N‐Benzoyl‐L‐threonine‐isopropyl‐ester‐mediated crystallization‐induced dynamic resolution (CIDR) of configurationally labile α‐bromo arylacetates has been investigated. The CIDR was successfully used for the asymmetric preparation of these compounds with up to 98:2 dr, under solution and solvent‐free conditions. Subsequent nucleophilic substitution reactions with sulfur and oxygen nulceophiles gave α‐thio and α‐oxy arylacetates with up to 98:2 dr. The method was further developed for the preparation of highly enantioenriched 2‐phenylthio‐2‐arylethanols with up to 97:3 er, and 1,4‐benzoxazin‐3‐ones with up to 94:6 er.

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...

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Tri‐ and tetrasubstituted diketopiperazines are synthesized by cyclization reaction of α‐bromo tertiary acetamides bearing a sterically bulky N‐alkyl group in high stereoselectivity.

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A general and efficient method was developed for the asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines. The asymmetric nucleophilic substitution of L-amino acid-derived α-bromo tertiary amides with aliphatic primary amines followed by spontaneous cyclization provides a rapid access to diverse 1,3,4,6-tetrasubstituted-2,5-diketopiperazines with high diastereoselectivities of up to 99:1 dr.