Reactions of Iminium Ions with Michael Acceptors through a Morita–Baylis–Hillman‐Type Reaction: Enantiocontrol and Applications in Synthesis

Abstract

a-Functionalization of alkenes activated by electron-withdrawing groups (EWGs) encompass an important CÀC bondforming strategy in organic synthesis, and can be realized in one of three ways: a) metal-catalyzed functionalization of ahalogeno [1] or a-metallo substrates; [2] b) a vinylogous enolization, a-alkylation, and isomerization sequence; [3] or c) nucleophilic catalysis: the Rauhut-Currier and MoritaBaylis-Hillman (MBH) reactions.[4] The MBH transformation (Scheme 1), [5] which is traditionally effected by catalytic amounts of a tertiary amine or phosphine and uses an aldehyde as the terminal electrophile, has become more recently a powerful synthetic tool with the increased scope in Michael acceptors (for example, vinyl sulfones [6a] and acrylamides [6] ) and electrophiles (for example, halides, [7a,b] epoxides, [7c] allyl carbonates, [7d] acetals, [7e-h] and aryl cation equivalents [7i] ). A class of electrophile that has received little attention is N-acyl iminium ions [8] which would lead to biologically important and highly functionalized b'-amidoa,b-unsaturated carbonyl compounds.[9] Herein, we describe our success in employing this class of substrates and also in rendering the reaction asymmetric.Initial investigations focused on the pyrrolidine 1 (PG = Cbz, m = 1; Scheme 1) and reaction conditions in which a combination of a Lewis acid (to form the iminium ion electrophile) and a weak Lewis base (to form the enolate nucleophile) were used.[10] The standard Lewis bases for the MBH reaction (phosphines and amines) were ineffective with BF 3 ·OEt 2 : use of PPh 3 resulted in a stable phosphine-iminium ion adduct [11] presumably because of the poor leaving group ability of the phosphine, [12] and pyridine caused dimerization of the pyrrolidine presumably through base-promoted enamine formation and subsequent attack on a second iminium ion.[13] In contrast, sulfides proved effective: treatment of a solution of pyrrolidine 1 and methyl vinyl ketone (MVK) with BF 3 ·OEt 2 and SMe 2 , [10a] followed by treatment of the resultant crude mixture with DBU, resulted in the isolation of the MBH-type adduct 2 a in 30 % yield. Other Lewis acid/Lewis base combinations were then investigated, namely TiCl 4 , [10c, 14]

A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B, D, and F

“…We next examined the MBH ring-closure reaction of 11. Initial investigations were focused on the solvent effect by using trimethylsilyl trifluoromethanesulfonate (TMSOTf) and Me 2 S. [11] Although the stereoselectivities were high, the chemical yields were fairly low in CH 2 Cl 2 , CH 3 NO 2 , or toluene ( Table 2, entries 1-3). Among the solvents, the use of acetonitrile afforded the best yield of the desired indolizidine 14 (entry 4).…”

“…The synthesis of 9 featured a highly stereoselective Brønsted acid mediated Morita-Baylis-Hillman (MBH) reaction via the N-acyl iminium ion. [7][8][9][10][11]…”

Brønsted Acid Catalyzed Morita–Baylis–Hillman Reaction: A New Mechanistic View for Thioureas Revealed by ESI‐MS(/MS) Monitoring and DFT Calculations

“…[11] MBH reactions are also "green" and highly atom efficient; they provide multifunctionalized derivatives have been used as for starting materials in the total syntheses of natural products, [12] heterocycles, [13] and drugs. [14] Despite the synthetic versatility, MBH reactions suffer from a serious drawback: for some substrates the reaction is very slow.…”

Asymmetric Organocatalysis

“…[31] The asymmetric epoxidation of olefins of various geometry using chiral ketones derived from d-fructose as catalysts is constantly enhanced by Yian Shi (see Figure 1).…”

“…A nitrogen-free nucleophilic catalyst is Varinder Aggarwal's chiral [2.2.1] bicyclic sulfide, synthesized from camphorsulfonyl chloride, which is a powerful catalyst in the catalytic asymmetric synthesis of epoxides [29] and aziridines, [30] and Morita-Baylis-Hillman reactions of enones with acyliminium species. [31] The asymmetric epoxidation of olefins of various geometry using chiral ketones derived from d-fructose as catalysts is constantly enhanced by Yian Shi (see Figure 1). [32] His reliable, stereopredictable method is often complementary to metal-catalyzed epoxidations and has attracted wide spread application in different total syntheses.…”