Asymmetric allylboration and ring closing alkene metathesis: A novel strategy for the synthesis of glycosphingolipids

Article abstract of DOI:10.1021/jo000690p

A novel strategy for the synthesis of D,L-glucosylceramide 1, a member of the glycosphingolipid class of natural products is described. Reagent-controlled asymmetric Brown allylboration gave excellent stereochemical control in the construction of adjacent stereocenters in the sphingoid base portion of the molecule. The trans-configured double bond was obtained as a single geometrical isomer by use of silicon-tethered olefin metathesis employing the Schrock carbene [(CF₃)₂MeCO]₂Mo-(= CHCMe₂Ph)(= NC₆H₃-2,6-i-Pr₂) and in situ PhLi-induced ring-opening of the intermediate 5,6-dihydro-2H-1,2-oxasiline followed by protodesilylation with TBAF in DMSO. The synthesis was completed by long chain amide formation and global deprotection.

Full text of DOI:10.1021/jo000690p

6508
J . Org. Chem. 2000, 65, 6508-6514
Asym m etr ic Allylbor a tion a n d Rin g Closin g Alk en e Meta th esis: A
Novel Str a tegy for th e Syn th esis of Glycosp h in golip id s
Anthony G. M. Barrett,* J ennifer C. Beall, D. Christopher Braddock, Kevin Flack,
Vernon C. Gibson,* and Matthew M. Salter
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, SW7 2AY, UK
agmb@ic.ac.uk
Received May 5, 2000
A novel strategy for the synthesis of D,L-glucosylceramide 1, a member of the glycosphingolipid
class of natural products is described. Reagent-controlled asymmetric Brown allylboration gave
excellent stereochemical control in the construction of adjacent stereocenters in the sphingoid base
portion of the molecule. The trans-configured double bond was obtained as a single geometrical
isomer by use of silicon-tethered olefin metathesis employing the Schrock carbene [(CF3)2MeCO]2Mo-
(dCHCMe2Ph)(dNC6H3-2,6-i-Pr2) and in situ PhLi-induced ring-opening of the intermediate 5,6-
dihydro-2H-1,2-oxasiline followed by protodesilylation with TBAF in DMSO. The synthesis was
completed by long chain amide formation and global deprotection.
In tr od u ction
However, the incorporation of the sphingoid trans-disub-
stituted double bond remains nontrivial, as its installa-
tion does not typically proceed with high trans selectivity
and the starting materials require prior derivatization.6a,7
We envisioned that the trans-disubstituted double bond
could be installed via alkene metathesis using the
molybdenum metathesis catalyst, 2, developed by Schrock,8
or the ruthenium-based catalyst 3 developed by Grubbs.9
We have recently published two efficient routes to trans-
disubstituted homoallylic alcohols employing the tandem
use of Brown’s asymmetric allylboration technology and
alkene metathesis.10,11 We now report the extension of
Glycosphingolipids are central components of a wide
variety of tissues and organs in biological systems.1 They
serve as structural support and shape determinants of
the cell membrane and, via protein binding, act as
mediators of biological events such as activation, cell
agglutination, intracellular communication, cell death,
and cell growth. Such cellular recognition events are
common to cancer, allergy, viral infection, inflammation,
and autoimmune disease.2,3 Each of these events is
executed by a specific glycosphingolipid such as a gan-
glioside, tumor antigen, or viral receptor.3,4 This exquisite
degree of specificity suggests that glycosphingolipid
analogues could be suitable candidates for new drugs,3
thus necessitating efficient synthetic routes to pure
glycosphingolipids and their derivatives.
The key synthetic concerns in synthesis of glycosphin-
golipids are the stereo- and regioselective construction
of the polysaccharide moiety (glycosyl donor) via O-
glycosylation, stereoselective construction of the sphin-
goid base (glycosyl acceptor), in which the asymmetric
constructions of the anti-amino alcohol and trans-olefin
units are of chief importance and the stereoselective and
regioselective coupling of the glycosyl acceptor to the
glycosyl donor. Excellent reviews address these concerns,
especially stereoselective O-glycosylations and anti-amino
alcohol construction related to sphingosine synthesis.5,6
this work to the synthesis of D,L-glucosylceramide, 1,12
a
simple member of the glycosphingolipid class of com-
pounds.
Resu lts a n d Discu ssion
Alkene metathesis has been shown to be amenable to
both cross metathesis13 and ring closing metathesis14 in
(7) For leading references, see (a) Nicolaou, K. C.; Caulfield, T.;
Kataoka, H.; Kumazawa, T. J . Am. Chem. Soc. 1988, 110, 7910. (b)
Schmidt, R. R.; Zimmermann, P. Tetrahedron Lett. 1986, 27, 481. For
comprehensive reviews, see (c) Handbook Of Lipid Research; Kanfer,
J . N., Hakomori, S., Eds.; Plenum: New York, 1983; Vol. 3, p 136. (d)
Byun, H.-S.; Bittman, R. In Phospholipids Handbook; Cevc, G., Ed.;
Dekker: New York, 1993; p 97. For examples of syntheses of glyco-
sphingolipids containing ceramide analogues and substituted unsatur-
ated fatty acids, see (e) Mori, K.; Nishio, H. Liebigs Ann. Chem. 1991,
253. (f) Yoshino, T.; Watanabe, K.; Hakomori, S. Biochemistry 1982,
21, 928.
(1) (a) Gigg, J .; Gigg, R. Topics Curr. Chem. 1990, 154, 79. (b)
Morrow, M. R.; Singh, D.; Lu, D.; Grant, C. W. M. Biophys. J . 1995,
68, l79. (c) Lasky, L. A. Science 1992, 258, 964.
(8) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .; DiMare,
M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875.
(2) Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500.
(3) Karlsson, K.-A. Trends Pharm. Sci. 1991, 12, 265.
(4) (a) Kanemitsu, K.; Sweeley, C. C. Glycoconjugate J . 1986, 3, 143.
(b) Lemieux, R. U. Chem. Soc. Rev. 1978, 7, 423.
(5) (a) Schmidt, R. R.; Klager, R. Angew. Chem., Int. Ed. Engl. 1985,
24, 65. (b) Gal, A. E.; Pentchev, P. G.; Massey, J . M.; Brady, R. O.
Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 3083.
(6) (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503. (b)
Schmidt, R. R. In Stereochemistry of Organic and Bioorganic Trans-
formations; Bartmann, W., Sharpless, K. B., Eds.; VCH: Weinhelm,
1987; p 169. (c) Schmidt, R. R. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Winterfeldt, E., Eds. Pergamon Press: Oxford,
1991; Vol. 1, p 33.
(9) (a) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100. (b) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(10) Barrett, A. G. M.; Beall, J . C.; Gibson, V. C.; Giles, M. R.;
Walker, G. L. P. Chem. Commun. 1996, 2229.
(11) Ahmed, M.; Barrett, A. G. M.; Beall, J . C.; Braddock, D. C.;
Flack, K.; Gibson, V. C.; Procopiou, P. A.; Salter, M. M. Tetrahedron
1999, 55, 3219.
(12) a) Numata, M.; Sugimoto, M.; Shibayama, S.; Ogawa, T.
Carbohydrate Res. 1988, 174, 73. (b) Zimmermann, P.; Bommer, R.;
Ba¨r, T.; Schmidt, R. R. J . Carbohyd. Chem. 1988, 7, 435. (c) Murakami,
T.; Minamikawa, H.; Hato, M. J . Chem. Soc., Perkin Trans. 1 1992,
1875.
10.1021/jo000690p CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Synthesis of Glycosphingolipids
J . Org. Chem., Vol. 65, No. 20, 2000 6509
Ta ble 1. Cr oss-Meta th esis of Su bstitu ted Styr en es w ith
Allyl Glycosid e 4a
no. equiv of
styrene
entry
X
product
time (h)
yield (%)b
1
2
3
4
H
Me
Cl
5a
5b
5c
5d
10
10
10
2
2
2
2
3
72
77
50
72
OMe
a
b
All reactions performed in CH2Cl2. Isolated yield after chro-
matography.
sugar systems. However, when we started our work on
glycosphingolipids, the use of alkene cross-metathesis on
carbohydrate substrates was unknown. Thus we initially
sought to examine allyl 2,3,4,6-tetra-O-tert-butyldimeth-
ylsilyl-â-D-glucose 4 as a suitable model system. Gluco-
side 4 was readily prepared from allyl â-D-glucopyrano-
side15 by reaction with tert-butyldimethylsilyl trifluoro-
methanesulfonate, in the presence of 2,6-lutidine. To
optimize the cross-metathesis selectivities in this pre-
liminary set of experiments, styrene was chosen as the
other metathetic partner, as it undergoes self-metathesis
only very slowly.16 Treatment of glucopyranoside 4 with
styrene in the presence of carbene 2 (1 mol %) provided
cinnamyl glucopyranoside 5a , exclusively as the trans
isomer, in 72% yield (Table 1). Cross metathesis of
glucopyranoside 4 with 4-substituted styrenes provided
adducts 5b-d , demonstrating the generality of the
method. The variation in chemical yield, and thus the
cross-metathesis selectivity of the reaction, reflects the
degree of styrene activation, as previously observed.16 In
all cases only the trans cinnamyl-glucopyranoside was
observed. In the case of 4-methoxystyrene (entry 4), the
yield of the corresponding product 5d was optimized by
conducting the cross-metathesis in the presence of only
2 equiv of 4-methoxystyrene. With these results in hand,
we felt confident to embark upon our synthesis of
ceramide 1.
Sch em e 1a
a
Reagents and conditions: (a) (i) O3, EtOH, Sudan Red, -78
°C, 10 min; (ii) Me2S, EtOH (85%); (b) (i) (Z)-(+)-Ipc2BCH2-
CHdCHOCH2OCH3, THF, -85 °C, 18 h; (ii) MeOH, NaBO3‚xH2O
(65%); (c) (i) Tf2O, pyridine, CH2Cl2, -10 °C, 30 min; (ii) NaN3,
DMF, -10 °C - 25 °C, 12 h (78%); (d) PhCH2Br, NaH, THF-DMF,
25 °C, 18 h (47%); (e) PPh3, H2O (1.5 equiv), THF, 25 °C, 5 d (75%)
or SmI2, THF-EtOH, 25 °C, 2 h (55-65%); (f) CH3(CH2)16COCl,
Et3N, CH2Cl2, 0 °C, 3 h (88%).
Ozonolysis of alkene 4 in ethanol solution afforded
aldehyde 6 in excellent yield (Scheme 1).17 Brown asym-
metric allylboration by slow addition of a THF solution
of aldehyde 6 to a cold (-85 °C) THF solution of [(Z)-γ-
(methoxoymethoxy)allyl]diisopinocampheylborane18 fol-
lowed by oxidative workup provided the expected MOM
protected syn-diol 7 as a single diastereomer in 65%
chemical yield after chromatography. To install the anti-
amino alcohol subunit of ceramide 11, the homoallylic
alcohol present in alcohol 7 required activation then
substitution by ammonia or an equivalent nucleophile.
Activation of alcohol 7 with trifluoromethanesulfonic
anhydride in the presence of pyridine, followed by direct
treatment with sodium azide in DMF,19 gave the anti
azido-ether 8 in 78% yield. Benzyl ether 9 was also
prepared from alcohol 7 for use in cross-metathesis
experiments. Subsequent reduction of azide 8 could be
accomplished with either triphenylphosphine20 or sa-
marium(II) iodide21 to give amine 10 which was N-
acylated using stearoyl chloride in the presence of
triethylamine to provide amide 11 in excellent yield.
(13) (a) Feng, J .; Schuster, M.; Blechert, S. Synlett 1997, 129. (b)
Blanco, O. M.; Castedo, L. Synlett 1999, 557.
(14) (a) Fu¨rstner, A.; Mu¨ller, T. J . Am. Chem. Soc. 1999, 121, 7814.
(b) Lee, W.-W.; Chang, S. Tetrahedron: Asymmetry 1999, 10, 4473.
(15) Allyl â-D-glucopyranoside was prepared according to known
methodologies from 2,3,4,6-tetra-O-acetyl-R-D-glucopyranosyl bromide
and allyl alcohol, followed by Zemplen methanolysis. See (a) Tietze,
L. F.; Eicher, T. H. Reactions and Syntheses in the Organic Chemistry
Laboratory; University Science Books: Mill Valley, CA, 1989; p 494.
(b) Rodriguez, E. B.; Stick, R. V. Aust. J . Chem. 1990, 43, 665. (c)
Schroeder, L. R.; Green, J . W. J . Chem. Soc. C 1966, 530.
(16) (a) Crowe, W. E.; Zhang, Z. J . J . Am. Chem. Soc. 1993, 115,
10998. (b) Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J . Tetrahedron
Lett. 1996, 37, 2117.
(17) The neat alcoholic solvent rendered the expected blue ozone
saturation endpoint difficult to observe. To avoid overoxidation of the
product, Sudan Red 7B was concurrently utilized as an indicator.
See: Veysoglu, T.; Mitscher, L. A.; Swayze, J . K. Synthesis 1980, 807.
(18) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 293.
(19) Zimmermann, P.; Schmidt, R. R. Liebigs Ann. Chem. 1988, 663.
(20) (a) Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr.
1985, 5, 815. (b) Kratzer, B.; Mayer, T. G.; Schmidt, R. R. Tetrahedron
Lett. 1993, 34, 6881.
(21) Goulaouic-Dubois, C.; Hesse, M. Tetrahedron Lett. 1995, 36,
7427.

6510 J . Org. Chem., Vol. 65, No. 20, 2000
Barrett et al.
subsequent step treated with phenyllithium25 to give
alkenylsilane 17, but higher yields were obtained with
the in situ procedure. As anticipated due to the cyclic
nature of the intermediate ring closing metathesis reac-
tion product, alkenylsilane 17 was generated exclusively
as the (Z)-isomer. The desired anti-amino alcohol entity
was installed via the Mitsunobu reaction using diphen-
ylphosphoryl azide26 (DPPA), generating azide 18 in
essentially quantitative yield. This procedure was found
to be a great improvement over activation with trifluo-
romethanesulfonic anhydride and in situ displacement
with sodium azide in DMF as used previously for the
conversion of alcohol 7 into azide 8. Azide 18 was treated
with tetrabutylammonium fluoride in DMSO in order to
bring about both the protodesilylation of the alkenyl-
(dimethyl)phenylsilane27 and silyl ether deprotection. In
situ reprotection of the â-glucopyranoside moiety using
acetic anhydride generated the peracetylated azide 19
in excellent yield. We were pleased to observe that azide
19 was formed as the (E)-isomer only, thereby demon-
strating that the phenyldimethylsilane moiety was cleaved
with complete retention of the double bond geometry.
Azide 19 was reduced to the corresponding amine, using
triphenylphosphine and water. Subsequent in situ N-
acylation, this time using palmitoyl chloride in the
presence of triethylamine provided amide 20 in excellent
yield. Saponification using 5% KOH in methanol and
acidification using 1% HCl in methanol gave glucosyl-
ceramide, 1, in excellent yield.28
Sch em e 2a
a
Reagents and conditions: (a) (i) 9-Br-BBN, Et2O, -78 °C; (ii)
AcOH; (iii) H2O2, NaOH, H2O (86%); (b) (i) t-BuLi, Et2O, -78 °C;
(ii) Me2SiCl2, Et2O, -78 °C (67%).
We initially sought to prepare ceramide 1 via alkene
cross metathesis between 1-pentadecene and amide 11
with catalysis by the Schrock carbene 2. To ascertain the
cross-metathesis selectivities, styrene was again chosen
as the reaction partner. However, to our dismay at-
tempted cross metathesis between azide 8, ether 9, or
amide 11 with styrene or 1-pentadececene using catalytic
or stoichiometric quantities of carbenes 2 or 3 at 25 °C
to 60 °C in benzene-d6, dichloromethane, or toluene
solution were all unsuccessful. It was soon evident that
an alternative protocol was necessary. We next consid-
ered whether recently published work on silicon-tethered
ring closing metathesis by our group11 and others22 could
be employed to circumvent this problem. Unlike cross
metathesis13a,16b where both E and Z isomers can form,
our silicon tether ring-closing metathesis strategy11 gives
products with E double bond configuration exclusively
after the ring closing metathesis event and silicon tether
removal. The required silicon tether was synthesized
from 1-pentadecyne via regioselective bromoboration
using B-bromo-9-borabicyclo[3.3.1]nonane followed by in
situ protodeboration23 to give 2-bromo-1-pentadecene, 12
(Scheme 2). Conversion to chloro(dimethyl)(1-pentadecen-
2-yl)silane, 13, was brought about by bromine-lithium
exchange using tert-butyllithium followed by condensa-
tion with dichloro(dimethyl)silane.
Alcohol 7 was found to undergo only slow silylation
with silyl chloride 13 in the presence of amine bases. In
consequence, the corresponding silyl triflate 14 was
generated in situ using silver(I) triflate24 and added
immediately to a premixed solution of alcohol 7 and 2,6-
lutidine resulting in an excellent yield of the desired
diene 15 (Scheme 3). Attempted ring closing metathesis
of diene 15 using the Grubbs catalyst 3 was unsuccessful;
such low reactivity has been observed for similar homo-
allylic vinyl siladienes.11 Treatment of diene 15 with the
molybdenum carbene 2 was then examined, initially in
dichloromethane solution. Much to our delight, ring
closing metathesis did occur to give the desired cyclic
ether 16, although significant quantities of an unidenti-
Con clu sion s
We have demonstrated a concise and high-yielding
synthesis of D,L-glucosylceramide, 1,29 a member of the
glycosphingolipid class of natural products. Excellent
control of both stereochemistry and alkene geometry in
the sphingoid base portion of the molecule have been
achieved using our previously reported allylboration-ring
closing metathesis-ring opening protocol.11 This route has
the potential to be extremely flexible as variation in the
amide or hydrocarbon chain areas of the molecule should
be easily controlled late in the side chain assembly.
Exp er im en ta l Section
Gen er a l. All reactions, except those involving alkene me-
tathesis catalysts 2 or 3, were run in oven-dried glassware
under a nitrogen atmosphere. Reactions involving alkene
metathesis catalysts 2 or 3 were performed in a glovebox under
a nitrogen atmosphere or using a Schlenk line. THF and Et2O
were distilled from Na/Ph2CO. CH2Cl2, DMF, pyridine, and
Et3N were distilled from CaH2. For reactions involving alkene
metathesis catalysts 2 or 3 solvents were degassed prior to
use by the freeze-pump-thaw method. n-BuLi, sec-BuLi, and
tert-BuLi were titrated against diphenylacetic acid or by acid-
base titration. Acid chlorides and dichloro(dimethyl)silane
1
fied side product were also observed by H NMR spec-
troscopy. In contrast, we found that upon treatment of
diene 15 with carbene 2 in heptane at 45 °C, ring closing
metathesis proceeded essentially quantitatively (>95%
as assessed by 1H NMR) to give the siloxacycle 16 which
was not isolated but directly treated in situ with phen-
yllithium to generate alkenylsilane 17 in excellent yield
over two steps. Siloxacycle 16 could be isolated and in a
(25) (a) Stork, G.; Hudrlik, P. F. J . Am. Chem. Soc. 1968, 90, 4464.
(b) House, H. O.; Gall, M.; Olmstead, H. D. J . Org. Chem. 1971, 36,
2361.
(26) (a) Anelli, P. L.; Lattuada, L.; Uggeri, F. Synth. Commun. 1998,
28, 109. (b) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977. (c) Mitsunobu, O. Synthesis, 1981, 1.
(27) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.;
Tetrahedron, 1985, 41, 3257.
(22) (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757.
(b) Cassidy, J . H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411. (c)
Cossy, J .; Meyer, C. Tetrahedron Lett. 1997, 38, 7861. (d) Hoye, H. R.;
Promo, M. A. Tetrahedron Lett. 1999, 40, 1429. (e) Evans P. A.; Murthy,
V. S. J . Org. Chem. 1998, 63, 6768.
(28) Shibuya, H.; Kurosu, M.; Minagawa, K.; Katayma, S.; Kitagawa,
I. Chem. Pharm. Bull. 1993, 41, 1534.
(23) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731.
(24) Williams, R. M.; Anderson, O. P.; Armstrong, R. W.; J osey, J .;
Meyers, H.; Eriksson, C. J . Am. Chem. Soc. 1982, 104, 6092.
(29) We were unable to obtain an authentic sample of D,L-glucosyl-
ceramide in order to unequivocally confirm the identity of our material;
however, all the characterizing data is consistent with the published
data (ref 12).

Synthesis of Glycosphingolipids
J . Org. Chem., Vol. 65, No. 20, 2000 6511
Sch em e 3a
a
Reagents and conditions: (a) AgOTf, CH2Cl2; (b) 2,6-lutidine, 7, CH2Cl2, 0-25 °C (79%); (c) 2, C7H16, 45 °C; (d) PhLi, THF, 0 °C
(83%); (e) DEAD, PPh3, PH2P(O)N3, THF, 45 °C (100%); (f) Bu4NF, DMSO, 60 °C; (ii) Ac2O, DMAP, pyridine (80%); (g) (i) PPh3, H2O,
THF, 45 °C; (ii) ClCO(CH2)14CH3, Et3N, CH2Cl2 (90%); (h) (i) 5% KOH in MeOH; Dowex-50W; (ii) 1% HCl in MeOH, 45 °C; Ag2CO3 (64%).
were distilled before use. All other reagents were purchased
from commercial sources and used without further purification.
Analytical thin-layer chromatography (TLC) was performed
on precoated glass-backed plates (Merck Kieselgel 60 F254) and
visualized with ultraviolet light (254 nm) or potassium per-
manganate as appropriate. Column chromatography was
performed under medium pressure using Merck Kieselgel 60
(230-400) mesh. Molybdenum carbene 2,8 ruthenium carbene
3,9 allyl â-D-glucoside,15 and allyl methoxymethyl ether30 were
synthesized according to literature procedures with minor
modifications where necessary.
4.75 (1H, d, J ) 6.8 Hz), 4.48 (1H, dd, J ) 5.7, 12.4 Hz), 4.11
(1H, dd, J ) 6.6, 12.4 Hz), 3.88 (1H, d, J ) 2.4 Hz), 3.79-3.68
(4H, m), 3.58 (1H, d, J ) 6.7 Hz), 0.84-0.80 (36H, m), 0.05 to
-0.01 (24H, m); 13C NMR (75 MHz, CDCl3) δ 137.0, 132.4,
128.5, 127.5, 126.5, 125.8, 100.8, 82.5, 79.2, 77.8, 70.1, 69.6,
64.1, 26.0, 25.9, 25.8, 18.3, 18.1, 17.8, -4.0, -4.4, -4.5, -4.7,
-4.9, -5.3; MS (CI+, NH3), m/z 770 (M + NH4)+. Anal. Calcd
for C39H76O6Si4: C, 62.18; H, 10.17. Found: C, 62.37; H, 10.17.
tr a n s-3-(4-Met h ylp h en yl)-2-p r op en yl 2,3,4,6-t et r a -O-
ter t-bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (5b). Color-
less oil (0.141 g, 77%): Rf (1:499 Et2O:hexane) 0.25; [R]25D -25
1-O-Allyl 2,3,4,6-t et r a -O-ter t-b u t yld im et h ylsilyl-â-D-
glu cop yr a n osid e (4). To a cooled (0 °C) mixture of â-D-allyl
glucopyranoside (2.55 g, 12 mmol) and 2,6-lutidine (14.7 g, 137
mmol) in CH2Cl2 (15 mL) was added t-BuMe2SiOTf (24 g, 91
mmol). The reaction mixture was stirred for 12 h at 40 °C,
allowed to cool, diluted with CH2Cl2 (50 mL), and washed with
aqueous CuSO4 (50% w/v). The organic phase was dried (Na2-
SO4), concentrated in vacuo, and chromatographed (1:49 Et2O:
hexanes) to give 4 (7.1 g, 93%) as a colorless oil: Rf (1:24 Et2O:
1
(c 1.2, CHCl3); IR (thin film) 3070, 3022 cm-1; H NMR (300
MHz, CDCl3) δ 7.17 (2H, d, J ) 8.0 Hz), 7.02 (2H, d, J ) 8.0
Hz), 6.48 (1H, d, J ) 15.9 Hz), 6.16 (1H, dt, J ) 15.9, 6.1 Hz),
4.71 (1H, d, J ) 6.7 Hz), 4.46-4.39 (1H, m), 4.08-4.02 (1H,
m), 3.84 (1H, d, J ) 2.6 Hz), 3.72-3.63 (4H, m), 3.53 (1H, d,
J ) 6.7 Hz), 2.24 (3H, s), 0.80-0.76 (36H, m), 0.00 to -0.06
(24H, m); 13C NMR (75 MHz, CDCl3) δ 137.3, 134.2, 132.4,
129.2, 126.4, 124.8, 100.8, 82.4, 79.2, 77.8, 70.1, 69.7, 64.1, 26.0,
26.0, 25.9, 25.8, 21.2, 18.3, 18.1, 18.0, 17.8, -4.0, -4.4, -4.5,
-4.7, -5.0, -5.3; MS (CI+, NH3) m/z 784 (M + NH4)+. Anal.
Calcd for C40H78O6Si4: C, 62.61; H, 10.25. Found: C, 62.31;
H, 10.28.
hexanes) 0.5; [R]25 +17 (c 1.1, CHCl3); IR (thin film) 3082,
D
3017, 1640 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.99-5.90 (1H,
m), 5.27 (1H, dq, J ) 17.2, 1.6 Hz), 5.15 (1H, dq, J ) 10.4, 1.5
Hz), 4.74 (1H, d, J ) 6.8 Hz), 4.38 (1H, dt, J ) 12.3, 5.3, 1.4
Hz), 3.98 (1H, ddt, J ) 12.4, 6.3, 1.3 Hz), 3.93 (1H, d, J ) 2.6
Hz), 3.82-3.71 (4H, m), 3.60 (1H, d, J ) 6.6 Hz), 0.89-0.86
(36H, m), 0.09-0.04 (24H, m); 13C NMR (100 MHz, CDCl3) δ
134.4, 116.9, 100.9, 82.4, 79.1, 77.7, 70.1, 70.0, 64.1, 26.0, 25.9,
25.9, 25.8, 18.3, 18.0, 18.0, 17.8, -4.2, -4.4, -4.6, -4.8, -5.1,
-5.3. MS (CI+, NH3) m/z 694 (M + NH4)+. HRMS (CI+, NH3)
Calcd for C33H76NO6Si4 (M + NH4)+; 694.4750. Found; 694.4743.
Anal. Calcd for C33H72O6Si4: C, 58.52; H, 10.72. Found: C,
58.37; H, 10.70.
tr a n s-3-(4-Ch lor op h en yl)-2-p r op en yl 2,3,4,6-t et r a -O-
ter t-bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (5c). Color-
less oil (0.126 g, 50%): Rf (3:497 Et2O:hexane) 0.2. [R]25 -25
D
(c 1.4, CHCl3): IR (thin film) 3032 cm-1; H NMR (300 MHz,
1
CDCl3) δ 7.19-7.16 (4H, m), 6.47 (1H, d, J ) 16.0 Hz), 6.18
(1H, dt, J ) 15.9, 6.2 Hz), 4.70 (1H, d, J ) 6.8 Hz), 4.42 (1H,
ddd, J ) 1.4, 5.6, 12.7 Hz), 4.06 (1H, ddd, J ) 1.2, 6.5, 12.7
Hz), 3.84 (1H, d, J ) 2.5 Hz), 3.72-3.63 (4H, m), 3.53 (1H, d,
J ) 6.7 Hz), 0.80-0.76 (36H, m), 0.00 to -0.05 (24 H, m); 13
C
NMR (75 MHz, CDCl3) δ 135.8, 133.5, 131.4, 129.0, 128.0,
126.9, 101.2, 82.9, 79.5, 78.1, 70.4, 69.7, 64.4, 26.32, 26.30, 26.2,
18.7, 18.4, 18.2, -3.7, -4.0, -4.2, -4.4, -4.6, -4.9; MS (CI+,
NH3) m/z 804 (M + NH4)+. Anal. Calcd for C39H75ClO6Si4: C,
59.46; H, 9.60. Found: C, 59.37; H, 9.31.
Gen er a l P r oced u r e for th e Cr oss Meta th esis of 4 w ith
Styr en es F u r n ish in g Glu cop yr a n osid es 5a -d . To catalyst
2 in CH2Cl2 (1 mol %, 20 µL CH2Cl2) was added a solution of
the appropriate styrene (4.55 mmol) in CH2Cl2 (0.2 mL), and
after 15 min, glycoside 4 (149 mg, 0.022 mmol) in CH2Cl2 (0.2
mL) was added dropwise. After 2 h, the mixture was removed
from the glovebox, diluted with CH2Cl2, and filtered through
silica. The resultant light yellow solution was concentrated in
vacuo and the crude oil chromatographed.
tr a n s-3-(4-Meth oxyp h en yl)-2-p r op en yl 2,3,4,6-tetr a -O-
ter t-bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (5d ). Color-
less oil (45 mg, 72%): Rf (1:49 Et2O:hexane) 0.25; [R]27 -35
D
(c 1.1, CHCl3); IR (thin film) 3034, 1609 cm-1; H NMR (300
1
tr a n s-Cin n a m yl 2,3,4,6-tetr a -O-ter t-bu tyld im eth ylsilyl-
â-D-glu cop yr a n osid e (5a ). Colorless oil (0.113 g, 72%): Rf
(3:247 EtOAc:hexane) 0.25; [R]25D -27 (c 2.00, CHCl3); IR (thin
film) 3054 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.33-7.15 (5H,
m), 6.56 (1H, d, J ) 15.9 Hz), 6.25 (1H, dt, J ) 15.9, 5.8 Hz),
MHz, CDCl3) δ 7.25 (2H, d, J ) 8.7 Hz), 6.79 (2H, d, J ) 8.7
Hz), 6.49 (1H, d, J ) 15.9 Hz), 6.12 (1H, dt, J ) 15.9, 6.5 Hz),
4.75 (1H, d, J ) 6.8 Hz), 4.44 (1H, ddd, J ) 1.3, 5.9, 12.1 Hz),
4.08 (1H, ddd, J ) 1.0, 6.8, 12.1 Hz), 3.89 (1H, d, J ) 2.5 Hz),
3.78-3.68 (7H, m), 3.57 (1H, d, J ) 6.7 Hz), 0.84-0.80 (36H,
m), 0.04 to -0.03 (24H, m); 13C NMR (75 MHz, CDCl3) δ 159.6,
132.5, 130.2, 128.0, 124.0, 114.3, 101.1, 82.8, 79.6, 78.2, 70.5,
(30) Gras, J .-L.; Chang, Y.-Y. K. W.; Guerin, A. Synthesis 1985, 74.

6512 J . Org. Chem., Vol. 65, No. 20, 2000
Barrett et al.
70.1, 64.5, 55.6, 26.4, 26.3, 26.1, 18.7, 18.5, 18.4, 18.2, -3.6,
-4.0, -4.2, -4.4, -4.6, -4.9; MS (CI, NH3) m/z 800 (M +
NH4)+.
MHz, CDCl3) δ 133.3, 120.6, 102.3, 93.7, 82.1, 78.7, 77.5, 77.4,
70.1, 68.0, 65.2, 64.2, 55.6, 25.9, 25.8, 25.8, 18.3, 18.03, 18.0,
17.9, -4.2, -4.4, -4.4, -4.5, -4.7, -5.1, -5.2; MS (CI+, NH3)
m/z 823 (M + NH4)+. Anal. Calcd for C37H79N3O8Si4: C, 55.11;
H, 9.87; N, 5.21. Found: C, 55.14; H, 9.81; N, 5.13.
2-Oxoeth yl 2,3,4,6-tetr a -O-ter t-bu tyld im eth ylsilyl-â-D-
glu cop yr a n osid e (6). Ozone was bubbled through a solution
of glycoside 4 (1.56 g, 2.30 mmol) in EtOH (100 mL) and Sudan
Red (0.03 mol % in EtOH, 20µL) at -78 °C until the pink color
was discharged (ca. 5 min). Oxygen was bubbled through the
colorless solution to remove excess ozone (ca. 2 min), and Me2S
(2.5 mL) was added. The solution was allowed to warm to room
temperature, stirred for 4 h, evaporated, and chromato-
graphed, providing 6 (1.2 g, 85%) as a colorless oil: Rf (1:24
1-O-((2R,3S)-2-Am in o-3-m eth oxym eth oxy-4-p en ten -1-
yl) 2,3,4,6-Tet r a -O-ter t-b u t yld im et h ylsilyl-â-D-glu cop y-
r a n osid e (10). Azide 8 (0.98 g, 1.2 mmol) was added to SmI2
(25 mL, 0.1 M in THF) in degassed EtOH (2.4 mL) at room
temperature. The blue solution was stirred for 10 min at room
temperature before the color discharged. An additional portion
of SmI2 (25 mL, 0.1 M in THF) was added. The reaction was
quenched after 30 min by the addition of ice-cold, saturated
aqueous K2CO3 (2 mL), and the mixture was stirred at room
temperature for 3 h. The organic solvents were removed by
evaporation, and the residual aqueous layer was extracted
with EtOAc. The combined organic layers were washed with
brine, dried (Na2SO4), concentrated, and chromatographed (3:
17 EtOAc:hexane) to provide amine 10 (0.66 g, 70%) as a
Et2O:hexane) ) 0.15; [R]25 +16 (c 1.3, CHCl3); IR (thin film)
D
2955, 2929, 1737 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.79 (1H,
dd, J ) 1.3, 1.5 Hz), 4.75 (1H, d, J ) 6.5 Hz), 4.20 (1H, dd,
J ) 1.8, 17.3 Hz), 4.09 (1H, dd, J ) 1.1, 17.3 Hz), 3.92 (1H, d,
J ) 2.9 Hz), 3.81-3.63 (5H, m), 0.90-0.87 (36H, m), 0.11-
0.04 (24H, m); 13C NMR (100 MHz, CDCl3) δ 201.9, 102.7, 82.5,
78.8, 77.5, 74.5, 70.0, 63.9, 25.9, 25.9, 25.8, 25.8, 18.3, 18.1,
18.0, 17.8, -4.2, -4.4, -4.6, -4.76, -4.79, -4.9, -5.3; MS (CI+,
NH3) m/z 696 (M + NH4)+. Anal. Calcd for C32H70O7Si4: C,
56.59; H, 10.38. Found: C, 56.51; H, 10.13.
colorless oil: Rf (1:4 EtOAc:hexane) 0.25; [R]26 +7 (c 1.7,
D
1
CHCl3); IR (thin film) 3393, 3080, 1643 cm-1; H NMR (300
MHz, CDCl3) δ 5.78-5.65 (1H, m), 5.27-5.22 (2H, m), 4.63
(1H, d, J ) 6.6 Hz), 4.62 (1H, d, J ) 6.3 Hz), 4.50 (1H, d, J )
6.6 Hz), 4.00 (1H, dd, J ) 5.3, 7.4 Hz), 3.85-3.81 (2H, m),
3.75-3.64 (4H, m), 3.52 (1H, d, J ) 6.2 Hz), 3.34 (1H, m), 3.3
(3H, s), 3.12 (1H, m), 1.73 (2H, br s), 0.82-0.81 (36H, m), 0.03
to -0.02 (24H, m); 13C NMR (75 MHz, CDCl3) δ 134.9, 119.4,
102.4, 94.1, 82.1, 79.0, 78.9, 76.6, 71.5, 70.2, 64.2, 55.6, 54.4,
30.3, 26.0, 25.9, 25.8, 18.4, 18.0, 17.9, -4.1, -4.2, -4.5, -4.7,
-4.8, -5.3; MS (CI+, NH3) m/z 780 (M + H)+. HRMS (CI+,
NH3) Calcd for C37H82NO8Si4 (M + H)+: 780.5118. Found:
780.5108. Anal. Calcd for C37H81NO8Si4: C, 56.95; H, 10.46;
N, 1.79. Found: C, 56.77; H, 10.23; N, 1.97.
1-O-((2S,3S)-2-Ben zyloxy-3-m eth oxym eth oxy-4-pen ten -
1-yl) 2,3,4,6-Tetr a -O-ter t-bu tyld im eth ylsilyl-â-D-glu cop y-
r a n osid e (9). Alcohol 7 (72 mg, 0.09 mmol) in DMF:THF (2:
1, 0.2 mL total) was added to a suspension of NaH (7 mg, 0.2
mmol) in DMF (0.5 mL). The mixture was stirred at room
temperature for 45 min and then treated with PhCH2Br (16
mg, 0.093 mmol), stirred for 18 h at room temperature, and
quenched by addition of water (0.5 mL). The mixture was
poured into water and extracted with Et2O, and the combined
organic extracts were washed with water and brine, dried (Na2-
SO4), evaporated, and chromatographed (1:99 EtOAc:hexane)
to give benzyl ether 9 (37 mg, 47%) as a colorless oil: Rf (1:49
EtOAc:hexane) 0.5; [R]25D +2 (c 1.3, CHCl3); IR (thin film) 3085
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.18 (5H, m), 5.86-
5.75 (1H, m), 5.26-5.15 (2H, m), 4.72 (1H, d, J ) 11.8 Hz),
4.66-4.50 (4H, m), 4.17 (1H, m), 3.87-3.80 (2H, m), 3.70-
3.58 (6H, m), 3.51 (1H, d, J ) 6.3 Hz), 3.29 (3H, s), 0.83-0.78
(36H, m), 0.03 to -0.04 (24H, m); 13C NMR (75 MHz, CDCl3)
δ 138.8, 135.0, 128.1, 128.0, 127.4, 118.0, 102.4, 94.4, 82.1, 80.6,
78.9, 77.7, 76.9, 73.1, 70.2, 69.3, 64.3, 55.6, 26.0, 25.9, 18.4,
18.1, 18.0, 17.9, -4.1, -4.3, -4.5, -4.7, -4.9, -5.2; MS (CI+,
NH3) m/z 888 (M + NH4)+. Anal. Calcd for C44H86O9Si4: C,
60.64, H, 9.95. Found: C, 60.40, H, 9.66.
1-O-((2S,3S)-2-Hyd r oxy-3-m eth oxym eth oxy-4-p en ten -
1-yl) 2,3,4,6-Tetr a -O-ter t-bu tyld im eth ylsilyl-â-D-glu cop y-
r a n osid e (7). sec-BuLi (4.0 mL, 5.2 mmol, 1.3 M in cyclohex-
ane) was added dropwise to solution of MeOCH2OCH2CHd
CH2 (0.529 g, 5.19 mmol) in THF (2 mL) at -85 °C. After 3 h
at -85 °C (+)-diisopinocampheylmethoxyborane (1.68 g, 5.31
mmol) in THF (2 mL) was added dropwise maintaining the
internal temperature at -85 °C. The resulting cloudy, white
solution was stirred at this temperature for 3 h and treated
with BF3‚OEt2 (0.363 g, 2.51 mmol). After 15 min, aldehyde 6
(1.71 g, 2.51 mmol) in THF (4 mL) was added over 1 h, via
syringe pump, maintaining the internal temperature at -85
°C. The mixture was stirred at -85 °C for 18 h and quenched
with MeOH (2 mL). After 15 min, aqueous saturated sodium
perborate (15 mL) was added, and the mixture was allowed
to warm to room temperature and stirred for 24 h. The
organics were removed by evaporation, and the resulting
aqueous layer was extracted with EtOAc. The combined
organic layers were washed with H2O and brine and dried
(Na2SO4). Evaporation and chromatography (1:49 Et2O:hex-
ane) gave alcohol 7 (1.2 g, 65%) as a colorless oil: Rf (9:241
Et2O:toluene) 0.2; [R]30 +7 (c 1, CHCl3); IR (thin film) 3463,
D
3081, 1640 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.91-5.82 (1H,
m), 5.33-5.27 (2H, m), 4.70 (1H, d, J ) 6.8 Hz), 4.67 (1H, d,
J ) 6.6 Hz), 4.59 (1H, d, J ) 6.7 Hz), 4.10 (1H, dd, J ) 4.2,
7.3 Hz), 3.93 (1H, dd, J ) 2.3, 11.4 Hz), 3.90-3.86 (2H, m),
3.86-3.84 (1H, m), 3.77 (1H, d, J ) 3.1 Hz), 3.70 (2H, d, J )
7.4 Hz), 3.64 (1H, dd, J ) 8.2, 11.4 Hz), 3.58 (1H, d, J ) 6.6
Hz), 3.47 (1H, q, J ) 7.1 Hz), 3.37 (3H, s), 0.89-0.86 (36H,
m), 0.09-0.02 (24H, m); 13C NMR (100 MHz, CDCl3) δ 134.6,
118.6, 103.2, 94.1, 82.4, 78.9, 77.9, 77.6, 74.1, 73.0, 69.9, 65.8,
63.8, 55.6, 25.9, 25.8, 25.8, 18.2, 18.0, 17.9, 17.8, -4.2, -4.4,
-4.6, -4.7, -4.8, -5.0, -5.4; MS (CI, NH3) m/z 798 (M +
NH4)+. Anal. Calcd for C37H80O9Si4: C, 56.87; H, 10.32.
Found: C, 57.15; H, 10.09.
1-O-((2S,3S)-3-Meth oxym eth oxy-2-octa d eca n a m id o-4-
p en ten -1-yl) 2,3,4,6-Tetr a -O-ter t-bu tyld im eth ylsilyl-â-D-
glu cop yr a n osid e (11). Stearoyl chloride (0.5 g, 1.6 mmol) was
added to amine 10 (0.63 g, 0.81 mmol) and Et3N (0.25 g, 3.2
mmol) in CH2Cl2 (7.5 mL) at 0 °C. After 3 h at 0 °C
3-dimethylaminopropylamine (8 mg, 0.81 mmol) was added,
and the mixture was allowed to warm to room temperature
and stirred for 15 min. The white precipitous mixture was
diluted with CHCl3 and poured into aqueous citric acid (0.25
M). The aqueous layer was extracted with CHCl3, and the
combined organic layers were washed with brine, dried (Na2-
SO4), concentrated, and chromatographed (1:19 EtOAc:hexane)
to afford amide 11 (0.75 g, 88%) as a colorless oil: Rf (3:47
1-O-((2R,3S)-2-Azid o-3-m et h oxym et h oxy-4-p en t en -1-
yl) 2,3,4,6-Tet r a -O-ter t-b u t yld im et h ylsilyl-â-D-glu cop y-
r a n osid e (8). Tf2O (0.57 g, 2.0 mmol) was added to alcohol 7
(1.20 g, 1.54 mmol) and pyridine (0.36 g, 4.6 mmol) in CH2Cl2
(5 mL) at -10 °C over 10 min. After 30 min at -10 °C, DMF
(30 mL) and NaN3 (0.75 g, 11.5 mmol) were added. The
mixture was allowed to warm to room temperature over 12 h.
The resulting yellow solution was diluted in Et2O, poured into
water, and extracted with further portions of Et2O. The
combined organic layers were washed with water and brine,
dried (Na2SO4), concentrated, and chromatographed to give
azide 8 (0.97 g, 78%) as a colorless oil: Rf (2:123 EtOAc:hexane)
0.15; [R]28D +12 (c 1.4, CHCl3); IR (thin film) 2127, 2097 cm-1
;
EtOAc:hexane) 0.3; [R]26 +10 (c 1.3, CHCl3); IR (thin film)
D
1H NMR (400 MHz, CDCl3) δ 5.81-5.73 (1H, m), 5.37-5.32
(2H, m), 4.70 (1H, d, J ) 6.8 Hz), 4.69 (1H, d, J ) 6.2 Hz),
4.58 (1H, d, J ) 6.7 Hz), 4.16 (1H, dd, J ) 3.9, 7.8 Hz), 3.90-
3.71 (7H, m), 3.59 (1H, d, J ) 6.1 Hz), 3.40 (1H, m), 3.38 (3H,
s), 0.89-0.88 (36H, m), 0.11-0.05 (24H, m); 13C NMR (125
3340, 3078, 1663 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.37 (1H,
d, J ) 7.9 Hz), 5.77-5.65 (1H, m), 5.21-5.15 (2H, m), 4.62
(1H, d, J ) 6.8 Hz), 4.59 (1H, d, J ) 6.9 Hz), 4.51 (1H, d, J )
6.5 Hz), 4.11-4.06 (3H, m), 3.83 (1H, d, J ) 3.0 Hz), 3.77-
3.50 (6H, m), 3.30 (3H, s), 2.11-1.99 (2H, m), 1.18 (30H, s),

Synthesis of Glycosphingolipids
J . Org. Chem., Vol. 65, No. 20, 2000 6513
0.84-0.81 (39H, m), 0.05 to -0.02 (24H, m). 13C NMR (75 MHz,
CDCl3) δ 170.6, 133.9, 117.2, 101.4, 92.6, 80.7, 77.2, 75.8, 75.4,
68.2, 67.9, 62.3, 53.8, 49.6, 35.1, 30.0, 27.8, 27.6, 27.5, 27.5,
27.4, 24.0, 24.0, 24.0, 23.9, 23.8, 20.8, 16.4, 16.1, 15.9, 12.2,
-6.1, -6.2, -6.4, -6.7, -6.8, -7.2; MS (CI+, NH3) m/z 1046
(M + H)+. Anal. Calcd for C55H115NO9Si4: C, 63.10; H, 11.07;
N, 1.34. Found: C, 62.88; H, 11.13; N, 1.33.
Hz), 5.61-5.5.60 (1H, m) 5.46 (1H, d, J ) 3.0 Hz), 5.32-5.20
(2H, m), 4.69 (1H, d, J ) 6.6 Hz), 4.63 (1H, d, J ) 8.7 Hz),
4.61 (1H, d, J ) 6.6 Hz), 4.16 (1H, dd, J ) 4.1, 6.8 Hz), 3.96-
3.88 (2H, m), 3.76-3.64 (6H, m), 3.55 (1H, d, J ) 6.3 Hz), 3.36
(3H, s), 2.14 (2H, m), 1.40 (2H, m), 1.26 (20H, s), 0.89-0.85
(39H, m), 0.21 (6H, s), 0.09-0.04 (24H, m); 13C NMR (CDCl3,
100 MHz) δ 150.7, 135.5, 125.5, 117.5, 102.6, 94.5, 82.1, 78.8,
77.7, 77.6, 74.4, 70.6, 70.1, 64.2, 55.5, 35.3, 31.9, 29.7, 29.6,
29.3, 28.9, 26.0, 25.8, 22.7, 18.3, 18.0, 17.9, 17.8, 14.1, -1.1,
-1.3, -4.2, -4.4, -4.6, -4.7, -4.8, -4.9, -5.3; MS (EI+.) m/z
1046 (M+). Anal. Calcd for C54H114O9Si5: C, 61.89; H, 10.97.
Found C, 62.13; H, 11.13.
2-Br om o-1-p en ta d ecen e (12). To a solution of B-bromo-
9-borobicyclo[3.3.1]nonane (27 mL, 1.0 M in CH2Cl2) was added
CH2Cl2 (150 mL). The solution was cooled to 0 °C, and a
solution of 1-pentadecyne (4.35 g, 21 mmol) in CH2Cl2 (10 mL)
was added slowly via cannula with stirring. The mixture was
stirred at 0 °C for 3.5 h, AcOH (15 mL) was added, and the
reaction was stirred for 1 h at 0 °C. Aqueous NaOH (3 M, 180
mL) was added, followed by H2O2 (26 mL, 35 wt %). The
mixture was stirred at room temperature for 30 min and
extracted with hexane. The combined organic layer was
washed with water, aqueous NaHCO3, water, dried (MgSO4),
evaporated, and chromatographed (hexane) to give 12 (5.24
g, 86%) as a colorless oil: Rf (hexane) 0.62; IR (thin film) 2925,
2854, 1630, 1466 cm-1; 1H NMR (250 MHz, CDCl3) δ 5.55 (1H,
m), 5.38 (1H, d, J ) 1.4 Hz), 2.41 (2H, dt, J ) 0.9, 6.9 Hz),
1.54 (2H, m), 1.26 (20H, br m), 0.88 (3H, t, J ) 6.6 Hz); 13C
NMR (62.9 MHz, CDCl3) δ 135.0, 116.1, 41.4, 31.9, 29.6, 29.5,
29.3, 29.3, 28.4, 27.9, 22.6, 14.1; MS (EI+) m/z 290 (M+.), 288
(M+.). HRMS (EI+) Calcd for C15H2981Br (M+.): 290.1432.
((5S,6S)-22-Dim et h yl-5-m et h oxym et h oxy-3-t r id ecyl-
5,6-d ih yd r o-2H-1,2-oxa silin -6-yl)m eth yl 2,3,4,6-tetr a -O-
ter t-bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (16). Molyb-
denum carbene 2 (9.1 mg, 12 µmol, 25 mol %) was added to a
stirred solution of diene 15 (50 mg, 0.05 mmol) in heptane (1
mL) and stirred at 45 °C for 24 h. The solvent was evaporated
to give a crude a yellow oil which was chromatographed (1:39
EtOAc:hexane) to give 16 (164 mg, 70%) as a colorless oil: Rf
1
(1:9 EtOAc:hexane) 0.53; IR (thin film) 1604 cm-1; H NMR
(250 MHz, CDCl3) 6.50 (1H, d, J ) 5.6 Hz), 4.75 (1H, d, J )
6.7 Hz), 4.71 (1H, d, J ) 6.5 Hz), 4.69 (1H, d, J ) 6.6 Hz),
4.16-4.08 (2H, m), 3.88 (1H, d, J ) 2.8 Hz), 3.79-3.66 (6H,
m), 3.56 (1H, d, J ) 6.3 Hz), 3.35 (3H, s), 2.09 (2H, m), 1.25
(22H, m), 0.88 (39H, m), 0.25 (3H, s) 0.18 (3H, s), 0.09-0.04
(24H, m); 13C NMR (CDCl3, 62.5 MHz) δ 144.9, 139.2, 102.7,
95.9, 82.2, 79.1, 73.0, 71.8, 70.6, 70.2, 64.2, 55.3, 35.1, 31.9,
29.7, 29.5, 29.4, 29.1, 26.0, 25.9, 25.8, 22.7, 18.3, 18.0, 17.9,
14.1, -0.6, -1.4, -4.1, -4.3, -4.5, -4.7, -4.9, -5.3; MS (ES+,
NaI) m/z 1042.2 (M + Na)+. The sensitive oxasiline 17 was
used directly in the next step without further purification.
(+)-1-O-[(2S,3S,4Z)-2-H yd r oxy-3-m et h oxym et h oxy-5-
d im et h ylp h en ylsilyl-oct a d ec-4-en -1-yl] 2,3,4,6-t et r a -O-
ter t-bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (17). PhLi
(1.8 M in cyclohexane/Et2O; 18 µL) was added to oxasiline 16
in THF (0.5 mL) at 0 °C. The reaction mixture was allowed to
warm slowly to room temperature over 18 h after which solid
NH4Cl (50 mg) was added to quench the reaction. After
filtration and concentration by rotary evaporation, the crude
product was chromatographed (1:39 EtOAc:hexane, then 1:19
EtOAc:hexane) to give 17 (19 mg, 83%) as a colorless oil: Rf
Found: 290.1419. Calcd for
C
15H2979Br (M+.): 288.1453.
Found: 288.1436. Anal. Calcd for C15H29Br: C, 62.28; H, 10.10.
Found: C, 61.97; H, 9.93.
Ch lor o(d im eth yl)(1-p en ta d ecen -2-yl)sila n e (13). t-BuLi
(1.66 M in pentane, 29 mL) was added to a stirred solution of
vinyl bromide 12 (5.0 g, 24 mmol) in Et2O (150 mL) at -65
°C. The resulting cloudy solution was stirred at -65 °C for 45
min and transferred via insulated cannula to Me2SiCl2 (6.52
g, 60 mmol) in Et2O (30 mL) at -78 °C. The mixture was
allowed to warm to room temperature over the course of 3.5
h. The solvent was removed under vacuum (Schlenk line), and
the crude mixture was redissolved in pentane and filtered. The
solvent was evaporated and the resultant oil distilled to give
silyl chloride 13 (4.7 g, 67%) as a colorless liquid: bp 55-58
1
°C (5 mmHg); IR (thin film) 2925, 2854 cm-1; H NMR (250
MHz, CDCl3) δ 5.70 (1H, m), 5.53 (1H, m), 2.21 (2H, m), 1.45
(2H, m), 1.26 (20 H, m), 0.88 (3H, app t, J ) 6.6 Hz), 0.50 (6H,
s); 13C NMR (62.9 MHz, CDCl3) δ 149.0 126.8, 34.9, 31.9, 31.2,
29.7, 29.5, 29.4, 28.9, 27.3, 26.3, 22.7, 14.1, 1.7. The moisture
sensitive silyl chloride was further characterized as methoxy-
(dimethyl)(1-pentadecen-2-yl)silane by quenching with excess
MeOH and Et3N: Rf (1:39 EtOAc:hexane) 0.30; IR (thin film)
3049, 1598 cm-1; 1H NMR (250 MHz, CDCl3) δ 5.66-5.63 (1H,
m), 5.43-5.41 (1H, m), 3.41 (3H, s), 2.13 (2H, m), 1.44-1.38
(2H, m), 1.26 (20H, m), 0.88 (3H, m), 0.19 (6H, s); 13C NMR
(62.5 MHz, CDCl3) δ 150.1, 125.8, 50.4, 35.7, 31.9, 29.6, 29.5,
29.3, 28.9, 22.7, 14.1, -2.7; MS (CI+, NH3) m/z 316 (M + NH4)+.
HRMS (CI+, NH3) Calcd for C18H42NOSi (M + NH4)+: 316.3036.
Found: 316.3040. Anal. Calcd for C18H38OSi: C, 72.41; H,
12.83. Found: C, 72.56; H, 12.63.
(1:4 EtOAc:hexane) 0.57; [R]26 ) +24 (c 1.0, CHCl3); IR (thin
D
film) 3462 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.55-7.51 (2H,
m), 7.36-7.32 (3H, m), 6.05 (1H, d, J ) 10.0 Hz), 4.57 (1H, d,
J ) 6.7 Hz), 4.56 (1H, d, J ) 6.8 Hz), 4.43 (1H, d, J ) 6.7 Hz),
4.02 (1H, m), 3.90-3.85 (3H, m), 3.77 (1H, d, J ) 3.9 Hz), 3.68
(2H, d, J ) 6.7 Hz), 3.53 (1H, d, J ) 6.7 Hz), 3.38 (3H, m),
3.27 (3H, s), 2.15 (2H, m), 1.31 (2H, m), 1.25 (20H, m), 0.90-
0.87 (39H, m), 0.48 (3H, s), 0.42 (3H, s), 0.09-0.02 (24H, m);
13C NMR (62.9 MHz, CDCl3) δ 144.3, 139.8, 139.5, 133.9, 129.1,
127.8, 103.2, 93.0, 82.4, 79.0, 78.0, 75.0, 74.1, 73.6, 69.9, 63.8,
55.1, 38.2, 31.9, 30.5, 29.6, 29.5, 29.3, 25.9, 25.8, 25.8, 22.7,
22.4, 18.2, 18.0, 18.0, 17.8, 14.0, -1.2, -1.7, -4.1, -4.5, -4.7,
-4.8, -5.0, -5.4; MS (CI+, NH3) m/z 1114 (M + NH4)+. Anal.
Calcd for C58H116O9Si5: C, 63.45; H, 10.65. Found: C, 63.51;
H, 10.73.
1-O-[(2S,3S)-2-Dim eth yl(pen tadecen -2-yl)siloxy-3-m eth -
oxym eth oxy-4-p en ten -1-yl] 2,3,4,6-Tetr a -O-ter t-bu tyld i-
m eth ylsilyl-â-D-glu cop yr a n osid e (15). Silyl chloride 13 (770
mg, 2.5 mmol) in CH2Cl2 (2 mL) was added to a vigorously
stirred suspension of silver triflate (520 mg, 2.0 mmol) in CH2-
Cl2 (2 mL) and stirred vigorously for 20 min at room temper-
ature. The mixture was transferred via filter cannula to alcohol
7 (1.23 g, 1.6 mmol) and 2,6-lutidene (1.2 mL, 10.1 mmol) in
CH2Cl2 (4 mL) at 0 °C. A further portion of CH2Cl2 (2 mL)
was used to wash the silver chloride and ensure complete
transfer of silyl triflate. The mixture was allowed to warm to
room temperature and stirred for 3 h, and MeOH (5 mL) was
added to quench the reaction. The solvent was evaporated and
the crude oil redissolved in hexane. Filtration and reconcen-
tration afforded a crude oil that was chromatographed (1:99
CH2Cl2:hexane followed by 1:40 EtOAc:hexane) to give 15 (1.3
(+)-1-O-[(2R,3S,4Z)-2-Azid o-3-m et h oxym et h oxy-5-d i-
m eth ylp h en ylsilyl-octa d ec-4-en -1-yl] 2,3,4,6-tetr a -O-ter t-
bu tyld im eth ylsilyl-â-D-glu cop yr a n osid e (18). PPh3 (26 mg,
100 µmol) and DEAD (16 µL, 100 µmol) were added to a stirred
solution of alcohol 17 (55 mg, 50 µmol) in THF (0.5 mL). DPPA
(22 µL, 100 µmol) was added, and the mixture stirred for 18
h. The solvent was evaporated and the resultant crude reaction
mixture chromatographed (1:39 EtOAc:hexane then 1:19
EtOAc:hexane) to give 18 (56 mg, 100%) as a colorless oil: Rf
(1:9 EtOAc:hexane) 0.67; [R]26 ) +23 (c 1.0, CHCl3); IR (thin
D
film) 2099 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55-7.52 (2H,
m), 7.37-7.34 (3H, m), 5.90 (1H, d, J ) 10.0 Hz, 4.65 (1H, d,
J ) 6.2 Hz), 4.51 (1H, d, J ) 6.7 Hz), 4.40 (1H, d, J ) 6.7 Hz),
4.22 (1H, dd, J ) 4.0, 9.9 Hz), 3.94 (1H, d, J ) 2.7 Hz), 3.79-
3.71 (5H, m), 3.59 (1H, d, J ) 6.2 Hz), 3.52 (1H, dt, J ) 3.77,
9.2 Hz), 3.37-3.27 (1H, m), 3.31 (3H, s), 2.14-2.08 (2H, m),
1.33-1.23 (22H, m), 0.94-0.87 (39H, m), 0.48 (3H, s), 0.45 (3H,
s), 0.10-0.06 (24H, m); 13C NMR (100 MHz, CDCl3) δ 146.6,
g, 79%) as a colorless oil: Rf (1:9 EtOAc:hexane) 0.54; [R]26
)
D
;
1H
-4 (c 1.0, CHCl3); IR (thin film) 3174, 1644, 1601 cm-1
NMR (CDCl3, 250 MHz) δ 5.83 (1H, ddd, J ) 6.9, 10.4, 17.4

6514 J . Org. Chem., Vol. 65, No. 20, 2000
Barrett et al.
138.8, 138.0, 133.9, 129.1, 127.9, 102.4, 93.3, 82.0, 78.8, 77.3,
74.6, 70.0, 68.1, 65.5, 64.0, 55.3, 38.2, 31.9, 31.6, 30.4, 29.7,
29.6, 29.5, 29.4, 29.3, 25.9, 25.8, 25.8, 22.7, 22.6, 18.3, 18.0,
18.0, 17.8, 14.1, -1.1, -1.2, -4.4, -4.4, -4.5, -4.7, -5.1, -5.3,
-5.3; MS (CI+, NH3) m/z 1139 (M + NH4)+. Anal. Calcd for
mp 94-96 °C; [R]26 ) +8 (c 1.0, CHCl3); IR (thin film) 1750,
D
1643 cm-1; H NMR (400 MHz, CDCl3) δ 5.73 (1H, d, J ) 9.3
1
Hz), 5.61 (1H, dt, J ) 6.7, 5.3 Hz), 5.26 (1H, dd, J ) 8.8, 15.4
Hz), 5.20 (1H, t, J ) 9.5 Hz), 5.07 (1H, t, J ) 9.7 Hz), 5.02
(1H, dd, J ) 8.1, 9.6 Hz), 4.67 (1H, d, J ) 6.6 Hz), 4.52 (1H,
d, J ) 8.0 Hz), 4.46 (1H, d, J ) 6.6 Hz), 4.27 (1H, dd, J ) 4.8,
12.3 Hz), 4.17-4.09 (2H, m), 3.93 (1H, t, J ) 8.4 Hz), 3.92-
3.84 (2H, m), 3.69 (1H, ddd, J ) 2.2, 4.8, 10.0 Hz), 3.33 (3H,
s), 2.32-1.93 (4H, m), 2.08 (3H, s), 2.07 (3H, s), 2.02 (3H, s),
2.01 (3H, s), 1.56 (2H, m), 1.24 (46H, s), 0.87 (6H, t, 6.8 Hz);
13C NMR (100 MHz, CDCl3) δ 172.5, 170.6, 170.2, 169.5, 169.4,
137.8, 126.4, 100.9, 93.4, 75.8, 72.6, 71.9, 71.2, 68.5, 68.3, 61.8,
55.6, 51.1, 36.9, 32.3, 31.9, 29.7, 29.54, 29.50, 29.44, 29.35,
29.28, 29.19, 29.09, 25.7, 22.7, 20.7, 20.6, 14.1; MS (EI+) m/z
911 (M+.). HRMS (EI+) Calcd for C50H89NO13 (M+.); 911.6334.
Found; 911.6311.
C
58H115N3O8Si5: C, 62.03; H, 10.32; N, 3.74. Found: C, 62.19;
H, 10.30; N, 3.64.
(+)-1-O-[(2R,3S,4E)-2-Azido-3-m eth oxym eth oxy-octadec-
4-en -1-yl] 2,3,4,6-tetr a -O-a cetyl-â-D-glu cop yr a n osid e (19).
Bu4NF (1.0 M in THF containing ∼5% water, 164 µL, 164
µmol) was added to a stirred solution of azide 18 (23 mg, 20
µmol) in DMSO (0.2 mL). The mixture was heated to 60 °C
and stirred for 3 h. The mixture was allowed to cool to room
temperature, DMAP (10 mg, 82 µmol) was added followed by
pyridine (0.2 mL) and Ac2O (0.1 mL), and the resultant
mixture was stirred at room temperature for 19 h. The mixture
was diluted with Et2O (20 mL) and poured into a saturated
aqueous NaHCO3 and stirred vigorously for 30 min. The
organic layer was separated and the aqueous layer extracted
with Et2O. The combined organic layers were washed with
aqueous CuSO4 (0.5 M), water, and brine and dried (MgSO4).
Filtration and concentration yielded the crude product which
was chromatographed (1:19 EtOAc:hexane then 1:1 EtOAc:
hexane) to give 19 as a white solid (11 mg, 80%): Rf (1:1
EtOAc:hexane) 0.47; mp 56-58 °C; [R]26D ) +20 (c 1.0, CHCl3);
D,L-Glu cosylcer a m id e (1). Amide 20 (72 mg, 79 µmol) was
dissolved in MeOH (3.5 mL) and treated with 5% KOH-MeOH
(3.5 mL) with stirring for 30 min at room temperature. The
mixture was neutralized with Dowex 50W × 8 resin (H+ form),
filtered, and concentrated. The crude product was redissolved
in MeOH (3.5 mL) and treated with 2% HCl-MeOH (3.5 mL)
at 45 °C for 5 h. The mixture was then neutralized using Ag2-
CO3, filtered, concentrated, and chromatographed (1:9 MeOH:
CHCl3) to give 1 (38 mg, 69%) as a white solid: Rf (1:9 MeOH:
1
IR (thin film) 2100, 1759 cm-1; H NMR (400 MHz, CDCl3) δ
CHCl3) 0.09; mp 184 °C (lit.12b 182-183 °C); [R]26 ) -9 (c
D
5.73 (1H, dt, J ) 15.2, 6.9 Hz), 5.30 (1H, dd, J ) 8.5, 15.4 Hz),
5.21 (1H, t, J ) 9.5 Hz), 5.10 (1H, t, J ) 9.6 Hz), 5.03 (1H, dd,
J ) 8.0, 9.5 Hz), 4.68 (1H, d, J 6.8 Hz), 4.58 (1H, d, J ) 8.0
Hz), 4.50 (1H, d, J ) 6.7 Hz), 4.27 (1H, dd, J ) 4.5 and 12.3
Hz), 4.13 (1H, dd, J ) 2.3 and 12.3 Hz), 4.06-4.01 (2H, m),
3.72-3.68 (2H, m), 3.48 (1H, dd, J ) 9.0 and 10.2 Hz), 3.33
(3H, s), 2.06 (3H, s), 2.05 (3H, s), 2.02 (3H, s), 2.00 (3H, s),
2.08-2.00 (2H, m), 1.36 (2H, m),1.29-1.24 (20H, m), 0.87 (3H,
t, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 170.6, 170.3 169.4,
169.4, 138.5, 124.6, 101.0, 93.2, 76.1, 72.8, 71.8, 71.0, 69.6, 68.3,
64.8, 61.8, 55.6, 32.3, 31.9, 29.6, 29.4, 29.3, 29.1, 28.9, 22.7,
20.7, 20.6, 20.6, 14.1. MS (CI+, NH3) m/z 717 (M + NH4)+. Anal.
Calcd for C34H57N3O12: C, 58.35; H, 8.21; N, 6.00. Found: C,
58.47; H, 8.34; N, 6.06.
1.0, 1:1 CHCl3:MeOH); IR (thin film) 3273, 2917, 2849, 1651,
1557, 1465 cm-1; 1H NMR (400 MHz, 9:1 CDCl3:CD3OD) δ 6.90
(1H, d, J ) 8.1 Hz), 5.64 (1H, dt, J ) 15.2, 6.8 Hz), 5.38 (1H,
dd, J ) 6.8, 15.2 Hz), 4.20 (1H, d, J ) 7.8 Hz), 4.03 (1H, t,
J ) 6.3 Hz), 3.95-3.86 (1H, m), 3.85-3.72 (3H, m), 3.67 (1H,
dd, J ) 4.3, 12.2 Hz), 3.40-3.27 (2H, m), 3.25-3.14 (2H, m),
2.10 (2H, t, J ) 7.6 Hz), 1.97-1.92 (2H, m), 1.56-1.45 (2H,
m), 1.30-1.10 (46H, m), 0.81 (6H, app t); 13C NMR (100 MHz,
9:1 CDCl3:CD3OD) δ 174.3, 134.1, 128.7, 103.3, 76.2, 75.9, 73.3,
72.4, 69.8, 69.2, 61.5, 53.3, 36.4, 32.2, 31.8, 29.6, 29.4, 29.3,
29.2, 29.1, 25.7, 22.5, 13.9; MS (FAB +ve) m/z 722(M + Na)+.
HRMS (FAB +ve) Calcd for C40H77NO8Na (M + Na)+: 722.5547.
Found: 722.5567.
(+)-1-O-[(2R,3S,4E)-2-n -H exa d eca n a m id o-3-m et h oxy-
m eth oxy-octa d ec-4-en -1-yl] 2,3,4,6-tetr a -O-a cetyl-â-D-glu -
cop yr a n osid e (20). PPh3 (12 mg, 47 µmol) and water (6 µL)
were added to a stirred solution of azide 19 (11 mg, 15.7 µmol)
in THF (1 mL), and the mixture was heated to 45 °C for 24 h.
After rotary evaporation, the residue was redissolved in CH2-
Cl2 (1 mL) and cooled to 0 °C. Et3N (11 µL, 78 µmol) and
palmitoyl chloride (14 µL, 47 µmol) were added. The reaction
mixture was allowed to warm to room temperature while
stirring for 16 h. The solvent was evaporated and the crude
solid chromatographed (2:3 EtOAc:hexane) to give amide 20
(13 mg, 90%) as a white solid: Rf (1:1 EtOAc:hexane) 0.31;
Ack n ow led gm en t. We thank Glaxo Wellcome for
the most generous research endowment (to A.G.M.B.),
the Wolfson Centre for Organic Chemistry in Medicinal
Science at Imperial College, and the EPSRC.
Su p p or t in g In for m a t ion Ava ila b le: 13C NMR spectra
1
available for 1, 7-11, and 15-20. H NMR, DEPT 90, DEPT
135, COSY, and HETCOR spectra available for 1 and 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000690P