important biological properties, synthetic methodology of the
common 11-oxabicyclo[6.2.1]undec-3-ene core has not been
reported so far. Therefore, the development of creative
solutions for the construction of a germacrane-type frame-
work is strongly demanded. Herein, we describe the stereo-
selective synthesis of a potential intermediate 8 for the
synthesis of this type of compound. The synthetic route
involves several significant transformations, such as formal
1,3-asymmetric induction, unusual ring-closing metathesis
(RCM) constructing a 10-membered carbocyclic core, and
unique lactone transposition.
steric and electronic effects of allylic substituents. Thus, we
planned two approaches by RCM: (i) direct disconnection
to diene B at C4-C5 (route A) and (ii) disconnection to
more reactive E at C5-C6 (route B). The latter approach
requires a lactone transposition from C to trans-lactone A
after ring closure. In both approaches, key intermediates F
and F′ could be readily prepared by the same strategy. For
stereocontrol at C7-C9, a formal 1,3-asymmetric induction
from the chirality at C10 was envisaged. We anticipated that
direct 1,3-asymmetric induction may be difficult due to the
tertiary hydroxyl nature of C10. Therefore, we employed an
aldol reaction of R,â-unsaturated imide 9 with epoxy
aldehyde (+)-10,6 followed by selective reduction of the
epoxide. Stereoselective oxyfunctionalization at C6 might
be possible either by trans-selenolactonization of unsaturated
carboxylic acid F (route A) or stereoselective dihydroxylation
of D (route B).
Retrosynthetic analysis of diversifolin (1) is depicted in
Scheme 1. We were particularly interested in employing
Scheme 1. Synthetic Strategy
At the outset, we attempted the syn-selective aldol reaction
of imide 9a (Scheme 2). The aldol reaction of R,â-
Scheme 2. Preparation of Carboxylic Acid 13
RCM for constructing a 10-membered carbocycle. RCM4 is
generally recognized as a pivotal methodology for the
construction of medium-sized ring systems. Interestingly,
however, there have been very few examples of the suc-
cessful cyclization of 10-membered carbocycles by RCM.5
Gennari et al. applied RCM at the later stage of the total
synthesis of eleutherobin.5c-g Therefore, the construction of
a 10-membered carbocycle using RCM might depend on
unsaturated imide 9a with (+)-10 under the standard Evans
protocol7 afforded aldol adduct 11 in 66% yield as a
geometric mixture (E/Z ) 1:4) along with 7% of (2R,3S)-
isomer (E/Z ) 2:3).8 The diastereofacial selectivity was
similar to that reported by Nacro et al.6 After reduction of
the imide moiety with NaBH4, the resulting epoxy diol (not
shown) was treated with LiAlH4 in refluxing THF to obtain
the triol 12 in 76% yield. The triol 12 was transformed into
the unsaturated carboxylic acid 13 in good yield by a
conventional four-step sequence. Carboxylic acid 13 could
be prepared from triol 12 without silica gel column purifica-
tion on a 10-g scale.
(3) (a) Hehner, S. P.; Heinrich, M.; Bork, P. M.; Vogt, M.; Ratter, F.;
Lehmann, V.; Schulze-Osthoff, K.; Dro¨ge, W.; Schmitz, M. L. J. Biol. Chem.
1998, 273, 1288-1297. (b) Lyss, G.; Knorre, A.; Schmidt, T. J.; Pahl, H.
L.; Merfort, I. J. Biol. Chem. 1998, 273, 33508-33516. (c) Ru¨ngeler, P.;
Castro, V.; Mora, G.; Go¨ren, N.; Vichnewski, W.; Pahl, H. L.; Merfort, I.;
Schmidt, T. J. Bioorg. Med. Chem. 1999, 7, 2343-2352. (d) Garc´ıa-Pin˜eres,
A. J.; Castro, V.; Mora, G.; Schmidt, T. J.; Strunck, E.; Pahl, H. L.; Merfort,
I. J. Biol. Chem. 2001, 276, 39713-39720.
(4) For reviews on RCM, see: (a) Deiters, A.; Martin, S. F. Chem. ReV.
2004, 104, 2199-2238. (b) Armstrong, Susan K. J. Chem. Soc., Perkin
Trans. 1 1998, 371-388. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413-4450.
(5) (a) Nevalainen, M.; Koskinen, A. M. P. Angew. Chem., Int. Ed. 2001,
40, 4060-4062. (b) Nevalainen, M.; Koskinen, A. M. P. J. Org. Chem.
2002, 67, 1554-1560. (c) Caggiano, L.; Castoldi, D.; Beumer, R.; Bayo´n,
P.; Telser, J.; Gennari, C. Tetrahedron Lett. 2003, 44, 7913-7919. (d)
Beumer, R.; Bayo´n, P.; Bugada, P.; Ducki, S.; Mongelli, N.; Sirtori, F. R.;
Telser, J.; Gennari, C. Tetrahedron 2003, 59, 8803-8820. (e) Castoldi,
D.; Caggiano, L.; Panigada, L.; Sharon, O.; Costa, A. M.; Gennari, C.
Angew. Chem., Int. Ed. 2005, 44, 588-591. (f) Castoldi, D.; Caggiano, L.;
Bayo´n, P.; Costa, A. M.; Cappella, P.; Sharon, O.; Gennari, C. Tetrahedron
2005, 61, 2123-2139. (g) Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon,
O.; Costa, A. M.; Gennari, C. Chem. Eur. J. 2006, 12, 51-62.
We next examined a selenolactonization9 of 13 (Scheme
3). Initial attempts using standard conditions (PhSeCl, CH2-
Cl2, -78 °C) were unsuccessful due to the high reactivity
of the trisubstituted double bond. Surprisingly enough, we
(6) (a) Nacro, K.; Baltas, M.; Escudier, J.-M.; Gorrichon, L. Tetrahedron
1996, 52, 9047-9056. (b) Escudier, J.-M.; Baltas, M.; Gorrichon, L.
Tetrahedron Lett. 1991, 32, 5345-5348.
(7) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957-4960.
(8) For details, see Supporting Information.
(9) For a recent review on selenolactonization, see: Jones, G. B.; Huber,
R. S.; Chau, S. Tetrahedron 1993, 49, 369-380.
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Org. Lett., Vol. 9, No. 26, 2007