Enantioselective reductive cyclization of 1,6-enynes via rhodium-catalyzed asymmetric hydrogenation: C-C bond formation precedes hydrogen activation

Article abstract of DOI:10.1021/ja042645v

Asymmetric hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alkylidene-substituted carbocycles and heterocycles in a completely atom economical fashion. Good to exce

Full text of DOI:10.1021/ja042645v

Published on Web 04/06/2005
Enantioselective Reductive Cyclization of 1,6-Enynes via Rhodium-Catalyzed
Asymmetric Hydrogenation: C-C Bond Formation Precedes Hydrogen
Activation
Hye-Young Jang, Freddie W. Hughes, Hegui Gong, Junmei Zhang, Jennifer S. Brodbelt, and
Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received December 7, 2004; E-mail: mkrische@mail.utexas.edu
Table 1. Enantioselective Hydrogen-Mediated Reductive
Cyclization of 1,6-Enynes 1a-12a Catalyzed by Rhodiuma
Although elemental hydrogen is the cleanest and most cost-
effective reductant available, the capture of organometallic species
generated via hydrogenation has, until recently, only been achieved
through migratory insertion of carbon monoxide (alkene hydro-
formylation and the Fischer-Tropsch reactions).1 The principal
challenge posed by hydrogen-mediated C-C bond formation
involves partitioning of conventional hydrogenation and reductive
coupling manifolds. Initial studies from our lab on hydrogen-
mediated reductive aldol coupling demonstrate that conventional
hydrogenation pathways are suppressed through the use of cationic
rhodium precatalysts and mild basic additives. Such conditions are
believed to induce heterolytic hydrogen activation.2,3 Subsequently
developed reductive couplings of R-keto aldehydes to 1,3-dienes,
1,3-enynes, and 1,3-diynes retain the requirement of a cationic
rhodium precatalyst, yet proceed in the absence of basic additives,
suggesting heterolytic hydrogen activation may not be operative.
In connection with our studies on hydrogen-mediated C-C bond
formation,1 an enantioselective variant of the hydrogen-mediated
reductive cyclization of 1,6-enynes was sought. While enantiose-
lective cycloisomerizations and hydrosilylative cyclizations of 1,6-
enynes are known, simple enantioselective reductive cyclizations
have not been described.4-7 Here, we report that asymmetric
hydrogenation of 1,6-enynes at ambient temperature and pressure
using chirally modified rhodium catalysts promotes highly enan-
tioselective reductive cyclization to afford a diverse range of
alkylidene-substituted carbocycles and heterocycles with complete
atom economy. Related hydrogen-deuterium crossover experiments
suggest oxidative cyclization to form a metallocyclic intermediate
occurs in advance of hydrogen activation.
Initial studies focused on the enantioselective reductive cycliza-
tion of 1,6-enyne 1a. Gratifyingly, hydrogenation of 1a at ambient
pressure and temperature using Rh(COD)2OTf (5 mol %) as
precatalyst and (R)-BINAP (5 mol %) as a chiral inducing element
gave the desired reductive cyclization product 1b in 69% yield and
94% ee. These reaction conditions proved to be applicable across
a structurally diverse set of 1,6-enynes 1a-12a. Interestingly, a
striking dependence of chemical yield and enantiomeric excess upon
the structural features of the chiral phosphine ligand is observed;
while 1a-6a and 9a-12a cyclize in good yield and excellent
enantiomeric excess using (R)-Cl,OMe-BIPHEP and (R)-BINAP,
(R)-PHANEPHOS delivers a complex distribution of conventional
hydrogenation products, yet (R)-PHANEPHOS is unique in its
ability to promote highly enantioselective cycloreduction of enynes
7a-8a.
a Procedure: To a solution of enyne 1a (100 mol %) in DCE or DCM
(0.1 M) at 25 °C were added rhodium catalyst and ligand. In the case of
substrates 1a-5a and 9a-12a, 5 mol % of catalyst and ligand was
employed. In the case of substrates 6a-8a, 3 mol % of catalyst and ligand
was employed. The system was purged with H2 (g), and the reaction was
allowed to stir under 1 atm of H2 (g) until complete consumption of 1a
was observed (2-3 h), at which point the reaction mixture was evaporated
onto silica gel and the product purified by silica gel chromatography.
Reductive cyclization products 1b-12b incorporate two nonex-
changeable hydrogen atoms. Homolytic and heterolytic hydrogen
activation pathways may now be discriminated on the basis of
hydrogen-deuterium crossover experiments. Reductive cyclization
of 13a under a mixed atmosphere of H2 and D2 or under an
atmosphere of DH does not provide crossover products, in
accordance with homolytic hydrogen activation. Exposure of 14a
9
6174
J. AM. CHEM. SOC. 2005, 127, 6174-6175
10.1021/ja042645v CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
a (Top) Reductive cyclization of 13a under a mixed atmosphere of H2 and D2 or under an atmosphere of DH does not provide crossover products.
(Bottom) Exposure of 14a and 15a to identical conditions under a D2 atmosphere provides cycloisomerization products 14c and 15c without deuterium
incorporation, even at stoichiometric catalyst loadings, thus suggesting hydrometallative pathways en route to 14c and 15c are not operative.
or 15a to identical conditions under a D2 atmosphere does not
induce reductive cyclization. Rather, cycloisomerization products
14c and 15c are formed.7 A hydrometallative mechanism for
cycloisomerization would be initiated by D2 oxidative addition and
propagated by rhodium hydrides derived upon â-hydride elimination
from intermediate A. Deuterium incorporation should occur in the
first turnover of the catalytic cycle, yet deuterium incorporation is
not observed, even at stoichiometric catalyst loadings. The extent
of deuterium incorporation for 13b-e, 14c, and 15c is established
by ESI-MS analysis with isotopic correction and is corroborated
Johnson, and Merck. Dr. Ulrich Scholz of Bayer Chemicals is
thanked for the generous donation of (R)-Cl,OMe-BIPHEP. Our
reviewers are thanked for helpful comments.
Supporting Information Available: Spectral data for new com-
pounds, absolute stereochemical assignments, and ESI-MS data. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For catalytic C-C bond-forming hydrogenations developed in our lab,
see: Jang, H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653.
(2) For a review covering heterolytic hydrogen activation, see: Brothers, P.
J. Prog. Inorg. Chem. 1981, 28, 1.
1
by H NMR analysis (Scheme 1).
Acquisition of 14c and 15c without deuterium incorporation is
inconsistent with a hydrometallative mechanism. This fact, along
with the absence of conjugated cycloisomerization products,
suggests â-hydride elimination from metallocycle B. If indeed
oxidative cyclization occurs initially, subsequent hydrogenolytic
cleavage must occur via (a) hydrogen oxidative addition, or (b)
hydrogen activation via σ-bond metathesis. Rh(I)-mediated oxida-
tive coupling of 1,6-enynes to form Rh(III) metallocycles is well
established.8 Additionally, an increasing body of evidence supports
participation of organorhodium(III) complexes in σ-bond metathesis
pathways,9 including reactions with hydrogen.10c Whereas hydrogen
oxidative addition to a Rh(III) metallocycle would afford a Rh(V)
intermediate, hydrogen activation via σ-bond metathesis would not.
In either case, C-C bond formation occurs in adVance of hydrogen
actiVation. Hydrogen oxidative addition followed by rhodium(V)
metallocycle formation is unlikely and, to our knowledge, without
precedent. As hydrogen oxidative addition is rate-determining for
asymmetric hydrogenations catalyzed by cationic rhodium com-
plexes,10 it is reasonable to suggest that oxidative cyclization is
faster than hydrogen activation. Finally, it is worth noting that the
1H NMR ratio of 13d:13e is 1:2.1, suggesting hydrogen activation
is rate-determining for reductive cyclization.
(3) Mild basic additives are believed to induce heterolytic activation of
hydrogen via deprotonation of cationic rhodium dihydride intermediates:
(a) Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2134. (b)
Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 2143. (c)
Schrock, R. R.; Osborn, J. A. J. Am. Chem. Soc. 1976, 98, 4450.
(4) For reviews encompassing the Pd-catalyzed cycloisomerization and
reductive cyclization of 1,6-enynes, see: (a) Trost, B. M. Acc. Chem.
Res. 1990, 23, 34. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R.
J. Chem. ReV. 1996, 96, 635. (c) Trost, B. M.; Krische, M. J. Synlett 1998,
1. (d) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813.
(5) For selected examples of the cycloisomerization of 1,6-enynes catalyzed
by metals other than palladium, see: (a) Titanium: Sturla, S. J.; Kablaoui,
N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 1976. (b)
Rhodium: Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122,
6490. (c) Nickel-Chromium: Trost, B. M.; Tour, J. M. J. Am. Chem.
Soc. 1987, 109, 5268. (d) Ruthenium: Nishida, M.; Adachi, N.; Onozuka,
K.; Matsumura, H.; Mori, M. J. Org. Chem. 1998, 63, 9158. (e) Trost, B.
M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 714. (f) LaPaih, J.;
Rodriguez, D. C.; Derien, S.; Dixneuf, P. H. Synlett 2000, 95. (g) Cobalt:
Ajamian, A.; Gleason, J. L. Org. Lett. 2003, 5, 2409. (h) Iridium: Chatani,
N.; Inoue, H.; Morimoto, T.; Muto, T.; Muria, S. J. Org. Chem. 2001,
66, 4433.
(6) For a review of the enantioselective catalytic cycloisomerization of 1,6-
and 1,7-enynes, see: Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2004, 43,
1048.
(7) For rhodium-catalyzed enantioselective enyne cycloisomerization and
hydrosilylation cyclization, see: (a) Ping, C.; Zhang, X. Angew. Chem.,
Int. Ed. 2000, 39, 4104. (b) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew.
Chem., Int. Ed. 2002, 41, 3457. (c) Lei, A.; Waldkirch, J. P.; He, M.;
Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 4526. (d) Lei, A.; He, M.;
Zhang, X. J. Am. Chem. Soc. 2003, 125, 11472. (e) Chakrapani, H.; Liu,
C.; Widenhoefer, R. A. Org. Lett. 2003, 5, 157.
(8) Rh(III) metallocycles derived from 1,6-enynes are postulated as reactive
intermediates in catalytic [4 + 2] and [5 + 2] cycloadditions, Pauson-
Khand reactions, and cycloisomerizations: Cao, P.; Wang, B.; Zhang, X.
J. Am. Chem. Soc. 2000, 122, 6490 and references therein.
(9) For σ-bond metathesis involving Rh(III) intermediates, see: (a) Hartwig,
J. F.; Cook, K. S.; Hapke, M.; Incarvito, C. D.; Fan, Y.; Webster, C. E.;
Hall, M. B. J. Am. Chem. Soc. 2005, 127, 2538. (b) Liu, C.; Widenhoefer,
R. A. Organometallics 2002, 21, 5666. (c) Hutschka, F.; Dedieu, A.;
Leitner, W. Angew. Chem., Int. Ed. Engl. 1995, 34, 1742.
(10) For selected reviews encompassing asymmetric hydrogenation catalyzed
by cationic rhodium complexes, see: (a) Halpern, J. J. Organomet. Chem.
1980, 200, 133. (b) Landis, C. R.; Brauch, T. W. Inorg. Chim. Acta 1998,
270, 285. (c) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.
While hydrogen-mediated enone couplings require basic additives
and, hence, may involve formal heterolytic hydrogen activation,
the present hydrogen-deuterium crossover experiments suggest
related reductive couplings under base-free conditions proceed
through rhodium(III) metallocycles, which form in adVance of
homolytic hydrogen activation. This oxidative coupling-hydro-
genolytic cleavage motif should play a key role in the design of
related hydrogen-mediated couplings.
Acknowledgment. Acknowledgment is made to the Research
Corporation Cottrell Scholar Award, the Sloan Foundation, the
Dreyfus Foundation, the Welch Foundation, Eli Lilly, Johnson &
JA042645V
9
J. AM. CHEM. SOC. VOL. 127, NO. 17, 2005 6175