Generation of (E)-Silylketene acetals in a Rhodium-DuPhos catalyzed two-step reductive aldol reaction

Article abstract of DOI:10.1021/ol016279l

(equation presented) Mechanistic studies employing in situ NMR analysis implicate intermediate silicon enolates as reactive intermediates in the Rh-DuPhos catalyzed two-step reductive aldol reaction with Cl₂MeSiH. These enolates undergo noncata

Full text of DOI:10.1021/ol016279l

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2839-2842
Generation of (E)-Silylketene Acetals in
a Rhodium-DuPhos Catalyzed Two-Step
Reductive Aldol Reaction
Cun-Xiang Zhao, Jonathan Bass, 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 June 14, 2001
ABSTRACT
Mechanistic studies employing in situ NMR analysis implicate intermediate silicon enolates as reactive intermediates in the Rh-DuPhos catalyzed
two-step reductive aldol reaction with Cl2MeSiH. These enolates undergo noncatalyzed reaction with a variety of aldehydes to give the derived
syn-aldol adduct in high yields and diastereoselection.
The aldol reaction is a well-developed and reliable process
for the stereoselective synthesis of â-hydroxy carbonyl
compounds.1 While ligand-based, auxiliary-based,2 and cata-
lyst-based3 asymmetric inductions have proven to be reliable
routes to homochiral aldol adducts, until recently these
methods have required stoichiometric preformation of a metal
or silicon enolate.4 The reductive aldol reaction (see eq 1,
Scheme 1) avoids such a requirement as the metal enolate
is presumably formed in situ by conjugate reduction of an
unsaturated carbonyl.5 We have begun to explore the
reductive aldol reaction as an alternative to traditional aldol
processes with the notion that this mode of bond formation
might provide stereoselectivity patterns that are complemen-
tary to current aldol processes.6 In this communication, we
describe our studies on the Rh-DuPhos catalyzed reductive
aldol reaction with Cl2MeSiH, which have allowed us to
introduce a practical method for the efficient and highly
selective preparation of erythro-aldol adducts derived from
simple esters.7
(4) For asymmetric aldol reactions employing unmodified commercial
substrates, see: (a) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc.
2001, 123, 3367. (b) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003. (c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (d) List,
B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (e)
Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (f)
Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742.
(g) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. (h) Yoshikawa, N.; Yamada, Y. M.
A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.
(i) Nakagawa, M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391.
(5) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b)
Isayama, S.; Mukaiyama, T. Chem. Lett. 1989 2005. (c) Matsuda, I.;
Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 31, 5331. (d) Kiyooka, S.;
Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237. For a recent
intramolecular version of this reaction, see: Baik, T. G.-; Luis, A. L.; Wang,
L. C.-; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112.
(6) (a) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121, 12202.
(b) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc. 2000,
122, 4528. (c) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P.
Org. Lett. 2001, 3, 1829.
(7) For boron-mediated syn-selective ester enolate aldol reactions, see:
(a) Ganesan, G.; Brown, H. C. J. Org. Chem. 1994, 59, 2336. (b) Abiko,
A.; Liu, J. F.; Masamune, S. J. Org. Chem. 1996, 61, 2590.
(1) For leading references on stereoselective aldol reactions, see: (a)
Mahrwald, R. Chem. ReV. 1999, 99, 1095. (b) Heathcock, C. H. Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, Chapter 1.6, p 181. (c) Kim, B. M.; Williams,
S. F.; Masamune, S. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.7, p
239. (d) Paterson, I. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, Vol. 2, Chapter 1.9, p
301. (e) Heathcock, C. H. In ComprehensiVe Carbanion Chemistry; Buncel,
E., Durst, T., Eds.; Elsevier: New York, 1984; Vol. 5B, p 177. (f) Evans,
D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(2) For overviews of ligand-based and auxiliary-based asymmetric
induction, see: (a) Arya, P.; Qin, H. P. Tetrahedron 2000, 56, 917. (b)
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1 and references therein.
(c) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3.
(d) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.
(3) For reviews on catalyst-based asymmetric induction, see: (a) Arya,
P.; Qin, H. P. Tetrahedron 2000, 56, 917. (b) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1353. (c) Nelson, S. G. Tetrahe-
dron: Asymmetry 1998, 9, 357.
10.1021/ol016279l CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/14/2001

We recently reported that an efficient syn-selective reduc-
tive aldol reaction of aromatic aldehydes may be catalyzed
by the combination of [(cod)RhCl]2 and nonracemic DuPhos
(see eq 1).6a Reactions with aliphatic aldehydes occurred with
diminished product yields, and with both aromatic and
aliphatic substrates, the reaction products are racemic. In an
effort to design metal-ligand complexes that provide the
high syn selectivity observed with the DuPhos ligand but
are also able to provide enantiomerically pure adducts in high
yields, we have investigated this reaction in further detail.
As depicted in Scheme 1, treatment of benzaldehyde,
addition step.10 Notably, Denmark has observed analogous
noncatalyzed aldol additions when enoxytrichlorosilanes,
trichlorosilyl ketene acetals, and dichloromethylsilyl ketene
acetals are treated with aldehydes.11
To establish the geometry of the silyl ketene acetal formed
by the Rh-DuPhos catalyzed hydrosilation of methyl acrylate,
the putative dichloromethylsilyl ketene acetal was generated
in ether and treated with 2 equiv of methyllithium at -90
°C followed by warming to room temperature (Scheme 2).
Scheme 2
Scheme 1
After isolation of the reaction product, comparison of the
1H and 13C NMR with literature data12 revealed that the
derived trimethylsilyl ketene acetal is in the E configuration
exclusively; the Z isomer could not be detected nor could
the C-silyl derivative.13 This observation is noteworthy in
light of the Z selectivity for the ClRh(PPh3)3-catalyzed
reduction of R,â-unsaturated esters with either t-BuMe2SiH
or catecholborane.14
Cyclic acrylate 1 was used as a probe to assess the
influence of acrylate conformation on silyl ketene acetal
geometry. Treatment of 1 with Cl2MeSiH and the Rh-DuPhos
catalyst for 12 h followed by addition of benzaldehyde and
quench with HCl afforded the lactone-opened aldol adduct
in 32% yield. X-ray analysis of the reaction product indicated
that the syn stereoisomer is formed.15 This observation
implies that the s-trans isomer of acrylate can lead to the
(E)-silylketene acetal in the Rh-DuPhos catalyzed reduction
of acrylates and that the subsequent aldol reaction likely
proceeds through a boatlike transition state (i.e., 2, Scheme
methyl acrylate, and Cl2MeSiH with Rh-DuPhos (herein
taken to mean the catalyst prepared in situ from [(cod)RhCl]2
and DuPhos8) provides the reductive aldol adduct in 60%
1
yield and 23:1 diastereoselection (eq 1). Using H NMR
spectroscopy to identify relevant reaction intermediates, we
examined the Rh-DuPhos catalyzed reaction between methyl
acrylate and Cl2MeSiH. One hour after addition of the silane
and acrylate to the catalyst in C6D6, the reagents were
completely converted to a new compound that is spectro-
scopically consistent with a single stereoisomer of the derived
silylketene acetal (eq 2).9 Subsequent introduction of ben-
zaldehyde led to rapid disappearance (20 min at room
temperature) of the silyl ketene acetal and formation of a
single stereoisomer of the reductive aldol adduct. To
determine whether the Rh-DuPhos catalyst was required for
reaction between the putative silyl ketene acetal and the
aldehyde, we carried out a second experiment where the
intermediate silyl ketene acetal was vacuum-distilled away
from the metal complex. Addition of benzaldehyde to the
metal-free and phosphine-free silyl ketene acetal provided
the aldol adduct in high stereoselection. These observations
suggest that the role of the Rh-DuPhos complex in the
reductive aldol reaction is to catalyze formation of the silicon
enolate and that the chiral catalyst is not involved in the aldol
(10) For transition metal catalyzed hydrosilation of unsaturated esters,
see: (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Lipshutz, B. H.;
Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627. (c) Ito,
H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett.
1997, 38, 8887. (d) Zheng, G. Z.; Chan, T. H. Organometallics 1995, 14,
70. (e) Doyle, M. P.; Devora, G. A.; Nefedov, A. O.; High, K. G.
Organometallics 1992, 11, 549. (f) Keinan, E.; Perez, D. J. Org. Chem.
1987, 52, 2576. (g) Takeshita, K.; Seki, Y.; Kawamoto, K.; Murai, S.;
Sonoda, N. J. Org. Chem. 1987, 52, 4864. (h) Keinan, E.; Greenspoon, N.
J. Am. Chem. Soc. 1986, 108, 7314.
(11) (a) Denmark, S. E.; Wong, K. T.; Stavenger, R. A. J. Am. Chem.
Soc. 1997, 119, 2333. (b) Denmark, S. E.; Winter, S. B. D. Synlett 1997,
1087. (c) For a related reaction of silylenol triflates, see: Kobayashi, S.;
Nishio, K. J. Org. Chem. 1993, 58, 2647.
(12) (a) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.; Suenobu,
T.; Fukuzumi, S. J. Am. Chem. Soc. 1995, 117, 11134. (b) Emde, H.;
Simchen, G. Synthesis 1977, 867.
(13) Yield of reaction product was determined by 1H NMR versus an
internal standard. Attempted purification resulted in substantial decomposi-
tion. Attempts to methylate the dichloromethylsilyl ketene acetal generated
in benzene provided complex product mixtures.
(8) Burk, M. J.; Feaster, J. E.; Harlow, R. L. Organometallics 1990, 9,
2653. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
(9) Pt-catalyzed reduction of methyl acrylate to the derived dichloro-
methylsilyl enolate has been reported; however, the reaction product was
only characterized by refractive index measurements. See: Petrov, A. D.;
Sadykh-Zade, S. I.; Filatova, E. I. Zh. Obshch. Khim. 1959, 29, 2936.
(14) (a) Slougui, N.; Rousseau, G. Synth. Commun. 1987, 17, 1. (b)
Evans, D. A.; Fu, G. C. J. Org. Chem. 1990, 55, 5678.
(15) Details of the X-ray analysis can be found in the Supporting
Information. Coordinates have been deposited at the Cambridge Crystal
Data Center under accession number CCDC 1681361.
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Org. Lett., Vol. 3, No. 18, 2001

Scheme 3
Table 1. Two-Step Rh-DuPhos Catalyzed Reductive Aldol
Reactiona
3) involving a pentacoordinate silicate as observed for the
enoxytrichlorosilanes.16,17
Although the observations described above do not appear
to bode well for eventual development of an enantioselective
reductive aldol reaction using chiral rhodium-phosphine
complexes and Cl2MeSiH, these studies delineate a procedure
for simple and high-yielding diastereoselective aldol reac-
tions. Suspecting that competitive carbonyl hydrosilation
accounted for low yields in the single-pot reductive aldol
reactions of aliphatic aldehydes, we attempted the two-step
process with these problematic substrates. In the optimal
procedure, Cl2MeSiH and methyl acrylate are allowed to
react with 2.5 mol % of the Rh-DuPhos catalyst at room
temperature in ether for 1 h. The aldehyde (0.5 equiv) is
then added to a precooled (-46 °C) solution of the derived
silylketene acetal, and the reaction is allowed to proceed for
4 h. As shown in Table 1, a range of functionality is tolerated
in the aldehyde, and yields are significantly higher than in
the single-step process. For instance, isobutyraldehyde
provides reductive aldol adduct in 15% isolated yield (6:1
syn:anti) in the single-step process; however, the two-step
procedure provides the same adduct in 89% yield and in a
9:1 stereoisomer ratio. Notably, alkoxy aldehydes, ynals, and
enals react with high syn selectivity, as do aliphatic, aromatic,
and R,â-unsaturated aldehydes.
a All reactions were carried out at -46 °C for 4 h. b Yields refer to
isolated material after column chromatography. c Ratios determined by GC
1
analysis for entry 1 and H NMR for entries 2-9.
In conclusion, we have documented the intermediacy of
silicon enolates in Rh-DuPhos catalyzed two-step reduc-
tive aldol reactions employing dichloromethylsilane as
reducing agent. While these studies do not necessarily
implicate silicon enolates in the Rh-DuPhos catalyzed single-
step process, their intermediacy is most consistent with our
experiments; the observation that the single-step process
catalyzed by enantiomerically pure Rh-DuPhos complex
affords racemic (<0.5% ee) product appears to exonerate
the transition metal from the stereochemistry-determining
step. While the reaction mechanism suggested by these
studies appears to preclude development of an enantiose-
lective Rh-DuPhos catalyzed reductive aldol reaction, the
two-step reductive aldol reaction process does appear to be
useful for simple diastereoselective propionate aldol reac-
tions. Current studies in regards to relative stereoinduction
with chiral aldehydes are in progress and will be reported in
due course.
(16) The correlation between E-enolate and syn aldol adduct implies
either a closed boatlike transition state or an open transition state. In anology
to reactions involving Lewis acidic Si, Zr, Ti, and Sn enolates, which are
postulated to proceed through boatlike transtition states, we expect that
reactions of dichloromethylsilyl enolates require precoordination of the
aldehyde to the enolate and that a closed boatlike transition state results.
See: (a) Evans, D. A.; McGee, L. R. Tetrahedron Lett. 1980, 21, 3975. (b)
Shenvi, S.; Stille, J. K. Tetrahedron Lett. 1982, 23, 627. (c) Nakamura, E.;
Kuwajima, I. Tetrahedron Lett. 1983, 24, 3343. (d) Kuwajima, I.; Nakamura,
E. Acc. Chem. Res. 1985, 18, 181. (e) Murphy, P. J.; Procter, G.; Russell,
A. T. Tetrahedron Lett. 1987, 28, 2037. (f) Myers, A. G.; Widdowson, K.
L.; Kukkola, P. J. J. Am. Chem. Soc. 1992, 114, 2765. (g) Myers, A. G.;
Kephart, S. E.; Chen, H. J. Am. Chem. Soc. 1992, 114, 7922. (h) Denmark,
S. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 5136. (i) Denmark, S. E.;
Wong, K. T.-; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333. (j)
Denmark, S. E.; Stavenger, R. A.; Wong, K. T.-; Su, X. J. Am. Chem. Soc.
1999, 121, 4982.
(17) For computational evidence that suggests boat transition structures
are preferred for reactions proceeding through pentavalent silicates, see:
Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am. Chem.
Soc. 1994, 116, 7026. For similar computational conclusions with enol
borates, see: (a) Gennari, C.; Todeshini, R.; Beretta, M. G.; Favini, G.;
Scolastico, C. J. Org. Chem. 1986, 51, 612. (b) Hoffmann, R. W.; Ditrich,
K.; Froech, S. Tetrahedron 1985, 41, 5517. (c) Li, Y.; Paddon-Row: N.;
Houk, K. N. J. Org. Chem. 1990, 55, 481. (d) Li, Y.; Paddon-Row: N.;
Houk, K. N. J. Am. Chem. Soc. 1988, 110, 3684.
Acknowledgment. The authors thank Steven J. Taylor
for helpful discussions and Albert Russell for experimental
assistance. We are also grateful to Dr. Peter White of UNC
Org. Lett., Vol. 3, No. 18, 2001
2841

for crystal structure analysis. The authors thank Amoco
Chemicals for unrestricted funding. J.P.M. gratefully ac-
knowledges funding in the form of a Glaxo-Wellcome
Scholars Award, a Packard Foundation Fellowship, a DuPont
Young Professor Grant, a Dow Innovation Recognition
Award, and an NSF CAREER award.
Supporting Information Available: Experimental pro-
cedures and compound characterization for reactions prod-
ucts. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL016279L
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