Enantioselective Phase‐Transfer Catalyzed α‐Sulfanylation of Isoxazolidin‐5‐ones: An Entry to β^2,2‐Amino Acid Derivatives

Abstract

An unprecedented enantioselective α-functionalization of C4-substituted N-alkoxycarbonyl isoxazolidin-5-ones, readily available platforms from Meldrum's acid derivatives, by N-sulfanylphthalimide (PhthSR) electrophiles was achieved upon an efficient phase-transfer catalytic approach, mediated by a commercial N-spiro quaternary ammonium catalyst. Two catalytic activities of the in situ formed R N Phth species were highlighted, the phtalimidate being involved in the anion metathesis event and likely as a Brønsted base. This sequence offers a straightforward access to α,α-disubstituted isoxazolidinones, which turned out to be useful precursors of α-sulfanyl-β -amino acid derivatives.

Recent Advances in the Catalytic Asymmetric Synthesis of β2‐ and β2,2‐Amino Acids

“…α‐Functionalization of racemic isoxazolidin‐5‐ones offers a straightforward approach to β 2 ‐ and β 2,2 ‐amino acids. Although diastereoselective α‐alkylation of isoxazolidin‐5‐ones has been reported for the synthesis of β 2,2,3 ‐amino acids, the development of catalytic asymmetric variants for the synthesis of β 2,2 ‐amino acids has been underexplored . In 2018, Shibasaki disclosed catalytic asymmetric decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones 36 (Scheme ) .…”

Palladium‐Catalyzed Asymmetric Allylic Alkylation of 4‐Substituted Isoxazolidin‐5‐ones: Straightforward Access to β2,2‐Amino Acids

“…In view of these results, we envisioned that a Pd‐AAA could potentially be applied to 4‐substituted isoxazolidin‐5‐ones to afford the corresponding α,α‐disubstituted products, which could in turn be readily converted to β 2, 2 ‐amino acids after subsequent reductive N−O bond cleavage (Figure B). This method appeared all the more appealing in that the only example reported in the literature featuring the use of α‐substituted isoxazolidin‐5‐ones was limited to the synthesis of α‐sulfanyl‐β 2, 2 ‐amino acid derivatives by an enantioselective organocatalytic phase‐transfer α‐sulfanylation …”

“…This method appeared all the more appealingi nt hat the only example reported in the literaturef eaturing the use of a-substituted isoxazolidin-5-ones was limited to the synthesis of a-sulfanyl-b 2, 2 -aminoa cidd erivativesb ya ne nantioselective organocatalyticp hase-transfer asulfanylation. [16] We thus initiated our study using 4-phenylisoxazolidin-5-one 1a as am odel substrate. The latter wasp repared in four steps startingf rom diethyl malonate by ap alladium-catalyzed arylation, as aponification, the formation of the corresponding C5substituted Meldrum's acids and af ormal[ 3 + +2]-cycloaddition.…”

Exploiting β‐Amino Acid Enolates in Direct Catalytic Diastereo‐ and Enantioselective C−C Bond‐Forming Reactions

“…[10] Althoughs ubstituted isoxazolidin-5-ones have often been utilized as b-amino acid precursors, [11,12] the functionalization of 4-substituted isoxazolidine-5-ones 3 for the synthesis of all carbon quaternary b 2, 2 -amino acids has been little explored. [13] Recently,w eh ave reported the Pd-catalyzed decarboxylative allylation of 4-substitutedi soxazolidin-5-onesa nd the transformation of the resulting allylated products into various b 2, 2amino acids (Scheme 1a). [14] The products were also readily incorporated into a/b-hybrid peptidesb ys tandard Fmoc-SPPS after decarboxylative amide formation with a-ketoacids [a-ketoacid-hydroxylamine (KAHA) ligation developed by Bode].…”