cal changes in osteoclast-like multinucleated cells (OCLs)
in a dose-dependent manner (0.01-0.05 µM).10 It has
recently been reported that 1 can also reduce ꢀ-amyloid
generation without affecting ꢀ-amyloid-cleaving enzyme
(BACE) or PS/γ-secretase activity similar to how bafilomycin
does.11,12 Several groups have previously reported the
synthesis of destruxin analogues and evaluated their biologi-
cal activities.13 These reports demonstrated that the epoxide
in the side chain could be crucial for exhibiting the biological
activity. The absolute stereochemistry of the epoxide,
however, has not been established. To elucidate the
structure-activity relationships involving destruxin E (1),
we are interested in the total synthesis and the library
synthesis of 1 via solid-phase synthesis. We thus report herein
a solid-phase-assisted total synthesis of the two possible
diastereomers of destruxin E in order to determine the
absolute stereochemistry of the epoxide and evaluate the
biological activity of destruxin E.
coupling of five fragments, ꢀ-alanine, NMe-alanine, NMe-
valine, isoleucine, and R-hydroxy acid-proline derivative
(HA-Pro-OH) 4, by a solid-phase peptide synthesis using a
trityl linker. Both diastereomers 4 will be prepared from
chiral lactones 5a and 5b by hydrolysis of the lactones,
followed by amidation with proline. The optically active
lactones 5 would be provided utilizing Evans asymmetric
allylation of 6, followed by dihydroxylation and concomitant
cyclization.
Initially, HA-Pro-OH 4a and 4b were prepared according
to Scheme 2. Acylation of Evans chiral auxiliary 7 with
Scheme 2. Synthesis of 4a and 4b
Scheme 1. Retrosynthetic Analysis of Destruxin E (1)
benzyloxyacetyl chloride, followed by removal of the benzyl
group and protection of the resulting alcohol with a TBS
group provided 6 in 98% yield. The Evans asymmetric
alkylation15 of 6 proceeded smoothly at -30 °C (LiHMDS/
allyl bromide) to afford allylated product 8 with high
diastereoselectivity (81%, dr >98:2). Dihydroxylation of 8
with OsO4/NMO induced concomitant formation of γ-lac-
tones, which were separated by silica gel column chroma-
tography to afford the two desired diastereomers 5a16 (44%)
and 5b17 (42%). Acid 9a was formed by hydrolysis of the
Our synthetic strategy is illustrated in Scheme 1. Destruxin
E (1) and epi-destruxin E (2) can be synthesized from
cyclization precursor 3a or 3b through macrolactonization,14
followed by formation of the epoxide in the side chain. The
cyclization precursor 3 would be obtained by sequential
(13) (a) Cavelier, F.; Jacquier, R.; Mercadier, J.-L.; Verducci, J.
Tetrahedron 1996, 52, 6173–6186. (b) Cavelier, F.; Jacquier, R.; Mercadier,
J.-L.; Verducci, J.; Traris, M.; Vey, A. J. Peptide Res. 1997, 50, 94–101.
(c) Caveliar, F.; Vercci, J.; Andre´, F.; Haraux, F.; Sigalat, C.; Traris, M.;
Vey, A. Pestic. Sci. 1998, 52, 81–89. (d) Ast, T.; Barran, E.; Kinne, L.;
Schmidt, M.; Germeroth, L.; Simmons, K.; Wenschuh, H. J. Peptide Res.
2001, 58, 1–11.
(9) Pe´rez-Saya´ns, M.; Somaza-Mart´ın, J. M.; Barros-Angueria, F.; Rey,
J. M. G.; Garc´ıa-Garc´ıa, A. Cancer Treat. ReV. 2009, 35, 707–713, and
refernces therein.
(14) Synthetic studies of destruxin derivatives by macrolactonization
have been reported. (a) Total synthesis of destruxin B was achieved using
macrolactonization though the yield was not reported: Kuyama, S.; Tamura,
S. Agric. Biol. Chem. 1965, 29, 168–169. (b) Macrolactonization failed in
the synthetic study for protodestruxin: Lee, S.; Izumiya, N.; Suzuki, A.;
Tamura, S. Tetrahedron Lett. 1975, 11, 883–886.
(10) Nakagawa, H.; Takami, M.; Udagawa, N.; Sawae, Y.; Suda, K.;
Sasaki, T.; Takahashi, N.; Wachi, M.; Nagai, K.; Woo, J. T. Bone 2003,
33, 443–455.
(11) Itoh, N.; Okochi, M.; Tagami, S.; Nishitomi, K.; Nakayama, T.;
Yanagida, K.; Fukutomi, A.; Jiang, J.; Mori, K.; Hosono, M.; Kikuchi, J.;
Nakano, Y.; Takinami, Y.; Dohi, K.; Nishigaki, A.; Takemoto, H.;
Minagawa, K.; Katoh, T.; Willem, M.; Haass, C.; Morihara, T.; Tanaka,
T.; Kudo, T.; Hasegawa, H.; Nishimura, M.; Sakaguchi, G.; Kato, A.;
(15) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737–1739. (b) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D.
Org. Lett. 2000, 2, 2165–2167.
(16) 5a was converted into reported (2R,4S)-2-hydroxy-4-hydroxy-
methyl-4-butanolide, whose spectral data were in good agreement with those
previously reported: Uchikawa, O.; Okukado, N.; Sakata, T.; Arase, T.;
Terada, K. Bull. Chem. Soc. Jpn. 1988, 61, 2025–2029.
Takeda, M. Neurodegener. Dis. 2009, 6, 230–239
.
(12) Knops, J.; Suomensaari, S.; Lee, M.; McConlogue, L.; Seubert,
P.; Sinha, S. J. Biol. Chem. 1995, 270, 2419–2422
Org. Lett., Vol. 12, No. 17, 2010
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