Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using automatically prepared chiral bromocarboxylic acid and Garner's aldehyde as versatile building blocks

Article abstract of DOI:10.1016/j.bmcl.2021.127961

An efficient method for the synthesis of substituted 5-(hydroxymethyl)piperazin-2-ones was established by using an automated synthesis process. Thirteen piperazinones were synthesized from chiral α-bromocarboxylic acids and Garner's aldehyde which were prepared by using our originally developed automated synthesizer, ChemKonzert. The automated method of synthesizing chiral α-bromocarboxylic acids was efficient and safe because the rate of the dropwise addition of the reagent can be controlled using the automated synthesizer. This method is expected to contribute to the synthesis of pharmaceuticals.

Full text of DOI:10.1016/j.bmcl.2021.127961

Bioorg. Med. Chem. Lett. 40 (2021) 127961
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis of 5-(hydroxymethyl)piperazin-2-ones using
automatically prepared chiral bromocarboxylic acid and Garner’s aldehyde
as versatile building blocks
,
Hisashi Masuia b, Kohei Naitoa, Mai Minoshimaa, Akira Kusayanagia, Sae Yosugia,
,c,*
Mitsuru Shojia, Takashi Takahashia
a Department of Pharmaceutical Sciences, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
b Graduate School of Pharmaceutical Sciences, Department of Basic Medicinal Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
c Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
An efficient method for the synthesis of substituted 5-(hydroxymethyl)piperazin-2-ones was established by using
Piperazione
an automated synthesis process. Thirteen piperazinones were synthesized from chiral α-bromocarboxylic acids
Amino acid analogs
Heterocycles
and Garner’s aldehyde which were prepared by using our originally developed automated synthesizer, Chem-
Konzert®. The automated method of synthesizing chiral α-bromocarboxylic acids was efficient and safe because
Automated synthesis
the rate of the dropwise addition of the reagent can be controlled using the automated synthesizer. This method
is expected to contribute to the synthesis of pharmaceuticals.
α
-Bromocarboxylic acid
Amino acids containing heterocycles such as diketopiperazine have
bromination of diazo intermediates that are readily prepared from
attracted significant attention because of their biological activities.1–4
Because these moieties can be construed as conformationally con-
strained amino acid analogs, they are often used as building blocks in the
synthesis of peptidemimetics. However, because of the high planarity of
diketopiperazine, its analogs with more sp3 carbon atoms have been
required to specifically control the interaction with target molecules. For
this purpose, the synthesis of diketopiperazine analogs, in which one of
the carbonyl groups is replaced by an oxetane ring, has been reported.5
Piperazinones can be simply synthesized by lactamization1,6–9 or
alkylation1,10–13 via nucleophilic attack by an amino group. Optically
active piperazinone can be constructed by the acylation of mono-
α
-amino acids.19–21 This method is very important because a sufficient
amount of chiral building blocks can be prepared from inexpensive
amino acids. In this paper, we focused on the synthesis of 5-(hydrox-
ymethyl)piperazin-2-ones because these compounds possess more sp3
carbons than diketopiperazine and retain a hydroxyl group for binding
to target compounds and further functional group modification.
Automated synthesis has attracted considerable attention in recent
years because the automation of synthetic operations improves both the
reproducibility and reliability of the synthesis.22–26 Synthetic chemists
frequently perform repetitive processes such as optimizing reaction
conditions, constructing compound libraries, and preparing synthetic
intermediates. In particular, the synthetic intermediates for natural
products and versatile building blocks for various applications may need
to be resynthesized, even after their initial synthesis on a large scale.
Synthetic chemists can automatically prepare the intermediates when
these compounds are needed by using an automated synthetic method
and stored procedure. Thus, researchers can spend more time on
addressing advanced and challenging problems. We previously reported
the automated syntheses of key intermediates for natural products,
including taxol,27 ent-pyripyropene A,28 spiruchostatin B,29 and nine-
membered masked enediyne30 by utilizing our originally developed
protected 1,2-diamine with chiral
α-bromocarboxylic acid, followed
by the deprotection of the amine and intramolecular nucleophilic sub-
stitution.4 The conventional method for synthesizing racemic
α-bro-
mocarboxylic acid is the Hell-Volhard-Zelinsky reaction,14–16 which
involves the α-bromination of acid halides. The preparation of chiral
α
-halocarboxylic acid by copper(II)-mediated resolution of racemic acid
has also been reported.17 Moreover, the elegant synthesis of chiral
α
-halocarboxylic acid by the enantioselective protonation of ketene
disilyl acetal has been investigated.18 Synthesis using chiral substrates is
also efficient. Chiral
α-bromocarboxylic acid can be synthesized via the
¯
* Corresponding author at: Omura Satoshi Memorial Research Institute, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan.
E-mail address: ttak@lisci.kitasato-u.ac.jp (T. Takahashi).
https://doi.org/10.1016/j.bmcl.2021.127961
Received 14 January 2021; Received in revised form 8 March 2021; Accepted 10 March 2021
Available online 17 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

H. Masui et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127961
automated synthesizer, ChemKonzert.31 We also synthesized Garner’s
aldehyde, a versatile building block, by using ChemKonzert.32 Herein,
we report the solution-phase automated synthesis of chiral α-bromo-
carboxylic acid as a versatile chiral building block and the construction
of a small library of 5-(hydroxymethyl)piperazin-2-one analogs using
the automatically prepared building blocks.
The strategy for synthesizing 5-(hydroxymethyl)piperazin-2-one
analogs is shown in Scheme 1. The piperazinone structure can be con-
structed by condensation with mono-protected 1,2-diamine and chiral
α
-bromocarboxylic acid, followed by deprotection and the intra-
molecular N-alkylation. Mono-protected 1,2-diamine can be prepared
by the reductive amination of Garner’s aldehyde. Chiral -bromo-
carboxylic acid can be obtained from the corresponding amino acid.
Garner’s aldehyde and chiral -bromocarboxylic acid were provided
using an automated synthesizer.
Initially, we examined the automated synthesis of chiral
carboxylic acid by the bromination of -amino acid using sodium bro-
α
α
α-bromo-
α
mide, sodium nitrite, and sulfuric acid (Table 1). In general, the
stereochemistry is retained in the bromination of amino acid because of
neighboring group participation. It is important to manually verify the
reaction conditions including the reaction time and the work-up method
previous to the automated synthesis to confirm that the automated
synthesis induces no significant decrease in the yield. Bromination had
to be carried out at low temperatures as it competes with the nucleo-
philic substitution of water at higher temperature.33,34 Therefore, the
addition of sodium nitrite solution at a constant rate is critical for pre-
venting an increase in the internal temperature. The crucial addition
rate of the reagent was controlled using an automated synthesizer;10 this
was achieved by repeatedly opening and closing the valve attached to
Scheme 1. Strategy for synthesizing 5-(hydroxymethyl)piperazin -2-ones.
Table 1
Automated and manual bromination of
α
-amino acid.
Substrate
Entrya
1
Product
Yieldb,c
80% (67%)
2
3
4
5
99% (99%)
57% (68%)
63% (67%)
42% (62%)
a
All reactions were performed on 1–10 gram scale. bIsolated yield. cYield of manual synthesis is shown in parentheses.
2

H. Masui et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127961
Scheme 2. Synthesis of highly functionalized 5-(hydroxymethyl) piperazin-
2-one.
by the reductive amination of Garner’s aldehyde (4) and benzyl amine
using palladium fibroin36 as a hydrogenation catalyst. The secondary
amine (5) was acylated with α-bromocarboxylic acid (2f) to give the
corresponding amide in 99% yield over two steps. The removal of tert-
butoxycarbonyl (Boc) and acetonide groups under acidic conditions,
followed by cyclization using sodium carbonate as a base, afforded the
desired 5-(hydroxymethyl)piperazin-2-one 8a in 89% yield over two
steps. No epimerization during the synthesis of piperazinone 8a was
confirmed by converting the obtained piperazinone into the known cy-
clic carbamate37 (see Supporting information).
The preparation of various 5-(hydroxymethyl)piperazin-2-ones was
examined using the same procedure under slightly modified reaction
conditions (Fig. 1). Twelve other piperazinone analogs were synthesized
using the automatically prepared versatile building blocks. The sec-
ondary amine was acylated with α-bromocarboxylic acid using EDCI.
The protected amino alkyl bromides were deprotected with trifluoro-
acetic acid (TFA). When the substrate with tert-butyl ether was used, the
deprotection
was
performed
using
trimethylsilyl
tri-
fluoromethanesulfonate and 2,6-lutidine.38 Cyclization via intra-
molecular N-alkylation was performed using sodium carbonate and
acetonitrile. The cyclization proceeded rapidly, except in the case of the
N-unsubstituted substrates (8 l and 8 m), which required mild heating.
All synthetic intermediates were used for the next reaction without
purification. The bromine atom on the
α-bromocarboxylic acids showed
excellent electrophilicity because of the electron-withdrawing neigh-
boring carbonyl group. Because α-bromocarboxylic acid has sufficient
Fig. 1. Synthesis of various substituted 5-(hydroxymethyl) piperazin-2-ones.c a
Trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine were used instead of
TFA. b The cyclization was performed at 50 ◦C. c All reactions were performed
in 100 mg-30 g scale.
reactivity as a synthetic intermediate, our established automated syn-
thesis is an effective tool and has various applications (See Scheme 2).
In conclusion, we established the automated synthesis of α-bromo-
carboxylic acid—a versatile building block—by using our originally
developed automated synthesizer, ChemKonzert. Thirteen piperazinone
the reagent inlet (the open and close times were 0.5 and 3 s, respec-
tively). The yields from the automated synthesis were comparable to
those of the corresponding manual syntheses (Table 1, Entries 1–4).35
When tyrosine analog 1e was used as a substrate, the target bromide 2e
was precipitated (Table 1, Entry 5). In the manual synthesis, the desired
product 2e could be obtained in 62% yield by filtration; in contrast, in
the automated synthesis, the precipitate had to be extracted once for the
transformation in the tube, and 2e was obtained in a slightly lower yield
of 42%.
analogs were synthesized from automatically prepared
α-bromo-
carboxylic acid and Garner’s aldehyde via the developed method.
-Bromocarboxylic acid has sufficient reactivity as a synthetic inter-
α
mediate, and the established automated synthesis of α-bromocarboxylic
acid is useful for the synthesis of various heterocycles. Further modifi-
cations of 5-(hydroxymethyl)piperazin-2-ones and the evaluation of
their activities are currently underway.
Furthermore, the synthesis of functionalized 5-(hydroxymethyl)
piperazin-2-one was examined using automatically prepared building
blocks. Garner’s aldehyde (4) was prepared from L-serine methyl ester
hydrochloride (3) using an automated synthesizer according to our
developed procedure.32 Mono-protected 1,2-diamine 5 was synthesized
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
3

H. Masui et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127961
13 Reginato G, Di Credico B, Andreotti D, Mingardi A, Paio A, Donati D. Tetrahedron
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Acknowledgments
14 Zelinsky, N. Ber. Dtsch. Chem. Ges. 1887, 20, 2026.
We thank Prof. Dr. Hiroyuki Kouji, Dr. Takenao Odagami, and Mr.
Yoichiro Hirose for fruitful discussions. We also thank Mr. Kazuhiro
Machida for assistance with the maintenance of ChemKonzert.
15 Volhard J, Liebigs Justus. Ann Chem. 1887;242:141.
16 Hell C. Ber Dtsch Chem Ges. 1881;14:891.
17 Xu H-W, Wang Q-W, Zhu J, et al. Org Biomol Chem. 2005;3:4227.
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21 Tka N, Kraïem J, Hassine BB. Synth Commun. 2013;43:735.
22 Cork DG, Sugawara T. Laboratory Automation in the Chemical Industries. New York:
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127961.
23 Coley CW, Thomas III DA, Lummiss JAM, et al. Science. 2019:365.
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