Asymmetric Synthesis of 3,4,6‐Trisubstituted 2,5‐Diketopiperazines by Using Dynamic Kinetic Resolution of α‐Bromo Tertiary Acetamides

Baek, Jinho; Kang, Seock Yong; Im, Chan; Park, Yong Sun

doi:10.1002/ejoc.201301936

Cited by 6 publications

(3 citation statements)

References 43 publications

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“…(Experimental procedures for the preparation of 1, 12, 13, 14, 15, 32, 33 and 34 were described in previous publications. 14 …”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the syntheses of tetrasubstituted diketopiperazines require either multistep sequences or harsh conditions and they are inefficient for asymmetric synthesis. [7][8][9][10][11][12][13] As an extension of our previous work on the asymmetric preparation of 3,4,6-trisubstituted 2,5-diketopiperazines, 14 we herein report a mild and versatile synthetic method for the asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines via one-pot substitution-cyclization of α-bromo tertiary acetamides ( Figure 1). access to diverse highly functionalized diketopiperazines.…”

Section: Introductionmentioning

confidence: 99%

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Convenient asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines

Lee¹,

Baek²,

Youk³

et al. 2016

Arkivoc

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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.

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“…(Experimental procedures for the preparation of 1, 12, 13, 14, 15, 32, 33 and 34 were described in previous publications. 14 …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Convenient asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines

Lee¹,

Baek²,

Youk³

et al. 2016

Arkivoc

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“…The inversion of dr for proline-based substrates compared to other amino acids was previously reported for the 2,5-diketopiperazine system. 11,12 Finally, the addition performed on seven-membered rings 5k and 5l led to the corresponding hemiaminals 6k and 6l in still good yields (62 and 55%, respectively) but with a lower dr (37 : 63), likely due to greater flexibility of the seven-membered ring. 13 As aforementioned for 6h and 6j, the X-ray diffraction analysis of 6l revealed that the major isomer was the C9-C2 cis-isomer.…”

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confidence: 98%

Diastereoselective synthesis of novel aza-diketopiperazines via a domino cyclohydrocarbonylation/addition process

et al. 2014

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Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino acids. The strategy is based on a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry.

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

Lee

Kim

Youk

et al. 2016

Bulletin Korean Chem Soc

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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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Asymmetric Synthesis of 3,4,6‐Trisubstituted 2,5‐Diketopiperazines by Using Dynamic Kinetic Resolution of α‐Bromo Tertiary Acetamides

Cited by 6 publications

References 43 publications

Convenient asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines

Convenient asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines

Diastereoselective synthesis of novel aza-diketopiperazines via a domino cyclohydrocarbonylation/addition process

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

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