Scheme 1
Scheme 2. Parallel Kinetic Resolution of 6 with Ethyl Vinyl
Ether and Catalyst 5a
unsaturated aldehydes (R1 * H), raising the possibility of
application to the stereoselective construction of bicyclic
pyran ring systems. We describe here the successful execu-
tion of this strategy and the formal total synthesis of a series
of stereochemically diverse iridoid natural products.
The model reaction of 1-cyclopentene-1-carboxaldehyde
and ethyl vinyl ether (eq 1) was catalyzed by 5 (5 mol %) at
room temperature to afford the desired cycloadduct with
excellent endo diastereoselectivity (>97:3 dr) and good
enantioselectivity (87% ee). With this promising result in
hand, we turned our attention toward the use of substituted
cyclopentenecarboxaldehydes such as those that would be
required for the synthesis of iridoid natural products. For
example, the use of 5-methyl-1-cyclopentene-1-carbox-
aldehyde (6) in the inverse-demand HDA reaction would
provide efficient access to targets such as boschnialactone
(1),5 teucriumlactone (2), iridomyrmecin (2), and iso-
iridomyrmecin (4) (Scheme 2). Interestingly, both absolute
stereochemistries at the methyl-bearing stereocenters are
displayed in the natural products.
a Key: (a) H2, PtO2, EtOAc, 12 h, quant; (b) (i) cat. p-
toluenesulfonic acid, acetone/H2O (1:1), 24 h, (ii) PCC, CH2Cl2,
16 h, 80% over three steps.
Initially, we evaluated a kinetic resolution approach to the
synthesis of 1-4 using racemic 6. The requisite aldehyde
was prepared from 2-methylcyclopentanone according to a
literature procedure, which involves tosyl hydrazone forma-
tion, subsequent vinyl anion formation (Shapiro reaction),
and trapping with dimethylformamide.6 Racemic 6 underwent
cycloaddition in the presence of 5 and ethyl vinyl ether within
2 days at room temperature to afford a 1.2:1 ratio of
diastereomers with complete conversion of the aldehyde
(Scheme 2). Chiral GC analysis revealed that the major
diastereomer (7a) was generated in 80% ee, while the minor
diastereomer (7b) was produced in 98% ee. Thus, the
“matched” aldehyde enantiomer had undergone reaction with
>100:1 dr, while the mismatched aldehyde enantiomer
afforded the diastereomeric cycloadduct with 8:1 dr. This
represents an interesting example of a selective parallel
kinetic resolution process.7
led to exclusive formation of two diasteromeric reduction
products that were separable by column chromatography.
Each diastereomer was subsequently hydrolyzed and the
resulting lactols oxidized to afford (-)-boschnialactone (1)8
from the matched aldehyde and (+)-7-epi-boschnialactone
(8)9,10 from the mismatched aldehyde. Thus, the absolute and
relative stereochemistry of each cycloadduct was established,
and the facial selectivity induced by the catalyst was
demonstrated to be consistent with previous results obtained
with prochiral substrates (Scheme 1).4 In addition, the
hydrogenation was determined to have yielded the cis-
cyclopenta[c]pyran for both diastereomers.
Although the parallel kinetic resolution provided a straight-
forward route to enantioenriched iridoids 1-4, the enantio-
(7) For reviews on the topic of parallel kinetic resolution, see: (a) Kagan,
H. Croat. Chem. Acta 1996, 69, 669. (b) Vedejs, E.; Chen, X. J. Am. Chem.
Soc. 1997, 119, 2584. (c) Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885.
(8) Sakan, T.; Murai, Y.; Hayashi, Y.; Honda, Y.; Shono, T.; Nakajima,
M.; Kato, M. Tetrahedron 1967, 23, 4635.
The cycloadducts were not readily separated, but hydro-
genation of the 1.2:1 mixture of diastereomers with H2/PtO2
(5) For a synthesis of ent-1 involving a catalytic, enantioselective
iodocarbocyclization, see: Inoue, T.; Kitagawa, O.; Saito, A.; Taguchi, T.
J. Org. Chem. 1997, 62, 7384.
(6) Barker, A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1983,
1901.
(9) Nangia, A.; Prasuna, G.; Rao, P. B. Tetrahedron Lett. 1994, 35, 3755.
(10) Compound 8 has been converted previously into 2, 3 and 4. This
work thus constitutes a formal total synthesis of these irodoids. (a) Schaffner,
K.; Demuth, M. Chimia 1981, 35, 437. (b) Demuth, M.; Schaffner, K.
Angew. Chem., Int. Ed. Engl. 1982, 21, 820.
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Org. Lett., Vol. 5, No. 14, 2003