Toward Enantiomerically Pure β-Seleno-α-amino Acids via Stereoselective Se-Michael Additions to Chiral Dehydroalanines

Abstract

The first totally chemo-and diastereoselective 1,4-conjugate additions of Se-nucleophiles to a chiral bicyclic dehydroalanine (Dha) are described. The methodology is simple and does not require any catalyst, providing exceptional yields at room temperature and involves the treatment of the corresponding diselenide compound with NaBH4 in the presence of the Dha. These Se-Michael additions provide an excellent channel for the synthesis of enantiomerically pure selenocysteine (Sec) derivatives, which pose high potential for chemical biology applications. ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.XXXX. Experimental procedures, characterization data, and copies of the NMR spectra (PDF). Crystallographic data (CIF)

Towards Enantiomerically Pure Unnatural α-Amino Acids via Photoredox Catalytic 1,4-Additions to a Chiral Dehydroalanine

“…In all adducts 3a , 3a – D , and 3b , the absolute configurations of the new stereogenic centers created in the 1,4-conjugate additions were assessed by two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) experiments and confirmed, in the case of 3b , by X-ray crystallography (SI). In view of these results, the reaction mechanism is hypothesized to be similar to that proposed for S - or Se -nucleophilic 1,4-additions to Dha 1 . The stereochemical outcome of these Michael reactions to Dha 1 suggests a conserved stereoinduction mechanism for the protonation of the enolate adduct formed after conjugate addition (SI).…”

“…First, we assayed the 1,4-conjugated addition of some carbanions, generated in situ from their corresponding precursors, to Dha 1 as a Michael acceptor, following our protocol described for S -, N -, or Se -nucleophiles . However, the scope was very limited (SI) because we only achieved good results with diethyl malonate 2a and a chiral bicyclic serine derivative 2b .…”

“… 7 However, only very few cases have been reported to obtain enantiopure UAAs or their precursors, 8 allowing the incorporation of different alkyl or aryl radicals at β-carbon, and most of them involved the use of a modified chiral Dha termed Karady–Beckwith alkene. 9 Hence, inspired by these works and following the methodology established by our group, 10 we envisioned the synthesis of enantiopure UAAs by using our 2nd-generation chiral Dha 1 as the starting material in both anionic carbon nucleophilic 1,4-attack and radical carbon photoredox catalytic 1,4-conjugate addition ( Scheme 1 ).…”

Stereoselective α-Deuteration of Serine, Cysteine, Selenocysteine, and 2,3-Diaminopropanoic Acid Derivatives

“…The reaction involves the formation of a chiral, slightly pyramidalized enolate, which reacts diastereoselectively with different electrophiles such as alkyl halides or Michael acceptors . More recently, chiral bicyclic dehydroalanine equivalent 4 has been reported as a versatile Michael acceptor reacting with diverse heteronucleophiles under mild conditions to form derivatives of cysteine, , selenocysteine, and 2,3-diaminopropanoic acid . We envisioned using deuterium as an electrophile to trap enolates formed from deprotonation of 1 in the presence of a base and from 4 upon nucleophile addition to selectively install a deuterium atom at the α position of amino acids.…”

“…We have recently reported a selective 1,4-conjugate addition of Se-nucleophiles to chiral dehydroalanine ent-4 as a methodology for the synthesis of selenocysteine (Sec) derivatives . Sec is the 21 st proteinogenic amino acid and is often present in enzymes, being usually pivotal for their catalytic efficiencies .…”