Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

Article abstract of DOI:10.3762/bjoc.14.19

A family of novel chloramphenicol base-amide organocatalysts possessing a NH functionality at C-1 position as monodentate hydrogen bond donor were developed and evaluated for enantioselective organocatalytic alcoholysis of meso-cyclic anhydrides. These structural diversified organocatalysts were found to induce high enantioselectivity in alcoholysis of anhydrides and was successfully applied to the asymmetric synthesis of (S)-GABOB.

Full text of DOI:10.3762/bjoc.14.19

Novel amide-functionalized chloramphenicol base
bifunctional organocatalysts for enantioselective
alcoholysis of meso-cyclic anhydrides
Lingjun Xu, Shuwen Han, Linjie Yan, Haifeng Wang, Haihui Peng* and Fener Chen*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 309–317.
Department of Chemistry, Fudan University, Shanghai 200433, PR
China
doi:10.3762/bjoc.14.19
Received: 09 November 2017
Accepted: 22 January 2018
Published: 31 January 2018
Email:
Haihui Peng* - haihui_peng@fudan.edu.cn; Fener Chen* -
rfchen@fudan.edu.cn
Associate Editor: M. Rueping
* Corresponding author
© 2018 Xu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alcoholysis desymmetrization; bifunctional organocatalysis;
chloramphenicol base
Abstract
A family of novel chloramphenicol base-amide organocatalysts possessing a NH functionality at C-1 position as monodentate
hydrogen bond donor were developed and evaluated for enantioselective organocatalytic alcoholysis of meso-cyclic anhydrides.
These structural diversified organocatalysts were found to induce high enantioselectivity in alcoholysis of anhydrides and was suc-
cessfully applied to the asymmetric synthesis of (S)-GABOB.
Introduction
Over the past decade, remarkable advances in the utilization of tional urea 1 [35], thiourea 2 and 3 [36,37], sulfonamide 4 [38-
natural products as chiral structural motifs for the design of 40] and squaramide 5 [38-40] catalysts derived from chlor-
bifunctional organocatalysts have been achieved. A high stereo- amphenicol base (Figure 1), which showed excellent reactivity
control in alcoholytic catalytic asymmetric desymmetrizations and enantioselectivity for this asymmetric transformation. A
of meso-cyclic anhydrides is of special interest [1-7]. Major typical example of the great utility of chloramphenicol base
families originating from natural products include cinchona scaffold in industrial production of enantiopure compounds is
alkaloids [8-17] and proteinogenic α-amino acids such as the synthesis of a precursor of biotin (vitamin H) by the chlor-
proline [18-20] and valine [21] etc. [22-29], while fully synthe- amphenicol base-promoted asymmetric methanolysis of meso-
tic catalysts are rare, only involving Brønsted acid/base cata- cyclic anhydrides [41-43].
lysts [30], cyclohexanediamine catalysts [31,32], and diphenyl-
ethylenediamine catalysts [33,34]. Significant progress in our Despite extensive studies on chloramphenicol-base-derived
laboratory has been made in the development of chiral bifunc- bifunctional derivatives catalyzed asymmetric alcoholysis of an-
309

Beilstein J. Org. Chem. 2018, 14, 309–317.
Figure 1: Chloramphenicol-base-derived bifunctional organocatalysts.
hydride, the exploration of new effective and easily accessible In the precedented urea- or thiourea-based organocatalytic
fully synthetic organocatalysts through further modification of methanolysis of anhydrides, one big problem is the homo-
this privilege motif are always needed. Our present design is aggregation of the catalysts via hydrogen bonding, which de-
inspired by cinchona-derived sulfonamides, first developed by creased the reactivity and enantioselectivity and required diluted
Song and co-workers [44-46]. Because of its easy availability concentrations with low temperatures [47]. With the new chlor-
and unique stereochemical aspect, we were therefore intrigued amphenicol base amide organocatalysts we envisioned that the
by the possibility of modifying the chloramphenicol base struc- presence of a bulky oxygen group could avoid the intermolecu-
tural backbone by virtue of substituting the hydroxy group at lar aggregation of the catalyst, while keeping the desired bifunc-
C-1 position by a simple amide moiety as monodentate hydro- tional Brønsted acid/base reactivity for enantioselective desym-
gen bond donor to activate the electrophile (anhydride), whilst metrization of anhydrides [48,49].
retaining the tertiary amine functionality to activate the nucleo-
phile (alcohol, Figure 2). As part of our ongoing research Results and Discussion
program on chloramphenicol base organocatalysis, herein, we A series of new chloramphenicol based-amide bifunctional
report a new class of chloramphenicol-derived bifunctional catalysts 7a–q (Scheme 1) were synthesized from the appro-
amide organocatalysts and their application for enantioselective priate optically pure (1R,2R)-diamine 6, prepared via several
alcoholysis of meso-cyclic anhydrides.
steps from chloramphenicol base [50]. In general, the synthesis
Figure 2: Design of new chloramphenicol base amide organocatalysts.
310

Beilstein J. Org. Chem. 2018, 14, 309–317.
Scheme 1: Synthesis of bifunctional amide catalysts 7a–q.
is straightforward and well-compatible to electronically-diversi- anhydride 8a was carried out in various conditions with
fied amides. Particularly, electron-deficient amides performed 10 equivalents of methanol. Resultingly, this novel Brønsted
better. With 3,5-(CF3)2-disubstituted amide, the corresponding acid/base catalysts 7a–q proved to be sufficiently active and
pruduct 7i was achieved with 90% yield. Different protecting gave the monoester product with high yield and superior enan-
groups for the nitrogen at the C-2 position and oxygen at C-3 tioselectivity, suggesting the unique reactivity of this amide-
are also investigated to yield the desired chiral catalysts using a based chloramphenicol scaffold.
simple procedure.
Electronic effects were first investigated. Generally, electron
With various bifunctional catalysts in hand, assessment of their deficient catalysts gave better reactivity and enantioselectivity
catalytic behavior in enantioselective alcoholysis of meso-cyclic than electron-rich variants (Table 1, entries 1–9). Among them,
Table 1: Conditions screening for asymmetric methanolysis of meso-cyclic anhydrides.
Entry
Cat.
Solvent
Conc. (M)
T (°C)
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
4
7a
7b
7c
7d
MTBE
MTBE
MTBE
MTBE
0.05
0.05
0.05
0.05
20
20
20
20
34
36
40
46
91
94
95
94
84
80
77
80
311

Beilstein J. Org. Chem. 2018, 14, 309–317.
Table 1: Conditions screening for asymmetric methanolysis of meso-cyclic anhydrides. (continued)
5
7e
7f
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Toluene
MeOH
MTBE
MTBE
MTBE
MTBE
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.0125
0.1
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
48
58
99
100
99
100
95
85
99
100
95
91
97
98
93
96
91
99
95
99
92
83
78
72
76
92
80
71
58
84
76
82
68
54
79
10
94
87
95
96
6
7
7g
7h
7i
96
8
48
9
17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
7j
20
7k
7l
58
216
28
7m
7n
7o
7p
7q
7i
24
192
240
58
14
7i
18
7i
86
7i
12
7i
0.05
0.05
120
384
7i
−20
aIsolated yield. bDetermined by HPLC after conversion to amide derivatives with (S)-1-phenylethylamine. cThe absolute configuration was determined
by comparing with literature report.
7i performed best with 95% yield and 92% ee in 17 h (Table 1, tion or low down the temperature of the reaction didn’t alter the
entry 9). The surprising reactivity with this electron-poor 7i yield or enantioselectivity, suggesting the concentration/temper-
suggested that the pKa is crucial for this catalysis. Further mod- ature independence of this catalytic system (Table 1, entries
ifications of the chloramphenicol skeleton with various 20–23). These results implicated that there is no significant
protecting groups on the nitrogen at C-2 position and oxygen at aggregation of catalysts in this system.
C-3 did not improve the reaction but with lowered enantioselec-
tivity (Table 1, entries 10–16). Notably, with methyl-protected This bifunctional Brønsted acid/base catalyst 7i proved to be
catalyst 7q, this reaction proceeded with longer reaction time highly active toward asymmetric methanolysis of various meso-
but with decreased enantioselectivity, suggesting the effects of a cyclic anhydrides. As shown in Table 2, various cyclic anhy-
bulky ether group (Table 1, entry 17). Solvent effects were then drides were conveniently converted into the corresponding
evaluated and aprotic solvent performed better than protic sol- monoester products in high yields and enantioselectivities.
vents (Table 1, entries 18 and 19), which is in accordance with Notably, bicyclic anhydrides (Table 2, entries 1 and 2) and
literature precedence [45]. Furthermore, changing concentra- tricyclic anhydrides (Table 2, entries 3 and 4) were more reac-
Table 2: Asymmetric methanolysis of meso-cyclic anhydrides.a,b.
Entry
Anhydride
Product
Time (h)
Yieldc (%)
eed (%)
1
17
98
95
9a
8a
312

Beilstein J. Org. Chem. 2018, 14, 309–317.
Table 2: Asymmetric methanolysis of meso-cyclic anhydrides.a,b. (continued)
2
60
66
66
97
94
95
90
73
84
9b
8b
3
9c
8c
4
9d
8d
5 e
84
84
84
84
60
72
84
87
91
90
97
89
87
92
81
80
94
81
77
78
79
9e
8e
6 e
9f
8f
7 e
9g
8g
8e
9h
8h
9
9i
8i
10
9j
8j
11
9k
8k
313

Beilstein J. Org. Chem. 2018, 14, 309–317.
Table 2: Asymmetric methanolysis of meso-cyclic anhydrides.a,b. (continued)
12
96
91
80
9l
8l
aUnless otherwise noted, reactions were carried out with anhydride (0.5 mmol), MeOH (5.0 mmol), and 7i (10 mol %) in MTBE (10 mL) at rt.
bAbsolute configuration was determined by comparing with literature report. cIsolated yield. dDetermined by HPLC after after derivatization. eIn MTBE
(40 mL) at 0 °C.
tive than mono-cyclic anhydrides (Table 2, entries 5–12). In the tanoic acid, was performed to illustrate the synthetic utility
case of mono-substituted cyclic substrates, including alkyl- [58,59] (Scheme 2). From commercially available diethyl
(Table 2, entries 5–7), ether- (entry 8), aryl-substitution (entries 3-hydroxyglutarate (10), anhydride 8h was prepared in three
9–11), moderate enantioselectivities were detected. Moreover, steps in 54% overall yield. The crucial chloramphenicol base
the chiral mono-substituted products are versatile key building amide 7i catalyzed enantioselective alcoholysis gave monoester
blocks for the synthesis of a variety of the industrially impor- 9h in multigram scale. The resulting monoester with the desired
tant pharmaceuticals, such as γ-aminobutyric acid (GABA) and stereocenter at C-3 was converted to triprotected derivative of
γ-amino-β-hydroxybutyric acid (GABOB) analogues (baclofen GABOB 11 via Curtius rearrangement in 75% yield over two
HCl and pregabalin) [51-54], HMG-CoA reductase inhibitors steps. After Pd/C-catalyzed hydrogenative deprotection of
(“statins”) [55-57], etc.
hydroxy group in methanol under acidic conditions, the corre-
sponding alcohol 12 was transferred to the product 13 via acid-
The generality and scope of this methodology was further promoted deprotection. A single recrystallization from ethanol
demonstrated in the alcoholysis of 8a with different alcohols allowed 13 to be isolated with 96% ee and 73% yield.
(Table 3). Excellent yields with high enantioselectivities were
obtained in all cases. The sterically more bulky 2-propanol Conclusion
worked well in this reaction. Allylic alcohol, benzyl alcohol and In conclusion, we developed a unique bifunctional chiral
cinnamyl alcohol were also well compatible in this bifunctional organocatalyst via introducing a simple amide functionality at
organocatalysis conditions to furnish the desired products.
C-1 of the easily available chloramphenicol scaffold, which
shows good catalytic reactivity and enantioselectivity in the
Application of this methodology to the synthesis of (S)-GABOB alcoholytic desymmetrization of meso-cyclic anhydrides. This
(13), a metabolic derivative of the neurotransmitter γ-aminobu- method proved to be generally applicable on various
Table 3: Asymmetric alcoholysis of anhydride 8a with various alcohols.a
Entry
ROH
Monoester
Time (h)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
methanol
ethanol
9a
9m
9n
9o
9p
9q
17
96
98
84
66
66
98
97
93
90
98
99
95
93
89
85
86
90
2-propanol
allylic alcohol
benzyl alcohol
cinamyl alcohol
aUnless otherwise noted, above reactions were carried out with anhydride (0.5 mmol), MeOH (5.0 mmol), and catalyst 7i (10 mol %) in MTBE (40 mL)
at rt. bIsolated yield. cDetermined by HPLC after derivatization. dAbsolute configuration was determined by comparing with the literature report.
314

Beilstein J. Org. Chem. 2018, 14, 309–317.
Scheme 2: Asymmetric synthesis of (S)-GABOB (13).
ORCID® iDs
anhydrides or alcohols to generate the desired monoesters in
good yield and enantioselectivity. The application of this
method to the synthesis of (S)-GABOB demonstrated the great
synthetic potential for pharmaceutically useful chemicals.
Further modification of this chloramphenicol scaffold as well as
total synthesis of other natural chemicals are right now ongoing
in our lab.
Lingjun Xu - https://orcid.org/0000-0001-7253-9185
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