Synthesis of a hybrid analog of the esperamicin and dynemicin cores

Tetrahedron Letters

Volumn 37, Issue 48, 1996, Pages 8687-8690

  Mastalerz, Harold ^a   Doyle, Terrence W ^a,b   Kadow, John F ^a   Vyas, Dolatrai M ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b Vion Pharmaceuticals Incorporated   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DYNEMICIN A; ESPERAMICIN; ESPERAMICIN DERIVATIVE;

ARTICLE; CHEMICAL REACTION; DRUG SYNTHESIS; EPOXIDATION; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS;

EID: 0030602215     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(96)02010-2     Document Type: Article

References (17)

1. 1. Mastalerz, H.; Doyle, T.; Kadow, J.; Vyas, D. preceding paper.
2. 2. This would be an intramolecular version of a type of Reissert reaction that has been explored by Fraenkel and Yamaguchi: (a) Fraenkel, G.; Cooper, J.W.; Fink, CM. Angew. Chem. internat. Edit. 1970, 9, 523;
3. (b) Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983, 24, 1801.
4. Interestingly, it had been considered as a way of constructing the dynemicin core (i to ii), see: (c) Nicolaou, K. C.; Smith, A. L.; Wendeborn, S. V.; Hwang, C.-K. J. Amer. Chem. Soc. 1991, 113, 3106;
5. (d) Danishefsky, S.; Shair, M. J. Org. Chem. 1996, 61, 16. However, that cyclization apparently does not proceed because the product ii is too strained. In our case, it was felt that the cyclization would occur because 3 would not be as strained, i.e., inspection of the 10-membered ring that incorporates the enediyne functionality in ii and 3 reveals that the former compound has a double bond which is transsubstituted (w.r.t. this 10-membered ring) while the analogous double bond is in a less strained exocyclic arrangement in 3. (Formula presented)
6. 3. Similar strategies for the construction of substituted tetrahydrophenathridines for the synthesis of the dynemicin core were reported during and after the completion of this work: (a) Dai, W.-M. J. Org. Chem., 1993, 58, 7581;
7. (b) Nishikawa, T.; Isobe, M. Tetrahedron 1994, 50, 5621;
8. (c) Myers, A.; Farley, M.; Tom, N. J. Amer. Chem. Soc. 1994, 116, 11556.
9. -1; MS (ESI) 273 (MH+).
10. 5. The coupling of 6 and 7 did not occur under the ligandless reaction conditions that were previously used (reference 1) to couple a para-substituted aryl stannane with 6. Others have reported difficulties with the palladium catalyzed coupling of ortho-substituted aryl stannanes with vinyl or aryl inflates and have developed different solutions to overcome the problem, see: Gomez-Bengoa, E.; Echavarren, A. J. Org. Chem. 1991, 56, 3497 and reference 2 b.
11. 3 was based on the Weinreb transamidation reaction: Levin, J.; Turos, E.; Weinreb, S. Syn. Commun. 1982, 72, 989.
12. 3 was based on the Weinreb transamidation reaction: Levin, J.; Turos, E.; Weinreb, S. Syn. Commun. 1982, 72, 989.
13. 7. Cacchi, S.; Ciattini, P.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27, 5541. The hydrogenolysis was accompanied by partial reduction of the enediyne part of 10. Fortunately this could be minimized by using a short reaction time.
14. 2Me were added before metallation was complete, significant amounts of other products (relatively unstable and not identified) were also formed.
15. 4, see: reference 2c.
16. 10. This amine exhibited a tendency to revert back to the uncyclized tetrahydrophenanthridine 11. For example, if a sample of 13 were applied onto a preparative silica gel tlsc plate and then developed after standing for 4 hr, a 48% yield of 11 was obtained.
17. 11. Rearrangement of the epoxide group to an allylic alcohol does not occur in the dynemicin system since this would result in the formation of a highly strained compound.