First 1,3-Dipolar Cycloaddition of Azomethine Ylides with (E)-Ethyl 3-Fluoroacrylate: Regio- and Stereoselective Synthesis of Enantiopure ­Fluorinated Prolines

Abstract

Enantiopure fluorinated prolines with four chiral centers were obtained from 1,3-dipolar cycloaddition of azomethine ylides and (E)-ethyl 3-fluoroacrylate.Nitrogen-containing heterocycles have attracted widespread attention in the field of synthetic organic chemistry as well as in medicinal chemistry. 1 In particular, the synthesis of pyrrolidines or prolines has received significant interest due to their known biological activity. 2 The 1,3-dipolar cycloaddition 3 (1,3-DC) of azomethine ylides with p-electronic-deficient olefins has emerged as a popular way for the obtainment of these heterocycles, 4 owing to its high synthetic efficiency and high regio-and stereoselectivity.It is also well known that the synthesis of organic molecules containing a stereogenic (sp 3 -hybridized) carbon atom bearing fluorine has increased greatly in the last decades, since enantiopure fluorine-containing heterocycles have shown great potential as drug candidates. 5While there is no doubt that the increasing need of structurally diverse fluorinated enantiopure heterocycles having biological relevancy calls for new synthetic strategies, few general methods to assemble enantiopure fluorinated heterocycles have been reported so far. 5a,bThe different fluorine substitution in hydroxyprolines has been recently used as probe for stereoelectronic effects in the Xaa position of collagen. 6 Furthermore, it has been demonstrated that both 3-fluoroprolines and pyrrolidines can also be used for the production of recombinant bioadhesive protein analogues. 7a These moieties have been also claimed as bactericides when incorporated in quinolone carboxylic acid based structures. 7bTo the best of our knowledge, no methods for the direct formation of fluorinated enantiopure prolines using 1,3-DC have been reported in the literature. Scheme 1 1,3-DC of 1 with chiral azomethine ylides Following our interest for the [3+2] cycloaddition of 1,3-dipoles with fluorine-containing dipolarophiles 8 we report herein the 1,3-DC of stabilized chiral N-metalated azomethine ylides with the F-containing p-deficient alkene (E)-ethyl 3-fluoroacrylate 9 (1) for the synthesis of enantiopure fluorinated prolines (Scheme 1).According to the Scheme 1 this approach should allow a general entry to fluorinated pyrrolidines/prolines having up to four chiral centers giving a satisfactory control of the regio-and stereochemistry of the final heteroycles. We decided to use a chiral auxiliary incorporated into the aimino esters in order to obtain in situ the chiral enantiopure azomethine ylides. 3aThus, a solution of the NHBoc glycine was esterificated with L-menthol under mild conditions with DCC, DMAP in CH 2 Cl 2 to give the ester in 86% yield and the removal of the Boc with TFA gave the free amine 2 in quantitative yield (Scheme 2). 10 We next prepared the a-imino esters 3a,b which were obtained after condensation of 2, with yields ranging between 86% and 90%, with two aromatic aldehydes (Scheme 2). 11Then we examined the conditions required for the cycloaddition of 1 with th...

Synthesis of Menthol Glycinates and Their Potential as Cooling Agents

“…1 (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-Aminoacetate (4). 12 Into a cooled (−78 °C) round-bottom flask, ammonia (ca. 2 mL, 80 mmol) is condensed and NaOH (0.5 g, 12.5 mmol) is added to the flask.…”

“…200 °C at 1 mm). 1 (12). Using the general procedure for 1°amines, (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2bromoacetate (2) is reacted with isopentylamine to provide methyl glycinate 12 in 90% yield as a clear oil (bp, ca.…”