Chiral Bronsted Acids as Catalysts

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1 Chiral Bronsted Acids as Catalysts Short Literature Seminar 6/3/08 Dustin aup

2 BIL Derived osphoric Acids - First reported in 1992 as a ligand by irrung and coworkers. 4 h 2 irrung Tet. Lett. 1992, 33, Developed in 2004 by Akiyama and coworkers and later, Terada and coworkers as a metal free catalyst. TMS 10 mol % cat -78 C, 24h C % yield up to 89% ee Akiyama, Itoh, Yokota, Fuchibe Angew. Chem. Int. Ed. 2004, 43, Boc 0.5 mol % cat -78 C, 24h Boc 95% yield 97% ee Uraguchi, Keiichi, Terada JACS 2004, 38, = 3,5-dimesityl phenyl

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4 β,γ-alkenyl α-amino Acids 2 -Useful as peptide mimics for enzyme inhibition -Example: 2 2 AM 2 1e- xfer or + abstraction Irreversible AM Inhibition AM = eptide α-aminating monooxygenase (implicated in sleep control and neuropeptide production) 2 C C 2 7 steps! C 2 C Is there a better way to build these structures? Andrews, M. D.; 'Callaghan, K. A.; Vederas, J. C. Tetrahedron 1997, 53,

5 A Better Way? Krische (2005): 2 3 S Et h(cd) 2 (5 mol%) BIE (5 mol%) 2 (1 atm) C 2 Cl C 2 3 S Et 66-99% yield 95:5 dr = vinyl or alkynyl 2 = Alkyl or yl 3 = tbu or 2,4,6-triisopropylphenyl Kong, J.-.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc., 2005, 127, Can the stereocenter be set catalytically? C 2 2 Et 2 C C 2 Et A (1 mol%) Et 2, rt C 2 Et 42-60% yield up to 95% ee A = 9-anthryl

6 ptimal Catalyst C 2 Et Et 2 C 2.2 eq C 2 Et A (5 mol%) Et 2, rt C 2 Et = A Si 3 aphthyl Si 3 aphthyl -22% ee -85% ee 57% ee 1-aphthyl: 82% ee 2-aphthyl: <1% ee 90% ee 92% ee in toluene 92% ee in toluene at 1 mol% loading

7 Substrate Scope C 2 2 Et 2 C 2.2 eq C 2 Et A (1 mol%) Et 2, rt C 2 2 A 2 14% yield 89% ee C 2 tbu 14% yield 89% ee (in toluene) Cl F C 2 tbu C 2 tbu 34% yield 92% ee (in toluene) 51% yield 95% ee 34% yield 92% ee (in toluene) 51% yield 95% ee C 2 tbu <5% yield 58% yield 94% ee

8 chanistic Study C 2 Et Et 2 C 1.5 eq C 2 Et A (1 mol%) Et 2, rt 36h.. C 2 Et Et 2 C 3.0 eq C 2 Et A (1 mol%) Et 2, rt 36h C 2 Et 45% yield 94% ee - The imine reduces faster than the alkyne. - The alkyne was reduced resulting in exclusively trans products. - o further reduction of the alkene was observed.

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10 1,3-Dipolar Cycloadditions: tal-free Catalysis - Most work has centered on chiral Lewis Acid chemistry. Jorgensen JACS, 2002, 41, Schreiber JACS, 2003, 125, Carriera Angew. Int. Ed., 2004, 43, tal-free reactions were developed utilizing amino acid derivatives. -First example mol% B C 3 2 / 2-20 C 2 endo C 2 3 exo C % yield 90-99% ee 80:20-99:1 endo:exo B MacMillan JACS, 2000, 122, 9874 For more recent work see: Angew. Int. Ed. 2007, 46, Tet. Lett. 2007, 48, reactive intermediate

11 A Bronsted Acid Alternative to 2 Amines reliminary esults C Et 2 Et C 2 C 2 10 mol% C 3Å MS C 2 Cl 2 2 C C 2 C 2 Et C 2 Et 78% yield 8% ee 2 C Changing substitution on the catalyst did not induce satisfactory ee's! CF 3 74% yield 6% ee 88% yield 25% ee CF 3 87% yield 46% ee 2 CF 3 CF3 CF 3 83% yield 43% ee 78% yield 23% ee

12 A ew Catalyst Structure? D Model for Asymmetric Induction: Ligand developed by Shibasaki and coworkers JACS, 2000, 122, C C 2 3 ptimized Conditions: C Et 2 C 2 Et C eq 1.0 eq 1.5 eq 10 mol% D 3Å MS C 2 Cl 2, rt 24h 2 C C 2 C 2 Et C 2 Et 96% yield 98% ee - Cooling the reaction to 0 C for 72h had no effect.

13 Substrate Scope Et 2 Et C 2 C eq 1.0 eq 1.5 eq 10 mol% D 3Å MS C 2 Cl 2, rt 2 C C 2 C 2 Et C 2 Et D D 2 C C 2 C 2 Et 2 C C 2 C 2 Et 2 C C 2 C 2 Et 2 C C 2 C 2 Et C 2 Et C 2 Et C 2 Et C 2 Et 2 95% yield 99% ee Br 67% yield 94% ee F 94% yield 98% ee 88% yield 98% ee 2 C C 2 C 2 Et 2 C C 2 C 2 Et 2 C C 2 C 2 Et 2 C C 2 C 2 Et C 2 Et C 2 Et C 2 Et C 2 Et 87% yield 90% ee 92% yield 87% ee 70% yield 92% ee 74% yield 76% ee

14 Additonal Substrates eq C 2 3 C eq 10 mol% D 3Å MS C 2 Cl 2, rt 3 2 C C 2 3 C 2 2 D D Et 2 C C 2 Et 95% yield 90% ee C 2 Et C 2 Et Bu 2 C C 2 Bu 77% yield 81% ee C 2 Et C 2 Et 2 C C 2 95% yield 96% ee C 2 C 2 Et 2 C C 2 Et 92% yield 91% ee C 2 C 2 2 C C 2 92% yield 97% ee C 2 2 C C 2 93% yield 97% ee C 2