Baran Group Meeting 04/07/04 The Total Synthesis of (+)-Ryanodol

Transcription

1 Baran Group eting 04/07/04 The Total Synthesis of ()-Ryanodol A. Bélanger; D. Berney;. Borschber; R. Brousseau; A. Doutheau; R. Durand;. Katayama; R. Lapalme; D. Leturc; C. Liao; F. MacLachlan; J. Maffrand; F. Marazza; R. Martino; C. Moreau; L. Saint-Laurent; R. Saintonge; P. Soucy; L. Ruest; P. Deslongchamps Can. J. Chem. 1979, 57, 334. Pierre Deslongchamps -Pyrrolecarboxylate ester the active insecticidal component in the roots and stems of Ryana speciosa; binds nearly irreversibly to sarcoplasmic reticulum vesicles; binding studies intentified calcium release channels now known as Ryanodine receptors -riginally reported in 194 by collaborators from rck and the Department of Entomology at Rutgers University -In 1967, Wiesner and co-workers elucidated the full structure 2 of natural ryanodine -The X-ray structure of the p-bromobenzyl ether 3 of ryanodol was reported in A B D E 1 C Figure 1. Ryanodol (1), Wiesner's proposed ryanodine (2) and a ryanodol dervative (3) assigned by X-ray crystallography. N Br 2 oxidation reductive dehomologation cyclization 4: anhydroryanodol () 2 C transannular aldol () 2 C MM 10 () 2 C PNB lactonization 5 Ms () 2 C fragmentation 7 Ring closure protection ozonolysis () 2 C aldol oxidation C() C C 3 15 Scheme 1. Retrosynthetic analysis of ryanodol (1). 13 Diels-Alder 6 aldol oxidation 12

2 Baran Group eting 16 X X = C, Ac, C 2 Scheme 2. Initial attempts at o-quinone Diels-Alder reactions. X Ph, D 23a 23b Cl 3 C Br 1. Cl, 1. Br, TiCl 4, C 2 Cl 2 Py., Ph 2. BBr 3, C 2 Cl 2 2. Na 2 C 3, C TF, D C 17 1 (64% from 17) 19 N 2 4,K, ethylene glycol, D; Ts, Ph, D, 0% (90%) Br Na NBS, C 3 CN C 3 C 3 C Scheme 3. Synthesis of an o-quinone surrogate diene. ()-carvone 1. Pt, 2, Et , EtAc; Pd/C, 2 (70% overall) 2 C Scheme 4. Synthesis of the optically active dienophile. 1. Ethylene glycol Ts; Na C 2. Li, TF; Li 22 (75% overall) 14 Ph, D 23c 23d Scheme 5. The Diels-Alder reaction and products formed. 23b 23d 23d Scheme 6. Isomer equivalency.

3 Baran Group eting 23b 23d 1 N Na TF Epimerization 13b Intramolecular Aldol Ac, 1 N Na, TF 2 Epimerization 12b 12a 24b 24a Intramolecular Aldol 13a C(C 3 ) 2 3, EtAc, Ts; DMS 90% ( 3 C) 2 C C(C 3 ) ( 3 C) 2 C ( 3 C) 2 C Scheme. The ozonolysis cascade to establish the A,B, and C rings of ryanodol (1). 26a 26b 1. C 3 C 3, 1. CCl 2, Py, C 3 C 2 Na Ph (6:1) A 2. ( 3 ) 3 C, 2. WCl 6, n-buli, Ts, TF, -7 C (27% from 15) 0% (two steps) C C(C 3 ) 2 C(C 3 ) ( 3 C) 2 C Scheme 7. Construction of the A ring of ryanodol (1). Scheme 9. Desired oxidation state changes between intermediate and ryanodol (1).

4 Baran Group eting ( 3 C) 2 C 1. LDA, TF, -7 C; Et 3 B, -25 C; C 3 I ( 3 C) 2 C 2. NaB 4, C 3, TF, 0 C (67 % overall) 27 ( 3 C) 2 C 30 CF 3 C 3, Na 2 P 4, ClC 2 C 2 Cl, 4 C (9%) ( 3 C) 2 C N Na 2. pnbcl, Py, 0 C 6 (77% overall) ( 3 C) 2 C ( 3 C) 2 C Ms 7 DMS, n-buli; 1. Na, TF, ClC 2 C 3 (76% overall) 2. LiAl 4, TF 1. Cr 3 py 2, C 2 Cl 2, -45Æ-22 C 2. MsCl, Py, 0 C ( 3 C) 2 C (6% overall) 0.3 N BF 4, TF, 0 C (9%) ( 3 C) 2 C Scheme 10. Synthesis of intermediate ( 3 C) 2 C 10 pnb 5 1. Cr 3 Py, C 2 Cl 2 2. LiB 4, TF, -30Æ-20 C (73% overall) Scheme 11. Synthesis of advanced intermediate 5. ( 3 C) 2 C 1. Ac 2, Py ( 3 C) 2 C pnb 31 Ac 2. Ts, Ph, D pnb pnb , C 2 Cl 2, -7Æ-55 C; DMS 2. Ac 2, AcNa, 100 C Ac 34 DBN, Ph, D (50% over 5 steps) Ac Ac pnb 33 Scheme 12. Formal reduction of C17 to achieve intermediate 34.

5 Baran Group eting 1. NaB Ac 4, TF,, 0 C 2. 1 N Na, TF (90% overall) 34 4: anhydroryanodol CF 3 C 3, 35 (5%) Na 2 P 4, Cl(C 2 ) 2 Cl Li, N 3, TF (60%) Your own disconnections: Scheme 13. Endgame construction of anhydroryanodol (4) and ryanodol (1). Scheme 14. Impromptu group disconnectrions of ryanodol (1).