Facile access to chiral β-homoglutamic acid from 3-cyclohexene-carboxylic acid

Article abstract of DOI:10.1080/00397911.2020.1802760

A convenient, safe, and effective synthetic protocol for the synthesis of chiral β-homoglutamic acid was described. The strategy started from 3-cyclohexenecarboxylic acid, followed by three steps classic reaction including Curtius Rearrangement, oxidative

Full text of DOI:10.1080/00397911.2020.1802760

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile access to chiral β-homoglutamic acid from 3-
cyclohexene-carboxylic acid
Jing Xu , Xuebo Zhang , Zhongxiang Chen , Zhaofeng Sun , Guangling Bian &
Ling Song
To cite this article: Jing Xu , Xuebo Zhang , Zhongxiang Chen , Zhaofeng Sun , Guangling Bian &
Ling Song (2020): Facile access to chiral β-homoglutamic acid from 3-cyclohexene-carboxylic acid,
Synthetic Communications
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1802760
Facile access to chiral b-homoglutamic acid from
3-cyclohexene-carboxylic acid
Jing Xua,b, Xuebo Zhanga,b, Zhongxiang Chenb,c, Zhaofeng Sunb,c
Guangling Bianb,c , and Ling Songb,c
,
b
aCollege of Chemistry and Materials Science, Fujian Normal University, Fuzhou, China; The Key
Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the
c
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, China; The University of Chinese
Academy of Sciences, Beijing, China
ABSTRACT
ARTICLE HISTORY
Received 9 July 2020
A convenient, safe, and effective synthetic protocol for the synthesis
of chiral b-homoglutamic acid was described. The strategy started
from 3-cyclohexenecarboxylic acid, followed by three steps classic
reaction including Curtius Rearrangement, oxidative cleavage of
alkene, and debenzylation by catalytic hydrogenation. The chiral
b-homoglutamic acid was prepared with a high yield and high
enantiomeric excess.
KEYWORDS
b-Amino acids;
b-homoglutamic acid;
chiral; Curtius
rearrangement; 3-
cyclohexenecarboxylic acid
GRAPHICAL ABSTRACT
Introduction
b-amino acids have unique bioactivity, stability in peptide, and the ability to self-assem-
bly into high-order structures. They have been used as very important scaffolds for pep-
tide drugs and composites.[1] b-homoglutamic acid is one of the most important
unnatural b-amino acids. In recent years, it has been widely used in the synthesis of
new peptide drugs and the development of nanomaterials.[2] Research on its efficient
synthetic method has also been gradually paid attention. There are currently two main
strategies to obtain chiral b-homoglutamic acid. One is the use of optically pure chiral
auxiliary reagents for chiral induction synthesis, such as the optically pure 2-tert-butyl-
perhydropyrimidinone induction method reported by Snieckus,[3] and the D-gulose
derived hydroxylamine induction method developed by Bode.[4] Although these meth-
ods can successfully prepare a variety of b-amino acid including chiral b-homoglutamic
acid, the desired chiral auxiliary reagent is usually not easy to obtain, and the
CONTACT Guangling Bian
glb@fjirsm.ac.cn; Ling Song
songling@fjirsm.ac.cn
The Key Laboratory of Coal to
Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
J. XU ET AL.
°
(1) DPPA, Et3N, 25 C, 1.5 h
O
°
(2) 110 C, 2.5 h
H
N
∗
O
∗
°
(3) BnOH, 110 C, 12 h
OH
O
Toluene
2, 80%
1
KMnO4
rt, 4 h
Acetone
H
H2N
O
O
N
∗
∗
H2, Pd/C
MeOH
COOH
COOH
COOH
COOH
4, 98%
3, 88%
Scheme 1. A new synthetic route of optically pure b-homoglutamic acid.
preparation procedure is tedious and costly. The other route is using chiral glutamic
acid as the starting material to prepare diazoketone with diazomethane at low tempera-
ture and then is rearranged to obtain b-homoglutamic acid.[2c,5] However, it is very
dangerous to use easily exploded diazomethane, which requires reaction at low tempera-
ture and is not suitable for amplification.
Here, a new route for the synthesis of b-homoglutamic acid is illustrated. (Scheme 1)
Chiral 3-cyclohexenecarboxylic acid (1) is used as a starting material. After a simple three-
step reaction of Curtius Rearrangement, oxidative cleavage of alkene, and debenzylation by
catalytic hydrogenation, chiral b-homoglutamic acid (4) can be obtained with a high yield.
Results and discussion
(S)-3-Cyclohexene formic acid is the starting material for the synthesis of Edoxaban[6]
(An anticoagulant drug as important as Fondaparinux[7] and Idraparinux[8]), which is
obtained by the resolution of optically pure a-methylbenzylamine. There are bulk com-
modities supplied by tonnage in the market with low price. 3-Cyclohexene formic acid
has one more carbon than b-homoglutamic acid. The carboxyl group of the chiral car-
bon link can be converted into amino group just by Curtius rearrangement, and the
stereo configuration can be maintained.[9] As to olefin double bonds, it is very easy to
be oxidized and cleaved into adipic acid to form the whole framework of b-homogluta-
mic acid. Therefore, we took the chiral cyclohexene carboxylic acid (1) as the starting
material, and obtained chiral cbz-3-cyclohexene amine (2) in 80% yield through the
optimized one-pot Curtius rearrangement reaction. Then, we used potassium perman-
ganate to oxidize cbz-3-cyclohexene amine (2) at room temperature in 88% yield and
99% enantiomeric excess (ee) obtaining CBZ protected b-homologic acid (3). And
finally CBZ was removed by catalytic hydrogenation at 5% Pd/C for 12 h to obtain
near-quantitative yield of b-homoglutamic acid (4).

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SYNTHETIC COMMUNICATIONSV
3
Experimental section
All commercial reagents were used as received without further purification unless other-
1
wise stated. H NMR (400 MHz), 13C NMR (100 MHz) spectra were recorded using a
400 MHz spectrometer. Chemical shifts were reported in parts per million (ppm), using
CDCl3 (dH ¼ 7.26, dC ¼ 77.12) or DMSO-d6 (dH ¼ 2.50, dC ¼ 39.9) or D2O (dH ¼ 4.79)
as internal standards. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet). High-resolution mass spectra (HRMS) were obtained by the
ESI ionization sources using TOF MS technique. Melting point was obtained on a
micromelting point apparatus.
Procedure for the synthesis of (S)-benzyl cyclohex-3-en-1-ylcarbamate ((S)-2)
To a solution of (S)-cyclohex-3-enecarboxylic acid (10.0 g, 79 mmol) in toluene
(100 mL) was added 8.8 g TEA (87 mmol) and 22.9 g DPPA (83 mmol). The mixture
was stirred at 25 ꢀC for 1.5 h under N2 atmosphere. Then, it was warmed to 110 ꢀC and
stirred for another 2.5 h. BnOH (9.4 g, 87 mmol) was added to the mixture and the
resulting mixture was stirred at 110 ꢀC for 12 h. The reaction was concentrated under
reduced pressure to give a residue. The residue was purified by recrystallization (ethyl
acetate/n-hexane ¼ 1/10) to obtain (S)-benzyl cyclohex-3-en-l-ylcarbamate ((S)-2) 14.6 g.
30
Yield 80%; white solid; mp 58-59 ꢀC (lit.[10] 54–56 ꢀC); [a]D ꢁ26.4 (c 1.0, MeOH)
25
1
(lit.[10][a]D ꢁ17.1 (c 0.36, CHCl3)). H NMR (400 MHz, CDCl3) d 7.26–7.37 (m, 5H),
5.57–5.69 (m, 2H), 5.10 (s, 2H), 4.80 (s, 1H), 3.88 (s, 1H), 2.37–2.42 (m, 1H), 2.07–2.20
(m, 2H), 1.84–1.94 (m, 2H), 1.52–1.61 (m, 1H). 13C NMR (100 MHz, CDCl3) d 155.7,
136.6, 128.5, 128.2, 128.1, 127.0, 124.3, 66.5, 46.2, 31.9, 28.3, 23.5. HRMS (ESI) m/z cal-
culated for [M þ Na]þ: 254.1157; found: 254.1154.
Using (R)-cyclohex-3-enecarboxylic acid as the starting material, (R)-Benzyl cyclohex-
3-en-1-ylcarbamate ((R)-2) was synthesized by the same method as (S)-2. Yield 79%,
30
mp 57-58 ꢀC, [a]D þ26.3(c 1.0, MeOH) .
Procedure for the synthesis of (S)-3-(((benzyloxy)carbonyl)amino)hexanedioic acid
((S)-3)
A solution of (S)-2 (10 g, 43.4 mmol) in acetone (500 ml) was slowly added 250 mL of
0.5 M potassium permanganate aqueous solution dropwise at 0 ꢀC. After the addition,
the reaction was continued at room temperature, and detected by TLC until the reac-
tion was complete. Sodium thiosulfate was added to quench the excess potassium per-
manganate, and then the solution was adjusted to pH < 2 with 3 M hydrochloric acid,
and stirring was continued for 20 min. Acetone was distilled off under reduced pressure,
and the aqueous phase was extracted three times with 250 mL of ethyl acetate. The
organic phases were combined, washed with saturated brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to obtain crude product,
which was then purified by recrystallization (ethyl acetate/n-hexane ¼ 1/1)to obtain (S)-
3 11.3 g. Yield 88%; white solid; ee value 99% ((S)-major)[11]; mp 182–183 ꢀC;
30
1
[a]D ꢁ9.8 (c 1.0, MeOH) . H NMR (400 MHz, DMSO) d 12.14 (s, 2H), 7.29–7.38 (m,
5H), 7.22 (d, J ¼ 8.6 Hz, 1H), 5.00 (s, 2H), 3.75–3.86 (m, 1H), 2.34–2.40 (m, 2H), 2.20
(t, J ¼ 7.5 Hz, 2H), 1.67–1.79 (m, 1H), 1.52–1.63 (m, 1H). 13C NMR (100 MHz, DMSO)

4
J. XU ET AL.
d 174.6, 172.8, 156.1, 137.7, 128.8, 128.2, 128.1, 65.6, 47.9, 40.0, 30.7, 29.9. HRMS (ESI)
m/z calculated for [M þ Na]þ: 318.0948; found: 318.0950.
Using (R)-2 as the starting material, (R)-3-(((benzyloxy)carbonyl)amino)hexanedioic
acid ((R)-3) was synthesized by the same method as (S)-3. Yield 87%; white solid; ee
30
value 99% ((R)-major)[11]; mp 182–183 ꢀC; [a]D þ 10.0 (c 1.0, MeOH) .
Procedure for the synthesis of L-3-aminohexanedioic acid (L-4)
(S)-3 (10 g, 33.9 mmol) was dissolved in 100 mL of methanol and was added 0.5 g of
10% Pd/C, replaced the air with hydrogen, and stirred under 15 psi H2 for 10 h at room
temperature. Then, the catalyst was filtered out and the reaction solution was concen-
trated under reduced pressure to obtain L-4 5.35 g, Yield 98%; white solid; mp
30
20
188–190 ꢀC (lit.[3] 200–202 ꢀC); [a]D þ30.7 (c 0.4, H2O) (lit.[3] [a]D þ29.3 (c 0.37,
1
H2O)). H NMR (400 MHz, D2O) d 3.50–3.54 (m, 1H), 2.59–2.63 (m, 1H), 2.39–2.51
(m, 3H), 1.86–1.93 (m, 2H). 13C NMR (100 MHz, D2O) d ¼ 178.3, 176.7, 48.5, 37.4,
30.9, 27.6. HRMS (ESI) m/z calculated for [M–H]-: 160.0610; found: 160.0616.
Using (R)-3 as the starting material, D-3-aminohexanedioic acid (D-4) was synthe-
30
sized by the same method as L-4. Yield 97%; white solid; mp 190–192 ꢀC; [a]D ꢁ36.0
(c 0.4, H2O).
Conclusions
We have developed a novel route for the synthesis of chiral b-homoglutamic acid. We
believe that these observations should further increase the potential application of
b-homoglutamic acid in the design and synthesis of drugs and the development of
new materials.
1
HPLC, H and13C NMR spectra. This material can be found via the “Supplementary
Content” section of this article’s webpage.
Funding
The authors gratefully acknowledge financial supports from the Strategic Priority Research
Program of the Chinese Academy of Sciences [No. XDB20000000] and the Natural Science
Foundation of Fujian Province, China [No. 2018J01029], the Key Laboratory of Coal to Ethylene
Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences.
ORCID
Guangling Bian
http://orcid.org/0000-0001-5824-7418
References
[1] (a) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki, Ł. Peptides Containing b-Amino
Acid Patterns: Challenges and Successes in Medicinal Chemistry. J. Med. Chem. 2014, 57,
9718–9739. DOI: 10.1021/jm5010896;. (b) Del Borgo, M. P.; Kulkarni, K.; Aguilar, M.-I.
Using beta;-Amino Acids and beta;-Peptide Templates to Create Bioactive Ligands and
Biomaterials. Curr. Pharm. Des. 2017, 23, 3772–3785. DOI: 10.2174/

R
SYNTHETIC COMMUNICATIONSV
5
1381612823666170622110654;.(c) Fulop, F.; Martinek, T. A.; Toth, G. K. Application of
Alicyclic beta-Amino acids in Peptide Chemistry. Chem. Soc. Rev. 2006, 35, 323–334.
DOI: 10.1039/b501173f;.(d) Fleming, S.; Ulijn, R. V. Design of Nanostructures Based on
Aromatic Peptide Amphiphiles. Chem. Soc. Rev. 2014, 43, 8150–8177. DOI: 10.1039/
c4cs00247d;.(e) Du, X.; Zhou, J.; Shi, J.; Xu, B. Supramolecular Hydrogelators and
Hydrogels: From Soft Matter to Molecular Biomaterials. Chem. Rev. 2015, 115,
13165–13307. DOI: 10.1021/acs.chemrev.5b00299;.(f) Reddy, K. R.; Sridhar, G.; Sharma,
G. V. M. Synthesis of b3-Amino acid and Peptides from D-Ribose. Synth. Commun. 2018,
48, 1487–1493. DOI: 10.1080/00397911.2018.1455213;.(g) Bhalla, J.; Bari, S. S.; Banik, B. K.
; Bhalla, A. Diastereoselective Synthesis of Novel 3-Aryloxy/alkoxy-4-benzothiazolylpyra-
zolyl-b-lactams: Potential Synthons for Novel Aminoacids/nanocopolymers. Synth.
Commun. 2017, 47, 1955–1962. DOI: 10.1080/00397911.2017.1357186;.(h) Sridhar, G.;
Hanumaiah, M.; Sharma, G. V. M. Synthesis of Novel Pyran b-Amino Acid and 5,6-
Dihydro-2h-pyran b-Aminoxy Acid from Carbohydrate Derivatives. Synth. Commun.
2015, 45, 1768–1776. DOI: 10.1080/00397911.2015.1043018;.(i) Pan, X.; Bai, S.; Yu, W.;
Ding, D.; Zhao, D.; Liu, F. Efficient Synthesis of 3-(R)-boc-amino-4-(2,4,5-trifluorophe-
nyl)butyric Acid. Synth. Commun. 2015, 45, 1451–1456. DOI: 10.1080/00397911.2015.
1028552.
[2] (a) Tabata, Y.; Takagaki, K.; Uji, H.; Kimura, S. Piezoelectric Property of Bundled Peptide
Nanotubes Stapled by Bis-cyclic-b-peptide. J. Pept. Sci. 2019, 25, e3134, DOI: 10.1002/psc.
3134;. (b) Katoh, T.; Suga, H. Ribosomal Incorporation of Consecutive b-Amino Acids. J.
Am. Chem. Soc. 2018, 140, 12159–12167. DOI: 10.1021/jacs.8b07247;.(c) Fears, K. P.;
Kolel-Veetil, M. K.; Barlow, D. E.; Bernstein, N.; So, C. R.; Wahl, K. J.; Li, X.; Kulp, I. I. I.
J. L.; Latour, R. A.; Clark, T. D. High-Performance Nanomaterials Formed by Rigid yet
Extensible Cyclic b-Peptide Polymers. Nat. Commun. 2018, 9, 1–8. DOI: 10.1038/s41467-
€
018-06576-5;.(d) Kirkland, T. A.; Adler, M.; Bauman, J. G.; Chen, M.; Haeggstrom, J. Z.;
King, B.; Kochanny, M. J.; Liang, A. M.; Mendoza, L.; Phillips, G. B.; et al. Synthesis of
Glutamic Acid Analogs as Potent Inhibitors of Leukotriene A4 Hydrolase. Bioorg. Med.
Chem. 2008, 16, 4963–4983. DOI: 10.1016/j.bmc.2008.03.042.
[3] Beaulieu, F.; Arora, J.; Veith, U.; Taylor, N. J.; Chapell, B. J.; Snieckus, V. 1,3-Asymmetric
Induction via 1,5-Hydrogen Atom Translocation Reactions. Highly Enantioselective
Synthesis of b-Substituted b-Amino Acids. J. Am. Chem. Soc. 1996, 118, 8727–8728. DOI:
10.1021/JA961484V.
[4] Yu, S.; Ishida, H.; Juarez-Garcia, M. E.; Bode, J. W. Unified Synthesis of Enantiopure b2h,
b3h and b2,3-Amino Acids. Chem. Sci. 2010, 1, 637–641. DOI: 10.1039/c0sc00317d.
[5] (a) Subasinghe, N.; Schulte, M.; Chan, M. Y. M.; Roon, R. J.; Koerner, J. F.; Johnson, R. L.
Synthesis of Acyclic and Dehydroaspartic Acid Analogs of Ac-Asp-Glu-OH and Their
Inhibition of Rat Brain N-Acetylated a-Linked Acidic Dipeptidase (NAALA Dipeptidase).
J. Med. Chem. 1990, 33, 2734–2744. DOI: 10.1021/jm00172a009;. (b) Gung, B. W.; Zou,
D.; Stalcup, A. M.; Cottrell, C. E. Characterization of a Water-Soluble, Helical b-Peptide.
J. Org. Chem. 1999, 64, 2176–2177. DOI: 10.1021/jo981070f;.(c) Gung, B. W.; Zou, D.;
Miyahara, Y. Synthesis of a Hybrid Peptide with Both a- and b-Amino Acid Residues:
Toward a New b-Sheet Nucleator. Tetrahedron. 2000, 56, 9739–9746. DOI: 10.1016/
S0040-4020(00)00881-4.
[6] Sato, K.; Kubota, k. Process for producing optically active carboxylic acid. Patent.
WO2010067824A1. 2010. Daiichi Sankyo Co Ltd [JP]. 2010.06.17. 32pp.
[7] Dey, S.; Lo, H.-J.; Wong, C.-H. Programmable One-Pot Synthesis of Heparin
Pentasaccharide Fondaparinux. Org. Lett. 2020, 22, 4638–4642. DOI: 10.1021/acs.orglett.
0c01386.
[8] Dey, S.; Lo, H.-J.; Wong, C.-H. An Efficient Modular One-Pot Synthesis of Heparin-Based
Anticoagulant Idraparinux. J. Am. Chem. Soc. 2019, 141, 10309–10314. DOI: 10.1021/jacs.
9b03266.
[9] (a) Spahn, H.; Langguth, P. Chiral Amines Derived from 2-Arylpropionic Acids: novel
Reagents for the Liquid Chromatographic (LC) Fluorescence Assay of Optically Active

6
J. XU ET AL.
Carboxylic Acid Xenobiotics. Pharm. Res. 1990, 7, 1262–1268. DOI: 10.1023/
A:1015985805042;. (b) Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F.; Knochel, P. Highly
Enantioselective Preparation of Tertiary Alcohols and Amines by Copper-Mediated
Diastereoselective Allylic SN2’ Substitutions. Angew. Chem. Int. Ed. 2005, 44, 4627–4631.
DOI: 10.1002/anie.200500672;.(c) Leogane, O.; Lebel, H. One-Pot Curtius Rearrangement
Processes from Carboxylic Acids. Synthesis 2009, 2009, 1935–1940. DOI: 10.1055/s-0029-
1216795;.(d) Iosub, V.; Haberl, A. R.; Leung, J.; Tang, M.; Vembaiyan, K.; Parvez, M.;
Back, T. G. Enantioselective Synthesis of a-Quaternary Amino Acid Derivatives by
Sequential Enzymatic Desymmetrization and Curtius Rearrangement of a,a-Disubstituted
Malonate Diesters. J. Org. Chem. 2010, 75, 1612–1619. DOI: 10.1021/jo902584r.
[10] Guo, J. Y.; Zhong, C. H.; He, Z. Y.; Tian, S. K. Benzyne-Promoted Curtius-Type
Rearrangement of Acyl Hydrazides in the Presence of Nucleophiles. Asian J. Org. Chem.
2018, 7, 119–122. DOI: 10.1002/ajoc.201700598.
[11] The ee value was determined by chiral stationary phase HPLC analysis [Daicel Chiralpak
OD-H, hexane/isopropanol/CF3COOH (90/10/0.3), 1.0 mL/min, k ¼ 210 nm, tS¼21.2 min,
tR¼23.3 min].