Sulfahydantoins as Tripeptide Constraints: Synthesis and Structure of Chiral Substituted 3-Oxo-1,2,5-thiadiazolidine 1,1-Dioxides

Abstract

A sulfahydantoin (3‐oxo‐1,2,5‐thiadiazolidine 1,1‐dioxides) motif is used as a new type of peptidic constraint to lock two consecutive amide nitrogens by a sulfonyl bridge. The 5‐membered heterocyclic motif was prepared starting from proteogenic and synthetic amino acids and chlorosulfonyl isocyanate. Constrained dipeptides were obtained under alkaline conditions (methoxide or tert‐butoxide) by cyclization of symmetric and dissymmetric sulfamides. The absolute configuration of the chiral centers for the derivative L‐Phe‐D‐Ala, a congener of the series, was established by X‐ray diffraction crystallographic analysis. In addition, the chemo‐, regio‐, and stereoselectivities of the reactions were studied. In the acylated derivatives, the sulfahydantoin constraint induces a unique backbone conformation with coplanarity of two consecutive peptide bonds.

Titanium-Mediated Diastereoselective Formation of (E)- or (Z)-2-Substituted 1-Vinylcyclopropanols: Scope and Limitation, Applications

“…H 2 O 2 , O°C) [52] of (Z)-69 produced a 78% yield of the single (Z)-azido acid 70a (RϭOH), while basic ozonolysis (O 3 , NaOH, MeOH/CH 2 Cl 2 , 78°C), [57] on the other hand, gave an 80% yield of a 84:16 mixture of azido esters (Z)-and (E)-70b (R ϭ OMe). However, RuO 4 -mediated (RuCl 3 , NaIO 4 ) double bond cleavage of (Z)-69 produced the corresponding cyclopropanecarboxaldehyde (Z)-70c (R ϭ H), [55] which upon further oxidation (NaClO 2 , NaH 2 PO 4 , tBuOH, 2-methylbut-2-ene) [58] also furnished the azido acid (Z)-70a in 85% yield. Finally, reduction of cyclopropylazide (Z)-70a [HS(CH 2 ) 3 SH, NEt 3 /MeOH] [59] and ion-exchange chromatography provided the (Z)-methanobishomo serine 71a (Y ϭ CH 2 OH).…”

“…However, oxidative cleavage (RuCl 3 /NaIO 4 ) of the prop-1-enylic double bond of (Z)-65a did not furnish the corresponding cyclopropanecarboxylic acid as reported from (1R,2S)-2-methyl-1-styrylcyclopropylamine, [10] but gave (Z)-N-tert-butyloxycarbonyl-2-ethylcyclopropanecarboxaldehyde in 97% yield, as recently observed for oxidation of such propenyl derivatives (Scheme 15). [55] Scheme 15. Synthesis of (Z)- 1-vinylcyclopropylamines In order to avoid the formation of volatile cyclopropylamines, the cyclopropylazide (Z)-64a could first be subjected to selective ozonolysis (O 3 , AcOH, HCO 2 H; aq.…”

Synthesis of New Fused Benzothiadiazepines and Macrocyclic Sulfamides Starting from N,N-Disubstituted Sulfamides and N(Boc)-Sulfamides

“…Our earlier studies involved the synthesis of heterocyclic compounds containing sulfonyl groups [9, 10, 15, 16]. Chlorosulfonyl isocyanate (CSI) and sulfuryl chloride (SO 2 Cl 2 ) have been shown to be versatile reagents in the synthesis of heterocyclic chemistry.…”

“…The synthesis of the compounds, starting from CSI, tert -butyl alcohol and methyl esters of amino acids (L-alanine 2j and L-phenylalanine 2 h) has been previously reported [9, 10]. …”

“…In addition, some cyclic sulfamide derivatives have been reported as nonhydrolyzable peptidomimetics [5, 6], metalloprotease inhibitors [7], and constrained peptides [8–10]. …”