Asymmetric synthesis of l-carnitine from (R)-3-chloro-1,2-propanediol

Article abstract of DOI:10.1016/j.cclet.2011.01.007

A practical chemical synthesis of l-carnitine (1) has been accomplished from (R)-3-chloro-1,2-propanediol ((R)-4), which is a main by-product originated from (R,R)-Salen Co(III) catalyzed hydrolytic kinetic resolution (HKR) of (±)-epichlorohydrin. (R)-4 was utilized as a chiral starting material to prepare the key intermediate cyclic sulfite ((R)-5). The new synthetic approach demonstrated an efficient utilization of organic by-product for the asymmetric synthesis of bioactive compounds.

Full text of DOI:10.1016/j.cclet.2011.01.007

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 765–767
www.elsevier.com/locate/cclet
Asymmetric synthesis of L-carnitine from
R)-3-chloro-1,2-propanediol
(
*
Xu Qin Li, Yun Xu Yang , Wei Li Wang, Bin Hu, Hui Min Xue,
Tian Yi Zhang, Xue Tao Zhang
Department of Chemistry, University of Science and Technology Beijing, Beijing 100083, China
Received 26 October 2010
Available online 17 April 2011
Abstract
A practical chemical synthesis of L-carnitine (1) has been accomplished from (R)-3-chloro-1,2-propanediol ((R)-4), which is a
main by-product originated from (R,R)-Salen Co(III) catalyzed hydrolytic kinetic resolution (HKR) of (ꢀ)-epichlorohydrin. (R)-4
was utilized as a chiral starting material to prepare the key intermediate cyclic sulfite ((R)-5). The new synthetic approach
demonstrated an efficient utilization of organic by-product for the asymmetric synthesis of bioactive compounds.
#
2011 Yun Xu Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: L-Carnitine; Cyclic sulfite; (R)-3-Chloro-1,2-propanediol
L-Carnitine (1) plays an important role in the transport of long-chain fatty acids into mitochondria where b-
oxidation takes place. Its relevance to the long-chain fatty acids degradation and the consequent energy production
makes it a widespread dietary supplement for athletic performance as well as for weight loss. L-Carnitine and its
derivatives also exhibit a noticeable antidiabetic activity because the long-chain free fatty acids transport by carnitine
is connected to the glucose metabolism [1–3]. Thus the increasing requirement led to the development of procedures
for synthesis of L-carnitine. Several approaches have been reported in the literature for the synthesis of carnitine and its
analogs including asymmetric syntheses [4], natural chiral resource oriented synthesis [5], chemical resolution [6] and
others [7], but only a few of them are practical.
Theconventionalsynthesis of L-carnitine is starting from (S)-epichlorohydrin (3) [8], whichcanbe prepared on a large
scale by Salen Co(III) catalyzed hydrolytic kinetic resolution (HKR) of (ꢀ)-epichlorohydrin (2) (Scheme 1) [9]. But at
the same time a large amount of by-product (R)-3-chloro-1,2-propanediol ((R)-4) was produced. According to
toxicological experiment, (R)-4 was genotoxic in humans and has anti-fertility effects in male rats [10], and the
discharged (R)-4 will cause serious environmental problems. As may be seen, this process embodies low atom-economy
and not good for environmental protection. This led us to investigate a synthetic method of L-carnitine from (R)-4.
We herein describe an efficient and distinctly different method for the synthesis of L-carnitine. The salient feature of
this approach resides in the use of (R)-4 as a chiral starting material and employing the cyclic sulfite (R)-5 as a key
*
Corresponding author.
E-mail address: yxyang63@yahoo.com.cn (Y.X. Yang).
1001-8417/$ – see front matter # 2011 Yun Xu Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.01.007

[()TD$FIG]
766
X.Q. Li et al. / Chinese Chemical Letters 22 (2011) 765–767
Scheme 1.
[()TD$FIG]
O
O
S
1) KCN
OH
H
OH
SOCl2
H
H
Cl
OH
Cl
O
Cl
CN
CH2Cl2
2) 20% H2SO4
(
R)-4
(R)-5
(R)-6
O
OH
H
N
OH
) H+
H
NMe3 HCl
1
CN
N
2
) ion exchange
resin
O
Cl
(
R)-7
L-carnitine 1
Scheme 2.
intermediate. The ready availability and its highly enantiopurity of by-product (R)-4 allow us to complete the
asymmetric synthesis of L-carnitine. The synthetic strategy is outlined in Scheme 2.
The HKR of (ꢀ)-epichlorohydrin (2) catalyzed by (R,R)-Salen Co(III) affords both recovered unreacted epoxide
(
S)-3 in 41% yield (99% ee) and 1,2-diol product (R)-4 in 40% yield (96% ee). Then (R)-4 was used as starting material
for the synthesis of L-carnitine. After reacted with thionyl chloride for 2 h, (R)-4 could be easily converted to cyclic
sulfite (R)-5 in 94% yield which was a key intermediate. We performed a regioselective ring-opening cyanation
reaction of (R)-5 with KCN at 45 8C for 4 h, subsequently treated with 20% H SO to afford (R)-4-chloro-3-
2
4
2
5
hydroxybutyronitrile ((R)-6) in a yield of 80% (½aꢁ +7.2 (c 3.0, CHCl )). (R)-6 was then treated with aqueous
D
3
trimethylamine according to the reported method to generate hydroxynitrile ammonium (R)-7, the crude product was
2
D
5
further recrystallized from ethanol to obtain pure (R)-7 in 80% yield (m.p. 246.7–247.9 8C, ½aꢁ ꢂ26.5 (c 1.0, H O)).
2
(R)-7 was hydrolyzed directly in the presence of concentrated HCl to obtain L-carnitine hydrochloride salt in 100%
yield, then the hydrocholoride in the salt was removed by anion exchange resin 717, after evaporation, the crude
2
5
product recrystallized from ethanol to obtain pure L-carnitine (m.p. 195.0 8C; ½aꢁ ꢂ31.0 (c 10, H O)) [11].
D
2
In summary, we report a new asymmetric synthetic method for L-carnitine utilizing a chiral propanediol precursor.
The key features in this strategy are the by-product (R)-3-chloro-1,2-propanediol as starting material, cyclic sulfite
formation reaction, the site-directed regiocontrolled cyanation reaction, good yield and high enantiomeric purity.
Additionally, the new synthetic route also demonstrated a potential utilization of organic by-product in the synthesis of
bioactive compounds.
Acknowledgments
The Project Sponsored by the National Natural Science Foundation of China (No. 20972015), the Natural Science
Foundation of Beijing (No. 2082016) and the Science and Technology Innovation Foundation for the College Students
of Beijing (No. B091000814).
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