Synthesis of both enantiomers of hemiesters by enantioselective methanolysis of meso cyclic anhydrides catalyzed by α-amino acid-derived chiral thioureas

Article abstract of DOI:10.1021/jo100792r

(Figure presented) Both ureas and thioureas derived from l- or d-valine act as bifunctional organocatalysts able to induce the enantioselective alcoholysis of mono-, bi-, and tricyclic meso anhydrides. The desymmetrization occurs in near quantitative yields and excellent enantiomeric ratios (up to >99:<1) under low catalyst loading. Both enantiomers of the hemiesters can be directly obtained by changing the configuration of the catalyst.

Full text of DOI:10.1021/jo100792r

pubs.acs.org/joc
alcohols promoted by cinchona alkaloids in both catalytic4
Synthesis of both Enantiomers of Hemiesters by
Enantioselective Methanolysis of Meso Cyclic
Anhydrides Catalyzed by r-Amino Acid-Derived
Chiral Thioureas†
or stoichiometric proportions5 have been described. Homo-
geneous6 or heterogeneous supported cinchona derivatives7
and some other amines8 have also been used in that trans-
formation. A good level of enantioselectivity is also obtained
in enzyme-catalyzed9 enantioselective desymmetrization of
anhydrides. Some of those protocols are of limited applica-
tion because of the need of high catalyst loading, long
reaction times, or low reaction temperature.
ꢀ
ꢀ
ꢀ
Ruben Manzano, Jose M. Andres,
ꢀ
Marıa-Dolores Muruzabal, and Rafael Pedrosa*
´
Instituto CINQUIMA and Departamento de Quımica
Recently, excellent yields and ee values have been obtained in
desymmetrization of meso anhydrides by methanolysis10 or
thiolysis11 by using bifunctional sulfonamides derived from
cinchona alkaloids. Interestingly, chiral ureas and thioureas
have been extensively employed as organocatalysts,12 but their
use for desymmetrization of meso anhydrides is scarcely re-
ported. Only a few bifunctional thioureas have been recently
described as excellent organocatalysts for these desymmetriza-
tions. The number of structures of these catalysts is limited
because the chiral environment is provided by quinine, dihydro-
quinine,13 or chiral 2,3-diaminopropanol derivatives.14
ꢀ
Organica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/n, 47011-Valladolid, Spain
pedrosa@qo.uva.es
Received June 11, 2010
It has been shown that quinidine-derived catalyst is less
enantioselective and efficient than the quinine analogue, but
quinine and quinidine derivatives do not behave as pseudo-
enantiomers in this reaction. Consequently, only one enantiomer
of the final hemiester was obtained in the reactions catalyzed by
thioureas derived from these alkaloids. To circumvent this
problem and obtain both enantiomers, a three-step procedure
Both ureas and thioureas derived from L- or D-valine act
as bifunctional organocatalysts able to induce the enan-
tioselective alcoholysis of mono-, bi-, and tricyclic meso
anhydrides. The desymmetrization occurs in near quan-
titative yields and excellent enantiomeric ratios (up to
>99:<1) under low catalyst loading. Both enantiomers
of the hemiesters can be directly obtained by changing the
configuration of the catalyst.
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1985, 1717. (b) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. J. Chem. Soc.,
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Enantioselective desymmetrization by alcoholysis of meso
anhydrides is one of the most simple methods to access chiral
building blocks with either single or multiple stereocenters.1
This reaction has attracted considerable attention, and
different methodologies have been developed to get desym-
metrization of meso cyclic dicarboxylic anhydrides.2 To
this end, diastereoselective desymmetrizations with chiral
alcohols,3 and enantioselective transformations with achiral
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Lett. 2001, 42, 411. (b) Okamatsu, T.; Irie, R.; Katsuki, T. Synlett 2007, 1569.
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Song, C. E. Angew. Chem., Int. Ed. 2008, 47, 7872. (b) Youk, S. H.; Oh, S. H.;
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†
ꢀ
Dedicated to Professor Jose Barluenga on the occasion of his 70th birthday.
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Am. Chem. Soc. 2000, 122, 8793. (c) Choi, C.; Tian, S.-K.; Deng, L. Synthesis
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metry 2007, 18, 1481. (e) Rome, D.; Johansson, M.; Sterner, O. Tetrahedron
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Lett. 2007, 48, 635. (f) Huang, J.; Xiong, F.; Chen, F.-E. Tetrahedron:
Asymmetry 2008, 19, 1436.
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Chem., Int. Ed. 2001, 40, 3131. (b) Chen, Y.; McDaid, P.; Deng, L. Chem.
Rev. 2003, 103, 2965. (c) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid,
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(c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
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DOI: 10.1021/jo100792r
r
Published on Web 06/30/2010
J. Org. Chem. 2010, 75, 5417–5420 5417
2010 American Chemical Society

Manzano et al.
JOCNote
TABLE 2. Effects of the Concentration and the Loading and Nature of
the Catalysta
concn
(M)
catalyst
(x mol %)
time
(h)
MeOH
equiv (n)
conversionb
(%)
entry
erc,d
1
2
3
4
5
6
7
8
9
10
0.150
0.030
0.015
0.005
0.015
0.015
0.015
0.015e
0.015
0.015
I (5)
I (5)
I (5)
I (5)
I (5)
I (10)
I (1)
I (5)
II (5)
III (5)
18
18
18
18
18
12
96
66
18
160
10
10
5
10
10
10
10
10
10
10
100
95
66
30
88:12
96:4
98:2
98:2
98:2
97:3
97:3
98:2
96:4
56:44
FIGURE 1. Bifunctional organocatalysts used for the alcoholysis
of meso anhydrides.
82
100
100
100
82
SCHEME 1. Methanolysis of Anhydride 1a in Different Solvents
42
aReaction performed on a 0.5 mmol of anhydride scale with n equiv of
methanol and x mol % of the catalyst in MTBE at rt. bConversions were
determined by 1H NMR of the reaction mixture. cDetermined by chiral
HPLC of 4-bromophenyl ester derivative (see the Supporting Infor-
mation). dAbsolute configuration was determined by comparing the
specific rotation of 2a with that of the literature data. eThe reaction was
carried out at 4 °C.
TABLE 1. Effects of the Solvent in the Enantioselective Methanolysis of
1a Promoted by Thiourea Ia
The best results in terms of enantioselectivity were ob-
tained by using ethereal solvents (entries 6-9 in Table 1) or
EtOAc (entry 5), while the reactions in THF or EtOAc were
very slow and only 29% and 35% yield of the product was
obtained after 18 h (entries 5 and 7 in Table 1). The hemiester
was formed in 82% yield when the reactions were carried out
in diethyl ether or MTBE as solvents for the same period of
time (entries 6 and 8) or quantitatively after 32 h in the last
case (entry 9 in Table 1). The reaction was completed in
hexane, but with low enantioselectivity (entry 3 in Table 1),
whereas the stereoselection was good, albeit the yield was
moderate in toluene (entry 4) or very low in DCM (entry 2).
As expected, the reaction was faster, but much less selective,
when methanol was used as solvent (entry 1), possibly
because of the competitive formation of hydrogen bonds
between the solvent and the catalyst.17
We next examined the influence of some other experimen-
tal parameters, such as the concentration, the temperature,
the loading and the nature of the catalyst, and the quantity of
methanol, and the results are collected in Table 2. Taking as a
reference the conditions summarized in entry 5 of Table 2
(i.e., 0.015 M of anhydride in MTBE, 5 mol % of catalyst, and
10 equiv of MeOH), it is clear that the reaction was faster and
less enantioselective at higher concentration of meso anhy-
dride (entries 1 and 2 in Table 2). On the contrary, the enan-
tioselection increased but the yield highly decreased in high
dilution conditions (entry 4). Excellent enantioselection, albeit
moderate yield, was obtained when the amount of methanol
was reduced to 5 equiv (entry 3). The reaction proceeded with
excellent enantioselectivity by using only 1 mol % of catalyst,
although it was necessary to increase the reaction time to
96 h (entry 7), whereas an increase of the catalyst loading to
10 mol % accelerated the reaction rate, which was completed
after 12 h (entry 6). Higher reaction time but no deterioration
of the enantiomeric excess was observed when the reaction was
run at 4 °C (entry 8).
entry solvent time (h) MeOH equiv (n) conversionb (%) erc,d
1
2
3
4
5
6
7
8
9
MeOH
DCM
hexane
toluene
EtOAc
Et2O
THF
MTBE
MTBE
18
18
18
18
18
18
18
18
32
100
28
100
67
35
82
29
82
55:45
90:10
71:29
91:9
96:4
98:2
96:4
98:2
98:2
10
10
10
10
10
10
10
10
100
aReaction performed on a 0.5 mmol of anhydride (0.015M) scale with
10 equiv of methanol and 5 mol % of the catalyst I at rt. bConversions
were determined by 1H NMR of the reaction mixture. cDetermined by
chiral HPLC of the hemiester and of 4-bromophenyl ester derivative (see
the Supporting Information). dAbsolute configuration was determined
by comparing the specific rotation of 2a with that of the literature data.
has been described.15 This method consists of the alcoholysis of
the meso anhydride with allyl alcohol, further esterification of
the hemiester with methanol, and selective hydrolysis of the
allylic ester.
It was necessary to search for novel structures able to catalyze
the enantioselective desymmetrization of meso anhydrides and
reach either enantiomer of hemiester in a single step. We have
recently described an easy and very modular synthesis16 of novel
chiral ureas and thioureas I-III (Figure 1) derived from small
1,2-diamines, readily obtained from natural and unnatural
amino acids. These compounds act as excellent organocatalysts
in nitro-Michael additions, and now we report on their use for
the enantioselective desymmetrization of mono-, bi-, and tri-
cyclic meso anhydrides by reaction with alcohols. These com-
pounds could work as bifunctional organocatalysts, activating
simultaneously the alcohol and the anhydride by means of
hydrogen bonding with the dimethylamino group and the urea
or thiourea moiety.
The solvent effects on the process were studied by taking as
reaction reference the enantioselective methanolysis of tri-
cyclic anhydride 1a and valine-derived thiourea I (5 mol %)
as catalyst (Scheme 1). These reactions were carried out at
room temperature, in a 0.015 M solution of anhydride in the
corresponding solvent for a fixed reaction time of 18 h, and
the results are collected in Table 1.
Interestingly, only small differences were observed in the
reactions catalyzed by urea II and thiourea I. In both cases
the methanolysis of the anhydride occurred in very good
yield, and only a slight decrease in the enantioselection was
(15) Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem. 2008, 73, 2454.
ꢀ
(16) Andres, J. M.; Manzano, R.; Pedrosa, R. Chem.;Eur. J. 2008, 14, 5116.
(17) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.; Song, C. E.
Chem. Commun. 2008, 1208.
5418 J. Org. Chem. Vol. 75, No. 15, 2010

Manzano et al.
JOCNote
SCHEME 2. Alcoholysis of 1a with Different Alcohols
TABLE 3. Enantioselective Methanolysis of Mono-, Bi-, and Tricyclic
Meso Anhydrides Catalyzed by Thioureas I or ent-Ia
observed when II was used as catalyst (compare entries 5 and
9 in Table 2). On the contrary, thiourea III, regioisomer of I,
was a poor catalyst for the desymmetrization of 1a, leading
to the hemiester 2a in poor yield and enantiomeric ratio after
160 h of reaction (entry 10).
A brief study was performed with different alcohols as
nucleophiles in the desymmetrization of 1a (Scheme 2).
Contrary to a previous report,14 excellent enantioselectivity
(98:2) was obtained by using allyl alcohol as alcoholysis
reagent, but the enantioselection decreased to 87:13 with
benzyl alcohol. The reaction did not take place with a more
sterically demanding alcohol such as tert-butanol.
The substrate scope under the optimized reaction conditions
was studied in the enantioselective methanolysis of mono-, bi-,
and tricyclic anhydrides 1a-h, and the results are summarized
in Table 3. The methanolysis of all of them occurred quickly in
excellent yields and enantioselectivity at low catalyst loading,
although some differences were observed depending on the
structure of the anhydride. For instance, the reaction was faster
for 3-methylglutaric anhydride (1h) but the enantiomeric ratio
decreased to 91:9 (entry 10 in Table 3). Longer reaction periods
were required for the methanolysis of bi- and tricyclic succinic
anhydrides, although the hemiesters were obtained with excel-
lent enantioselection. An exception of that general behavior was
the tricyclic anhydride 1e, which led to the hemiester in moder-
ate yield and very modest enantioselection after 120 h of
reaction (entry 7). As expected, the reaction time increased
when the desymmetrization was carried out at lower tempera-
ture, albeit no appreciable modifications in the yield or en-
antiomeric ratio were observed (compare entries 5 versus 6 or 10
versus 11 in Table 3). An important fact is that our method
allows the direct preparation of both enantiomers of a given
hemiester starting from the same anhydride and using either
enantiomeric thioureas I or ent-I as catalyst (entry 2 in Table 3).
It is noteworthy that the stereochemical outcome of the
reaction is independent of the relative stereochemistry of the
starting meso anhydride: both, endo (1a-e) and exo tricyclic
anhydrides (1f and 1g) reacted by the same carbonyl group
(compare entries 1, 7, 8, and 9 in Table 3). Catalysts I and II,
with S configuration at the diamine stereocenter, promoted the
reaction of the pro-R carbonyl group of all the anhydrides (1g
was an exception because of the change in the priority of the
substituents), whereas ent-I activated the enantiotopic pro-S
counterpart (entry 2 in Table 3). Computational calculations
on the mechanism of methanolysis of meso anhydrides cata-
lyzed by thioureas10a,14,17 have pointed out that the tertiary
amino group of the catalyst interacts with methanol, while the
thiourea moiety establishes hydrogen bonding with the anhy-
dride. Taking these studies as a basis, the transition state
analogue for the methanolysis of meso anhydrides 1a catalyzed
by thiourea I is proposed in Figure 2. This model rationalizes
the sense of the observed enantioselection.
aReaction performed on a 0.5 mmol of anhydride (0.015M) scale with
10 equiv of methanol and 5 mol % of catalyst I in MTBE at rt. bNumbers
refer to isolated yield. cDetermined by chiral HPLC of the hemiester or
of 4-bromophenyl ester derivative (see the Supporting Information).
dAbsolute configurations were determined by comparing the specific
rotations of 2 with those of the literature data. eThe reaction was carried
out with ent-I as catalyst. fReaction at 4 °C.
FIGURE 2. Schematic proposed transition state analogue for
methanolysis of meso anhydrides 1a.
In summary, we have shown that our thioureas and ureas,
which are easily prepared from cheap and accessible natural
and unnatural valines, behave as excellent organocatalysts in
J. Org. Chem. Vol. 75, No. 15, 2010 5419

Manzano et al.
JOCNote
the enantioselective alcoholic desymmetrization of cyclic
meso anhydrides. Both enantiomers of the hemiesters can
be prepared simply by changing the stereochemistry of the
catalyst. The catalyst derived from L-valine leads to the
1R,2S-hemiesters whereas the thiourea derived from unna-
tural D-valine gives the antipodal desymmetrization product.
These results also demonstrate that (thio)ureas bearing only
one stereocenter are as enantioselective or more than those
previously reported for the desymmetrization of cyclic meso
anhydrides.
afford the pure hemiester 2a as a white solid (98 mg, 99% yield).
[R]25D -5.8 (c 2.3, CCl4, 98:2 er). ent-2a: [R]25D þ7.6 (c 1.9, CCl4,
3:97 er). 1H NMR (300 MHz, CDCl3) δ 1.34 (br d, J = 8.8 Hz,
1H), 1.50 (dt, J = 8.8, 1.9 Hz, 1H), 3.17-3.20 (m, 2H); 3.29 (dd,
J = 10.2, 3.0 Hz, 1H), 3.34 (dd, J = 10.2, 3.0 Hz, 1H), 3.60 (s,
3H), 6.22 (dd, J = 5.5, 3.1 Hz, 1H), 6.33 (dd, J = 5.6, 3.0 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ 45.9 (CH), 46.4 (CH), 47.9
(CH), 48.1 (CH), 48.6 (CH2), 51.4 (CH3), 134.2 (CH), 135.4
(CH), 172.8 (C), 178.6 (C). HRMS calcd for C10H12O4 þ Naþ
219.0633, found 219.0630. The er was determined by chiral
HPLC analysis of the hemiester and of its 4-bromophenyl ester
derivative (see the Supporting Information).
Experimental Section
Acknowledgment. We acknowledge financial support by
the Spanish MICINN (Project CTQ2008-03960/BQU) and
General Procedure for Enantioselective Alcoholysis of Meso
Anhydrides. Methanol (203 μL, 5.0 mmol) was added dropwise
to a 0.015 M solution of anhydride 1a (85 mg, 0.5 mmol) and
catalyst I (10.0 mg, 0.025 mmol) in MTBE (33 mL) at room
temperature. The reaction mixture was stirred until the anhy-
dride was consumed (TLC). The solvent was evaporated in
vacuo and the residue was dissolved in CH2Cl2 (5 mL). The
solution was extracted with saturated aqueous Na2CO3 (2 ꢀ
5 mL). The combined aqueous layers were acidified with 2 M
HCl and extracted with EtOAc (3 ꢀ 20 mL). The organic phase
was dried over MgSO4, filtered, and concentrated in vacuo to
ꢀ
Junta de Castilla y Leon (Project GR 168). R.M. and M.-D.
M. also thank the MEC and J C y L, respectively, for
predoctoral fellowships.
Supporting Information Available: Experimental procedures,
C
spectral data for all new compounds, copies of 1H NMR and 13
NMR spectra for all compounds, and copies of the HPLC
chromatograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
5420 J. Org. Chem. Vol. 75, No. 15, 2010