Short Literature Presentation 10/4/2010 Erika A. Crane

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1 Copper-Catalyzed Enantioselective Synthesis of trans-1- Alkyl-2-substituted Cyclopropanes via Tandem Conjugate Additions-Intramolecular Enolate Trapping artog, T. D.; Rudolph, A.; Macia B.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2010, ASAP. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-Catalyzed Reactions Employing Mn2 as a Stoichiometric xidant Liu, L.; Floreancig, P. E. rg. Lett. 2010, ASAP. Short Literature Presentation 10/4/2010 Erika A. Crane

2 et the P.I.? : PhD from the University of Groningen with Prof. Dr. ans Wynberg : Research Chemist at Royal Dutch Shell : rganic Chemistry Lecturer at University of Groningen present: Appointed to Professor and Chair of rganic Chemistry Prof. Dr. Ben L. Feringa

3 The Feringa Group is pursuing new enantioselective catalytic methods for key synthetic transformations and catalytic strategies for the efficient construction of complex (biological active) chiral molecules. They have developed monodenate phosphoramidite ligands for use in asymmetric catalysis... P N Angew. Chem. Int. Ed. Engl. 1997, 36, Angew. Chem. Int. Ed. Engl. 1996, 20, And used these ligands to develop the first enantioselective, catalytic 1,4-addition of organometallic reagents to enones with absolute stereocontrol...

4 The Feringa Group is pursuing new enantioselective catalytic methods for key synthetic transformations and catalytic strategies for the efficient construction of complex (biological active) chiral molecules. They have developed monodenate phosphoramidite ligands for use in asymmetric catalysis... The Feringa Group also... Pioneered low-molecular weight organogels Reported the first optical molecular switch in which chirality is controlled by light in 1991 as made several advances in the field of molecular motors (lightdriven & rotary, speed enhancement, etc.) Achieved the first design and synthesis of a light-driven unidirectional rotary motor P N Angew. Chem. Int. Ed. Engl. 1997, 36, Angew. Chem. Int. Ed. Engl. 1996, 20, And used these ligands to develop the first enantioselective, catalytic 1,4-addition of organometallic reagents to enones with absolute stereocontrol...

5 The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes Utilizing Chiral Auxillaries/Substrates: C 2 i-pr C 2 i-pr Et 2 Zn C 2 I 2 C 2 i-pr C 2 i-pr 90 % yield 94% de 92% ee Arai, I.; Mori, A.; Yamamoto,. J. Am. Chem. Soc. 1985, 107, Catalytic Asymmetric Epoxidation Intramolecular thylene Transfer: Bn 5 mol% La(Tf) 3 5 mol% 2,6-lutidine LiCl 4 DCE, 40 C Bn 72% yield >20:1 dr Tf Tf La Tf Bn Tf Tf La Tf Bn epoxide opening semi-pinacol rearrangement ardee, D. J.; Lambert, T.. J. Am. Chem. Soc. 2009, 131,

6 The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes Utilizing Chiral Auxillaries/Substrates: C 2 i-pr C 2 i-pr Et 2 Zn C 2 I 2 C 2 i-pr C 2 i-pr 90 % yield 94% de 92% ee Arai, I.; Mori, A.; Yamamoto,. J. Am. Chem. Soc. 1985, 107, Catalytic Asymmetric Epoxidation Intramolecular thylene Transfer: Bn 5 mol% La(Tf) 3 5 mol% 2,6-lutidine LiCl 4 DCE, 40 C Bn 72% yield >20:1 dr Via Chiral Cyclopropenes: ardee, D. J.; Lambert, T..; Yamamoto,. J. Am. Chem. Soc. 2009, 131, C( 2 C) 4 N 2 Et 0.5 mol % 1 C 2 Et C 2 Cl 2 3 C( 2 C) 4 90% yield 95% ee 5% Pd/CaC 3 2, EtAc 92% yield C 2 Et 3 C( 2 C) 4 Lou, Y.; orikawa, M.; Kloster, R. A.; awryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,

7 The Synthesis of Trans-1-alkyl-2-substituted Cyclopropanes Asymmetric Simmons-Smith Cyclopropanation: The Benchmark Reaction R 2 R 3 R 6 R 6 B Bu Et 2 Zn R 5 CI 2 DME/DCM R 5 R 2 R 3! 80% yields 91-94% ee -4 =, substituted alkyl & aryl; R 5 =,, phenyl; R 6 = CN 2 Charette, A. B.; Juteau,. J. Am. Chem. Soc. 1994, 116, In This Paper, A Catalytic, Asymmetric MIRC reaction: (a Michael addition initiated ring-closure reaction) Cl R 2 MgBr CuI (R)-TolBINAP t-bu/c 2 Cl 2 4h, 78 C Cl R 2 MgBr 2 h 78 C to rt R 2

8 A Regioselective Grignard Addition to a 4-halocrotonate 1,4 Br 1,2 SN 2' S N 2 4-halocrotonate potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent! den artog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352,

9 A Regioselective Grignard Addition to a 4-halocrotonate 1,4 Br MgBr CuBr S 2 (R,R)-1 C 2 Cl 2, 78 C rt N PPh 2 2 Fe Ph 2 P 1, TaniaPhos 1,2 SN 2' S N 2 4-halocrotonate potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent! den artog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352,

10 A Regioselective Grignard Addition to a 4-halocrotonate 1,4 Br MgBr R 2 * X 1,2 S N 2' S N 2 4-halocrotonate potential chemo-, regio- and stereoselectivity issues with the addition of a Grignard reagent! den artog, T.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2010, 352,

11 Substrate Screening X SEt C 3 (C 2 ) 5 MgBr 1 mol% CuI 1.5 mol% (R)-TolBINAP t-bu/c 2 Cl 2 4h, 78 C X ex SEt + ex SEt when X = Br < 20 % yield when X = Cl 83 % yield 94% ee when X = Cl with warming to room temperature* 87 % yield 94% ee Pp-Tol 2 Pp-Tol 2 (R)-TolBINAP

12 Substrate Screening Cl SEt RMgBr 1 mol% CuI 1.5 mol% (R)-TolBINAP t-bu/c 2 Cl 2 4h, 78 C R SEt R % yield % ee i-pr i-bu 89% 70% 91% 84% but-3-enyl 88% 94% (C 2 ) 3 t-bu >95% 96% BnC 2 92% 84% Ph 50% 26% Pp-Tol 2 Pp-Tol 2 (R)-TolBINAP

13 Substrate Screening Cl R 2 MgBr 1 mol% CuI 1.5 mol% (R)-TolBINAP t-bu/c 2 Cl 2 4h, 78 C R R 2 % yield % ee C BnC 2 87% 98% 68% >95% Pp-Tol 2 Pp-Tol 2 (R)-TolBINAP

14 et the P.I. and Past Work Prof. Paul Floreancig Ac University of Pittsburgh DDQ, 2,6-Cl 2 Py C 6 13 DCE 10 min, 77% C 6 13 Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem. Int. Ed. 2008, 47, Pr Ac DDQ, 2,6-Cl 2 Py LiCl 4, DCE 58% Pr B.S. from Indiana Ph.D. from Stanford (Wender) Postdoc at Caltech (Dervan) Pr neopeltolide N N Tu, W.; Floreancig, P. E. Angew. Chem. Int. Ed. 2009, 48,

15 Past Work (Cont.) Ac DDQ, 2,6-Cl 2 Py N 2 78% yield Ac 84% yield nly moderate stereocontrol obtained with the usual solvent, DCE They postulate the more polar N2 is necessary the provide more stabilization for the intermediate oxocarbenium ion Liu, L.; Floreancig, P. E. Angew. Chem. Int. Ed. 2010, 49,

16 Can This Reaction Be Rendered Catalytic in DDQ? N3? FeCl3? oxidant Cl Cl CN CN product Mn(Ac)3? Pb2? reduction product Cl Cl CN CN substrate DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone $526/mol (Aldrich) modest toxicity concerns

17 Substrate Scope Ac TBS 20 mol % DDQ, Pb2 (8 equiv), 2,6-Cl2Py, N2 48 h, 75% 15 mol % DDQ, Mn2 (6 equiv), 2,6-Cl2Py, N2 48 h, 79% TBS oxidative cyclization is slower in N2, but the regeneration of DDQ is much faster Ac 83% yield Ac 75% yield All yields were within ~10% of the yields to the corresponding reactions with 2.0 equiv. of DDQ!

18 Can It Do ther DDQ-diated Transformations? PMB ether deprotection: 15 mol % DDQ, Mn 2 (6 equiv),, N 2, 60 C 48 h, 90% Dehydrogenation: 15 mol % DDQ, Mn 2 (6 equiv), N 2, rt 24 h, 96% xazole Synthesis: N 20 mol % DDQ, Mn 2 (6 equiv), C 6 6, 80 C 48 h, 86% N