Direct Catalytic Aldol Reactions

Transcription

1 Direct Catalytic Aldol eactions Shibasakiʼs and Trostʼs contributions toward the development of catalytic enolate reactions. Li Li Ln Li ʻThe time has come,ʼ the Walrus said, ʻTo talk of many things: f shoes and ships and sealing wax f cabbages and kings And why the sea is boiling hot And whether pigs have wings.ʼ Zn Zn N N

2 The Definition of a Direct Catalytic Enolate Addition A large number of enantioselective aldol reactions exist: Si 3 CuF 2 Tol-Binap SnBu 3 BINAP AgTf TBS Et Carriera, 1998 Yamamoto, 1997 Chen, 1997 Preconversion to the ketone is a prerequisite for the reactions. These are not direct aldol reactions. 1 1 A route to this reaction without stoichiometric amounts of base and/or adjunct reagents was desirable

3 Aldolases as Inspiration fructose-1,6-bisphosphate and dihydroxyacetone phosphate (DAP) aldolases are found in E. coli. P 3 2 enzyme P 3 2 L-fuculose P 3 2 Glu C 2 is 2 Is Zn is P 3 2 deprotonation Key Points facilitates both electrophilic activation and proton abstraction C-C bond formation Zn P 3 2 Tyr Glu C 2 Zn Glu C 2 Zn P 3 2 Lewis acid and Brønsted base Multifunctional P 3 2 Fessner, W.-D.; Schneider, A.; eld,.; Sinerius, G.; Walter, C.; ixon, M.; Schloss, J. V. ACIE 1996, 35,

4 Professor Masakatsu Shibasaki. D, University of Tokyo, 1974 (Yamada) Post-doc, arvard, , (Corey) Associate Prof, Teikyo, (Ikegama) Professor, okkaido, Professor, University of Tokyo, 1991-present To date, 465 publications The 1970ʼs Corey Group Shibasaki Nicolau Boger Tius Fuchs Seebach Noyori. Yamamoto B. Snider Takeda Lipshutz Mulzer Danheiser Keck Enders

5 Professor Masakatsu Shibasaki The : Li Li Ln Li N 2 N 2 91% yield 90% ee The lithium is important, Na gave much lower selectivities and yields small amounts of 2 are needed Uncertain of success in aldol reaction due to low basicity of alkoxide Sasai,.; Suzuki, T.; ai, S.; ai, T.; Shibasaki, M. JACS 1992, 114, Sasai,.; Suzuki, T.; Ito, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, Sasai,.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; kamura, K.; Shibasaki, M. JACS 1993, 115,

6 S-U-C-C-E-S-S thatʼs the way you spell Success TF 81% yield 91% ee In this case, the rxn worked better without the addition of water. Positives A variety of ketones are compatible A variety of aldehydes are compatible selectivity is generally high Negatives Long reaction times (up to 253 h) Large excess of ketone (up to 50 equiv) igh loading (20 mol %) chanistic Insight: Employment of the Pr related resulted upfield shift of the aldehyde proton Using dilithium salt of ()-binapthol resulted in no chemical shift, afforded racemate Yamada, Y. M. A.; Yoshikawa, N.; Sasai,.; Shibasaki, M. ACIE 1997, 36,

7 Improvement to the eaction TF trace amount Bn Bn LiMDS, 2 C 2 Bn 12 h 99% yield 97% ee Bn 2 C ai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai,.; Shibasaki, M. Chem. Eur. J. 1996, 2, Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai,.; Shibasaki, M. JACS 1999, 121,

8 Improvement to the eaction TF with KMDS and 2 as an additive with only 8 mol % 5 h 74% yield 84% ee Bn Bn LiMDS, 2 C 2 Bn 12 h 99% yield 97% ee Bn 2 C ai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai,.; Shibasaki, M. Chem. Eur. J. 1996, 2, Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai,.; Shibasaki, M. JACS 1999, 121,

9 Improvement to the eaction TF with KMDS and 2 as an additive with only 8 mol % 5 h 74% yield 84% ee N 2 Bn 75%, 88% ee 68%, 70% ee 70%, 93% ee 72%, 88% ee TBS N 2 48 h 73% yield 99% ee no racemization of pre-existing stereocenter Self-condensation of the aldehyde was not observed. Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai,.; Shibasaki, M. JACS 1999, 121,

10 New Player in the Game Zn Zn N N This uses Zn, which mimics aldolases. It is easily prepared from 2,6-(bromomethyl)-p-cresol. Similarly, phenoxide should assist in both deprotonation and then protonation of alkoxide in product. ne Zn is used for formation of enolate, the other for aldehyde coordination

11 Professor Barry M. Trost.D- MIT, 1965 (ouse) Assistant Prof.- University of Wisconsin, Associate Prof.- University of Wisconsin, Professor- University of Wisconsin, Professor- Stanford, 1987-present ver 720 publications Best known for p-allyl palladium chemistry. Former Students/Post-docs: Curran Ferreira Frontier Molander Toste Krische Stambuli Taber Lautens McIntosh Parquette

12 Substrate Scope 5 mol % ligand 10 mol % ZnEt 2 N 15 mol % 3 PS 4Å MS Notice two equiv of ZnEt2 and use of triphenylphosphine sulfide Zn Zn N 49%, 68% ee 60%, 98% ee 79%, 99% ee 67%, 2:1 dr, 94% ee TBS 61%, 93% ee 66%, 97% ee 48%, 97% ee Trost, B. M.; Ito,. JACS 2000, 122,

13 Trostʼs Explanation of Pathway Zn Zn N N Zn Zn N N Zn Zn N N 3 active ʼs suggest that 2 Zn atoms may be involved 2 equiv of ZnEt2 per 1 equiv of ligand liberates 3 equiv of ethane Addition of 2, liberates 4 equiv of ethane

14 Application to ther Manifolds enry eaction: N 2 N 2 90% yield 92% ee Trost, B. M.; Yeh, V. S. C. ACIE 2002, 41, Mannich eaction: N Et 2 C N Et 2 C Trost, B. M.; Terrell, L.. JACS 2003, 125, Diol Desymmetrization: 70% yield 15:1 dr 99% ee C 93% yield 99% ee Trost, B. M.; Mino, T. JACS 2003, 125,

15 Incorporation of thyl Vinyl Ketone MVK is extremely unstable in both acidic and basic conditions Main problems associated with elimination of b-hydroxy ketone product There is a profound negative nonlinear effect Bn 53%, 92% ee 74%, 86% ee 64%, 83% ee 49%, 98% ee Trost, B. M.; Shin, S.; Sclafani. JACS 2005, 127,

16 ecent Advances Secondary Amine Catalysis: (S)-proline 68% yield 76% ee N 2 N 2 Palladium Catalysis: List, B.; Lerner,. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122, Tf 2 P Pd 2 P 2 84% yield 90% ee amashima, Y.; otta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, Nickel Catalysis: S S N () 3 C Ni(II) tol-binap BF 3 Et 2 S S N 73% yield 97% ee Evans, D. A.; Thomson,. J. J. Am. Chem. Soc. 2005, 127, 10506