Intramolecular Tandem Michael-Type Addition/Aldol Cyclization Induced by TiCl₄−R₄NX Combinations

Abstract

[reaction: see text] Treatment of formyl alpha,beta-enones with a TiCl(4)-R(4)NX combination induces an intramolecular aldol cyclization to furnish 2-acyl-3-halocyclohexanol with three controlled consecutive stereogenic centers. The reaction of bis-alpha,beta-enones with the combination provides cyclic diketones with high stereoselectivity via an intramolecular Michael addition reaction.

TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study

“…The goal of this work was to gain an insight into the mechanism of the entire trimolecular process, with particular regard to the Michael addition of step (3). Although the use of Ti(IV) in Michael-type reactions has been known for almost forty years 12 with important applications in organic synthesis, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] the number of mechanistic studies on such reactions is limited. [18][19][20][21][22][23][32][33][34][35][36][37][38][39] This study might contribute to elucidation of the trimolecular Scheme 1 TiCl 4 -promoted trimolecular condensation.…”

Enantioselective, Organocatalytic Morita-Baylis-Hillman and Aza-Morita-Baylis-Hillman Reactions: Stereochemical Issues

“…The standard reactions typically require bulky, conformationally rigid, basic tertiary amines such as quinuclidines [ 11 , 12 , 13 ], though DBU [ 14 ], DMAP [ 15 ], imidazoles [ 16 ], guanidine [ 17 ], or even heterocyclic carbenes [ 18 , 19 ] or nucleophilic phosphines [ 20 , 21 ] acting as Lewis base catalysts [ 22 ] have been used as well for promoting the condensation of an؟ α,β-unsaturated systems (aldehydes, ketones, esters, nitriles, amides, phosphonates, sulphonates, sulfones, sulfoxides or nitro compounds have been employed) with either the C=O functionality present in aldehydes, ketones or α-keto esters for the case of MBH reactions, or with the C=N moiety of N -sulfonyl, N -acyl, N -phosphinoyl, and N -alkoxycarbonyl imines in the case of aza-MBH reactions. The products are densely functionalized small molecules whose basic skeleton is that of a chiral, cyclic, or acyclic, α-methylene-β-hydroxycarbonyl, or α-methylene-β-aminocarbonyl, compound for MBH [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ], or aza-MBH reactions [ 32 , 33 , 34 , 35 ], respectively. Both skeletons have attracted great synthetic interest, especially when derived from prochiral C=O or C=N funcionalities since enantioselective versions could then be designed ( Scheme 1 ).…”

Formal Synthesis of Merrilactone A Using a Domino Cyanide 1,4-Addition–Aldol Cyclization

“…Previous work in our group established the iodo-aldol reaction as a useful protocol for the synthesis of highly hindered vic -quaternary and tertiary alcohol stereocenters. , Compound 5 , for example, undergoes treatment with iodide and TiCl 4 to afford the cyclopentane 6 in good yield and excellent selectivity for the trans diastereoisomer.…”