Decarboxylative Radical Addition to Methylideneoxazolidinones for Stereocontrolled Synthesis of Selectively Protected Diamino Diacids

Abstract

Syntheses of stereochemically pure and selectively protected diamino diacids can be achieved by redox decarboxylation of distal N-hydroxyphthalimide esters of protected aspartic, glutamic or α-aminoadipic acids via radical addition to methylideneoxazolidinones. The products are useful for solidsupported syntheses of robust bioactive carbocyclic peptide analogs. Yields of reactive primary radical addition are superior to those of more stabilized radicals, and the reaction fails if the alkylideneoxazolidinone has a methyl substituent on its terminus (i.e., 13a/13b).

Photocatalytic Reductive Olefin Hydrodifluoroalkylation Enabled by Tertiary Amine Reductants Compatible with Complex Systems

“…A free Cterminal carboxylic acid also participates in the coupling, as 17 is obtained in 43% yield. Incorporation of a chiral auxiliary, for example in analogy to the recent work of Vederas, 17 is quite advantageous, as derivative 18 is obtained in 65% yield, with near total diastereoselectivity. Products lacking an α-amino substituent, but retaining a purely electron-withdrawing group, work well, with compound 19 obtained in 74% yield.…”

Photoredox Catalytic Installation of an Alkyl/Aryl Side Chain and Deuterium into (S)-Methyleneoxazolidinone: Synthesis of Enantioenriched α-Deuterated α-Amino Acid Derivatives

“…Among them, chiral methyleneoxazolidinone (the Beckwith−Karady alkene) 35 has been transformative with respect to the asymmetric synthesis of structurally diverse αamino acid derivatives showing high substrate adaptability and high diastereoselectivity in photoredox catalysis by Jui, 36,37 Guant, 38 us, 39 Goḿez-Suaŕez, 40 Shubert, 41 and Vederas. 42 In our decarboxylative synthesis of chiral α-amino acids, 39,43 we incorporated enantioselective protonation of the anion formed in situ with D 2 O to deliver α-deuterated α-amino acid derivatives (Scheme 1B1). However, the decarboxylative process with carboxylic acids was capable of engineering only aliphatic side chains.…”

“…In this context, photocatalytic redox strategies have been applied to the synthesis of amino acids − by way of de novo approaches or by introducing side chains, particularly highly branched bulky groups. Among them, chiral methyleneoxazolidinone (the Beckwith–Karady alkene) has been transformative with respect to the asymmetric synthesis of structurally diverse α-amino acid derivatives showing high substrate adaptability and high diastereoselectivity in photoredox catalysis by Jui, , Guant, us, Gómez-Suárez, Shubert, and Vederas . In our decarboxylative synthesis of chiral α-amino acids, , we incorporated enantioselective protonation of the anion formed in situ with D 2 O to deliver α-deuterated α-amino acid derivatives (Scheme B1).…”

“…Arylboronic acids as radical precursors were tested first with chiral ( S )-oxazolidinone 2 . The reaction could deliver aryl side chain-containing chiral α-amino acid derivatives, which cannot be accessed by photoredox-mediated decarboxylative approaches. − The results of the study revealed that thiomethyl-, acetamido-, and phenyl-substituted phenylboronic acid worked smoothly under the standard conditions and generated useful aromatic amino acids 3b – 3d , respectively (Scheme ). Excellent diastereoselectivity and a high level of deuterium incorporation were achieved in these cases.…”

“…We first examined primary alkylboronic acids as alkyl radical progenitors. It is noted that it has been challenging for the alkyl radicals to be generated by photoredox decarboxylative methods. − As shown in 3f and 3g , good yields and a high level of D incorporation were obtained with the protocol. Next, we probed the cyclic secondary alkyl radicals containing various rings (e.g., five-, six-, and seven-membered rings).…”