Scheme 5. Preparation of polycyclic chemotypes using [2+2] cycloaddi-
tion. a) [Rh2{(S)-dosp}4], 2,3-dihydropyran, hexanes, ꢀ508C; b) Et2AlCl,
CH2Cl2, two step 58% yield, d.r.=9:1; c) hn, pyrex tube, quartz filter,
benzene/acetone (3:1), 60%, d.r.=9:1; d) [Rh2{(S)-dosp}4], 2,3-dihy-
dropyran, hexanes, ꢀ508C, 63%, d.r. =6:6:1:1; e) Et2AlCl, CH2Cl2,
80%, d.r.=5:5:1:1; f) hn, pyrex tube, quartz filter, benzene/acetone
(3:1), 20–30%, single diastereomer. For detailed reaction conditions
see the Supporting Information.
cycloaddition.[18] The stereochemistry of 17 was assigned by
NOESY NMR experiments, which indicated that the cyclo-
addition occurred from the convex face of the bicyclic
framework in a similar manner as 15. Overall, the photo-
cycloaddition incorporates extended substituents for further
diversification and illustrates the effective final pairing of the
functionality installed by both of the asymmetric operations
(crotylation and cyclopropanation/rearrangement) of the
reaction sequence.
In summary, we have demonstrated the utility of sequen-
tial asymmetric processes utilizing organosilane-based croty-
lation followed by a rhodium(II)-catalyzed asymmetric car-
benoid transformation, thereby enabling a significant exten-
sion of the substrate scope of vinyl diazoacetates. Diastereo-
meric rhodium carbenoids exhibited good to moderate levels
of selectivity in the cyclopropanation, while a substrate-
dependent endo/exo selectivity was observed with vinyl
cyclopropane rearrangements. Further elaboration of the
cyclopentene products through Heck cyclization and
[2+2] photocycloaddition allowed for the effective pairing
of functional groups installed in the sequential process,
resulting in tetracyclic, pentacyclic, and condensed polycyclic
chemotypes, which are not readily accessible by other
methods. Each final compound was prepared in either four
or five steps from silane (R)-1 or (S)-1. A similarity search in
PubChem (score ꢁ 80%)[19] of one structural type from this
study, that is the pentacyclic indole framework of 13, revealed
a number of structures, including several indoloterpene
alkaloid natural products with biological activity.[20] Biological
evaluation of the polycyclic chemotypes from this study are
currently underway and will be reported in due course.
Scheme 4. A) Sequential reactions with N-methylindole: a) [Rh2{(S)-
dosp}4], N-methylindole, hexanes, CH2Cl2, ꢀ408C, 65%, d.r.=4.2:1;
b) Pd(OAc)2, tri-o-tolylphosphine, K2CO3, DMF, 1208C, 60%, d.r.=4:1.
B) Sequential reactions with N-Boc indole: c) [Rh2{(S)-dosp}4], 1-Boc-
indole, hexanes, ꢀ508C, 53%, d.r.=4:1; d) Et2AlCl, CH2Cl2, 45%,
d.r.=3:1; e) Pd(OAc)2, tri-o-tolylphosphine, K2CO3, DMF, 1208C, 52%,
d.r.=3:1. For detailed reaction conditions see the Supporting Informa-
tion. Boc=tert-butoxycarbonyl.
variants,[15] there are few examples of the [2+2] cyclization
between a,b-unsaturated esters and isolated olefins.[16] The
[2+2] cycloaddition of cyclopentene 14 proceeded smoothly
to afford tetracyclic product 15 when irradiated through a
quartz UV filter with benzene/acetone (3:1) as the solvent.[17]
NOESY NMR measurements indicated that the product
possessed a cis-syn-cis structure.[11] We believed that the
observed facial selectivity of the cycloaddition may be due to
the terminal olefin approaching the unsaturated ester from
the convex face of bicyclic precursor 14. Treatment of
compound 16 under the photocycloaddition reaction condi-
tions afforded the fused-ring product 17 as a single diaste-
reomer in 20–30% yield. Notably, the cycloaddition precursor
16 contained two major diastereomers, which resulted from
the utilization of either chiral or racemic cyclohex-2-enol;
however, only the S-allylic ether participated in the photo-
Received: February 23, 2011
Published online: May 10, 2011
Keywords: carbenoids · cyclization · diastereoselectivity ·
.
diversity-oriented synthesis · sequential transformations
Angew. Chem. Int. Ed. 2011, 50, 5938 –5942
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5941