Enantiomerically Pure Bithiophene Diphosphine Oxides as Catalysts for Direct Double Aldol Reactions

Abstract

The direct aldol reaction between aryl methyl ketones with aromatic aldehydes in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine oxide was studied; the product of double aldol addition was isolated as diacetate in good diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some cases with excellent stereoselectivities.

DFT investigation on Lewis base-catalyzed Lewis acid-mediated reactions: hypervalent silicon species as chiral organocatalysts in (direct) aldol reactions

“…33 Also our group successfully extended the direct aldol condensation between carbonyls and aromatic aldehydes using the more electron-rich (S)-tetramethylbisthiophenphosphinoxide (S)-Tetra-Me-BITIOPO and its derivatives, obtaining the corresponding aldol products (6) often with higher yields and stereoselectivities compared to those observed using (S)-BINAPO. [34][35][36][37][38][39][40] In this transformation, as postulated by Nakajima and co-workers, the interaction of a ketone with the hypervalent silicon species generated by the phosphinoxide-SiCl4 coordination leads to the in situ formation of a trichloro silylenol ether. As consequence, this enol ether results activated by the phosphinoxide to react with the aldehyde, allowing the formation of the desired -hydroxy ketone.…”

Synthesis of novel chiral bithiophenebased phosphine oxides as Lewis bases in organocatalytic stereoselective reactions

“…[31] As previously reported, tetraMe-BITIOPO (6) can be employed as an efficient metal-free catalyst in many organic reactions giving often better results than when the corresponding binaphtyl analogue (S)-BINAPO (5) is employed. [15,16,25,26] The ability of tetraMe-BITIOPO to promote a reaction is related to its electronic properties; tetraMe-BITIOPO is indeed more electron rich than BINAPO because of the presence of two thiophene rings in place of the binaphthyl scaffold. This electronic difference is responsible for difference in chemical efficiency, as seen in the direct aldol addition of activated thioesters to benzaldehyde promoted by SiCl 4 (Scheme 2).…”

“…Phosphine oxides have been employed as organocatalysts in several chemical transformations including enantioselective addition of allyltrichlorosilanes to aldehydes [3][4][5], ring opening of meso-epoxides [3,[6][7][8], the Abramov-type phosphonylation of carbonyl compounds [8,9] and for the synthesis of γ-amino alcohols [10] and oxazines [11]. Furthermore, phosphine oxides are excellent catalysts for aldol reactions involving trichlorosilyl enolethers [12] and silyl ketene acetals, [13] and also for direct, cross, intermolecular, [14] and double aldol-type reactions involving aldehydes, ketones [15][16][17][18][19][20][21][22][23][24] or thioesters [25,26]. More recently, this class of compounds have found application in reductive aldol reactions in the presence of tertiary amines, [27,28] and in the Morita-Baylis-Hillman reaction [29].…”

3,3′-Bithiophene-Based Chiral Bisphosphine Oxides as Organocatalysts in Silicon-Derived Lewis Acid Mediated Reactions

“…In both cases, product 35a was isolated in good yield, high chiro:meso ratio and up to 75% ee, showing higher diastereoselectivities and comparable enantioselectivities than those observed with (S)-BINAPO (Table 5, entry 1-3). 35 Under the optimized reaction conditions (CH 2 Cl 2 as solvent, -40 °C, 20 h of reaction time) different aldehydes were reacted with acetophenone 34a in the presence of stoichiometric amounts of SiCl 4 and iPr 2 NEt. It was found that aldehydes bearing electron-withdrawing groups reacted with acetophenone in higher yields, while electron-rich aldehydes were less reactive; however, the opposite trend was observed for the enantioselectivity (entries 4-9).…”