Synthesis (and alternative proof of configuration) of the scyphostatin C(1')-C(20') trienoyl fragment.

Article abstract of DOI:10.1021/ol0058386

[reaction--see text] Each of four diastereomers of structure 2, corresponding to the lipophilic side chain of scyphostatin (1), were prepared. Careful analysis of their NMR spectral data and comparison with those of the natural product corroborates the re

Full text of DOI:10.1021/ol0058386

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1481-1483
Synthesis (and Alternative Proof of
Configuration) of the Scyphostatin
C(1′)−C(20′) Trienoyl Fragment
Thomas R. Hoye* and Manomi A. Tennakoon
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hoye@chem.umn.edu
Received March 21, 2000
ABSTRACT
Each of four diastereomers of structure 2, corresponding to the lipophilic side chain of scyphostatin (1), were prepared. Careful analysis of
their NMR spectral data and comparison with those of the natural product corroborates the recently reported (Org. Lett. 2000, 2, 505)
stereochemical assignment. A strategy for the stereoselective synthesis of 2 has been achieved.
Scyphostatin (1) was isolated from the mycelial extract of
Trichopeziza mollissima by Ogita et al. (Sankyo Co., Ltd.,
Japan) in 1997.1 It is the most potent (IC50 ) 1.0 µM)2 of
the few known small molecule inhibitors of membrane-bound
neutral sphingomyelinase (N-SMase). N-SMase inhibitors3
recently have attracted considerable interest since they are
believed to be promising candidates for the treatment of
inflammation and autoimmune disease.
studies.1 However, in that initial report the absolute and
relative configurations of the three stereocenters at C(8′),
C(10′), and C(14′) within the lipid moiety had not yet been
addressed. We, therefore, initiated a study aimed at deducing
the relative configuration of the C(1′)-C(20′) trienoyl side
chain in 1 while simultaneously establishing an efficient
synthesis of that subunit. Very recently, the Sankyo group
deduced and reported the absolute and relative configuration
of the lipophilic moiety, determined by degradation of 1 and
chemical correlation to synthetic fragments of unambiguous
stereoisomeric composition.4 In our studies presented here,
we have developed a synthesis of the C(1′)-C(20′) side chain
and independently determined the relative configuration
within that subunit.
The structure of scyphostatin (1) consists of a lipophilic
side chain [C(1′)-C(20′)] and a polar cyclohexenone moiety.
Our approach involved the comparison of proton and
carbon NMR data from each of the four diastereomeric
(2) (a) Nara, F.; Tanaka, M.; Hosoya, T.; Suzuki-Konagai, K.; Ogita, T.
J. Antibiot. 1999, 52, 525-30. (b) Nara, F.; Tanaka, M.; Masuda-Inoue,
S.; Yamasato, Y.; Doi-Yoshioka, H.; Suzuki-Konagai, K.; Kumakura, S.;
Ogita, T. J. Antibiot. 1999, 52, 531-5.
(3) (a) Tanaka, M.; Nara, F.; Yamasato, Y.; Masuda-Inoue, S.; Doi-
Yoshioka, H.; Kumakura, S.; Enokita, R.; Ogita, T. J. Antibiot. 1999, 52,
670-3. (b) Tanaka, M.; Nara, F.; Yamasato, Y.; Ono, Y.; Ogita, T. J.
Antibiot. 1999, 52, 827-30.
(4) Saito, S.; Tanaka, N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2,
505-6.
The relative and absolute configuration of the cyclohexenone
core was assigned on the basis of NMR and derivatization
(1) Tanaka, M.; Nara, F.; Suzuki-Konagai, K.; Hosoya, T.; Ogita, T. J.
Am. Chem. Soc. 1997, 119, 7871-2.
10.1021/ol0058386 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

synthetic fragments of constitution 2 with those resonances
from analogous protons and carbons in the intact natural
product 1.5 Anisotropic chemical shift effects within dia-
stereomers often operate over relatively long distances.
Hence, we were optimistic that the substituents at the pair
of stereogenic centers among C(8′)/C(10′)/C(14′) (1,3-, 1,5-,
and 1,7-disposed across an intervening E-alkene) in each of
the four possible diastereomers of 2 would communicate to
a sufficient extent to give rise to distinct sets of NMR data.
The synthesis began (Scheme 1) with the known nonra-
cemic alcohol 3 (92% ee), available in multigram quantities
Dimethyl cuprate displacement of the tosylate11 and TBDPS
removal gave alcohol 9ss. TPAP oxidation of 9ss gave
aldehyde 10ss (not shown) and immediate Horner-Wad-
sworth-Emmons olefination with phosphonate 1112 gave the
E,E,E-triene13 ester 12ss, thereby completing the synthesis
of the C(1′)-C(20′) fragment.
Two variations (Scheme 2) to the above theme allowed
access to the three additional diastereomers (i.e., “sa”, “as”,
Scheme 2
Scheme 1
(a ) steps e-f from Scheme 1. (b) steps g-k from Scheme 1.
(c) KF, florisil, MeOH, rt. (d) step l from Scheme 1. (e)
TBSO(CH2)2NH2, Me3Al, CH2Cl2, then 12, rt.
(a ) TBDPSCl, Et3N, DMAP, CH2Cl2, rt, 99%. (b) K2CO3,
MeOH:H2O (1:1, v/v), reflux, 88%. (c) p-TsCl, Et3N, DMAP,
CH2Cl2, rt, 99%. (d) TMSCtCLi, THF/DMSO, -78 °C to rt; then
K2CO3, MeOH, 67%. (e) (i) Me3Al, Cp2ZrCl2, then 4, CH2Cl2, rt;
(ii) MeLi, hexanes, -40 °C. (f) (S)-6, hexanes, -40 °C to rt, 51%.
(g) DIBAL, CH2Cl2, -78 °C to 0 °C, 77%. (h) p-TsCl, Et3N,
DMAP, CH2Cl2, rt, 97%. (i) Me2CuLi, Et2O, -40 °C to rt. (j)
TBAF, THF, rt, 72%, two steps. (k) TPAP, NMO, CH2Cl2, rt. (l)
(EtO)2P(O)CH2(CHdCH)2CO2Et, LDA, -78 to 0 °C, 81%, two
steps.
and “aa”). First, coupling 5 with triflate (R)-6 instead of (S)-6
gave the anti,syn ester 7as. Second, each of the syn,syn- and
(5) For example, see: (a) Cha, J. K.; Christ, W. J.; Finan, J. M.; Fujioka,
H.; Kishi, Y.; Klein, L. L.; Ko, S. S.; Leder, J.; McWhorter, W. W., Jr.;
Pfaff, K.-P.; Yonaga, M.; Uemura, D.; Hirata, Y. J. Am Chem. Soc. 1982,
104, 7369-7371 and preceding papers. (b) Hoye, T. R.; Suhadolnik, J. C.
J. Am. Chem. Soc. 1987, 109, 4402-4403. (c) Gale, J. B.; Yu, J.-G.; Khare,
A.; Hu, X. E.; Ho, D. H.; Cassady, J. M. Tetrahedron Lett. 1993, 34, 5851-
4. (d) Oikawa, H.; Matsud, I.; Ichihara, A.; Kohmoto, K. Tetrahedron Lett.
1994, 35, 1223-6. (e) Boyle, C. D.; Harmange, J.-C.; Kishi, Y. J. Am.
Chem. Soc. 1994, 116, 4995-6. (f) Harmange, J.-C.; Boyle, C. D.; Kishi,
Y. Tetrahedron Lett. 1994, 35, 6819-22. (g) Kishi, Y.; Boyle, C. D.
Tetrahedron Lett. 1995, 36, 5695-8. (h) Kishi, Y.; Boyle, C. D. Tetrahedron
Lett. 1995, 36, 4579-82. (i) Zheng, W.; DeMattei, J. A.; Wu, J. P.; Duan,
J. J. W.; Cook, L. R.; Oinuma, H.; Kishi, Y. J. Am Chem. Soc. 1996, 118,
7946-68. (j) Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.;
Murata, M.; Tachibana, K.; Yasumoto T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1672-5. (k) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata,
M.; Tachibana, K.; Yasumoto T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1675-8. (l) Kishi, Y. Pure Appl. Chem. 1998, 70, 339-344. (m) Kobayashi,
Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2177-80. (n) Lee, J.;
Kobayashi, Y.; Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2181-4.
from the porcine pancreatic lipase (PPL) catalyzed resolution
of meso-2,4-dimethyl-1,5-pentanediol.6,7 Protection of the
alcohol as its TBDPS ether, acetate cleavage, tosylation,
displacement with TMSCtC-Li,8 and TMS removal gave
alkyne 4. The third stereocenter [C(14′)] was introduced by
reaction of the triflate of S-methyl lactate [(S)-6] with the
alkenylalanate 5,9 which was derived from zirconocene
dichloride-promoted addition of trimethylaluminum10 to
alkyne 4. The resulting syn,syn-(E)-â,γ-unsaturated ester 7ss
[“ss” ) syn,syn ) Me(17′)/Me(19′)-syn,Me(19′)/Me(20′)-
syn] was reduced (DIBAL) and tosylated to provide 8ss.
1482
Org. Lett., Vol. 2, No. 10, 2000

anti,syn-aldehydes 10ss and 10as was epimerized with KF
and Florisil in methanol to give access to diastereomeric
aldehydes 10sa and 10aa, respectively. In each case the
equilibrium slightly favored (Keq ) ∼1.5) the C(8′)-C(10′)
anti diastereomer (i.e., 10sa over 10ss and 10aa over 10as).
Each of these epimeric mixtures was subjected to coupling
with phosphonate 11. The resulting diastereomeric pairs of
trienoates (12ss/12sa and 12as/12aa) were separable by
MPLC on silica gel.
1
To compare the H and 13C NMR spectral data of our
synthetic C(1′)-C(20′) fragments with those of the natural
scyphostatin (1), we chose to convert the ethyl esters 12ss-
12aa to the 2-hydroxyethylamides 2ss-2aa. This was
accomplished by reacting each of the four diastereomers of
12 with “TBSO(CH2)2NHAlMe2”,14 followed by desilylation.
1
Each of the four diastereomers of 2 gave distinctive H
and 13C NMR spectra. The proton spectra of 2ss-2aa (as
well as of 12ss-12aa) showed small but perceptible differ-
ences in many of the chemical shifts and splitting patterns
of analogous resonances. The proton chemical shift differ-
ences (∆δH) for H(2′)-H(20′) between scyphostatin (1)15 and
each of the diastereomers 2 (∆δ ) δ1 - δ2) are plotted in
Figure 1 (all data recorded in CD3OD). Simple visual
inspection of these data indicate that the spectrum of the
syn,syn isomer 2ss most closely matches that of the natural
product. To make this a more objective exercise, we also
calculated the ø-squared value for the aliphatic protons
20
H(8′)-H(20′) {ø2 ) [∑ (δ1 - δ2)2] × 105} for each of the
8′
four sets of 1H NMR data (see insets in the upper right corner
of each graph). Again, the best correlation (smallest ø2) is
between 1 and 2ss. Analogous analysis of the 13C NMR data
Figure 1. Graphical representation of the differences in 1H NMR
chemical shifts between each of the diastereomers of 2 vs
scyphostatin (1) for ppotons 2′-20′ and the values of ø squared
(ø2, defined in text) for nontrienic protons 8′-20′.
20′
{graphs not shown; ø2 ) [∑ (δ1 - δ2)2] × 102 ) 1.3, 6.2,
8′
166, and 170 for 2ss, 2as, 2sa, and 2aa, respectively} led to
the same conclusionsnamely, the relative configuration of
the C(1′)-C(20′) fragment is 8′R*,10′S*,14′R*.
Happily, the relative configuration we have deduced is
identical to that recently reported by the Sankyo group.4
Moreover, one of the initial degradation products of scy-
phostatin (1) they prepared was the methyl ester analogue
of trienoate 12ss. Its specific rotation was similar to that of
the ethyl ester we synthesized {methyl ester: [R]rDt ) -2.5
(6) Lin, G.; Xu, W. Tetrahedron 1996, 52, 5907-12.
(7) meso-2,4-Dimethyl-1,5-pentanediol was prepared from the LiAlH4
reduction of meso-R,R′-dimethyl glutaric anhydride, which in turn was
prepared by the method described by Wiley: P. F.; Gerzon, K.; Flynn, E.
H.; Sigal, M. V.; Weaver, O.; Quarck, U. C.; Chauvette. R. R.; Monahan,
R. J. Am. Chem. Soc. 1957, 79, 6062-70.
(8) Lautens, M.; Tam, W.; Lautens, J.; Edwards, L.;. Crudden, C.; Smith,
C. J. Am. Chem. Soc. 1995, 117, 6863-79.
(9) Hoye, R. C.; Baigorria, A.; Danielson, M.; Pragman, A.; Rajapakse,
H. J. Org. Chem. 1999, 64, 2450-3.
(c 0.50, CHCl3) vs ethyl ester (12ss) [R]rt ) -2.35 (c 0.34,
D
CHCl3)}, thereby affirming the absolute configuration as
well. In conclusion, we have developed both an efficient
stereoselective synthesis of the scyphostatin (1) lipophilic
trienoyl side chain and an alternative proof of its relative
and absolute configuration.
(10) (a) Okukado, N.; Negishi, E.-I. Tetrahedron Lett. 1978, 19, 2357-
60. (b) Negishi, E.-I. Pure. Appl. Chem. 1981, 53, 2333-56.
(11) Guanti, G.; Banfi, L.; Narisano, E.; Zannetti, M. T. J. Org. Chem.
1993, 58, 1508-14.
Acknowledgment. This research was supported by the
National Institutes of Health (CA-76497). We thank Dr.
1
Masahiro Tanaka, Sankyo Co., Ltd., for providing the H
(12) (a) Kinoshita, M.; Takami, H.; Taniguchi, M.; Tamai, T. Bull. Chem.
Soc. Jpn. 1987, 60, 2151-61. (b) Be´rube´, G.; Deslongchamps, P. Can. J.
Chem. 1990, 68, 404-11.
and 13C NMR spectra of natural 1, which were instrumental
in our analyses.
(13) Analysis of the crude 1H NMR spectrum showed less than ∼8% of
the (SiO2 separable) E,E,Z-isomer.
(14) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
4171-4.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
(15) Original proton and carbon NMR spectra were kindly provided by
Dr. M. Tanaka. Since we observed several small but important differences
between the spectral data listed in the original report1 and the values we
read from the provided spectra, we have used the latter set for the analyses
summarized in Figure 1. The values that we recorded from the provided
proton and carbon spectra of scyphostatin can be found in Table C in the
Supporting Information.
1
Tables of H and 13C NMR spectral data for 2ss, 2as, 2sa,
2aa, and 1. This material is available free of charge via the
Internet at http://pubs.acs.org/.
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