Concise and efficient synthesis of eliglustat

Article abstract of DOI:10.1080/00397911.2017.1416636

Eliglustat, a ceramide glucosyltransferase inhibitor, was synthesized in six steps with 28.4% overall yield. The key features include the use of a diastereoselective aldol reaction to construct two contiguous stereocenters and a selective sulfonylation of a 1,3-diol catalyzed by dibutyltin oxide.

Full text of DOI:10.1080/00397911.2017.1416636

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Concise and efficient synthesis of eliglustat
Xiaoyu Liu, Xiaoyu Li, Hongguang Yang, Xiang Shi, Feilong Yang, Xiaozhen
Jiao & Ping Xie
To cite this article: Xiaoyu Liu, Xiaoyu Li, Hongguang Yang, Xiang Shi, Feilong Yang, Xiaozhen
Jiao & Ping Xie (2018) Concise and efficient synthesis of eliglustat, Synthetic Communications,
48:5, 594-600, DOI: 10.1080/00397911.2017.1416636
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 5, 594–599
https://doi.org/10.1080/00397911.2017.1416636
Concise and efficient synthesis of eliglustat
Xiaoyu Liu, Xiaoyu Li, Hongguang Yang, Xiang Shi, Feilong Yang, Xiaozhen Jiao,
and Ping Xie
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of
Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing, China
ABSTRACT
ARTICLE HISTORY
Received 8 October 2017
Eliglustat, a ceramide glucosyltransferase inhibitor, was synthesized
in six steps with 28.4% overall yield. The key features include the use
of a diastereoselective aldol reaction to construct two contiguous
stereocenters and a selective sulfonylation of a 1,3-diol catalyzed by
dibutyltin oxide.
KEYWORDS
Aldol reaction; eliglustat;
selective sulfonylation;
stereogenic centers
GRAPHICAL ABSTRACT
Introduction
Gaucher disease (GD), one of the commonest lysosomal storage disorder, is caused by
a deficiency of GBA1 gene, which encodes the β-glucocerebrosidase enzyme. It has been
estimated that the incidence in GD was approximately one in 57,000–75,000 globally.[1,2]
Although GD is relatively rare, it results in serious symptoms such as hepatomegaly,
splenomegaly, bone fraction, anemia, and even death. Based on the neurological
manifestations, GD is classified into three types. Type 1 GD, the most common style,
displays without neurological manifestations, types 2 and 3 GD are related to neurological
impairment.[3] Usually, enzyme replacement therapy or substrate reduction therapy is used
to cure type 1 GD.
Eliglustat (1) (Fig. 1), an orphan drug developed by Genzyme, is a ceramide glucosyl-
transferase inhibitor.[4–8] In 2014, eliglustat tartrate was granted approval by FDA (trade
name Cerdelga) for the treatment of adults suffering with Gaucher’s disease type I, a rare
genetic disease.
Due to the expensive cost of the treatment of the rare disease, an increasing number of
attention has been paid to find a concise and efficient route to synthesis of eliglustat. To
date, several elegant synthesis of eliglustat have been reported[9–14] (Scheme 1). The key
synthetic challenge toward its synthesis is how to construct the two contiguous stereogenic
CONTACT Xiaozhen Jiao
jiaoxz@imm.ac.cn
Institute of Materia Medica, Chinese Academy of Medical Sciences,
1st Xian Nong Tan St., Beijing 100050, China.
Supplemental data (full experimental detail, 1H and 13C NMR spectra) can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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Figure 1. The structure of eliglustat (1).
Scheme 1. Previous preparations of eliglustat (1).

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X. LIU ET AL.
centers with high efficiency. Genzyme corporation and Javed reported in the patent
literature the synthesis of eliglustat utilizing (s)-(þ)-2-phenylglycinol as a chiral source
via a seven-step synthesis.[9,11] Husain and Ganem devised a new route toward the key
intermediate of eliglustat utilizing a selective syn-addition of aryl Grignard reagents to
the Garner aldehyde.[12] Van den Berg et al. have also reported a novel synthesis of
eliglustat from a fully protected aminodiol (A).[13]
Recently, Xu, used by Suzhou MiracPharma Technology Co., Ltd, focused on the
construction of two contiguous stereogenic centers by an asymmetric Henry reaction.[14]
However, these methods above are either inefficient, lengthy or involving hazardous
conditions, expensive starting materials or reagents. Herein, we report a novel and efficient
synthesis of eliglustat in six linear steps utilizing the Crimmins aldol reaction.
Results and discussion
Our retrosynthesis of eliglustat is shown in Scheme 2. We envisioned the octanamide
portion could be installed via the reduction of the key azide 2 followed by simple acylation.
Intermediate 2 could be furnished from 3a or 3b, which is easily obtained via an
asymmetric aldol reaction.
Our synthesis began with Crimmins aldol reaction between auxiliary 4a or 4b[15] and
1,4-benzodioxan-6-carbaldehyde, using Frenck’s procedure[16] (TiCl4, DIPEA, N-methyl
pyrrolidone, −78 to −30 °C) to furnish the chiral azide alcohol 3a and 3b in good yields.
Initially, we utilized the thiazolidinethione, as we reasoned that we could take advantage
of its well characterized reactivity toward nucleophilic displacement as well as its facile
hydrolysis. After constructing the required stereocenters in eliglustat, we tried to directly
install the pyrrolidine moiety. We treated intermediate 3b with 4 equiv. pyrrolidine in
DMF to afford compound 8 in 56% yield.[17] However, all attempts to reduce 8 with LiAlH4
resulted in trace amounts of the required product 7 (Scheme 3).
Unsatisfied with the above result, and in addition, during our experiments toward above-
mentioned aldol reaction, we found that compound 3a is more stable compared with
compound 3b. As a result, we selected 3a as our advanced intermediate for large-scale prep-
aration. A four steps route was used to synthesize compound 7 from 3a (Scheme 4).
Reduction of compound 3a with NaBH4 in THF/H2O gave 1,3-diol 5 in 94% yield. With
5 in hand, we next investigated the introduction of the pyrrolidine moiety of eliglustat.
We initially attempted to use mesylate as a leaving group, however we observed formation
of the elimination product as the major product. We then turned our attention to selective
tosylation of the primary alcohol. All traditional attempts to tosylate the alcohol failed,
Scheme 2. Our retrosynthesis of eliglustat (1).

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Scheme 3. Preparation of 7. Reagents and conditions: (a) TiCl4, DIPEA, N-methyl pyrrolidone, −78 to
−30 °C, 40 min, for 3a 79%, dr > 98:2; for 3b 77%, dr 97:3 (diastereomeric ratio of 3a and 3b were
1
evaluated by H NMR analysis); (b) pyrrolidine, DMF, rt, 56%; (c) LiAlH4, 0–50 °C.
Scheme 4. Preparation of eliglustat. Reagents and conditions: (a) NaBH4, 0 °C, 0.5 h, 94%; (b) 0.02
equiv. Bu2SnO, 1 equiv. TsCl, Et3N, 0 °C to rt, 2 h, 72%; (c) pyrrolidine, DMF, 60 °C, 10 h, 87%;
(d) AlCl3/LiAlH4, THF, rt, 1 h; (e) 2,5-dioxopyrrolidin-1-yl octanoate, DIPEA, rt, 18 h, 61% for two steps.
however, to our delight when we performed the reaction under Bu2SnO catalysis for selective
sulfonylation of the primary hydroxyl group,[18] compound 6 was produced in excellent
yield. Treatment of compound 6 with 4 equiv. of pyrrolidine in DMF gave 2 in 87% yield.
Reduction of azide 2 in the presence of AlCl3/LiAlH4 gave 7 in high yield, which after acyla-
tion of the crude amine gave eliglustat (1) in 61% yield over two steps.
Conclusion
In conclusion, a concise and efficient synthesis of eliglustat has been achieved. Key steps of the
synthesis include a diastereoselective aldol reaction to construct two contiguous stereocenters
and a dibutyltin oxide catalyzed selective sulfonylation of a 1,3-diol. This proposed synthetic
route is straightforward, effective, and meaningful for commercial production.

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X. LIU ET AL.
Experimental
All the chemicals were purchased from commercial sources: Sigma-Aldrich Chemical Co.,
Arcos Chemical Co., and J&K Chemical Co. with the purity of more than 95%. Solvents
were dried according to standard procedures when needed. Flash column chromatography
was performed on Biotage Isolera one or performed on silica gel (200–300 mesh). IR
spectra were recorded on a Thermo Nicolet 5700 FT-IR microscope Centaurμs
spectrophotometer. 1H NMR and 13C NMR were recorded on Mercury 300, Mercury
400, Bruker AV500, AV600, JEOL ECZ400S spectrometer. Coupling constants are given
in Hz and chemical shifts are expressed as δ values in ppm. The following multiplicity
abbreviations are used: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet.
ESI-HRMS data were measured on Thermo Exactive Orbitrap plus spectrometer.
Typical experimental procedure for the key compounds
(2S,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-1-((S)-4-phenyl-2-
thioxooxazolidin-3-yl)propan-1-one (3a) and (2S,3R)-2-azido-3-(2,3-dihydrobenzo[b]
[1,4]dioxin-6-yl)-3-hydroxy-1-((S)-4-phenyl-2-thioxothiazolidin-3-yl)propan-1-one (3b)
Compound 4a or 4b (5 mmol) in CH2Cl2 was cooled to −78 °C, the mixture was treated
with TiCl4 (0.58 mL, 5.25 mmol), and stirred for 15 min. iPr2NEt (0.96 mL, 5.5 mmol)
was then added to the reaction mixture and stirred for 1 h. NMP (0.96 mL, 10 mmol)
was added and then the reaction mixture was stirred for 15 min, after which 1,4-benzo-
dioxan-6-carbaldehyde (1.23 g, 7.5 mmol) was added and stirred for 40 min at −30 °C.
Then the reaction was quenched by saturated NH4Cl aqueous solution, diluted with ethyl
acetate (150 mL) and washed with brine, dried and evaporated to afford the crude product,
which was purified by recrystallization (EtOAc/petroleum ether, �1:15, 0 °C) to give 3a
(yellow solid, 1.2 g, dr > 98:2), yielded 79%; 3b (yellow solid, 1.7 g, dr 97:3), yielded 77%
separately. For 3a mp 55–57 °C; ½a�2D0 þ 39 (c, 1.0, CHCl3); H NMR (400 MHz, CDCl3)
1
δ 7.27–7.42 (m, 5H), 6.86–7.02 (m, 3H), 6.31 (d, J ¼ 4.8 Hz, 1H), 5.52 (dd, J ¼ 2.8 Hz,
8.0 Hz, 1H), 5.23 (d, J ¼ 5.2 Hz, 1H), 4.63 (t, J ¼ 8.8 Hz, 1H), 4.43 (dd, J ¼ 3.2 Hz,
9.2 Hz, 1H), 4.26 (s, 4H); 13C NMR (150 MHz, CDCl3) δ 184.9, 169.0, 143.8, 143.6,
137.7, 132.1, 129.3, 129.1, 125.8, 119.3, 117.4, 115.4, 74.5, 74.0, 65.3, 64.4, 64.3, 62.8;
HR-MS (ESI) calcd for C20H18O5N4SNa (M þ Na)þ: 449.0890, found 449.0870. For 3b
mp 57–59 °C; ½a�2D0 þ 219 (c, 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.27–7.40 (m,
1
5H), 6.87–7.00 (m, 3H), 6.21 (d, J ¼ 5.6 Hz, 1H), 5.77 (d, J ¼ 7.2 Hz, 1H), 5.07 (d, J ¼ 6.0
Hz, 1H), 4.27 (s, 4H), 3.55 (dd, J ¼ 7.6 Hz, 10.8 Hz, 1H), 3.02 (dd, J ¼ 1.2 Hz, 10.8 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 202.7, 169.7, 143.9, 143.7, 134.0, 131.9, 129.1, 128.6, 125.2,
119.4, 117.4, 115.4, 74.9, 70.4, 66.8, 64.4, 64.3, 37.5; HR-MS (ESI) calcd for C20H18O4S2-
N4Na (M þ Na)þ: 465.0662, found 465.0642.
(2R,3R)-2-azido-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropyl
4-methylbenzenesulfonate (6)
To a solution of the alcohol 5 (1.15 g, 4.58 mmol) in CH2Cl2 (60 mL) were added Bu2SnO
(23 mg, 0.1 mmol), the reaction was stirred at 0 °C for 5 min, then Et3N (0.67 mL,
4.58 mmol) was added dropwise, at last, p-TsCl (873 mg, 4.58 mmol) was added to the
mixture. The reaction mixture was stirred at 0–10 °C for 4 h. H2O was added, then the
mixture was extracted with EtOAc (3 � 50 mL), and the combined organic layers were

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washed with brine (50 mL) and then dried (MgSO4). The mixture was filtered, and the
filtrate was concentrated in vacuo to give the crude product, which was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 1:5) to give 6 (1.3 g, 72%) as a color-
less oil. ½a�2D0 À 47 (c, 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 7.78 (d, J ¼ 8.4 Hz, 2H),
1
7.36 (d, J ¼ 8.4 Hz, 2H), 6.83 (d, J ¼ 6.4 Hz, 1H), 6.82 (s, 1H), 6.73–6.76 (m, 1H), 4.59
(d, J ¼ 6.4 Hz, 1H), 4.26 (s, 4H), 4.09 (dd, J ¼ 3.6 Hz, 10.4 Hz, 1H), 3.90 (dd, J ¼ 7.2 Hz,
10.4 Hz, 1H), 3.68–3.73 (m, 1H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 145.2,
143.9, 143.8, 132.3, 129.9, 128.0, 119.2, 117.6, 115.2, 72.97, 68.8, 65.8, 64.3; HR-MS (ESI)
calcd for C18H19O6 N3SNa (M þ Na)þ: 428.0887, found 428.0869.
Funding
We are grateful to CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3-009) for
financial support.
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