6646
J. Org. Chem. 1996, 61, 6646-6650
Biomimetic Cyclization of Enamide-Containing Polyenes as a New Route to Azapolycycles† Stephanie E. Sen* and Steven L. Roach Department of Chemistry, Indiana University-Purdue University at Indianapolis (IUPUI), 402 North Blackford Street, Indianapolis, Indiana 46202 Received May 20, 1996X
Enamide 4 was studied for its effectiveness as a polyene precursor in biomimetic cyclizations. While most conventional Lewis acids were poor cyclization promoters, FeCl3‚6H2O initiated the conversion of 4 into tricycles 6 and 7 in excellent yield. The two isomeric products result from the cyclization of intermediate aldehyde 5 by either a chair or boat B-ring transition state. These results suggest that enamides may be incorporated into polyene precursors for the construction of larger azapolycycles such as azasteroids. Introduction Biomimetic polyene cyclizations provide an elegant and efficient means of preparing polycycles with stereochemical control at several ring fusion centers.1 Carbocationstabilizing (CS) auxiliaries, such as the isobutenyl2 and fluoride3 moieties, have recently been shown to enhance both the yield and rate of polyene cyclizations. These functionalities apparently mimic a putative function of cyclase enzymes by lowering the energy of the cationic transition state(s) and/or intermediate(s) in the process.4 We now report an extension of this methodology to the efficient synthesis of the ABC ring nucleus of a 7-azasteroid by inclusion of an enamide within the polyene chain as the CS auxiliary. Since azasteroids have been shown to be both potent enzyme inhibitors5 and difficult compounds to synthesize,6 new routes for their construction are expected to be of great utility in the development of new chemotherapeutic agents.
A general approach to the construction of nitrogencontaining polycycles by biomimetic polyene cyclization methodology is depicted in Scheme 1. Incorporating an appropriately positioned enamide functionality into a polyene chain was expected to provide a dual electronic benefit during the cyclization process. First, we anticipated that initial cyclization would be enhanced by the increased nucleophilicity of the β-carbon center. Next, once partial cyclization had proceeded, we envisioned that the resulting N-acyliminium ion would function as a stabilized cation/initiation site for further cyclization processes. Because monocyclizations of transient iminium and N-acyliminium ions are well-known,7 it seemed likely that the reaction, once initiated, would proceed as planned. To determine the possible utility of the enamide moiety as a CS auxiliary in biomimetic polyene cyclizations, the tricyclization of enamide 4 was examined. Results and Discussion
†
This paper is dedicated to the memory of William Summer Johnson. X Abstract published in Advance ACS Abstracts, August 15, 1996. (1) For a review on biomimetic polyene cyclizations, see: Johnson, W. S. Tetrahedron 1991, 47, xi. (2) (a) Johnson, W. S.; Telfer, S. J.; Cheng, S.; Schubert, U. J. Am. Chem. Soc. 1987, 109, 2517. (b) Johnson, W. S.; Lindell, S. D.; Steele, J. J. Am. Chem. Soc. 1987, 109, 5852. (c) Guay, D.; Johnson, W. S.; Schubert, U. J. Org. Chem. 1989, 54, 4731. (3) (a) Johnson, W. S.; Chenera, B.; Tham, F. S.; Kullnig, R. K. J. Am. Chem. Soc. 1993, 115, 493. (b) Johnson, W. S.; Fletcher, V. R.; Chenera, B.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K. J. Am. Chem. Soc. 1993, 115, 497. (c) Johnson, W. S.; Buchanan, R. A.; Bartlett, W. R.; Tham, F. S.; Kullnig, R. K. J. Am. Chem. Soc. 1993, 115, 504. (d) Johnson, W. S.; Plummer, M. S.; Reddy, S. P.; Bartlett, W. R. J. Am. Chem. Soc. 1993, 115, 515. (e) Fish P. V.; Johnson, W. S. Tetrahedron Lett. 1994, 35, 1469. (4) (a) Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93, 2189. (b) Corey, E. J.; Virgil, S. C.; Sarshar, S. J. Am. Chem. Soc. 1991, 113, 8171. (c) Corey, E. J.; Virgil, S. C.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Singh, V.; Sarshar, S. J. Am. Chem. Soc. 1995, 117, 11819. (5) Examples of biologically active azasteroids include: (a) Li, X.; Singh, S. M.; Labrie, F. J. Med. Chem. 1995, 38, 1158. (b) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; van Arnold, J.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. J. Med. Chem. 1994, 37, 2352. (c) Bakshi, R. K.; Patel, G. F.; Rasmusson, G. H.; Baginsky, W. F.; Cimis, G.; Ellsworth, K.; Chang, B.; Bull, H.; Tolman, R. L.; Harris, G. S. J. Med. Chem. 1994, 37, 3871. (d) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. J. Med. Chem. 1986, 29, 2298. (e) Dolle, R. E.; Allaudeen, H. S.; Kruse, L. I. J. Med. Chem. 1990, 33, 877. (f) Sampson, W. J.; Houghton, J. D.; Bowers, P.; Suffolk, R. A.; Botham, K. M.; Suckling, C. J.; Suckling, K. E. Biochim. Biophys. Acta 1988, 960, 268.
S0022-3263(96)00924-3 CCC: $12.00
Enamide 4 was constructed in nine steps from geraniol in a 33% overall yield, as outlined in Scheme 2. The acetal initiator was introduced by conversion of the ∆-6,7 olefin into the corresponding trisnoraldehyde 1 by mCPBA epoxidation of TBDPS-protected geraniol, followed by periodic acid cleavage.8 Subsequent Wittig homologation and reaction of the resulting enol ether with ethylene glycol/TsOH gave, after silyl deprotection, alcohol 2 (67% overall yield, three steps). The allylic alcohol was converted to amine 3 under mild conditions via conversion to the allylic phthalimide and subsequent phthalimide removal with methylamine.9 Enamide 4 was prepared by a one-pot procedure involving condensation of allylic amine 3 with cyclohexanone (benzene, K2CO3, reflux for 12 h), followed by reaction of the resulting unisolated imine with acetyl chloride and pyridine.10 (6) (a) Huisman, H. O. Angew. Chem., Int. Ed. Engl. 1971, 10, 450. (b) Morzycki, J. W. Pol. J. Chem. 1995, 69, 321. (7) For reviews on iminium and N-acyl iminium ion cyclizations, see: (a) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857. (b) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC Press: Boca Raton, FL, 1994; Chapter 1. (c) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367. (d) Overman, L. E. Aldrichchimica Acta 1995, 28, 107. (8) Davisson, V. J.; Neal, T. R.; Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1235. (9) Sen, S. E.; Roach, S. L. Synthesis 1995, 756. (10) For a review on the construction of enamides, see: Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421.
© 1996 American Chemical Society
Biomimetic Cyclization of Azapolyenes
J. Org. Chem., Vol. 61, No. 19, 1996 6647 Scheme 1
Scheme 2. Synthesis of Enamide 4a
Table 1. Cyclization Study of Enamide 4, Using Several Different Lewis Acids Lewis acida
a (a) m-CPBA, NaHCO ; (b) H IO , THF/H O; (c) MeOCHdPPh ; 3 5 6 2 3 (d) ethylene glycol, TsOH; (e) TBAF; (f) DIAD, PPh3, phthalimide; (g) MeNH2, EtOH, reflux; (h) cyclohexanone, benzene, reflux; followed by AcCl, pyridine.
To determine conditions for the cyclization of enamide 4, small-scale (3-5 mg) cyclization studies were performed. Reactions with standard Lewis acid promoters, such as SnCl4, TiCl4, EtAlCl2, and Me2AlCl, at several different temperatures resulted in either no reaction or decomposition of the starting material (Table 1). BF3‚Et2O was a more effective cyclization promoter, yielding a small (18%) amount of cyclic product, with the remaining material consisting of unreacted polyene and aldehyde 5 which results from Lewis acid promoted acetal hydrolysis. We attribute these results to strong coordination of the metals to the amide functionality of 4, which inhibits the ability of the nitrogen to participate in the cyclization process. In contrast, enamide 4 was effectively cyclized with the use of the iron-based Lewis acid FeCl3‚6H2O. A more detailed examination of the FeCl3‚6H2Opromoted cyclization of enamide 4 showed that the reaction is sensitive to small changes in reaction conditions. Efficient cyclization is only achieved at higher temperatures; thus, reaction of 4 with FeCl3‚6H2O at 0 °C resulted in no reaction, even with prolonged (6 h) reaction times (Table 1). However, after the solution was warmed to room temperature, rapid cyclization proceeded within 1 h to yield up to 95% cyclic products. GLC analysis of preparative-scale reaction mixtures revealed complete consumption of starting material and the pres-
equiv
temp (°C)
resultb
SnCl4 SnCl4 SnCl4
5 5 5
-40 0 23
no reaction
