Macrocyclic Triarylethylenes via Heck Endocyclization: A System Relevant to Diazonamide Synthesis

Received September 3, 1998 Diazonamide A (1, Figure 1) and its congeners1 are impressive products of invertebrate secondary metabolism wherein at least three proteinogenic amino acids have been incorporated, perhaps by posttranslational modification of a short oligopeptide, into a heterocyclic network of considerable complexity. Notably, 1 has shown potent cytotoxicity in vitro toward a transformed human cell line (HCT-116),1a but a subsequent lack of natural material1c has prevented further study. To enable future mode-of-action studies and to access a range of related polycyclic structures, we outline here our approach to diazonamide synthesis and describe initial results demonstrating that Heck endocyclization can form highly functionalized lactam rings containing an imbedded 1,2-diaryl-1-(5′-oxazoyl)ethylene. When considering possible routes to assemble the diazonamide skeleton,2 it was evident that potentially complicating issues of atropisomerism could be avoided if the D-E biaryl linkage was designated as the final carbon-carbon bond to be formed (Figure 1). In the presence of a conformationally rigid, correctly configured A-F macrolactam, intramolecular biaryl formation at C16 in 2 necessitates that the relative rotational orientation of rings A-E adopt a desired atropisomeric relationship (as depicted in 2) to bring C18 within bonding distance of C16. We currently envision that halogenation at C25 and C27 can occur late in the synthesis and that the D-E linkage can be established by intramolecular orthophenolic coupling. This implicates either serotonin or a derivative of 5-HT as the original source of carbons 18-27. Lactam 3 therefore contains all the stereochemical information needed to complete natural diazonamides. A protected derivative of this molecule, with the C11 hemiacetal in open tautomeric form, is seen as the ring-contracting pinacol rearrangement product of vicinal diol 4 or its functional equivalent. To the extent that C10 stereochemistry in 4 correlates to that sought in 3 through inversion of configuration at the migrating terminus, macrocyclic olefin 5 is a reasonable link to 3 through a sequence beginning with face-selective oxidation. Functionalized lactams related to 5 were without precedent prior to this study,3 although it was fairly obvious how two (A and F) of the three-component rings in this structure were related to natural amino acids. The A ring (C29-C33) was synthesized in one step from commercial materials by treating N-Boc-L-Val-OH (6) with aminomalononitrile ptoluenesulfonate and EDC4 in pyridine (Scheme 1). Following trituration of a concentrated residue with water, aminooxazole 7 was isolated by filtration (>95% purity) and converted directly to bromide 8 through in situ bromination of a derived nitrosamine.5 This succinct preparation of a fully functionalized A-ring, combined with the availability of several halogenated tyrosine derivatives, led us to consider a third building block (E-ring) which would permit consecutive formation of the C8-C11 and C10-C30 bonds in 5 via metal-catalyzed cross-couplings. A trifluoroacetate salt derived from 8 was condensed independently (TBTU, DIPEA, CH3CN) with 3,5-dibromo-N-Boc-L-Tyr-OH (9) and 3-iodoN-Boc-L-Tyr-OH (10) to afford dipeptides 11a and 11b, respectively (Figure 2). Interestingly, when 11b was treated with bis-stannyl styrene 13c in the presence of 5 mol % PdCl2(CH3CN)2, a single adduct assigned as R-styryl stannane 12b was isolated in 30% yield. Intractables and starting material accounted for the remaining mass. Resubjecting 12b to the reaction conditions did not induce a second, ring-closing Stille coupling. The same net results were observed in reactions between tribromide 11a and 13c. While synthetically unproductive, it was during these experiments that we observed a marked susceptibility to (1) (a) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303-2304. (b) Lindquist, N. L. Ph.D. Thesis, University of California, San Diego, CA, 1989. (c) Petit, C. San Francisco Chronicle, Friday Jan 31, 1997, A4. (2) For other approaches to diazonamide synthesis, see: (a) Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223-2226. (b) Jamison, T. F. Ph.D. Thesis, Harvard University, Cambridge, MA, 1997. (c) Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc., Perkin Trans. 1 1997, 16, 2413-2419. (d) Vedejs, E.; Wang, J. B. Abstracts of Papers, 212th National Meeting of the American Chemical Society, Orlando, FL; American Chemical Society: Washington, DC, 1996; ORGN 93. (e) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Veliz, E. A.; Yang, Z. C. Synlett 1996, 609611. (f) Moody, C. J.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. Pure Appl. Chem. 1994, 66, 2107-2110. (3) Shortly after we began our studies Jamison and Schreiber reported the preparation of cyclic 3-aryl-2-(5′-oxazoyl)benzofurans related to lactams 5. In this approach 3-iodo-N-Cbz-L-Tyr-OMe was acylated with 3-iodo-7methoxybenzofuran-2-carboxylic acid and the C8-C11 bond was formed by internal coupling of the incipient diiodide with excess Ni(PPh3)4. The product coumarin was reduced to provide a C30 alcohol from which the A-ring oxazole was assembled. Lactamization subsequently closed the 13membered ring. See ref 2b. (4) This modified version of Freeman’s oxazole synthesis simplifies product isolation and eliminates the need for a purification step. Confer: Freeman, F.; Chen, T.; van der Linden, J. B. Synthesis 1997, 861-862. (5) Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J. Org. Chem. 1977, 42, 2426-2430. (6) (a) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488-6499. (b) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447-471. (7) Energy profiles for a simulated torsion about the C10-C30 bond in low-energy conformers of 16d and 16f were generated within the dihedral driver subroutine of Macromodel V6.0. Figure 1. 8640 J. Org. Chem. 1998, 63, 8640-8641