Total synthesis of sphingofungin E from D-glucose.

Article abstract of DOI:10.1021/ol0171620

[reaction: see text] Total synthesis of sphingofungin E (1) is described. Overman rearrangement of an allylic trichloroacetimidate derived from diacetone-D-glucose generated tetra-substituted carbon with nitrogen, and subsequent Wittig olefination afforde

Full text of DOI:10.1021/ol0171620

ORGANIC
LETTERS
2002
Vol. 4, No. 1
151-154
Total Synthesis of Sphingofungin E
from D-Glucose
Takeshi Oishi, Koji Ando, Kenjin Inomiya, Hideyuki Sato, Masatoshi Iida, and
Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology,
Keio UniVersity, Hiyoshi, Kohoku-ku, Yokohama, 223-8522 Japan
chida@applc.keio.ac.jp
Received December 3, 2001
ABSTRACT
Total synthesis of sphingofungin E (1) is described. Overman rearrangement of an allylic trichloroacetimidate derived from diacetone-D-
glucose generated tetra-substituted carbon with nitrogen, and subsequent Wittig olefination afforded the highly functionalized part in
sphingofungin E (4) stereoselectively. Coupling reaction of 4 with the C12 hydrophobic part, followed by further manipulation, completed the
total synthesis.
Sphingofungins are a new class of antifungal agents isolated
from Aspergillus and Paecilomyces and are reported to be
potent and specific inhibitors of serine palmitoyl trans-
ferase.1,2 The structure elucidation study revealed that
sphingofungins are novel polyhydroxy amino acid derivatives
bearing a C20 straight carbon chain with E-olefin and four
contiguous asymmetric centers.3 While sphingofungins A,
B, C, and D have one distal (R)-hydroxy group at C-14,
sphingofungins E (1) and F (2) own a ketone carbonyl at
C-14 instead and have another characteristic structural
feature: they bear an extra carbon unit at C-2 possessing
R,R-disubstituted R-amino acid structures. It was also shown
that sphingofungin E is a 5-hydroxy derivative of myriocin
3,4 which has recently attracted renewed interest because of
its potent immunosuppressive activity.5 Such interesting
structures and their potent biological properties have naturally
received sizable attention of the synthetic community, and
several reports on total synthesis of sphingofungins D, B,
and F have been described.6 Recently, total synthesis of
(4) For total synthesis of myriocin, see: (a) Banfi, L.; Beretta, M. G.;
Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc., Chem. Commun.
1982, 488; J. Chem. Soc., Perkin Trans. 1 1983, 1613. (b) Yoshikawa, M.;
Yokokawa, Y.; Okuno, Y.; Murakami, N. Chem. Pharm. Bull. 1994, 42,
994; Tetrahedron 1995, 51, 6209. (c) Sano, S.; Kobayashi, Y.; Kondo, T.;
Takebayashi, M.; Maruyama, S.; Fujita, T.; Nagao, Y. Tetrahedron Lett.
1995, 36, 2097. (d) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi,
Y.; Irie, H.; Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahderon Lett.
1997, 38, 7887. (e) Oishi, T.; Ando, K.; Chida, N. Chem. Commun. 2001,
1932.
(5) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T.
Biochem. Biophys. Res. Commun. 1995, 211, 396.
(6) For total synthesis of sphingofungin D, see: (a) Chida, N.; Ikemoto,
H.; Noguchi, A.; Amano, S.; Ogawa, S. Nat. Prod. Lett. 1995, 6, 295. (b)
Mori, K.; Otaka, K. Tetrahedron Lett. 1994, 35, 9207. (c) Otaka, K.; Mori,
K. Eur. J. Org. Chem. 1999, 1795. For total synthesis of sphingofungin B,
see: (d) Kobayashi, S.; Hayashi, T.; Iwamoto, S.; Furuta, T.; Mataumura,
M. Synlett 1996, 672. For total synthesis of sphingofungins B and F, see:
(e) Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto, S.
Synlett 1997, 301. (f) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima,
M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. (g) Kobayashi, S.; Furuta,
T. Tetrahedron 1998, 54, 10275. For total synthesis of sphingofungin F,
see: (h) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818. (i)
Liu, D.-G.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2000, 65, 9114.
(1) van Middlesworth, F.; Giacobbe, R. A.; Lopez, M.; Garrity, G.; Bland,
J. A.; Bartizal, K.; Fromtling, R. A.; Polishook, J.; Zweerink, M.; Edison,
A. M.; Rozdilsky, W.; Wilson, K. E.; Monaghan, R. L. J. Antibiot. 1992,
45, 861.
(2) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G.
L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandala, S. M. J. Antibiot. 1992, 45, 1692.
(3) van Middlesworth, F.; Dufresne, C.; Wincott, F. E.; Mosley, R. T.;
Wilson, K. E. Tetrahedron Lett. 1992, 45, 861.
10.1021/ol0171620 CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/15/2001

sphingofungin E has been reported from three laboratories,
which successfully assigned the absolute structure of the
natural product.7 For construction of the tetra-substituted
carbon in sphingofungins E and F, previous successful
syntheses adopted Scho¨llkopf’s bislactim method,6e-g Pd-
catalyzed asymmetric alkylation of azlactone,6h,7c Lewis acid
catalyzed cyclization of an epoxytrichloroacetimidate,6i,7a and
the Darzen reaction.7b In this communication, we report the
alternative and efficient total synthesis of sphingofungin E
starting from D-glucose.
tively. On the basis of these considerations, the functionalized
part, allyl bromide 4, was to be prepared from a furanose
derivative with a tetra-substituted carbon (6). The furanose
6 would derive from Overman rearrangement of an allylic
trichloroacetimidate 7, which was envisioned as arising from
diacetone-D-glucose.
Synthesis of the functionalized part 4 commenced with
1,2-O-isopropylidene-3-O-methoxymethyl-R-D-glucofura-
nose 810 prepared from diacetone-D-glucose in two steps in
90% yield (Scheme 1). The primary hydroxy group in 8 was
Our previous success in total synthesis of lactacystin from
D-glucose8 and myriocin from D-mannose4e suggested that
the Overman rearrangement9 on furanose scaffolds, followed
by further transformation utilizing the functional groups in
the carbohydrate residue, would provide the highly func-
tionalized intermediate of sphingofungin E in a stereoselec-
tive manner and short reaction steps. This idea involves
disconnection of the carbon framework of 1 into allyl
bromide 4 and the hydrophobic C12 counterpart, sulfone 5
(Figure 1). The sulfone-allyl bromide coupling reaction,
Scheme 1
Figure 1. Structures of sphingofungins and myriocin and retrosyn-
thetic route to sphingofungin E.
selectively benzylated11 to afford 912 in 95% yield. Swern
oxidation of 9 generated ketone, which was submitted to
Wittig reaction to provide an inseparable mixture of alkenes
which had been employed in our previous total synthesis of
sphingofungin D6a and myriocin,4e was expected to construct
the carbon backbone possessing E-olefin in 1 stereoselec-
(8) (a) Chida, N.; Takeoka, J.; Tstutsumi, N.; Ogawa, S. J. Chem. Soc.,
Chem. Commun. 1995, 793. (b) Chida, N.; Takeoka, J.; Ando, K.; Tsutstumi,
N.; Ogawa, S. Tetrahedron 1997, 53, 16287.
(9) (a) Overman, L. E. J. Am. Chem. Soc. 1978, 98, 2901. (b) Overman,
L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(7) For total synthesis of sphingofungin E, see: (a) Wang, B.; Yu, X.-
M.; Lin, G.-Q. Synlett 2001, 904. (b) Nakamura, T.; Shiozaki, M.
Tetrahedron Lett. 2001, 42, 2701. (c) Lee, C. B. Ph.D. Dissertation, Stanford
University, Stanford, CA, 1999.
152
Org. Lett., Vol. 4, No. 1, 2002

10 (E:Z ) 1:4) in 95% yield from 9. Reduction of 10 with
DIBAL-H and subsequent chromatographic separation gave
geometrically pure Z-allyl alcohol 11 in 71% isolated yield
along with its E-isomer (13%). The observed NOEs of 11
(between H-6 and H-1′, and H-4 and H-2′) clearly assigned
its Z-geometry. Treatment of 11 with trichloroacetonitrile
and DBU afforded trichloroacetimidate 7, which without
bromide to furnish the highly functionalized part (4) of
sphingofungin E in 85% yield.
The hydrophobic counterpart, sulfone 5, was synthesized
from cyclohexanone by the same procedure employed for
the total synthesis of myriocin.4e The sulfone 5 was lithiated
by treatment with n-BuLi and then reacted with the allyl
bromide 4 to provide the coupling product 19 in 86% yield
as a mixture of diastereomers (Scheme 3). Treatment of 19
with Li and naphthalene17,18 in THF successfully removed
both sulfonyl and O-benzyl groups to give primary alcohol
20 in 55% yield. Swern oxidation of 20 and subsequent
treatment with NaClO2 provided carboxylic acid 21, whose
acidic hydrolysis, followed by conventional acetylation,
afforded γ-lactone 22 in 68% yield from 20. Finally,
saponification of 22 followed by neutralization with acidic
resin (Amberlite IRC-76) furnished sphingofungin E (1) in
88% yield. The physical properties as well as spectroscopic
data19 showed good accordance with those reported for the
authentic sample.
13
isolation was heated in xylene in the presence of K2CO3
in a sealed tube at 140 °C for 140 h to give products of the
Overman rearrangement, 12 and its C-5 epimer 13, in 60%
and 14% isolated yields from 11, respectively.14 Ozonolysis
of 12 (Me2S workup) followed by reduction with ZnBH4
afforded 1415 in 93% yield. The newly formed stereochem-
istry in 12 was assigned by transformation of 14 into bicyclic
compound 15. Thus, treatment of 14 with DBU smoothly
induced the carbamate formation, and subsequent treatment
with aqueous acid, followed by conventional acetylation,
afforded crystalline 15 in 26% overall yield from 14, whose
single crystal X-ray analysis unambiguously revealed that
the major isomer in Overman rearrangement 12 possessed
5R configuration.16
In summary, total synthesis of sphingofungin E (1) starting
from D-glucose was accomplished. This work established the
novel synthetic pathway to sphingofungins and their ana-
logues. This synthesis and previous successes in total
Having established the structure of the rearranged product,
transformation of 14 into allyl bromide 4 was then explored.
Treatment of 14 with aqueous HCl gave furanose derivative
6 in 91% yield (Scheme 2). Reaction of 6 with Ph3PdCHCO2-
(15) Selected data for 14: [R]24D +8 (c 1.0, CHCl3); 1H NMR (270 MHz,
CDCl3) δ 1.32 and 1.49 (2s, each 3 H), 3.28 (s, 3 H), 3.90 (s, 2 H), 3.92
and 4.25 (2d, each 1 H, J ) 12.5 Hz), 4.29 (m, 2 H), 4.40-4.62 (m, 5 H),
5.89 (d, 1 H, J ) 3.7 Hz), 7.26-7.35 (m, 5 H), 8.66 (bs, 1 H); HRMS (EI)
m/z 527.0882, calcd for C21H28NO835Cl3 (M + H)+ 527.0880. For 4: [R]24
D
Scheme 2
1
+6 (c 1.2, CHCl3); H NMR (300 MHz, CDCl3) δ 1.40-1.44 (bs, 21 H),
1.62 (bs, 1 H), 3.74 and 3.83 (2d, each 1 H, J ) 9.8 Hz), 3.86-3.90 (m,
3 H), 3.94 (bs, 1 H, J ∼ 0 Hz), 3.98 (bd, 1 H, J ) 8.5 and ∼0 Hz), 4.33,
4.42 and 4.51 (3d, each 1 H, J ) 11.9 Hz), 4.45 (dd, 1 H, J ) 7.6 and 8.5
Hz), 5.56 (dd, 1 H, J ) 7.6 and 15.1 Hz), 5.97 (dt, 1 H, J ) 15.1 and 7.3
Hz), 6.16 (bs, 1 H), 7.24-7.39 (m, 5 H); HRMS (FAB) m/z 572.2059,
calcd for C27H4181BrNO7 (M + H)+ 572.2046. For 20: [R]24D +3 (c 0.45,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.87 (t, 3 H, J ) 6.7 Hz), 1.23-
1.37 (m, 16 H), 1.40 and 1.44 (2s, each 6 H), 1.45 (s, 9 H), 1.53-1.63 (m,
4 H), 2.06 (dt, 2 H, J ) 6.8 and 6.8 Hz), 3.54-3.61 (m, 2 H), 3.71 (d, 1
H, J ) 8.3 Hz), 3.77 and 4.22 (2d, each 1 H, J ) 12.5 Hz), 3.87-3.94 (m,
1 H), 3.92 (s, 4 H), 4.37 (dd, 1 H, J ) 8.3 and 8.3 Hz), 4.43 (dd, 1 H, J )
3.4 and 9.0 Hz), 5.40 (dd, 1 H, J ) 8.3 and 15.3 Hz), 5.76 (dt, 1 H, J )
15.3 and 6.8 Hz), 6.07 (bs, 1 H); HRMS (FAB) m/z 628.4424, calcd for
C34H62NO9 (M + H)+ 628.4424. For 22: [R]24D +49 (c 0.27, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 0.87 (t, 3 H, J ) 6.7 Hz), 1.18-1.36 (m, 12
H), 1.46-1.61 (m, 4 H), 1.96-2.05 (m, 2 H), 2.02 (s, 6 H), 2.09 and 2.12
(2s, each 3 H), 2.38 (t, 2 H, J ) 7.4 Hz), 4.49 and 4.56 (2d, each 1 H, J
) 11.4 Hz), 4.76 (dd, 1 H, J ) 4.9 and 7.8 Hz), 5.33 (dd, 1 H, J ) 7.8 and
15.3 Hz), 5.53 (dd, 1 H, J ) 7.8 and 7.8 Hz), 5.80 (d, 1 H, J ) 4.9 Hz),
5.86 (dt, 1 H, J ) 15.3 and 7.2 Hz), 5.97 (bs, 1 H); 13C NMR (75 MHz,
CDCl3) δ 14.0, 20.5, 20.6, 21.1, 22.5, 22.7, 23.7, 23.8, 28.2, 28.9, 29.0,
31.6, 32.3, 42.7, 42.8, 62.4, 62.9, 70.4, 71.6, 77.2, 80.6, 122.0, 139.5, 168.1,
169.2, 169.6, 170.2, 171.7, 211.6; HRMS (EI) m/z 567.3046, calcd for
C29H45NO10 (M+) 567.3044.
(16) Kani, Y.; Ohba, S.; Oishi, T.; Ando, K.; Inomiya, K.; Chida, N.
Acta Crystallogr., Sect. C 2000, C56, e223.
(17) (a) Liu, H.-J.; Yip, J. Tetrahedron Lett. 1997, 38, 2253. (b)
Shimshock, S. T.; Waltermire, R. E.; DeShong, P. J. Am. Chem. Soc. 1991,
113, 8791.
(18) Birch reduction (Li or Ca in liquid NH3-THF, -78 °C) of 19 gave
less satisfactory and reproducible results; compound 20 was obtained in
only 0-15% yields.
Et afforded only E-alkene, which was treated with 2,2-
dimethoxypropane in the presence of CSA to afford di-
acetonide 16 in 53% yield from 6. Reaction of 16 with
DIBAL-H at -78 °C reduced the ester function as well as
the N-trichloroacetamide moiety to afford amine, which was
isolated as its N-Boc derivative 17 in 90% yield. The primary
hydroxy group in 17 was converted into the corresponding
(10) Mulzer, J.; Angermann, A.; Mu¨nch, W.; Schlichtho¨rl, G.; Hentzschel,
A. Liebigs Ann. Chem. 1987, 7.
(11) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(12) All new compounds described in this letter were characterized by
300 MHz 1H NMR, 75 MHz 13C NMR, IR, and mass spectrometric and/or
elemental analyses.
(13) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998,
63, 188.
(14) Overman rearrangement of the E-isomer of 11 afforded 12 and 13
in 11% and 41% isolated yields, respectively.
(19) Mp 144-146 °C; [R]25D -5.6 (c 0.14, MeOH); lit.7b mp 145-147
°C, [R]25D -5.43 (c 0.48, MeOH); 1H NMR (300 MHz, MeOH-d4) δ 0.94
(t, 3 H, J ) 6.7 Hz), 1.21-1.45 (m, 12 H), 1.48-1.60 (m, 4 H), 2.04 (dt,
2 H, J ) 6.3 and 6.3 Hz), 2.43 (t, 4 H, J ) 7.4 Hz), 3.63 (d, 1 H, J ) 7.3
Hz), 3.84 (d, 1 H, J ) 11.0 Hz), 3.94 (bs, 1 H), 3.97 (d, 1 H, J ) 11.0 Hz),
4.10 (dd, 1 H, J ) 7.6 and 7.6 Hz), 5.44 (dd, 1 H, J ) 7.6 and 15.4 Hz),
5.77 (dt, 1 H, J ) 15.4 and 6.3 Hz); 13C NMR (75 MHz, MeOH-d4) δ
14.4, 23.6, 24.9, 30.02, 30.03, 30.15, 30.18, 32.8, 33.4, 43.47, 43.51, 64.9,
70.0, 71.2, 75.6, 76.3, 130.2, 135.7, 173.2, 214.4; HRMS (FAB) m/z
418.2805, calcd for C21H40NO7 (M + H)+ 418.2805.
Org. Lett., Vol. 4, No. 1, 2002
153

Scheme 3
syntheses of lactacystin8 and myriocin4e also revealed that
Acknowledgment. We thank Drs. T. Nakamura and M.
Shiozaki (Exploratory Chemistry Reseach Laboratories,
Sankyo Co. Ltd., Tokyo, Japan) for providing us with spectral
data of an authentic sample.
the methodology involving Overman rearrangement on
furanose scaffolds, followed by further manipulation by use
of the residual functional groups in carbohydrates, is quite
effective for the chiral synthesis of natural products pos-
sessing complex R,R-disubstituted R-amino acid structures.
OL0171620
154
Org. Lett., Vol. 4, No. 1, 2002