Enantioselective synthesis of cyclopentenones via rhodium-catalyzed kinetic resolution and desymmetrization of 4-alkynals

Article abstract of DOI:10.1021/ja0266161

We have developed two new catalytic processes that provide efficient access to interesting chiral building blocks, cyclopentenones that bear tertiary and quaternary stereocenters, in high enantiomeric excess and very good yield. Structures such as these h

Full text of DOI:10.1021/ja0266161

Published on Web 08/13/2002
Enantioselective Synthesis of Cyclopentenones via Rhodium-Catalyzed
Kinetic Resolution and Desymmetrization of 4-Alkynals
Ken Tanaka and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received April 20, 2002
Scheme 1
We have recently described a new method for synthesizing
cyclopentenones via the rhodium-catalyzed cyclization of 4-alkynals
(eq 1; Scheme 1).1 With regard to asymmetric catalysis of this
transformation, for simple substrates, no stereocenter is generated
in the process. Nevertheless, one can envision that a chiral catalyst
could be applied to kinetic resolution (e.g., eq 2) and/or desym-
metrization (e.g., eq 3) reactions.2
In view of the well-known propensity of 12-electron [RhL2]+-
based catalysts to participate in hydroxy- and alkoxy-directed
reactions,4 perhaps most notably hydrogenation processes, we
postulated that the anomalously efficient cyclization of 1b might
be attributable to coordination of the methoxy group to rhodium.
Because two-point (more generally, multi-point) complexation of
a substrate to a catalyst often provides a level of organization
conducive to high selectivity,4 we decided to attempt to capitalize
on this observation by developing an enantioselective cyclization.
Enantiopure 4-hydroxycyclopent-2-enones are of interest due to
their utility as intermediates in the synthesis of natural products
such as prostaglandins5 and pentenomycins.6,7
We are pleased to report that rhodium/(chiral bisphosphine)
catalysts can indeed achieve intramolecular hydroacylation reactions
of 4-alkynals with high levels of stereoselection. For example, Rh/
(i-Pr-DUPHOS) serves as an efficient catalyst for the kinetic
resolution8 of substrates in which the â carbon is a tertiary
The data illustrated in eq 4 provided the stimulus for our efforts
to pursue these possibilities. In early work, we had determined that
the use of a coordinating solvent such as acetone (eq 1) is usually
stereocenter (Table 1, entries 1-3).9 Selectivity factors (s ) [rate
critical for obtaining a good yield of the desired cyclopentenone.
of fast-reacting enantiomer]/[rate of slow-reacting enantiomer]) of
For example, for the methyl-substituted substrate (1a) depicted in
∼20-40 can be obtained, values that are sufficiently high to allow
eq 4, the cyclization proceeds in only 31% yield when the reaction
the unreacted aldehyde or the cyclopentenone to be isolated in good
is run in CH2Cl2,3 versus an 88% yield in acetone. We were
enantiomeric excess.10 If the â carbon is a quaternary stereocenter,11
surprised, therefore, to discover that closely related methoxy-
substituted 4-alkynal 1b cyclizes in CH2Cl2 in essentially quantita-
tive yield (eq 4).
then Tol-BINAP is the ligand of choice,12 providing very good
selectivity factors when the â position bears a methyl group (s ≈
20; entries 4 and 5), although the presence of a bulky isopropyl
substituent leads to lower enantioselection (entry 6).
Our successful kinetic resolutions with Rh/(Tol-BINAP) of
4-alkynals in which the â carbon is a quaternary stereocenter (Table
1, entries 4 and 5) suggested to us that we might also be able to
effect catalytic enantioselective desymmetrizations of prochiral
diynes. As illustrated in Table 2, this has proved to be possible.
Thus, Rh/(Tol-BINAP) catalyzes the cyclization of an array of
diynes to generate the desired cyclopentenones in excellent yield
* To whom correspondence should be addressed. E-mail: gcf@mit.edu.
and enantioselectivity.13
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10.1021/ja0266161 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Rhodium-Catalyzed Kinetic Resolution of 4-Alkynals
blocks, cyclopentenones that bear tertiary and quaternary stereo-
centers, in high enantiomeric excess. Future work will include
additional studies of the scope and mechanism of this and related
transformations.
Acknowledgment. We thank Dr. Bruce A. Pearlman (Pharma-
cia), Dr. James R. Gage (Pharmacia), and Ryo Shintani (MIT) for
assistance in determining the absolute configuration of the reaction
products, Ivory D. Hills for help in preparing the manuscript, and
Johnson Matthey Inc. for supplying [Rh(nbd)2]BF4. Support has
been provided by Bristol-Myers Squibb, Mitsubishi Chemical
(postdoctoral fellowship to K.T.), and Novartis. Funding for the
MIT Department of Chemistry Instrumentation Facility has been
furnished in part by NSF CHE-9808061 and NSF DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492-11493.
(2) (a) For a single example of an analogous kinetic resolution of a 4-alkenal
that bears an R stereocenter, see: James, B. R.; Young, C. G. J. Chem.
Soc., Chem. Commun. 1983, 1215-1216. James, B. R.; Young, C. G. J.
Organomet. Chem. 1985, 285, 321-332. (b) For a single example of an
analogous kinetic resolution of a 4-alkenal that bears a â stereocenter,
see: Barnhart, R. W.; Bosnich, B. Organometallics 1995, 14, 4343-4348.
The moderate selectivity is probably due to the reversibility of a number
of steps in the catalytic cycle. (c) For analogous desymmetrizations of
4-alkenals, see: Wu, X.-M.; Funakoshi, K.; Sakai, K. Tetrahedron Lett.
1993, 34, 5927-5930. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.;
Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.;
Suemune, H. J. Org. Chem. 2000, 65, 5806-5816.
(3) The major product is a cyclohexenone derived from a [4 + 2] annulation/
dimerization. See: Tanaka, K.; Fu, G. C. Org. Lett. 2002, 4, 933-935.
(4) For an overview of directed reactions, see: Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(5) For reviews, see: (a) Noyori, R.; Suzuki, M. Science 1993, 259, 44-45.
(b) Straus, D. S.; Glass, C. K. Med. Res. ReV. 2001, 21, 185-210.
(6) For leading references to pentenomycins, see: Seepersaud, M.; Al-Abed,
Y. Tetrahedron Lett. 2000, 41, 4291-4293.
(7) For leading references to jasmone and its derivatives, see: (a) Dobbs, D.
A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch, V.; Lenoir, J.-Y.;
Geneˆt, J.-P.; Wiles, J.; Bergens, S. H. Angew. Chem., Int. Ed. 2000, 39,
1992-1995. (b) Fra`ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998,
54, 7633-7703.
(8) For reviews of kinetic resolution, see: (a) Kagan, H. B.; Fiaud, J. C. Top.
Stereochem. 1988, 18, 249-330. (b) Hoveyda, A. H.; Didiuk, M. T. Curr.
Org. Chem. 1998, 2, 489-526. (c) Keith, J. M.; Larrow, J. F.; Jacobsen,
E. N. AdV. Synth. Catal. 2001, 1, 5-26.
(9) Notes: (a) Other ligands (e.g., CHIRAPHOS and JOSIPHOS) furnish
lower enantioselection. For Table 1, entry 1, Et-DUPHOS provides a
selectivity factor of 14; the reaction rate is faster than with i-Pr-DUPHOS.
(b) We obtain more modest selectivity factors in more coordinating
solvents (e.g., acetone or THF). (c) Substrates that lack a methoxy group
are not effectively resolved.
a Value for a specific run. b Average of two runs. c Carried out at 40
°C.
Table 2. Rhodium-Catalyzed Desymmetrization of 4-Alkynalsa
(10) For a kinetic resolution that proceeds with a selectivity factor of 30, one
can obtain a 48% (out of 50%) yield of aldehyde of 90% enantiomeric
excess (ref 8a). To generate the cyclopentenone in very high ee, the best
approach is to carry out the kinetic resolution to the conversion that
provides aldehyde with the target enantiomeric excess, and then to cyclize
the aldehyde to the cyclopentenone with a catalytic amount of [Rh(dppe)]2
(BF4)2.
(11) The development of catalytic, enantioselective methods for generating
quaternary stereocenters is one of the more difficult challenges in
stereoselective organic synthesis. For leading references, see: Corey, E.
J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-401. See
also: Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
entry
R
yield (%)b
ee (%)
1
2
3
4
n-C5H11
Cy
(CH2)3Cl
CH2OMe
95
94
91
93
92
95
91
82
(12) (S,S)-i-Pr-DUPHOS furnishes higher enantioselectivity (and the same
sense) as (R)-Tol-BINAP, but the reactions proceed very slowly.
(13) The use of other chiral phosphines (e.g., the DUPHOS family, BINAP,
and JOSIPHOS) leads to lower enantioselectivity.
a All data are the average of two runs. b Isolated yield.
In conclusion, we have developed two new catalytic asymmetric
processes that provide efficient access to interesting chiral building
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