Total Synthesis of ( )-Virginiamycin M2 Jie Wu and James S. Panek, Angewandte Chemie International Edition, 2010, 49, 6165-6168 btained from the CDC Public ealth Image Library. Image credit: CDC/Dr. David Berd (PIL #2983), 1972. lissa Sprachman @ Wipf Group Page 1 of 11 lissa Sprachman Current Literature September 4, 2010 9/26/2010
Antibiotics from Streptomyces Et 2 S Combination therapy against staphylococci and vancomycin-resistant Enterococcus faecium, administered intravenously, approved in 1999. Dalfopristin (Type A) Quinupristin (Type B) Synercid -Type A and Type B streptogramins act in synergy; the in vitro activity of the mixture is at least 10 times greater than the sum of the individual activities. -Both Type A and Type B streptogramins inhibit protein synthesis via action on the peptidyltransferase domain of 50S ribosomal subunits. -The compounds bind specifically to non-overlapping regions of the ribosome in a 1:1 stoichiometry. -Binding of Type A antibiotics increases the binding affinity for Type B antibiotics, but the opposite scenario does not occur. Barrière, J. C.; Bouanchaud, D.; Desnoottes, J. F.; Paris, J. M. Expert pin. Invest. Drugs 1994, 3, 115-131. lissa Sprachman @ Wipf Group Page 2 of 11 9/26/2010
Viriginiamycin Synthesis and Semisynthesis 1 st Total Synthesis: Schlessinger, R..; Li, Y.-J. J. Am. Chem. Soc. 1996, 118, 3301. 3 C LDA 3 C TF, -78 to 0 o C Troc TES C 3 TBDPS C3 TBS TBS TBDPS 2 1. Li, TF/ 2 2. I n 3 0.001 in C 2 2 52% TBDPS Stereochemistry of vinylogous aldol product and diene controlled by chiral auxiliary; macrocycle closed via amide bond formation; 21 steps, 2.2% yield, 16 steps longest linear (numbers do not include auxiliary attachment). TES Troc lissa Sprachman @ Wipf Group Page 3 of 11 9/26/2010
Panek Group Retrosynthesis Barbier-type Cyclization TBDPS TBS Alkyne-alkyne reductive coupling C 2 Si 2 Ph C Panek group crotylation methodology TBS lissa Sprachman @ Wipf Group Page 4 of 11 9/26/2010
Terminal Alkyne Synthesis: Asymmetric Crotylation C 2 Si 2 Ph C Ti 4 C 2 2, -20 o C 63%, d.r. > 20:1, 95% ee Al 3, C 2 87% 2 Silane synthesis via Si- insertion (Davies et al. TL 1997, 38, 1741-1744.) 2 C 2 Ph 2 Si (R)-Rh 2 (DSP) 4 (1-5 mol%) hexane 65-70%, up to 95% ee C 2 Si 2 Ph Rh Rh S 2 Ar 4 (R)-Rh 2 (DSP) 4 Ar = p-c 12 25 C 6 4 Application of optically active crotyl silanes toward vinylogous aldol products (rg. Lett. 2010, 12, 2112-2115. Previously cited methodology: Asymmetric additions of optically active (E)-crotyl silanes (Panek et al. J. rg. Chem. 1992, 57, 5790-5792. Si 2 Ph SiR 3 (aisen Rearrangement via (E)-enolate) C 2 RC, TMSR' TMSTf C 2 Si 2 Ph R R' d.r. up to > 20 : 1 ee up to 97% TMSBn, -50 o C, 20 h 94% Bn d.r. 30:1 C 2 Vinyl silane synthesis and application: Sparks, M. A.; Panek, J. S. J. rg. Chem. 1991, 56, 3431-3438. lissa Sprachman @ Wipf Group Page 5 of 11 9/26/2010
Alkyne-Alkyne Reductive Coupling Stereoselective Synthesis of Functionalized Conjugated Dienes Bn Ti(-i-Pr) 2 (1.25 equiv) (0.8 equiv) Ti(-i-Pr) Et 2, -50 o 2 C, 2 h Et 2, -50 o C, 1 h (1 equiv) Ti(-i-Pr) 2 Bn E ( ) 81% Bn Reaction tolerates amides, esters, alkynyl silanes, and silyl ethers in good yields and fair regioselectivities (3:2 to 9:1 to single regioisomer). amada, T.; Suzuki, D.; Urabe,.; Sato, F. J. Am. Chem. Soc. 1999, 121, 7342-7344. ote: Characterization of Group 4 tal-alkyne complexes: chwald et al. J. Am. Chem. Soc. 1987, 109, 2544-2546. Application to Polyketide atural Product Synthesis TBS TMS Ti(iPr) 3 c-c 5 9 Mg, tol -78 to -30 o C add ipr warm to -30 o C then 4 (aq) TBS TMS ipr 75%, r.r. 5:1 Callystatin A Reichard,. A.; Rieger, J. c.; Micalizio, G. C. Angew. Chem. Int. Ed. 2008, 47, 7837-7840. General methodology development: Shimp,. L.; Micalizio, G. C. rg. Lett. 2005, 7 5111-5114. lissa Sprachman @ Wipf Group Page 6 of 11 9/26/2010
Application of Reductive Coupling Synthesis of coupling partner: TBS (2 steps from 1,3-propanediol) 1. Zn(Tf) 2, (-)--methylephedrine propyne, Et 3 80%, 95% ee 2. TBSTf, 2,6-lutidine, 96% TBS TBS Carreira s alkyne addition protocol (general: J. Am. Chem. Soc. 2000, 122, 1806-1807. R 1 R 2 TBS Conditions A: Ti(iPr) 3, c-c 5 9 Mg, toluene or -78 o C to -30 o C Conditions B: n-li, Ti(iPr) 3, c- C 5 9 Mg, Et 2, -78 o C to -30 o C R 1 TBS TBS R 2 R 1 R 1 1 2 3 R 2 TBS R 1 R 2 Conditions Yield 1 Yield 2 Yield 3 Bn TBS A 0% 19% 45% Ac TBS A 0% 39% 49% B 58% 16% 0% Ac B 71% 0% 0% Most favorable substrate for synthesis lissa Sprachman @ Wipf Group Page 7 of 11 9/26/2010
Proposed Alkyne-Titanium Intermediates R 1 R 2 TBS R 1 TBS Unfavorable due to strain associated with a bridgehead alkene R 1 R 2 TBS lissa Sprachman @ Wipf Group Page 8 of 11 9/26/2010
Completion of the Synthesis C 10 mol% a Ser (88% crude) 1.a,, 10 o C 2. CSA, toluene, 70 o C ermitage et al. rg. Process Res. Dev. 2001, 5, 37-44. 1. Li, TF/ 2 (4:1), 95% 2. EDC, (R)-()-Pro-Bn, 80% 3. B 3, -20 o C to 0 o C, 70% TBS TBDPS, imid. 92% DIPEA, DMAP 2 C 86% TBDPS TBS TBS TBDPS 1. CSA C 2 2,, 0 o C 62% (85% BRSM) 2. IBX, DMS, 92% (-)-Virginiamycin M 2 1. TFAA, DMS C 2 2, Et 3-78 o C to -45 o C, 84% 2. F pyridine C 2 2, 70% TBDPS SmI 2, benzene 40% TBDPS lissa Sprachman @ Wipf Group Page 9 of 11 9/26/2010
Barbier Cyclizations in atural Product Synthesis Review: icolaou et al. Angew. Chem. Int. Ed. 2009, 48, 7140-7165. R 1 -X 2 SmI 2 -SmI 2 X X =, Br, I, S 2 R I R 1 SmI 2 R 1 R 2 SmI 2 ii 2 (cat.), TF 82-88% R 1 R 3 R 2 Synthesis of Phorbol (Carrol and Little, 2000) Synthesis of Kendomycin (Lowe and Panek, 2008) Model system of vinigrol (Matsuda et al., 1997). MM phorbol Bn SmI 2, MPA, TF 98% MM vinigrol model Bn Matsuda et al. Tetrahedron 1999, 55, 14369-14380. Carroll, G. L.; Little, R. D. rg. Lett. 2000, 2, 2873-2876. TBS TBS Br SmI 2, TF 60% TBS TBS intermediate in kendomycin synthesis -1 st example of Samarium-mediated Barbier cyclization for macrocycle closure in natural product synthesis (16-membered) Lowe, J. T.; Panek, J. S. rg. Lett. 2008, 10, 3813-3816. lissa Sprachman @ Wipf Group Page 10 of 11 9/26/2010
Summary and utlook The antibiotic ( )-Virginiamycin M 2 was synthesized in 19 steps and 6.0% overall yield from the optically active (E) chiral silane. The longest linear sequence was 10 steps. Key transformations include application of crotyl silane addition toward a vinylogous aldol product, a regio- and stereo-selective titanium mediated alkyne-alkyne coupling reaction, and a samarium diodide mediated Barbiertype cyclization. The 23-membered macrocycle is the largest ring reported to be synthesized by a Barbier type reaction to date. lissa Sprachman @ Wipf Group Page 11 of 11 9/26/2010