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DOI: 10.1055/s-0029-1216931
Total Synthesis of Largazole - Devolution of a Novel Synthetic Strategy
Publication History
Publication Date:
14 August 2009 (online)

Abstract
The cyanobacterial isolate largazole embodies a compelling combination of a relatively simple, yet unique cyclic depsipeptide structure with remarkable levels of selective cytotoxicity against cancer cell lines versus nontransformed cells. The unique structure of largazole inspired a strategically novel and aggressive approach towards its expedient total synthesis. This involved an initial dissection into an epoxy aldehyde and an unprotected tetrapeptide, representing the polyketide and polypeptide domains of largazole, respectively. These fragments were successfully joined using NHC-mediated amidation, but subsequent assembly of the cyclic depsipeptide via lactonization was thwarted. A reordering of key couplings led to a successful assembly of largazole.
Key words
total synthesis - heterocycles - depsipeptide - N-heterocyclic carbene - thiazoline
- 1
Taori K.Paul VJ.Luesch H. J. Am. Chem. Soc. 2008, 130: 1806 - 2a
Ying Y.Taori K.Kim H.Hong J.Luesch H. J. Am. Chem. Soc. 2008, 130: 8455Reference Ris Wihthout Link - 2b
Nasveschuk CG.Ungermannova D.Liu X.Phillips AJ. Org. Lett. 2008, 10: 3595Reference Ris Wihthout Link - 2c
Seiser T.Kamena F.Cramer N. Angew. Chem. Int. Ed. 2008, 47: 6483Reference Ris Wihthout Link - 2d
Bowers A.West N.Taunton J.Schreiber SL.Bradner JE.Williams RM. J. Am. Chem. Soc. 2008, 130: 11219Reference Ris Wihthout Link - 2e
Ghosh AK.Kulkarni S. Org. Lett. 2008, 10: 3907Reference Ris Wihthout Link - 2f
Ren Q.Dai L.Zhang H.Tan W.Xu Z.Ye T. Synlett 2008, 15: 2379Reference Ris Wihthout Link - 2g
Numajiri Y.Takahashi T.Takagi M.Shin-ya K.Doi T. Synlett 2008, 16: 2483Reference Ris Wihthout Link - 3a
Chow KY.Bode JW. J. Am. Chem. Soc. 2004, 126: 8126Reference Ris Wihthout Link - 3b
Bode JW.Sohn SS. J. Am. Chem. Soc. 2007, 129: 13798Reference Ris Wihthout Link - 3c
Vora HU.Rovis T. J. Am. Chem. Soc. 2007, 129: 13796Reference Ris Wihthout Link - 4a
Smith ND.Goodman M. Org. Lett. 2003, 5: 1035Reference Ris Wihthout Link - 4b
Avenoza A.Cativiela C.Corzana F.Peregrina JM.Sucunza D.Zurbanoa MM. Tetrahedron: Asymmetry 2001, 12: 949Reference Ris Wihthout Link - 5a
Chen J.Forsyth CJ. Org. Lett. 2003, 5: 1281Reference Ris Wihthout Link - 5b
Chen J.Forsyth CJ. J. Am. Chem. Soc. 2003, 125: 8734Reference Ris Wihthout Link - 6
Moody CJ.Bagley MC. J. Chem. Soc., Perkin Trans. 1 1998, 601 - 7
Boden EP.Keck GE. J. Org. Chem. 1985, 50: 2394 - 8
Inanaga J.Hirata K.Saeki H.Katsuki T.Yamaguchi M. Bull. Chem. Soc. Jpn. 1979, 52: 1989 - 9
Mukaiyama T.Usui M.Saigo K. Chem. Lett. 1976, 49 - 10
Kurihara T.Nakajima Y.Mitsunobu O. Tetrahedron Lett. 1976, 2455 - 11
Shiina I.Kubota M.Ibuka R. Tetrahedron Lett. 2002, 43: 7535 - 12a . inventors; Kokai
Tokkyo Koho JP 03141296.
Reference Ris Wihthout Link
- 12b
Ueda H.Nakajima H.Hori Y.Fujita T.Nishimura M.Goto T.Okuhara M. J. Antibiot. 1994, 47: 301Reference Ris Wihthout Link - 12c
Shigematsu N.Ueda H.Takase S.Tanaka H. J. Antibiot. 1994, 47: 311Reference Ris Wihthout Link - 12d
Ueda H.Manda T.Matsumoto S.Mukumoto S.Nishigaki F.Kawamura I.Shimomura K. J. Antibiot. 1994, 47: 315Reference Ris Wihthout Link - 12e
Masuoka Y.Nagai A.Shin-ya K.Furihata K.Nagai K.Suzuki K.Hayakawa Y.Seto H. Tetrahedron Lett. 2001, 42: 41Reference Ris Wihthout Link - 13
Kang SH.Kang SY.Choi H.Kim CM.Jun H.Youn J. Synthesis 2004, 1102 - 14 Thiooctanoic S-acid 6 was prepared
from octanoyl chloride according to Quinn’s method:
Shin H.Quinn DM. Lipids 1993, 28: 73 ; the crude product was purified by Kugelrohr distillation (Büchi Glass Oven B-585, 110 ˚C, 6-7 mbar)