Stereocontrolled organocatalytic synthesis of prostaglandin PGF 2 in seven steps
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1 Stereocontrolled organocatalytic synthesis of prostaglandin PGF 2 in seven steps Graeme Coulthard, William Erb, Varinder K. Aggarwal Nature. August 15, DI: /nature11411 N C 2 then [Bn 2 N 2 ][CF 3 C 2 ] C 2 Christopher Rosenker Wipf Group - Current Literature August 25, 2012
2 Biosynthetic Pathway to Prostaglandins Tyr cyclooxygenase archidonic acid 2 C 2 C 2 C peroxidase Tyr- C 2 C 2 C 2 C 2 C 2 PG 2 Rouzer, C. A.; Marnet, L. J. Chem. Rev. 2003, 103, 2239.
3 Biosynthetic Pathway to Prostaglandins PGJ 2 6-keto-PGF α C 2 PGD 2 Δ deoxy-PGJ 2 PGI 2 PGF 2 C 2 C 2 PGE 2 archidonic acid PG 2 TXA 2 PGC 2 PGA 2 Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Rev. 2007, 107, PGB 2
4 Biological Properties of Prostaglandins Implicated in a variety of biological processes: Sleep, pain, fever, inflammation, menstruation, birth, blood vessel constriction, and blood clotting Synthesized immediately in response to stimuli Lantanoprost is used for treatment of glaucoma $1.75 billion sales in step synthesis based on Corey s original synthetic strategy C 2 C 2 i-pr C 5 11 Ph Lantanoprost Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
5 Prostoglandin Synthesis and Biological Actions Funk, C. D.; Science 2001, 294, 1871.
6 Previous Prostaglandin Syntheses Wittig C 2 iodolactonization WE C 5 11 Ac C Me Ac Corey lactone Me Me Me Me Cl C Baeyer-Villiger oxidation Diels-Alder Corey: 17 steps; ~24% yield; >90% per step Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; uber, W. J. Am. Chem. Soc. 1969, 91, Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VC: Weinheim, 1996, p
7 Previous Prostaglandin Syntheses Stork: 30 steps; 0.002% yield C-C bond formation C 5 11 C 2 Ts NC EE EE C 5 11 TBDPS lactonization C-C bond formation TBDPS C 2 Me Johnson ortho ester Claisen rearrangement Me α-d-glucose Stork, G.; Takahashi, T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 1978, 100, Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VC: Weinheim, 1996, p
8 Previous Prostaglandin Syntheses Stork: 11 steps; 15% yield; 84% per step Conjugate addition Alkylation C 2 C 5 11 C 5 11 Ph BM Conjugate addition Ph Noyori: 8 steps Alkylation C 2 C 2 Me C 5 11 C 5 11 TBS TBS TBS Conjugate addition Stork, G.; Isobe, M. J. Am. Chem. Soc.1975, 97, Stork G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, Suzuiki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 4718.
9 Previous Prostaglandin Syntheses Danishefsky: 8 steps Wittig Michael addition C 2 TBS C 2 Et Aldol TBS C 5 11 C 5 11 C 5 11 Ac Ac Ac Allylic transposition Danishefsky, S. J.; Cabal, M. P.; Chow, K. J. Am. Chem. Soc. 1989, 111, 3456.
10 Retrosynthesis of PGF 2 Wittig C 2 Conjugate addition FGI Aldol reaction EWG Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
11 Proline Catalyzed Aldol Dimerization ligomer aldol aldol - 2 N C 2 intramolecular aldol reaction and A A B B dehydration aldol aldol ligomer Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
12 Test Reactions for Aldol Reaction Me N C 2 (10 mol%) TF, rt Me 61%, 3.6:1 dr Me 3, Me catalyst (20 mol%) -78 C, Me 2 S TF, rt, 14 h Catalyst A: (S)-Proline - 5% Catalyst B: [Bn 2 N 2 ][C 2 CF 3 ] - 51% Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
13 Me Me Synthesis of PGF 2 2, 75 C (S)-proline (2 mol%) 4 h; then 115 C TF, rt, 20 h; 69% N Me then [Bn 2 N 2 ][C 2 CF 3 ] Me, amberlyst 15 MgS 4, C 2 Cl 2 (2 mol%), rt, 14 h 14 h, rt 65% per bond formation/ breaking step 14% (over two steps) 99:1 er; 15 g prepared from 110 g aldehyde Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
14 Synthesis of PGF 2 S Me Li 2 (NC)Cu C 5 11 TBS Me 3, C 2 Cl 2 :Me (3:1) Me TF; then TMSCl, Et 3 N TMS C 5 11 TBS -78 C, then NaB 4 (3 equiv.) -78 C to rt C 5 11 TBS 60% (over two steps) g 49% (over two steps) g 1.5 % aq. Cl:TF (3:2) BrPh 3 P C 2 C 2 rt, 16 h C 5 11 t-buk, TF, 0 C to rt 57% (over two steps) mg 47% (over two steps) g Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature DI: /nature11411
15 Conclusion Seven step synthesis of prostaglandin from 2,5- dimethoxytetraydrofuran Total yield % (58-61% per step) Synthesis is shorter than the state of the art. Key organocatalytic aldol dimerization reaction in high enantiomeric purity (99:1 er) 4 bond forming/breaking reactions during process (~65% per rxn) Can be performed on +100 g scale Bicyclic enal is a useful intermediate for exploring prostaglandin derivatives. Me 4 steps R 1 R 2
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