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Total synthesis of the putative structure of the proposed Banyasin A.

Gao X, Ren Q, Choi S, Xu Z, Ye T - Front Chem (2015)

Bottom Line: The first total synthesis of four possible isomers of a molecule possessing the configuration proposed for Banyasin A is described.The structure synthesized appears to be different from that of the natural product.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School Shenzhen, China.

ABSTRACT
The first total synthesis of four possible isomers of a molecule possessing the configuration proposed for Banyasin A is described. The structure synthesized appears to be different from that of the natural product.

No MeSH data available.


Completion of the total synthesis of banyasin A (1).
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Figure 7: Completion of the total synthesis of banyasin A (1).

Mentions: With the critical amoa fragment in hand, we then turned our attention to the assembly of the remaining amino acids to a tetrapeptide and further elaboration to the linear precursor 3. Thus, the 2-(trimethylsilyl)-ethoxycarbonyl (Teoc) protecting group was installed on the the alpha amino group of N-δ-Cbz-L-ornithine to afford the orthogonally protected ornithine 5 in 81% yield, which underwent a HATU-mediated coupling reaction with N-methyl-L-phenylalanine methyl ester (6) to provide dipeptide 24 in 59% yield (Figure 6) (Carpino, 1993). Saponification of the methyl ester of 24 produced the corresponding acid, which was then condensed with aspartate 7 in the presence of HATU and triethylamine to provide tripeptide 25 in 83% yield. Tripeptide 25 was submitted to catalytic hydrogenation to remove the benzyl protecting group, and the guanidine function was introduced by reaction with 1,3-di-Boc-2-(trifluoromethanesulfonyl)guanidine (26) (Feichtinger et al., 1998) to give 27 in 91% yield. Tripeptide 27 was further elongated to tetrapeptide 28 in 61% yield by a two step sequence, involving (1) hydrolysis of the methyl ester to its free acid, and (2) HATU-mediated condensation of the acid with L-alanine 9-fluorenylmethyl ester (8). This set the stage for the introduction of the 3-amino-2-methyl-5E-octenoic acid 4 to complete the synthesis of linear precursor 3. In the event, the Teoc protecting group of 28 was removed in one step using TBAF in THF to provide the corresponding free amine. Unfortunately, condensation of this amine with acid 4a using various coupling agents, including HATU, PyAOP, DCC and EDCI, turned out to be relatively slow and led to the formation of 3a with significant epimerization at the center adjacent to the newly formed amide carbonyl. In general, formation of 20–35% of undesired epimer could be observed during the coupling reaction depending on the reagent employed. We speculated that the conformation of the tetrapeptide 28 may significantly affect the reactivity of the amine and resulted in a slow condensation reaction. Despite this significant setback to our synthetic plan toward banyasin A, we sought that to install the 3-amino-2-methyl-5E-octenoic acid unit (4 or its masked form 22) to the peptide at earlier stage might avoid epimerization of the C2-methyl group. Gratifyingly, HATU-mediated coupling reaction of azido acid 22a with the amine derived from tripeptide 27 afforded 29a in 93% yield. That no epimerization had occurred during this coupling reaction was confirmed by synthesizing the corresponding epimeric material through the condensation of the same amine with azide acid 22c. Saponification of the methyl ester of 29a and subsequent condensation of the resultant acid with L-alanine 9-fluorenylmethyl ester (8) afforded 30a in 82% yield. Of the various reduction protocols that were examined for converting azido acid 30a into the corresponding amine, the Staudinger reduction with PMe3 in THF:H2O (7:1) proved the most successful. In the event, the Staudinger reduction of the azide and the cleavage of 9-fluorenylmethyl ester with aqueous NH4OH were carried out in a one-pot procedure to afford the resultant amino acid, which was immediately activated by diethyl cyanophosphonate (DEPC) (Yamada et al., 1973) in the presence of collidine to afford cyclopeptide 2a in 56% yield over two steps. Simultaneous removal of the tert-butyl ester and Boc-protecting group was achieved by treatment of 2a with trifluoroacetic acid in dichloromethane at room temperature. The guanidino group of the resultant cyclopeptide was mono-acylated with N-succinimidyl N-methylcarbamate (31) in the presence of DBU to afford banyasin A 1a in 66% yield. (Dixon et al., 2005) Having one diastereomer (1a), and a practical route to bayansin A in hand, we set out to pursue total syntheses of the other three possible diastereomers. This was readily achieved by following the same synthetic procedure as for 1a, by employing azido acids 22b, 22c, and 22d as key building blocks. These syntheses proceeded smoothly under the previous conditions to give rise to three diastereomers of banyasin A, 1b, 1c, and 1d in 28, 27, and 30% overall yield from tripeptide 27 (Figure 7).


Total synthesis of the putative structure of the proposed Banyasin A.

Gao X, Ren Q, Choi S, Xu Z, Ye T - Front Chem (2015)

Completion of the total synthesis of banyasin A (1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362330&req=5

Figure 7: Completion of the total synthesis of banyasin A (1).
Mentions: With the critical amoa fragment in hand, we then turned our attention to the assembly of the remaining amino acids to a tetrapeptide and further elaboration to the linear precursor 3. Thus, the 2-(trimethylsilyl)-ethoxycarbonyl (Teoc) protecting group was installed on the the alpha amino group of N-δ-Cbz-L-ornithine to afford the orthogonally protected ornithine 5 in 81% yield, which underwent a HATU-mediated coupling reaction with N-methyl-L-phenylalanine methyl ester (6) to provide dipeptide 24 in 59% yield (Figure 6) (Carpino, 1993). Saponification of the methyl ester of 24 produced the corresponding acid, which was then condensed with aspartate 7 in the presence of HATU and triethylamine to provide tripeptide 25 in 83% yield. Tripeptide 25 was submitted to catalytic hydrogenation to remove the benzyl protecting group, and the guanidine function was introduced by reaction with 1,3-di-Boc-2-(trifluoromethanesulfonyl)guanidine (26) (Feichtinger et al., 1998) to give 27 in 91% yield. Tripeptide 27 was further elongated to tetrapeptide 28 in 61% yield by a two step sequence, involving (1) hydrolysis of the methyl ester to its free acid, and (2) HATU-mediated condensation of the acid with L-alanine 9-fluorenylmethyl ester (8). This set the stage for the introduction of the 3-amino-2-methyl-5E-octenoic acid 4 to complete the synthesis of linear precursor 3. In the event, the Teoc protecting group of 28 was removed in one step using TBAF in THF to provide the corresponding free amine. Unfortunately, condensation of this amine with acid 4a using various coupling agents, including HATU, PyAOP, DCC and EDCI, turned out to be relatively slow and led to the formation of 3a with significant epimerization at the center adjacent to the newly formed amide carbonyl. In general, formation of 20–35% of undesired epimer could be observed during the coupling reaction depending on the reagent employed. We speculated that the conformation of the tetrapeptide 28 may significantly affect the reactivity of the amine and resulted in a slow condensation reaction. Despite this significant setback to our synthetic plan toward banyasin A, we sought that to install the 3-amino-2-methyl-5E-octenoic acid unit (4 or its masked form 22) to the peptide at earlier stage might avoid epimerization of the C2-methyl group. Gratifyingly, HATU-mediated coupling reaction of azido acid 22a with the amine derived from tripeptide 27 afforded 29a in 93% yield. That no epimerization had occurred during this coupling reaction was confirmed by synthesizing the corresponding epimeric material through the condensation of the same amine with azide acid 22c. Saponification of the methyl ester of 29a and subsequent condensation of the resultant acid with L-alanine 9-fluorenylmethyl ester (8) afforded 30a in 82% yield. Of the various reduction protocols that were examined for converting azido acid 30a into the corresponding amine, the Staudinger reduction with PMe3 in THF:H2O (7:1) proved the most successful. In the event, the Staudinger reduction of the azide and the cleavage of 9-fluorenylmethyl ester with aqueous NH4OH were carried out in a one-pot procedure to afford the resultant amino acid, which was immediately activated by diethyl cyanophosphonate (DEPC) (Yamada et al., 1973) in the presence of collidine to afford cyclopeptide 2a in 56% yield over two steps. Simultaneous removal of the tert-butyl ester and Boc-protecting group was achieved by treatment of 2a with trifluoroacetic acid in dichloromethane at room temperature. The guanidino group of the resultant cyclopeptide was mono-acylated with N-succinimidyl N-methylcarbamate (31) in the presence of DBU to afford banyasin A 1a in 66% yield. (Dixon et al., 2005) Having one diastereomer (1a), and a practical route to bayansin A in hand, we set out to pursue total syntheses of the other three possible diastereomers. This was readily achieved by following the same synthetic procedure as for 1a, by employing azido acids 22b, 22c, and 22d as key building blocks. These syntheses proceeded smoothly under the previous conditions to give rise to three diastereomers of banyasin A, 1b, 1c, and 1d in 28, 27, and 30% overall yield from tripeptide 27 (Figure 7).

Bottom Line: The first total synthesis of four possible isomers of a molecule possessing the configuration proposed for Banyasin A is described.The structure synthesized appears to be different from that of the natural product.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School Shenzhen, China.

ABSTRACT
The first total synthesis of four possible isomers of a molecule possessing the configuration proposed for Banyasin A is described. The structure synthesized appears to be different from that of the natural product.

No MeSH data available.