Efficient preparation of β-hydroxy aspartic acid and its derivatives

Article abstract of DOI:10.1016/j.cclet.2018.05.012

We report 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 is prepared from cheap chiral precursor L-diethyl tartrate in six steps without the need of column purification. The modified form of 7 serves as a versatile precursor to various β-alkoxyl analogs of erythreo-β-OH-Asp. In addition, we successfully performed a model study toward the total synthesis of coralmycin A, featuring a late stage installation of the side chain primary amide group of erythreo-β-OMe-Asn.

Full text of DOI:10.1016/j.cclet.2018.05.012

Chinese Chemical Letters 29 (2018) 1113–1115
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Efficient preparation of
b-hydroxy aspartic acid and its derivatives
Long Liua, Bo Wanga, Cheng Bia, Gang Hea,b, Gong Chena,b,
*
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
b
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We report an efficient and practical synthetic route to various properly-protected erythreo-b-OH-Asp
Received 4 April 2018
Received in revised form 2 May 2018
Accepted 3 May 2018
Available online 5 May 2018
compounds, which are key
products. Fmoc and cyclic ketal-protected erythreo-
b
-branched
a
-amino acid units in coralmycin A and other peptide natural
-OH-Asp 7 is prepared from cheap chiral precursor
-diethyl tartrate in six steps without the need of column purification. The modified form of 7 serves as a
b
L
versatile precursor to various
performed a model study toward the total synthesis of coralmycin A, featuring a late stage installation of
the side chain primary amide group of erythreo- -OMe-Asn.
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
b-alkoxyl analogs of erythreo-b-OH-Asp. In addition, we successfully
Keywords:
Amino acid
Natural product
b
Erythreo-
b
-OH-Asp
-OMe-Asn
Erythreo-
b
Antibiotics
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 amide-
linked para-aminobenzoic acid units [1]. More recently, Kim
reported the isolation of coralmycins A and B, which have very
similar structure with cystobactamid 919-2 (Scheme 1A) [2]. While
been investigated to construct these seemly simple
b-oxygenated
non-proteinogenic -amino acid [7–16]: asymmetric Mannich
a
type reaction [7], C-H bond hydroxylation [10], alkene dihydrox-
ylation-intermolecular SN2 reaction [11], reaction of optically pure
Garner’s aldehyde [12], halogenation-SN2 reaction [13], resolution
of racemic D,L-tHyAsp mixture [14], Sharpless asymmetric amino-
hydroxylation of alkene [15] and conversion of tartaric acid [16].
However, most of these methods could not provide a practical
coralmycin A shares the same central erythreo-
agine ( -OMe-Asn) residue with cystobactamid 919-2, coralmycin
B carries a central threo- -methoxyaspartic acid ( -OMe-Asp)
b-methoxyaspar-
b
synthesis of the properly protected
blocks.
b-OMe-Asp or Asn building
b
b
residue. Notably, these compounds show excellent antibacterial
potency against several Gram-negative pathogens including
Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumanii,
While our work is in progress, the groups of Trauner [17] and
Müller [18] independently published their total syntheses of
cystobactamids. As shown in Scheme 1B, Trauner used
substituted succinic anhydride as the key intermediate for
-OMe-Asn, which was prepared from -diethyl tartrate 1.
a
and Klebsiella pneumoniae, with MICs of 0.1 À 4
mg/mL. Further-
more, cystobactamids have been identified as inhibitors of
bacterial type IIa topoisomerases [3]. Intrigued by their unique
structures, we started a synthetic study to understand how the
b
L
However, the ring opening of the anhydride suffered from low
regioselectivity [7]. On the other hand, Müller took advantage of
the Sharpless asymmetric dihydroxylation route originally devel-
oped by Boger [8]. However, the need of oxidative degradation of
phenyl ring to liberate the carboxyl group caused low atom
economy.
central
b-OMe-Asp or -Asp residue influences their antibacterial
activity [4–6]. We speculated that varying the
b-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-
Asp building block and its derivatives in various protected form.
Erythreo- -OH-Asp or Asn building blocks have been found in a
b
-OH-
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 [19]. We initially
attempted to hydrolyze 2 to the corresponding dicarboxylic acid,
b
wide range of peptide natural products. A number of methods have
* Corresponding author at: State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
E-mail address: gongchen@nankai.edu.cn (G. Chen).
https://doi.org/10.1016/j.cclet.2018.05.012
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

1114
L. Liu et al. / Chinese Chemical Letters 29 (2018) 1113–1115
Scheme 1. Occurrence and strategy for synthesis of
b
-MeO-Asp/Asn building block.
Scheme 2. Synthesis of
b
-MeO-Asp and model study toward total synthesis of coralmycin A. (a) Preparation of Fmoc and Boc-protected
b
-OH-Asp. (b) Installation of para-
aminobenzoic acid on C terminus of
to -MeO-Asn.
b-OMe-Asp. (c) Preparation of ether derivatives of b-MeO-Asp. (d) Installation of benzoic acid on N terminus and conversion of b-OH-Asp
b

L. Liu et al. / Chinese Chemical Letters 29 (2018) 1113–1115
1115
which could selectively react with boronic acid at the hydroxyl-
substituted end. However, hydrolysis of 2 under basic conditions
caused racemization of the azido-linked carbon.
total synthesis of coralmycin A, featuring a late stage installation of
a side chain primary amide group of erythreo-b-OMe-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 [20]. 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
[21]. 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 chromatog-
raphy purification was needed from 1 to 7.
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.
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
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b-OH-Asp com-
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column purification. The modified form of 7 serves as a versatile
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