Stereoselective Nucleophilc Substitution of α‐Bromo Tertiary Amides for Asymmetric Synthesis of Highly Substituted 2,5‐Diketopiperazines

Abstract

The diketopiperazine core is an important scaffold in medicinal chemistry and drug discovery. Diketopiperazines bearing diverse substituents can exhibit numerous medicinally relevant properties such as antifungal, antibacterial, antitumor, and antiviral activity. 1 Therefore, asymmetric synthesis of highly substituted diketopiperazine is an interesting research area of organic synthesis. 2 In our previous report regarding the asymmetric preparation of 3,4,6-trisubstituted 2,5-diketopiperazines, the dynamic kinetic resolution of L-amino acid-derived α-bromo tertiary acetamides 1 and 5 in the nucleophilic substitution with p-anisidine afforded highly diastereoenriched dipeptide analogs 7 and 11, respectively, and subsequent deprotectioncyclization process afforded 3,4,6-trisubstituted 2,5-diketopiperazines. Starting from L-proline-derived α-bromo acetamide 1, trans-configured 2,5-diketopiperazine 13 was selectively synthesized with 99:1 diastreomeric ratio (dr), whereas cis-configured 2,5-diketopiperazine 14 was selectively synthesized with 97:3 dr from N-benzyl substituted α-bromo tertiary amide 5. 2e Toward better understanding of the effect of the N-alkyl group (R 1 ) on the reversed stereochemical outcome, herein, we investigated the reactions of four N-(α-bromo-α-phenylacetyl)-L-alanine methyl esters 2, 3, 4, and 6 bearing different N-alkyl groups (R 1 ). The reactions of 2 (R 1 = H), 3 (R 1 = CH 3 ), 4 (R 1 = n-Bu), and 6 (R 1 = Me 3 SiCH 2 ) with p-anisidine (1.2 equiv), tetra-butylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH 3 CN for 20 h at room temperature afforded the corresponding dipeptide analogs 8, 9, 10, and 12 with stereoselectivities of 90:10, 61:39, 15:85, and 1:99 drs (αR:αS), respectively (Scheme 1). The absolute configurations of the α-position of 8, 9, 10, and 12 were determined by comparing the 1 H NMR spectrum of the authentic dipeptide derivatives prepared from commercially available L-alanine and (S)-or (R)-phenylglycine. 3 The brief investigation of the N-substituents (R 1 ) indicates that the subtle N-alkyl group modifications can reverse the stereoselection. Although the reactions of α-bromo tertiary acetamides 1, 2, and 3 afforded (αR)-products as the major products, that of N-n-butyl substituted α-bromo tertiary acetamide 4 afforded (αS)-10 as the major diastereomer with 15:85 dr. The more sterically demanding benzyl and trimethylsilylmethyl groups showed much higher selectivities favoring (αS)-11 and (αS)-12 as the major products. The steric bulk of the N-alkyl group (R 1 ) may induce changes in the amount of cis-rotamer and the major transition-state structure of the substitution, favoring the (αS)-product. 4 As shown in Table 1, trisubstituted 2,5-diketopiperazine 14 was prepared from dipeptide 11 in 56% yield with 97:3 dr by removing the p-methoxyphenyl group using the reported method with trichloroisocyanuric acid (TCCA) and subsequent cyclization. 2e To improve this two-step process, we envisaged a novel synthetic method for trisubstit...

The Fascinating Chemistry of α‐Haloamides

“…However, the less sterically demanding amine nucleophile reacted with the N ‐Bn α‐bromo phenylacetyl L ‐AlaOMe A affording the 2( S ),5( S )‐disubstituted diketopiperazine B with 98 : 2 dr (Scheme ). Thus, the switching from secondary to tertiary amides ( N ‐Bn derivatives) favored the (α S )‐selectivity in the αC−N bond forming step …”

“…Among them, α‐haloamides have been attracting increasing attention in view of their high reactivity as building blocks for the preparation of a variety of intermediates for the synthesis of biologically active molecules and pharmaceuticals. These compounds are used as starting materials for the preparation of a myriad of compounds including α‐, β‐ and γ‐lactams, dioxopiperazines,– 2,5‐dioxopyrrolidines, oxazolidinones,– thiazolidin‐4‐ones, tetramic acids,– glycoside amides, and peptidomimetics –…”