The first total synthesis of the complex pentacyclic Stemona alkaloid tuberostemonine was accomplished in 24 steps and in 1.4% overall yield from a hydroindole intermediate which is readily obtained in three steps from Cbz-l-tyrosine. An innovative synthetic strategy was applied that relays the single stereocenter of the amino acid precursor into nine of the ten stereogenic carbons of the target molecule. Among the highlights of the synthetic methodology are the 3-fold use of ruthenium catalysis, first in an azepine ring-closing metathesis and then in an alkene isomerization followed by a cross-metathesis propenyl-vinyl exchange, as well as the stereoselective attachment of the gamma-butyrolactone moiety to the core tetracycle by use of a lithiated ortho ester.

Furans are common substructures in numerous natural products, such as the cembranolides lophotoxin, 1 kallolides, 2 and pukalide. 3 These heterocycles are also found in numerous commercial products, including pharmaceuticals, fragrances, and dyes. Accordingly, many strategies have been developed for the preparation of furans. 4 Marshall and coworkers utilized 3-alkynyl allylic alcohols in S N 2′ reactions to provide 2,3-disubstituted furans. 5 Another method for the formation of 2,3-disubstituted furans from the same laboratory employed Ag(I)-or Rh(I)-catalyzed cyclizations of allenyl ketones and aldehydes. 6 Palladium catalysis has also been used for the synthesis of furans. Coupling of terminal acetylenes and γ-hydroxyalkynoates followed by Pd(II)catalyzed cyclization produced 2,4-disubstituted furans. 7 Wakabayashi et al. have used Pd(II) to promote intramolecular cyclizations of 3-alkynyl-1,2-diols to give either 2,3disubstituted or 2,3,4-trisubstituted furans from ,γ-acetylenic ketones. 8 Numerous literature protocols for the formation of furans employ 1,3-dicarbonyl compounds. Paquette and co-workers used these starting materials to prepare a 2,3,5-trisubstituted furan as an intermediate in the total synthesis of gorgiacerone, a furanocembranolide. 9 Larock and Cacchi studied the Pd(0)-mediated cyclizations of 2-propargylic-1,3-dicarbonyl compounds, 10 and Tsuji et al. used Pd(0) catalysis for the formation of furans in the intramolecular annelation reaction of -keto esters and either propargylic carbonates or oxiranes. 11 Other strategies based on dicarbonyl substrates use the Feist-Benary condensation of 1,2-dibromoacetate with acetoacetate to provide 2,3-disubstituted furans or the cyclocondensation of acetone dicarboxylate with 1,4-dibromobut-2-yne to give 2-vinylidenehydrofurans. 12,13 As part of our approach toward the total synthesis of lophotoxin, we were interested in a general protocol for 2-alkenylfurans. In this paper, we present the first use of unstabilized monocarbonyl systems in the formation of substituted furans. Our methodology employs alkynyl ketone enolates which undergo a thermal S N 2′ O-alkylation to provide the desired heterocycles. Furthermore, we were able to extend this strategy toward novel syntheses of 1,3-oxazoles and -thiazoles. Supporting Information Available: Experimental details and characterization for all new compounds. Copies of 1 H and 13 C NMR spectra (78 pages). (17) Thionation of amide 15 with Lawesson's reagent led, in lower yield, to the identical vinylthiazoline, and no thioamide intermediate was observed in this reaction either. Scheme 3 Scheme 4 Scheme 5 Scheme 6 Communications

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Two consecutive intramolecular cyclization reactions of alkenyl 2-bromo-3-nitrobenzyl ethers give access to a variety of indoles fused at the 3,4-position with six-, seven-, or eight-membered rings. The sequence can be also performed with analogous amides and a malonic acid derivative. -(SOEDERBERG*, B. C. G.; HUBBARD, J. W.; RECTOR, S. R.; O'NEIL, S. N.; Tetrahedron 61 (2005) 15, 3637-3649; Dep. Chem., W. Va. Univ., Morgantown, WV 26506, USA; Eng.) -Klein 32-125