Total Synthesis of Cyclosporine: Access to N-Methylated Peptides via Isonitrile Coupling Reactions
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1 Total Synthesis of Cyclosporine: Access to -thylated Peptides via Isonitrile Coupling Reactions Xiangyang Wu, Jennifer L. Stockdill, Ping Wang, Samuel J. Danishefsky* J. Am. Chem. Soc. 2010,132, R C R' Adam T. oye Current Literature March 27, 2010 Adam Wipf Group Page 1 of 24 4/26/2010
2 istorical perspective and hypothesis Passerini reaction R 3 + C + C R 3 + R 3 1,4! acyl transfer R 3 Ugi four-component coupling reaction R 3 C + R 4 2 R R 4 C + C R 3 R 4 + R 3 R4 1,4! acyl transfer R 3 R 4 Current hypothesis R R C + R ' R ' + C?? R' R Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, Adam Wipf Group Page 2 of 24 4/26/2010
3 Initial discovery C CCl 3 microwave 150 C C 1,3! acyl transfer 83% [2 + 2] -formyl imide concerted pseudopericyclic [1,3]-acyl rearrangement FCMA Formamidine Carboxylate Mixed Anhydride Jones, G..; Li, X.; ayden, A. E.; ouk, K.,.; Danishefsky, S. J. rg. Lett. 2008, 10, Adam Wipf Group Page 3 of 24 4/26/2010
4 Probing reaction conditions C 2 t-bu CCl 3 Fmoc C microwave 150 C 82% C 2 t-bu Fmoc C 2 t-bu Fmoc C CCl 3 rt, 24 h no detectable reaction rt, 24 h 2 C 2 t-bu Fmoc 10-15% C 2 t-bu Fmoc C 2 CCl 3 microwave 130 C, 30 min C 2 t-bu Fmoc C 2 t-bu Fmoc C 2 t-bu Fmoc 1.3 : 1.0 : 2.0 C 2 t-bu Fmoc common intermediate Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, Adam Wipf Group Page 4 of 24 4/26/2010
5 Application to asparagine-linked glycopeptides C 2 Anomerically-specific glycosidic imidations Ac Ac Ac 3 X = 3 X = C X 1. i. ( 4 )MoS 4 ii., 53% 2. triphosgene, 90% Fmoc C 2 C 2 t-bu CCl 3, µw, 150 C, min 82% β α X = 3 X = C Ac Ac Ac Bn Bn Bn Bn 3 Bn Bn Bn Bn C X 1. i. Pd/C, 2, ii. 2. triphosgene, 75% C Fmoc Fmoc C 2 C 2 t-bu CCl 3, µw, 150 C, min 85% C 2 t-bu CCl 3, µw, 150 C, min 85% C 2 t-bu Fmoc Bn Bn Bn Bn Bn Bn C Bn Bn C C 2 t-bu Fmoc Glycosidic esterification C 2 C 2 t-bu Fmoc Ac Ac C Ac Also see: Li, X.; Danishefsky, S. J. at. Protoc. 2008, 3, Fmoc C 2 t-bu CCl 3, µw, 150 C, min 50% Ac Ac Ac t-bu 2 C Ac Fmoc Adam Wipf Group Page 5 of 24 4/26/2010
6 -Formyl imide manipulations Deformylation C a, quant. Bn Bn Bn C Bn C 2 t-bu Fmoc a, quant. Bn Bn Bn Bn C 2 t-bu Fmoc Reduction R C 2 t-bu TFA, Et 3 Si C 2 t-bu Fmoc C 2 Cl 2 90% Fmoc ab 4, 85% R = C R = C 2 Tertiary - amides! Bn Bn Bn R Bn C 2 t-bu Fmoc TFA, Et 3 Si C 2 Cl 2 52% (2 steps) Bn Bn Bn Bn C 2 t-bu Fmoc ab 4, R = C R = C 2 Adam Wipf Group Page 6 of 24 4/26/2010
7 -Formyl imide manipulations Further functionalization 1. ab 4, C 2. TFA, allyltms 64% cy-c CCl C, 30 min 75% C 1. LiMDS, TF 2. TFA, C 2 Cl 2 75% Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, Adam Wipf Group Page 7 of 24 4/26/2010
8 chanistic investigations C + FCMA 1,3! acyl transfer R2 R1 C -acylation -acylation FCMA 1,3! acyl transfer C C 2 C CCl 3 µw, 150 C C Formamidine Carboxylate Mixed Anhydride 85% 2 2 C CCl 3 µw, 150 C 16% 2 C -Anhydride mechanism could be minor contributor to mechanism -Possibility of anydride conversion to FCMA and acyl transfer Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, Adam Wipf Group Page 8 of 24 4/26/2010
9 Iterative isonitrile couplings th C 2 C C 2 t-bu CCl 3, µw, 150 C 30 min th C 2 t-bu th 2 SM C 2 C C 2 t-bu DCE, µw, 160 C 30 min 70% th R = t-bu R = C C 2 R C 2 C C 2 t-bu CCl 3, µw, 150 C 30 min 41% (2 steps) th, = C, = C 2 t-bu ac 3, 60% Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, Adam Wipf Group Page 9 of 24 4/26/2010
10 Interception of FCMA sacrificial isonitrile Boc C 2 C 2 Bn C CCl C, µw C 2 Bn C C 2 Bn C 2 Bn Boc Boc Boc 1 eq. 38% 30% 4% 5 eq. 41% 14% 11%, µw Rationale: Boc C 2 C 2 Bn C Boc C 2 Bn? Solution: need better (faster) acyl donor for successful interception of FCMA intermediate C 2 Boc C 2 Bn Adam Wipf Group Page 10 of 24 4/26/2010
11 oxo-fcma formation and rearrangement Sulfur effect thio-fcma formation and rearrangment RT C + RT C + S R2 µw S R2 RT S thio-fcma Room temp. acyl shift Fmoc 60% (82% brsm) S C 2 Bn S Fmoc 59% S C 2 Bn 1.0 eq. thioacid 1.0 eq. isonitrile CCl 3 RT 12 h Fmoc 50% C 2 Bn t-bu t-bu Fmoc Rao, Y.; Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, Yuan, Y.; Zhu, J.; Li, X.; Wu, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, % S C 2 Bn 1. mcpba 2. ac 3, 80% (2 steps) Fmoc C 2 Bn More reactive, but better acyl donors? Adam Wipf Group Page 11 of 24 4/26/2010
12 Sulfur effect DCM, RT Fmoc CS Fmoc CS C 2 Allyl 55% C + Cy C 2 Allyl DCM, RT - 2 Fmoc C 2 Allyl 75% S Fmoc CS DCM, RT t-bu S Fmoc CS not observed C 2 Allyl C + t-bu C 2 Allyl DCM, RT - 2 Fmoc t-bu S C 2 Allyl 77% Adam Wipf Group Page 12 of 24 4/26/2010
13 Substrate scope Secondary amides Tertiary amides RT C + t-bu R 3 t-bu S R S 1 FAST vs. S = Rao, Y.; Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, R 3 S t-bu Adam Wipf Group Page 13 of 24 4/26/2010
14 Substrate scope Esterification Fmoc S C + t-bu DCM RT Fmoc S C t-bu Fmoc 43% Boc Bn 2 C 64% Tertiary amide formation C 2 Fmoc S C + t-bu (3.0 eq.) DCM, RT Fmoc t-bu S Fmoc 1,4! acyl transfer 75% DCM, RT C 2 Fmoc C 2 TMSC % Fmoc C 2 (3.0 eq.) Adam Wipf Group Page 14 of 24 4/26/2010
15 Cyclosporine A Fungal metabolite from Tolypocladium inflatum gams Initially isolated in early 1960s at Sandoz (later ovartis) in Basel, Switz. arrow antibiotic activities, shelved until 1970s Crude fungal extract inhibited lymphocyte proliferation w/out affecting somatic cells Structure reported in 1976 (chem degradation, MR, X-ray) Dr. Thomas E. Starzl (Univ. of Pittsburgh) established clinical utility of cyclosporine in liver transplants (preventing organ rejection) in landmarks around Pitt campus Acts by inhibiting cytokines (via calcineurin) that stimulate growth, differentiation, and survival of T-cells. Corey, E. J.; Czakó, B.; Kürti, L. Molecules and dicine; Wiley: oboken, J, 2007; p. 124 Adam Wipf Group Page 15 of 24 4/26/2010
16 Previous syntheses of cyclosporine A Total synthesis reported by Wenger in 1984 Unusual amino acid (Bmt) critical to activity; considerable attention, synthetically Bioavailability (proteolysis) dependent on - amide pattern in 7 of 11 amide bonds (SAR crucial) (Wenger, Rich, Galpin) Synthesis: Wenger, R. M. elv. Chim. Acta. 1984, 67, SAR studies: Wenger, R. M. Angew. Chem. Ind. Ed. Engl. 1985, 24, Colucci, W. J.; Tung, R. D.; Petri, J. A., Rich, D.. J. rg. Chem. 1990, 55, Rich, D..; Sun, C.-Q.; Guillaume, D.; Evans, D. A.; Weber, A. E. J. d. Chem. 1989, 32, Galpin, I. J.; Mohammed, A. K. A.; Patel, A. Tetrahedron 1988, 44, Adam Wipf Group Page 16 of 24 4/26/2010
17 Retrosynthetic analysis peptide coupling peptide coupling macrolactamization peptide coupling A Boc Bn Bn B Boc C peptide coupling Adam Wipf Group Page 17 of 24 4/26/2010
18 Fragment A Boc S C Bn 1. CCl 3 2. Bu 3 Sn, AIB 100 C, 62% (2 steps) Boc Bn 1. C 2 Cl 2, TFA 2. cyclopentadiene 2, C Bn Bn 3. Et 3 Si, TFA 52% (3 steps) Cl Bn dipeptide Boc S C Bn 1. CCl 3 2. Bu 3 Sn, AIB 100 C, 59% (2 steps) Boc Bn 1. 2, 10% Pd/C, 2. DEPBT, DIPEA, TF, dipeptide 90% (2 steps) Boc A Bn Grieco, P. A.; Bahsas, A. J. rg. Chem. 1987, 52, Adam Wipf Group Page 18 of 24 4/26/2010
19 Fragment B Route by Evans and Weber: Bn CS Sn(Tf) 2, -ethyl piperidine, TF, -78 C Bn CS SnL R 73% Bn S 1. Mg, BF 4 - S % 1. acetonide K formation saponification 70% 2 C B Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, Adam Wipf Group Page 19 of 24 4/26/2010
20 Fragment C 3 C t-bu DCE 155 C µw 85% 3 C t-bu 1. C 2. Cl 2 -Ala-Bn, ATU, DIPEA, DMF 81% (2 steps) 3 C Bn 1. LiB 4, C 2 Cl 2, n-pr, Ac 2, -50 C 2. TF 2, Et 3 Si, C 2 Cl 2, -50 C 62% (2 steps) 3 Bn P 3, TF, 2 75% 2 Bn 1. Boc-Leu-, ATU, DIPEA, DMF 2. TFA, C 2 Cl 2 82% (2 steps) TFA tetrapeptide Bn Boc S Ts Bn Cy C CCl 3 80% Boc Bn 1. Pd/C, 2, 100% 2. Lawesson's reagent, C 2 Cl 2 65% Boc S 1. Cy-C, CCl 3, tetrapeptide 2. TFA, DCM TFA Bn C 63% (2 steps) Adam Wipf Group Page 20 of 24 4/26/2010
21 Completion of cyclosporine B TFA Bn 1. DCC, Bt, MM, TF C 2. Cl (aq.), 75% (2 steps) Bn Boc A Bn 1. 2, Pd/C, PyBP, MM, C 2 Cl 2 52% (2 steps) Bn Boc Adam Wipf Group Page 21 of 24 4/26/2010
22 Completion of cyclosporine Bn Boc 1. a (aq.), Et 2. TFA, C 2 Cl 2, -20 C 3. Cy-C, Bt, C 2 Cl 2, 70 C, µw 54% (3 steps) 19 steps (longest linear) 3.5%* overall yield Adam Wipf Group Page 22 of 24 4/26/2010
23 Conclusions Synthesis of cyclosporin in a fashion that allows for more detailed mapping of SAR Excellent showcase of methodology- power and diversity (-formyl imide and acyl transfer chemistry) Thiol effect in mechanism (acyl donor capabilities) Diversity of -formyl imide products 1. ab 4, 2. TFA, allyltms C a, i. ab 4, ii. TFA, Et 3 Si Application to glycopeptides Bn Bn Bn Bn C C 2 t-bu Fmoc Bn Bn Bn C Bn C 2 t-bu Fmoc Ac Ac Ac t-bu 2 C Ac Fmoc Adam Wipf Group Page 23 of 24 4/26/2010
24 Conclusions We note in passing that amines, isonitriles, and thioacids are very old functional groups which go back to the beginnings of organic chemistry. The amide forming construction described here could, in principle, have been conducted in 1909 without difficulty. It is not unlikely that careful mechanistically based revisitation of the foundations of organic chemistry might yield additional surprises of considerable value Rao, Y.; Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, Adam Wipf Group Page 24 of 24 4/26/2010
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