Table 1. Relative Strain Energies for the Diastereomers of Alleged Sclerophytin Aa
a The stereodescriptors pertain to C-7 and C-3, respectively. Each vertical pair represents two conformers of the same stereoisomer.
fact that the resident stereocenters C-1, C-2, C-9, C-10, and
C-14 generally possess the R configuration in common.7
The published data can be construed to be equally
compatible with the 7R configuration as in 2. An appreciation
of the conformational energetics and relative thermodynamic
stabilities of the four possible C-3/C-7 diastereomers of
sclerophytin A has been derived from MM3 calculations
(Table 1). It is noteworthy that “oxygen-up” conformations
are favored for three of the isomer pairs, with A serving as
the least strained standard. These results do not speak to the
possible existence of kinetically stable atropisomers, but did
focus our attention on preparing 2()A). This epimeric
formulation conforms additionally to the low-temperature
boron trifluoride-catalyzed cyclization of cladiellin 3 to 4
The convergent assembly began with (5S)-5-(d-menthyl-
oxy)-2(5H)-furanone (5), an enantiopure unsaturated lactone9
previously recognized for its useful dienophilic properties.10
Heating of 5 with the Danishefsky diene in toluene gave a
sensitive (4 + 2) cycloadduct, which could be efficiently
transformed into the cyclohexenone 6 by Vorndam’s pro-
tocol.11 Conventional Luche reduction12 followed (Scheme
1). These three steps gave 7a in 71% overall yield. After
initial attempts to convert 7b into the C-allylated bicyclic
lactone 8 met with difficulties,13 the discovery was made
that hydrolysis to the γ-hydroxy-γ-lactone and Barbier-type
condensation with the allylindium reagent under aqueous
conditions proceeded with high diastereoselection for the R
isomer 9 (NOE analysis). The stereochemical course of this
important carbon-carbon bond-forming step is attributed to
operation of a chelated transition state involving the neigh-
boring carboxyl group.14
To set the stage for the tandem Tebbe-Claisen ring
expansion,15 we next undertook stereocontrolled installation
(9) High quality 5 was routinely obtained by crystallization-induced
epimerization of the diastereomeric mixture with CSA in CH2Cl2. Details
will be provided in the full paper.
(10) (a) de Jong, J.; van Bolhuis, F.; Feringa, B. L. Tetrahedron:
Asymmetry 1991, 2, 1247. (b) de Jong, J.; Jansen, J. F. G. A.; Feringa, B.
L. Tetrahedron Lett. 1990, 31, 3047.
previously delineated by Hochlowski and Faulkner.8 Herein
we illustrate a potentially generic protocol for accessing these
marine metabolites.
(11) Vorndam, P. E. J. Org. Chem. 1990, 55, 3693.
(12) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(13) Bernardelli, P. Ph.D. Dissertation, The Ohio State University, 1997.
(14) Bernardelli, P.; Paquette, L. A. J. Org. Chem. 1997, 62, 8284.
(15) (a) Kinney, W. A.; Coghlan, M. J.; Paquette, L. A. J. Am. Chem.
Soc. 1985 107, 7352. (b) Kang, H.-J.; Paquette, L. A. J. Am. Chem. Soc.
1991, 113, 2610. (c) Paquette, L. A.; Sweeney, T. J. Tetrahedron 1990,
46, 4487. (d) Friedrich, D.; Paquette, L. A. J. Org. Chem. 1991, 56, 3831.
(f) Friedrich, D.; Paquette, L. A.; Rogers, R. D. J. Org. Chem. 1991, 56,
3841. (f) Paquette, L. A.; Philippo, C. M. G.; Vo, N. H. Can. J. Chem.
1992, 70, 1356.
(5) (a) Ochi, M.; Futatsugi, K.; Kume, Y.; Kotsuki, H.; Asao, K.; Shibata,
K. Chem. Lett. 1988, 1661. (b) Bowden, B. F.; Coll, J. C.; Dai, M. C. Aust.
J. Chem. 1989, 42, 665. (c) Ochi, M.; Yamada, K.; Futatsugi, K.; Kotsugi,
H.; Shibata, K. Chem. Lett. 1990, 2183. (d) Miyamoto, T.; Yamada, K.;
Ikeda, N.; Komori, T.; Higuchi, R. J. Nat. Prod. 1994, 57, 1212.
(6) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117,
10391.
(7) Sharma, P.; Alam, M. J. Chem. Soc., Perkin Trans. 1 1988, 2537.
(8) Hochlowshi, J. E.; Faulkner, D. J. Tetrahedron Lett. 1980, 21, 4055.
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