A direct catalytic enantioselective aldol reaction via a novel catalyst design [5]

Full text of DOI:10.1021/ja003033n

J. Am. Chem. Soc. 2000, 122, 12003-12004
12003
that they might serve as good templates on which to construct
asymmetric catalysts. Surprisingly, very few catalytic asymmetric
processes based upon chiral crown complexes have been devel-
oped.10 One of the issues may be the different requirements
associated with high binding affinities versus catalysis. For
catalysis, turnover at reasonable rates must accompany the
molecular recognition events. To approach both requirements, a
semi-crown design would provide the opportunity for good chiral
recognition and might also provide a path for facile exchange of
product to overcome problems of product inhibition. This
contribution reports the realization of this goal in a direct
asymmetric aldol reaction.
The design incorporated a phenoxide as a base as depicted in
1 to promote a catalytic process whereby the alkoxide generated
in the aldol reaction would rapidly be protonated by the phenol
fragment but the phenoxide might still be adequate to form the
enolate. To regain any loss in binding energy by going to the
less well-organized semi-crown design, replacing oxygen (i.e.,
1, X ) O) by stronger coordinating elements for some metals
such as nitrogen (i.e., 1, X ) NR) was envisioned. Chiral ligand
A Direct Catalytic Enantioselective Aldol Reaction
via a Novel Catalyst Design
Barry M. Trost* and Hisanaka Ito
Department of Chemistry
Stanford UniVersity
Stanford, California 94305-5080
ReceiVed August 15, 2000
Few chemical reactions have reached the promise of the aldol
reaction in its importance in the synthesis of complex molecules.1
Almost all of the reactions are performed by preformation of an
enolate, enol, or an equivalent with one of the most important
versions being the Mukaiyama aldol reaction involving enol silyl
ethers. In these cases, stoichiometric amounts of base and/or
adjunct reagents (such as silylating agents to form the enol silyl
ethers) are requiredsthus decreasing the atom efficiency of the
process. The classical aldol reaction is highly atom economic2
but suffers from selectivity, notably chemo- and regioselectivity
problems. A further challenge is to perform these reactions
asymmetrically. Indeed, most of the asymmetric versions of the
aldol reaction rely upon the use of chiral auxiliaries;3 however,
it must be noted that there have been some successes of using
asymmetric catalysts although they normally rely on a Mukaiyama
type process.4 An exciting challenge to enhance the efficiency of
the aldol reaction is to find a compound that will catalyze the
direct aldol addition without prior stoichiometric formation of
the nucleophile and to do so asymmetrically. Biological-type
catalysts (enzymes and antibodies) have had selected successes.5
The first reports of chemical catalysts for this process from the
groups of Shibasaki et al.6 and List et al.7 have just appeared.8
In developing a semi-rational strategy for designing catalysts
for this process, the use of crown compounds seemed very
attractive.9 Their ability to tightly bind metal ions and to achieve
high levels of molecular recognition in binding events suggested
2, readily synthesized in four steps from p-cresol, meets these
design criteria. Thus, the known 2,6-bis(bromomethyl)-p-cresol,
prepared in two steps from p-cresol using formaldehyde followed
by HBr,11 reacts smoothly with the hydrochloride of methyl
prolinate in the presence of triethylamine in methylene chloride
at room temperature (85% yield). Addition of phenylmagnesium
chloride in THF at room temperature completes the synthesis of
2 (>99.5% ee by chiral HPLC) in 74% yield. In a series of
preliminary experiments examining lithium, magnesium, and zinc,
zinc appeared to give the highest ee. The solution formed by
treating the ligand 2 in THF with a solution of diethylzinc in
hexane was used as the catalyst for the aldol reaction of eq 1.
(1) Mukaiyama, T. Org. React. 1982, 28, 203. Kim, B. M.; Williams, S.
F.; Masamune, S. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.7, pp 239.
Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, part B, p 111.
(2) For a general discussion of atom economy in organic synthesis, see:
Trost, B. M. Science 1991, 254, 1471; Angew. Chem., Int. Ed. Engl. 1995,
34, 259.
(3) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995; Chapter 6, pp 306-361.
(4) For the general review on enantioselective Mukaiyama aldol reaction,
see: Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer, Heidelberg, 1999; Vol. 3, p
998. Mahrwald, R. Chem. ReV. 1999, 99, 1095. Gro¨ger, H.; Vogl, E. M.;
Shibasaki, M. Chem. Eur. J. 1998, 4, 1137. Nelson, S. G. Tetrahedron:
Asymmetry 1998, 9, 357. Bach, T. Angew. Chem., In. Ed. Engl. 1994, 33,
417. Also see: Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(5) Takayama, S.; McGarvey, G. J.; Wong, C. H. Chem. Soc. ReV. 1997,
26, 407. Rasor, J. P. Chim. Oggi. 1995, 13, 9. Barbas, C. F., III; Heine, A.;
Zhory, G.; Hoffmann, T.; Gramatikova, S.; Bjo¨rnestedt, R.; List, B.; Anderson,
J.; Stura, E. A.; Wilson, E. A.; Lerner, R. A. Science 1997, 278, 2085. Also
see: Kajimoto, T. Yakugaku Zasshi 2000, 120, 42; Chem. Abstr. 2000, 132,
194551. Hiratake, J.; Oda, J. Yuki Gosei Kagaku Kyokaishi 1997, 55, 452;
Chem. Abstr. 1997, 127, 17218.
(6) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. Yamada, Y. M. A.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 5561. Yoshikawa, N.; Yamada, Y. M. A.; Das,
J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. For a review,
see: Shibasaki, M., Sasai, H. Top. Stereochem. 1999, 22, 201.
(7) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. For an intramolecular variant differentiating prochiral carbonyl
groups, see: Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Agami,
C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987, 358.
The addition of molecular sieves increased the turnover frequency
but was still rather slow. Adding a weak coordinating agent for
zinc that might help displace the product was explored. A
phosphate such as trimethyl phosphate did improve the turnover
frequency in contrast to a phosphine oxide such as tri-n-
butylphosphine oxide which hindered the reaction. The best results
were obtained with triphenylphosphine sulfide in terms of turnover
and ee. Thus, the reaction conditions stated in eq 1 were adopted
as our standard to explore a range of substrates.
Table 1 summarizes our results. Recovery of 96% of excess
acetophenone has been demonstrated in entry 4. Using a chiral
but racemic aldehyde, 2-phenylpropenal, a 2:1 diastereomeric
mixture of adducts with both having high ee was obtained (entry
(10) Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981,
1981, 625. Cram D. J.; Sogah, G. D. Y J. Am. Chem. Soc. 1985, 107, 207.
To˜ke, L.; Bako´, P.; Keseru, G. M.; Albert, M.; Fenichel, L. Tetrahedron 1998,
54, 213 and references therein.
(11) Van der Boom, M. E.; Liou, S.-Y.; Ben-David, Y.; Shimon, L. J. W.;
Milstein, D. J. Am. Chem. Soc. 1998, 120, 6531. Arnaud, N.; Picard, C.;
Cazaux, L.; Tisne`s, P. Tetrahedron 1997, 53, 13757.
(8) For an early examination using a zinc complex of R-amino esters which,
however, did not report any ee’s, see: Nakayawa, M.; Nakao, H.; Watanabe,
K. Chem. Lett. 1985, 391.
(9) Lehn, J.-M. Supramolecular Chemistry; VCH Verlagsgessellschaft:
Weinheim, 1995 and references therein.
10.1021/ja003033n CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/17/2000

12004 J. Am. Chem. Soc., Vol. 122, No. 48, 2000
Communications to the Editor
Scheme 1. Proposed Catalytic Cycle
Table 1. Enantioselective Aldol Reaction of Aryl Methyl Ketonea
observations support structures such as 3a and 4a invoking a
bimetallic catalyst as the initial species which reacts with ketone
to liberate the fourth equivalent of ethane and initiate the catalytic
cycle as depicted in Scheme 1. X-ray structures of somewhat
related aminoether complexes suggest that N coordination to zinc
might be included.13 The role of two proximal zinc species is to
provide both a zinc to form the requisite enolate and a second
zinc to function as a Lewis acid to coordinate the aldehyde. The
picture that emerges for the catalytic cycle then parallels proposals
for the ability of amino alcohols to effect the asymmetric addition
of organozinc reagents to aldehyde partners.14
To determine which catalyst, 3 or 4, is favored, we calculated
the energy of both using an MM2 force field on the CAChe
system. Since in the catalytic cycle, an alkoxy group not an ethyl
group is envisioned to be on zinc, the calculation were performed
on the structures 3b and 4b wherein ethyl was replaced by ethoxy.
The calculations indicate that 3b is about 7 kcal/mol more stable
than 4b and leads us to favor structure 3 at present. This structure
suggests the enolate approaches the re face of the aldehyde to
give the observed products. This new catalyst design offers much
opportunity for variationsa task under current investigation.
a Reactions performed according to eq 1 at 5 °C for 2 d using
aldehyde:ketone ratio of 1:10 unless otherwise noted. b Absolute
stereochemistries were determined by the comparison with optical
rotation value of literature value12. c Enantiomeric excess was deter-
mined with chiral HPLC column (Chiracel OD column). d Reaction
f
performed at -5 °C. e Reaction performed at -15 °C. A 96% recovery
of excess acetophenone was demonstrated in this case. g Diastereomers
were not separated. h ee of major diastereomer. i ee of minor diastereo-
mer. j Reaction time of 4 d. k Aldehyde:ketone ratio of 1:5 was
employed.
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences for their
generous support of our programs. H.I. thanks the Uehara Memorial
Foundation for a partial support of his postdoctoral studies. Mass spectra
were provided by the Mass Spectrometry Regional Center of the
University California-San Francisco supported by the NIH Division of
Research Resources.
7). The absolute configurations for the aldol adducts of entries 1,
4, and 5 are assigned by comparison to the literature.12 It is likely
that the absolute configuration for the remaining examples can
be assigned by analogy as the same.
To establish the nature of the catalyst, the stoichiometry of
the metal to ligand was examined by the evolution of ethane gas.
The presence of three active hydrogens suggests the possible
involvement of more than one zinc. Indeed, addition of 2 equiv
of diethylzinc per ligand 2 liberates 3 equiv of ethane to form 3a
or 4a. That one additional alkylmetal bond remained was revealed
by addition of water which liberated the fourth equivalent. These
Supporting Information Available: Characterization data for all the
aldol adducts, typical experimental procedure, and Figure 1, Proposed
Intermediate Responsible for Asymmetric Induction (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA003033N
(13) Sakiyama, H.; Mochizuki, R.; Sugawara, A.; Sakamoto, M.; Nishida,
Y.; Yamasaki, M. J. Chem. Soc., Dalton Trans. 1999, 997. For other zinc
complexes derived from 2,6-di(dialkylaminomethyl)-p-cresol, see: Uhlenbrock,
S.; Wegner, R.; Krebs, B. J. Chem. Soc., Dalton Trans. 1996, 3731. For bis-
ligated dinuclear zinc complexes, see: Fahrni, C. J.; Pfaltz, A.; Neuburger,
M.; Zehnder, M. HelV. Chim. Acta 1998, 81, 507.
(12) Narasaka, K.; Miwa, T.; Hayashi, H.; Ohta, M. Chem. Lett. 1984,
1984, 1399. Veeraraghavan Ramachandran, P.; Xu, W.-C.; Brown, H. C.
Tethrahedron Lett. 1996, 37, 4911.
(14) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833.