Enantioselective Synthesis of a 2,3,4-Trisubstituted Pyrrolidine from 1-Hydroxymethyl-4-phenylsulfonylbutadiene

Abstract

A chiral 2,3,4-trisubstituted pyrrolidine glycosidase inhibitor has been obtained from 1-hydroxymethyl-4-sulfonylbutadiene.As part of a program seeking to exploit the reactivity of 1-hydroxymethyl-4-sulfonylbutadienes in the synthesis of oxygen and nitrogen heterocycles we have prepared a chiral 2,3,4-trisubstituted pyrrolidine, 9, recently synthesized by several groups for its glycosidase inhibitor activity. 1 1,3-dienes with a sulfone or sulfoxide group have been the object of study of many research groups in recent years. 2 In our case we want to exploit the presence of an allylic alcohol that opens the door to enantioselective syntheses.The versatility of this kind of compound is illustrated in Scheme 1. Scheme 1In previous work we have reported the synthesis of isosorbide analogues that exploit the chemo-and enantioselective epoxidation of a sulfonylbutadiene and the reactivity towards electrophiles of the a position of the resultant vinyl sulfone. 3 In the work reported in this paper we wished to investigate the possibility of performing, in a one pot reaction, an S N2 displacement at an appropriately activated hydroxymethyl group and a Michael addition to the vinyl sulfone. With a nitrogen nucleophile, this methodology was expected to give pyrrolidines in chiral form, the enantiomer being accessed depending upon the Sharpless conditions. The presence of these pyrrolidines in natural and pharmaceutical products with interesting biological activities, 1,4 and their use as conformationally constrained amino acid analogues 4b , makes them interesting targets, and this procedure provides a versatile method for their synthesis. The retrosynthetic analysis for 9 is shown in Scheme 2. Scheme 2As can be appreciated, the trans stereochemistry in the D 2 double bond of 1 will lead to the trans epoxide and thus frustrate any attempt at direct cyclization of 2 or derivatives such as 3. It is necessary to change this configuration in order to produce the required ring. This was done by the Wershofen-Scharf procedure 5 -treatment of the tosyl epoxide 3 with AlCl 3 in acetone -which in one step gave the required stereochemistry and protection of the two hydroxy groups (Scheme 3).Scheme 3 a) Sharpless, L(+)-DET, 85%; b) TsCl, Py., 80%; c) AlCl 3 , acetone, 65%; d) BnNH 2 , MeOH, Et 3 N, 78%; e) H 2 , Pd/C, MeOH, 95% Downloaded by: East Carolina University. Copyrighted material.

Chemistry of sulfones: synthesis of a new chiral nucleophilic catalyst

“…10,11 In contrast, all attempts to use this methodology with 4-aminopyridine and vinylsulfone 3 failed to give any of the desired product. Therefore, we decided to use the coupling of a pyrrolidine to a pyridine.…”

1-Hydroxymethyl-4-phenylsulfonybutadiene, a Versatile Building Block for the Synthesis of 2,3,4-Trisusbtituted Tetrahydrothiophenes

“…Other polyhydroxylated chiral thiolanes have been obtained by introduction the thiol group by conjugate addition, followed by internal displacement of a sulfonyloxy group [7]. This tandem reaction has been used by us in the synthesis of pyrrolidines such as 5 [4]. In order to apply the same methodology for the synthesis of tetrahydrothiophenes, we decided to react 3 with sodium sulfide under the usual conditions, thus obtaining the tetrahydrothiophene 7 in low yield (8%).…”

“…The reaction mixture was then diluted with 100 mL of Et 2 O and 2 M HCl (1.5 mL). After stirring for 1h the mixture was dried over Na 2 SO 4 To a solution of 10 (37 mg, 0.12 mmol) in DCM (1.5 mL) was added PPh 3 (31 mg, 0.12 mmol) and CBr 4 (40 mg, 0.12 mmol). The mixture was heated at 50ºC for 12 h under an argon atmosphere.…”

“…This interest is also due to the use of such molecules for understanding the recognition processes of sugar-binding proteins [3]. Our group is involved in a program seeking to exploit the reactivity of 1-hydroxymethyl-4-sulfonylbutadiene for the synthesis of highly functionalized oxygen, nitrogen and sulfur five-membered heterocycles [4]. Chemo-and enantioselective epoxidation of 1-hydroxymethyl-4-sulfonylbutadiene (1), under Sharpless conditions [5] gives rise to epoxide 2.…”

Oxygenated Stereotriads with Definite Absolute Configuration by Lipase‐Mediated Kinetic Resolution: De Novo Synthesis of Imino Sugars and 6‐Deoxy‐C‐glycosides

“…The employment of stereoselective heteroDiels-Alder reactions either with chiral N-dienylpyroglutamates or with chiral p-tolylsulfinyl-1,3-pentadiene with nitrosoformates, followed by osmylation and suitable chemical transformations, afforded (2S,3R,4S)- [17] and (2S,3S,4R)-3, [18] and a derivative of the latter. [19] Compound (2S,3R,4S)-3 was also obtained [20] as a hydrochloric acid salt from 1-hydroxymethyl-4-sulfonylbutadiene, employing a Sharpless epoxidation. In 2002, [21] (2S,3S,4S)-3 was prepared by MeMgBr addition to the succinimide derived from -tartaric acid, followed by stereocontrolled triethylsilane-promoted reduction of the resulting cyclic amidol.…”