Visible Light‐Mediated Synthesis of Enantiopure γ‐Cyclobutane Amino and 3‐(Aminomethyl)‐5‐phenylpentanoic Acids

Abstract

A visible light-mediated [2 + 2] photocycloaddition of amide-linked dienes using [Ir(dtbbpy)(dF(CF 3 )ppy) 2 ]PF 6 as triplet sensitizer was applied to generate a variety of N-tert-butyl, Nbenzyl-and N-tert-butoxycarbonyl-protected 3-azabicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2 + 2] photocycloaddition. The bicyclic key structures could be readily transformed into g-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobutane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant, is described.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…It was shown that dienes 101 undergo the cycloaddition upon UV irradiation with λ max = 366 nm, which provided the possibility for performing the reaction in common glassware. [460] Furthermore, such transformations could be promoted by visible light using flavin- [461] or iridium-based [462][463][464] photosensitizers. An alternative version of this approach was based on the intramolecular [2 + 2] cycloaddition of allenes; it could be performed in an enantioselective version.…”

Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity

“…Serendipitously and somewhat surprisingly, it was found that treatment of 7e with LiOH led to the selective and quantitative removal of a Boc-group rather than ring opening to provide tetracycle 7g , which could not be accessed directly from the [2 + 2] cycloaddition. Indeed, attempts at ring opening the pyrrolidinone of both 7c and 7e to their corresponding γ-amino acids under both basic and acidic conditions were unsuccessful . These tetracycles ( 7c and 7e ) showed remarkable chemical stability and no ring opening was observed under a range of reaction conditions at 100 °C.…”

Photocatalyzed Intramolecular [2+2] Cycloaddition of N‐Alkyl‐N‐(2‐(1‐arylvinyl)aryl)cinnamamides

“…Based on our findings and on previous studies by Reiser and Kwon, [16, 18] the mechanistic considerations for the reaction are shown below in Scheme 4. We also considered a strong dependence between the reaction outcome and conformation adopted by the aryl‐cinnamide, since the rotational barriers around the amide (15–20 kcal mol −1 ) and the ( ortho ‐substituted) Ar‐N (∼20–30 kcal mol −1 ) bonds need to be overcome to achieve a conformation, in which the olefin moieties are close enough to react (Scheme 4, centre) [23] .…”