Stereodivergency of triazolium and imidazolium-derived NHcs for catalytic, enantioselective cyclopentane synthesis

Article abstract of DOI:10.1021/ol802739d

(Chemical Equation Presented) Chiral triazolium- and imidazolium-derived N-heterocyclic carbene catalysts promote the direct annulation of α,β-unsaturated aldehydes and achiral α-hydroxy enones to afford cyclopentane-fused lactones with high enantioselect

Full text of DOI:10.1021/ol802739d

ORGANIC
LETTERS
2009
Vol. 11, No. 3
677-680
Stereodivergency of Triazolium and
Imidazolium-Derived NHCs for Catalytic,
Enantioselective Cyclopentane
Synthesis
Juthanat Kaeobamrung and Jeffrey W. Bode*
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
bode@sas.upenn.edu
Received November 26, 2008
ABSTRACT
Chiral triazolium- and imidazolium-derived N-heterocyclic carbene catalysts promote the direct annulation of r,ꢀ-unsaturated aldehydes
and achiral r-hydroxy enones to afford cyclopentane-fused lactones with high enantioselectivity. Remarkably, otherwise structurally
identical imidazolium and triazolium precatalysts afford different major products. These studies provide both an efficient entry to valuable
chiral structures and a dramatic demonstration of stereodivergency of chiral imidazolium versus triazolium-derived N-heterocyclic carbene
catalysts.
Intense interest in the use of azolium salts as precursors to
N-heterocyclic carbene catalysts has led to a new generation
of stereoselective transformations under exceptionally mild
and convenient reaction conditions.1 Underlying this explo-
sion of new methods are intricate and subtle effects of the
reagents and catalysts in selecting discrete mechanistic
manifolds,2 making possible the catalytic generation of acyl
anions,3 homoenolates,4 enolates,5 and activated carboxy-
lates6 from a common R,ꢀ-unsaturated aldehyde starting
material.
As part of these efforts, we reported a cis-selective, highly
enantioselective cyclopentene-forming annulation of enals
and enones promoted by chiral triazolium precatalyst 1·Cl.7
This work complimented the elegant report of Nair on
cyclopentene-forming annulations of R,ꢀ-unsaturated alde-
hydes and chalcones catalyzed by achiral imidazolium-
derived carbenes.8 The unexpected formation of cyclo-
pentenes was rationalized by spontaneous decarboxylation
of a ꢀ-lactone intermediate,9 a facet of the reactions that
initially appeared to limit them to substrates containing
(3) (a) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim.
Acta 1996, 79, 1899–1902. (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
J. Am. Chem. Soc. 2002, 124, 10298–10299. (c) Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 6284–6289. (d) Johnson, J. S. Angew.
Chem., Int. Ed. 2004, 43, 1326–1328.
(4) For the first reports, see: (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W.
J. Am. Chem. Soc. 2004, 126, 14370–14371. (b) Burstein, C.; Glorius, F.
Angew. Chem., Int. Ed. 2004, 43, 6205–6208.
(5) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418–8420. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 15088–15089. (c) Phillips, E. M.; Wadamoto, M.; Chan, A.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 3107–3110.
(6) (a) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873–3876. (b) Chan,
A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908.
(1) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107,
5606–5655. (b) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988–3000.
(7) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc.
2007, 129, 3520–3521.
(8) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc.
2006, 128, 8736–8737.
(2) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506–7510.
10.1021/ol802739d CCC: $40.75
Published on Web 01/12/2009
2009 American Chemical Society

aromatic ketones; enones that would give stable lactone
products were unsuccessful.10 In this paper, we document
the use of R-hydroxy enones11 as reactive substrates that trap
the products at the lactone stage, thereby capturing the
stereochemical and functional complexity of these previously
transient intermediates (Scheme 1).12 Furthermore, we
Scheme 2
Scheme 1
disclose a remarkable stereochemical divergence of reactions
promoted by otherwise structurally identical chiral triazolium
and imidazolium precatalysts that offers both synthetic utility
and a window on the divergent reaction cascades of these
two catalyst types.
Our attempts to trap the postulated activated carboxylate
IV (see Scheme 2) with a pendant nucleophile began by
investigating hydroxy enone 3a as an annulation substrate.
Following reaction optimization, we identified conditions
that afforded high yields of a mixture of lactone products.
Careful structure determination of the products by X-ray
revealed that only three lactone products were formed,
with the major component constituting >65% of the
isolated material. To our surprise, this product was cis-
substituted ꢀ-lactone 4a (Table 1). The minor products
were trans-substituted γ-lactone 5a and a small amount
of ꢀ-lactone 6a, with pseudoenantiomeric stereochemistry
at the cyclopentane substitutents. The expected cis-
substituted γ-lactone 7a (see Table 2) was not detected
in reactions employing 1 as precatalyst. Although the
product ratios varied somewhat depending on the cinna-
maldehyde employed, annulations with 3a promoted by
1·Cl consistently provided the cis-substituted ꢀ-lactone as
the major product in 99% ee (Table 1, entries 1-6).
Interestingly, albeit in accord with our prior work,7 aryl-
substituted enones 3b and 3c afforded trans-substituted
cyclopentane lactones (entries 7 and 8). In our prior
studies, the trans products were formed in lower (∼60%)
ee. In this case, the enantiomeric, catalyst-bound inter-
mediates partition at the lactone-forming step into isomeric
products 5 and 6, and each are formed with excellent
enantioselectivity.
In surprising contrast, the use of imidazolium-derived
13,14
precatalyst 2·ClO4
resulted in preferential formation of
cis-substituted γ-lactone 7, to the complete exclusion of cis-
substituted ꢀ-lactone 4, which was the major product with
triazolium 1 (Table 2). This is the first example of a high-
yielding and highly enantioselective annulation reaction
catalyzed by a chiral imidazolium-derived carbene. The
minor product of the reaction, 5, was identical to that from
the triazolium catalyst reaction but was formed in only 6%
enantiomeric excess. The minor trans-substituted ꢀ-lactone
6 was not observed.
(9) For reviews on ꢀ-lactone chemistry, see: (a) Pommier, A.; Pons,
J.-M. Synthesis 1993, 441–459. (b) Yang, H. W.; Romo, D. Tetrahedron
1999, 55, 6403–6434. (c) Romo has reported that [3.2.0]bicyclic ꢀ-lactone
bearing aliphatic substituents do not undergo spontaneous decarboxylation:
Henry-Riyad, H.; Lee, C; Purohit, V. C.; Romo, D. Org. Lett. 2006, 8,
4363–4366.
(10) This limitation can be overcome if the reaction is run in an
intramolecular fashion: Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.;
Scheidt, K. A J. Am. Chem. Soc. 2007, 129, 10098–10099.
(11) For the use of achiral R-hydroxy enones in asymmetric catalysis,
see: (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.; Arceo, E.
J. Am. Chem. Soc. 2003, 125, 13942–13943. (b) Palomo, C.; Oiarbide, M.;
Halder, R.; Keiso, M.; Go´mez-Bengoa, E.; Garc´ıa, J. M. J. Am. Chem. Soc.
2004, 126, 9188–9189.
Subtle effects in the conditions or catalysts employed for
NHC-catalyzed annulations can have dramatic effects on the
products. In this case, an atomic substitution of carbon for
nitrogen at a remote site of the precatalysts leads to a
complete change in diastereoselectivity, resulting in the
formation of the γ-lactone.
(12) We have reported the synthesis of ꢀ-lactams from chalcone-derived
imines: He, M.; Bode, J. J. Am. Chem. Soc. 2008, 130, 418–419.
Imidazolium 2·ClO4 is ineffective for these reactions.
Consideration of the reaction cascade leading to the
formation of the lactone products can shed some light on
678
Org. Lett., Vol. 11, No. 3, 2009

Table 1. Triazolium-Catalyzed Annulations of Enals and R-Hydroxy Enonesa
entry
R1 )
R2 )
% yieldb
4:5:6c
% eed
1 (a)
2 (b)
3 (c)
4 (d)
5 (e)
6 (f)
Ph
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
p-BrC6H4 (3b)
p-CF3C6H4 (3c)
95 (65)
90 (60)
91 (62)
89 (35)
(45)
(40)
73 (50)
91 (71)
7e:2:1
6:2:1
6:2f:1
2:1:2
nd
99; 88; 99
99
99
99
99
99
-; 93; 99
-; 92; 99
p-MeOC6H4
p-BrC6H4
p-CF3C6H4
1-naphthyl
2-furyl
nd
7 (g)
8 (h)
Ph
Ph
-:3f:1f
-:4:1
a See the Supporting Information for reaction details. b Total isolated yields of lactone products; yields of the major product in parentheses. c Determined
by 1H NMR analysis of unpurified reaction mixtures. d Enantiomeric excesses of 4-6 as determined by SFC analysis on chiral columns. The ee of the minor
products in entries 2-7 were not determined. e Structure determined by X-ray analysis of the corresponding methyl ester. f Structure determined by X-ray
analysis.
the stereochemical divergence. The initial bond-forming
event for the formation of cis-configured products 4 and
7 is likely to be a tandem or concerted benzoin-oxy-
Cope reaction via a boatlike transition state (Scheme 2).
This mechanism, rather than direct conjugate addition of
an extended Breslow intermediate, provides a basis for
both the observed cis-selectivity as well as a platform for
the high levels of enantioinduction. The fate of resulting
intermediate III appears to depend on the nature of the
catalyst employed via differences in the facial selectivity
of the intramolecular aldol reaction. We initially hypoth-
esized that intermediate III, when formed with the
imidazolium catalyst (cat ) 2), was slow to undergo aldol
reaction; however, all attempts to trap it by addition of
nucleophiles failed. We therefore speculate that both
catalysts initially provide product IV, but the imidazolium-
derived activated carboxylate (IV, cat ) 2) is not
competent for ꢀ-lactone formation. The poor enantiose-
lectivity for the formation of 5 when the imidazolium
precatalyst 2 is employed, in contrast to the high levels
observed with triazolium precatalyst 1, reflects the inability
of the imidazolium catalyst to form ꢀ-lactone 6, thereby
funneling both diastereomers of VII to a nearly racemic
mixture of γ-lactone 5.
These observations demonstrate a discrete difference
in reactivity between otherwise identical imidazolium and
triazolium-derived N-heterocyclic carbenes. Based on our
current observation and understanding, we attribute this
not, in this case, to a mechanistic difference between the
reactions of the two catalysts or their interactions with
the enal substrates but rather to a discrete difference in
the reactivity of the acyl azolium species involved in the
lactone-forming step. The fate of postulate tetrahedral
intermediate A (Scheme 3) appears to be determined by
the leaving group ability of the N-heterocyclic carbene.
In the case of the triazolium catalyst, the NHC is a
sufficiently good leaving group to afford ꢀ-lactones as the
major products. In contrast, the identical intermediate
derived from the imidazolilum catalyst prefers to eliminate
alkoxide, leading to acyl imidazolium B, which undergoes
a retro-aldol-aldol sequence mutating the stereochemistry
Table 2. Chiral Imidazolium-Catalyzed Annulationsa
entry
R
% yieldb
7:5c
% eed
1 (a)
2 (b)
3 (c)
4 (d)
Ph
p-BrC6H4
2-furyl
85
76
80
68
5:1
3e:1
3:1
99; 6
99; 4
99; 8
99; 28
2-thiophenyl
3:1
(13) Due to availability at the onset of our studies, ent-2·ClO4 was used
for some entries (see the Supporting Information). Identical results were
obtained with 2 for the preparation of the other enantiomers. No effect of
the counterion was detected, and the change in counterion between the
catalysts types does not affect the stereochemical outcome.
(14) For the synthesis of 2·ClO4, see: (a) Struble, J. R.; Kaeobamrung,
J.; Bode, J. W. Org. Lett. 2008, 10, 957–960. (b) Struble, J. R.; Bode, J. W.
Tetrahedron 2008, 64, 6961–6972.
a See the Supporting Information for reaction details. b Total isolated
yields of lactone products. c Determined by 1H NMR analysis of
unpurified reaction mixtures. d Determined by SFC analysis on chiral
columns. e Structure determined by X-ray analysis of the product from
ent-2·ClO4.
Org. Lett., Vol. 11, No. 3, 2009
679

example, lactone 4 is readily transformed to enantiopure
cyclopentanone 8 (eq 1).
Scheme 3
Our findings establish that otherwise identical triazolium-
and imidazolium-derived NHC-catalysts can effect stereo-
divergent transformations. These intriguing results make a
compelling case for further design of chiral azolium salts
and investigations into the remarkable properties of these
catalysts and the powerful synthetic transformation they
enable under simple, operationally friendly reaction condi-
tions.
Acknowledgment. We are grateful to the NIH (GM-
079339) and for generous gifts from Boehringer-Ingelheim,
Bristol Myers Squibb, Eli Lilly, and Roche for support of
this research program. J.K. is a predoctoral fellow of the
Royal Thai Government. We thank Justin Struble for 1 and
2 and Guang Wu (UCSB) and Pat Sheppard (UPenn) for
X-ray analyses.
and leading to the formation of the more stable γ-lactone
product 7a.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In addition to serving as an auxiliary for enhancing the
reactivity of enone 3 and, in the case of 7, trapping
activated carboxylate VI (Scheme 2), the pendant alcohol
offers a synthetic handle for product processing. For
OL802739D
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Org. Lett., Vol. 11, No. 3, 2009