Enantio- and diastereoselective reductive aldol reactions with iridium-pybox catalysts

Article abstract of DOI:10.1021/ol015859f

(formula presented) A catalytic amount of [(cod)IrCl]₂ and indane-pybox converts diethylmethylsilane, methyl acrylate, and certain aldehydes to the derived reductive aldol adduct with good enantio- and diastereocontrol.

Full text of DOI:10.1021/ol015859f

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1829-1831
Enantio- and Diastereoselective
Reductive Aldol Reactions with
Iridium-Pybox Catalysts
Cun-Xiang Zhao, Matthew O. Duffey, 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
morken@unc.edu
Received March 16, 2001
ABSTRACT
A catalytic amount of [(cod)IrCl]2 and indane-pybox converts diethylmethylsilane, methyl acrylate, and certain aldehydes to the derived reductive
aldol adduct with good enantio- and diastereocontrol.
Although the 2,6-bis(oxazolinyl)pyridine (pybox) ligands
introduced by Nishiyama1 are used for a number of late
transition metal catalyzed enantioselective reactions,2 they
have not proven to be highly effective for asymmetric
reactions when complexed to iridium salts. In the context of
catalytic reductive aldol reactions,3 we presumed that pybox
ligands (i.e., 1-5) would be ineffective with group 9 metals
containing coordinating counterions. Suspecting the initial
step in this reaction to be oxidative addition of silane to the
M(I) center,4 we reasoned that insertion reactions in the
resulting 18-electron octahedral complex would occur with
diminished rate since no coordination site would be available
for substrate preassociation. Consistent with this conjecture,
we have found that in the reductive aldol reaction with
[(cod)RhCl]2-binap catalyst,5 addition of 1 equiv of tri-
phenylphosphine is sufficient to suppress the catalytic
transformation.6 Additionally, in all previous reports con-
cerning hydrosilation of carbonyls with Rh(I) pybox com-
plexes1 and Ir(I)-PNP7 complexes, addition of AgBF4 or
NaClO4 is required to generate an effective catalyst. Con-
sidering this, it was particularly exciting that an arrayed
catalyst evaluation revealed i-Pr-pybox (2) and [(cod)IrCl]2
as one metal-ligand combination able to effect enantio-
selective reductive aldol reaction (1:1 syn:anti, 24% ee anti,
12% ee syn).8 With respect to catalyst development, this
metal-ligand combination is attractive because a variety of
pybox ligands may be accessed through efficient synthesis
routes from commercially available materials.9 In this
(1) (a) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Organometallics 1989, 8, 846. (b) Nishiyama, H.;
Kondo, M.; Nakamura, T.; Itoh, K. Organometallics 1991, 10, 500. (c)
Nishiyama, H.; Park, S.-B.; Itoh, K. Tetrahedron: Asymmetry 1992, 3, 1029.
(2) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45. (b) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325.
(3) (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. (d) Matsuda, I.;
Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331.
(5) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000,
122, 4528-4529.
(6) Taylor, S. J.; Morken, J. P. Unpublished results.
(7) Sablong, R.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 4937.
(8) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121, 12202.
For recent reviews of high-throughput screening, 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, 4, 1885. (c) Francis, M. B.; Jamison, T. F.;
Jacobsen, E. N. Curr. Opin. Chem. Biol. 1998, 2, 422.
(9) (a) Nishiyama, H.; Yamaguchi, S.; Kondo, M.; Itoh, K. J. Org. Chem.
1992, 57, 4306. (b) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes,
D. M.; Campos, K. R.; Woerpel, K, A. J. Org. Chem. 1998, 63, 4541. (c)
Reference 10.
(4) For the oxidative addition of silanes to Ir(I), see: Corey, J. Y.;
Braddock-Wilking, J. Chem. ReV. 1999, 99, 175.
10.1021/ol015859f CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/12/2001

communication we report that Ir(I) salts, when complexed
to an appropriate pybox ligand, are able to catalyze reductive
aldol reactions and that, with certain substrates, the reaction
provides the highest level of enantio- and diastereoselectivity
yet reported.
precatalysts may be converted to a common catalytic
intermediate in the presence of the silane and pybox ligand.
The reductive aldol reaction catalyzed by [(cod)IrCl]2-
indane-pybox shows remarkable enantioselectivity with benz-
aldehyde and R-alkoxy aldehydes;11 however, it is a poor
reaction with simple aldehydes. Comparison of entries 2-4
in Table 2 indicates that oxygenation adjacent to the aldehyde
Table 2. Ir-Pybox Catalyzed Asymmetric Reductive Aldol
Reactiona
Figure 1.
An initial survey of the impact of ligand architecture
revealed that the nature of the pybox ligand substitution has
a significant impact on stereoselectivity in the iridium-
catalyzed reductive aldol reaction. As might be expected,
the more bulky ligands tend to give higher enantioselection,
although this does not necessarily translate to higher dia-
stereoselection (compare entries 2 and 3, Table 1). It is also
Table 1. Ir-Pybox Catalyzed Asymmetric Reductive Aldol
Reactiona
a All reactions were carried out at room temperature for 24. See
Supporting Information for experimental procedures. b Percent yield is of
isolated material. Satisfactory elemental analysis was obtained for all
products. c Ratios determined by GC or HPLC analysis, see Supporting
Information. d Configuration determined by comparison to authentic enan-
tiomers. e Ethyl acrylate and [(coe)2IrCl]2 were used. f Reaction carried out
on 35 mmol scale with 1 mol % [(cod)IrCl]2 and 3 mol % ligand at 0.45
M substrate concentration for 48 h.
enhances reactivity relative to non-oxygenated aliphatic
substrates, although it seems unlikely that the function of
the heteroatom is to associate with the metal when one
considers the lower coordinating ability of silyl ethers relative
to benzyl ethers12 (cf. entries 2 and 3, Table 2). While simple
inductive effects may provide an explanation for enhanced
reactivity with R-alkoxy aldehydes, it is difficult to imagine
that they play a role in the pronounced reactivity of
â-benzyloxypropionaldehyde (entry 5) where such field
effects would have to operate over three σ-bonds.
a All reactions were carried out at room temperature for 24 h in
dichloroethane. b Ratios determined by GC analysis of the unpurified esters.
c Absolute configuration established by optical rotation. Enantiomer ratio
determined by chiral GC analysis. d In this experiment ethyl acrylate and
[(coe)2IrCl]2 were used and the reaction was allowed to proceed 45 h.
(10) Davies, I. W.; Gerena, L.; Lu, N.; Larsen, R. D.; Reider, P. J. J.
Org. Chem. 1996, 61, 9629. Marked differences between reactions catalyzed
by metal complexes of Ph-pybox and in-pybox have been observed
previously; see: Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-
1004.
(11) For highly stereoselective asymmetric Mukaiyama aldol reactions
where benzyloxyacetaldehyde binds in a bidentate fashion, see: Evans, D.
A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell,
B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references
therein.
apparent that there is a nonlinear correlation between the
size of the ligand substituent and reaction enantioselection
(see entries 1-3). The best ligand in regards to both enantio-
and diastereoselectivity is the aminoindanol-derived indane-
pybox (5).10 Notably, there is not a substantial variation in
selectivity when various iridium salts are used with the
indane-pybox ligand. This observation suggests that the Ir(I)
(12) (a) Keck, G. E.; Castellino, S. Tetrahedron Lett. 1987, 28, 281-
284. (b) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem.
Soc. 1992, 114, 1778-1784.
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Org. Lett., Vol. 3, No. 12, 2001

The influence of preexisting substrate chirality was
analyzed with reactions utilizing chiral nonracemic alkoxy
aldehydes. Although â-alkoxyaldehydes exhibit little double
stereodifferentiation (entries 3 and 4, Table 3) and therefore
a common iridium hydride intermediate, and this is consistent
with our observation that many of the iridium salts exhibit
similar reactivity.14 While we have not been able to crystal-
lize any metal-ligand complexes, we suspect that the pybox
ligand binds in a three coordinate fashion,15 since reaction
with ligand 6 (Figure 2) provides no selectivity and reaction
with 7 provides only carbonyl reduction.
Table 3. Double Stereodifferentiation in the Ir-Pybox
Catalyzed Asymmetric Reductive Aldol Reactiona
Figure 2.
In conclusion, we have reported a highly enantio- and
diastereoselective reductive aldol reaction albeit with limited
substrate scope. Experiments in regards to elucidating the
reaction mechanism, expanding the useful substrate scope,
and exploring the utility of these reactions in the context of
complex natural products synthesis are in progress and will
be reported in due course.
a All reactions were carried out at room temperature for 24 h in
dichloroethane solvent. b Yield is of purified reductive aldol adduct.
Satisfactory elemental analysis was obtained for all products. c syna:synb
refers to the ratio of major syn diastereomer (shown) to minor syn
diastereomer. d Refers to collective syn diastereomers:collective anti dia-
stereomers.
Acknowledgment. M.O.D. and S.J.T. are grateful for
Wellcome Foundation fellowships in synthetic chemistry
(1998 and 1999). S.J.T. is grateful for an ACS Organic
Division Fellowship sponsored by Abbott Labs (2000). The
authors thank Amoco Chemicals for unrestricted funding.
J.P.M. gratefully acknowledges a Packard Foundation Fel-
lowship, an NSF CAREER Award, a DuPont Young Profes-
sor Grant, and a Glaxo-Wellcome Scholars Award.
may be useful substrates in double asymmetric synthesis, as
shown in entries 1 and 2 (Table 3), there is a significant
level of double stereodifferentiation in reductive aldol
reactions with R-alkoxyaldehydes. Notably, the matched
substrate enantiomer is one where catalyst control and Felkin
stereoselection (entry 1) (OBn ) large group) act in concert,
and in this case, the reductive aldol adduct is furnished with
high 1,2- and 2,3-stereocontrol. In contrast, reductive aldol
reaction with the mismatched R-alkoxyaldehyde enantiomer
(entry 2) provides only carbonyl reduction; the reductive
aldol adduct could not be detected. While the double
stereodifferentiation observed with R-alkoxyaldehydes is
substantial, we have not been able to transform this observa-
tion into a useful kinetic resolution process.
Supporting Information Available: Experimental and
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pbs.acs.org.
OL015859F
(13) For lead references, see: (a) Aizenberg, M.; Milstein, D. J. Am.
Chem. Soc. 1995, 117, 6456. (b) Hays, M. K.; Eisenberg, R. Inorg. Chem.
1991, 30, 2623. (c) Thompson, J. S.; Atwood, J. D. Organometallics 1991,
10, 3525. (d) Rappoli, B. J.; Janik, T. S.; Churchill, M. R.; Thompson, J.
S.; Atwood, J. D. Organometallics, 1988, 7, 1939. (e) Johnson, C. E.;
Eisenberg, R. J. Am. Chem. Soc. 1985, 107, 6531.
(14) Formation of a C-bound Ir(I) enolate was proposed to occur by
reaction of an Ir(I) hydride with methyl acrylate; see: Drouin, M.; Harrod,
J. F. Can. J. Chem. 1985, 63, 353.
(15) For 2,6-pyridyl-bisimines that bind in a bidentate fashion, see: (a)
Orrell, K. G.; Osborne, A. G.; Sik, V.; de Silva, M. W.; Hursthouse, M.
B.; Hibbs, D. E.; Malik, K. M. A.; Vassilev, N. G. J. Organomet. Chem.
1997, 538, 171. (b) Haarman, H. F.; Ernsting, J. M.; Kranenburg, M.;
Kooijman, H.; Veldman, N.; Spek, A. L.; van Leeuwen, P. W. N. M.; Vrieze,
K. Organometallics 1997, 16, 887. (c) Albon, J. M.; Edwards, D. A.; Moore,
P. J. Inorg. Chim. Acta 1989, 159, 19. See also: Creber, M. L.; Orrell, K.
G.; Osborne, A. G.; Sik, V.; Coles, S. J.; Hibbs, D. E.; Hursthouse, M. B.
Inorg. Chim. Acta 2000, 299, 209.
Considering that reductive elimination reactions to form
C-C, C-H, C-Si, O-Si, and Si-Cl bonds (among others)
are known for iridium(III) complexes,13 overly detailed
speculation into the reaction mechanism is unwarranted. We
do suspect that oxidative addition of silane to the Ir-X (X )
Cl, O) center, followed by elimination of Si-X, may generate
Org. Lett., Vol. 3, No. 12, 2001
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