A convenient and highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics

Article abstract of DOI:10.1080/00397911.2021.1961155

A novel and enantioselective synthesis of (S)-2-pipecolic acid (5) has been achieved from Oppolzer’s sultam (1) and ethyl N-(diphenylmethylene)glycinate (2) as readily available starting materials. The highly stereoselective alkylation of chiral glycine intermediate (3) with 1,4-dibromobutane afforded the key backbone of (S)-2-pipecolic acid (5) in one-step that was utilized into the preparation of the local anesthetics mepivacaine, ropivacaine and bupivacaine.

Full text of DOI:10.1080/00397911.2021.1961155

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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A convenient and highly enantioselective synthesis
of (S)-2-pipecolic acid: an efficient access to caine
anesthetics
Yuyan Yang, Hua Li, Zhonglin You & Xingxian Zhang
To cite this article: Yuyan Yang, Hua Li, Zhonglin You & Xingxian Zhang (2021): A convenient and
highly enantioselective synthesis of (S)-2-pipecolic acid: an efficient access to caine anesthetics,
Synthetic Communications, DOI: 10.1080/00397911.2021.1961155
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2021.1961155
A convenient and highly enantioselective synthesis of (S)-2-
pipecolic acid: an efficient access to caine anesthetics
Yuyan Yang, Hua Li, Zhonglin You, and Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 18 April 2021
A novel and enantioselective synthesis of (S)-2-pipecolic acid (5) has
been achieved from Oppolzer’s sultam (1) and ethyl N-(diphenylme-
thylene)glycinate (2) as readily available starting materials. The highly
stereoselective alkylation of chiral glycine intermediate (3) with 1,4-
dibromobutane afforded the key backbone of (S)-2-pipecolic acid (5)
in one-step that was utilized into the preparation of the local anes-
thetics mepivacaine, ropivacaine and bupivacaine.
KEYWORDS
Oppolzer’s sultam; N-
(diphenylmethylene)glyci-
nate; (S)-2-pipecolic acid;
caine anesthetics;
asymmetric synthesis
GRAPHICAL ABSTRACT
Introduction
Local anesthetics have been widely used for over a hundred years in diverse areas of
medicine, mainly in stomatology, surgery, gynecology and obstetrics. Apart from that,
they are used as ingredients in many drugs and cosmetics of daily use. Among them,
mepivacaine, ropivacaine and bupivacaine as the chiral local anesthetic to be marketed
as an optically active agent, have been widely used for spinal anesthesia including infil-
tration, nerve block, epidural, and intrathecal anesthesia, with a long duration of
action.[1–4] Furthermore, (S)-2-pipecolic acid ((S)-2-PA) is the key constituent of
mepivacaine, bupivacaine and ropivacaine (Figure 1).[5] As a proline analogue (homo-
proline), 2-pipecolic acid has been used in many modified peptides and many biologic-
ally and medicinally important molecules such as rapamycin,[6] FK506/tacrolimus,[7]
sandramycin,[8] and has also been utilized into the field of organo-catalysis.[9]
To date, several synthetic routes to (S)-2-pipecolic acid have been reported. An enantiose-
lective hydrogenation of methyl (Z)-2-acetamidopenta-2,4-dienoate in the presence of a
chiral catalys (R,R)-Et-DuPHOS-Rh(I) was furnished to prepare (S)-2-pipecolic acid at room
temperature under 30–90 psi pressure.[10] Hou and coworkers have completed the synthesis
of (S)-2-pipecolic acid by diastereoselective alkylation of (R)-5-phenylmorpholin-2-one.[11]
CONTACT Xingxian Zhang
zhangxx@zjut.edu.cn
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, P. R. China
ß 2021 Taylor & Francis Group, LLC

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Y. YANG ET AL.
Figure 1. Caine anesthetics containing (S)-2-pipecolic acid.
Scheme 1. Synthetic strategy for (S)-2-pipecolic acid 5.
In addition, the total synthesis of (S)-pipecolic acid has been accomplished by Chavan and
coworkers from cis-aziridine-2-carboxylate as a common synthetic precursor, followed by
the regioselective cleavage of the aziridine ring and Wittig olefination as the key transforma-
tions.[9] Ginesta and coworkers have been developed a new enantioselective synthesis of
N-protected pipecolic acid starting from 2,3-epoxy-5- hexen-1-ol through Sharpless epoxida-
tion.[12] Recently, a stereoselective synthesis of (S)-pipecolic acid was achieved from a chiral
N-imino-2-phenyl-1,2-dihydropyridine as a key intermediate.[13] However, many of these
routes have such disadvantages as expensive catalysts, reagents or chiral auxiliaries and low
yields. Therefore, the development of a shorter, convenient and highly enantioselective
methodology for the practical synthesis of (S)-2-pipecolic acid is highly desirable.
The use of chiral auxiliaries to establish chiral centers in a highly stereoselective man-
ner is one of the most important strategies in organic synthesis.[14,15] The well-known
commercial Oppolzer chiral sultam and its derivatives have been widely used in
asymmetric synthesis, such as Diels-Alder cycloaddition, 1,2-addition, 1,3-dipolar
cycloaddition, aldol condensation, asymmetric alkylation, asymmetric epoxidation, and
bis-hydroxylation.[16] Herein, we will wish to report a convenient and highly enantiose-
lective synthesis of (S)-2-pipecolic acid 5 via an alkylation of Oppolzer’s chiral sultam of
glycine 3 with 1,4-dibromobutane as a key step. (Scheme 1).
Results and discussion
The Oppolzer sultam has been successfully utilized for the asymmetric synthesis of
a-amino acids, which initiated to investigate a novel synthetic route to prepare enantio-
merically pure (S)-2-pipecolic acid 5. This synthetic strategy was furnished by alkylation
of the chiral Oppolzer’s sultam of glycine 3 with 1,4-dibromobutane. The ability of the
chiral glycine intermediate 3 to the direct highly diastereoselective alkylation has been
demonstrated, which provides the unnatural chiral amino acids with predictably abso-
lute configuratoin.[17] On the basis of this methodology, we endeavored to perform the
stereocontrolled synthesis of (S)-2-pipecolic acid 5 (Scheme 2).

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Scheme 2. Asymmetric synthesis of (S)-2-pipecolic acid 5 and its corresponding anesthetic drugs.
The sultam derivative of ethyl N-(diphenylmethylene) glycinate 3 was prepared via
Me3Al-mediated acylation of sultam 1 with ethyl N-(diphenylmethylene) glycinate 2 at
50 ꢀC for 24 h in 86% yield. The chiral glycine intermediate 3 was smoothly alkylated
with 1,4-dibromobutane in the presence of n-BuLi at ꢁ78 ꢀC to provide 4 as a pale
1
yellowish oil in a moderate yield (74%) with up to 98% de, as observed by H NMR
spectroscopy. It is worthy to be noted that the benzophenone protecting group was sim-
ultaneously removed upon workup and the intramolecular cyclization was efficiently
carried out to afford the key backbone of (S)-2-pipecolic acid 5 in one-step.
Gratifyingly, only one single diastereoisomer of the key intermediate 4 was obtained, as
determined by its NMR analysis. This was also confirmed as the desired S-configuration
by the validation of the targeted product (S)-2-pipecolic acid 5. Subsequently,
removal of the chiral auxiliary sultam was readily accomplished by the treatment with
2.5 mol/L LiOH aqueous in THF at 0 ꢀC to give the desired (S)-2-pipecolic acid 5 in
81% yield.
We would like to point out that, according to the literature,[18] (S)-2-pipecolic acid 5
can be utilized into the preparation of the local anesthetic drugs shown in Scheme 2.
(S)-2-pipecolic acid 5 was first converted into its acid chloride hydrochloride 6 after
treatment with HCl gas and thionyl chloride in toluene. The crude acid chloride
hydrochloride 6 was then condensed with 2,6-dimethylaniline at 55 ꢀC for 5 h to form
(S)-N-(2,6-dimethylphenyl)piperidin-2-carboxamide 7 in 68% overall yield with up
to 99% ee, as determined by chiral HPLC analysis. Treatment of compound 7 with
methyl iodide or alkyl bromide in dimethylformamide at 80 ꢀC in the presence of
K2CO3 produced mepivacaine 8a, ropivacaine 8b and bupivacaine 8c in 85-88% yield,
respectively.

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Conclusion
In summary, we have developed an efficient and convenient route for the synthesis of
(S)-2-pipecolic acid with excellent enantiomeric purity. Inexpensive reagents, readily
available chiral auxiliary, high yields, and simplicity, make this method attractive for
preparing local anesthetics such as mepivacaine, ropivacaine and bupivacaine. The
asymmetric total synthesis of other natural products and drugs bearing (S)-2-pipecolic
acid is currently underway in our laboratory.
Experimental section
General information
All reagents were commercially available and directly used without further treatment.
1H NMR spectra were recorded at 400 MHz or 500 MHz in CDCl3 and D2O using TMS
as an internal standard. 13C NMR spectral measurements were performed at 125 MHz
or 100 MHz using TMS as an internal standard. MS (ESI) was determined on a Thermo
LCQ TM Deca XP plus spectrometer. For product purification by flash column chroma-
tography, silica gel (200 ꢂ 300 mesh) and light petroleum ether (PE, b.p. 60 ꢂ 90 ꢀC)
were used. The optical rotation was measured at 25 ꢀC using the sodium D line fre-
quency on Autopol IV-T apparatus. Melting points were measured on Buchi B-540
apparatus and are uncorrected.
((6R,7aR)-8,8-dimethyl-2,2-dioxidotetrahydro-3H-3a,6-methanobenzo[c]isothiazol-
1(4H)-yl) ((S)-piperidin-2-yl) methanone (4)
To a solution of N-(diphenylmethylene)glycine sultam 3 (1.05 g, 2.41 mmol) in anhyd-
rous THF (10 mL) was added dropwise n-BuLi in hexane (1.1 mL, 2.75 mmol, 2.5 mol/L)
at ꢁ78 ꢀC under argon. The reaction mixture was stirred for 10 min at ꢁ78 ꢀC and 1,4-
dibromobutane (0.57 g, 2.65 mmol) was added dropwise. The reaction mixture as
quenched by adding glacial acetic acid (1 mL) dropwise, and extracted with water and
ethyl acetate (3 ꢃ 15 mL). The combined organic phase was washed with saturated
NH4Cl solution, water and brine, and then evaporated to dryness under reduced pres-
sure. The residue was purified by silica gel flash column chromatography, eluting with
petroleum ether/EtOAc, to give 1.48 g of 4 as a pale yellowish oil in 74% yield with up
1
to 98% de. Rf ¼ 0.24 (silica gel, petroleum ether/EtOAc 4/1); H NMR (400 MHz,
CDCl3) d 3.43 (q, J ¼ 6.3 Hz, 1H), 3.19–3.10 (m, 3H), 3.07 (dd, J ¼ 8.0, 4.7 Hz, 1H),
2.81–2.70 (m,1H), 2.18–1.55 (m, 10H), 1.49–1.38 (m, 1H), 1.34–1.21 (m, 2H), 1.14 (s,
3H), 0.92 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) d 67.9, 49.8, 47.5, 44.6, 43.2, 43.1,
35.7, 33.2, 32.2, 30.4, 30.2, 26.9, 26.4, 25.2, 20.4, 20.0 ppm. HRMS(ESI): calcd. for
C16H27N2O3S [M þ H]þ 327.1737; found 327.1740.
(S)-2-pipecolic acid (5)
Lithium hydroxide solution (1.78 mL, 4.4 mmol, 2.5 mol/L) was added to a stirred solu-
tion of 4 (0.48 g, 1.5 mmol) in THF (5 mL) at 0 ꢀC.[9] The resulting mixture was stirred

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5
at this temperature for an additional 1.0 h. THF was evaporated, the aqueous solution
was acidified with 1.0 mol/L hydrochloric acid to pH 2 and the mixture was extracted
with ethyl acetate (3 ꢃ 15 mL). The aqueous phase was neutralized with saturated
sodium bicarbonate solution to pH 6–7. and then evaporated to dryness under reduced
pressure. The residue was purified by flash column chromatography on silica gel, elut-
ing with EtOAc/MeOH, to give 152 mg of (S)-2-pipecolic acid 5 as a white solid in 81%
yield with 97.3% ee. Rf ¼ 0.28 (EtOAc/MeOH 2/1); m.p. 271-272 ꢀC (lit.[2] 271–274 ꢀC);
1
[a]2D5 ¼ ꢁ25.20 (c ¼ 1, H2O) (lit.2 [a]2D5 ¼ ꢁ25.90 (c ¼ 1, H2O));; H NMR (400 MHz,
D2O) d 3.47–3.43 (m, 1H), 3.30–3.26 (m, 1H), 2.91–2.84 (m, 1H), 2.11–2.06 (m, 1H),
1.77–1.70 (m, 2H), 1.55–1.43 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3) d 174.5, 58.9,
43.6, 26.5, 21.8, 21.5 ppm.
Funding
We are grateful to the National Natural Science Foundation of China [21877099], and Zhejiang
Provincial College Students’ Science and Technology Innovation Project and the National
Undergraduate Innovative Program [202010337038].
ORCID
Xingxian Zhang
http://orcid.org/0000-0003-4474-7600
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