Highly enantioselective reductive cyclization of acetylenic aldehydes via rhodium catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ja0637954

Catalytic hydrogenation of acetylenic aldehydes 1a-12a using chirally modified cationic rhodium catalysts enables highly enantioselective reductive cyclization to afford cyclic allylic alcohols 1b-12b. Using an achiral hydrogenation catalyst, the chiral r

Full text of DOI:10.1021/ja0637954

Published on Web 08/01/2006
Highly Enantioselective Reductive Cyclization of Acetylenic Aldehydes via
Rhodium Catalyzed Asymmetric Hydrogenation
Jong Uk Rhee and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received May 30, 2006; E-mail: mkrische@mail.utexas.edu
Table 1. Enantioselective Reductive Cyclization of Acetylenic
The invention of catalytic methods for the reductive coupling
of alkynes and aldehydes is currently the subject of intensive
investigation.1,2 Seminal contributions to this area include the
rhodium-catalyzed reductive cyclization of acetylenic aldehydes
reported by Ojima (1994),3 corresponding titanocene-catalyzed
cyclizations disclosed by Crowe (1995),4 and the nickel-catalyzed
reductive cyclization of acetylenic aldehydes reported by Mont-
gomery (1997).5a-c,e Through further modification of the nickel
based catalysts, corresponding intermolecular couplings have been
achieved, as described by Jamison (2000)6 and Montgomery
(2004).5d Additionally, intermolecular reductive coupling of con-
jugated alkynes to vicinal dicarbonyl compounds and R-iminoac-
etates may be carried out via rhodium catalyzed hydrogenation, as
described by the present author (2003).7 Asymmetric variants of
the intermolecular processes have been devised,6b,7a,d,e but are
restricted to aryl-substituted acetylenes introduced via syringe pump
addition6b or use of conjugated alkynes (1,3-enynes and 1,3-
diynes).7a,d,e Remarkably, catalytic enantioselective methods for the
reductive cyclization of acetylenic aldehydes are absent from the
literature.8,9
Aldehydes via Rhodium Catalyzed Hydrogenationa
In this account, we disclose that hydrogenation of acetylenic
aldehydes using chirally modified cationic rhodium catalysts enables
formation of cyclic allylic alcohols in good yield and with
exceptionally high levels of asymmetric induction. These transfor-
mations are facilitated by our recent finding that Brønsted acid
additives greatly enhance both rate and conversion in hydrogen-
mediated C-C coupling reactions of alkynes to carbonyl partners.7d
Additionally, we demonstrate that acetylenic aldehydes possessing
preexisting stereogenic centers engage in highly diastereoselective
reductive cyclization. These studies represent the first examples of
the catalytic enantioselective reductive cyclization of acetylenic
aldehydes.
Our initial efforts focused on the hydrogen-mediated cyclization
of acetylenic aldehyde 3a. Exposure of a 1,2-dichloroethane solution
(0.1 M) of 3a to one atmosphere of hydrogen at 45 °C in the absence
of a Brønsted acid additive using the cationic catalyst precursor
Rh(COD)2OTf and (R)-Cl,MeO-BIPHEP10 as ligand resulted in
the formation of the cyclized product 3b in 24% yield and 95%
enantiomeric excess. In contrast, in the presence of substoichio-
metric loadings of 2-naphthoic acid (5 mol %), but under otherwise
identical conditions, lactam 3b is obtained in 67% yield and 98%
enantiomeric excess.
a Cited yields are of isolated material and represent the average of two
runs. The absolute stereochemical assignment of 1b-12b is based upon
X-ray crystallographic analysis of the 2,4-dinitrobenzolate derived from
lactam 1b. Enantiomeric excess was determined by chiral stationary phase
HPLC. See Supporting Information for further details.
lactams 1b-3b in highly optically enriched form, demonstrating
applicability of the cyclization to electron deficient alkynes. Simple
unactivated alkynes were explored next. As demonstrated by the
formation of 4b-8b, sulfonamide-tethered acetylenic aldehydes
possessing a geminal substituent adjacent to the aldehyde cyclize
readily. Aryl, alkyl, and cyclopropyl substituents at the acetylenic
terminus are tolerated (4b-7b) but are not a prerequisite for
efficient cyclization (8b). Acetylenic aldehydes that are geminally
substituted at the propargylic position also cyclize efficiently with
high levels of asymmetric induction (9b). As demonstrated by the
formation of 10b-12b, alkylidene furans form readily via hydrogen-
mediated cyclization (Table 1).
The cyclizations of acetylenic aldehydes that embody preexisting
stereogenic centers were conducted using the parent achiral ligand
BIPHEP to afford 13b-15b with good to excellent levels of
These conditions were applied to acetylenic aldehydes 1a-12a.
The R,â-acetylenic amides 1a-3a provide the corresponding
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10.1021/ja0637954 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Diastereoselective Reductive Cyclization of Acetylenic
Acknowledgment. Acknowledgment is made to the Robert A.
Welch Foundation, Johnson & Johnson, and the NIH-NIGMS
(Grant RO1-GM69445) for partial support of this research. Dr.
Ulrich Scholz is thanked for a generous donation of (R)-Cl,MeO-
BIPHEP.10
Aldehydes via Rhodium Catalyzed Hydrogenationa
Supporting Information Available: Spectral data for all new
1
compounds; scanned images of H and 13C NMR spectra and chiral
stationary phase HPLC traces; single-crystal X-ray diffraction data for
the 2,4-dinitrobenzoate derived from compound 1b and the p-bro-
mobenzoate derived from 14b. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Cited yields are of isolated material. See Supporting Information for
further details.
Table 3. Optically Enriched R-Hydroxy Ketones via Ozonolysis of
Reductive Cyclization Products 7b and 9ba
References
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a Cited yields are of isolated material. See Supporting Information for
further details.
Scheme 1. Plausible Catalytic Cycle as Supported by 2H-Labeling
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of this assignment to systems that differ significantly in structure
should be made with caution. The relative stereochemical assign-
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may assist cleavage of the metallacyclic intermediate, as previously
proposed.7d Alternatively, it may suppress proton loss from cationic
rhodium dihydrides to afford neutral monohydride complexes,
which appear less prone to engage in oxidative coupling pathways
(Scheme 1).11
In summary, exposure of acetylenic aldehydes to gaseous
hydrogen in the presence of chirally modified rhodium catalysts
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underscore the key role of acidic additives in hydrogen-mediated
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