C O M M U N I C A T I O N S
Table 2. Scope of the MeMAHT Aldol Reaction
Scheme 2a
a Reagents and conditions: 10 mol % Pd(dppf)Cl2, 25 mol % tri-
furylphosphine, 2 equiv of Cu(I), 1 equiv of i-Pr2NEt, DMF, 50 °C, 6 h.
it to be compatible with hydroxyl groups, phenols, enolizable
aldehydes, enolizable methyl ketones, and carboxylic acidss
functionalities that would normally be incompatible with ester
enolates. Third, MAHTs provide a unique way of activating esters
as nucleophilessa carboxylate group that is lost as CO2 during the
course of the reaction provides traceless activation. The functional
group compatibility and the utility of the thioester group in the
products may make this aldol reaction useful in complex molecule
synthesis.
Acknowledgment. We gratefully acknowledge support from
Novartis, Merck Research Labs, GlaxoSmithKline, and the Arthur
C. Cope Fund.
Supporting Information Available: Representative experimental
procedures and characterization data. This material is available free of
a 1.2 equiv of 1, 1.0 equiv of aldehyde. b 0.1 M for 48 h. c For 60 h.
d Syn:anti ratios were determined by HPLC or by NMR analysis. e Enantio-
meric excess was determined by chiral HPLC. f Configuration of the
secondary alcohol provided in parentheses when determined, or assigned
by analogy. g With 2 equiv of aldehyde.
References
(1) Recent review of catalytic, enantioselective aldol reactions: (a) Palomo,
C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. ReV. 2004, 33, 65-75. For a
review of catalytic, enantioselective Mukaiyama aldol reactions with silyl
ketene acetals, see: (b) Carreira, E. M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 3, pp 997-1065.
(2) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706-8707.
withdrawing groups, both of which were unreactive; however,
octynal (entry 8) was reactive.
(3) For other catalytic enantioselective aldol reactions with esters or their
derivatives involving in situ generation of the nucleophile, see: (a) Zhu,
C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352-5353.
(b) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001,
123, 7945-7946. (c) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken,
J. P. Org. Lett. 2001, 3, 1829-1831.
Notably, enantioselectivites were g89% for the aldehydes listed
in Table 2, irrespective of their steric and electronic properties. In
each reaction, little or no aldehyde self-condensation was detected,
and no more than 2% R,â-unsaturated thioester was observed,
highlighting the selective activation of MeMAHTs in the presence
of enolizable aldehydes and the mildness of the reaction conditions.
One advantage of using thioesters as carboxylic acid equivalents
is their participation in Pd-catalyzed cross-couplings to generate
ketones under neutral conditions.8 An exemplary reaction is
provided in Scheme 2 in which unprotected aldol adduct 7 (from
entry 11, Table 2) was directly coupled with 5-hexyne-2-one to
afford 8.8b In principle, MeMAHT aldol reactions combined with
Pd-catalyzed cross-couplings should provide rapid access to a wide
range of enantiomerically enriched R-methyl-â-hydroxyketones
without recourse to protecting groups.
There are several reasons why these aldol reactions are unique.
First, in most cases two-point binding aldehydes are required to
achieve >90% ee in Cu(II)(box)-catalyzed reactions.9 This is one
of the few reactions that achieve high enantioselectivities with one-
point binding aldehydes.10 This could be due to the two-point
binding capability of the MeMAHT, a hypothesis that awaits future
mechanistic studies. Second, the conditions are remarkably mild.
The reaction reported here is formally an aldol reaction between a
thioester and an aldehyde where the strongest base is 3 mol % of
excess 2. The lack of strong Lewis acids or strongly basic
intermediates generated during the course of the reaction enables
(4) (a) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125,
2852-2853. (b) Orlandi, S.; Benaglia, M.; Cozzi, F. Tetrahedron Lett.
2004, 45, 1747-1749. See also: (c) Lou, S.; Westbrook, J. A.; Schaus,
S. E. J. Am. Chem. Soc. 2004, 126, 11440-11441.
(5) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209-217.
(6) MeMAHT (1) was prepared in 12 g batches in one step from commercially
available starting materials, in 94% yield, and without chromatography
following crystallization (see Supporting Information). 1 is a colorless
solid that can be stored on the benchtop for at least 2 months without
loss of activity in the aldol reaction.
(7) (a) Thorhauge, J.; Roberson, M.; Hazell, R. G.; Jorgensen, K. A. Chem.
Eur. J. 2002, 8, 1888-1898. (b) 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. (c) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325-335. (d) Jorgensen, K. A.; Johannsen, M.;
Yao, S.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605-613.
For an exception, see: (e) Juhl, K.; Jorgensen, K. A. J. Am. Chem. Soc.
2002, 124, 2420-2421.
(8) (a) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37, 87-96.
(b) Tokuyama, H.; Miyazaki, T.; Yokoshima, S.; Fukuyama, T. Synlett
2003, 1512-1514. (c) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69,
3554-3557 and references therein.
(9) See, for example: (a) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras,
N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936-7943. (b) Evans,
D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118,
5814-5815.
(10) (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692-12693. (b) Evans,
D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S.
J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 7582-7594.
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