Enantioselective reductive coupling of 1,3-enynes to glyoxalates mediated by hydrogen: Asymmetric synthesis of β,γ-unsaturated α-hydroxy esters

Article abstract of DOI:10.1021/ol7015548

Catalytic hydrogenation of 1,3-enynes 1a-8a in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst modified by (R)-(3,5-^tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding a-hydroxy esters 1b-8b. As demonstrated by the elaboration of a-hydroxy ester 1b, the terminal and internal olefin moieties embodied by the diene side chain are subject to selective manipulation, one over the other.

Full text of DOI:10.1021/ol7015548

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3745-3748
Enantioselective Reductive Coupling of
1,3-Enynes to Glyoxalates Mediated by
Hydrogen: Asymmetric Synthesis of
â,γ-Unsaturated r-Hydroxy Esters
Young-Taek Hong,† Chang-Woo Cho,†,‡ Eduardas Skucas,† and
Michael J. Krische*,†
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712, and Kyungpook National UniVersity, Department of Chemistry,
Daegu 702-701, Korea
mkrische@mail.utexas.edu
Received July 2, 2007
ABSTRACT
Catalytic hydrogenation of 1,3-enynes 1a
modified by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding
-hydroxy esters 1b 8b. As demonstrated by the elaboration of -hydroxy ester 1b, the terminal and internal olefin moieties embodied by the
−8a in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst
r
−
r
diene side chain are subject to selective manipulation, one over the other.
The Fischer-Tropsch reaction1a,b and alkene hydroformyla-
tion1c are practiced on enormous scale and may be viewed
as prototypical hydrogen-mediated C-C bond formations.
Whereas these processes rely upon the use of carbon
monoxide as a coupling partner, only recently has it been
shown that catalytic hydrogenation may induce C-C cou-
pling between π-unsaturated reactants and conventional
electrophilic partners in the form of carbonyl compounds
and imines.2-7 Through the use of cationic rhodium and
iridium precatalysts, the hydrogenative coupling of conju-
gated enones,3 conjugated alkenes,4 and both conjugated5a-g
and nonconjugated alkynes5h,i,j,k to carbonyl and imine3h,5c,j,k
partners have been devised. In addition, hydrogenation of
1,6-diynes, 1,6-enynes, and 1,6-alkynals is found to provide
products of reductive carbocyclization.6
In the course of studies aimed at the development of
methods for alkyne-carbonyl reductive coupling,8-10 highly
enantioselective direct hydrogen-mediated couplings of 1,3-
enynes to pyruvates and R-ketoesters using cationic rhodium
catalysts modified by (R)-xylyl-WALPHOS were developed.5e
More recently, related couplings of trialkylsilyl-substituted
1,3-diynes to glyoxalates using cationic rhodium catalysts
modified by (R)-Cl,MeO-BIPHEP were devised.5f Parallel
efforts toward the enantioselective reductive coupling of 1,3-
enynes to glyoxalates were impeded by the fact that
commercially available chelating chiral phosphine ligands
(3) For hydrogen-mediated reductive aldol and Mannich couplings, 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) Jung, C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8,
519. (f) Han, S. B.; Krische, M. J. Org. Lett. 2006, 8, 5657. (g) Jung, C.-
K.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 17051. (h) Garner, S. A.;
Krische, M. J. J. Org. Chem. 2007, 72, 5843.
(4) For hydrogen-mediated couplings of alkenes to carbonyl compounds,
see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. Angew. Chem., Int.
Ed. 2003, 42, 4074. (b) Hong, Y.-T.; Barchuk, A.; Krische, M. J. Angew.
Chem., Int. Ed. 2006, 128, 6885. Also see ref 7b.
† University of Texas at Austin.
‡ Kyungpook National University.
(1) Fischer, F.; Tropsch, H. Brennstoff Chem. 1923, 4, 276. (b) Fischer,
F.; Tropsch, H. Chem. Ber. 1923, 56B, 2428. (c) Roelen, O. German Patent
DE 1938, 849,548.
(2) For recent reviews, see: (a) Ngai, M.-Y.; Kong, J.-R.; Krische, M.
J. J. Org. Chem. 2007, 72, 1063. (b) Iida, H.; Krische, M. J. Top. Cur.
Chem. 2007, 279, 77.
10.1021/ol7015548 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/18/2007

alate under hydrogenation conditions to furnish the corre-
sponding R-hydroxy esters 1b-8b in good to excellent yield
and with high levels of asymmetric induction (Scheme 1).
Scheme 1. R-Hydroxy Esters via Direct Enantioselective
Reductive Coupling of Conjugated Alkynes to Pyruvates and
Glyoxalates Mediated by Hydrogen
Preliminary studies involved a ligand assay, wherein 1,3-
enyne 1a (200 mol %) was hydrogenated in the presence of
ethyl glyoxalate (100 mol %) at ambient temperature and
pressure in dichloroethane (0.2 M) using a catalyst derived
from Rh(cod)2OTf (5 mol %) and a chiral bidentate phos-
phine ligand (5 mol %). Using (R)-BINAP as the ligand,
the desired product of reductive coupling 1b was obtained
in 84% yield and 63% enantiomeric excess as a single
regioisomer and with complete control of olefin geometry.
This promising result stimulated further efforts toward the
identification of highly enantioselective catalysts for the
reductive coupling of enyne 1a to ethyl glyoxalate. Numerous
commercially available chiral bidentate phosphine ligands
were assayed under the standard coupling conditions speci-
fied above, which enabled a rough correlation between ligand
structural features vis-a`-vis conversion and enantioselection
(Table 1). In general, aryl substitution at phosphorus is
required for high levels of conversion. A single alkyl
substituent at phosphorus, as in the case of WALPHOS type
ligands, significantly decreases the isolated yield (Table 1,
entries 7-9). In the BINAP, PHANEPHOS and WALPHOS
series of ligands, the xylyl derivatives were slightly better
at enforcing asymmetric induction than the corresponding
phenyl derivatives (Table 1, entries 1-2, 3-4, and 7-9,
respectively). Among the phenyl-substituted chiral chelating
phosphine ligands assayed, (R)-MeO-BIPHEP enforced the
highest levels of asymmetric induction (Table 1, entry 16).
Stimulated by this result and the aforementioned trends, (R)-
uniformly failed to promote high levels of asymmetric
induction. Here, we report that cationic rhodium complexes
modified by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP catalyze
the reductive coupling of 1,3-enynes 1a-8a to ethyl glyox-
Table 1. Enantioselective Hydrogen-Mediated Reductive Coupling of Conjugated Enyne 1a to Ethyl Glyoxalatea
a Cited yields are of isolated material. Enantiomeric excess was determined via chiral stationary-phase HPLC analysis using a Chiralcel OD-H column.
Eluant: 2% i-PrOH in hexane. Flow rate: 0.5 mL/min. Detection wavelength: 254 nm. Retention times: tmajor ) 16.7 min, tminor ) 18.6 min. NPOH )
2-naphthoic acid. TPPA ) triphenylacetic acid. See the Supporting Information for further details.
3746
Org. Lett., Vol. 9, No. 19, 2007

(3,5-tBu-4-MeOPh)-MeO-BIPHEP was investigated. Gratify-
ingly, R-hydroxy ester 1b was obtained in 65% isolated yield
and 91% enantiomeric excess (Table 1, entry 17). Further
assay of the rhodium counterion, [Rh(cod)2]X, where X )
OTf, BF4, and “BARF” (BARF ) B(3,5-(CF3)2C6H3)4),
revealed no significant change in isolated yield or enanti-
oselection in response to variation of counterion (Table 1,
entries 17-19). In contrast, Brønsted acid additives were
found to have a profound effect on both isolated yield and
enantioselection. Brønsted acid additives are believed to
facilitate the catalytic process by circumventing highly
energetic 4-centered transition structures for σ-bond metath-
esis, as required for direct hydrogenolysis of metallacyclic
intermediates, with 6-centered transition structures for hy-
drogenolysis of rhodium carboxylates derived upon proto-
nolytic cleavage of the metallacycle.2 Whereas 2-naphthoic
acid (5 mol %) significantly increases the isolated yield of
1b, a dramatic decrease in enantioselection is observed (Table
1, entry 20). For couplings conducted in the presence of
triphenylacetic acid, which provide R-hydroxy ester 1b in
78% isolated yield and 95% enantiomeric excess, an increase
in both isolated yield and enantioselection was observed
(Table 1, entry 20). Accordingly, these latter conditions were
adopted as standard conditions.
glyoxalate under standard conditions (Figure 1). In all cases,
C-C coupling occurs at the acetylenic terminus of the
conjugated enyne to furnish R-hydroxy esters 1b-8b as single
constitutional isomers with complete control of alkene
geometry. The coupling was applicable to conjugated enynes
possessing aryl (1a, 2a, 3a), heteroaryl (4a, 8a), primary alkyl
(6a, 7a), and secondary alkyl (5a) substituents at the
acetylenic terminus. Isolated yields of the R-hydroxy esters
1b-8b ranged from 70 to 82%, and the levels of enantio-
selection ranged from 86 to 97% ee (Figure 1). Notably, over-
To assess scope, conjugated enynes 1a-8a possessing
structurally diverse acetylenic termini were coupled to ethyl
(5) For hydrogen-mediated couplings of alkynes to carbonyl compounds
and imines, see: (a) Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am.
Chem. Soc. 2003, 125, 11488. (b) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4664. (c) Kong, J.-R.; Cho, C.-W.;
Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269. (d) Cho, C.-W.; Krische,
M. J. Org. Lett. 2006, 8, 891. (e) Kong, J.-R.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2006, 128, 718. (f) Cho, C.-W.; Krische, M. J. Org.
Lett. 2006, 8, 3873. (g) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 16448. (h) Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 16040. (i) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem.
Soc. 2007, 129, 280. (j) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 7242. (k) Barchuk, A.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 8432.
(6) For hydrogen-mediated carbocyclizations, see: (a) Jang, H.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2004, 126, 7875. (b) Jang, H.-Y.; Hughes,
F. W.; Gong, H.; Zhang, J.; Brodbelt, J. S.; Krische, M. J. J. Am. Chem.
Soc. 2005, 127, 6174. (c) Rhee, J.-U.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 10674. (d) Jung, I. G.; Seo, J.; Lee, S. I.; Choi, Y.; Chung, Y.
K. Organometallics 2006, 25, 4240. (e) Smith, D. M.; Pulling, M. E.;
Norton, J. R. J. Am. Chem. Soc. 2007, 129, 770 and ref 7a.
Figure 1. Enantioselective catalytic reductive coupling of substi-
tuted 1,3-enynes to ethyl glyoxalate mediated by hydrogen. Cited
yields are of isolated material. See the Supporting Information for
detailed experimental procedures. Enantiomeric excess was deter-
mined via chiral stationary phase HPLC analysis.
(7) Prior to our work, two isolated examples of hydrogen-mediated C-C
bond formation that did not involve couplings to carbon monoxide 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.
reduction of the diene side chain of adducts 1b-8b was not
observed under the conditions of hydrogen-mediated cou-
pling. Absolute stereochemical assignment of R-hydroxy
esters 1b-8b is based upon X-ray diffraction analysis of
the amide derived from 1b and (R)-1-(2-naphthyl)ethylamine.
Each olefin of the diene side chain of the reductive
coupling products 1b-8b is subject to selective manipulation.
To illustrate, R-hydroxy ester 1b was subjected to the
(8) Indirect asymmetric alkyne-aldehyde reductive coupling has been
achieved via stoichiometric alkyne hydrometallation (hydroboration or
hydrozirconation) followed by transmetallation to afford vinylzinc reagents,
which engage in enantioselective catalytic additions to aldehydes; see: (a)
Oppolzer, W.; Radinov, R. HelV. Chim. Acta 1992, 75, 170. (b) Oppolzer,
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Tetrahedron Lett. 1994, 35, 5197. (e) Oppolzer, W.; Radinov, R. N.; De
Brabander, J. Tetrahedron Lett. 1995, 36, 2607. (f) Wipf, P.; Ribe, S. J.
Org. Chem. 1998, 63, 6454. (g) Oppolzer, W.; Radinov, R. N.; El-Sayed,
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(9) For indirect catalytic enantioselective alkyne-ketone reductive
couplings analogous to those described in the preceding reference, see: (a)
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538. (b) Li, H.; Walsh,
P. J. J. Am. Chem. Soc. 2005, 127, 8355. (c) Jeon, S.-J.; Li, H.; Garcia, C.;
La Rochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70, 448.
(10) Direct alkyne-aldehyde reductive coupling to furnish allylic alcohols
has been achieved under the conditions of nickel catalysis; see: (a) Oblinger,
E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. (b) Huang, W.-S.;
Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. (c) Mahandru, G. M.;
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Org. Lett., Vol. 9, No. 19, 2007
3747

following transformations. Hydroxy-directed epoxidation of
1b catalyzed by OV(acac)211 stereoselectively delivers vinyl
epoxide 1c. Oxidative cleavage of the diene terminus using
the Lemieux-Johnson protocol furnishes the conjugated enal
1e12 Exhaustive reduction of the diene side chain to form
the saturated R-hydroxy ester 1d is achieved upon hydro-
genation of 1b using Crabtree’s catalyst.13 Finally, exposure
of diene 1b to conditions for ruthenium catalyzed cross
metathesis with 1,4-diacetoxy-2-butene14 enables formation
of allylic acetate 1f. The structural assignment of 1c-1f is
made in analogy to the corresponding pyruvate coupling
products (Figure 2).5e
glyoxalate catalyzed by rhodium. Good to excellent levels
of asymmetric induction are achieved using (R)-(3,5-tBu-4-
MeOPh)-MeO-BIPHEP as chiral ligand with triphenylacetic
acid as a Brønsted acid cocatalyst. A stereochemical model
accounting for the high levels of enantioselection enforced
by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP will be disclosed
in due course. These studies serve as a prelude to our long-
term goal of developing hydrogenation catalysts enabling
reductive C-C coupling of simple, commercially available
nonconjugated alkynes to diverse aldehydes en route to
optically enriched allylic alcohols.
Acknowledgment is made to the Robert A. Welch
Foundation, Johnson & Johnson, Merck, and the NIH-
NIGMS (RO1-GM69445) for partial support of this research.
Drs. Hans Ulrich Bla¨ser, Matthias Lotz, and Marc Thommen
of Solvias are thanked for a generous donation of (R)-3,5-
tBu-4-MeOBIPHEP.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS). Single-
crystal X-ray diffraction data corresponding to the amide
derived from 1b and (R)-(+)-1-(2-naphthyl)ethylamine. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL7015548
Figure 2. Elaboration of coupling product 1b.
(12) (a) Lemieux; R. U.; von Rudloff, E. Can. J. Chem. 1955, 33, 1701.
(b) Pappo, R.; Allen, D. S., Jr.; Lemieux;, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(13) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem.
1977, 141, 205. (b) For a review, see: Crabtree, R. H. Acc. Chem.
Res. 1979, 12, 331. (c) For hydrogenation of conjugated dienes cata-
lyzed by iridium, see: Cui, X.; Burgess, K. J. Am. Chem. Soc. 2003, 125,
14212.
In summary, we report a regio- and enantioselective
hydrogenative coupling of substituted 1,3-enynes to ethyl
(11) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973,
95, 6136. (b) For a review, see: Sharpless, K. B.; Verhoeven, T. R.
Aldrichim. Acta 1979, 12, 63.
(14) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187.
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