Tris(trimethylsilyl)silane: an unprecedented enhancement in the diastereoselectivity of radical cyclisations to give 2,4-disubstituted piperidines

Abstract

Cyclisation of bromides 4a-f mediated by tributyltin hydride affords predominantly the trans piperidines 5a-f with modest diastereomeric ratios, while cyclisation with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99 : 1.

Thirty Years of (TMS)3SiH: A Milestone in Radical-Based Synthetic Chemistry

“…TTMSS-mediated 6- exo -trig cyclization of alkyl radicals produced from bromides 303 was also developed to access diastereomeric piperidines 304a and 304b with moderate to high level of diastereocontrol, depending essentially on the nature of the R 1 substituent in the α-position to nitrogen (Scheme ). , A 1,3 strain induced by the R 1 group is supposed to be at the origin of the diastereoselectivity, which expectedly improves as R 1 size increases. In contrast, the nature of the R 2 group on the ester has little influence on the stereocontrol.…”

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

“…When compared with O‐nucleophiles, N‐nucleophiles exhibited a decreased tendency for the second cyclization, based on the presence of as much as 24 % of enamide 13 (Table 1, entries 9 and 10). The isolation of these specific bicycles was not successful because of the formation of a complex mixture of isomers (( S )‐ 10 , ( R )‐ 10 , and 13 ) in addition to the dipeptide produced by acrolein elimination 31,41. In addition, by changing the N‐substituent of the internal nucleophile from sulfonamide (Nos) to carbamate (Alloc), only enamide 13{1,9,1,1} was formed due to decreased nucleophilicity (entry 11).…”

“…The isolation of these specific bicycles was not successful because of the formation of ac omplex mixture of isomers ((S)-10,( R)-10,a nd 13)i n addition to the dipeptide produced by acrolein elimination. [31,41] In addition, by changing the N-substituent of the internal nucleophile from sulfonamide (Nos) to carbamate (Alloc), only enamide 13{1,9,1,1} was formed duet od ecreased nucleophilicity (entry 11).…”

Stereoselective Formal Synthesis of (+)-Allokainic Acid <i>via</i> Thiol-Mediated Acyl Radical Cyclization

“…We expected that the construction of N-containing heterocycles would be realized by utilizing this cyclization reaction (Chart 1). [28][29][30][31][32][33][34][35][36] The acyl radical cyclization of N-containing cyclic formylalkenoate 1 would proceed via conformer A with the minimum 1,3-allylic strain to preferentially give trans-2, rather than via conformer B that gives cis-2.…”

“…Concentration of the filtrate and column chromatography (hexane/AcOEtϭ1/2) twice gave aldehyde 1 (4.4 g, 75%) as colorless oil: Rf 0. 35 Entry 4) A solution of aldehyde 1 (3.5 g, 17 mmol), AIBN (2.7 g, 17 mmol), and tert-dodecanethiol (38 ml, 170 mmol) in toluene (1.1 l) was heated at 70°C for 86 h. During that period, additional portions of AIBN (2.7 g, 17 mmol each) were added after 12, 36, and 60 h. Concentration of the reaction mixture and column chromatography (hexane/ AcOEtϭ1/1) of the resulting crude material gave a 10 : 1 mixture of trans-2 and 10 (1.56 g, 38% and 4%, respectively) as yellow oil and 10 (84 mg, 3%) as yellow oil. The ratio of trans-2 and 10 was determined based on the integration area of 1 H-NMR signals at 3.58 (the a-CH 2 of the ketone moiety of trans-2 in CDCl 3 ) and 2.87 ppm (NCH 3 of 10).…”