Anion-Catalyzed Addition of γ-Silylallenyl Esters to Aldehydes: A New Entry into [3.2.1] Bicyclic Natural Products

Abstract

A significant improvement in generality and reactivity of MBH-type reactions made possible by anion-catalysis and a 1,3-Brook rearrangement. In this new reaction, both aliphatic and aromatic aldehydes are rapidly added to silylallenes leading to γ-carbinol allenoates at cold temperatures. The utility of these reaction products is demonstrated by a fast-tracked synthesis of a [3.2.1] bisoxabicycle which makes up the framework of many biologically active natural products including vitisinol D, an anti-thrombotic agent.Catalytic reactions that lead to functionally dense intermediates are of great value in targetoriented synthesis. We are particularly interested in allenyl carbonyls and their synthetic utilization owing to the unique juxtaposition of functional groups including the reactively distinct cumulated double bonds. As part of our ongoing efforts in the total synthesis of vitisinol D, an anti-thrombotic natural product, 1 we required a general and robust method for the preparation of γ-carbinol allenoates as a multifunctional coupling partner for maximal convergency. A review of existing methods including those developed in our lab 2 revealed no efficient catalytic approach to the synthesis of these allenoates save Mukaiyama aldol-type reactions. 3 Seeking a Lewis basic approach, we were intrigued by a report demonstrating an amine-catalyzed Morita-Baylis-Hillman (MBH) coupling of an allenyl ketone to aldehydes. 4 However, this reaction only appears to work with electron-deficient aromatic aldehydes and requires forcing conditions (DMSO, 80 °C).From a mechanistic perspective, two possible rate limiting steps have been attributed to MBH reactions. 5 In the context of allene synthesis, these would be the nucleophilic addition to form C and a proton transfer and catalyst elimination to regenerate the orginal unsaturation giving product D (Scheme 1). 6 Neutral nucleophiles, especially tertiary amines, have been used exclusively as catalysts in this reaction leading to zwitterionic intermediates B (where Nuc is positively charged). Probably due to their overall neutral charge, intermediates such as B have poor nucleophilicities leading to slow addition. We hypothesized that the unique combination of an anionic catalyst and a 1,3-Brook rearrangement would address reactivity problems associated with these two slow steps. By analogy with other systems, 8 we reasoned that silyl-substituted allenoates would lead to intermediates C in which the Nuc would eliminate to form allenic unsaturation with greater facility due to the enhanced propensity of the silyl group to undergo a 1,3-shift relative to the proton of the classic MBH reaction (X = R 3 Si vs H).To test our hypothesis, we first prepared γ-TMS allenylester 1 from 2-benzyl-2,3-butadienoic ethyl ester. 9 Our initial optimization involved the addition of 1 to p-anisaldehyde while varying nucleophilic catalysts and reaction parameters (table 1). We were gratified to discover that LiOPr i led to regiospecific γ-carbinol products 3 in most cases within severa...

Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes

“…In the same manner, platensimycin possesses a potent and broad-spectrum Gram-positive antibacterial activity, with no cross-resistance to an array of major antibiotic-resistant microbes and has been synthesized several times [3,4]. Vitisinol D, which has not been synthesized in enantiomeric form and only one racemic total synthesis has been described [5], presents antithrombotic properties [6], and finally compounds that are inhibitors of phenylethanolamine N -methyltransferase as PNMT inhibitor [7] are shown in Figure 1. Recently, the [3.2.1] bicyclic moiety has been included in more complex synthetic structures as (+)-dendrowardol C [8] and isopalhinine [9], a fact that has awaken the interest of researchers.…”

From Vinylogation to Alkynylogation: Extending the Reactivity of Enolates

“…16 Cyclic b-keto ester 16 was successfully added to allenoate 15 to give enol-containing lactone 17 with loss of triethylsilyl alcohol (Scheme 12). The required bicyclo[3.2.1] compound was then formed by the reduction of lactone 17, presumably to give the corresponding lactolate, which then underwent an intramolecular aldol reaction to give the bicyclic product.…”

“…Subsequent Dess-Martin periodinane oxidation led to product 18 in an unoptimized twostep yield of 32%. 16 …”

Diversification reactions of γ-silyl allenyl esters: selective conversion to all-carbon quaternary centers and γ-allene dicarbinols

“…3 Importantly, this asymmetric conversion was accomplished under mild phase-transfer conditions due to facile γ-deprotonation of a γ-silylallenoate resulting from stabilization of the conjugate base by the silyl group (Scheme 1). We also have also taken advantage of the unique properties of γ-silyl allenoates in developing a highly selective γ-aldol addition 4 and α-additions leading to azaprolines. 5 Specifically, silyl allenes A , easily accessible from ketoesters, 6 when treated with an anionic nucleophilic catalyst (e.g.…”