Studies toward the Total Synthesis of Scyphostatin: First Entry to the Highly Functionalized Cyclohexenone Segment

Article abstract of DOI:10.1021/ol015873s

(matrix presented) The cyclohexenone segment 2 of scyphostatin (1), a potent inhibitor of neutral sphingomyelinase, was synthesized in an enantioselective manner starting from the bromo ether 5 and D-serinal derivative 3. The synthetic method features a c

Full text of DOI:10.1021/ol015873s

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1653-1656
Studies toward the Total Synthesis of
Scyphostatin: First Entry to the Highly
Functionalized Cyclohexenone Segment
Takashi Izuhara† and Tadashi Katoh*
Sagami Chemical Research Center, Nishi-Ohnuma, Sagamihara,
Kanagawa 229-0012, Japan
takatoh@alles.or.jp
Received March 21, 2001
ABSTRACT
The cyclohexenone segment 2 of scyphostatin (1), a potent inhibitor of neutral sphingomyelinase, was synthesized in an enantioselective
manner starting from the bromo ether 5 and D-serinal derivative 3. The synthetic method features a coupling reaction of 5 with 3 to construct
the asymmetric quaternary carbon center and a stereospecific epoxide ring formation as the key steps.
Scyphostatin (1, Figure 1), isolated from the culture broth
of Dasyscyphus mollissimus SANK-13892 by Ogita et al. at
the Sankyo research group in 1997, is a powerful and specific
inhibitor of neutral sphingomyelinase (N-SMase).1-3 This
natural product is the most potent of the few known small
molecule inhibitors of N-SMase.4 Ceramide, the product of
sphingomyelin hydrolysis by N-SMase, has been recognized
to be a lipid second messenger in cell membranes and plays
key roles in the regulation of cell proliferation, differentiation,
and apoptosis. Since the use of N-SMase inhibitors can
regulate the level of ceramide in a wide variety of cells, 1 is
anticipated to be a promising agent for the treatment of
ceramide-mediated pathogenic states such as inflammation
and immunological and neurological disorders.5
† Graduate student from Department of Electronic Chemistry, Tokyo
Institute of Technology, Yokohama 226-8502, Japan.
(1) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T. J.
Am. Chem. Soc. 1997, 119, 7871.
(2) Nara, F.; Tanaka, M.; Hosoya, T.; Suzuki-Konagai, K.; Ogita, T. J.
Antibiot. 1999, 52, 525.
(3) Nara, F.; Tanaka, M.; Masuda-Inoue, S.; Yamamoto, Y.; Doi-
Yoshioka, H.; Suzuki-Konagai, K.; Kumakura, S.; Ogita, T. J. Antibiot.
1999, 52, 531.
(4) It is reported that 1 exhibits N-SMase and acidic SMase (A-SMase)
with IC50 values of 1.0 and 49.3 µM, respectively.
Figure 1. Structures of scyphostatin (1) and the cyclohexenone
segment 2.
10.1021/ol015873s CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

The structure of 1 was revealed by extensive spectroscopic
studies to have a novel, highly oxygenated cyclohexane ring
incorporated with a C-20 unsaturated fatty acid substituted
amino propanol side chain.1 This initial structure elucidation
only determined the relative and absolute stereochemistry
of the cyclohexenone moiety in 1. Recently, Kogen et al. at
the Sankyo research group elucidated and reported the
relative and absolute configurations of the three stereocenters
within the C-20 unsaturated fatty acid moiety.6 Subsequently,
Hoye et al. disclosed an enantioselective synthesis of the
C-20 unsaturated fatty acid moiety, leading to alternative
proof of its stereostructure including the absolute configu-
ration.7 Its remarkable biological properties as well as its
unique structural features make 1 an exceptionally intriguing
and timely target for total synthesis.
believed that 3 would access exclusively from the less
hindered R-face of the enolate generated from II under the
influence of the â-oriented O-isopropylidene moiety, leading
to construction of the desired asymmetric quaternary carbon
center at C-6. The coupling product I would be converted
into 2 by sequential functional group manipulation and
deprotection or vice versa; the sequence involves regeneration
of the cyclohexenone olefin moiety and stereospecific
epoxide ring formation as the pivotal steps. The olefin-
masked enone II bearing three contiguous oxygen function-
alities with correct stereochemistries at C-4, C-5, and C-6
has been already prepared starting with commercially avail-
able (-)-quinic acid (4) in our previous work.8
As shown in Scheme 2, the synthesis commenced with
the crucial coupling reaction of the bromo ether 5,8
a
In the course of our ongoing project directed toward the
total synthesis of 1, we have recently developed a synthetic
pathway to (4S,5S,6S)-6-benzyl-4,5-epoxy-6-hydroxy-2-cy-
clohexen-1-one, which represents a model compound for the
cyclohexenone segment 2.8 In this communication, we
present an efficient and facile method for the synthesis of 2
possessing the N,O-protected amino propanol side chain with
the requisite asymmetric carbon center. To the best of our
knowledge, this is the first entry to the highly and densely
functionalized cyclohexenone moiety of 1. Quite recently, a
synthetic study toward this type of cyclohexenone system
was reported by Gurjar et al.9
Scheme 2. Synthesis of the Key Intermediate 13a
The retrosynthetic plan for 2 was designed as outlined in
Scheme 1, which is based upon our preliminary studies.8 The
Scheme 1. Retrosynthetic Plan for the Cyclohexenone
Segment 2
a Reagents and conditions: (a) LiN(TMS)2, THF, -78 °C; (R)-
N-(p-toluenesulfonyl)-N,O-isopropylidene serinal (3), -78 °C, 95%;
(b) NaN(TMS)2, THF, -78 °C; CS2, -78 f -50 °C; MeI, -78
f -50 °C, 88%; (c) n-Bu3SnH, Et3B, toluene, rt, 95%; (d) 1.0 M
HCl, THF, 55 °C; (e) Cl3COCOCl, pyridine, THF, rt, 67% (two
steps); (f) TMSI, CCl4-CH2Cl2, -20 °C, 74%; (g) Zn, AcOH,
MeOH, 60 °C, 95%; (h) Ph2O, 230 °C, 59%.
key feature in this plan is an aldol-type coupling of the olefin-
masked enone II with D-serinal derivative 3,10 where we
(5) For a recent excellent review on the catabolites of sphingolipids as
novel therapeutic targets, see: Kolter, T.; Sandhoff, K. Angew. Chem., Int.
Ed. 1999, 38, 1532.
(6) Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2,
505.
synthetic equivalent of the olefin-masked enone II, with
D-serinal derivative 310 [(R)-N-(p-toluenesulfonyl)-N,O-
(7) Hoye, T. R.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481.
(8) Izuhara, T.; Katoh, T. Tetrahedron Lett. 2000, 41, 7651.
(9) Gurjar, M. K.; Hotha, S. Heterocycles 2000, 53, 1885.
Org. Lett., Vol. 3, No. 11, 2001
1654

isopropylidene serinal]. The enolate anion generated in situ
by treatment of 5 with lithium bis(trimethylsilyl)amide [LiN-
(TMS)2] (2.2 equiv) in THF at -78 °C was allowed to react
with 3, providing an excellent yield (95%) of the coupling
product 6 as a hardly separable mixture of the epimeric
Scheme 3. Synthesis of the Cyclohexenone Segment 2a
1
alcohols (ca. 9:1 by 500 MHz H NMR). In this reaction,
intramoleculer cyclopropane ring formation occurs prior to
the coupling reaction with 3. Removal of the sterically
hindered hydroxy group in 6 was best achieved by applying
the Barton procedure11 with some improvements in the
reaction conditions. Thus, reaction of 6 with sodium bis-
(trimethylsilyl)amide [NaN(TMS)2] followed by carbon
disulfide and iodomethane gave the corresponding methyl
xanthate 7 in 88% yield, which was then treated with tri-n-
butyltinhydride and triethylborane12 in toluene at ambient
temperature, providing the desired deoxygenated product 8
in 95% yield.
a Reagents and conditions: (a) MsCl, DMAP, pyridine, 0 °C f
rt, 83%; (b) TFA, H2O, 0 °C, 100%; (c) 0.1 M NaOH, CH2Cl2, 0
°C, 75%.
To differentiate the two isopropylidene protecting groups
in 8, it was converted to the corresponding cyclic carbamate
10. Thus, treatment of 8 with aqueous hydrogen chloride in
THF at 55 °C furnished an equilibrium mixture of the Ts-
protected â-amino alcohol 9a and the cyclic hemiacetal 9b
(ca. 1:1); this mixture was then allowed to react with
phosgene dimer (trichloromethyl chloroformate) in the pres-
ence of pyridine in THF, affording the desired cyclic
carbamate 10 in 67% yield for the two steps.
2 in 75% yield. The stereostructure of 2 was unambiguously
confirmed by single X-ray crystal structure analysis as
depicted in Figure 2.
With the key intermediate 10 possessing the requisite N,O-
protected amino propanol side chain with correct stereo-
chemistry in hand, our next efforts were devoted to regen-
eration of the cyclohexenone olefin moiety. Toward this end,
regioselective cleavage of the cyclopropane ring in 10 by
reaction with iodotrimethylsilane (TMSI) provided the γ-iodo
ketone 11 (74%), which was further treated with zinc powder
in methanol containing acetic acid to furnish the endo-alcohol
12 in 95% yield. Retro-Diels-Alder reaction of 12 proceeded
effectively by thermolysis at 230 °C in diphenyl ether,13
leading to the formation of the cyclohexenone 13 in 59%
yield.
The final route that led to completion of the synthesis of
the targeted cyclohexenone segment 2 is summarized in
Scheme 3, which involves the critical epoxide ring formation
utilizing the two oxygen functionalities present at C-4 and
C-5 in 13. After mesylation of the hydroxy group in 13 under
conventional conditions (83%), the resulting mesylate 14 was
then subjected to acid hydrolysis of the isopropylidene moiety
by reaction with aqueous trifluoroacetic acid at 0 °C,
affording the corresponding diol 15 in quantitative yield.
Finally, exposure of 15 to aqueous sodium hydroxide in
dichloromethane at 0 °C for 30 min led to the formation of
Figure 2. Chem 3D representation of 2 from the X-ray coordinates.
In summary, we have succeeded in developing a facile
synthetic pathway to the cyclohexenone segment 2, which
is the first entry to the highly and densely functionalized
cyclohexenone moiety of 1. The explored synthetic method
features an aldol-type coupling of the bromo ether 5 with
D-serinal derivative 3 to construct the requisite asymmetric
quaternary carbon center at C-6 and the final epoxide ring
formation as the key steps. Further investigation toward the
total synthesis of 1 and analogues is now in progress and
will be reported in due course.
(10) (a) Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz,
P. Tetrahedron 1998, 54, 6051. (b) Uchida, H.; Nishida, A.; Nakagawa,
M. Tetrahedron Lett. 1999, 40, 113.
(11) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(12) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991,
64, 403. (b) Yorimitsu, K.; Nakamura, T.; Shinokubo, H.; Oshima, K. J.
Org. Chem. 1998, 63, 8604 and references therein.
(13) Ogasawara, K. J. Synth. Org. Chem. Jpn. 1999, 57, 957 and
references therein.
Acknowledgment. We are grateful to Drs. H. Kogen and
T. Ogita, Sankyo Co., Ltd., for many useful suggestions and
Org. Lett., Vol. 3, No. 11, 2001
1655

encouragement. We kindly thank Mr. Y. Ijuin, Sagami
Chemical Research Center, for the X-ray crystallographic
analysis of 2.
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedure and characterization data for all new compounds. This
OL015873S
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Org. Lett., Vol. 3, No. 11, 2001