The first enantioselective total synthesis of (+)-preussin B and an improved synthesis of (+)-preussin by step-economical methods

Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions

“…The relative configuration of the products has been attributed based on NOE difference spectra and by analogy to literature precedents. 6,7,21,22 In the case of 18, the corresponding substituted pyrrole side product 19 was also isolated.…”

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (−)-Preussin B, and 3-Deoxy-(+)-preussin B

“…Hydrolysis of 68 gave ketone 69 in 58% isolated yield, and hydrogenolysis of 69 gave an 85:15 mixture of two compounds, assigned as the C(5)-epimeric pyrrolidines 70 and 71 ; hydrogenation of this mixture in the presence of aqueous formaldehyde gave an 85:15 mixture of pyrrolidines 72 and 73 , with purification giving the major product 72 in 75% yield (from 69 ), although only an impure sample of 73 was isolated. In this instance, the spectroscopic data of 72 matched perfectly with those reported for the sample of (+)-preussin B isolated from the natural source by Igarashi et al and those of the synthetic sample prepared by Huang et al Furthermore, the specific rotation value of our sample of 72 {[α] D 25 +22.9 ( c 1.0 in CHCl 3 )} was also in excellent agreement with the values reported for these samples {Igarashi et al report [α] D 26 +22 ( c 0.19 in CHCl 3 ) for the sample isolated from the natural source; Huang et al report [α] D 26 +23.1 ( c 0.19 in CHCl 3 ) for their synthetic sample}. On this basis, the configurations of all the intermediates 64 and 68 − 71 , as well as the regiochemistry of monomesylate 60 , could be confidently inferred, and 73 was therefore identified as the C(5)-epimer of (+)-preussin B (Scheme ).…”

“…These desirable biological properties, together with the unique structure (“all- cis ” relative configuration of the three substituents at the stereogenic centers around the pyrrolidine ring) of (+)-preussin, quickly made it a popular target for synthesis: the first total synthesis of (+)-preussin was reported in 1991 (starting from d -glucose), and to date, more than twenty five different routes to (+)-preussin have been developed. A large number of these rely on derivatization of readily available chiral pool materials: elaboration of l -phenylalanine facilitated the second synthesis of (+)-preussin that was reported, and this material (or derivatives thereof) has proven to be the most popular starting material by far in subsequent syntheses, − although (in chronological order) d -phenylalanine, d -arabinose, l -aspartic acid, l -pyroglutaminol, , l -serine, , and ( S )-malic acid , (or derivatives thereof) have also been employed as the sources of chirality. Other de novo asymmetric syntheses have been developed, − along with one formal synthesis of (+)-preussin − and two syntheses of (−)-preussin. , Moreover, the synthesis of all eight possible stereoisomers (using an enantiopure phenylalanine derivative as the starting material, proceeding via two nonselective reactions and chromatographic separation) has been reported, − as well as one synthesis of (±)-preussin. , The truncated analogue (+)-preussin B, (2 S ,3 S ,5 R )- N (1)-methyl-2-benzyl-5-(1′-heptyl)­pyrrolidin-3-ol (Figure ), was isolated [along with (+)-preussin] in 2014 from Simplicillium lanosoniveum TAMA 173 and was shown to exhibit weak antifungal activity .…”

“…Other de novo asymmetric syntheses have been developed, − along with one formal synthesis of (+)-preussin − and two syntheses of (−)-preussin. , Moreover, the synthesis of all eight possible stereoisomers (using an enantiopure phenylalanine derivative as the starting material, proceeding via two nonselective reactions and chromatographic separation) has been reported, − as well as one synthesis of (±)-preussin. , The truncated analogue (+)-preussin B, (2 S ,3 S ,5 R )- N (1)-methyl-2-benzyl-5-(1′-heptyl)­pyrrolidin-3-ol (Figure ), was isolated [along with (+)-preussin] in 2014 from Simplicillium lanosoniveum TAMA 173 and was shown to exhibit weak antifungal activity . The first and, to date, the only synthesis of (+)-preussin B to be reported is that of Huang et al, who employed ( S )-malic acid as their starting material . Herein, we report the development of a de novo asymmetric synthesis of (+)-preussin B, and also report for the first time the preparation of the C(2)-epimer of (−)-preussin B, the C(3)-epimer of (+)-preussin B, and the C(3)-deoxy derivative of (+)-preussin B.…”

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

“…When the O -protected ester 163b was subjected to methylation and the corresponding aziridinium ion was treated with phenylmagnesium bromide a regioselective opening of the aziridine ring occurred at the less substituted carbon atom to give the protected pentanoate (3 S ,4 S )- 166 . After catalytic debenzylation it was transformed into a silylated (4 S ,5 S )-5-benzyl-4-hydroxy-1-methylpyrrolidin-2-one 167 , a molecule having a structural core of antifungal (+)-preussin [98].…”