Chiral Catalysts Dually Functionalized with Amino Acid and Zn2+ Complex Components for Enantioselective Direct Aldol Reactions Inspired by Natural Aldolases: Design, Synthesis, Complexation Properties, Catalytic Activities, and Mechanistic Study
✍ Scribed by Susumu Itoh; Masanori Kitamura; Yasuyuki Yamada; Shin Aoki
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 863 KB
- Volume
- 15
- Category
- Article
- ISSN
- 0947-6539
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✦ Synopsis
Abstract
Aldolases are enzymes that catalyze stereospecific aldol reactions in a reversible manner. Naturally occurring aldolases include class I aldolases, which catalyze aldol reactions via enamine intermediates, and class II aldolases, in which Zn^2+^ enolates of substrates react with acceptor aldehydes. In this work, Zn^2+^ complexes of L‐prolyl‐pendant[15]aneN~5~ (ZnL^3^), L‐prolyl‐pendant[12]aneN~4~ (ZnL^4^), and L‐valyl‐pendant[12]aneN~4~ (ZnL^5^) were designed and synthesized for use as chiral catalysts for enantioselective aldol reactions. The complexation constants for L^3^ to L^5^ with Zn^2+^ [log__K__~s~(ZnL)] were determined to be 14.1 (for ZnL^3^), 7.6 (for ZnL^4^), and 9.6 (for ZnL^5^), indicating that ZnL^3^ is more stable than ZnL^4^ and ZnL^5^. The deprotonation constants of Zn^2+^‐bound water [p__K__~a~(ZnL) values] for ZnL^3^, ZnL^4^, and ZnL^5^ were calculated to be 9.2 (for ZnL^3^), 8.2 (for ZnL^4^), and 8.6 (for ZnL^5^), suggesting that the Zn^2+^ ions in ZnL^3^ is a less acidic Lewis acid than in ZnL^4^ and ZnL^5^. These values also indicated that the amino groups on the side chains weakly coordinate to Zn^2+^. We carried out aldol reactions between acetone and 2‐chlorobenzaldehyde and other aldehydes in the presence of catalytic amounts of the chiral Zn^2+^ complexes in acetone/H~2~O at 25 and 37 °C. Whereas ZnL^3^ yielded the aldol product in 43 % yield and 1 % ee (R), ZnL^4^ and ZnL^5^ afforded good chemical yields and high enantioselectivities of up to 89 % ee (R). UV titrations of proline and ZnL^4^ with acetylacetone (acac) in DMSO/H~2~O (1:2) indicate that ZnL^4^ facilitates the formation of the ZnL^4^⋅(acac)^−^ complex (K~app~=2.1×10^2^ M^−1^), whereas L‐proline forms a Schiff base with acac with a very small equilibrium constant. These results suggest that the amino acid components and the Zn^2+^ ions in ZnL^4^ and ZnL^5^ function in a cooperative manner to generate the Zn^2+^‐enolate of acetone, thus permitting efficient enantioselective CC bond formation with aldehydes.