The development of new reaction methodologies requiring only a catalytic amount of promoter are fundamentally important to the advancement of organic synthesis. 1 Coupled with a mode for enantioinduction, these strategies become indispensable tools for the generation of optically pure molecules in a reasonably atom-economical and environmentally conscious manner. Cycloaddition reactions constitute a special class since such multiple bond forming processes create much greater molecular complexity than single bond forming reactions.The palladium-catalyzed [3+2] cycloaddition of trimethylenemethane (Pd-TMM) to electron deficient π-systems was introduced almost thirty years ago by our laboratory and constitutes a highly efficient synthesis of substituted cyclopentanes, tetrahydrofurans, and pyrrolidines. Initial efforts to render the reaction enantioselective relied on the commercially available ligand L1 9 (Figure 1). Unfortunately, although giving high conversion to product, the enantioselection was rather poor (37% ee). Likewise, phosphoramidite ligand L2 9 possessing no chirality in the amine component was largely ineffective for promoting enantioselection. In contrast to these standard phosphoramidites, the cyclic pyrrolidine phosphoramidite ligands L3-5 4 all gave excellent levels of enantioinduction. Various aryl substituents were examined with bis-(4-biphenyl)phosphoramidite ligand L5 attaining near perfect enantioselection in 75% isolated yield (see Table 1 Based on these promising results, an examination of other tropone systems was undertaken (Table 1). To explore the effect of the position of the ester functionality, both the 3-carboethoxy and 2-carboethoxy tropones 7 (3b, 3c) were synthesized. Gratifyingly, both tropones gave comparable reaction yields and excellent diastereo-and enantioselectivity (entries 2 and 3). In both cases, only one [6+3] regioisomer was obtained and followed what was predicted from electronic considerations. 10 We also examined less electron deficient tropones, such as tropone (3d) itself. Although a higher temperature was required to obtain good conversion, the cycloaddition reaction proceeded to give the desired product 4d in good yield, diastereomeric ratio, and enantioselectivity (entry 4).A series of 2-substituted tropones, readily available from tropolone, 11 were also prepared and examined. The reaction of 2-chlorotropone (3e) proceeded very well to give the bicycle 4e in 94% yield and 94 % ee (entry 5). X-ray crystallographic analysis on the 2-chloro TMM adduct 4e unambiguously established both the absolute and relative configuration as depicted. Interestingly, 2-bromotropone failed to give any desired cycloaddition. While 2-methoxytropone also displayed no reactivity, 2-acetoxytropone (3f) delivered cycloadduct 4f, again with excellent yield and enantioinduction (entry 6). Likewise, while 2-dimethylamino tropone was unreactive, 2-phthalimido tropone (3g) was well suited to the reaction conditions, although a slightly diminished ee of 86% was observed (entry 7). These r...

[reaction: see text] A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an N-glycolyloxazolidinethione with titanium (IV) chloride and (-)-sparteine followed by addition of an aldehyde activated with additional TiCl(4) resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.

A concise approach to the core skeleton of the welwitindolinone alkaloids was developed based on sequential cycloaddition reactions. First, a palladium catalyzed enantioselective [6 + 3] trimethylenemethane cycloaddition onto a tropone nucleus was used to generate the requisite bicyclo [4.3.1]decadiene. Subsequent modifications to the cycloadduct allowed for an intramolecular [4 + 2] cycloaddition to generate the oxindole and complete the core of the natural product family.The palladium catalyzed trimethylenemethane (Pd-TMM) cycloaddition reaction represents a highly effective tool for the rapid synthesis of complex carbocycles. 1 A rather useful extension to the widely studied [3 + 2] cycloaddition to electron deficient olefins is a [6 + 3] The advent of such methodology opens the door for a unique, enantioselective, synthesis of bioactive molecules possessing the [4.3.1] bicyclic motif. Of these, we chose to initiate a program to develop a synthesis of the welwitindolinone B & C class of marine alkaloids (1-7; Figure 1). 5 These particular compounds are characterized by a highly functionalized [4.3.1] bicyclic carbon skeleton containing an oxindole, two quaternary stereocenters, and multiple sensitive functional groups. While the bioactivity of these molecules varies, the more potent of these, N-methylwelwitindolinone C isothiocyanate (1), acts as a powerful antagonist for the over expression of P-glycoprotein, offering a potential therapeutic benefit against multiple drug resistant tumors. 6 bmtrost@stanford.edu. Supporting Information Available Full characterization and NMR spectra of all new compounds is available free of charge at http://pubs.acs.org. Although a total synthesis of any member of this class of compounds has yet to be accomplished, 7 several approaches to a core structure have been reported. 8 The majority of these syntheses rely on using an intact oxindole or indole moiety as a starting point, followed by stepwise construction of the bicyclo[4.3.1]decane core. In contrast, we envisioned a novel approach that would rely on a series of sequential cycloadditions to rapidly build the common core structure 8 (Scheme 2). Central to this theme was an enantioselective [6 + 3] cycloaddition that would rapidly construct the bicyclic fragment 10 from a suitable tropone (11 or 12) and the cyano TMM donor 13. Based on work by Padwa, 9 an intramolecular [4 + 2] cycloaddition reaction between a pendent amidofuran and the endocyclic olefin would then be used to generate the oxindole core 8 in a single operation. This core structure could conceivably be elaborated to any of the natural products 1-7. NIH Public AccessIdeally, a tropone system bearing a 2-amino-5-ester substitution pattern, as in compound 12, would provide the most straightforward synthetic approach. However, in order to attain high levels of regioselectivity for the TMM cycloaddition, the unusual isophthalimide group was required. 4 Unfortunately, this unstable protecting group led to numerous difficulties in carrying out furth...

A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process, followed by methylenation.The exquisite structures of marine polycyclic ether natural products have captured the imagination of synthetic chemists for over two decades. The structures of the polyether ladder toxins characteristically contain a linear series of trans fused ether rings of varying sizes from five to nine members with assorted methyl and hydroxyl substituents appended. As novel technologies for the convergent preparation of these targets have emerged, a number of total syntheses of the ladder toxins have been completed. 1 The structure of brevetoxin A (1), a representative member of this class, was first elucidated in 1986 by Shimizu 2a,b , and coworkers by X-ray analysis and independently determined by Nakanishi through spectroscopic studies. 2c Brevetoxin A (1) contains ten rings (including five-, six-, seven-, eight, and ninemembered oxacycles) fused in a linear array adorned by 22 tetrahedral stereocenters. A metabolite of Karenia brevis, brevetoxin A is a toxic component of the infamous red tide phenomenon, which has been responsible for massive fish kills as well as neurotoxic shellfish poisoning and bronchial irritation in humans. 3 The potent activity of brevetoxin A is attributed to strong binding to the α subunit of the voltage-sensitive sodium ion channels effecting an increase in the mean channel open time and inhibiting channel inactivation. The planned approach for the total synthesis of brevetoxin A 5 focused on a versatile endgame that would exploit the selective manipulation of tetraol 2 (Scheme 1), which would derive from mixed methyl ketal 3 via stereoselective reductive etherification. Ketal 3 would be obtained through the stereoselective Horner-Wittig coupling 6 of phosphine oxide 5 and aldehyde 6. This route was attractive not only because it allowed for optimal convergence by simplifying the natural product into two halves of similar complexity, but also because it found precedent in the strategy previously reported by Nicolaou. 4 Further, it was reasoned that the dithioketal moiety of aldehyde 6 could serve as a stabilized precursor to mixed ketal 3, or lead to sulfone 4 in the event that formation or reductive etherification of mixed ketal 3 proved problematic. The Horner-Wittig coupling partners 5 and 6 would be obtained from advanced fragments 7 and 8, respectively. The BCDE fragment 7 and GHIJ subunit 8 had been previously prepared in significant quantities through similar highly convergent [X+2+X] strategies based on a Horner-Wadsworth-Emmons coupling of the B and E ring units (and the G and J subunits) and subs...

A second-generation synthesis of the BCDE fragment of brevetoxin A is described. Novel reactions were developed that extend the utility of the asymmetric glycolate alkylation reaction and improve scale-up to provide gram quantities of the B and E subunits. Significant improvements to the convergent assembly of the tetracycle were also realized. In addition, formation of the A ring lactone was accomplished to complete the ABCDE pentacycle.