Direct asymmetric aldol reactions of acetone using bimetallic zinc catalysts

Article abstract of DOI:10.1021/ol0161211

(Equation presented) The enantioselective aldol reaction using a novel binuclear zinc catalyst of acetone with several aldehydes gave products in good yields (62-89%) with a high level of enantioselectivity (ee = 76-92%).

Full text of DOI:10.1021/ol0161211

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2497-2500
Direct Asymmetric Aldol Reactions of
Acetone Using Bimetallic Zinc Catalysts
Barry M. Trost,* Elliad R. Silcoff, and Hisanaka Ito
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received May 14, 2001
ABSTRACT
The enantioselective aldol reaction using a novel binuclear zinc catalyst of acetone with several aldehydes gave products in good yields
(62−89%) with a high level of enantioselectivity (ee ) 76−92%).
The aldol reaction1 represents a very good example of an
atom economic reaction.2 However, in most cases, the
transformation of the active methylene partner stoichio-
metrically to its enolate or an enol derivative is a necessary
drawback.3 Few examples exist of direct catalytic asym-
metric aldol reactions, among them recent work by Shibasaki4
et al., List5 et al., and ourselves.6,7 The work in our lab-
oratories employing acetophenone and hydroxyacetophenone
appeares to involve two zincs organized in a chiral space by
reacting diethylzinc with phenol 1. Previous work has
highlighted some of the difficulties in employing R-un-
branched aldehydes in such direct aldol addition reactions
with acetone and acetophenone.5a In this Letter, we explore
the ability to use acetone as the active methylene partner,
R-unbranched aldehydes as the carbonyl partner, and a
second generation ligand 28 in the dinuclear zinc catalyzed
reaction.
(1) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2,
Chapter 1.5 and 1.6. Kim, B. M.; Williams, S. F.; Masamune, S. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter 1.7.
(2) Trost, B. M. Science 1991, 254, 1471. Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(3) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. Mukaiyama, T.;
Kobayashi, S. Org. React. 1994, 46, 1. 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.
(4) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 4168. Yoshikawa, N.; Kumagai, N.;
Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2466.
(5) (a) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (b)
List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122,
2395. (c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(6) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. Trost, B.
M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2000, 123, 3367.
(7) For a review of biological methods, see: Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352. For leading references on
the use of catalytic antibiotics, see: Turner, J. M.; Bui, T.; Lerner, R. A.;
Barbas, C. F., III; List, B. Chem. Eur. J. 2000, 2772. List, B.; Shabat, D.;
Barbas, C. F., III; Lerner, R. A. Chem. Eur. J. 2000, 881.
The active catalyst 3, prepared in situ by treatment of
ligands 1 or 2 with 2 equiv of diethylzinc (see Scheme 1),
involves initiation by liberation of 3 equiv of ethane followed
by a fourth by reaction with the active methylene partner
(acetone in this case). The chiral space derives from the
conformational preferences of the diphenylcarbinol moieties.
Thus, the two zincs act in concert to activate each of the
two partners.9
(8) Made from the known 2,6-di(hydroxymethyl)-3,5-dimethylphenol
(Fitzgerald, J. S. J. Appl. Chem. 1995, 289. Bertz, S. H. Synthesis
1980, 708. Fahrni, C. J.; Pfaltz, A. HelV. Chim. Acta 1998, 81, 491) by
sequential treatment with HBr, proline methyl ester, and phenylmagnesium
bromide.
(9) The mechanism is related to the amino alcohol catalyzed asymmetric
addition of organozinc reagents to aldehydes, cf. Rasmussen, T.; Norrby,
P.-O. J. Am. Chem. Soc. 2001, 123, 2464.
10.1021/ol0161211 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/10/2001

Scheme 1. Proposed Catalytic Cycle of the Asymmetric Aldol Reaction
Table 1. Optimization of the Reaction between Acetone and Cyclohexanecarboxaldehydea
a All reactions performed in 10 vol % acetone in THF for 48 h except where noted otherwise. b Reaction performed in neat acetone. c In addition to 12%
of dehydration product obtained.
2498
Org. Lett., Vol. 3, No. 16, 2001

Table 2. Catalytic Asymmetric Aldol Reactions of Acetone with Aldehydesa
a Standard conditions were 0.5 mmol aldehyde, 0.5 mL of acetone, 100 mg of 4 Å molecular sieves, and the catalyst added as a 0.1 M solution in THF.
b 82% conversion. c 80% conversion. d ee’s determined by chiral HPLC using chiracell OD or OJ columns. e 5% catalyst used. f 10% catalyst used. g 5%
catalyst and 5 equiv (per catalyst) of PPh3S used. h 10% catalyst and 5 equiv (per catalyst) of PPh3S used. i Isolated yield. j Determined by 1H NMR spectroscopy
on the crude mixture.
The reaction of acetone with cyclohexanecarboxaldehyde
was explored as a test (eq 1). Initial experiments were
yields were low. Additives such as 4 Å MS, 2-propanol,
phosphate, or phosphinethioxide seem to increase rate as
reflected in the higher yields. Switching to a 1:2 ratio of
ligand to diethylzinc (entries 10-17) in THF did increase
conversions within the same time period. Use of 10% gave
a yield boost compared to 2.5 and 5 mol % with little effect
on ee. Switching to ligand 2 showed little effect (Table 1,
entry 14 vs 16). Addition of Ph3PS slowed the reaction while
retaining high ee.
performed using a 1:1 ratio of ligand 1 to diethylzinc (Table
1, entries 1-9). Reactions proceeded bettter in THF than in
pure acetone in terms of ee; however, conversions and thus
Org. Lett., Vol. 3, No. 16, 2001
2499

Using 4 Å MS (100 mg per 0.5 mmol of aldehyde) at 0.1
M in THF with 10-15 equiv of acetone at 5 °C as standard
conditions, the examples shown in Table 2 were performed
with both ligands 1 and 2.10 Except for entry 1, somewhat
improved results were obtained using ligand 2 over 1 under
otherwise identical conditions. For an R-branched aldehyde
(Table 2, entry 4), a slight improvement in yield and a
significant improvement in ee was obtained. In the difficult
cases of R-unbranched and aryl aldehydes, significant
improvements arose using ligand 2. In all cases (entries 5-9),
improvements in yields were obtained. In many cases, the
improved yields arose because the amount of the elimination
product 5 decreased. Attempts to reduce the amount of
elimination by adding triphenylphosphine sulfide with ligand
1 (entries 7 and 8) failed. In some cases, the ee’s were also
higher with ligand 2, notably entry 5. The absolute config-
uration in many cases was assigned by comparison to the
literature and assumed to be the same in the other cases.10b
For R-unbranched aldehyde partners, the catalysts derived
from ligands 1 and 2 with 2 equiv of diethylzinc give the
best recorded results to date. Using proline with such
aldehydes, yields and ee’s ranged from 22 to 35% and 36 to
73%, respectively.3 In the present case for similar aldehyde
partners using ligand 2, yields and ee’s range from 59 to
76% and 82 to 89% ee. Furthermore, the results are
considerably improved over the use of Ipc-X (X ) Cl or
OSO2CF3) which is required, stoichiometrically, as a chiral
auxiliary.11 More generally, the enantioselectivities observed
with acetone are lower than with acetophenone as the aldol
donor with branched aldehydes. For example, the ee’s for
the aldehydes of entries 1, 2, and 4 in their reactions with
acetophenone were 98-99%. The absolute configuration
with the same ligand is the same for both acetone and
acetophenone. A rationale derives from the role the phenyl
rings of the diphenylcarbinol moiety play in the chiral
recognition (see Scheme 1). The planar aryl rings of
acetophenone and related ketones cause less steric distortion
of the chiral pocket than the bulk of a tetrahedral carbon
such as methyl in the case of acetone. The improved results
obtained with ligand 2 over 1 may result from, in the former,
minimization of the distortion of the chiral pocket in the case
of acetone because of the buttressing effects with the 3,5-
dimethyl groups of the phenol ring. It appears this new
catalyst will prove more generally useful for the direct aldol
reaction.
Acknowledgment. We thank the National Science Foun-
dation 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
of California-San Francisco supported by the NIH Division
of Research Resources.
(10) (a) New compounds have been fully characterized spectroscopically
and elemental composition established by high-resolution mass spectrometry
and/or combustion analysis. (b) The absolute configurations of the aldol
products of entry 1 [Silverman, I. R.; Edington, C.; Eliott, J. D.; Johnson,
W. S. J. Org. Chem. 1987, 52, 180], entry 2 [ref 5b and 11], entry 3 [ref
11a], entry 6 [Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc.
1995, 117, 3649], and entries 7 and 8 [ref 11b]. The products of entries 5
(ref 5a) and 9 [Grayson, D. H.; Tuite, M. R. J. J. Chem. Soc., Perkin Trans.
I 1986, 2137] are known although the absolute configurations are not
identified.
Supporting Information Available: Sample experimen-
tal procedure and characterization data of aldol adducts. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Ramachandran, P. V.; Xu, W.-C.; Brown, H. C. Tetrahedron
Lett. 1996, 37, 4911; (b) Paterson, I.; Goodman, J. M. Tetrahedron Lett.
1989, 30, 997.
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