Parallel kinetic resolution of 4-alkynals catalyzed by Rh(I)/Tol-BINAP: Synthesis of enantioenriched cyclobutanones and cyclopentenones

Article abstract of DOI:10.1021/ja035489l

A Rh(I)/(R)-Tol-BINAP catalyst reacts with a racemic mixture of 4-alkynals to selectively furnish a cyclobutanone from the (R)-substrate and a cyclopentenone from the (S)-substrate. This method is noteworthy from several standpoints, including the scarcit

Full text of DOI:10.1021/ja035489l

Published on Web 06/12/2003
Parallel Kinetic Resolution of 4-Alkynals Catalyzed by Rh(I)/Tol-BINAP:
Synthesis of Enantioenriched Cyclobutanones and Cyclopentenones
Ken Tanaka1 and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received April 6, 2003; E-mail: gcf@mit.edu
Kinetic resolution is a powerful, widely used strategy for
obtaining nonracemic compounds.2 In most kinetic resolutions, one
enantiomer is transformed into a product relatively rapidly, while
the other enantiomer reacts slowly to form the enantiomeric product
(Figure 1). In contrast, in a parallel kinetic resolution, both
enantiomers react efficiently, but they are converted into non-
enantiomeric products (Figure 1).3 Not surprisingly, parallel kinetic
resolutionssespecially catalytic processes that form carbon-carbon
bonds3a,4sare much less common than conventional kinetic resolu-
tions. In this communication, we describe an intriguing new
example of a parallel kinetic resolution: a rhodium-catalyzed
cyclization that furnishes enantioenriched cyclobutanones and
cyclopentenones (eq 1).
Figure 1. Examples of kinetic resolutions.
We have recently reported that Rh(I)/(i-Pr-DUPHOS) can
efficiently kinetically resolve 4-alkynals (eq 2).5 During the course
of that study, we determined that Rh(I)/(Tol-BINAP) is not effective
for this process, providing a poor mass balance of unreacted
4-alkynal 1 and cyclopentenone 2. However, a careful examination
of the reaction mixture revealed that an unanticipated product,
cyclobutanone 3, is generated in good yield by Rh(I)/(Tol-BINAP)
(eq 3).
Figure 2. Possible pathways for the rhodium-catalyzed formation of
cyclobutanones and cyclopentenones from 4-alkynals.
Possible pathways for the formation of the two cycloalkanones
are illustrated in Figure 2. Initially, the Rh(I) catalyst oxidatively
This observation is noteworthy for a number of reasons, including
the scarcity of metal-catalyzed methods for the synthesis of
cyclobutanones6 and the dramatic dependence of the fate of the
starting material on the structure of the ligand (eq 2 vs eq 3). Equally
exciting was our discovery that both of the cycloalkanones are
produced in very good enantiomeric excess (eq 3)! To the best of
our knowledge, all previously described catalytic methods for the
synthesis of enantioenriched cyclobutanones are based on chiral,
nonracemic starting materials.7,8
inserts into the aldehyde C-H bond, affording rhodium hydride
A. Cis addition of the Rh-H to the alkyne provides rhodacycle B,
which reductively eliminates to generate strained cyclobutanone
D.9 Cyclopentenone E can also be produced from rhodium hydride
A, via a (net) trans addition of the Rh-H to furnish a six-membered
metalacycle (C), which reductively eliminates to afford E.10
We have explored the scope of the Rh(I)/(Tol-BINAP)-catalyzed
parallel kinetic resolution of 4-alkynals (Table 1).11,12 Electron-
rich (entry 2) and electron-poor (entry 3) aromatic groups are
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J. AM. CHEM. SOC. 2003, 125, 8078-8079
10.1021/ja035489l CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Parallel Kinetic Resolution of 4-Alkynals To Generate
Enantioenriched Cyclobutanones and Cyclopentenones
Acknowledgment. We thank Ivory D. Hills for help in preparing
the manuscript and Johnson Matthey for supplying [Rh(nbd)2]BF4.
Support has been provided by Bristol-Myers Squibb, Merck,
Mitsubishi Chemical (postdoctoral fellowship to K.T.), and No-
vartis. Funding for the MIT Department of Chemistry Instrumenta-
tion Facility has been furnished in part by NSF CHE-9808061 and
NSF DBI-9729592.
cyclobutanone
ee (%) yield (%)
cyclopentenone
ee (%) yield (%)
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.
entry
R
1
2
Ph
84
81
>99
>99
98
47
43a
32
27
26
25
88
81
62
85
46
84
45
36a
58
41
66
41
4-MeO(C6H4)
4-CF3(C6H4)
o-tol
2-furyl
Cy
3b
4b
5
References
(1) Present address: Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan.
(2) For reviews of kinetic resolution, see: (a) Keith, J. M.; Larrow, J. F.;
Jacobsen, E. N. AdV. Synth. Catal. 2001, 1, 5-26. (b) Hoveyda, A. H.;
Didiuk, M. T. Curr. Org. Chem. 1998, 2, 489-526. (c) Kagan, H. B.;
Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.
(3) (a) For reviews, see: Dehli, J. R.; Gotor, V. Chem. Soc. ReV. 2002, 31,
365-370. Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885-888. (b)
Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584-2585.
(4) See also: Hayashi, T.; Yamamoto, M.; Ito, Y. Chem. Lett. 1987, 177-
180.
(5) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296-10297.
(6) For an example, see: Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc.
1986, 108, 6062-6063.
(7) Enantiopure 4-hydroxycyclopent-2-enones are of interest due to their utility
as intermediates in the synthesis of natural products such as prostaglandins
and pentenomycins. (a) For a discussion of the emergence of cyclopen-
tenone prostaglandins as important biologically active compounds, see:
Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem. Soc., Perkin Trans.
1 2002, 1735-1742. (b) For leading references on pentenomycins, see:
Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41, 4291-4293.
(8) (a) For examples of previous routes to nonracemic cyclobutanones, see:
Nemoto, H.; Fukumoto, K. Synlett 1997, 863-875. Hiroi, K.; Nakamura,
H.; Anzai, T. J. Am. Chem. Soc. 1987, 109, 1249-1250. Houge, C.;
Frisque-Hesbain, A. M.; Mockel, A.; Ghosez, L.; Declercq, J. P.; Germain,
G.; Van Meerssche, M. J. Am. Chem. Soc. 1982, 104, 2920-2921. (b)
For reviews of the use of cyclobutanes in organic synthesis, see: Lee-
Ruff, E.; Mladenova, G. Chem. ReV. 2003, 103, 1449-1483. Namyslo,
J. C.; Kaufmann, D. E. Chem. ReV. 2003, 103, 1485-1537.
6
>99
All yields are isolated yields. a Isolated as a mixture of cyclobutanone
and cyclopentenone (the yields are distributed according to the 1H NMR
spectrum). b The reaction was carried out at 40 °C.
tolerated in the 5 position, as are sterically demanding (entry 4)
and heteroaryl (entry 5) substituents. Furthermore, efficient resolu-
tion does not require an aromatic groupsalkynes that bear an
aliphatic substituent are also suitable substrates (entry 6).
To provide additional evidence that the matched or mismatched
nature of the catalyst versus substrate configurations determines
the partitioning between cyclobutanone and cyclopentenone forma-
tion, we treated enantiopure 1 with rhodium catalysts derived from
(R)- and from (S)-Tol-BINAP (eq 4). In the case of (R)-Tol-BINAP,
(9) The stereochemistry of the olefin has been assigned in analogy with:
Iwasawa, N.; Matsuo, T.; Iwamoto, M.; Ikeno, T. J. Am. Chem. Soc. 1998,
120, 3903-3914.
(10) Essentially no cyclobutanone is generated when CHIRAPHOS, DUPHOS,
BPE, and JOSIPHOS are employed as ligands.
(11) Notes: (a) Use of BINAP leads to lower enantiomeric excess. (b) When
reactions are stopped at partial conversion, significant quantities of both
the cyclobutanone and the cyclopentenone are observed, indicating that
the enantiomeric 4-alkynals are reacting in parallel, not sequentially. (c)
To date, we have only observed effective parallel kinetic resolutions for
4-alkynals that bear a methoxy group in the 3 position.
(12) Sample procedure (Table 1, entry 1): In the air, [Rh(nbd)((S)-Tol-BINAP)]-
BF4 (19.4 mg, 0.0199 mmol) was placed into a Schlenk tube, which was
then flushed with argon. CH2Cl2 (1.0 mL) was added, and then H2 was
introduced into the Schlenk tube. The mixture was stirred at rt for 0.5 h,
and then the H2 was removed by flushing with argon. 3-Methoxy-5-
phenylpent-4-ynal (75.0 mg, 0.398 mmol) and CH2Cl2 (1.0 mL) were
added, and then the mixture was stirred at rt for 21 h. Next, the solution
was concentrated, and the residue was purified by preparative TLC
(hexanes:EtOAc ) 4:1), which furnished (S)-2-benzylidene-3-methoxy-
cyclobutanone (35.2 mg, 0.187 mmol, 47%; 84% ee) and (R)-4-methoxy-
2-phenylcyclopent-2-enone (33.8 mg, 0.180 mmol, 45%; 88% ee).
(13) Thus, as an alternative to a parallel kinetic resolution, one can generate a
cyclobutanone in very high ee through a two-step process: kinetic
resolution of a 4-alkynal (ref 5), followed by cyclization with the
appropriate enantiomer of Rh(I)/Tol-BINAP.
the alkynal reacts to generate the cyclobutanone preferentially,
whereas for (S)-Tol-BINAP, the cyclopentenone is produced with
excellent selectivity. Thus, simply by choosing the appropriate
enantiomer of Tol-BINAP, one can dictate whether a cyclobutanone
or a cyclopentenone is formed.13
In conclusion, we have discovered a Rh(I)/Tol-BINAP-catalyzed
parallel kinetic resolution of 4-alkynals that generates cyclobu-
tanones and cyclopentenones in good enantiomeric excess. In view
of the scarcity of examples of parallel kinetic resolutions (particu-
larly, catalyzed processes that involve carbon-carbon bond forma-
tion) and of catalytic methods for the synthesis of cyclobutanones,
we believe these observations are noteworthy. We hope that future
work will elucidate the origin of the remarkable dependence of the
course of the reaction on the structure of the ligand.
JA035489L
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J. AM. CHEM. SOC. VOL. 125, NO. 27, 2003 8079