Enantioselective, cyclopentene-forming annulations via NHC-catalyzed benzoin-oxy-Cope reactions

Article abstract of DOI:10.1021/ja0705543

Chiral N-heterocyclic carbene catalysts generated from triazolium salts promote the cyclopentene-forming annulation of α,β-unsaturated aldehydes and 4-oxoenoates with excellent levels of enantioinduction and preference for the cis-1,3,4-trisubstituted cyclopentene diastereomer. Although the observed products could arise by conjugate additions of catalytically generated homoenolates, our mechanistic and stereochemical investigations strongly support a novel reaction manifold featuring an intermolecular crossed-benzoin reaction and an NHC-catalyzed oxy-Cope rearrangement. Copyright

Full text of DOI:10.1021/ja0705543

Published on Web 03/03/2007
Enantioselective, Cyclopentene-Forming Annulations via NHC-Catalyzed
Benzoin-Oxy-Cope Reactions
Pei-Chen Chiang, Juthanat Kaeobamrung, and Jeffrey W. Bode*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
Received January 24, 2007; E-mail: bode@chem.ucsb.edu
Scheme 1. Cyclopentenes via NHC-Catalyzed Oxy-Cope RAR
N-Heterocyclic carbene (NHC)-catalyzed redox transformations
of functionalized aldehydes1 enable the catalytic generation of
reactive intermediates including activated carboxylates,2,3 enolates,4,5
and homoenolates.6,7 Recently, Nair described the synthesis of
racemic trans-1,3,4-triarylcyclopentenes by a remarkable annulation
of enals and chalcones catalyzed by achiral imidazolium-derived
carbenes, reportedly via a homoenolate equivalent.8 As part of our
own ongoing studies aimed at developing NHC-catalyzed annulation
reactions, we now document a highly enantioselective cis-cyclo-
pentene-forming annulation9 mediated by chiral triazolium pre-
catalyst 1 (eq 1 in Table 1). Mechanistic and stereochemical
Table 1. Catalytic Enantioselective Annulations of 4-Oxoenoates
trans-diastereomers occurred with considerably less enantioinduc-
tion. In accord with Nair’s findings, the substrate scope presently
appears to be limited to enones bearing an aromatic substituent, as
only these lead to intermediates that undergo facile decarboxyla-
tion.10
entry
R1
R2
% yielda
cis:transb
% eec
The incongruity between the optimized conditions for the
cyclopentene-forming annulations and the usual protocols employed
for NHC-catalyzed homoenolate generation invited further consid-
eration of the reaction pathway. Triazolium-derived NHCs are
known to be outstanding catalysts for benzoin-forming reactions.
Although the intermolecular crossed aldehyde-ketone benzoin is
thought to be disfavored,11 an intramolecular variant is catalyzed
by both thiazolium and triazolium salts.12 Crossed benzoin reaction
between cinnamaldehyde (2) and enone 3 would lead to an
intermediate (4) poised for an oxy-Cope rearrangement that would
give 5 (Scheme 1), the identical product invoked in the proposed
conjugate addition of a homoenolate to the enone. As previously
suggested by Nair, 5 would undergo tautomerization, stereoselective
intramolecular aldol addition, lactonization, and decarboxylation
to afford cyclopentene product 7. Indeed, a similar cyclopentanone-
forming aldol cascade initiated by an anionic oxy-Cope reaction
has been reported,13 and formal conjugate additions of allylic anions
to enones that proceed via 1,2-addition/oxy-Cope rearrangement
are well-known.14
Several control experiments support the viability of this pathway,
at least when triazolium precatalysts are utilized. Exposure of
acyloin 8 to the reaction conditions resulted in facile retro-benzoin
reaction, demonstrating both the feasibility and reversibility of a
benzoin-type process (Scheme 2a). When O-TMS-protected ketone
10 was allowed to react with the catalyst in the presence of a
nucleophile, such as ethanol, oxy-Cope reaction followed by
formation and trapping of the catalyst-bound activated carboxylate
occurred (i.e., 11 in Scheme 2b), leading to acyclic ester 12.15 In
contrast, coupling of cinnamaldehyde and chalcone under identical
conditions (1:1 DCE/EtOH) provided only the cyclopentene product,
1
2e
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
78
58
50
93
58
68
53
25
11:1
5:1
11:1
>20:1
6:1
4:1
5:1
14:1
99 (68)d
99 (68)d
99 (79)d
98
p-MeOC6H4
p-BrC6H4
2-furyl
Ph
Ph
Ph
p-BrC6H4
p-CF3C6H4
2-furyl
99 (67)d
98 (67)d
99 (82)d
96 (32)d
n-Pr
Ph
a Isolated yield after chromatography. b Approximate ratio of cis:trans
cyclopentene diastereomers as determined by HPLC analyses at several
wavelengths. In most cases, the diastereomers cannot be distinguished by
1H NMR analysis. c Determined by HPLC analysis. d The % ee of the minor
diastereomer. e The ethyl ester was used as the 4-oxoenoate substrate.
evidence supports a cascade sequence involving a catalytic,
asymmetric intermolecular aldehyde-ketone crossed benzoin reac-
tion and a novel NHC-promoted oxy-Cope rearrangement (Scheme
1).
A study of reaction conditions for enantioselective, cyclopentene-
forming annulations with cinnamaldehyde and 4-oxoenone 3
identified 10 mol % of triazolium precatalyst 1,5 15 mol % of DBU,
dichloroethane (0.1 M), and a reaction temperature of 0 °C to room
temperature as optimal. In contrast to the use of chalcone deriva-
tives, which provided the trans-cyclopentene products (eq 2), 3 and
related enones gave the cis-cyclopentenes selectively (Table 1). In
all cases examined, cis-cyclopentenes were obtained with a high
degree of enantioselectivity (>96% ee), while the formation of the
9
3520
J. AM. CHEM. SOC. 2007, 129, 3520-3521
10.1021/ja0705543 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
the standard catalytic conditions, cyclopentene 14 was obtained
in moderate yield but in >20:1 dr, favoring the cis-diastereomer
(eq 3).
Acknowledgment. This work was supported by predoctoral
fellowships from the governments of Taiwan (P.C.C.) and Thailand
(J.K.). Further support was generously provided by Amgen, Eli
Lilly, AstraZeneca, and the Dreyfus Foundation. J.W.B. is a fellow
of the Packard Foundation, the Beckman Foundation, and a
Research Corporation Cottrell Scholar. Valuable preliminary work
was performed by Evelyn Rosen and Ming He, and triazolium
precatalysts were prepared by Justin Struble and Ji Young Yoon.
Supporting Information Available: Experimental procedures and
characterization data for all compounds and X-ray analysis. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
demonstrating that the reaction shown in Scheme 2b does not occur
simply by retro-benzoin followed by catalytic homoenolate addition
(Scheme 2c). At the present time, we cannot distinguish between
a stepwise benzoin reaction followed by oxy-Cope rearrangement
of intermediate 4 (Scheme 1) and a concerted pathway that leads
directly to 5 without the intermediacy of 4.16
(1) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506-7510.
(2) (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-
8127. (b) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873-3876.
(3) (a) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518-9519. (b) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7,
905-908. (c) Zeitler, K. Org. Lett. 2006, 8, 637-640.
(4) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406-16407.
(5) (a) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088-
15089. (b) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418-8120.
(6) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370-14371. (b) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131-3134.
(7) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-
6208. (b) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006,
2418-2439.
(8) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006,
128, 8736-8737.
(9) For elegant intermolecular, catalytic enantioselective approaches to chiral
cyclopentenes, see: (a) Davies, H. M. L.; Xiang, B.; Kong, N.; Stafford,
D. G. J. Am. Chem. Soc. 2001, 123, 7461-7462. (b) Wilson, J. E.; Fu,
G. C. Angew. Chem., Int. Ed. 2006, 45, 1426-1429.
The seemingly disparate stereochemical outcomes between
chalcones and the 4-oxoenoates, coupled with the diminished levels
of enantioinduction in the trans-diastereomers, provide a mecha-
nistically revealing insight that strongly supports a benzoin-oxy-
Cope pathway. Enones, including chalcone and related structures,
are known to exist as equilibrating mixtures of s-cis and s-trans
conformers.17 The 4-oxoenoates apparently prefer to react with the
catalyst-bound Breslow intermediate as the s-cis conformation
shown in Figure 1a. Benzoin-type addition leads to an intermediate
poised for oxy-Cope rearrangement via a boat transition state that
gives rise to the cis-stereochemistry observed in the cyclopentene
products.18 In contrast, chalcones appear to react from the s-trans
conformation (Figure 1b), which leads to an intermediate poised
for oxy-Cope reaction via a chair transition state that predicts the
stereochemical outcome observed in the trans-products.19
(10) Romo has reported that [3.2.0]-bicyclic â-lactones bearing aliphatic
substituents do not undergo spontaneous decarboxylation: Henry-Riyad,
H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett. 2006, 8, 4363-4366.
(11) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326-1328.
(12) (a) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125,
8432-8433. (b) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K.
Angew. Chem., Int. Ed. 2006, 45, 3492-3494. (c) Enders, D.; Niemeier,
O. Synlett 2004, 2111-2114.
(13) Saito, S.; Yamamoto, T.; Matsuoka, M.; Moriwake, T. Synlett 1992, 239-
To test our hypothesis that the reactive conformation of the enone
determined the relative stereochemistry of the annulation products,
we prepared chalcone-type enone 13, which is locked into an s-cis
conformation. Upon treatment of 13 with cinnamaldehyde under
240.
(14) (a) Ziegler, F. E.; Chakraborty, U. R.; Wester, R. T. Tetrahedron Lett.
1982, 23, 3237-3240. (b) Haynes, R. K.; Schober, P. A.; Binns, M. R.
Aust. J. Chem. 1987, 40, 1223-1247. (c) Binns, M. R.; Haynes, R. K.;
Katsifis, A. G.; Schober, P. A.; Vonwiller, S. C. J. Org. Chem. 1989, 54,
1960-1968.
(15) Products arising from retro-silyl benzoin reactions and those of silyl Stetter
reactions of these products were also detected. For reports of silyl benzoin
and Stetter reactions, see: (a) Linghu, X.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2003, 42, 2534-2536. (b) Mattson, A. E.; Bharadwaj, A. R.;
Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715-5724. (c)
Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
1833-1840.
(16) For concerted C-H insertion/Cope rearrangement reactions, see: (a)
Davies, H. M. L.; Jin, Q. J. Am. Chem. Soc. 2004, 126, 10862-10863.
(b) Davis, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5472-
5475.
(17) (a) Montaudo, G.; Librando, V.; Caccamese, S.; Maravigna, P. J. Am.
Chem. Soc. 1973, 95, 6365-6370. (b) Chamberlin, A. R.; Reich, S. H. J.
Am. Chem. Soc. 1985, 107, 1440-1441. (c) Oelichmann, H.-J.; Bougeard,
D.; Schrader, B. Angew. Chem. Suppl. 1992, 1404-1415.
(18) Dudding, T.; Houk, K. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5770-
5775.
(19) Both chair and boat conformations are invoked in the transition states of
oxy-Cope rearrangements to explain the observed stereochemical out-
comes: (a) Evans, D. A.; Nelson, J. V. J. Am. Chem. Soc. 1980, 102,
774-782. (b) Paquette, L. A. Tetrahedron 1997, 53, 13971-14020.
Figure 1. Transition states for NHC-promoted oxy-Cope rearrangements
predicting the observed relative and absolute stereochemical outcomes. For
clarity, ent-1 is shown as the catalyst.
JA0705543
9
J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007 3521