 g, 4.73 mmol) and the reaction mixture was stirred
for 24 h at rt. Next the mixture was neutralized with
Et3N, diluted with toluene and concentrated under
diminished pressure. The obtained residue was purified
/
4:1 petroleum etherꢃEtOAc) to
/
on silica gel (1:1 petroleum etherꢃ
(95% yield) of product ( )-30 as a white solid; TLC (2:1
petroleum etherꢃEtOAc): Rf 0.25; mp 123 8C; [a]D
318 (c 1, CHCl3); H NMR (600 MHz, CDCl3): d
2.5 (s, 2 H, OH), 3.41 (dd, 1 H, J5,6 J5,4 9.4 Hz, H-5),
3.44ꢃ3.47 (m, 2 H, H-1, H-3), 3.70 (dd, 1 H, J6,1 J6,5
9.4 Hz, H-6), 3.92 (dd, 1 H, J4,5 J4,3 9.4 Hz, H-4),
4.21 (dd, 1 H, J2,3 J2,1 3.0 Hz, H-2), 4.22ꢃ4.28,
4.39ꢃ4.44 (m, 2 H, CH2CHÄCH2), 4.68ꢃ4.70, 4.76ꢃ
4.89 (m, 6 H, CH2ÃPh), 5.16ꢃ5.18; 5.25ꢃ5.29 (m,
2 H, CH2CHÄCH2), 5.92ꢃ5.98 (m, 1 H, CH2CH Ä
CH2), 7.25ꢃ7.34 (m, 15 H, ArH). Anal. Calcd for
/EtOAc) to give 17 g
/
L
/
1
ꢂ
/
ꢁ
/
/
ꢁ
/
ꢁ
/
graphy of the residue (3:10
EtOAc) afforded ( )-32 (14 g, 71% over 2 steps). TLC
(3:1 petroleum etherꢃEtOAc): Rf 0.40. [a]D 418 (c 1,
CHCl3). H NMR (600 MHz, CDCl3): d 2.38 (s, 1 H,
OH), 3.20 (dd, 1 H, J1,2 2.0, J1,6 9.9 Hz, H-1a), 3.28ꢃ
3.40 (m, 3 H, H-5a, H-3a, H-6b), 3.50 (dd, 1 H, Jgem
10.7, Jvic 3.2 Hz, H-6b), 3.69 (dd, 1 H, J6,1 J6,5 9.5 Hz,
H-6a), 3.76 (s, 3 H, OMe), 3.78ꢃ3.86 (m, 2 H, H-4a, H-
3b), 3.92 (dd, 1 H, J4,5 J4,3 9.7 Hz, H-4b), 4.06 (m, 1
H, H-2b), 4.12ꢃ4.17 (m, 1 H, H-5b), 4.25ꢃ4.31 (m, 1 H,
CH2ꢁCH ÃCH2), 4.32 (m, 1 H, H-2a), 4.34ꢃ4.40, 4.5ꢃ
4.56, 4.57ꢃ4.73, 4.74ꢃ4.88 (m, 15 H, CH2ÃPh, CH2ꢁ
CHÃCH2), 5.13 (dd, 1 H, Jgem 10.3 Hz, CH2ꢁCHÃ
CH2), 5.25 (dd, 1 H, CH2ꢁCHÃCH2), 5.38 (d, 1 H,
J B1 Hz, H-1b), 5.89ꢃ6.0 (m, 1 H, CH2ꢁCH ÃCH2),
6.72ꢃ6.81 (m, 2 H, HPMB), 7.06ꢃ7.38 (m, 32 H, ArH);
13C NMR (150.9 MHz, CDCl3): d 55.20 (OMe), 68.55
(C-6b), 68.65 (C-2b), 70.90 (C-5b), 72.10ꢃ76.19 (9C,
CH2ÃCHÄCH2, CH2Ph, C-4b), 78.44 (C-1a), 79.61 (C-
3b), 80.75 (C-3a), 81.04 (C-6a), 81.42 (C-4a), 83.44 (C-
5a), 99.97 (C-1b), 113.65 (CPMB), 116.57 (CH2ÃCHÄ
CH2), 127.46ꢃ138.70 (40 C, Ph, CH2ÃCHÄCH2),
/
2:1 petroleum etherꢃ
/
ꢁ
/
/
L
/
/
/
/
/
ꢂ
/
1
/
/
/
/
/
/
/
/
C30H34O6 (490.6): C, 73.45; H, 6.99. Found: C, 73.50;
H, 6.87.
ꢁ
/
/
ꢁ
/
/
/
/
/
/
/
3.22. 6-O-Allyl-3,4,5-tri-O-benzyl-1-O-(4-
methoxybenzyl)-
/
/
/
/
L
-myo-inositol [(
L)-31]
/
/
/
/
/
Compound (L)-30 (15.1 g, 30.77 mmol), in anhyd
/
/
/
/
toluene (500 mL), was treated with dibutyltin oxide
(8.43 g, 1.1 equiv) and the reaction mixture was refluxed
in a Dean and Stark apparatus for 3 h. To the reaction
mixture was added TBAI (17 g, 46 mmol) and 4-
methoxybenzyl chloride (9.1 mL, 67 mmol). Stirring
was maintained at 110 8C for 1.5 h, then evaporated and
diluted with EtOAc, washed with water, brine, dried
(MgSO4) and concentrated. Silica gel column chroma-
/
/
/
/
/
/
/
/
/
/
159.00 (COMe). Anal. Calcd for C65H70O12 (1043.3): C,
tography of the residue (6:10
EtOAc) yielded ( )-31 (14.85 g, 79%) as a slightly brown
solid; TLC (2:1 petroleum etherꢃEtOAc): Rf 0.43; mp
/
5:1 petroleum etherꢃ
/
74.80; H, 6.76. Found: C, 74.92; H, 6.51.
L
/
3.24. 3,4,5-Tri-O-benzyl-1-O-(4-methoxybenzyl)-2-O-
2)-L-
myo-inositol [(L)-33]
1
106 8C; [a]D
ꢂ9.18 (c 1, CHCl3); H NMR (250 MHz,
/
(2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl)-(10
/
CDCl3): d 2.41 (s, 1 H, OH), 3.29 (dd, 1 H, J 9.6, J 2.7
Hz, Hinositol), 3.36 (dd, 1 H, J 9.7, J 2.8 Hz, Hinositol),
3.38 (dd, 1 H, J 9.5 Hz, Hinositol), 3.81 (s, 3 H, OMe),
3.81 (dd, 1 H, J 9.5 Hz, Hinositol), 3.94 (dd, 1 H, J 9.6
Hz, Hinositol), 4.16 (dd, 1 H, J 2.7 Hz, Hinositol),
Compound (L)-32 (3 g, 2.88 mmol) was dissolved in
EtOH (45 mL) by heating, then DBU (43 mL, 0.29
mmol) and (Ph3P)3RhCl (750 mg, 0.81 mmol) were
added. The mixture was stirred for 1.5 h under reflux
and then concentrated under diminished pressure (pro-
penyl intermediate: Rf 0.54, 2:1 petroleum etherꢃ
EtOAc). The residue was dissolved in 1:9 1 m HClꢃ
acetone (50 mL), and the soln was heated under reflux
for 15 min. Acidity was neutralized by adding triethyl-
amine, then the mixture was diluted with EtOAc,
4.28, 4.95 (m, 2 H, CH2CHÄ
4.93 (m, 8 H, CH2ÃPh), 5.12ꢃ
CH2), 5.90ꢃ6.08 (m, 1 H, CH2CH Ä
2 H, HPMB), 7.22ꢃ7.40 (m, 17 H, ArH). Anal. Calcd for
/
CH2), 4.59ꢃ
5.34 (m, 2 H, CH2CHÄ
CH2), 6.83ꢃ6.92 (m,
/
4.74, 4.78ꢃ
/
/
/
/
/
/
/
/
/
/
C38H42O7 (610.8): C, 73.64; H, 6.99. Found: C, 73.70; H,
6.74.

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2567
washed with water, dried (MgSO4) and concentrated.
Flash chromatography (4:105:2 petroleum etherꢃ
EtOAc) of the residue gave ( )-33 (2.5 g, 87%); TLC
EtOAc): Rf 0.38. [a]D
0 8C, the reaction was allowed to reach rt. The mixture
was stirred for 1.5 h, diluted with EtOAc, washed with
satd aq NaHCO3-soln, dried (MgSO4) and concen-
/
/
L
(2:1 petroleum etherꢃ
/
ꢂ8.58 (c
/
trated. Flash chromatography (4:10
etherꢃEtOAc) of the residue gave ( )-35 (2.2 g, 94%)
as a colourless syrup; TLC (5:2 petroleum etherꢃ
/3:1 petroleum
0.25, CHCl3); 1H NMR (600 MHz, CDCl3): d 2.39 (s, 2
H, OH), 3.06 (dd, 1 H, J1,2 2.4, J1,6 10.0 Hz, H-1a), 3.32
/
L
/
1
(dd, 1 H, J5,6
10.0, J3,2 2.4 Hz, H-3a), 3.42 (dd, 1 H, Jgem
Jvic 2.1 Hz, H-6b), 3.56 (dd, 1 H, Jgem 10.6, Jvic 3.8 Hz,
H-6b), 3.77 (s, 3 H, OMe), 3.8 (dd, 1 H, J4,5 J4,3 9.4
Hz, H-4a), 3.84 (dd, 1 H, J3,4 9.4, J3,2 3.2 Hz, H-3b), 3.9
(dd, 1 H, J4,5 J4,3 9.7 Hz, H-4b), 3.94 (dd, 1 H, J6,1
J6,5 9.7 Hz, H-6a), 4.05 (dd, 1 H, J2,3 1 Hz, H-2b), 4.15
(ddd, 1 H, Jvic 1.8, 3.5, J5,4 10.0 Hz, H-5b), 4.35 (dd, 1
H, J2,3 J2,1 2.4 Hz, H-2a), 4.36ꢃ4.47, 4.56ꢃ4.61, 4.63ꢃ
4.73, 4.77ꢃ4.88 (m, 14 H, CH2ÃPh), 5.37 (d, 1 H, J B
Hz, H-1b), 6.78ꢃ6.80 (m, 2 H, HPMB), 7.08ꢃ7.39 (m, 32
H, ArH); 13C NMR (150.9 MHz, CDCl3): d 55.24
(OMe), 68.65 (C-2b), 68.79 (C-6b), 71.02 (C-5b), 71.35ꢃ
ꢁ/J5,4 9.1 Hz, H-5a), 3.34 (dd, 1 H, J3,4
EtOAc): Rf 0.26. [a]D
(250 MHz, CDCl3): d 2.45 (s, 1 H, OH), 3.37ꢃ
H), 3.53ꢃ3.81 (m, 6 H), 3.90 (dd, 1 H, J 8.7 Hz), 4.01ꢃ
4.11 (m, 1 H), 4.21 (dd, 1 H, J2,1 J2,3 2.3 Hz, H-2a),
4.42ꢃ4.93 (m, 16 H, CH2ÃPh), 5.22 (d, 1 H, J 1.20 Hz,
H-1b), 7.13ꢃ
7.41 (m, 40 H, ArH). MALDIMSꢂ (matrix
DHB, THF):, m/z 1086.3 [Mꢂ
Na]ꢂ. Found: m/z
H2O (1081.3): C,
ꢂ
/
10.88 (c 1, CHCl3); H NMR
ꢁ/10.4,
/
3.49 (m, 3
ꢁ
/
/
/
ꢁ
/
ꢁ
/
/
/
ꢁ
/
ꢁ
/
/
B
/
/
1086.8. Anal. Calcd for C68H70O11×
/
ꢁ
/
/
/
/
75.53; H, 6.71. Found: C, 75.48; H, 6.50.
/
/
/
1
/
/
3.27. Dimethylammonium [3,4,5,6-tetra-O-benzyl-2-O-
/
(2,3,4,6-tetra-O-benzyl-a-
inosit-1-yl]-[(2R)-2,3-bis(myristoyloxy)propyl]-phosphate
[( )-36]
D-mannopyranosyl)-L-myo-
75.79 (10 C, CH2Ph, C-2a, C-6a, C-4b), 77.63 (C-1a),
79.68 (C-3b), 80.81 (C-3a), 81.28 (C-4a), 83.31 (C-5a),
100.0 (C-1b), 113.86 (CPMB), 127.52ꢃ
/
138.62 (39 C, Ph),
L
159.18 (COMe). Anal. Calcd for C62H66O12×
/
0.25 H2O
(1007.7): C, 73.90; H, 6.65. Found: C, 73.81; H, 6.67.
Tetrazole (172 mg, 2.46 mmol) was dried for 1 h under
high diminished pressure. Compound ( )-35 (1 g, 0.94
L
mmol) was dissolved in anhyd CH2Cl2 (50 mL), added
to the tetrazole and stirred at rt under Ar. To this
reaction mixture was added dropwise benzyl N,N-
diisopropylphosphoramidite (18)14 (1.35 g, 1.89 mmol)
and the soln was stirred for 2 h, then treated with tert-
butylhydroperoxide in isooctane (4.7 M, 3.76 mL). After
15 min, the reaction mixture was concentrated to 10 mL,
treated with dimethylamine soln (20 mL, 33% in anhyd
EtOH) and stirred for 1 h. Then the reaction mixture
was again concentrated to 10 mL, diluted with CH2Cl2,
saturated NaHCO3-soln was added and the two layers
were separated. The organic layer was washed with
brine, dried (MgSO4) and concentrated. The residue was
3.25. 3,4,5,6-Tetra-O-benzyl-1-O-(4-methoxybenzyl)-2-
O-(2,3,4,6-tetra-O-benzyl-a-
D
-mannopyranosyl)-(10
/2)-
L
-myo-inositol [(
L)-34]
To a soln of (L)-33 (2.5 g, 2.49 mmol), in dry DMF (50
mL), was added BnBr (0.75 mL, 6.31 mmol) and NaOH
(150 mg, 6.25 mmol). The reaction mixture was stirred
at rt for 3 h, quenched with MeOH and concentrated.
The residue was partitioned between EtOAc and water.
The organic layer was washed with brine, dried
(MgSO4) and evaporated under diminished pressure.
Silica gel column chromatography (4:1 petroleum
etherꢃ
less syrup; TLC (4:1 petroleum etherꢃ
[a]D ꢂ
208 (c 1, CHCl3); 1H NMR (250 MHz, CDCl3): d
3.23ꢃ3.49 (m, 4 H), 3.59 (dd, 1 H, Jgem 10.6, Jvic 3.5 Hz,
H-6b), 3.66ꢃ3.88 (m, 4 H), 3.76 (s, 3 H, OMe), 4.0ꢃ4.2
(m, 2 H), 4.32ꢃ4.96 (m, 19 H, CH2ÃPh, H-2a), 5.42 (d, 1
H, J 1.4 Hz, H-1b), 6.70ꢃ6.80 (m, 2 H, HPMB), 7.09ꢃ
/EtOAc) afforded (
L)-34 (2.5 g, 86%) as a colour-
purified by flash chromatography (9:10
acetone) to afford ( )-36 (1.17 g, 76%) as a colourless
syrup; 31P NMR (242.9 MHz, 1:1 CD3ODꢃ
CDCl3): d
2.927 (s, 1P); 1H NMR (600 MHz, 1:1 CD3ODꢃ
CDCl3): d 0.89 (t, 6 H, Me), 1.1ꢃ1.40 (s, 40 H,
(CH2)n), 1.45ꢃ1.60 (m, 4 H, COCH2CH2R), 2.15ꢃ
(m, 4 H, COCH2CH2R), 3.40ꢃ
5a), 3.67 (dd, 1 H, J4,5 J4,3 9.4 Hz, H-4a), 3.71ꢃ
(m, 2 H, H-2b, H-6a), 3.79ꢃ
3.99 (m, 4 H, H-1, H-3, H-6b), 4.0ꢃ
H-1), 4.09ꢃ4.18 (m, 2 H, H-4b, H-5b), 4.19ꢃ
H, H-3), 4.38ꢃ4.93 (m, 17 H, CH2ÃPh, H-2a), 5.14ꢃ
(m, 1 H, H-2), 5.31 (d, 1 H, J B1 Hz, H-1b), 7.10ꢃ
/
1:10 tolueneꢃ
/
/EtOAc): Rf 0.27;
L
/
/
/
ꢀ
/
/
/
/
/
/
/
/
/2.30
/
/
/3.54 (m, 2 H, H-3a, H-
7.42 (m, 42 H, ArH). Anal. Calcd for C76H78O12
(1183.5): C, 77.10; H, 6.64. Found: C, 77.06; H, 6.73.
ꢁ
/
/3.78
/
3.84 (m, 1 H, H-3b), 3.87ꢃ
4.07, (m, 2 H, H-1a,
4.25 (m, 1
/
/
/
/
3.26. 3,4,5,6-Tetra-O-benzyl-2-O-(2,3,4,6-tetra-O-
L
/
/
/5.20
benzyl-a-
35]
D
-mannopyranosyl)-(10
/2)-
-myo-inositol [(L)-
/
/7.42
(m, 40 H, ArH). MALDIMSꢀ (matrix ATT, water):
[Mꢀ
(matrix NBOHꢂ
1684. Found: m/z 1684.
/
H]ꢀ, m/z 1636.2. Found: m/z 1635.8. FABMSꢂ
NaI, CHCl3): [(MꢀNaꢂ)ꢂNa]ꢂ, m/z
A soln of (
tolueneꢃwater (3 mL), was cooled to 0 8C and treated
with Ce(NH4)2(NO3)6 (6 g, 10.94 mmol). After 0.5 h at
L)-34 (2.6 g, 2.20 mmol), in 60:3:4 MeCNꢃ
/
/
/
/

2568
A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ2569
/
(d) Chatterjee, D.; Khoo, K.-H. Glycobiology 1998, 8 (2),
113ꢃ120.
2. (a) Brennan, P. J.; Ballou, C. E. J. Biol. Chem. 1967, 242,
3046ꢃ3056;
3.28. Triethylammonium-[2-O-(a-D-mannopyranosyl)-l-
myo-inosit-1-yl]-[(2R)-2,3-bis(myristoyloxy)propyl]-
phosphate [( )-1b]
/
L
/
(b) Besra, G. S.; Morehouse, C. B.; Rittner, C. M.;
Waechter, C. J.; Brennan, P. J. Am. Soc. Biochem. Mol.
A vigorously stirred mixture of (
L
)-36 (394 mg, 0.24
water (5 mL) and
mmol), 7.5:7.5:1 CH2Cl2ꢃMeOHꢃ
/
/
Biol. 1997, 272, 18460ꢃ18466.
/
Pearlman’s catalyst (0.2 equiv) was degassed under
diminished pressure and saturated with H2 (H2-filled
balloon) three times. The suspension was stirred at rt
overnight, filtered over celite and washed with 7.5:7.5:1
3. Theler, J. -M.; Brennan, P. J.; Nasir-ud-Din; Ilangumaran,
S.; Arni, S.; Poincelet, M.; Hoessli, D. C. J. Immunol.
1995, 155, 1334ꢃ1342.
/
4. Stadelmaier, A. Diplomarbeit, Universitat Konstanz,
¨
1999.
5. Stadelmaier, A. Dissertation, Universitat Konstanz, 2003.
CH2Cl2ꢃ
/
MeOHꢃ
/
water (2 mL). The filtrate was diluted
with water, treated with Et3N and further removal of the
¨
6. (a) Stepanov, A. E.; Shvets, V. I.; Evstigneeva, R. P. Zh.
solvents by lyophilization afforded (
L
)-1b (162 mg, 74%)
as a white solid; 31P NMR (242.9 MHz, Me2SO-d6): d
Obshch. Kim. 1977, 47, 1653ꢃ
(b) Zamyatina, A. Y.; Shvets, V. I. Chem. Phys. Lipids
1995, 76, 225ꢃ240;
(c) Elie, C. J. J.; Dreef, C. E.; Verduyn, R.; Van der Marel,
G. A.; Van Boom, J. H. Tetrahedron 1989, 45, 3477ꢃ
/1656;
1
0.963 (s, 1P); H NMR (600 MHz, Me2SO-d6): d 0.76ꢃ
/
/
0.91 (t, 6 H, Me), 1.0ꢃ
1.41ꢃ1.57 (m, 4 H, COCH2CH2R), 2.15ꢃ
COCH2CH2R), 2.85ꢃ2.95 (dd, 1 H, H-5a), 2.96ꢃ
(m, 6 H, HN(CH2ÃCH3)3), 3.22 (dd, 1 H, H-4b), 3.23
/
1.40 (m, 49 H, (CH2)n, MeEt N),
3
/
/2.32 (m, 4 H,
/
/
/
3.15
3486.
7. (a) Elie, C. J. J.; Verduyn, R.; Dreef, C. E.; Van der Marel,
G. A.; Van Boom, J. H. J. Carbohydr. Chem. 1992, 11,
/
(m, 1 H, H-6b), 3.24 (m, 1 H, H-3a), 3.34, (dd, 1 H, H-
4a), 3.45 (dd, 1 H, H-3b), 3.46 (dd, 1 H, H-6a), 3.61 (dd,
1 H, H-1), 3.64 (dd, 1 H, H-2b), 3.72 (m, 1 H, H-6b),
3.76 (m, 1 H, H-1), 3.9 (m, 1 H, H-1), 4.00 (dd, 1 H, H-
2a), 4.06 (m, 1 H, H-3), 4.08 (ddd, 1 H, H-5b), 4.28 (m, 1
H, H-3), 4.95 (d, 1 H, H-1b), 5.09 (m, 1 H, H-2); 13C
715ꢃ
(b) Watanabe, Y.; Yamamoto, T.; Ozaki, S. J. Org. Chem.
1996, 61, 14ꢃ15;
(c) Watanabe, Y.; Yamamoto, T.; Okazaki, T. Tetrahe-
dron 1997, 53, 903ꢃ918.
8. (a) Massy, D. J. R.; Wyss, P. Helv. Chim. Acta 1990, 73,
1037ꢃ1057;
(b) Mayer, T. G.; Schmidt, R. R. Liebigs Ann. Recueil
1997, 859ꢃ863;
/
739;
/
/
NMR (150.9 MHz, Me2SO-d6): d 8.5 (3 C, MeEt N),
3
13.87 (2 C, Me), 22.04/28.42ꢃ29.03/31.26 (CH2)n) 24.36/
/
/
24.47 (2 C, COCH2CH2R), 33.34/33.57 (2 C,
COCH2CH2R), 45.1 (3 C, CH2CH3Et N), 62.04 (C-3?),
/
3
(c) Pekari, K.; Schmidt, R. R. In Lipases and Lipids:
Structure, Function and Biotechnological Applications;
Kokotos, G.; Constantinou-Kokotou, V., Eds. Recent
results in glycosyl phosphatidyl inositol (GPI) anchor
synthesis; Crete University Press: Heraklion, 2000; pp
62.55 (C-1?), 62.6 (C-6b), 68.53 (C-4b), 70.05 (C-2b),
70.24 (C-2?), 70.51 (C-6a), 71.65 (C-3a), 71.95 (C-3b),
72.16 (C-4a), 72.28 (C-5b), 73.85 (C-1a), 75.21 (C-5a),
76.97 (C-2a), 100.2 (C-1b), 172.25/172.51 (2C, COR).
FABMSꢀ (matrix 1:1:1 Me2SOꢃ
/
glycerolꢃNBOH):
/
233ꢃ
9. Pekari, K.; Tailler, D.; Weingart, R.; Schmidt, R. R. J.
Org. Chem. 2001, 66, 7432ꢃ7442.
10. Maki, T.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett.
1998, 39, 5601ꢃ5604.
11. (a) Mayer, T. G.; Kratzer, B.; Schmidt, R. R. Angew.
Chem. 1994, 106, 2289ꢃ2293; Angew. Chem. Int. Ed. Engl.
1994, 33, 2177ꢃ2181.;
(b) Kartha, K. P. R.; Jennings, H. J. J. Carbohydr. Chem.
1990, 777ꢃ781;
(c) Bore´n, H. B.; Ekborg, G.; Ekland, K. Acta Chem.
Scand. 1973, 27, 2639ꢃ2644;
(d) Kaur, K. J.; Hindsgaul, O. Carbohydr. Res. 1992, 226,
219ꢃ231;
(e) Ponpipom, M. M. Carbohydr. Res. 1977, 59, 311ꢃ
/
252.
[Mꢀ
/
H]ꢀ, m/z 915.7. Found: m/z 915, [Mꢀ
/
C14H27O]ꢀ, m/z 705.3. Found: 705.
/
/
Acknowledgements
/
/
This work was supported by the Deutsche Forschungs-
gemeinschaft, 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.
/
/
/
/
317;
(f) Yamazaki, F.; Kitajima, T.; Nukada, T.; Ito, Y.;
References
Ogawa, T. Carbohydr. Res. 1990, 201, 31ꢃ
12. Schmidt, R. R.; Toepfer, A. Tetrahedron Lett. 1991, 32,
3353ꢃ3356.
13. (a) Bock, K.; Pederson, C. J. Chem. Soc. Perkin Trans. II
1974, 293ꢃ297;
(b) Yonezawa, T.; Morishma, I. J. Mol. Spectrosc. 1968,
27, 210ꢃ217;
/
50.
1. (a) Draper, P. In The Biology of Mycobacteria; Ratledge,
C.; Standford, J., Eds. The Anatomy of Mycobacteria; Vol.
/
2; Academic Press: London, 1982; pp 9ꢃ
(b) Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995,
64, 887ꢃ888;
(c) Chatterjee, D.; Khoo, K.-H. Cell. Mol. Life Sci. 2001,
58, 2018ꢃ2042;
/52;
/
/
/
/

A. Stadelmaier, R.R. Schmidt / Carbohydrate Research 338 (2003) 2557ꢃ
/2569
2569
(c) Albrand, J. P.; Cogne, A.; Gagnaire, D.; Robert, J. B.
Tetrahedron 1971, 27, 2453ꢃ2461.
14. (a) Mayer, T. G.; Weingart, R.; Munstermann, F.;
¨
(b) Billington, D. C.; Baker, R.; Kulagowski, J. J.; Mawer,
I. M. J. Chem. Soc., Chem. Commun. 1987, 314ꢃ316.
17. (a) Aguilo´, A.; Mart´ın-Lomas, M.; Penade´s, S. Tetrahe-
dron Lett. 1992, 33, 401ꢃ404;
/
/
Kawada, T.; Teymuras, T.; Schmidt, R. R. Eur. J. Org.
/
Chem. 1999, 10, 2563ꢃ
(b) Beaucage, S. L.; Caruthers, M. H. Tetrahedron Lett.
1981, 22, 1859ꢃ1862;
(c) Beaucage, S. L.; Iyer, R. P. Tetrahedron 1993, 49,
10441ꢃ10488;
(d) Bannwarth, W.; Trzeciak, A. HeIv. Chim. Acta 1987,
70, 175ꢃ186.
15. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997,
62, 8932ꢃ8936.
/2572;
(b) Anderson, L. The Carbohydrates, Chemistry and
Biochemistry, 2nd ed.; Pigman, W., Horton, D., Eds.;
/
Academic Press, New York, 1972, Vol. 1A, pp. 519ꢃ
(c) Plouvier, V. Bull. Soc. Chim. Biol. 1963, 45, 1079ꢃ
1118;
/579.;
/
/
(d) Angyal, S. J.; Bender, V. J. Chem. Soc. 1961, 4718ꢃ
/
/
4720;
(e) Post, G. G.; Anderson, L. J. Am. Chem. Soc. 1962, 84,
/
471ꢃ
(f) Post, G. G.; Anderson, L. J. Am. Chem. Soc. 1962, 84,
478ꢃ480.
/
478;
16. (a) Vacca, J. P.; deSolms, S. J.; Huff, J. R.; Billington, D.
C.; Baker, R.; Kulagowski, J. J.; Mawer, I. M. Tetrahe-
/
dron 1989, 45, 5679ꢃ5702;
/