A Concise Enantioselective Synthesis of (S)-Preclamol via Asymmetric Catalytic Negishi Cross-Coupling Reaction

Article abstract of DOI:10.1055/s-0037-1611759

A novel, concise, and efficient enantioselective synthesis of (S)-preclamol (87% ee, 51% total yield) has been developed. The key steps of this synthetic approach included cobalt-catalyzed asymmetric catalytic cross-coupling of α-bromo ester with arylzinc and the reduction of chiral ester to diol with a tertiary carbon atom. Moreover, it was demonstrated that our enantioselective Negishi cross-coupling was a powerful tool to construct stereogenic benzylmethyl center in chiral drugs on a gram scale.

Full text of DOI:10.1055/s-0037-1611759

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© Georg Thieme Verlag Stuttgart · New York
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Y. Zhou et al.
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A Concise Enantioselective Synthesis of (S)-Preclamol via Asymmetric
Catalytic Negishi Cross-Coupling Reaction
Yun Zhou◊
ZnBr
O
O
Chunxiao Liu◊
Lifeng Wang
Leng Han
BnO
OBn
O
O
OMe
BnO
OBn
Br
10 mol% CoI2
12 mol% L1
Shicong Hou
Qinghua Bian
Jiangchun Zhong*
OMe
F
F
HO
N
Department of Applied Chemistry,China Agricultural University2,
West Yuanmingyuan Road, Beijing 100193, P. R. of China
zhong@cau.edu.cn
O
O
(S)-preclamol
87% ee, 51% total yield
N
N
L1
Bn
Bn
◊ These authors contributed equally to this work and should be
considered as co-first authors
Received: 21.02.2019
Accepted after revision: 21.02.2019
Published online: 26.03.2019
through 10 steps.13 Moreover, Thorberg and Imhof founded
the drawback of conventional resolution processes from ra-
cemic 3-(3-methoxyphenyl)-N-propyl piperidine or prec-
lamol was that the maximum yield of desired enantiomer
was limited to 50%.11,12 Therefore, it remains highly desir-
able to develop more concise and efficient enantioselective
synthesis of (S)-preclamol.
DOI: 10.1055/s-0037-1611759; Art ID: st-2019-r0020-l
Abstract A novel, concise, and efficient enantioselective synthesis of
(S)-preclamol (87% ee, 51% total yield) has been developed. The key
steps of this synthetic approach included cobalt-catalyzed asymmetric
catalytic cross-coupling of -bromo ester with arylzinc and the reduc-
tion of chiral ester to diol with a tertiary carbon atom. Moreover, it was
demonstrated that our enantioselective Negishi cross-coupling was a
powerful tool to construct stereogenic benzylmethyl center in chiral
drugs on a gram scale.
HO
N
Key words (S)-preclamol, enantioselective Negishi cross-coupling,
(S)-preclamol
cobalt, asymmetric synthesis, chiral drug
Figure 1 The structure of (S)-preclamol
(S)-Preclamol [(–)-3-PP, Figure 1] is a central dopamine
(DA) receptor agonist, which activates DA autoreceptors,
and acts as an antagonist at postsynaptic DA receptors con-
comitantly.1,2 Therefore, (S)-preclamol may be used to treat
neurological disorders such as schizophrenia3,4 and Parkin-
son's disease, while lacking the side effect of motor dys-
functions.5 Furthermore, (S)-preclamol has been as a phar-
macological tool to study dopaminergic mechanisms.6–9
Due to its significant pharmacological activities, (S)-prec-
lamol has been attracting many chemist’s interesting. The
main synthetic strategies are based on the resolution of ra-
cemic compounds including methyl 5-oxo-4-phenylpenta-
noate,10 3-(3-methoxyphenyl)-N-propylpiperidine,11 and
preclamol;12 deriving from L-pipecolinic acid,13 and asym-
metric catalytic reactions involving Suzuki–Miyaura cou-
pling of heterocycles,14 hydrogenation of -substituted lac-
tones,15 allylic alkylation of branched carbonates,16 allylbo-
ration of alkenes,17 or allyl-allyl cross-coupling of allylic
alcohols.18 However, there are some limitations associated
with these reported processes. For example, Wu and co-
workers demonstrated that (S)-preclamol could be pre-
pared from stoichiometric amounts of L-pipecolinic acid
Asymmetric cross-coupling reactions of organic halides
with organozinc reagents can construct tertiary and quater-
nary stereogenic centers.19 Recently, we have disclosed en-
antioselective cross-coupling of racemic -bromo esters
with arylzincs (up to 97% ee and 98% yield), which was the
first cobalt-catalyzed enantioselective Negishi cross-cou-
pling.20 To search more efficient and convenient asymmet-
ric synthesis of (S)-preclamol and to expand application of
our methodology, herein, we have developed a novel, con-
cise, and efficient asymmetric catalytic synthesis of (S)-
preclamol with 87% ee in 51% total yield and demonstrated
that cobalt-catalyzed enantioselective Negishi cross-cou-
pling of -bromo esters with arylzincs is a powerful tool to
construct stereogenic benzylmethyl center in chiral drugs
on a gram scale.
In view of retrosynthetic analysis of (S)-preclamol
(Scheme 1), the key step is the construction of tertiary ste-
reogenic center at the benzylmethyl position, which is envi-
sioned to be formed by (R,R)-L1/CoI2-catalyzed asymmetric
cross-coupling of racemic dibenzyl 2-bromopentanedioate
(1) with (3-methoxyphenyl)zinc bromide (2) directly. Sub-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C

B
Y. Zhou et al.
Paper
Synlett
sequent reduction of chiral ester (S)-3 with LiAlH4 can af-
ford the main chiral intermediate (S)-4. The chiral diol (S)-4
can be converted into the target (S)-preclamol via sequen-
tial reactions of activation with methanesulfonyl chloride,
the ring-closing amination with n-propylamine, and de-
methylation with hydrobromic acid.
Table 1 The Asymmetric Negishi Cross-Coupling of 2-Bromopentanedioatea
F
F
ZnBr
O
O
2
N
N
O
O
OMe
Bn
Bn
L1
+
BnO
OBn
HO
OH
O
O
CoI2, THF, –25 °C
HO
N
BnO
OBn
OMe
Br
OMe
rac-1
(S)-3
(S)-preclamol
(S)-4
Entry
Catalyst (%)
Yield (%)b
ee (%)c
O
O
1
10
5
90
78
43
93
87
86
81
87
BnO
OBn
2
3
2
4d
10
OMe
(S)-3
a All reactions were performed on 0.5 mmol unless specified otherwise.
b Isolated yield after chromatographic purification.
c Determined by chiral HPLC with a Daicel Chiralcel OD-H column.
d The reaction was conducted on 5.0 mmol.
ZnBr
O
O
BnO
OBn
Br
OMe
rac-1
2
with the catalyst of bisoxazoline L1 and CoI2. This stereo-
convergent reaction furnished 1.94 g of (S)-dibenzyl 2-(3-
methoxyphenyl)pentanedioate (3) with 87% ee in 93%
yield.20,22 Subsequent reduction of chiral ester (S)-3 with Li-
AlH4 afforded (S)-2-(3-methoxyphenyl)pentane-1,5-diol (4)
without erosion of ee.23 Finally, chiral diol (S)-4 was activat-
ed with methanesulfonyl chloride followed by the ring-
closing amination with n-propylamine and cleavage of the
methyl ether with hydrobromic acid to give the target (S)-
preclamol (87% ee, 61% yield, over 3 steps).17 The specific
rotation and NMR spectrum of (S)-preclamol prepared
herein ([]D23 –16.3 (c 2.5, CHCl3)) were matched to the lit-
erature value ([]D20 –16.7 (c0.33, CHCl3)).17
Scheme 1 Retrosynthetic analysis of (S)-preclamol
Based on the retrosynthetic analysis of (S)-preclamol,
our research began with the asymmetric catalytic cross-
coupling of dibenzyl 2-bromopentanedioate (1) with (3-
methoxyphenyl)zinc bromide (2, Table 1). Although this en-
antioselective cross-coupling was not examined in our pre-
vious research,20 it was very lucky that ester 1 and arylzinc
reagent 2 were compatible with our bisoxazoline L1/CoI2
catalyst system. The chiral coupling product (S)-3 was ob-
tained with 87% ee in 90% yield under optimal reaction con-
ditions (Table 1, entry 1). To reduce the cost, we surveyed
the effect of catalyst loading on the synthesis of chiral ester
(S)-3. As the mount of catalyst was decreased to 5 mol%,
eantioseletivity was remained high (86%) with a small drop
of reactivity (78% yield, Table 1, entry 2). Further decrease
in catalyst loading to 2 mol% had a detrimental impact on
the product ee, but a dramatic decline in yield (Table 1, en-
try 3 vs entry 1). To our pleasure, this stereoconvergent re-
action could easily be performed on gram scale with high
eantioseletivity and reactivity (Table 1, entry 4).
O
O
ZnBr
10 mol% CoI2
12 mol% L1
BnO
OBn
OBn
+
THF, –25 °C
Br
OMe
93% yield, 87% ee
2
rac-1, 5 mmol, 1.97 g
O
O
HO
OH
BnO
LiAlH4, THF
–78 °C to rt
90% yield, 87% ee
OMe
(S)-4
OMe
With the success of the enanotioselective cross-cou-
pling, asymmetric synthesis of (S)-preclamol was explored
(Scheme 2). The initial step was the preparation of arylzinc
reagent 2 from (3-methoxyphenyl)magnesium bromide
and ZnBr2.21 A gram-scale enantioselective cross-coupling
of racemic dibenzyl 2-bromopentanedioate (1, 5 mmol,
1.97 g) with the arylzinc reagent 2 was then conducted
(S)-3, 1.94 g
(1) MsCl, Et3N, CH2Cl2, 0 °C to rt
HO
N
(2) n-PrNH2, rt
(3) HBr, 120 °C
(S)-preclamol
61% yield, 3 steps, 87% ee
Scheme 2 Enantioselective synthesis of (S)-preclamol
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C

C
Y. Zhou et al.
Paper
Synlett
In conclusion, we have developed a novel, concise, and
efficient enantioselective synthesis of (S)-preclamol with
87% ee in 51% total yield. The main strategies in our syn-
thetic approach involed cobalt-catalyzed asymmetric cata-
lytic cross-coupling of -bromo ester with arylzinc and the
reduction of chiral ester to diol with a tertiary stereogenic
center. Furthermore, we also demonstrated that our enanti-
oselective Negishi cross-coupling was a powerful tool to
construct stereogenic benzylmethyl center in chiral drugs
on a gram scale.
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(b) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756. (c) Binder,
J. T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 17003.
(d) Choi, J.; Martín-Gago, P.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
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(S)-3
Funding Information
We are thankful to the National Key Technology Research and Devel-
opment Program of China (No. 2017YFD0201404) for the financial
support.()
Magnesium turnings (1.46 g, 60 mmol) were placed in a two-
neck 250 mL Schlenk flask equipped with funnel, and the flask
was heated at 80 °C for 1 h under an argon atmosphere. After
being cooled to room temperature, anhydrous THF (50 mL) and
1-bromo-3-methoxybenzene (1.87 g, 10 mmol) were added
sequentially. The reaction was initiated by gently heating with a
heat gun, and additional 1-bromo-3-methoxybenzene (7.48 g,
40 mmol) in THF (10 mL) was added dropwise. The resulting
mixture was stirred and refluxed for 2 h. The concentration of pre-
pared (3-methoxyphenyl)magnesium bromide was titrated with I2.
ZnBr2 (10.12 g, 45 mmol) was placed in another 250 mL Schlenk
flask and was heated at 100 °C for 1.5 h under an argon atmo-
sphere. After being cooled to ambient temperature, anhydrous
THF (68.8 mL) was added, and the resulting mixture was stirred
for 10 min. The prepared (3-methoxyphenyl)magnesium
bromide (30 mmol, 0.586 M in THF, 51.2 mL) was added via
syringe over 25 min. The resulting mixture was stirred for 2 h at
room temperature.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611759.
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References and Notes
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a separate 100 mL Schlenk tube and heated at 80 °C for 2 h in
vacuo. After being cooled to room temperature under an argon
atmosphere, anhydrous THF (10 mL) and L1 (330 mg, 0.60
mmol) in THF (5 mL) were added. The mixture was stirred for 2
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ate (1, 1.97 g, 5.0 mmol) was added via syringe. The resulting
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mL). The combined organic layers were dried over anhydrous
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methoxyphenyl)pentanedioate (3, 1.94 g, 93% yield, 87% ee) as a
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220 nm, minor tR = 22.27 min (R), major tR = 25.49 min (S)).
[]D23 + 24.6 (c 1.3, CHCl3). 1H NMR (300 MHz, CDCl3):  = 7.34–7.18
(m, 11 H), 6.84–6.79 (m, 3 H), 5.15–5.04 (m, 4 H), 3.74 (s, 3 H), 3.64
(t, J = 7.4 Hz, 1 H), 2.45–2.33 (m, 1 H), 2.31 (t, J = 7.4 Hz, 2 H), 2.20–
2.09 (m, 1 H).13C NMR (75 MHz, CDCl3):  = 173.0, 172.6, 159.8,
139.5, 135.87, 135.80, 129.7, 128.5, 128.4, 128.2, 128.1, 127.9,
120.4, 113.5, 113.1, 66.5, 66.3, 55.1, 50.5, 31.8, 28.2. HRMS (ESI):
m/z calcd for C26H27O5 [M + H]+419.1853; found: 419.1840.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C