“Synthesis of 12-S-HETE using asymmetric phase-transfer catalysis” Spring 2009 ACS Meeting Mike A. Christiansen, Merritt B. Andrus Brigham Young University.

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Presentation transcript:

“Synthesis of 12-S-HETE using asymmetric phase-transfer catalysis” Spring 2009 ACS Meeting Mike A. Christiansen, Merritt B. Andrus Brigham Young University Department of Chemistry & Biochemistry

Obtaining Asymmetrically Pure C-C Bonds Three ways of obtaining asymmetrically pure products: Using optically pure starting materials from nature (the “chiral pool”) Separating racemates (classical resolution, crystallization, kinetic resolution using an enzyme) Asymmetric synthesis (enzyme-mediated, non-catalytic, catalytic) Enzyme-Mediated Asymmetric Bond Formation: 1 Ankati, H. et al. J. Org. Chem. 2008, 73, 6433-6436. Non-Catalytic Asymmetric C-C Bond Formation: 3 4 2 Crimmins, M. T. et al. Org. Lett. 2000, 2, 2165-2167. Ager, D. J. et al. Chem. Rev. 1996, 96, 835-875.

Catalytic C-C Bonds Via Asymmetric Alkylation Catalytic Asymmetric Synthesis

Catalytic C-C Bonds Via Asymmetric Phase-Transfer-Catalyzed (PTC) Alkylation 6 5 7 Figure 1. The mechanism of phase-transfer catalyzed alkylation, aldol, or Michael addition reactions1 CH3Cl, PhMe, 50% KOH 8 10: 98% y, 94% ee2 R = CH3, H, CH2COOEt, or CH2COOH 9 (10 mol%) Hicken, E. J. Ph.D. thesis, Brigham Young University, Provo, UT, 2005. (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 (PTC) Alkylation BnBr, CH2Cl2, 50% NaOH 11 O’Donnell et al. J. Am. Chem. Soc. 1989, 111, 2353-2355. 13: 75%, 66% ee1 12 (10 mol %) BnBr, Catalyst (10 mol%), conditions 11 15 14 * * Lygo2 50% eq. KOH, PhMe, 25ºC 18 h, 68%, 91% ee Corey3 CsOH (H2O), CH2Cl2, -78ºC 23 h, 87%, 94% ee Lygo: R = H, X =Cl Corey: R = allyl, X = Br Lygo, B. et al. Tetrahedron Lett. 1997, 38, 8595-8598. Corey, E. J. et al. J. Am. Chem. Soc. 1997, 119, 12414-12415.

Asymmetric Phase-Transfer-Catalyzed (PTC) Alkylation Andrus group attempts: Base, BnBr, catalyst Low yield/selectivity 15 16 Alternative Approach: Base, BnBr catalyst Baeyer-Villiger oxidation 17

Asymmetric PTC Alkylation with 18 Andrus, M. B.; Hicken, E. J.; Stephens, J. C. Org. Lett. 2004, 6, 2289-2292.

The Asymmetric Total Synthesis of Kurasoin A 24% yield over seven steps Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J. Org. Chem. 2006, 71, 8651-8654.

Attempts at Kurasoin B Evans’ work: . MeI, DMF, 60 C, 24 h . Nuc (-) at rt 24 25 (a) Evans, D. A et al. J. Am. Chem. Soc. 2005, 127, 8942-8943. (b) Org. Lett. 2006, 8, 2249-2252. (c) Org. Lett. 2006, 8, 3351-3354. Nuc = ROH, RNH2, morph.

The Results: Selective Alkylation of Substrate 25 MeOTf, CH2Cl2 MeOH, NaOMe quant., no racemization 26, CsOH•H2O, CH2Cl2, RBr -40 °C 25 27 28 = NAP DDQ, rt, 5h, 70% (for R=Bn only) R= %yield %ee 90 88 85 91 84 86 >99 75 92 80 77 79 S - 292 [α]D – 6.25° Lit. [α]D –6.8° 26 A 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.

The Total Synthesis of Kurasoin B (COCl)2, morph., 16 h, 73% 20h, 134% crude yield 86% (84% from BnOH BuLi 31 32 +16.75 ° 30 26, 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% 34 +17.72 ° 33 +34.68 ° 35 -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% 36 +8.16 37 -13.79 ° Christiansen, M. A.; Butler, A. W.; Hill, A. R. Andrus, M. B. Synlett. 2009, 4, 653-657.

The Total Synthesis of (S)-Naproxen 38 41 48% yield (five steps) Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A. J. Org Chem. submitted for publication.

Proposed Total Synthesis of (S)-Equol 42 43 46 45 44 47 Andrus group, unpublished work

An Introduction to 12-S-HETE 12(S)-hydroxy-6(E),8(Z),10(E),14(Z)-eicosatetraenoic acid (12-S-HETE) A product of the 12-lipoxygenase pathway from arachidonic acid Discovered by Hamberg and Samuelsson in 1974 (see Proc. Natl. Adam. Sci. U.S.A. 1974, 71, 3400) Plays a role in multiple biological pathways and conditions, including angiogenesis, cancer metastasis, atherogenesis, coronary thrombosis, type I diabetes, inflammation, psoriasis, and apoptosis (see Org. Lett. 2000, 2, 2543-44). It possesses potential as a pharmaceutical lead in investigating and treating various clinical processes and conditions.

Total Syntheses of 12-S-HETE 48 49 50 51 52 53 54 55 56 57 59 Corey, E. J. et al. J. Am. Chem. Soc. 1978, 100, 1942-1943. 60 61 62

Total Syntheses of 12-S-HETE (continued) Two racemic syntheses: Gunn, B. P.; Brooks, D. W. J. Org. Chem. 1985, 50, 4418-4420. Rodríguez, A.; Nomen, M. Spur, B. W.; Godfroid, J. J.; Lee, T. H. Tetrahedron 2001, 57, 25-37. Separation of racemates by classic resolution: Shimazaki, T.; Kobayashi, Y.; Sato, F. Chem. Lett. 1988, 17. 1785-1788. Separatiion of racemates by kinetic resolution using an enzyme: Suh, Y.-G.; Min, K.-H.; Lee, Y.-S.; Seo, S.-Y.; Kim, S.-H.; Park, H.-J. Tetrahedron Lett. 2002, 43, 3825-3828. 64 63 65 67 (±)-12-HETE

Our Proposed Approach to 12-S-HETE red. 68 30 69 70 71 64 72 73 Our initial screens: 75 74 68

Improving the Synthesis of Electrophile 68 75 74 78 77 75 74 = 68 68 30 69

Optimizing the Catalyst and Conditions 68 30 69

Our Total Synthesis of 12-S-HETE to Date 75 74 68 30 69 70 64 73 71 72

Conclusions A new method of asymmetric phase-transfer-catalyzed alkylation has been described. The synthetic utility of this method has been demonstrated with the total syntheses of kurasoin A, kurasoin B, and S-naproxenTM, with current work toward S-equol. This methodology is currently being applied to an improved asymmetric total synthesis of the natural compound 12-S-HETE.

Acknowledgements 2007-2008 Garth L. Lee Fellowship Professor Merritt Andrus, Erik Hicken, Morgan Gainer, Karl Bedke, Kaid Harper, Aaron Butler, Amanda Hill, Meisha Binkley, Jason Nielson, and Adam Calvert 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

How the Catalyst Work 14 (10 mol%), CsOH (H2O), * CH2Cl2, BnBr 11 S-13 ‡ 14 (10 mol%), CsOH (H2O), CH2Cl2, BnBr * 11 S-13 -78ºC, 23 h, 94% ee, 87% yield 14 Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-12415.