Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric stetter reaction

Article abstract of DOI:10.1021/ja047644h

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods. Copyright

Full text of DOI:10.1021/ja047644h

Published on Web 07/03/2004
Enantioselective Synthesis of Quaternary Stereocenters via a Catalytic
Asymmetric Stetter Reaction
Mark S. Kerr and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received April 23, 2004; E-mail: rovis@lamar.colostate.edu
The asymmetric formation of quaternary stereocenters remains
Table 1. Aromatic Substrates
1
a formidable challenge in organic synthesis. While the use of
2
Meyers’ chiral bicyclic lactam auxiliaries continues to be the
benchmark for versatility and predictability in this challenging bond
construction, a number of elegant methods for catalytic formation
of quaternary stereocenters have recently been reported. Included
3
in this company are the intramolecular Heck reaction, rearrange-
4
ment of enol carbonates, transition metal-mediated π-allyl chem-
5
6
istry, copper-catalyzed S
N
2′ displacement of allylic leaving groups
1b
and conjugate additions of â-keto esters to acrylates, phase-transfer
7
8
alkylation of 1-indanones, and arylation of ketone enolates, among
others. Each of these approaches, however, is necessarily limited
to specific substrates and many substitution patterns are unattainable
by these or even stoichiometric methods. We report herein that the
catalytic asymmetric intramolecular Stetter reaction is capable of
forming tertiary ether, thioether, and quaternary stereocenters with
excellent enantioselectivity.
Research in these laboratories has been directed toward exploiting
the reactivity of carbenes of type 1 and 2, easily formed in situ
from highly stable and readily prepared triazolium salt precursors
3
, Scheme 1. We have previously reported that these carbenes are
9
effective at catalyzing the intramolecular Stetter reaction with good
levels of enantiocontrol.10 Our successes with this reaction prompted
us to investigate the more challenging construction of quaternary
stereocenters.
a
Absolute configuration assigned by analogy to 10. b Enantiomeric
c
excess determined by HPLC analysis on a chiral stationary phase.
Absolute configuration established by single-crystal X-ray analysis.
d
Scheme 1
Catalyst added in two portions.
Anisyl-substituted catalyst 5a, which has been shown to be highly
effective in the intramolecular Stetter reaction, provided a disap-
pointing 45% yield, albeit with 99% ee. Interestingly, parent phenyl-
substituted catalyst 5b, while typically underperforming 5a in terms
Trost and co-workers had illustrated that the Stetter reaction is
capable of cyclizing an aldehyde onto a â,â-disubstituted Michael
acceptor during the synthesis of hirsutic acid;11 however, three
equivalents of achiral thiazolium salt were required to effect the
reaction. The apparent inefficiency of this catalyst was a significant
cause for concern, and although they are somewhat electronically
dissimilar, it was not obvious that our triazolium catalysts would
lend themselves to an efficient catalytic process. Nevertheless, we
initiated our investigation into rendering this reaction enantio-
selective by examining vinylogous carbonate 4 as a test substrate
with a series of aminoindanol-derived catalysts. Gratifyingly, tertiary
ether 6 was formed in excellent enantioselectivity in all cases, eq 1.
of conversion,10a gave the product benzofuranone in 80% yield.
This result suggests the presence of subtle mechanistic differences
between this system and â-monosubstituted substrates. Further
screening identified pentafluorophenyl catalyst 5c as the most
effective under these conditions. Subsequent optimization indicated
that triethylamine12 was optimal for providing a balance of the
highest reactivity and selectivity.13,14
With the optimized conditions in hand, a series of aromatic
aldehyde substrates was prepared to test the scope of this
transformation, Table 1. Reaction of aldehydes 4 and 7 at room
temperature for 24 h provided benzofuranones 6 and 8 in high yield
and enantiomeric excess, entries 1 and 2. Thioether 9 similarly
undergoes cyclization in good yield and selectivity to form
benzothiophenone 10, entry 3. Exposure of ethyl ester 11 to the
reaction conditions led to the formation of indanone 12 in 95%
yield and remarkable selectivity, entry 4. The corresponding six-
membered ring may also be formed with concomitant generation
of a quaternary stereocenter, although a lower yield accompanies
this reaction. Nevertheless, chromanone 14 can be isolated in
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10.1021/ja047644h CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
moderate yield and excellent enantioselectivity, entry 5.
We have previously shown that aliphatic aldehydes are also
competent substrates in the asymmetric intramolecular Stetter
reaction.10 These systems allowed us to readily compare the effect
of alkene geometry. Exposure of R,â-unsaturated phenyl ketone
E-15 to the reaction conditions provided an 85% yield of cyclo-
pentanone 16 bearing the quaternary stereocenter with 96% ee.15
The corresponding isomer Z-15 was examined under identical
reaction conditions and found to proceed more sluggishly to give
a lower yield and ee. This spurred us to focus on substrates
possessing a trans relationship between the pendant aldehyde and
activating group for the rest of this study.
In conclusion, we have demonstrated the feasibility of enanti-
oselective formation of quaternary stereocenters via a catalytic
asymmetric Stetter reaction. This process delivers the product 1,4-
dicarbonyl compounds bearing a quaternary stereocenter in high
yield and selectivity under exceedingly mild conditions. We have
also described a new electron-deficient catalyst with improved
performance in these reactions, illustrating that subtle electronic
requirements are present in this and related transformations. Efforts
aimed at elucidating the factors responsible for this effect and
expanding the reactivity of these carbenes are ongoing.
Acknowledgment. We thank the National Science Foundation
and Colorado State University for support. T.R. thanks Merck
Research Laboratories, GlaxoSmithKline, and Amgen for unre-
stricted support. M.S.K. thanks Boehringer-Ingelheim for a graduate
fellowship. We thank Professor Albert I. Meyers, for helpful
discussions, and Dr. Jerry Murry (Merck Research Laboratories),
Table 2. Aliphatic Substrates
for a generous gift of both antipodes of aminoindanol.
Supporting Information Available: Experimental procedures and
characterization data for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(
1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
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(3) Shibasaki, M.; Vogl, E. M. In ComprehensiVe Asymmetric Catalysis;
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(
4) (a) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921-3924.
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(
1
(
(
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Angew. Chem., Int. Ed. 2001, 40, 1456-1460.
a
Absolute configuration assigned by analogy to 22. b Enantiomeric
(7) Battacharya, A.; Dolling, U.-H.; Grabowski, E. J. J.; Karady, S.; Ryan,
K. M.; Weinstock, L. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 476-
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excess determined by GC or HPLC analysis on a chiral stationary phase;
c
see Supporting Information for details. Absolute configuration established
(
8) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L.
J. Am. Chem. Soc. 1998, 120, 1918-1919.
by comparison of optical rotation to known compound, see Supporting
Information for details.
(
9) The Stetter Reaction: (a) Stetter, H.; Kuhlmann, H. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1991; Vol. 40, pp 407-496. (b)
Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890-2896. Intra-
molecular Stetter: (c) Ciganek, E. Synthesis 1995, 1311-1314. Enantio-
selective Intramolecular Stetter: (d) Enders, D.; Breuer, K.; Runsink, J.;
Teles, J. H. HelV. Chim. Acta 1996, 79, 1899-1902. (e) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, published online March 25, http://
dx.doi.org/10.1021/ar030050j.
The reaction of a variety of aliphatic substrates was subsequently
investigated, Table 2. Other aromatic ketones react in similar fashion
to give high yields of the product cyclopentanones 18 and 20, entries
1
and 2. An excellent ee is obtained in the cyclization of 4-pyridyl
ketone 17, while a slight decrease in selectivity accompanies the
reaction of p-nitrophenyl ketone 19. Furthermore, aliphatic ketones
(10) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298-10299. (b) Kerr, M. S.; Rovis, T. Synlett 2003 1934-1936.
(
11) Trost, B. M.; Shuey, C. D.; Dinnino, F.; McElvain, S. S. J. Am. Chem.
Soc. 1979, 101, 1284-1285.
12) This product is prone to racemization, presumably through a phenoxide
elimination/conjugate addition sequence. Stirring a toluene solution of 6
of 98% ee for 24 h with DBU results in quantitative recovery of 6 of
2
2
1 and 23 react under these conditions to give products 2216 and
4, entries 3 and 4, in excellent selectivity and good yield. Moderate
(
changes in sterics are also tolerated in the reaction as n-butyl
substituted 25 cyclizes with a 71% yield and 98% ee, entry 5.
Attempts to perform the Stetter reaction on the less activated
alkene in methyl ester 27 failed, and starting material was recovered
nearly quantitatively, eq 5. However, a second activating group on
the olefin allows for cyclization of bis-methyl ester 29 in 78% yield,
although with an enantioselectivity of only 65%. Fortunately, steric
and electronic properties of these easily tunable carbene catalysts
can be exploited, as catalyst 31 allows for cyclization to proceed
in 90% ee and good yield.
66% ee.
(
13) Catalyst screening was also performed under these conditions. Triazolium
chloride 31 provided product 6 in quantitative yield, although with a
modest 86% ee. Catalyst 5b gave only trace amounts of product.
14) Other solvents typically provide poorer selectivity but can allow for much
lower catalyst loading. For example, reaction of 4 with 1% triazolium
(
3
salt 5c with 10 equiv Et N in i-PrOH for one week provides a 78% yield
of 6 with 83% ee. Toluene provides consistently high yields and
enantioselectivity.
(
(
15) Triethylamine provided the product in 90% yield and 88% ee.
16) The apparent reversal in stereoinduction between the aliphatic and aromatic
series is presently under investigation.
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