Total synthesis of sphingofungin E

Article abstract of DOI:10.1016/S0040-4039(01)00246-5

Total synthesis of sphingofungin E (1) using an already known D-glucose derivative as a chiral synthon is described.

Full text of DOI:10.1016/S0040-4039(01)00246-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2701–2704
Total synthesis of sphingofungin E
Tsuyoshi Nakamura and Masao Shiozaki*
Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan
Received 27 December 2000; revised 8 February 2001; accepted 9 February 2001
Abstract—Total synthesis of sphingofungin E (1) using an already known
© 2001 Elsevier Science Ltd. All rights reserved.
D-glucose derivative as a chiral synthon is described.
Sphingofungins have been isolated by the Merck group
as new antifungal agents.1,2 These compounds have a
unique mechanism in their biological activity. They
inhibit serinepalmitoyl transferase, an enzyme essential
in the biosynthesis of sphingolipids.1a,c The sphingofun-
gins have four consecutive chiral centers and a trans
olefinic group in their polar head moiety. In particular,
sphingofungin E (1) and F contain a quaternary center
at the C2 position. Their structures, especially the struc-
ture of sphingofungin E, are strikingly similar to myri-
Based on the retrosynthetic analysis depicted in Fig. 1,
the molecule of 1 is divided into two fragments. We
adopted the reported method2d,5 for coupling the
hydrophilic polar head 17 and the lipophilic side chain
18.2d Compound 17 possesses four contiguous chiral
centers and one trans olefin. The C1ꢀC7 fragment of 17
should be able to be derived from the azide derivative
7, which may be obtainable6 from the already-identified
D
-glucose derivative 2.
ocin which has been reported as
a
potent
We attempted to synthesize the polar head of 17 start-
ing from the benzylidene compound 2, which was easily
prepared by a modification of the procedure reported
by Fukase et al.7 (Scheme 1).
immunosuppressive agent.3 Many organic chemists
have been interested in the structure of myriocin and its
unique biological activity, and myriocin and its related
compounds have already been successfully synthesized.4
The total synthesis of sphingofungin E by Trost et al.
based on the procedure of sphingofungin F synthesis
has also been achieved.5 Here we describe an alternative
method for the synthesis of sphingofungin E using an
Swern oxidation of 2 afforded ketone 3 as a crystalline
solid (mp 77–79°C) in 76% yield. Addition of
dichloromethyllithium to the ketone moiety of 3
afforded C2-dichloromethylated tertiary alcohol 4,
exclusively, in 70% yield without detection of the C2-
already-identified
D
-glucose derivative.
9-BBN
OH OH
OH
O
O
CO2H
NH2
OH
18
+
O
SEMO
sphingofungin E (1)
H
O
O
I
NHBz
O
O
O
O
O
BzO
OTBDPS
TBDMSO
N3
17
Ph
O
OH
PMBO
OTBDPS
OBn
2
OBn
7
Figure 1. Structure and retrosynthetic analysis of sphingofungin E.
Keywords: antifungals; asymmetric synthesis; natural products; stereocontrol.
* Corresponding author. Fax: +81-3-5436-8570; e-mail: shioza@shina.sankyo.co.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00246-5

2702
T. Nakamura, M. Shiozaki / Tetrahedron Letters 42 (2001) 2701–2704
O
O
O
O
O
O
O
b
O
O
a
O
O
c, d, e
84%
CHCl2
76%
70%
Ph
Ph
O
O
OH
Ph
O
Ph
O
OH
OBn
OBn
2
OBn
3
4
O
OH
N3
O
O
O
O
TBSO
RO
l, m
94%
j, k
82%
f, g
N3
N3
OTBDPS
R'O
PMBO
86%
OTBDPS
OH
OBn
OBn
5
OBn
8
h, i
64%
6 : R = H, R' = H
7 : R = TBS, R' = PMB
OR OBn
OH OBn
q
n, o
TBSO
CONHMe
N3
TBSO
CONHMe
N3
82%
100%
PMBO
10 : R = H
PMBO
OTBDPS
OTBDPS
9
p
85%
11 : R = SEM
SEMO
SEMO
SEMO
TBSO
OBn
H
H
O
O
O
TBSO
O
RO
r, s
u, v
80%
CONMe2
N3
N3
62%
NHBz
PMBO
RO
BzO
OTBDPS
OTBDPS
12
OTBDPS
t
13 : R = Bn
14 : R = H
w
87%
15 : R = TBS
61%
16 : R = H
Scheme 1. Reagents and conditions: (a) Swern oxidation, −78°C, 1 h; (b) LiCHCl2, THF, −78°C, 30 min; (c) DBU, DMSO, 0°C,
3 h; (d) NaN3, cat. 15-crown-5, HMPA, 70°C, 17 h; (e) NaBH4, MeOH, 0°C, 1.5 h; (f) TBDPSCl, imidazole, DMF, 60°C, 3 h;
(g) cat. CSA, MeOH, rt, 26 h; (h) TBSCl, imidazole, DMF, 0°C, 2 h; (i) PMBCl, NaH, DMF, −23°C, 5 h; (j)
[Ir(COD)(PMePh2)2]PF6, THF, rt, 2.5 h; (k) NBS, H2O, THF, 0°C, 2 h; (l) Dess–Martin periodinane, CH2Cl2, rt, 2 h; (m)
H2NMe, MeOH, rt, 1.5 h; (n) Swern oxidation, −78°C, 1 h; (o) L-Selectride, THF, −78°C, 30 min; (p) SEMCl, EtN(iPr)2, DCE,
60°C, 4 h; (q) MeI, NaH, DMF, 0°C, 1.5 h; (r) DDQ, H2O, CH2Cl2, 0°C, 3 h; (s) PPTS, toluene, 70°C, 24 h; (t) NaBrO3,
NaHSO3, H2O, AcOEt, rt, 1 h; (u) Pd/C, H2, AcOEt, rt, 14 h; (v) PhCOCl, Et3N, CH2Cl2, rt, 2 h; (w) 5% aq. H2SO4, acetone,
rt, 13 h.
epimer, due to the steric hindrance by the anomeric
axial allyloxy group. Treatment of a solution of 4 in
DMSO with DBU gave an epoxy-chloride, which was
then treated with NaN3 in the presence of 15-crown-5
using HMPA as a solvent to give an azidoaldehyde
with an accompanying inversion of configuration.6 The
attack of the azide anion was regiospecific at the C2
carbon. The aldehyde was immediately reduced with
NaBH4 to afford primary alcohol 5 in 84% yield in
three steps. Protection of the primary hydroxyl group
of 5 with t-butyldiphenylsilyl chloride (TBDPSCl) and
imidazole using DMF as a solvent, and successive
deprotection of the 4,6-O-benzylidene group with CSA
afforded diol 6 in 86% yield. The regioselective silyla-
tion at the C6 hydroxyl group of 6 with t-butyl-
methylsilyl chloride (TBDMSCl) and imidazole, and
the p-methoxybenzyl (PMB) ether formation at the C4
hydroxyl group with PMBCl and NaH in DMF at
−23°C for 5 h afforded 7 in 64% yield. The deprotection
of the C1 anomeric O-allyl with an Ir complex8 and
NBS–H2O gave pyranose 8 in 82% yield. Compound 8
was oxidized to a lactone using Dess–Martin periodi-
nane, and was successively treated with methylamine in
MeOH to afford stable amide 9 in 94% yield. Since the
configuration of the C5 hydroxyl group of 9 was the
reverse of that of the natural sphingofungin E, we
needed to inverse the configuration from R to S. Com-
pound 9 was oxidized by Swern oxidation to give a
ketone, which was then reduced to alcohol 10 by
L-
Selectride reduction. This hydride reduction was
achieved in a >95:<5 ratio diastereoselectively. After the
purification by silica gel column chromatography, an
inverted alcohol 10 was obtained in 82% yield in two
steps. The C5 hydroxyl group of 10 was protected by
treatment with (trimethylsilylethoxy)methyl chloride
(SEMCl) and diisopropylethylamine in dichloroethane
to give SEM ether 11 in 85% yield.
Based on our preliminary experiment, difficulties were
expected in hydrolyzing the C1 N-methylamide group
to a carboxylic acid after introducing the lipophilic side
chain. Thus, we carried out the cleavage of the amide
bond via the formation of a five-membered lactone by
the removal of C4 PMB ether. Treatment of 11 with
MeI in the presence of NaH as a base in DMF afforded
N-dimethylamide 12 in quantitative yield. Treatment of
the resulting compound 12 with DDQ–H2O to remove
the p-methoxybenzyl group followed by PPTS gave
lactone 13 in 62% yield. The pre-conversion to dimethyl-
amide 12 was essential to achieve lactone formation
under these moderately acidic conditions.9

T. Nakamura, M. Shiozaki / Tetrahedron Letters 42 (2001) 2701–2704
SEMO SEMO
2703
H
H
O
O
a, b
c
O
O
d, e
C6H13
I
( )5
16
O
O
69%
81%
63%
NHBz
NHBz
BzO
BzO
19
OTBDPS
OTBDPS
17
HO
H
O
f
O
C6H13
sphingofungin E (1)
( )5
88%
NHBz
OH
O
BzO
20
Scheme 2. Reagents and conditions: (a) Dess–Martin periodinate, CH2Cl2, rt, 1.5 h; (b) CHI3, CrCl2, THF, rt, 2 h; (c)
organoborane 18, PdCl2(dppf), Ph3As, Cs2CO3, THF–DMF, rt, 2 h; (d) 5% aq. H2SO4, acetone, rt, 5 h; (e) HF–Py complex, THF,
rt, 5.5 h; (f) NaOH, H2O, dioxane, 70°C, 7.5 h, then neutralized with Amberlite IR-120.
Based on the preliminary experiment, difficulties were
expected in the deprotection of the C3 O-benzyl group
in the final stage. Therefore, we removed the benzyl
group at this stage. However, applying hydrogenolytic
conditions using Pd/C as a catalyst or other methods10
to cleave the benzyl group proved fruitless. Finally,
treatment of 13 with NaBrO3 and NaHSO3 gave 14 in
61% yield.11 After the reduction of the azide group of
14 under hydrogen using Pd on carbon as a catalyst in
ethyl acetate, the following treatment with 3 equivalents
of benzoyl chloride and excess triethylamine afforded
the O-benzoylated benzoylamide 15 in 80% yield. Selec-
tive cleavage of the C6 O-TBS group of 15 by treat-
ment with 5% aqueous H2SO4 in acetone was
accomplished to give alcohol 16 in 87% yield without
cleavage of both the TBDPS and SEM groups.
References
1. Isolation of sphingofungins A–D: (a) VanMiddlesworth,
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. A. J. Antibiot. 1992, 45, 861–867.
Structure elucidation: (b) VanMiddlesworth, F.;
Dufresne, C.; Wincott, F. E.; Mosley, R. T.; Wilson, K.
E. Tetrahedron Lett. 1992, 33, 297–300. Isolation of
sphingofungins E–F: (c) Horn, W. S.; Smith, T. L.; Bills,
G. F.; Raghoobar, S. L.; Helms, G. L.; Kurts, M. B.;
Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandara, S. M. J. Antibiot. 1992, 45, 1692–1696.
2. For total synthesis of the sphingofungins. 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.; Otaka, K.;
Mori, K. Eur. J. Org. Chem. 1999, 1795–1802. Sphingo-
fungins B and F, see: (c) Kobayashi, S.; Matsumura, M.;
Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett 1997, 301.;
Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.;
Hanada, K. J. Am. Chem. Soc. 1998, 120, 908–919 and
4256; Kobayashi, S.; Furuta, T. Tetrahedron 1998, 54,
10275–10294. Sphingofungin F, see: (d) Trost, B. M.;
Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818–6819.
3. (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.;
Sasaki, S.; Toyama, R.; Yoneta, M.; Hoshino, Y.; Oku-
moto, T. J. Antibiot. 1994, 47, 208; (b) Miyake, Y.;
Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T.
Biochem. Biophys. Res. Commun. 1995, 211, 396.
4. For total syntheses of myriocin, see: (a) Banfi, L.; Bretta,
M. G.; Colombo, L.; Gennari, C.; Scolastico, C. J. Chem.
Soc., Chem. Commun. 1982, 488.; Banfi, L.; Bretta, M.
G.; Colombo, L.; Gennari, C.; Scolastico, C. J. Chem.
Soc., Perkin Trans. 1 1983, 1613. (b) Yoshikawa, M.;
Yokokawa, Y.; Okuno, Y.; Murakami, N. Chem. Pharm.
Bull. 1994, 42, 994. Yoshikawa, M.; Yokokawa, Y.;
Okuno, Y.; Murakami, N. Tetrahedron 1995, 51, 6209.
(c) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi,
M.; Maruyama, S.; Fujita, T.; Nagano, Y. Tetrahedron
Lett. 1995, 36, 2097. (d) Hatakeyama, S.; Yoshida, M.;
Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto, T.;
Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 45,
7887.
The following steps to introduce the lipophilic side
chain with an E-geometrical alkene part to compound
16 were achieved by applying the reported method2d,5
(Scheme 2).
Thus, Dess–Martin periodinate oxidation of the C6
hydroxyl group of 16 to an aldehyde, followed by iodo
olefination of the resulting aldehyde, exclusively
afforded (E)-iodoolefin 17 in 69% yield without any
detection of the (Z)-isomer. Suzuki coupling12 of vinyl
iodide 17 and organoborane 18 using PdCl2(dppf),
Ph3As and Cs2CO3 in THF–DMF provided the desired
(E)-alkene 19 in 81% yield. The deprotection reactions
to convert 19 to 1 were carried out as follows. The C14
ethylene acetal of 19 was removed by hydrolysis with
5% aqueous H2SO4 in acetone. Treatment of the
obtained ketone with a HF–pyridine complex in THF
cleaved both TBDPS and SEM ethers to give keto diol
20 in 63% yield. Finally, the lactone ring, benzamide
and benzoyl ester groups of 20 were saponified in the
presence of NaOH in dioxane–H2O, and neutralization
with Amberlite IR-120 ion-exchange resin afforded sph-
ingofungin E (1)13 in 88% yield.
Thus, we were able to accomplish the synthesis of
sphingofungin E from the already-identified
D-glucose
derivative 2 in a stereocontrolled manner in 29 steps in
1.1% overall yield.

2704
T. Nakamura, M. Shiozaki / Tetrahedron Letters 42 (2001) 2701–2704
5. Lee, C. B. Dissertation of Stanford University, directed
by Trost, B. M., 1999.
Guariniello, L.; Iadonisi, A.; Mangoni, L. Synlett 2000,
9, 1277–1278.
6. (a) Sato, K.; Suzuki, K.; Ueda, M.; Katayama, M.;
Kajihara, Y. Chem. Lett. 1991, 1469–1472.; Sato, K.;
Kajihara, Y.; Nakamura, Y.; Yoshimura, J. Chem. Lett.
1991, 1559–1562. (b) Deloisy, S.; Thang, T.; Olesker, A.;
Lukacs, G. Tetrahedron Lett. 1994, 35, 4783–4786.
7. Fukase, K.; Matsumoto, T.; Ito, N.; Yoshimura, T. Bull.
Chem. Soc. Jpn. 1992, 65, 2643–2654.
8. Preactivated [Ir(COD)(PMePh2)2]PF6 by hydrogen was
used as a catalyst. (a) Haines, L. M.; Singleton, E. J.
Chem. Soc., Dalton Trans. 1972, 1891–1896. (b) Oltvoort,
J. J.; van Boeckel, C. A. A.; de Koning, J. H.; van Boom,
J. H. Synthesis 1981, 305–308.
9. The lactone formation from methylamide 11 did not
proceed under these conditions. Treatment of 11 under
more acidic conditions (e.g. CSA in toluene) caused
deprotection of the SEM group.
10. Protective Groups in Organic Synthesis, 3rd ed.; Greene,
T. W.; Wuts, P. G. M., Eds.; John Wiley and Sons, 1999;
pp. 76–86.
12. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111,
314–321.
13. The melting point, optical rotatory value, and spectral
data of the synthetic compound agreed closely with those
of both natural and synthetic sphingofungin E reported
by the Merck group1c and Trost,5 respectively. Mp 145–
147°C. [h]2D4 −5.43 (c 0.48, CH3OH). IR (KBr) 3532,
1
3198, 2928, 2855, 1711, 1637 cm−1. H NMR (500 MHz,
CD3OD) l 0.90 (t, 3H, J=6.8 Hz), 1.24–1.46 (m, 12H),
1.50–1.56 (m, 4H), 2.06 (q, 2H, J=6.8 Hz), 2.44 (t, 2H,
J=7.3 Hz), 2.45 (t, 2H, J=7.3 Hz), 3.64 (d, 1H, J=6.9
Hz), 3.85 (d, 1H, J=11.7 Hz), 3.94–4.00 (m, 2H, involv-
ing a doublet at l 3.98, J=11.7 Hz), 4.11 (t, 1H, J=7.3
Hz), 5.45 (dd, 1H, J=7.8 Hz, 15.6 Hz), 5.77 (dt, 1H,
J=15.6 Hz, 6.8 Hz). 13C NMR (125 MHz, CD3OD)
14.37, 23.58, 24.84, 24.86, 29.99, 30.01, 30.14, 30.16,
32.81, 33.42, 43.45, 43.48, 64.95, 70.03, 71.11, 75.52,
76.27, 130.14, 135.70, 173.42, 214.34. HRMS (FAB, posi-
tive) calcd for C21H40NO7 (M+H)+: 418.2805. Found:
418.2806.
11. Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 1999, 40, 8439–8441; Adinolfi, M.;
.
.