Highly enantioselective direct reductive coupling of conjugated alkynes and α-ketoesters via rhodium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ja056474l

Catalytic hydrogenation of 1,3-enynes 1a-7a in the presence of ethyl pyruvate and related activated ketones using chirally modified cationic rhodium catalysts results in reductive coupling to afford dienylated α-hydroxy esters 1b-7b and 3c-3f with exceptional levels of regio- and enantiocontrol. These studies represent the first highly enantioselective direct catalytic reductive couplings of alkynes to ketones. As illustrated by the conversion of 6b to 6c-6h, the diene containing the side chain of the coupling products is subject to diverse chemo- and regioselective manipulation. Reductive coupling of enyne 6a and ethyl pyruvate using elemental deuterium provides the monodeuterated product deuterio-6b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle, as corroborated by ESI-MS analysis. Copyright

Full text of DOI:10.1021/ja056474l

Published on Web 12/22/2005
Highly Enantioselective Direct Reductive Coupling of Conjugated Alkynes
and r-Ketoesters via Rhodium-Catalyzed Asymmetric Hydrogenation
Jong-Rock Kong, Ming-Yu Ngai, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received September 20, 2005; E-mail: mkrische@mail.utexas.edu
Asymmetric hydrogenation is the most broadly utilized catalytic
enantioselective process employed industrially and accounts for over
half the chiral compounds made by man not produced via resolu-
tion.1 The enormous impact of asymmetric hydrogenation portends
an equally powerful approach to enantioselective reductive C-C
bond formation mediated by elemental hydrogen. However, since
the discovery of the Fischer-Tropsch reaction and alkene hydroform-
ylation, which are restricted to the migratory insertion of carbon
monoxide, the field of hydrogen-mediated C-C bond formation
has lain fallow. Recognizing the potential of catalytic hydrogenation
to serve as a fully atom economical means of reductive C-C bond
formation, this topic has become the focus of research in our lab.2
To date, the hydrogen-mediated reductive coupling of conjugated
enones,2a-d dienes,2e enynes,2f and diynes2g to carbonyl and imine2j
partners has been devised, as well as the reductive carbocyclization
of 1,6-diynes and 1,6-enynes.2h,i These studies are among the first
examples of hydrogen-mediated C-C bond formation that proceed
in the absence of carbon monoxide.3 As part of a continuing effort
to broaden this emergent class of C-C bond formations, the use
of activated ketones as electrophilic partners in hydrogen-mediated
C-C bond formation was explored. Here, we disclose that hydro-
genation of conjugated enynes in the presence of R-ketoesters using
chirally modified rhodium catalysts enables formation of R-hydroxy
esters with high levels of asymmetric induction and complete
regiocontrol. Further, we find that reaction rate and chemical yield
are dramatically enhanced through use of Brønsted acid additives.
These studies, which enable concise access to optically enriched
R-hydroxy esters, represent the first highly enantioselective direct
catalytic reductive couplings of alkynes to activated ketones.14b
Catalytic enantioselective additions of preformed organometallics
to aldehydes have reached a sophisticated level.4 Corresponding
ketone additions remain a challenge.5 In the case of carbonyl
vinylation, an effective strategy involves tandem hydrometalation-
transmetalation of alkynes to afford organozinc reagents, which
participate in catalyzed additions to aldehydes6,7 and ketones.8,9 This
approach necessitates stoichiometric use of two metallic reagents.
An alternate strategy involves the direct reductive coupling of
π-unsaturated substrates to carbonyl compounds10-14 or imines,2j,15
which presently encompasses the use of alkenes,10 alkynes,11
allenes,12 enones,2a-d,13 1,3-dienes,2e,11,1,3-enynes,2f,14 and 1,3-
diynes2g as pronucleophiles.
distilled DCE reproducibly gave the coupling product 1b in 88%
isolated yield and 90% ee. In the absence of the Brønsted acid
additive, but under otherwise identical conditions, 1b is produced
in only 42% yield and 87% ee.
Table 1. Enantioselective Hydrogen-Mediated Reductive Coupling
of Conjugated Enynes 1a-7a to R-Ketoestersa
Our initial efforts on hydrogen-mediated reductive couplings to
ketones involved the hydrogenation of 1,3-enyne 1a in the presence
of methyl pyruvate. Gratifyingly, formation of R-hydroxy ester 1b
was observed. Through an assay of chiral ligands, it was revealed
that (R)-xylyl-Walphos provides excellent levels of asymmetric
induction. However, chemical yields varied dramatically in response
to aging of the solvent 1,2-dichloroethane (DCE), with older batches
of solvent providing better results. It was reasoned that adventitious
HCl may promote reductive coupling. Indeed, an assay of Brønsted
acid additives reveals that reactions performed with substoichio-
metric quantities of triphenylacetic acid (1 mol %) in freshly
a Cited yields are of pure isolated material and represent the average of
two runs. Reaction times are typically less than 3 h. See Supporting
Information for detailed experimental procedures.
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10.1021/ja056474l CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Elaboration of Coupling Product 6ba
Acknowledgment is made to the Welch Foundation, Johnson
& Johnson, and the NIH-NIGMS (RO1-GM69445) for partial
support of this research.
Supporting Information Available: Single crystal X-ray diffraction
data for derivatives of 6d and 6f, and ESI-MS data. Spectral data for
all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Thayer, A. M. Chem. Eng. News 2005, 83, 40.
(2) For hydrogen-mediated C-C bond formations developed in our lab, see:
(a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 15156. (b) Huddleston, R. R.; Krische, M. J. Org. Lett. 2003,
5, 1143. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691. (d)
Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J. Org. Chem.
2004, 69, 1380. (e) Jang, H.-Y.; Huddleston, R. R.; Krische, M. Angew.
Chem., Int. Ed. 2003, 42, 4074. (f) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4664. (g) Huddleston, R. R.; Jang,
H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488. (h) Jang, H.-
Y.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875. (i) Jang, H.-Y.;
Hughes, F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. Am.
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a Cited yields are of pure isolated material and represent the average
of two runs. See Supporting Information for detailed experimental pro-
cedures.
These conditions are applicable to the reductive coupling of
conjugated enynes 1a-7a to methyl and ethyl pyruvate.16 Other
R-ketoesters also participate, as demonstrated by the coupling of
enyne 3a to afford products 3c-3f, which are obtained in high
yield and good to excellent enantiomeric excess. In all cases, the
diene containing coupling products are not subject to over-reduction
under the conditions of hydrogen-mediated coupling, and the
trisubstituted alkene forms as a single geometrical isomer (Table
1). The functional group array presented by the reductive coupling
products offers numerous prospects for further elaboration. For
example, the diene containing side chain of 6b is subject to selective
reduction (6c, 6d), selective oxidation (6e, 6f, 6h), and alkene cross-
metathesis (6g) (Table 2). The absolute and relative stereochemical
assignments of all new compounds are based upon X-ray diffraction
analysis of the amides derived from compounds 6d and 6f with
(R)-1-(2-naphthyl)ethylamine.
Reductive coupling of enyne 6a and ethyl pyruvate under a
deuterium atmosphere provides deuterio-6b. This result is consistent
with a catalytic mechanism involving oxidative coupling followed
by hydrogenolytic cleavage of the resulting metallacycle via σ-bond
metathesis. Even when using 50 mol % loadings of Brønsted acid
under otherwise standard conditions that involve 2 mol % loadings
of the rhodium catalyst, clean monodeuteration persists. This result
excludes mechanisms involving protonolytic cleavage of the
rhodium-carbon bond of the oxametallacycle and suggests a
plausible role for the acidic additive might involve protonolytic
cleavage of the rhodium-oxygen bond. Alternatively, protonation
of the pyruvate may facilitate oxidative coupling by lowering the
LUMO of the ketone partner. Oxidative coupling is suggested
further by ESI-MS analysis of the coupling reaction of Boc-
protected enyne 1a and phenyl glyoxal using a Rh(COD)2OTf-
BIPHEP catalyst.17 Here, the mass of the most abundant ion
observed matches that of Rh(BIHPEP)(1a)(phenylglyoxal) or Rh-
(BIPHEP)(metallacycle). Hydride intermediates are not observed.
(3) Prior to our work, the following hydrogen-mediated C-C bond formations
under CO-free conditions were reported: (a) Molander, G. A.; Hoberg,
J. O J. Am. Chem. Soc. 1992, 114, 3123. (b) Kokubo, K.; Miura, M.;
Nomura, M. Organometallics 1995, 14, 4521.
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Chem. ReV. 2003, 103, 2763.
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S. C. J. Org. Chem. 2003, 68, 1589. (j) Lurain, A. E.; Walsh, P. J. J. Am.
Chem. Soc. 2003, 125, 10677. (k) Ko, D.-H.; Kang, S.-W.; Kim, K. H.;
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Chem., Int. Ed. 2001, 40, 3667. (b) Wipf, P.; Stephenson, C. R. J. Org.
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therein.
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126, 6538. (b) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355.
(10) Alkenes: (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995,
117, 6785. (b) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995,
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12. (b) Jang, H.-Y.; Krische, M. J. Eur. J. Org. Chem. 2004, 3953.
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(16) Exposure of ethyl pyruvate to cyclohexadiene or diphenylbutadiyne under
these precise conditions provides only trace quantities of reductive coupling
product.
(17) See Supporting Information for ESI-MS data.
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