ORGANIC
LETTERS
2012
Vol. 14, No. 9
2346–2349
Stereoselective Synthesis of the
Macrolactone Core of (þ)-Neopeltolide
Sadagopan Raghavan* and Pradip Kumar Samanta
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad
500007, India
Received March 26, 2012
ABSTRACT
A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis
include asymmetric allylation using Krische’ protocol, conjugate reduction using MacMillan’s methodology, and an asymmetric hetero-
DielsꢀAlder reaction using Jacobsen’s catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction
followed by IrelandꢀClaisen rearrangement, oxymercuration, and reductive lithiation are other key steps.
Neopeltolide 1 is a macrolide isolated by Wright and co-
workers in 2007 from a Caribbean sponge of the neopelto-
lide family collected off the Jamaican coast.1 Neopeltolide
exhibits potent cytotoxic activity against several cancer cell
lines (e.g., IC50 0.56, 1.2, and 5.1 nM against P388 murine
leukemia, A-549 human lung adenocarcinoma, and NCI-
ADR-RES humanovarian sarcomarespectively) aswellas
DLD-1 colorectal cell lines and the PAWC-1 pancreatic
cell line1,2 in addition to inhibiting the growth of the fungal
pathogenic yeast Candida albicans with an MIC value of
0.62 μg mLꢀ1 in liquid cultures. The key structural char-
acteristics of neopeltolide include a 2,4,6-trisubstituted
tetrahydropyran ring contained in a 14-membered macro-
lactone framework, an oxazole having an unsaturated
chain appended through an ester linkage, and six stereo-
genic centers.
The complex macrolide structure and potent biological
activity of neopeltolide have stimulated extensive enthu-
siasm among synthetic chemists, and several total3 and
formal4 synthesis have been reported. The initial indepen-
dent reports of Panek3a and Scheidt3b led to a revision of
the original stereochemical configuration at C11 and C13.
Kozmin and co-workers,5 on the basis of biological testing
of neopeltolide and of a simplified analogue, identified
cytochrome bc1 complex as the cellular target.
Herein, we report a new synthesis of the macrolactone core
of (þ)-neopeltolide adopting a strategy wherein three of the
six stereocenters were introduced using organocatalytic or
metal complex promoted catalytic asymmetric transformations
(4) For the formal synthesis of neopeltolide, see: (a) Vintonyak,
V. V.; Maier, M. E. Org. Lett. 2008, 10, 1239. (b) Kartika, R.; Gruffi,
T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047. (c) Tu, W.; Floreancig,
P. E. Angew. Chem., Int. Ed. 2009, 48, 4567. (d) Kim, H.; Park, Y.; Hong,
J. Angew. Chem., Int. Ed. 2009, 48, 7577. (e) Yadav, J. S.; Kumar, G. G.
K. S. N. Tetrahedron 2010, 66, 480. (f) Fuwa, H.; Saito, A.; Sasaki, M.
Angew. Chem., Int. Ed. 2010, 49, 3041. (g) Martinez-Solorio, D.;
Jennings, M. P. J. Org. Chem. 2010, 75, 4095. (h) Yang, Z.; Zhang, B.;
Zhao, G.; Yang., J.; Xie, X.; She., X. Org. Lett. 2011, 13, 5916.
(5) For structure activity studies, see: (a) Ulanovskaya, O. A.; Janjic, J.;
Suzuki, M.; Sabharwal, S. S.; Schumacker, P. T.; Kron, S. J.; Kozmin, S. A.
Nat. Chem. Biol. 2008, 4, 418. (b) Vintonyak, V. V.; Kunze, B.; Sasse, F.;
Maier, M. E. Chem.; Eur. J. 2008, 14, 11132. (c) Custar, D. W.; Zabawa,
T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131,
12406. (d) Fuwa, H.; Saito, A.; Naito, S.; Konoki, K.; Yotsu-Yamashita,
M.; Sasaki, M. Chem.;Eur. J. 2009, 15, 12807. (e) Cui, Y.; Tu, W.;
Floreancig, P. E. Tetrahedron 2010, 66, 4867. (f) Cui, Y.; Balachandram,
R.; Day, B. W.; Floreancig, P. E. J. Org. Chem. 2012, 77, 2225.
(1) (a) Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.;
Linley, P.; McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J.
Nat. Prod. 2007, 70, 412. (b) Wright, A. E.; Pomponi, S. A.; McCarthy,
P. J. U.S. Patent 7179828B2, 2007.
(2) Wright, A. E.; Pomponi, S. A.; McCarthy, P. J. U.S. Patent
7179828B2, 2007, European Patent 1644380, 2007.
(3) For the total synthesis of neopeltolide, see: (a) Youngsaye, W.;
Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S. Angew. Chem., Int. Ed.
2007, 46, 9211. (b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am.
Chem. Soc. 2008, 130, 804. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 3242. (d) Paterson, I.; Miller, N. A. Chem.
Commun. 2008, 4708. (e) Fuwa, H.; Naito, S.; Goto, T.; Sasaki, M.
Angew. Chem., Int. Ed. 2008, 47, 4737. (f) Guinchard, X.; Roulland, E.
Org. Lett. 2009, 11, 4700.
r
10.1021/ol3007698
Published on Web 04/19/2012
2012 American Chemical Society