Angewandte
Chemie
Table 1: Catalytic enantioselective ring opening of the cyclic anhydride
1a with MeOH.[a]
EntryCastaly
T
[8C]
t
[h]
Major
isomer
Yield[b]
[%]
ee[c]
[%]
1
2
3
I (10 mol%)
I (5 mol%)
I (1 mol%)
I (0.5 mol%)
II (110 mol%)
III (5 mol%)
IV (10 mol%)
20
20
20
1
2
6
20
60
48
10
2a
2a
2a
2a
2a
2a
2a
91
92
92
89
91
95
85
96
95
95
93
87
93
96
4[d]
5[e]
6[f]
7[g]
20
À55
À20
20
[a] Unless otherwise indicated, reactions were carried out with 1a
(0.5 mmol), methanol (10 equiv, 5 mmol), and the catalyst in Et2O
(5 mL) at room temperature. [b] Yield of the isolated product after
chromatographic purification. [c] Determined byHPLC (see the Support-
ing Information). [d] MeOH was added with a syringe pump over 20 h to
minimize the uncatalyzed reaction. [e] From reference [14a] (with
3 equivalents of MeOH). [f] From reference [14b] (with 10 equivalents
of MeOH). [g] From ref. [5] (with 10 equivalents of MeOH).
Figure 1. Effect of a) concentration and b) temperature on the enantio-
selectivityof I in the methanolysis of 1a.
afford the chiral hemiester 2a with excellent enantioselectiv-
ity (96% ee; Table 1, entry 1). A lower catalyst loading of
0.5 mol% still resulted in excellent catalytic activity and
enantioselectivity (93% ee; Table 1, entry 4). Previously
reported cinchona-alkaloid-based catalysts require much
longer reaction times (Table 1, entries 5–7).[5,14] To the best
of our knowledge, the sulfonamide-based catalyst I is the most
active catalyst reported to date for the alcoholytic desymmet-
rization of meso cyclic anhydrides.
Scheme 2. Methanolytic desymmetrization of 1a with catalysts I and
IV.
The methanolysis of 1a with the catalyst I was examined
under various experimental conditions. We observed the
highest enantioselectivities (> 94%) with aprotic, hydrogen-
bond-accepting solvents, such as Et2O (96% ee), THF
(94% ee), and dioxane (95% ee), whereas the lowest enan-
tioselectivities were observed with protic solvents, such as
methanol (44%). (For more experimental results, see Table S-
1 in the Supporting Information). More interestingly, the
stereoselectivity of the sulfonamide catalyst I does not show a
significant dependence on concentration (Figure 1A) or the
reaction temperature (Figure 1B), in contrast to the thiourea-
based catalyst IV.[5] On the basis of these experimental results,
it is clear that the self-association phenomenon is not as
significant in the methanolysis of cyclic anhydrides with the
bifunctional sulfonamide catalyst I as it is in the process
catalyzed by IV. The comparative data in Scheme 2 highlight
the superior catalytic efficiency of the sulfonamide I relative
to the thiourea catalyst IV. Under the same reaction
conditions (1a (0.5 mmol), MeOH (5 mmol), Et2O (5 mL),
catalyst (1 mol%)), excellent enantioselectivity was observed
with the sulfonamide catalyst I (95% ee; Table 1, entry 3) and
only moderate enantioselectivity (62% ee) with the thiourea
catalyst IV. The stereoselectivity of IV could be increased
under conditions of high dilution to give the product with up
to 88% ee, but with a sacrifice in reactivity.
We investigated the generality of the reaction under
optimized reaction conditions. The methanolysis of mono-
cyclic (Table 2, entries 5–7), bicyclic (entry 1), and tricyclic
anhydrides (entries 2–4) in the presence of I proceeded
rapidly. All reactions were complete within a few hours to
give the corresponding hemiesters in excellent yields with
high ee values.
We showed recently that DFT computation can be used to
explain the observed sense of stereoselectivity for the
methanolytic desymmetrization of meso anhydrides with the
bifunctional thiourea-based organocatalyst IV.[5] Herein we
show that the computational approach[15] can also be used to
explain the observed sense of stereoselectivity for the
reaction catalyzed by the bifunctional sulfonamide I. In this
computational approach, two zwitterionic transition-state
analogues for the methanolysis reaction,
3 and ent-3
(Scheme 3a), are considered for their ability to bind to the
catalyst I by hydrogen bonding. It is well known that the
mechanism for many hydrolysis and alcoholysis reactions
involves the formation of high-energy tetrahedral intermedi-
ates, such as 3 and ent-3.[16] As the quinuclidine group is
expected to act as a general base, it is used to accept a
hydrogen bond from the methanol group of the transition-
state analogues. The sulfonamide group is expected to
Angew. Chem. Int. Ed. 2008, 47, 7872 –7875
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7873