Direct asymmetric Zn-aldol reaction of methyl vinyl ketone and its synthetic applications

Article abstract of DOI:10.1021/ja051526s

A direct catalytic asymmetric aldol reaction of methyl vinyl ketone is described using our dinuclear zinc catalyst. The obtained aldol adduct functions as a bifunctional building block by utilization of the vinyl functionality. For example, convergent fra

Full text of DOI:10.1021/ja051526s

Published on Web 05/24/2005
Direct Asymmetric Zn-Aldol Reaction of Methyl Vinyl Ketone and Its
Synthetic Applications
Barry M. Trost,* Seunghoon Shin, and Joseph A. Sclafani
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received March 9, 2005; E-mail: bmtrost@Stanford.edu
Scheme 1. Utility of Zn-Aldol Addition
The aldol reaction is one of the most widely utilized C-C bond-
forming reactions in organic chemistry, because of the importance
of â-hydroxy carbonyl compounds in many natural products.1
Recently, several groups have reported a direct catalytic enanti-
oselective version without resorting to preactivation of the pronu-
cleophile using biological catalysts2a-g and nonbiological transition-
metal catalysts,2h-j including our own dinuclear Zn complex 2.2h,3
Typically, however, successful donors have included simple ketones,
such as methyl, and hydroxylmethyl ketones, and limited progress
has been made in catalytic enantioselective aldol reactions of more
functionalized or functionalizable nucleophiles, such as methyl vinyl
ketone (MVK). Enantioenriched â-hydroxyketones derived from
MVK are particularly interesting, because stereocenters created in
the aldol reactions can be propagated further in a sequence of highly
diastereoselective transformations, where MVK functions as a
bifunctional building block (Scheme 1).
Table 1. Reactions of Various Aldehydes
Despite tremendous synthetic potential,4 base instability of MVK
and its aldol products has hampered its development.5 To the best
of our knowledge, there is no general asymmetric aldol reaction of
MVK reported to date. Herein we report an atom-economical and
direct route to the hydroxy ketones from MVK as well as synthetic
applications of resulting hydroxy enones.
Initially, on the basis of the promising catalytic activity displayed
by dinuclear Zn complex 2,3 we set out to examine the reaction of
MVK as an aldol donor. The precataylst was prepared as previously
reported by treating ligand 1 with 2 equiv of Et2Zn in THF at RT.
Subjection of this precatalyst (10 mol %) to a mixture of MVK,
cyclohexane carboxaldehyde, 4Å molecular sieve, and isopropyl
alcohol (5 equiv) in THF at -35 °C led to irreproducible yields of
the desired aldol product (10-30%) and dehydration product,
resulting from removal of the â-hydroxy stereocenter (60-80%).
Although the reaction was highly enantioselective (90-95% ee),
the product profile was time dependent, and more dehydration
byproduct formed upon longer reaction time. The effect of additives
and change of reaction parameters (temperature/time) did not much
improve the result. On the other hand, we found that there is
significant negative nonlinear effect in accord with an aggregation
effect (see Figure 1).6
Along this line, the effect of concentration and solvent was
examined. Gratifyingly, we observed an improved yield of the
desired aldol addition vs elimination (entry 1, Table 1) with
excellent enantioselectivity by using an increased concentration of
MVK. Catalyst (10 mol %) prepared in THF or toluene (0.5 mL)
was added to a combination of freshly distilled MVK (1 mL),
cyclohexane carboxaldehyde (0.5 mmol), i-PrOH (5 equiv), and
4Å molecular sieve. The reaction was generally faster in THF
(Method A, Table 1) than in toluene (Method B), although toluene
had better control over the elimination problem. As shown in Table
1, a variety of aliphatic aldehydes led to the corresponding
â-hydroxy vinyl ketones in reproducible yields and high enantio-
selectivities. In the case of R- or â-hydroxyaldehydes, the presence
a All yields are for isolated pure product. b The ee’s were determined
by chiral HPLC.
of bulkier, noncoordinating silyl protecting group seem to give better
turnover as well as better chiral recognition (entry 3 vs 4 and entry
8 vs 9). Entry 7 deals with the issue of catalyst-controlled
diastereoselectivity. In a matched case (entry 7a), exclusive Felkin-
Anh product (1,2-anti-diol) was obtained with excellent selectivity
and good yield, where intrinsic bias is reinforced by the catalyst in
the same direction. In a mismatched case (entry 7b), 1,2-syn-diol
formed with catalyst-controlled diastereoselectivity (dr 6/1) in
modest yield. Some â-branched aldehydes can also be employed
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C O M M U N I C A T I O N S
via stereoselective reactions into a variety of useful intermediates,
showcasing MVK as a useful bifunctional building block.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
(GM-13598), for their generous support of our programs. 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.
Figure 1. Nonlinear effect (% ee of aldol product vs % ee of ligand 1).
Chart 1. Cycloaddition Partners
Supporting Information Available: Experimental procedures for
the preparation of new compounds as well as characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Table 2. Mg-Mediated Cycloaddition of Nitrile Oxide
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to give modest yield and excellent % ee (entry 10), although
R-branched aliphatic aldehydes gave better results.
(3) For aldol reactions: (a) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367. (b) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett.
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We envisioned propagation of the existing stereocenter created
in the aldol addition through successive highly diastereoselective
transformations. The obtained â-hydroxy enones were diastereo-
selectively reduced to 1,3-syn- (dr > 99:1) or 1,3-anti-diols (dr >
90:10) in excellent yields using Et2B(OMe)/NaBH4 and Me4NBH-
(OAc)3, respectively (Chart 1).6,7 These diols were used directly
without protection in a Mg-mediated diastereoselective cycloaddi-
tion of nitrile oxide.8 When the 1,3-diols were treated with 3 equiv
of EtMgBr in CH2Cl2 followed by a preformed solution of a nitrile
oxide at -25 °C, the corresponding dihydro-isoxazoles formed
smoothly in excellent diastereoselectivities and good yields (Table
2). Notably, the obtained diastereoselectivity depends only on the
stereocenter of the allylic alcohol in the dipolarophile, and
stereocenters elsewhere had no stereo-directing effect, thus provid-
ing an effective method for convergent fragment coupling.
In contrast to alkynylmethyl ketones,3d vinylmethyl ketone donors
require their use in excess, thus necessitating readily available
donors. Resolution of this issue resides in the recent developments
in the cross-metathesis reaction which allows a liberal modification
on the terminal olefin end also reinforcing the bifunctionality of
MVK as a synthetic building block.9 As shown in eq 1, the desired
vinyl-modified ketone 6 was obtained from 5 in 65% yield with
excellent E/Z selectivity (>15:1).
(4) (a) Joo, J. M.; Kwak, H. S.; Park, J. H.; Song, J. H.; Lee. E. Bioorg. Med.
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Chem. 1998, 63, 916.
(5) One account was described on Mukaiyama-type aldol reaction of MVK
where instability was noted for the adduct derived from benzaldehyde
and MVK: Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000,
122, 8837. However, for a successful reaction using lanthanides, see:
Hong, B. C.; Chin, S.-F. Synth. Commmun 1997, 27, 1191. Antibody-
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ketone has recently been published. However, no enantioselectivity was
observed for â-hydroxy ketone derived from MVK: Baker-Glenn, C.;
Hodnett, N.; Reiter, M.; Ropp, S.; Ancliff, R.; Gouverneur, V. J. Am.
Chem. Soc. 2005, 127, 1481.
(6) See Supporting Information for details.
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Int. Ed. 2003, 42, 1900. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783. (c) Chatterjee, A. K.;
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11360.
In conclusion, we have demonstrated dinuclear Zn complex 2
catalyzes the aldol reaction of methyl vinyl ketone in good yield
and excellent % ee. The resulting product could be transformed
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