A concise synthesis of tetrahydroxy-LCB, α-galactosyl ceramide, and 1,4-dideoxy-1,4-imino-L-ribitol via D-allosamines as key building blocks

Article abstract of DOI:10.1021/jo051518u

The total syntheses of tetrahydroxy-LCB 1, α-galactosyl ceramide 2, and 1,4-dideoxy-1,4-imino-L-ribitol 3 via D-allosamine derivatives as common synthons are described here.

Full text of DOI:10.1021/jo051518u

a new cerebroside was isolated from the latex of Euphorbia
characias L., and its structure was elucidated a decade back.6
R-Galactosyl ceramide (KRN 7000) 2, a potent analogue of the
natural agelasphins isolated from the marine sponge Agelas
mauritianus,7 is an important cerebroside exhibiting immuno-
stimulatory activity and antitumor properties. It contains a
R-linked D-galactose with phytosphingosine8-derived ceramide.
Some reports have revealed that 2 is not only a ligand to bind
with CD1d molecule and activate natural killer T-cells (NKT
cells) to suppress tumor metastases9 but also a potential agent
A Concise Synthesis of Tetrahydroxy-LCB,
r-Galactosyl Ceramide, and
1,4-Dideoxy-1,4-imino-L-ribitol via D-Allosamines
as Key Building Blocks
Shun-Yuan Luo,† Suvarn S. Kulkarni,‡ Chien-Hung Chou,‡
Wei-Meen Liao,§ and Shang-Cheng Hung*,†,‡
Department of Chemistry, National Tsing Hua UniVersity,
Hsinchu 300, Taiwan, Genomics Research Center and Institute
of Chemistry, Academia Sinica, Taipei 115, Taiwan, and
Department of Chemistry, National Central UniVersity,
Chungli 320, Taiwan
to prevent autoimmune diseases such as type I diabetes.10
A
few syntheses of 211 and its derivatives12 have been documented
in the literature so far. Recently, a C-glycoside analogue of KRN
7000 was synthesized and shown to exhibit remarkably en-
hanced activity.13 Iminocyclitols is yet another interesting class
of biomolecules. A number of polyhydroxylated piperidines and
pyrrolidines, both natural and synthetic, have come up over the
past two decades as useful potent glycosidase inhibitors. These
are analogues of pyranoses or furanoses with the ring oxygen
replaced by an imino group and the anomeric hydroxyl group
replaced by hydrogen. Some representatives of iminocyclitols
are already marketed as pharmaceuticals and are used in
treatment of a certain kind of diabetes, while quite a few others
have promising therapeutic potential as antibacterial, anticancer,
and antiviral agents.14 The discovery that certain iminocyclitols
inhibit glycoprotein processing and thereby possess anti-HIV
activity stimulated interest in this area, and not surprisingly they
hung@mx.nthu.edu.tw
ReceiVed July 21, 2005
(6) Falsone, G.; Cateni, F.; Katusian, F. Z. Naturforsch. B. 1993, 48,
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50, 2771-2784.
(8) Synthesis of phytosphingosine: (a) Howell, A. R.; Ndakala, A. J.
Curr. Org. Chem. 2002, 6, 365-391 and references therein. (b) Luo, S.-
Y.; Thopate, S. R.; Hsu, C.-Y.; Hung, S.-C. Tetrahedron Lett. 2002, 43,
4889-4892. (c) Chiu, H.-Y.; Tzou, D.-L. M.; Patkar, L. N.; Lin, C.-C. J.
Org. Chem. 2003, 68, 5788-5791. (d) Naidu, S. V.; Kumar, P. Tetrahedron
Lett. 2003, 44, 1035-1037.
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2005, 5, 31-42.
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1062.
The total syntheses of tetrahydroxy-LCB 1, R-galactosyl
ceramide 2, and 1,4-dideoxy-1,4-imino-L-ribitol 3 via D-
allosamine derivatives as common synthons are described
here.
Lipids and glycolipids play significant roles in numerous
biological processes.1 For example, a number of 2-amino-
1,3,4,5-tetrahydroxyoctadecene derivatives have been isolated
from bovine spinal cords,2 human brains,2 and green3 as well
as red algae.4 Of these, (2S,3S,4R,5R,6Z)-2-amino-1,3,4,5-
tetrahydroxyoctadecene 1,5 the long chain base (LCB) part of
(11) (a) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa,
E.; Yamaji, K.; Kobayashi, E.; Fukushima, H.; Koezuka, Y. J. Med. Chem.
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Kobayashi, E.; Shimosaka, A.; Koezuka, Y. Cancer Res. 1998, 58, 1202-
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95-102. (f) Plettenburg, O.; Bodmer-Narkevitch, V.; Wong, C.-H. J. Org.
Chem. 2002, 67, 4559-4564. (g) Du, W.; Gervay-Hague, J. Org. Lett. 2005,
7, 2063-2065.
† National Tsing Hua University.
‡ Academia Sinica.
§ National Central University.
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of Chemistry, Special Publications: Cambridge, 1994. (b) Kolter, T.;
Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532-1568.
(2) Prosˇtenik, M.; CÄ osovic´, Cˇ .; Gospocˇic´, L.; Jandric´, Z.; Ondrusˇek, V.
Rad. Jugosl. Akad. Znan. Umjet., Kem. 1984, 407, 5-12.
(3) Garg, H. S.; Sharma, M.; Bhakuni, D. S.; Pramanik, B. N.; Bose, A.
K. Tetrahedron Lett. 1997, 33, 1641-1644.
(4) Rao, Ch. B.; Satyanarayana, Ch. Indian J. Chem. 1994, 33B, 97.
(5) Synthesis: (a) Li, Y.-L.; Wu, Y.-L. Tetrahedron Lett. 1995, 36,
3875-3876. (b) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron Asymmetry
1996, 7, 2113-2116. (c) Shimizu, M.; Kawamoto, M.; Niwa, Y. Chem.
Commun. 1999, 1151-1152.
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10.1021/jo051518u CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/04/2006
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J. Org. Chem. 2006, 71, 1226-1229

SCHEME 1. Retrosynthetic Plan of Target Molecules 1-3 via D-Allosamines as Common Building Blocks
received a great attention from synthetic chemists.15 As a part
of our ongoing research program to synthesize biologically
important lipids, glycolipids, and rare L-form sugars,16 we report
herein a straightforward synthesis of tetrahydroxy-LCB 1, KRN
7000 2, and 1,4-dideoxy-1,4-imino-L-ribitol 317 via D-allosamine
derivatives as common synthons.
The common precursor approach demands a careful identi-
fication of the similarity between the arrangement of chiral
centers in the target molecules and that of the common
intermediate. Our retrosynthetic plan, as illustrated in Scheme
1, entails D-allosamine 4 as a common chiral template for the
synthesis of 1, 2, and 3; the stereochemical resemblance between
compounds 1-4 is indicated by the boldfaced carbon frame-
work. It was envisaged that the aldehyde 5, which can be
generated by oxidation of the corresponding semiprotected
D-allosamine-derived 6-alcohol, may undergo Wittig olefination
followed by deprotection to furnish tetrahydroxy-LCB 1. On
the other hand, the hydroxyl-aldehyde (or hemiacetal) 6,
accessible from the corresponding D-allosamine-derived 1,5,6-
triol through oxidative cleavage of the C5-C6 bond, may couple
with a Wittig reagent to construct the phytosphingosine skeleton.
It can be directly used as the aglycone part in subsequent
assembly with an appropriate D-galactose-derived donor to get
to the expected target molecule 2. In addition, reductive
amination of the common building block 6 under hydrogenation
conditions may provide the final L-form iminocyclitol 3.
The success of the above synthetic strategy relied on the
development of an efficient route to prepare D-allosamine
derivatives, amenable to scale-up operations. Some methods
have been reviewed in the literatures for their preparations and
applications to the total synthesis of naturally occurring allosa-
midin.18 To tackle this problem, we have introduced a four-
stepped procedure starting from cheaply available D-glucosamine
hydrochloride 7, a C3-epimer of D-allosamine.
Compound 7 was first transformed into the corresponding
1,3-diol 8 through a combination of amino-azido conversion19
and 4,6-O-benzylidenation20 in 75% overall yield. Differentiation
of the free secondary hydroxyl groups in 8 was investigated,
and a highly regio- and stereoselective benzoylation, acetylation,
and silylation at the O1 position was observed (Table 1).
Treatment of 8 with benzoyl chloride in pyridine at 0 °C led to
a mixture of 1-OBz, 3-OBz, and 1,3-di-OBz, while use of 1-N-
benzyloxy-1,2,3-benzotriazole21 (BzOBT, entry 1) and benzoic
anhydride22 (entry 2) together with triethylamine as a base
provided only the â-benzoate 9 (J1,2 ) 8.4 Hz) in 89% and
93% yields, respectively. In entry 3, a similar phenomenon was
observed when acetic anhydride was utilized, and the corre-
sponding â-form acetate 10 (92%) was isolated in excellent
yield. Although reaction of 8 with tert-butyldimethylsilyl
chloride and triethylamine (entry 4) failed, employment of
imidazole as the base furnished the expected â-silylated product
1123 (entry 5, 89%).
(14) (a) Laver, W. G.; Bischofberger, N.; Webster, R. G. Sci. Am. 1999,
Jan, 78-87. (b) Zitzmann, N.; Mehta, A. S.; Carroue´e, S.; Butters, T. D.;
Platt, F. M.; McCauley, J.; Blumberg, B. S.; Dwek, R. A.; Block, T. M.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11878-11882.
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385. (b) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH Verlag: Weinheim, 1999. (c) Lillelund, V. H.;
Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV. 2002, 102, 515-553.
(16) (a) Hung, S.-C.; Puranik, R.; Chi, F.-C. Tetrahedron Lett. 2000,
41, 77-80. (b) Hung, S.-C.; Wang, C.-C.; Thopate, S. R. Tetrahedron Lett.
2000, 41, 3119-3122. (c) Hung, S.-C.; Chen, C.-S. J. Chin. Chem. Soc.
2000, 47, 1257-1262. (d) Hung, S.-C.; Thopate, S. R.; Chi, F.-C.; Chang,
S.-W.; Lee, J.-C.; Wang, C.-C.; Wen, Y.-S. J. Am. Chem. Soc. 2001, 123,
3153-3154. (e) Hung, S.-C.; Thopate, S. R.; Puranik, R. Carbohydr. Res.
2001, 331, 369-374. (f) Hung, S.-C.; Wang, C.-C.; Chang, S.-W.; Chen,
C.-S. Tetrahedron Lett. 2001, 42, 1321-1324. (g) Wang, C.-C.; Luo, S.-
Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002, 4, 847-849. (h) Lee, C.-J.;
Lu, X.-A.; Kulkarni, S. S.; Wen, Y.-S.; Hung, S.-C. J. Am. Chem. Soc.
2004, 126, 476-477. (i) Kulkarni, S. S.; Lee, J.-C.; Hung, S.-C. Curr. Org.
Chem. 2004, 8, 475-509. (j) Kulkarni, S. S.; Chi, F.-C.; Hung, S.-C. J.
Chin. Chem. Soc. 2004, 51, 1193-1200. (k) Lee, J.-C.; Chang, S.-W.; Chi,
F.-C.; Chen, C.-S.; Wen, Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.;
Liu, Y.-H.; Hung, S.-C. Chem. Eur. J. 2004, 10, 399-415.
(17) (a) Setoi, H.; Kayakiri, H.; Takeno, H.; Hashimoto, M. Chem.
Pharm. Bull. 1987, 35, 3995-3999. (b) Fleet, G. W. J.; Son, J. C.; Green,
D. C.; Bello, I. C.; Winchester, B. Tetrahedron 1988, 44, 2649-2655. (c)
Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1989, 37, 1087-1089. (d) Takano,
S.; Moriya, M.; Ogasawara, K. Tetrahedron: Asymmetry 1992, 3, 681-
684. (e) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R. Synlett
1995, 1014-1016. (f) Huang, Y.; Dalton, D. R.; Carroll, P. J. J. Org. Chem.
1997, 62, 372-376. (g) Defoin, A.; Sifferlen, T.; Streith, J. Synlett 1997,
11, 1294-1296.
The formation of a single â-diastereoisomer in acylation or
silylation opens up a more plausible route for C3-epimerization
of D-glucosamine into D-allosamine, since the corresponding
R-isomer is expected to pose an unfavorable 1,3-diaxial repul-
sion for the concomitant SN2 reaction. As outlined in Scheme
(18) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV. 1999,
99, 779-844.
(19) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6032.
(20) Palme, M.; Vasella, A. HelV. Chim. Acta 1995, 78, 959-969.
(21) Hung, S.-C.; Thopate, S. R.; Wang, C. C. Carbohydr. Res. 2001,
330, 177-182.
(22) Lu, X.-A.; Chou, C.-H.; Wang, C.-C.; Hung, S.-C. Synlett 2003,
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J. Org. Chem, Vol. 71, No. 3, 2006 1227

TABLE 1. Regioselective and Stereoselective Protection of
D-Glucosamine-Derived 1,3-Diol 8 at the O1 Position
SCHEME 3. Synthesis of Tetrahydroxy-LCB
entry
electrophile
base
Et3N
Et3N
Et3N
Et3N
imidazole
T (°C)
product
yield (%)
1
2
3
4
5
BzOBT
Bz2O
Ac2O
TBDMSCl
TBDMSCl
rt
rt
rt
0 to rt
0 to rt
9
9
10
11
11
89
93
92
0
94
SCHEME 2. Synthesis of D-Allosamine Derivative 13
SCHEME 4. Synthesis of 1,4-Dideoxy-1,4-imino-L-ribitol
2, O1-benzoylation of compound 8 followed by O3-triflation
afforded the corresponding 1-OBz-3-OTf 12 (78%) in a one-
pot manner. Nucleophilic substitution of 12 with sodium nitrite
in HMPA proceeded well, and the desired C3-epimerized
alcohol 13 was obtained in 74% yield. An X-ray single-crystal
analysis of 13 was carried out to confirm its absolute config-
uration (see Supporting Information). Through this efficient and
convenient protocol, the D-allosamine derivative 13 was prepared
from D-glucosamine in just four steps and in 44% overall yield.
With this potent building block 13 in hand, we further
investigated the total synthesis of tetrahydroxy-LCB 1 (Scheme
3). Benzylation of 13 with silver oxide and benzyl bromide
yielded the 3-OBn derivative 14 (81%), which was subjected
to regioselective ring opening of benzylidene acetal at O6 in
the presence of VO(OTf)2 as a catalyst to furnish the primary
alcohol 15 in 90% yield.16g Oxidation of 15 with PCC provided
the corresponding 6-aldehyde, which was not stable during
column chromatography purification on silica gel.
which was characterized as its peracetylated derivative 19 that
revealed identity with the literature data5a with respect to the
1H and 13C NMR spectra (see Supporting Information).
Scheme 4 summarizes our synthesis of 1,4-dideoxy-1,4-
imino-L-ribitol 3 from the versatile synthon 15 in three
straightforward steps. Our strategy is based on the head to tail
inversion of 15 followed by preferential N-cyclization under
hydrogenolytic conditions. In contrast to the hydride reduction
of compound 16, treatment of 15 with NaBH4 in methanol
directly led to the triol 20 (76%), which underwent oxidative
cleavage with NaIO4 to provide the cyclic hemiacetal 21 in 94%
yield. Hydrogenolysis of 21 using palladium on charcoal as a
catalyst furnished the final L-form iminocyclitol 3 (91%). The
structural identity of compound 3 was confirmed by comparison
of its 1H and 13C spectra with the literature data (see Supporting
Information).17f
Alternatively, Swern oxidation of 15 followed by consecutive
Wittig olefination [n-C12H25Ph3P+Br-, KN(SiMe3)2, THF, -78
°C] afforded the requisite Z-olefin 16 in two steps in a modest
overall yield (31%). The cis-stereochemistry of the newly
1
generated double bond of 16 was identified from its H NMR
spectrum, which exhibited two distinct downfield signals at δ
5.72 (dt, J ) 10.8, 7.4 Hz, 1H, H-7) and δ 5.32 (dd, J ) 10.8,
9.0 Hz, 1H, H-6). Direct reduction of 16 to the 1,5-diol 18 using
excess NaBH4 gave disappointing results. Instead, regioselective
removal of the anomeric benzoyl group with ammonia led to
the corresponding lactol 17 (94%), which was reduced by
NaBH4 to get the desired product 18 in excellent yield (91%).
Finally, Birch reduction of 18 furnished the target molecule 1,
The frequently encountered problems for the preparation of
R-galactosyl ceramide 2 include the stereocontrol of R-galac-
tosylation and the generation of the phytosphingosine skeleton
with three appropriate chiral centers and a free hydroxyl group
at C1 for further coupling. Our approach starting from the
1228 J. Org. Chem., Vol. 71, No. 3, 2006

TABLE 2. Coupling of Compound 22 with Various
D-Galactopyranosyl Donors To Yield the Product 26
SCHEME 5. Synthesis of r-Galactosyl Ceramide 2
3.1/1). While the preparation of this manuscript was in progress,
Gervay-Hague and co-workers reported a remarkable stereose-
lectivity in this glycosylation using glycosyl iodide as donors.11g
The high selectivity is achieved via in situ anomerization of
the R-galactosyl iodide to a more reactive â-iodide and its
concomitant SN2 displacement by an electron-rich phytosphin-
gosine acceptor.
Finally, transformation of compound 26 into R-galactosyl
ceramide 2 was carried out in three steps (Scheme 5). Reduction
of the azido group in 26 with 3 equiv of PPh3 in a mixed THF/
H2O (2/1) solvent took a rather extended time (5 d), whereas
addition of pyridine in the reaction mixture greatly speeded up
the conversion (12 h). The subsequent amide bond formation
posed no problems under standard conditions, and the corre-
sponding amide 27 was obtained in 71% overall yield in two
steps. Hydrogenolysis of 27 catalyzed by degussa-type reagent
under moderate hydrogen pressure (60 psi) led to the final target
2 in excellent yield (87%). The 1H and 13C NMR spectral data
of 2 corroborated well with the literature report (see Supporting
Information).11a
In conclusion, we have successfully synthesized biologically
potent tetrahydroxy-LCB 1, R-galactosyl ceramide 2, and 1,4-
dideoxy-1,4-imino-L-ribitol 3 using a common precursor ap-
proach from D-allosamine. The new strategies described here
for their syntheses should provide access to lipid, glycolipid,
and iminocyclitol libraries for exploring their immunostimulating
activities and other biological properties. The lipid chains can
be easily modified, and the stereochemistry can be altered by
use of different starting sugars or via epimerization of individual
chiral centers.
entry
donor
activator
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/dioxane
CH2Cl2
yield (%)
R/â
1
2
3
4
5
23
23
24
24
25
TMSOTf
BF3‚Et2O
TMSOTf
TMSOTf
Me2S, Tf2O
66
53
77
64
73
1/1.2
1/0.9
1/1.2
1/1.3
3.1/1
hemiacetal 21 is described in Table 2. Wittig olefination of
compound 21 with Ph3PdCHC12H25 at low temperature gave
the Z-olefin 22 in 87% yield.8b It should be noted that several
preliminary attempts to effect this reaction under standard
conditions met with little success. In situ generation of the
phophorane via a slow addition of the base to the well-stirred
suspension of 21 and the phosphonium salt at low temperature
cleanly afforded the desired product 22. We then proceeded to
study R-galactosylation employing the primary alcohol 22 as
an acceptor. Coupling of the dibenzyl phosphite 23 with 22 in
the presence of either TMSOTf (entry 1) or BF3‚Et2O (entry 2)
as an activator did furnish the expected product 26, in reasonably
good yields but as a mixture of anomers in almost equal
proportions.24 TMSOTf-promoted coupling of the trichloroace-
timidate 24 was tried next,25 and compound 26 was obtained
with the ratio lying slightly in favor of the unwanted â-isomer
(entry 3). Inclusion of 1,4-dioxane as a cosolvent in the reaction,
with the hope to alter the R/â ratio via solvent effect,26 gave
similar results (entry 4). Nevertheless, Gin’s sulfide-mediated
dehydrative glycosylation27 using the 1-OH donor 25 offered
better yield and selectivity, generating the expected adduct 26
(73%) with the predominance of the R-isomer (entry 5, R/â)
Acknowledgment. S.S.K. thanks the Academia Sinica for
postdoctoral fellowship. This work was supported by the
Academia Sinica and the National Science Council of Taiwan
(NSC 92-2113-M-001-028 and NSC 92-2113-M-001-061).
(24) Sim, M. M.; Kondo, H.; Wong, C.-H. J. Am. Chem. Soc. 1993,
115, 2260-2267.
Supporting Information Available: Copies of 1H and 13C NMR
spectra of all new compounds, spectral comparison for final
compounds 2, 3 and 19, and X-ray structural information in CIF
format for compound 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21-123.
(26) Izumi, M.; Shen, G.-J.; Wacowich-Sgarbi, S.; Nakatani, T.; Plat-
tenberg, O.; Wong, C.-H. J. Am. Chem. Soc. 2001, 123, 10909-10918.
(27) Nguyen, H. M.; Chen, Y.; Duron, S. G.; Gin, D. Y. J. Am. Chem.
Soc. 2001, 123, 8766-8772.
JO051518U
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