b Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Tianjin 300071, China
In 2014, Müller reported the isolation of an unusual group of antibacterial nonribosomal peptide natural products named cystobactamids featuring a central modified aspartic acid (Asp) or asparagine (Asn) residue and two flanking arms made of amidelinked para-aminobenzoic acid units . More recently, Kim reported the isolation of coralmycins A and B, which have very similar structure with cystobactamid 919-2 (Scheme 1A) . While coralmycin A shares the same central erythreo-β-methoxyasparagine (β-OMe-Asn) residue with cystobactamid 919-2, coralmycin B carries a central threo-β-methoxyaspartic acid (β-OMe-Asp) residue. Notably, these compounds show excellent antibacterial potency against several Gram-negative pathogens including Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumanii, and Klebsiella pneumoniae, with MICs of 0.1 - 4 μg/mL. Furthermore, cystobactamids have been identified as inhibitors of bacterial type IIa topoisomerases . Intrigued by their unique structures, we started a synthetic study to understand how the central β-OMe-Asp or -Asp residue influences their antibacterial activity [4-6]. We speculated that varying the β-alkoxyl group might alter the spatial conformation of the parent scaffold and therefore influence its activity. Herein, we report the initial progress on an efficient and practical synthesis of erythreo-β-OHAsp building block and its derivatives in various protected form.
|Scheme 1. Occurrence and strategy for synthesis of β-MeO-Asp/Asn building block.|
Erythreo-β-OH-Asp or Asn building blocks have been found in a wide range of peptide natural products. A number of methods have been investigated to construct these seemly simple β-oxygenated non-proteinogenic α-amino acid [7-16]: asymmetric Mannich type reaction , C-H bond hydroxylation , alkene dihydroxylation-intermolecular SN2 reaction , reaction of optically pure Garner's aldehyde , halogenation-SN2 reaction , resolution of racemic D, L-tHyAsp mixture , Sharpless asymmetric aminohydroxylation of alkene  and conversion of tartaric acid . However, most of these methods could not provide a practical synthesis of the properly protected β-OMe-Asp or Asn building blocks.
While our work is in progress, the groups of Trauner  and Müller  independently published their total syntheses of cystobactamids. As shown in Scheme 1B, Trauner used a substituted succinic anhydride as the key intermediate for β-OMe-Asn, which was prepared from L-diethyl tartrate 1. However, the ring opening of the anhydride suffered from low regioselectivity . On the other hand, Müller took advantage of the Sharpless asymmetric dihydroxylation route originally developed by Boger . However, the need of oxidative degradation of phenyl ring to liberate the carboxyl group caused low atom economy.
Similar to Trauner's approach, we wanted to use L-diethyl tartrate 1 as the starting material due to its low cost as an easily accessible chiral precursor. The key to achieve high efficiency of this strategy lies on the selective differentiation of the two carboxylate groups. As shown in Scheme 2A, 1 was first treated with SOCl2 in the presence of catalytic amount of DMF in CCl4 to furnish cyclic sulfate. Opening of the sulfate by NaN3 in DMF led to azido alcohol 2 in 90% yield over two steps . We initially attempted to hydrolyze 2 to the corresponding dicarboxylic acid, which could selectively react with boronic acid at the hydroxylsubstituted end. However, hydrolysis of 2 under basic conditions caused racemization of the azido-linked carbon.
|Scheme 2. Synthesis of β-MeO-Asp and model study toward total synthesis of coralmycin A. (a) Preparation of Fmoc and Boc-protected β-OH-Asp. (b) Installation of paraaminobenzoic acid on C terminus of β-OMe-Asp. (c) Preparation of ether derivatives of β-MeO-Asp. (d) Installation of benzoic acid on N terminus and conversion of β-OH-Asp to β-MeO-Asn.|
To circumvent this racemization issue, the azido group of 2 was first reduced to free amine via Pd/C-catalyzed hydrogenation and then protected by Boc2O to give 3 . Hydrolysis of compound 3 by aq. NaOH gave the desired dicarboxylic acid without any racemization. The subsequent treatment of the di-acid with 2, 2- dimethoxypropane (2, 2-DMP) and catalytic amount of TsOH gave the desired cyclic acetal-protected mono acid 4 in excellent yield. Reaction of 4 with allyl bromide cleanly formed the allyl ester 5 . By altering the order of ester hydrolysis and amino group protection, Fmoc and cyclic acetal-protected intermediate 7 was prepared in high yield (Scheme 2A). Notably, no flash chromatography purification was needed from 1 to 7.
As shown in Scheme 2B, amide coupling of 7 with para-aminobenzoate ester 8 proceeded with low yield and considerable racemization under a variety of conditions tested presumably due to the steric congestion around the β carbon. To alleviate the steric congestion, we decided to open the cyclic ketal and install the β-MeO group before the amide coupling. Benzyl protection of 7 , opening of the cyclic acetal with acid, and methyl esterification with MeI and K2CO3 gave compound 12 in good yield. Compound 12 can be recrystallized from MeOH. Treatment of 12 with MeI and Ag2CO3 at 45 ℃ gave the desired β methyl ether 13 in excellent yield. The Bn group of 13 was deprotected by Pdcatalyzed hydrogenolysis, and the subsequent amide coupling with para-aminobenzoate ester 20 under the optimized conditions using HATU and NaHCO3 at -5 ℃ proceeded in good yield to give 10 with excellent chiral integrity.
As shown in Scheme 2C, compound 12 can react with various alkyl halides under the same conditions for 13 to give the corresponding β-alkoxyl analogs, which would be useful for future structure activity relationship study.
As shown in Scheme 2D, Fmoc deprotection of 10 by the treatment of TBAF and the subsequent amide coupling with para-nitrobenzoyl chloride afforded the tripeptide 18 in 88% yield. Hydrolysis of the side chain methyl ester of 18 with aq. NaOH cleanly gave the carboxylic acid intermediate. The acid was then converted to the desired side chain primary amide of β-OMe-Asn via the treatment of HATU, NH4HCO3 in DMF at room temperatuer, finishing a successful model study toward the total synthesis of coralmycin A.
In conclusion, we developed an efficient and practical synthetic route to various properly-protected erythreo-β-OH-Asp compounds, which are key β-branched α-amino acid units in coralmycin A and other peptide natural products. Fmoc and cyclic ketal-protected erythreo-β-OH-Asp 7 can be prepared from cheap chiral precursor L-diethyl tartrate in six step without the need of column purification. The modified form of 7 serves as a versatile precursor to various β-alkoxyl analogs of erythreo-β-OMe-Asp. In addition, we successfully performed a model study toward the total synthesis of coralmycin A, featuring a late stage installation of a side chain primary amide group of erythreo-β-OMe-Asn.Acknowledgment
We gratefully thank the National Natural Science Foundation of China (Nos. 21421062, 21672105, 91753124) for financial support of this work.Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.cclet.2018.05.012.
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