Enantioselective Allylation of Thiophene‐2‐carbaldehyde: Formal Total Synthesis of Duloxetine

Abstract

Abstract:The enantioselective allylation of thiophene-2-carbaldehyde with allyltrichlorosilane under Lewis base catalysis has been studied. The use of catalytic amount (1 mol%) of chiral bipyridine N,N'-dioxides provided the corresponding 1-(thiophen-2-yl)-but-3-en-1-ol with asymmetric induction reaching 97% ee. The prepared chiral (S)-1-(thiophen-2-yl)-but-3-en-1-ol was used as the crucial chiral building block in a formal total synthesis of duloxetine.

Chiral Unsymmetrically Substituted Bipyridine N,N′‐Dioxides as Catalysts for the Allylation of Aldehydes

“…The results obtained for the allylation reactions of thiophenecarbaldehyde ( 11e ) were rather puzzling; they did not match those previously obtained with ( S a ,R )‐ 5 , which gave 97 % ee at 1 mol‐% (–40 °C) To shed some light on this discrepancy, further screening of allylation reactions with different amounts of catalyst ( S a ,R )‐ 5 (1–5 mol‐%) were carried out (Table ). The reactions were run for 15 h at –78 °C.…”

Heteroaromatic N-Oxides in Asymmetric Catalysis: A Review

“…Generally, for both isomers, 34a results were very good, but (aS,R)-34a worked better as a catalyst for highly enantioselective allylation of benzaldehydes, bearing electron-withdrawing as well as electron-donating groups. Slightly better yield can be observed in the case of p-substituted benzaldehydes than for m-substituted (Table 4, entries 5-9, [11][12][13][14]. A drastic decrease in the yield and asymmetric induction was observed for o-chlorobenzaldehyde (Table 4, entry 15).…”

“…Additionally, the resulting homoallylic alcohols are considered the cornerstones of organic synthesis. Mostly, they are used in the synthesis of numerous natural products as building blocks but also in the synthesis of drug candidates and other functional molecules [11][12][13][14][15][16][17]. Apart from allylation there were also reported examples of using N-oxides in the catalytic ring-opening of meso-epoxides [18][19][20][21], propargylation [22], allenylation [23], aldol reaction [24,25] and reduction of ketoimines [26,27].…”

“…Noxide catalysts were successfully applied to the synthesis of a few natural products [12][13][14][15][16][17]. For example, duloxetine, which is used in the treatment of major depression, was synthesized involving the allylation of 2-thiophenecarboxaldehyde with (aR,S)-34a as catalyst (see Scheme 7) [12]. The advantage of the N,N'-dioxide catalysts is in their rather low loading, (only 1 mol%) being sufficient to bring about the desired allylation.…”

“…The advantage of the N,N'-dioxide catalysts is in their rather low loading, (only 1 mol%) being sufficient to bring about the desired allylation. In the case of phosphorous catalyst TRIP PA, the level Allylation of 2-thiophenecarboxaldehyde using (aR,S)-34a in total synthesis of duloxetine [12].…”