A novel cost-effective thiourea bifunctional organocatalyst for highly enantioselective alcoholysis of meso-cyclic anhydrides: Enhanced enantioselectivity by configuration inversion

Article abstract of DOI:10.1002/adsc.200800761

A novel inexpensive thiourea bifunctional organocatalyst which can promote the highly enantioselective (up to 95% ee) alcoholysis of mesocyclic anhydrides has been developed. Computational studies on the catalytic process as well as a synthetic application of this new catalyst are also presented.

Full text of DOI:10.1002/adsc.200800761

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DOI: 10.1002/adsc.200800761
A Novel Cost-Effective Thiourea Bifunctional Organocatalyst for
Highly Enantioselective Alcoholysis of meso-Cyclic Anhydrides:
Enhanced Enantioselectivity by Configuration Inversion
Su-Xi Wanga and Fen-Er Chena,*
a
Fudan-DSM Joint Lab for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, 220
Handan Road, Shanghai 200433, Peopleꢀs Republic of China
Fax : (+86)-21-65643811; e-mail: rfchen@fudan.edu.cn
Received: December 9, 2008; Published online: March 5, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800761.
Abstract: A novel inexpensive thiourea bifunctional
organocatalyst which can promote the highly enan-
tioselective (up to 95% ee) alcoholysis of meso-
cyclic anhydrides has been developed. Computa-
tional studies on the catalytic process as well as a
synthetic application of this new catalyst are also
presented.
breakthrough has been achieved by Connon et al.[5]
and Song et al.[6], who independently observed the
highly stereoselective methanolysis of cyclic anhy-
drides catalyzed by Cinchona-derived amine-thiourea
bifunctional organocatalyst 1 (Figure 1) at room tem-
perature, with ꢀ10 mol% catalyst loading.
Keywords: alcoholysis; asymmetric catalysis; bi-
functional organocatalyst; meso-cyclic anhydrides;
thioureas
Peptide-like bifunctional catalysts with high activity
and broad substrate applicability have emerged as
powerful reagents in organic synthesis over the past
few decades.[1] The combination of two active sites
within an asymmetric space in a catalyst leads to syn-
ergistic activation of both electrophilic and nucleo-
philic substrates, providing extremely high enantiose-
lectivity. Recent efforts toward the development of
chiral thiourea-based bifunctional organocatalysts
have produced outstanding efficiency in a wide varie-
ty of asymmetric transformations.[2]
The stereoselective alcoholysis of meso-cyclic anhy-
drides is a proven strategy to conveniently access op-
tically active hemiesters as valuable building blocks
for many natural products and biologically active sub-
stances.[3] Since the first non-enzymatic and metal-free
catalytic process reported by Oda and co-workers,[4a,b]
impressive progress has been made in the opening of
Figure 1. Structures of chiral organocatalysts.
Despite the numerous advances in thiourea-based
anhydrides by chiral Lewis bases,[4] as demonstrated bifunctional catalysis, the structures of these organo-
by Cinchona alkaloids and their derivatives. Those catalysts are limited, and some are even unfavorable
protocols, however, are limited by the requirements for commercial applications. This problem prompted
for high catalyst loading, low temperatures, and long us to initiate an exploration of novel organocatalysts
reaction periods. Until quite recently, a remarkable with easy accessibility and high efficiency. Previously,
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547

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Table 1. Catalyst evaluation and optimization of reaction condi-
our laboratory employed the derivative of the inex-
pensive (1S, 2S)-2-amino-1-(p-nitrophenyl)propane-
1,3-diol (2), a by-product in the industrial production
of chloramphenicol, as a ligand in the asymmetric
synthesis of (+)-biotin.[7] Later, the distinct potency of
this chiral scaffold in transferring stereochemical in-
formation was further demonstrated in the enantiose-
lective alkynylation of various substrates.[8] In our
design for new catalysts, some appealing features of
this amino alcohol aroused our attention. First, both
its enantiomers are readily available and much cheap-
er than Cinchona alkaloids. Second, the convenient
modification at the nitrogen atom and amino func-
tionality at C-1 could easily form a chiral 1,2-diamine
scaffold, which appears to be the most prevalent
structure for the introduction of a thiourea moiety.
Third, the opportunity for inversion of configuration
at C-1 of this chiral scaffold is an attractive advantage
for catalyst optimization. Finally, the substituent at
the terminal hydroxy is readily tunable, permitting ad-
justment of the steric hindrance of the skeleton. With
the above features in mind, we envisaged that the
chiral amino alcohol 2 would be the starting material
of choice to generate a new class of cost-effective and [b]
tions.
Entry Catalyst Solvent Concentration t
Yield ee
(equiv.)
[M][a]
[h] [%][b] [%][c,d]
1
2
3
4
5
6
7
8
3a (0.1)
3a (0.1)
3a (0.1)
3a (0.1)
3a (0.1)
3b (0.1)
3b (0.1)
3b (0.1)
3b (0.2)
Toluene 0.05
CH2Cl2 0.05
MTBE 0.05
24 94
24 89
24 94
24 85
24 94
24 96
24 95
24 94
12 95
30 93
48 85
72 81
60 88
56
63
82
77
80
89
91
93
94
95
95
92
91
THF
0.05
Dioxane 0.05
MTBE 0.05
MTBE 0.025
MTBE 0.0125
MTBE 0.0125
9
10
11
12
3b (0.05) MTBE 0.0125
3b (0.02) MTBE 0.0125
3b (0.01) MTBE 0.0125
13[e] 3b (0.05) MTBE 0.0125
[a]
Refers to the concertration of the anhydride in the solvent.
Yield of isolated product.
Determined by HPLC (see Supporting Information).
Absolute configuration was determined by comparing the
sign of the optical rotation of the major enantiomer with
known data.[5]
[c]
powerful bifunctional organocatalysts. In this paper,
we report the synthesis of novel chiral amine-thiour-
eas 3a and b (Figure 1) and their first applications for
the highly enantionselective alcoholysis of meso-cyclic
[d]
[e]
Reaction was performed at 08C.
anhydrides. We also present computational studies on
the catalytic process.
Catalysts 3a and b were prepared from (1S, 2S)-2-
amino-1-(p-nitrophenyl)propane-1,3-diol (2) via ex- deterioration in enantiomeric excess was observed
perimentally conventional four- and five-step proto- when the reaction was run at 08C (Table 1, entry 13).
cols, respectively.[9]
To provide a theoretical explanation for both the
The results of our preliminary evaluation of the predominant configuration of the product and the su-
novel organocatalysts 3a and b by methanolysis of perior enantioselectivity of catalyst 3b, we have thus
cyclic anhydride 4 and the optimization of reaction initiated quantum chemical calculations in the catalyt-
conditions are presented in Table 1. Initially, different ic methanolysis of 4. As proposed by Song et al.,[6] the
solvents were screened with 10 mol% 3a and 5 equiv- complexes of catalysts 3a and b and the transition
alents of methanol at room temperature (Table 1,en- state analogues of the uncatalyzed methanolysis reac-
tries 1–5). The reaction proceeded best in methyl tert- tion (TS4-5 and TS’4-5, Scheme 1) could be regarded as
butyl ether with a yield of 94% and an ee of 82%. En- transition state analogues for the catalytic process.
couraged by the promising results obtained with cata- The structures of these complexes, which involve two
lyst (R,R)-3a, we next examined the effectiveness of complementary hydrogen bonding interactions, were
its isomer (S,R)-3b. We were delighted to observe an optimized by molecular mechanics computation per-
even higher ee of 89%, furnished with no loss of formed at the B3LYP/6-31G* level (Figure 2). The
chemical yield (Table 1, entry 6). Interestingly, the calculations show that 3a-TS4-5 complex is
hemiester was formed in the same configuration as
that induced by catalyst 3a. An even more satisfactory
ee of 93% was obtained by diluting the reaction mix-
ture from 0.05M to 0.0125M (Table 1, entry 8). We
also investigated the effect of catalyst loading (en-
tries 9–12) and found that 5 mol% catalyst was suffi-
cient to maintain the high chemical yield (93%) and
ee (95%) with a satisfactory reaction rate. A further
decrease in the catalyst loading resulted in relatively
lower yield and longer reaction time. Notably, a slight nolysis of 4.
Scheme 1. Transition state analogues of uncatalyzed metha-
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A Novel Cost-Effective Thiourea Bifunctional Organocatalyst
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(Table 2, entries 6 and 7), and while nearly quantita-
tive yields were obtained, the ee values decreased,
which could be ascribed to the lack of rigidity of the
substrates.
Subsequently, different alcohols were examined as
nucleophiles in the desymmetrization of the model
substrate 10 under the optimized conditions (Table 3).
The steric hindrance of the alcohol had a limited
impact on enantioseletivity since excellent ee values
were furnished with alcohols more sterically bulky
than methanol, such as ethanol, 1-propanol, and even
2-propanol. These results are at odds with the obser-
vations made by Bolm et al.[4l] in the quinidine-cata-
lyzed alcoholysis of cyclic anhydride 10. With respect
to unsaturated alcohols, propargyl alcohol still led to
a good selectivity (91% ee, Table 3, entry 6); however,
considerably lower ee values were obtained with allyl
alcohol (35% ee, Table 3, entry 5) and trans-cinnamyl
alcohol (75% ee, Table 3, entry 8).
We have demonstrated a practical use of the cur-
rent study by the conversion of cyclic anhydride 25
into (3aS,6aR)-lactone 27, the key chiral building
block for asymmetric total synthesis of (+)-biotin
(Scheme 2).[4i,10] Due to the bulky size and the pres-
ence of multiple polar functionalities, a catalyst load-
ing of 30 mol% was needed for desymmetrization of
25 with propargyl alcohol at room temperature, gen-
erating the (4S,5R)-hemiester 26 in 96% yield and
Figure 2. Optimized structures of transition state analogues
yielding hemiester 5.
5.2 kcalmolÀ1 more stable than 3a-TS’4-5 and, similarly, 82% ee. After a single recrystallization, 26 was sub-
3b-TS4-5 is likewise found to be 7.0 kcalmolÀ1 more fa- jected to reductive ring closure[10] to yield (3aS,6aR)-
vored than its counterpart. Moreover, the optimized lactone 27 in 97% ee, which was previously converted
structure of 3b-TS4-5 complex is 1.5 kcalmolÀ1 more to (+)-biotin via four steps.[4i,10] It is worth mentioning
stable in comparison with 3a-TS4-5. These energy dif- that the catalyst used in the alcoholysis of 25 could be
ferences explain the generation of the same isomer 5 easily separated and quantitatively recovered by basi-
from catalysts 3a and 3b which have two different fication of the reaction mixture.[9]
configurations, and also indicate the higher selectivity
of catalyst 3b which is in qualitative agreement with novel series of readily available amine-thiourea bi-
experimental findings. functional organocatalysts, which exhibit catalytic ac-
In conclusion, we have successfully developed a
With the optimal catalyst and reaction conditions tivity that is readily enhanced by changing the config-
established, we next examined the scope and limita- uration of the chiral scaffold. Quantum chemical cal-
tions of the methodology by surveying a series of culations provided the theoretical explanation for the
meso-cyclic anhydrides in the methanolysis reaction observed stereoinduction of the catalysts. In the pres-
(Table 2). In general, the bi- and tricyclic succinic an- ence of a catalytic amount of 3b, asymmetric metha-
hydrides were readily desymmetrized to give the cor- nolysis of various meso-cyclic anhydrides proceeded
responding hemiesters in good yields and with excel- smoothly to afford the corresponding hemiesters in
lent enantioselectivities (90–95% ee). The reaction high yields and with good to excellent enantioselectiv-
was most effective for bicyclic substrates (Table 2, en- ities. Alcohols other than methanol were effective nu-
tries 1 and 2), which underwent rapid methanolysis cleophiles in the desymmerization reaction and also
with low catalyst loading (5 mol%). In contrast, provided excellent enantiomeric excesses. Further-
longer reaction periods (72–96 h) were required for more, a synthetic utility of this catalyst was demon-
complete conversion of the more sterically hindered strated in the asymmetric synthesis of (+)-biotin. In-
tricyclic substrates (Table 2, entries 3, 4 and 5). Nota- vestigations on the full scope of this new catalyst in
bly, for the anhydrides bearing multiple polar func- asymmetric transformations are currently in progress
tionalities (8 and 12), the use of an increased catalyst and will be reported in due course.
loading (20 mol%) was needed to generate compara-
ble results. The methanolytic desymmetrization of
monocyclic glutaric anhydrides was also attempted
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549

Su-Xi Wang and Fen-Er Chen
COMMUNICATIONS
Table 2. Enantioselective methanolysis of various meso-cyclic anhydrides by catalyst 3b.[a]
Entry
1
Anhydride
Product[b]
t [h]
Yield [%][c]
ee [%][d]
30
93
95
2
30
96
72
94
89
90
95
90
95
3[e]
4
5[e]
96
18
88
97
90
82
6
7
24
95
85
[a]
Unless otherwise noted, all reactions were carried out with anhydride (0.5 mmol), MeOH (2.5 mmol) and 3b
(0.025 mmol) in MTBE (40 mL) at room temperature.
[b]
Absolute configurations were determined by comparing the sign of the optical rotation of the major enantiomer with
known data.[4h,5]
[c]
[d]
[e]
Yield of isolated product.
Determined by HPLC or H NMR (see Supporting Information).
1
Reaction performed with 3b (0.1 mmol) in MTBE (80 mL).
was evaporated under vacuum and the residue was dissolved
Experimental Section
in CH2Cl2 (10 mL). The solution was washed with saturated
Na2CO3 (2ꢂ5 mL) and the combined aqueous layers were
acidified with excess 2N HCl, followed by extraction with
EtOAc (3ꢂ20 mL). The combined organic layers were dried
over Na2SO4 and concertrated to afford the hemiester 5
(yield: 86 mg, 93%) as a white solid without further purifica-
tion by chromatography. HPLC analysis of the correspond-
ing amide-ester[9] of hemiester 5 (Chiralcel OD-H, hexane/2-
propanol 93/7, flow rate=0.5 mLminÀ1, l=220 nm): reten-
tion time tr (major)=38.6 min, tr (minor)=54.4 min; mp
Typical Procedure for the Asymmetric Alcoholysis of
meso-Cyclic Anhydrides using Catalyst 3b
The following procedure for the methanolysis of cis-cyclo-
hexane-1,2-dicarboxylic acid anhydride (4) using catalyst 3b
is representative. Methanol (80 mg, 2.5 mmol) was added
dropwise to a stirred solution of the anhydride 4 (77 mg,
0.5 mmol) and 3b (15.6 mg, 0.025 mmol) in MTBE (40 mL)
at room temperature under nitrogen. When TLC analysis in-
dicated complete consumption of the anhydride, the solvent
1
68.2–69.18C; [a]2D5: 3.7 (c 2.0, CHCl3); H NMR (400 MHz,
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A Novel Cost-Effective Thiourea Bifunctional Organocatalyst
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Scheme 2. Synthetic application of 3b in the total synthesis of (+)-biotin.
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Table 3. Asymmetric alcoholysis of cyclic anhydride 10 with
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[2] For selected examples using chiral thiourea-based bi-
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Entry ROH
Hemiester Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
Methanol
Ethanol
1-Propanol
2-Propanol
Allyl alcohol
Propargyl alcohol
Benzyl alcohol
trans-Cinnamyl al-
cohol
11
18
19
20
21
22
23
24
94
93
89
87
83
92
88
89
95
92
95
91
35
91
89
75
[a]
Reactions were carried out with 10 (0.5 mmol), ROH
(1.5 mmol) and 3b (0.025 mmol) in MTBE (40 mL) at
room temperature.
Yield of isolated product.
Determined by HPLC (see Supporting Information).
[b]
[c]
CDCl3): d=3.68 (s, 3H), 2.91–2.80 (m, 2H), 2.10–1.96 (m,
2H), 1.84–1.73 (m, 2H), 1.61–1.37 (m, 4H); 13C NMR
(75 MHz, CDCl3): d=179.3, 173.5, 51.2, 42.1, 41.8, 25.8,
25.4, 23.3, 23.1.
[3] For reviews on asymmetric alcoholysis of cyclic anhy-
drides, see: a) I. Atodiresei, I. Schiffers, C. Bolm,
Chem. Rev. 2007, 107, 5683–5712; b) Y.-G. Chen, P.
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Chem. Commun. 1985, 1717–1719; b) J. Hiratake, M.
Inagaki, Y. Yamamoto, J. Oda, J. Chem. Soc. Perkin
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J. A. Hirst, J. Chem. Soc. Chem. Commun. 1988, 632–
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