Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides

Article abstract of DOI:10.1002/cctc.201600228

The synthesis of new chloramphenicol-base-derived thiourea organocatalysts, (1S,2R)-12 a–f and (1R,2R)-15 a–c, and their use in the enantioselective alcoholysis of meso-anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)-12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)-15 a–c. This technique was used to synthesize (R)-(?)-baclofen.

Full text of DOI:10.1002/cctc.201600228

DOI: 10.1002/cctc.201600228
Full Papers
Development of Bifunctional Thiourea Organocatalysts
Derived from a Chloramphenicol Base Scaffold and their
Use in the Enantioselective Alcoholysis of meso Cyclic
Anhydrides
Lin-Jie Yan, Hai-Feng Wang, Wen-Xue Chen, Yuan Tao, Kai-Jun Jin, and Fen-Er Chen*[a]
The synthesis of new chloramphenicol-base-derived thiourea
organocatalysts, (1S,2R)-12a–f and (1R,2R)-15a–c, and their use
in the enantioselective alcoholysis of meso-anhydrides are de-
scribed. In particular, hemiesters afforded excellent enantio-
selectivities if low loadings of (1S,2R)-12a–f were used. Almost
no enantioselectivities were achieved with the use of (1R,2R)-
15a–c. This technique was used to synthesize (R)-(À)-baclofen.
Introduction
The importance of the catalytic asymmetric desymmetrization
of meso cyclic anhydrides by alcoholysis in the formation of
chiral hemiesters with multiple stereocenters is difficult to
overestimate.[1] In recent decades, this method has become
a routine tool for the preparation of fine chemicals and phar-
maceutical compounds in the laboratory and on an industrial
scale and is used widely in asymmetric synthesis.[2] A range of
bifunctional organocatalysts based on thiourea (1) and sulfona-
mide (2) with several chiral scaffolds can be used in asymmet-
ric anhydride desymmetrization, for example, 1,2-diphenyl eth-
ylene diamine (3), 1,2-cyclohexanediamine (4), and 1,1’-bi-2-
naphthol (5; Figure 1). This field is largely dominated by the
use of cinchona alkaloids and their derivatives as catalysts.[3]
Previously,[4] we developed the bifunctional thiourea organo-
catalyst 6 derived from chloramphenicol base, a byproduct of
chloramphenicol production, as a chiral scaffold for the asym-
metric alcoholysis of meso cyclic anhydrides with excellent
enantioselectivities (up to 95% ee) and yields (up to 97%). In
this thiourea organocatalyst, the thiourea moiety is linked at
C-1 to the chloramphenicol base backbone. This profile over-
came the disadvantages that result from the high cost of cin-
chona alkaloids. The salient feature of these catalysts is benefi-
cial for further efficient catalyst development with substantially
reduced costs, which attracts our continuous endeavors into
this catalysis field. The effects of the positions of the thiourea
and amine moieties in this motif on the enantioselectivity and
efficiency of anhydride alcoholysis have been investigated ex-
Figure 1. Structures of the reported bifunctional organocatalysts.
tensively. An additional advantage of this strategy is that it en-
ables the investigation of the influence of the inversion of the
configuration at the C-1 position on the catalytic performance.
In this study, we concentrated on the regioisomers 12a–f
and 15a–c of organocatalyst 6, in which the thiourea unit is
linked to the chloramphenicol base scaffold at the C-2 posi-
tion, and evaluated the reactivities and enantioselectivities of
the new structural catalysts.
[a] L.-J. Yan, H.-F. Wang, Dr. W.-X. Chen, Y. Tao, K.-J. Jin, Prof. F.-E. Chen
Department of Chemistry
Fudan University
Shanghai 200433 (P.R. China)
E-mail: rfchen@fudan.edu.cn
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cctc.201600228.
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Desymmetrization of cyclic anhydrides with alcohols using
12a–f and 15a–c as catalysts
Results and Discussion
Synthesis of bifunctional thiourea organocatalysts derived
from (1S,2S)-2-amino-1-(p-nitrophenyl) propane-1,3-diol
The efficiencies of organocatalysts 12a–f and 15a–c in asym-
metric methanolysis were assessed using a representative sub-
strate, that is, meso cyclic anhydride 16a, in methyl tert-butyl
ether (MTBE) at room temperature. The results, which are sum-
marized in Table 1, show that the reaction varied greatly de-
pending on the organocatalyst used. Catalysts 12a–f, with the
(1S,2R) configuration, gave smooth desymmetrization to hemi-
esters 17a in moderate to high yields (86–93%) and with
A family of organocatalysts, that is, (1S,2R)-12a–f and (1R,2R)-
15a–c, was prepared from (1S,2S)-2-amino-1-(p-nitrophenyl)
propane-1,3-diol (7), that is, chloramphenicol base
(Scheme 1).[5] Treatment of 7 with di-tert-butyl dicarbonate
[(Boc)2O] in MeOH heated to reflux followed by O-silylation
with tert-butyldimethylsilyl chloride (TBSCl) in the presence of
imidazole and a catalytic amount of 4-dimethyl aminopyridine
(DMAP) provided the secondary alcohol 8 in 78% yield over
two steps. The secondary hydroxyl group in 8 was mesylated
with methanesulfonyl chloride (MsCl) and Et3N at 08C for
30 min. The resulting methanesulfonate was reacted directly
with sodium azide in DMF at room temperature. Subsequent
reduction by NaBH4/1,3-propanedithiol/Et3N in MeOH/iPrOH/
THF gave amine 13 in an overall yield of 30–45%.[6] Amino
group alkylation using a haloalkane and potassium carbonate
in acetonitrile heated to reflux produced amines 14a–c in
56–95% yields.[7] Amines 14a–c were coupled with isothiocya-
nate after the removal of the Boc group to yield the corre-
sponding catalysts 15a–c in 52–57% yields.
Catalysts 12a–e were synthesized by the inversion of the
configuration at C-1 in alcohol 8 under Mitsunobu reaction
conditions (PPh3/diisopropyl azodicarboxylate (DIAD)/benzoic
acid/THF), followed by a six-step transformation following the
same procedure as for the conversion of 8 to catalysts 15a–
c in overall yields of 4–13%. The catalyst 12 f was obtained in
an overall yield of 9% by removal of the Boc and TBS group of
dimethylamine 11 a with 2n HCl in boiling MeOH and coupling
with the isothiocyanate in CH2Cl2.
Table 1. Catalytic enantioselective alcoholysis of cyclic anhydride 16a
with MeOH.[a]
Entry
Catalyst
t
[h]
Yield
[%][b]
ee
[%][c,d]
1
2
3
4
5
6
7
8
9
12a
12b
12c
12d
12e
12 f
15a
15b
15c
36
36
36
36
36
36
48
48
48
93
87
92
88
86
90
43
61
65
92
90
79
90
88
74
À7
À12
À17
[a] Unless otherwise noted, all reactions were performed with anhydride
(0.5 mmol), MeOH (5.0 mmol), and catalyst (5 mol%) in MTBE (40 mL) at
RT. [b] Yield of isolated product. [c] Determined by HPLC after derivatiza-
tion. [d] Absolute configuration was determined by comparing the sign
of the optical rotation of the major enantiomer with known data.
Scheme 1. Synthesis of thiourea-based bifunctional organocatalysts derived from chloramphenicol base in this study. Conditions: a) (Boc)2O, MeOH, reflux,
20 min, then TBSCl, imidazole, DMAP, CH2Cl2, 08C~RT, 2 h, 78% yield over two steps. b) Ph3P, DIAD, benzoic acid, THF, 16 h, then K2CO3, MeOH, 1.5 h, 79%
yield over two steps. c) MsCl, Et3N, CH2Cl2, 08C, 0.5 h, then NaN3, DMF, RT, 16 h, then NaBH4, Et3N, iPrOH/MeOH/THF, 1,3-propanedithiol, 30–45% yield over
three steps. d) K2CO3, RX, MeCN, reflux, 16–36 h, 56–95% yield. e) CF3COOH, CH2Cl2, 08C, 24 h, then isothiocyanate, CH2Cl2, RT, 3 h, 31–58% yield over two
steps. f) 2n HCl, MeOH, reflux, 0.5 h, then isothiocyanate, CH2Cl2, RT, 3 h, 65% yield.
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good to excellent enantioselectivities (74–92%; Table 1, en-
tries 1–6). The (1S,2R)-12a catalyst gave the most promising re-
sults in terms of ee (92%) and chemical yield (93%) (Table 1,
entry 1). However, catalyst 12 f, without a TBS group, gave
a low enantioselectivity (74% ee; Table 1, entry 6).
Table 3. Asymmetric methanolysis of various cyclic anhydrides catalyzed
by 12a.[a]
Encouraged by the excellent results obtained with catalysts
12a–c, we next explored the effectiveness of the C-1 diastereo-
isomers 15a–c of these catalysts in the same anhydride alco-
holysis. Three catalysts, namely, 15a–c, with the opposite
stereochemistries, gave low chemical yields (43–65%) and
almost no enantioselectivities (7–17%) under the same reac-
tion conditions (Table 1, entries 7–9).
Entry
1
Anhydride
Product[b]
t
[h]
Yield
[%][c]
ee
[%][d]
36
93
92
Once we had identified the thiourea catalyst 12a as the best
catalyst, we investigated the solvent effect. The solvent affect-
ed the reactivity and enantioselectivity of the asymmetric
methanolysis of 16a at room temperature significantly. MTBE
was the best solvent tested (Table 2, entry 1); THF, acetonitrile,
2
3
4
5
6
36
48
88
86
80
85
90
91
87
91
90
77
120
48
Table 2. Optimization of the reaction conditions with catalyst 12a.[a]
96
Entry
x
n
Solvent
Concentration
[mol/L][b]
t
[h]
Yield
[%][c]
ee
7
72
96
96
96
96
96
84
96
98
95
87
97
70
79
79
75
82
83
[%][d,e]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
1
2
10
20
5
10
10
10
10
10
10
10
10
10
10
10
10
3
MTBE
THF
0.0125
0.0125
0.0125
0.0125
0.0125
0.025
36
36
36
36
36
24
12
12
62
42
18
12
48
36
93
82
90
81
92
87
93
98
69
68
92
93
73
76
92
83
68
71
64
89
89
87
87
88
92
90
91
89
8
toluene
MeCN
CH2Cl2
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
9
0.05
0.1
10
11
12
9
0.0125
0.0125
0.0125
0.0125
0.0125
0.0125
10
11
12
13
14
5
5
[a] Unless otherwise noted, all reactions were performed with anhydride
(0.5 mmol), MeOH (5.0 mmol), and catalyst in solvent at RT. [b] Refers to
the concentration of the anhydride in the solvent. [c] Yield of isolated
product. [d] Determined by HPLC after derivatization. [e] Absolute config-
uration was determined by comparing the sign of the optical rotation of
the major enantiomer with known data.
[a] Unless otherwise noted, all reactions were performed with anhydride
(0.5 mmol), MeOH (5.0 mmol), and catalyst 12a (5 mol%) in MTBE (40 mL)
at RT. [b] Absolute configuration was determined by comparing the sign
of the optical rotation of the major enantiomer with known data. [c] Yield
of isolated product. [d] Determined by HPLC or 1H NMR spectroscopy
after derivatization.
toluene, and CH2Cl2 gave moderate enantioselectivities and
moderate to good yields (Table 2, entries 2–5). Optimization of
the reaction concentration showed that the optimum value
was 0.0125m; the ee value reached 92%, which is better than
that achieved with a concentration of 0.025–0.1m (Table 2,
entry 1 vs. entries 6–8). Further investigation of the catalyst
loading disclosed that 5 mol% catalysts were sufficient to
maintain the chemical yield (93%) and the enantioselectivity
(92% ee; Table 2, entry 1 vs. entries 9–12). The proportion of
MeOH had little effect on the enantioselectivies (Table 2,
entry 1 vs. entries 13–14).
With the optimum catalyst 12a and reaction conditions es-
tablished, various meso cyclic anhydrides were evaluated as
substrates (Table 3). Bicyclic (Table 3, entries 1 and 2) and tricy-
clic (Table 3, entries 3–5) anhydrides were converted successful-
ly to the corresponding hemiesters in good yields (80–93%)
and with good enantioselectivities (87–92%). In contrast, the
methanolysis of various glutaric anhydrides required long reac-
tion periods; the enantioselectivities were lower (70–83%), but
nearly quantitative yields (95–98%) were obtained (Table 3, en-
tries 6–12).
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The strength and scope of the reaction were further evaluat-
ed, using model anhydride 16a and various alcohols under the
optimum conditions (Table 4). If methanol was replaced by
bulkier alcohols, the enantioselectivities decreased (Table 4, en-
tries 2–4 and 6); this is ascribed to steric hindrance. Propargyl
alcohol gave 90% enantioselectivity (Table 4, entry 5).
Table 4. Asymmetric alcoholysis of cyclic anhydride 16a with various al-
cohols.[a]
The proposed mechanism of catalytic methanolysis of meso-
anhydride 16a by catalyst 12a shown in Scheme 2 was consis-
tent with the mechanism reported previously by our group[4]
and others.[3r] The catalyst stabilized the transition state ana-
logues through hydrogen bonding between the tertiary amino
group and the protonated ether as well as between the thiour-
ea group and the oxyanion to form the catalyst-transition state
analogue complexes.
Entry
ROH
Hemiester
t
[h]
Yield
[%][b]
ee
[%][c,d]
1
2
3
4
5
6
methanol
ethanol
2-propanol
allyl alcohol
propargyl alcohol
benzyl alcohol
17a
17m
17n
17o
17p
17q
36
93
83
80
89
89
89
92
78
78
61
90
88
48
120
120
120
120
[a] Reactions were performed with anhydride 16a (0.5 mmol), ROH
(5.0 mmol), and catalyst 12a (0.025 mmol) in MTBE (40 mL) at RT. [b] Yield
of isolated product. [c] Determined by HPLC after derivatization. [d] Abso-
lute configuration was determined by comparing the sign of the optical
rotation of the major enantiomer with known data.
Catalysis of the asymmetric synthesis of (R)-(À)-baclofen by
12a
The synthetic utility of this method was investigated in the
enantioselective synthesis of (R)-(À)-baclofen, which is used
widely as an antispastic agent (Scheme 3).[8–10] The meso-anhy-
dride 16i was prepared, using the reported procedure, from
4-chlorobenzaldehyde 18 in 54% yield over three steps.[5b,11]
The asymmetric methanolysis of meso-anhydride 16i using
12a (10 mol%) at room temperature generated the corre-
sponding hemiester (R)-17i in 98% yield and with 80% ee. The
ee value improved to 95% after recrystallization from n-
hexane/EtOAc 20:1. The hemiester (R)-17i was converted to
(R)-(À)-baclofen hydrochloride (20) in 80% yield in two steps,
namely, the Curtius rearrangement and hydrolysis.[2d] M.p.
Scheme 2. Proposed mechanism for the catalytic methanolysis of meso-an-
hydride 16a by catalyst 12a.
Scheme 3. Application of 12a in the asymmetric synthesis of (R)-(À)-baclofen.
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182.1–185.68C, optical rotation: =À1.7 (c=0.5 in H2O) (lit.[2d]
=
´
ˇ
´
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We have developed a series of new bifunctional thiourea orga-
nocatalysts derived from a chloramphenicol base for the alco-
holysis of meso cyclic anhydrides. High enantioselectivity can
be achieved by the inversion of the configuration at C-1 in the
catalyst. The promising catalyst 12a was used to convert vari-
ous meso cyclic anhydrides to the corresponding hemiesters in
good yields and with good enantioselectivities. The use of al-
cohols other than methanol as nucleophiles in the desymmet-
rization reaction gave moderate enantioselectivities. This
method was used successfully in the synthesis of a g-aminobu-
tyric acid agonist, (R)-(À)-baclofen. Further investigation of the
applications of these new catalysts in other asymmetric trans-
formations is in progress.
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Experimental Section
Typical procedure for the alcoholysis of meso-anhydrides
An alcohol (5 mmol) was added dropwise at RT under N2 to
a stirred solution of an anhydride (0.5 mmol) and 12a (15.6 mg,
0.025 mmol) in MTBE (40 mL). The reaction was monitored by
using TLC. Once anhydride consumption was complete, the solvent
was evaporated under reduced pressure, and the residue was dis-
solved in CH2Cl2 (10 mL). The solution was washed with saturated
Na2CO3 (2ꢁ5 mL) and the combined aqueous layers were acidified
with excess 2n HCl, followed by extraction with EtOAc (3ꢁ20 mL).
The combined organic layers were dried over Na2SO4 and concen-
trated to afford the corresponding hemiester without further purifi-
cation by flash chromatography.
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Keywords: asymmetric catalysis · chirality · enantioselectivity ·
organocatalysis · synthesis design
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Received: February 25, 2016
Revised: April 15, 2016
Published online on && &&, 0000
ChemCatChem 2016, 8, 1 – 6
www.chemcatchem.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

FULL PAPERS
L.-J. Yan, H.-F. Wang, W.-X. Chen, Y. Tao,
K.-J. Jin, F.-E. Chen*
&& – &&
Development of Bifunctional Thiourea
Organocatalysts Derived from
a Chloramphenicol Base Scaffold and
their Use in the Enantioselective
Alcoholysis of meso Cyclic Anhydrides
Conversion by inversion: A series of
new chloramphenicol-base-derived thio-
urea organocatalysts is synthesized and
applied for the enantioselective alcohol-
ysis of meso-anhydrides. Hemiesters are
afforded with excellent enantioselectivi-
ties with a low loading of catalysts with
a (1S,2R) configuration. Almost no enan-
tioselectivity is achieved with the use of
their diastereoisomers, the (1R,2R) cata-
lysts. The utility of this technology is
demonstrated by the synthesis of (R)-
(À)-baclofen.
&
ChemCatChem 2016, 8, 1 – 6
www.chemcatchem.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!