Total Synthesis of Asteriscanolide

The synthesis of asteriscanolide has been achieved using our regioselective intermolecular alkynoate Pauson-Khand reaction¹ and a ring closing alkene metathesis as key elements of the strategy.²

Interestingly, the synthesis proceeds through an inside-out bridging intermediate. We have also demonstrated that a number of inside-out bridged ring systems can be synthesized using ring closing metathesis.³ Using a bicyclo[3.3.0] template, eight membered rings are readily synthesized via alkene metathesis.

Synthesis and Reactions of New Molybdenum Dicarbonyl Complexes Bearing Tethered Homoallylic Amines and Sulfides

Allylmetal complexes, as organic reagents or reaction intermediates, are of significant utility in organic chemistry. Amongst the most noteworthy and commonly used are allylpalladium(+2) complexes which react with nucleophiles and allylstannanes and allylboranes which react with electrophiles. p-Allyl-molybdenum¹ complexes are particularly versatile reagents since they have been shown to react with both electrophiles and nucleophiles, depending on the nature of the other ligands on the complex. As part of our ongoing effort to develop new heteroatom directed organic reactions, we now report the synthesis of new organomolybdenum complexes bearing a p-allyl ligand tethered to a chelating heteroatom.²

X-Ray structural analysis established the relative configuration at the metal center.² These new complexes were found to undergo regio- and diastereoselective reactions with electrophiles.³ Treatment of the allyl molybdenum complexes with benzaldehyde or hydrocinnamaldehyde in CH₂Cl₂ at room temperature yielded amino alcohols with complete regioselectivity. Unlike the crotyl molybdenum complexes reported by Faller,¹ the allylation of carbonyls occurred preferentially through the unsubstituted terminus of the p-allyl system. Substitution at both allylic termini led to the formation of anti products exclusively with very high regioselectivity.

Regioselective Additions to p-Allyl Pd Complexes

The regioselectivity of addition to p-allyl Pd complexes is generally determined by steric interactions with the less hindered end undergoing substitution. We have demonstrated that thioether or amino substituted allylic acetates can be "directed" to undergo regioselective substitution at the internal carbon of the allyl metal system.^1,2 Substrates substituted with an ether functionality undergo nucleophilic addition at the allyl terminus distal to the heteroatom on the attached chain. In addition, we have demonstrated that, in cyclic allylic acetates, the heteroatom controls the stereochemistry of allylation and the reaction occurs with overall inversion of configuration instead of the expected retention. Further stereochemical studies are in progress to determine the origin of the unprecedented selectivity.³

Cobalt Mediated Alkene-Alkyne Cycloaddition Reactions: The Pauson-Khand Reaction

Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968. Krafft, M. E. Tetrahedron Lett. 1988, 29, 999. Krafft, M. E.; Juliano, C. A.; Scott, I. L.; et. al. J. Am. Chem. Soc. 1991, 113, 1693. Krafft, M. E.; Juliano, C. A. J. Org. Chem. 1992, 57, 5106. Krafft, M. E.; Scott, I. L.; Romero, R. H. J. Org. Chem. 1992, 57, 5277. Krafft, M. E.; Wright, C. Tetrahedron Lett. 1992, 33, 151. Krafft, M. E.; Scott, I. L. Tetrahedron Lett. 1992, 33, 3829. Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelman, S.; Van Pelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199. Krafft, M. E.; Romero, R. H.; Scott, I. L. Synlett 1995, 577-578. Krafft, M. E.; Chirico, X. Tetrahedron Lett. 1994, 35, 4511. Krafft, M. E.; Wilson, A. M.; Dasse, O. A.; Cheung, Y. Y.; Shao, B.; Fu, Z.; Bonaga, L. V. R.; Mollman, M. K. J. Am. Chem. Soc. 1996, 18, 6080-6081. Krafft, M. E.; Wilson, A. M.; Dasse, O. A.; Bonaga, L. V. R.; Cheung, Y. Y.; Fu, Z.; Shao, B.; Scott, I. L. Tetrahedron Lett. 1998, 39, 5911-5914. Breczinski, P. M.; Stumpf, A.; Hope, H.; Krafft, M. E.; Casalnuovo, J. A.; Schore, N. E. Tetrahedron 1999, 55, 6797.

The Interrupted Pauson-Khand Reaction

Thermal cycloaddition of a cobalt-complexed enyne under a nitrogen atmosphere gives rise to a bicyclic enone - the "normal" Pauson-Khand product. Use of an oxygenated atmosphere apparently disrupts the normal mechanistic pathway and a monocyclic enone is formed in excellent yield.¹ Heating the cobalt-complexed enyne in refluxing toluene also disrupts the normal Pauson-Khand process and dienes are formed in excellent yields.²

Approaches to the Synthesis of Xestobergsterol-B

Our routes to the functionalization of the A/B and C/D/E rings of the histamine release inhibitor xestobergsterol-B are shown below. Incorporation of the strategies into the total synthesis of xestobergsterol is currently underway.^1,2