Applications of Asymmetric PTC Alkylation to Total Synthesis

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Presentation transcript:

Applications of Asymmetric PTC Alkylation to Total Synthesis By Mike Christiansen Brigham Young University

Asymmetric Phase-Transfer Catalyzed (PTC) C-C Bond Formation Merck1: CH3Cl, PhMe, 50% KOH 1 98% y, 94% ee R = CH3, H, CH2COOEt, CH2COOH 2 (10 mol%) 1. (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am Chem. Soc. 1984, 106, 446-447. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745-4752.

Asymmetric Phase-Transfer Catalyzed C-C Bond Formation O’Donnell2: BnBr, CH2Cl2, 50% NaOH 3 5 75%, 66% ee 4 (10 mol %) Corey and Lygo3,4: Catalyst: BnBr, Catalyst (10 mol%) 3 5 6 Corey3 (R=allyl, X=Br) CsOH (H2O), CH2Cl2, -78ºC 23 h, 94% ee, 87% yield Lygo4 (R=H, X=Cl) 50% eq. KOH, PhMe, 25ºC 18 h, 91% ee, 68% yield 2. J. Am. Chem. Soc. 1989, 111, 2353-2355. 3. J. Am. Chem. Soc. 1997, 119, 12414-12415. 4. Tetrahedron Lett. 1997, 38, 8595-8598.

Asymmetric PTC C-C Bond Formation Corey3: ‡ Base, BnBr catalyst 3 * S-5 Andrus group attempts3: Alternative substrate? Base, BnBr, catalyst Low yield/selectivity A B C 3. J. Am. Chem. Soc. 1997, 119, 12414-12415

Asymmetric PTC C-C Bond Formation Later Andrus Group Work5 5. Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Org. Lett. 2004, 6, 2289-2292.

The Asymmetric Total Synthesis of Kurasoin-A Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J. Org. Chem. 2006, 71, 8651-8654.

Attempts at Kurasoin-B Evans6 . MeI, DMF, 60 C, 24 h . Nuc (-) at rt Nuc = ROH, RNH2, morph. 6. (a) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942-8943. (b) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252. (c) Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351-3354.

The Results: Selective Alkylation of Substrate 12 MeOTf, CH2Cl2 MeOH, NaOMe quant., no racemization (for R= a-d only) 14, CsOH•H2O, CH2Cl2, RBr -40 °C 12 15 16 = NAP DDQ, rt, 5h, 70% (for R=Bn only) R= %yield %ee 90 88 85 91 84 86 >99 75 92 80 77 79 a b S - 172 [α]D – 6.25° Lit. [α]D –6.8° c 14 d Andrus, M. B.; Christiansen, M. A.; Hicken, E. J.; Gainer, M. J.; Bedke, D. K.; Harper, K. C.; Mikkelson, S. R.; Dodson, D. S.; Harris, D. T. Org. Lett. 2007, 9, 4865. Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998, 120, 4345-4353.

Applying Our Methodology to the Synthesis of Kurasoin B 182 14, DCM, -40 °C, CsOH, 60 h, 91%, >99% ee 12 13 MeOTf, CH3CN, rt MeOH, DBU, 75%, 84% ee DDQ or H2, Pd X AlMe3 THF 19 TESCl base BnMgCl THF TBAF kurasoin B3 Andrus, M. B.; Christiansen, M. A.; Hicken, E. J.; Gainer, M. J.; Bedke, D. K.; Harper, K. C.; Mikkelson, S. R.; Dodson, D. S.; Harris, D. T. Org. Lett. 2007, 9, 4865. Christiansen, M. A.; Butler, A. W.; Hill, A. R. Andrus, M. B. Synlett, in press.

A Modified Approach to Kurasoin B (COCl)2, morph., 16 h, 73% 20h, 134% crude yield 86% (84% from 28) BuLi 18 21 +16.75 ° 20 14, CH2Cl2, CsOH, -40°C, 3.5 h 98%, >99% ee . MeOTf, CH3CN (2 h) . MeOH, DBU (4 h) 94%, 88% ee BCl3, THF, -78°C  -20 °C 18 h, 100% HN(OCH3)CH3 AlMe3, reflux 18 h, 92% 23 +17.72 ° 22 +34.68 ° 24 -2.5 ° TESCl, imidazole, DMF, rt, 2 h, 70% kurasoin B +45 ° 43% yield over 10 steps BnMgCl THF, 0°C, 99% TBAF, THF 87% 25 +8.16 26 -13.79 °

PTC Alkylation of Arylacetates Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A. Org. Lett., submitted for publication.

PTC Alkylation of Arylacetates (cont.) Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A. Org. Lett., submitted for publication.

Total Synthesis of (S)-Naproxen Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A. J. Org Chem. submitted for publication.

Proposed Total Synthesis of (S)-Equol Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256-257. Christiansen, M. A.; Butler, A. W.; Hill, A. R. Andrus, M. B. Synlett, in press. Andrus, M. B.; Hicken, E. J.; Meredith, E. L. Simmons, B. L.; Cannon, J. F. Org. Lett. 2003, 5, 3859-3862.

Proposed Total Synthesis of 12-(S)-HETE* *12-(S)-HETE = 12(S)-hydroxy-6(E),8(Z),10(E),14(Z)-eicosatetraenoic acid

Acknowledgements 2007-2008 Garth L. Lee Fellowship Professor Merritt Andrus, Erik Hicken, Morgan Gainer, Karl Bedke, Kaid Harper, Aaron Butler, Amanda Hill, Shawn Mikkelson, Daniel Dodson, David Harris Financial Support Provided by: Department of Chemistry & Biochemistry 2007-2008 Garth L. Lee Fellowship BYU Graduate Research Presentation Award 2007-2008 Roland K. Robins Graduate Research Fellowship 2008-2009 Telford and Frank Woolley Memorial Research Award 2008-2009 Charles E. and Margaret P. Maw Fellowship