Catalytic diastereoselective reductive aldol reaction: Optimization of interdependent reaction variables by arrayed catalyst evaluation [10]

Full text of DOI:10.1021/ja992952e

12202
J. Am. Chem. Soc. 1999, 121, 12202-12203
able interdependence of reaction variables and thereby presuppose
arrayed catalyst evaluation for future catalyst development.7
From the outset, we expected that the transition metal salt,
ligand, and hydride source would affect reactivity and selectivity
in the catalytic reductive aldol reaction. We also expected that,
in the absence of substantial mechanistic data, proper choice of
each variable would be challenging. Therefore, we chose to
evaluate a number of different combinations of these reaction
components (Figure 1). To examine the effect of the above-
mentioned reaction variables, we performed an array of experi-
ments in glass 96-well plates. In our initial array, we employed
four transition metal salts, seven ligands (plus a blank), and six
hydride sources. The metals and hydrides included those known
for catalytic alkene reduction.8 Ligands9 were chosen to achieve
the greatest functional group diversity. In the experiment, the
metals and ligands were premixed at 50 °C in dichloroethane for
1 h. After incubating each catalyst with the hydride reagent for
30 min at room temperature, benzaldehyde and methyl acrylate
(20:1 substrate:catalyst) were added and the reaction was allowed
to proceed at room temperature for 16 h. After acidic workup,
each reaction was analyzed by chiral GC versus an internal
standard. In this manner, relative conversion and stereoisomer
ratios were determined for every experiment.
Catalytic Diastereoselective Reductive Aldol
Reaction: Optimization of Interdependent Reaction
Variables by Arrayed Catalyst Evaluation
Steven J. Taylor and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories
The UniVersity of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290
ReceiVed August 16, 1999
Introduction of mild, stereoselective, and catalytic processes
for the synthesis of polypropionates is a topic of current interest.
While most approaches to such bond formation employ silyl enol
ethers and Lewis acid catalysts,1 reports of Co-, Rh-, Pt-, and
Pd-catalyzed condensation between acrylate esters, aldehydes, and
silanes (eq 1) have also shown promise for the synthesis of aldol
Figure 1 shows the relative yield for each of the 192
independent experiments described above10 and reveals a number
of noteworthy relationships between reaction conditions and yield.
First, catechol borane tends to give reaction with the largest
number of catalysts whereas Cl3SiH is effective only with [(allyl)-
PdCl]2 in the presence of MOP ligand. Second, reactivity
characteristics are often opposed when substituting one hydride
source for another: [(cod)IrCl]2 is poisoned by the addition of
Ph-semicorrin ligand when Et2MeSiH is used (78% relative yield
without ligand, 0% relative yield with ligand) although the same
metal salt is activated by Ph-semicorrin when PhSiH3 is used (2%
relative yield without ligand, 24% relative yield with ligand). This
interdependence of reaction variables is reflected in the observa-
tion that none of the three most active catalyst systems ([(cod)-
RhCl]2-DuPhos-Cl2MeSiH, Co(acac)2-MOP-PhSiH3, and [(cod)-
RhCl]2-binap-catechol borane) are related by the permutation of
a single reaction component. Last, it should be noted that reactivity
and selectivity (data not shown) have no correlation; the three
most active catalyst systems, [(cod)RhCl]2-binap-catechol borane
(100% relative yield), Co(acac)2-MOP-PhSiH3 (94% relative
yield), and [(cod)RhCl]2-DuPhos-Cl2MeSiH (94% relative yield),
show syn:anti selectivity of 7:1, 2:1, and 23:1, respectively.
adducts.2-4 One advantage of such a reductive aldol reaction is
that stoichiometric preformation of an activated enolate is not
required. While there is only scant literature precedent describing
the reductive aldol coupling of R,â-unsaturated esters and
aldehydes, it is apparent from these reports that a variety of late
transition metal catalysts may be used. Although useful product
yields are often realized for these reactions, diastereoselection
remains challenging (maximum 4:1 syn:anti selectivity). No
efforts have been made in regards to asymmetric catalysis and
little is known about the reaction mechanism. Herein, we disclose
the discovery of an effective catalyst system for the stereoselective
reductive aldol reaction obtained from high-throughput evaluation
of 192 independent catalytic systems.5,6 In addition to revealing
a catalyst with synthetic utility, these studies illustrate a remark-
(1) For lead references in regards to enantioselective catalysis, see: Nelson,
S. G. Tetrahedron Asymmetry 1998, 9, 357. For catalytic diastereoselective
processes, see: Mahrwald, R. Chem. ReV. 1999, 99, 1095. For recent work
not covered in these references, see: (a) Yanagisawa, A.; Matsumoto, Y.;
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Evans, D. A.; Kozlowski, M. C.; Murray, J. A.; Burgey, C. S.; Campos, K.
R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669. (d) Evans,
D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc.
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(2) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b) Isayama,
S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (c) Kiyooka, S.; Shimizu, A.;
Torii, S. Tetrahedron Lett. 1998, 39, 5237. For a reductive aldol reaction with
unsaturated ketones, see: Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron
Lett. 1990, 31, 5331.
(5) For recent reviews of high-throughput and combinatorial approaches
to catalyst development, see: (a) Bein, T. Angew. Chem., Int. Ed. 1999, 38,
323. (b) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur. J. 1998,
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Biol. 1998, 2, 422. (d) Weinberg, W. H.; Jandeleit, B.; Self, K.; Turner, H.
Cur. Op. Solid State Mater. Sci. 1998, 3, 104.
(3) For group 9 and group 10 transition metal-catalyzed aldol reactions of
silyl enol ethers, see: (a) Sato, S.; Matsuda, I.; Izumi, Y. Tetrahedron Lett.
1986, 27, 5517. (b) Reetz, M. T.; Vougioukas, A. E. Tetrahedron Lett. 1987,
28, 793. (c) Slough, G. A.; Bergman, R. G.; Heatchcock, C. H. J. Am. Chem.
Soc. 1989, 111, 938. (d) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org. Chem.
1995, 60, 2648. (e) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474. (f) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032.
(4) For related catalytic, reductive condensation between alkenes or alkynes
and carbonyls, see: (a) Ojima, I.; Tzamarioudaki, M.; Tsai, C.-Y. J. Am. Chem.
Soc. 1994, 116, 3643. (b) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara,
T.; Takagi, K.; Mori, M. J. Am. Chem. Soc. 1994, 116, 9771. (c) Kablaoui,
N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 6785. (d) Crowe, W.
E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787. (e) Kablaoui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 3182. (f) Sato, Y.; Takimoto,
M.; Mori, M. Tetrahedron Lett. 1996, 37, 887. (g) Oblinger, E.; Montgomery,
J. J. Am. Chem. Soc. 1997, 119, 9065. (h) Kimura, M.; Ezoe, A.; Shibata, K.;
Tamaru, Y. J. Am. Chem. Soc. 1998, 120, 4033. (i) Tang, X.-Q.; Montgomery,
J. J. Am. Chem. Soc. 1999, 121, 6098. For catalyzed and noncatalyzed two-
step sequential acrylate reduction-aldol addition, see: Evans, D. A.; Fu, G.
C. J. Org. Chem. 1990, 55, 5678. Boldrini, G. P.; Bortolotti, M.; Mancini, F.;
Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1991, 56, 5820.
(6) For catalyst lead discovery, as opposed to optimization, with combi-
natorial chemistry, see: Francis, M. B.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 937.
(7) For a fractional factorial approach to multivariant optimization of
organometallic reactions, see: Schwindt, M. A.; Lejon, T.; Hegedus, L. S.
Organometallics 1990, 9, 2814.
(8) For a review of transition metal-catalyzed hydroboration, see: Be-
letskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957-5026. For transition metal-
catalyzed hydrosilation, see: Ojima, I. Catalytic Asymmetric Synthesis; VCH
Publishers: New York, 1993; Chapter 6.
i
(9) Abbreviations: Pr-pybox, 2,6-bis(4-isopropyl-2-ozazolin-2-yl)pyridine-
binap; tBu-box, 2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline); Ph-semicorrin,
4-phenyl-R-[4-phenyloxazolidin-2-ylidene]-2-oxazoline-2-acetonitrile; MOP,
2-(diphenylphosphino-2′methoxy-1,1′-binaphthyl; BINAP, 2,2′-bis(diphe-
nylphosphino)-1,1′-binaphthyl; DUPHOS, 1,2-bis(2,5)-dimethylphospholano)-
benzene; QUINAP, 1-(2-diphenylphospino-1-naphthyl)isoquinoline.
(10) Most catalytic reactions showed low diastereoselection (<5:1 syn:
anti). Other than those mentioned in the text, catalyst systems exhibiting notable
selectivity are as follows: [(allyl)PdCl]2, quinap, Ph2SiH2 (10.9:1 syn:anti);
[(cod)RhCl]2, quinap, Ph2SiH2 (8.6:1 syn:anti); [(allyl)PdCl]2, MOP, Cl3SiH
(5.8:1 syn:anti). See Supporting Information for selectivity of all reactions.
10.1021/ja992952e CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/14/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 51, 1999 12203
Figure 1. Relative yield for each of 192 independent catalytic reductive aldol reactions.
Table 1. Catalytic Stereoselective Reductive Aldol Reaction
unsaturated aldehydes can participate in the reaction without
interference from competitive conjugate reduction (1H NMR
analysis of unpurified reaction mixture shows product, unchanged
starting materials, and ∼5% side-product). It is important to note
that, when larger scale reactions (1.5 mmol substrate) were
performed using the same conditions as in the microscale assay
([substrate] ) 0.2 M), good conversion was observed although
the reaction proceeded with low diastereoselection (3:1 syn:anti).
As reaction concentration was increased ([substrate] ) 1.5 M),
diastereoselection increased to 23:1 syn:anti.12 We made no other
attempts to optimize product yields or diastereoselection.
In conclusion, we have uncovered an effective catalyst for the
diastereoselective reductive aldol reaction discovered with the aid
of an arrayed catalyst evaluation protocol. This approach has
revealed a significant interdependence of metal, ligand, and
hydride source for reactivity and selectivity. Due to this interde-
pendence of reaction parameters, it is reasonable to expect that
an empirical catalyst development approach, wherein reaction
variables are independently optimized, would not have revealed
all highly active catalysts. Further experiments in regards to
reaction optimization, synthesis utility, mechanism, and enanti-
oselective catalysis13 involving reductive aldol reactions are in
progress.
a Stereochemistry determined by comparison to authentic syn and
anti stereoisomers (entry 1 and 3-5) or analysis of coupling constants
(entry 2). b Yield of isolated material after chromatography. Adequate
elemental analysis was obtained for all reaction products. c Stereo-
chemical ratios determined by GC (entries 1, 3, and 4) or H NMR
(entry 2 and 5).
Supporting Information Available: The authors are grateful to
Amoco Chemicals for unrestricted research funding. J.P.M. gratefully
acknowledges receipt of an NSF CAREER award, a Packard Foundation
Fellowship and a DuPont Young Professor Grant. S.J.T. gratefully
acknowledges receipt of a Burroughs-Wellcome graduate student fel-
lowship.
1
Of the catalysts examined, we chose to explore the synthetic
utility of the catalyst system derived from the combination of
[(cod)RhCl]2, DuPhos, and Cl2MeSiH (94% relative yield, 23:1
syn:anti selectivity, 0% ee). As shown in Table 1, moderate yields
and useful levels of diastereoselectivity may be achieved in
reactions that employ aromatic aldehydes as reaction substrates
(entries 1 and 2). While reported reductive aldol reactions2a,b
involving nonaromatic aldehydes and either RhCl3-Me3SiH or Co-
(dpm)2-PhSiH3 proceed in good yield but with no diastereose-
lection, we have found that analogous reactions with [(cod)RhCl]2-
DuPhos-Cl2MeSiH (entries 3-5) provide diminished product
yields but high syn stereoselection.11 Entry 5 indicates that
Supporting Information Available: Characterization data for all
compounds (Table 1), tabular numerical relative yields and diastereomer
ratios (Figure 1), and experimental details (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA992952E
(12) This surprising discrepancy between large-scale and microscale
reactions is not general. Other scaled-up reactions perform as in the 96-well
plate. Further, the reaction with [(cod)RhCl]2, DuPhos, and Cl2MeSiH
reproducibly provides 23:1 syn:anti selectivity in a 96-well plate at 0.2 M
substrate concentration. In general, reactions in the 96-well plate format
proceed without noticeable loss in reaction volume over the course of the
experiment.
(13) Enantioselective transformation was observed with a few of the catalyst
systems described in Figure 1. Further discussion at this point is unwarranted
as ee values were lower than 30%.
(11) While we have no experimental evidence in regards to reaction
mechanism, it is plausible that insertion of the acrylate alkene into a metal
hydride provides a metal enolate. It is known that similar rhodium enolates
will add to nonenolizable aldehydes in an aldol fashion but are protonated by
aldehydes bearing an R-hydrogen (ref 3c). This may offer an explanation for
diminished product yield with isobutyraldehyde.