Highly enantioselective desymmetrizations of meso-anhydrides

Article abstract of DOI:10.1016/j.tet.2010.04.121

Readily available, low molecular cyclohexane-based organocatalysts promote highly enantioselective desymmetrizations of cyclic meso-anhydrides applying alcohols and benzyl mercaptan as nucleophiles. Both succinic and glutaric anhydrides furnished the corresponding products with up to 96% ee in mostly quantitative yields.

Full text of DOI:10.1016/j.tet.2010.04.121

Tetrahedron 66 (2010) 6349e6357
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective desymmetrizations of meso-anhydridesq
*
Ellen Schmitt, Ingo Schiffers, Carsten Bolm
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52076 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Readily available, low molecular cyclohexane-based organocatalysts promote highly enantioselective
desymmetrizations of cyclic meso-anhydrides applying alcohols and benzyl mercaptan as nucleophiles.
Both succinic and glutaric anhydrides furnished the corresponding products with up to 96% ee in mostly
quantitative yields.
Received 10 March 2010
Received in revised form 14 April 2010
Accepted 22 April 2010
Available online 24 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
acceptable reactivities and enantioselectivities. Although recently,
cinchona-derived thioureas6 and sulfonamides7 have been shown
The enantioselective desymmetrization of cyclic meso-anhy-
drides offers access to optically active compounds, which represent
important chiral intermediates in the synthesis of many natural
products and biologically active substances.1 In most cases, an
achiral alcohol is combined with an enantiopure base. Since the
initial discoveries by Oda2 and Aitken,3 the use of cinchona alka-
loids in asymmetric alcoholyses of meso-anhydrides became most
common. Both the stoichiometric protocols developed by Bolm4
(Scheme 1) and the catalytic methods using cinchona alkaloid
ether derivatives introduced by Deng5 lead to products with
to catalyze highly enantioselective alcoholyses at ambient tem-
perature and with low catalyst loadings, it is remarkable how often
the stoichiometric protocol has found application in complex total
synthesis.8 Apparently, the advantage of having large quantities of
natural cinchona alkaloids, which can even be recovered and
reused, commercially available at low cost, overrides the desire to
use modern catalytic versions of this synthetically highly valuable
transformation.
Only a few non-alkaloid-based catalysts for enantioselective
alcoholyses have recently been described.9 Furthermore, the
O
3 (1.1 equiv),
ROH (3.0 equiv)
4 (1.1 equiv),
ROH (3.0 equiv)
COOR
COOH
COOH
O
COOR
O
2
ent-2
1a
OMe
OH
OMe
up to 99% ee
up to 99% ee
R = Me or Bn
N
N
OH
N
N
3
4
Scheme 1. Asymmetric alcoholysis of meso-anhydrides by Bolm.
excellent enantioselectivities in high yields. Despite these
advances, it should also be noted that mostly high catalyst loadings,
low temperatures, and long reaction times are required for
organocatalytic conversion of meso-anhydrides with other nucle-
ophiles is less common.10 The finding of novel catalysts and new
protocols for reactions with diverse nucleophiles still remains
challenging.
Here, we are presenting the application of several easily acces-
sible, low molecular organocatalysts, which are effective in both
enantioselective alcoholyses and asymmetric thiolyses of cyclic
meso-anhydrides.
q
As part of the Steven Ley Prize Symposium in Print.
* Corresponding author. E-mail address: carsten.bolm@oc.RWTH-Aachen.de
(C. Bolm).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.121

6350
E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
2. Results and discussion
derivatives 8 and 9 the highest enantioselectivity (82% ee for ent-
2a) was observed when 8a having a piperidinyl substituent was
applied (Table 2, entry 1). Surprisingly, use of the corresponding N,
N-dimethyl derivative led to ent-2a with only 20% ee (entry 2), and
the quinidine-derived 9 proved inefficient affording ent-2a with
39% ee (entry 3). In all cases the yields were high (ranging from 89
2.1. Methanolysis of meso-anhydrides
Cinchona alkaloids, which are efficient mediators in the enan-
tioselective methanolyis of meso-anhydrides, possess a b-amino-
alcohol core structure. Assuming that this structural element
to 94%). As observed in catalyses with b-aminoalcohols the ste-
played a significant role in the catalysis, several low molecular
reochemistry of the imine-bearing carbon atom determined the
absolute configuration of the product.
To introduce a better hydrogen bond donor into the catalyst,
sulfonamides 10 and thioureas 11 were synthesized. To our disap-
pointment, all derivatives showed only low to moderate enantio-
trans-cyclohexane-based
b-aminoalcohol derivatives were syn-
thesized11 and tested in the methanolysis of anhydride 1a. In these
experiments, 10 mol % of the catalyst and toluene as the solvent
were applied.12 The results are summarized in Table 1.
Table 1
Screening of b
-aminoalcohols as organocatalysts for the asymmetric methanolysis of anhydride 1aa
O
cat (10 mol%),
COOMe
COOH
COOH
MeOH (3.0 equiv)
+
O
toluene, 24 h, rt
COOMe
O
1a
2a
ent-2a
OH
N
OH
OH
Me
Me
R
R
OH
N
OH
N
N
Me
Me
N
R
N
R
Me
Me
OH
5a: R = Me
6a: R = Me
6b: R = -C5H10
5b: R = -C5H10
-
5d
5e
5f
7
-
ent-5c: R = -C2H4-O-C2H4-
Entry
Aminoalcohol
Product
% Yieldb
% eec
1
2
3
4
5
6
7
8
9
5a
2a
2a
ent-2a
2a
ent-2a
2a
2a
2a
2a
98
99
98
95
97
92
99
97
96
33
72
71
17
10
16
16
57
31
5b
ent-5c
5d
5e
5f
6a
6b
7
a
The reactions were carried out using anhydride 1a (1.0 mmol), 10 mol % of the catalyst, and 3.0 equiv of methanol in toluene (5 mL) for 24 h at room temperature.
Yield of isolated product after extraction.
Determined by GC analysis of the corresponding lactone using a chiral column. For details see Experimental section.
b
c
All
b
-aminoalcohol derivatives were highly active organo-
selectivities in the asymmetric opening of 1a. Noteworthy in this
context is a recent report on the use of a sulfonamide with a N,N-
dimethyl-1,2-diphenyl-1,2-ethanediamine scaffold, which led to
very high enantioselectivities.9b Compared to the catalytic behavior
of the cyclohexane-derived sulfonamides reported here (Table 2,
entries 4 and 5), those results were by far superior.
Surprising effects were observed in catalyses with thioureas 11.
There, phenyl-substituted derivative 11d gave the best result (Table
2, entry 9). This was unexpected because in previous reports,16
catalysts with 3,5-bis(trifluoromethyl)-substituted phenyl groups
appeared to be advantageous over their phenyl analogues. Fur-
thermore, compared with other N-substituents, a dimethylamino
group in the thioureas (as in 11c and 11d) was beneficial for the
enantioselectivity (Table 2, entries 8 and 9). This was in accord with
observations made with sulfonamides 10 (Table 2, entry 4 vs entry
catalysts. The products could be isolated without requiring column
chromatography in excellent yields.13 Both the scaffold as well as
the substitution pattern of the b-aminoalcohol core significantly
influenced the selectivity of the reaction (Table 1). Piperidinyl- and
morpholinyl-substituted cyclohexane-based catalysts 5b and 5c
were the most selective and furnished product 2a with 72 and 71%
ee, respectively (Table 1, entries 2 and 3). As already observed in
catalyses with cinchona alkaloids,2 the stereochemistry of the hy-
droxyl-bearing carbon atom determined the absolute configuration
of the product, resulting in the (S)-hemiester 2a employing (1S)-2-
aminocyclohexanol derivatives (Table 1, entries 1, 2, 4, and 6).12
Guided on these results and with the goal to find alternative low
molecular weight catalysts with improved properties, various cyclo-
hexane-based diamines and derivatives thereof were synthesized
next. For their preparations, well-established routes starting from
enantiopure 1,2-diamino cyclohexane could be utilized.14 These
compounds were then applied in catalytic anhydride openings of 1a
using toluene as solvent.15 In Table 2 the results are summarized.
Also here, the catalyst properties were strongly affected by the
substitution pattern of the amino group, and among imine
5), but it contrasted the catalytic results obtained with b-amino-
alcohol dervatives 5aec, where the dimethylamino-substituted
compound 5a led to 2a with the lowest ee (Table 1, entries 1e3).
Furthermore, sulfonamide and thiourea analogues of the cor-
responding aminoalcohols and imines generated the opposite en-
antiomer of the product (Table 1, entry 1 and Table 2, entry 1 vs

E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
6351
Table 2
Screening of
b
-diamino derivatives as organocatalysts for the asymmetric methanolysis of anhydride 1aa
O
cat (10 mol%),
COOMe
COOH
MeOH (3.0 equiv)
+
O
toluene, 24 h, rt
COOH
COOMe
O
1a
2a
ent-2a
Me
OH
Me
OMe
CF3
CF3
OH
H
N
H
N
S
CF3
N
N
S
CF3
O2
O2
Me
N
N
R
N
Me
N
R
N
8a: R= -C5H10
8b: R= Me
-
9
10a
10b
F3C
CF3
F3C
CF3
F3C
S
CF3
S
NH
S
NH
NH
S
NH
NH
NH
NH
NH
Me
Me
N
N
N
N
O
Me
Me
11a
11b
11c
11d
Entry
Catalyst
Product
% Yieldb
% eec
1
2
3
4
5
6
7
8
9
8a
8b
9
10a
10b
11a
11b
11c
11d
ent-2a
ent-2a
ent-2a
ent-2a
2a
ent-2a
2a
2a
91
94
89
96
82
20
39
15
45
10
28
39
45
99
75d
77d
75d
98
2a
a
The reactions were carried out using anhydride 1a (1.0 mmol), 10 mol % of the catalyst, and 3.0 equiv of methanol in toluene (5 mL) for 24 h at room temperature.
Yield of isolated product after extraction.
Determined by GC analysis of the corresponding lactone using a chiral column. For details see Experimental section.
Yield of isolated product after column chromatography.
b
c
d
Table 2, entries 4 and 6). From this observation we concluded that
slightly lower yields after the same reaction time. The enantiose-
lectivities, however, were superior with phenyl-substituted 11d in
most cases, and taking into account the cost for catalyst prepara-
tion, the subsequent study of the substrate scope was done with
this catalyst. Thus, the conditions were as follows: use of 0.1 equiv
of 11d in a 0.0125 M solution of diethyl ether with 10 equiv of
methanol.17
Various substituted succinic anhydrides afforded products with
enantioselectivities ranging from 90 to 94% ee in very high yield (up
to 99%; Table 4, entries 1e5). Openings of 3-substituted glutaric
anhydrides proved less enantioselective, and products 2f and 2g
were obtained with only 81 and 80% ee, respectively (entries 6 and
7). Bicyclic glutaric anhydrides 1h and 1i reacted very well leading
to the corresponding hemiesters with 96 and 94% ee, respectively
(entries 8 and 9).18 In contrast, oxygen-bridged 2j, which was
obtained by asymmetric opening of anhydride 1j, had only 72% ee
(entry 10), indicating that the oxygen atom had a negative effect on
the enantioselectivity. The lower ee of 2j was mirrored by the
moderate yield of this product (65%), which contrasted the excel-
lent yields achieved in the openings of substrates 1h and 1i (97 and
depending on the nature of the catalyst either two very distinct
reaction mechanisms were operating, or other factors played a de-
cisive role.
As observed in other anhydride openings,6,9a thioureas can form
inactive dimers, which lower the enantioselectivities. In order to
study if such effects were also important here, catalyses with
thioureas 11c and 11d were performed at various concentrations
(Table 3). Again, anhydride 1a served as substrate, and this time,
diethyl ether, which proved superior to toluene (Table 2, entry 9 vs
Table 3, entry 1), was used as solvent.
As the data in Table 3 reveal, the reaction showed a very strong
dilution effect. Decreasing the concentration of the anhydride in
a catalysis with (10 mol % of) thiourea 11d from 0.2 mol Lꢀ1 to
0.025 mol Lꢀ1 led to a significant increase in enantioselectivity and
2a was obtained with 90 instead of 65% ee (entries 1 and 2). At
0.0125 mol Lꢀ1 the ee of 2a was even 93% (entry 3). Both phenyl- as
well as bis(trifluoromethyl) phenyl-substituted catalysts 11d and
11c, respectively, performed well under diluted conditions. In terms
of reactivity, 11d appeared to be less active than 11c giving 2a in

6352
E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
Table 3
Table 4
Optimization of the reaction conditions in the asymmetric anhydride opening of
anhydride 1a (in diethyl ether at room temperature) with organocatalysts 11 to give
hemiester 2a
Enantioselective methanolysis of various meso-anhydrides using catalyst 11da
O
11d (10 mol%),
COOMe
MeOH (10.0 equiv)
O
R*
R
O
O
COOMe
Et2O, 24 h
11, MeOH
COOH
O
Et2O, rt
COOH
O
Entry
1
Anhydride
Product
COOMe
% Yieldb
% eec
1a
2a
O
Entry
Catalyst
Concentration
MeOH
(equiv)
Time
% Yieldb
% eec
a
(equiv)
(mol Lꢀ1
)
(h)
O
89
99
99
93
COOH
2a
1
2
3
4
5
6
7
8
9
11d (0.10)
11d (0.10)
11d (0.10)
11c (0.10)
11c (0.05)
11c (0.01)
11d (0.01)
11d (0.05)
11c (0.05)
11d (0.05)
0.2000
0.0250
0.0125
0.0125
0.0125
0.0125
0.0125
0.0250
0.0125
0.0125
3
10
10
10
10
10
10
5
24
24
24
24
48
96
96
48
72
72
96
99
89
95
89
75
64
90
81
79
65
90
93
92
92
90
93
92
93
94
O
1a
1b
1c
O
COOH
O
2
94
5
5
COOMe
10
O
2b
a
Concentration of anhydride 1a in diethyl ether.
Yield of isolated product after extraction.
Determined by GC analysis of the corresponding lactone using a chiral column.
b
c
For details see Experimental section.
O
COOMe
COOH
96%, respectively). Noteworthy, to the best of our knowledge, there
is only one other report9d on enantioselective openings of such type
of bicyclic glutaric anhydrides.
O
3
90
O
2c
Recently, Rawal applied organocatalysts with a squaramide
scaffold as effective hydrogen bond donors.19 Testing 12, as repre-
sentative catalyst of this class, in the methanolysis of 1a under the
standard conditions shown in Scheme 2 (right), the enantiose-
lectivity was only moderate and 2a had 62% ee. However, applying
the optimized dilution conditions described above (Scheme 2, left)
changed the picture, and 2a was now obtained with 94% ee. This
value compared well with the one achieved in the catalysis with
thiourea 11d (93% ee). Hence we conclude that squaramide 12 is
also a highly suitable catalyst for the enantioselective methanolysis
of meso-anhydrides.
O
COOMe
COOH
O
4
5
6
7
99
77
95
94
91
93
81
80
O
2d
1d
O
COOMe
COOH
Me
Me
Me
Me
O
2.2. Thiolysis of meso-anhydrides
O
2e
Next, we focused our attention on the development of suitable
conditions for the less common catalytic asymmetric thiolysis.
Because the natural cinchona alkaloids performed so well in the
enantioselective alcoholysis and since they have not been yet
applied in the thiolysis, they were tested first. To our surprise, the
usual test substrate 1a did not react with benzyl mercaptan to the
desired thioester, and thus, anhydride 1c was chosen as starting
material for this study. The reactions were performed in diethyl
ether and terminated by the addition of TMSCHN2 and methanol.
This treatment led to an in situ derivatization of the in-
termediately formed labile hemithioester and afforded thioester
13c as stable product.
The application of 1 mol % of quinidine (3) as catalyst led to
13c with a moderate ee of 39%. With the goal to improve the
enantioselectivity, the alkaloid loading was increased (to
1.1 equiv), and to our surprise, a product with much lower ee
resulted (7%). Furthermore, ent-13c, the other enantiomer of
thioester 13c, was formed in preference. Hence, the ee as well as
the absolute configuration of the product were strongly de-
pendent on the catalyst loading. Figure 1 illustrates this effect
showing data from various catalyses.
1e
O
COOMe
COOH
Me
Me
O
O
2f
1f
O
O
O
COOMe
COOH
Ph
Ph
2g
1g
COOMe
O
O
O
8
97
96
These observations were in accord with those recently made in
the alcoholysis of 3-substituted meso-glutaric anhydrides by Ivesic
and Hamersak,20 who noticed a change in the absolute product
COOH
1h
2h

E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
6353
Table 4 (continued)
Entry Anhydride
configuration when increasing the quinine loading from 0.1 to
1.6 equiv.21 Applying those substrates (represented by glutaric an-
hydride 1f and bicyclic substrate 1h) in the quinidine-accelerated
ring opening reported here showed that the thiolysis was much less
affected by the catalyst loading. While the yields remained almost
the same, the enantioselectivities increased (up to 77% ee) when
the quinidine loadings were reduced. The best results were ach-
ieved in catalyses with only 1 mol % of quinidine (Table 5, entries
1 and 4).
Product
% Yieldb
% eec
COOMe
O
O
O
9
96
94
COOH
1i
2i
Next, the low molecular cyclohexane-based catalysts were
tested in the catalyzed asymmetric thiolysis of anhydride 1c with
benzyl mercaptan (Table 6). In this screening, 5 mol % of the catalyst
was applied, and diethyl ether served as solvent.22 As before,
product isolation and ee analysis followed an in situ derivatization
with TMSCHN2 and methanol.
COOMe
O
O
O O
10
65
72
COOH
O
1j
2j
Both aminoalcohol 5b and imine 8b led to products with low ee
values (Table 6, entries 1 and 2). In contrast, sulfonamides 10 and
thioureas 11 performed better, yielding products with enantio-
selectivities in the range of 43e65% ee (Table 6, entries 3e7).
Among the latter catalysts, compounds 10a, 11a, and 11b having
piperidinyl or morpholinyl substituents, respectively, gave higher
ee’s than dimethylamino-substituted 10b or 11c. This is particu-
larly noteworthy, because it contrasted the behavior of those
a
The reactions were carried out using the anhydride (0.5 mmol), catalyst 11d
(10 mol %), and MeOH (10.0 equiv) in diethyl ether (40 mL) for 24 h at room
temperature.
b
Yield of isolated product after extraction.
Determined by HPLC or GC analysis using chiral columns.
c
O
12 (10 mol%),
12 (10 mol%),
COOMe
COOMe
MeOH (10.0 equiv)
MeOH (3.0 equiv)
O
COOH
2a
Et2O (0.0125 M),
24 h, rt
toluene (0.2 M),
24 h, rt
COOH
2a
O
O
1a
99% yield,
94% ee
90% yield,
62% ee
CF3
O
N
H
Me
N
H
CF3
N
Me
12
Scheme 2. Squareamide catalyst 12 in the methanolysis of 1a.
quinidine (3, 0.01 equiv),
BnSH (1.2 equiv),
Et2O, rt, 24 h
quinidine (3, 1.1 equiv),
BnSH (1.2 equiv),
Et2O, rt, 24 h
O
COSBn
COOMe
COOMe
COSBn
O
then: TMSCHN2 (2.0 equiv),
MeOH, rt
then: TMSCHN2 (2.0 equiv),
MeOH, rt
O
13c
ent-13c
7% ee
1c
39% ee
% ee
10
0
-10
-20
-30
-40
-50
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
c(quinidine) / c(anhydride)
Figure 1. Dependence of the absolute product configuration on the catalyst loading in the quinidine-accelerated thiolysis of 1c.

6354
E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
Table 7
Table 5
Enantioselective thiolysis of various meso-anhydrides catalyzed by thiourea 11ba
Quinidine-accelerated thiolysis of glutaric anhydridesa
11b (5 mol%),
BnSH (1.2 equiv),
Et2O, 24 h
quinidine (3),
BnSH (1.2 equiv),
Et2O, 24 h
O
O
O
O
COSBn
COOMe
COSBn
COOMe
R*
R
O
O
R*
R
then: TMSCHN2,
MeOH
then: TMSCHN2,
MeOH
Entry
1
Anhydride
Product
% Yieldb
% eec
Entry
Cat.
(equiv)
Anhydride
Product
% Yieldb
% eec
O
COSBn
COOMe
13c
O
O
O
COSBn
COOMe
O
79
65
1
2
3
0.01
0.05
1.10
83
84
85
64
64
57
Me
Me
O
1c
13f
1f
O
O
O
4
5
6
0.01
0.05
1.10
85
90
88
77
75
68
COSBn
COSBn
COOMe
O
Me
Me
2
3
88
93
85
90
O
O
13f
COOMe
1f
1h
13h
COSBn
O
O
O
a
The reactions were carried out using the anhydride (1.0 mmol), quinidine (3),
and benzyl mercaptan (1.2 equiv) in diethyl ether (10 mL) for 24 h at room
temperature.
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis using a chiral column.
c
COOMe
1h
13h
COSBn
O
Table 6
Catalyst screening for the asymmetric thiolysis of anhydride 1ca
O
O
catalyst (5 mol%),
BnSH (1.2 equiv),
Et2O, 24 h
4
94
89
O
COSBn
COOMe
COOMe
COSBn
COOMe
+
O
1i
13i
then: TMSCHN2,
MeOH
O
COSBn
O
O
1c
13c
ent-13c
O O
O
5
48
49
Entry
Catalyst
% Yieldb
% eec
Product
1
2
3
4
5
6
7
5b
8b
59
80
81
71
80
79
75
11
23
64
59
50
65
43
13c
COOMe
ent-13c
ent-13c
13c
ent-13c
13c
1j
13j
10a
10b
11a
11b
11c
a
The reactions were carried out using the anhydride (1.0 mmol), thiourea 11b
(5 mol %), and benzyl mercaptan (1.2 equiv) in diethyl ether (10 mL) for 24 h at
room temperature.
13c
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis using a chiral column.
c
a
The reactions were carried out using anhydride 1c (1.0 mmol), the catalyst
(5 mol %) and benzyl mercaptan (1.2 equiv) in diethyl ether (10 mL) for 24 h at room
temperature.
3. Conclusion
b
Yield of isolated product after column chromatography.
c
Determined by HPLC analysis using a chiral column.
Various low molecular cyclohexane-based organocatalysts have
been applied in the desymmetrization of cyclic meso-anhydrides.
Using alcohols or benzyl mercaptan as nucleophiles readily avail-
compounds in the methanolysis (comp. Table 6, entries 3e7 with
Table 2, entries 4e8).
able b-aminoalcohols, imines, sulfonamides, and thioureas led to
Attempts to apply thiourea catalyst 11b at high dilution did not
improve the results, and thus, the subsequent substrate screening
was done under the standard thiolysis conditions (with 5 mol % of
catalyst in diethyl ether). The results are summarized in Table 7.
All reactions proceeded well, and in most cases the yields were
in the 90% range. The only exceptions were transformations of
anhydrides 1c and 1j, which gave the corresponding products in
only 79 and 48% yield, respectively (Table 7, entries 1 and 5). Also
here, the oxygen atom in the bridging core of 1j appeared to
hamper the catalysis. Interestingly, yields and enantioselectivities
went in parallel, and thus, the best enantioselectivities (up to 90%
ee for 13h) were achieved in conversions of glutaric anhydrides 1f,
1h, and 1i (Table 7, entries 2e4).
the corresponding ring-opened products in high yields. The most
selective catalyst was a (Takemoto type) thiourea, which furnished
hemiesters in enantioselective alcoholyses of succinic and glutaric
anhydrides in up to 96% ee. A related catalyst gave products with up
to 90% ee in catalytic asymmetric thiolyses of glutaric anhydrides.
4. Experimental
4.1. General information
All reactions were carried out under argon using standard
Schlenk and vacuum line techniques. Before use the solvents

E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
6355
21
were dried and freshly distilled under argon according to stan-
C
16H24N2O ([Mþ]) 260.1883. Found: 260.1883; [
a
]
ꢀ134.3 (c
D
dard procedures. Anhydrides 1ge1j were prepared from the
corresponding diacids by dehydration with trifluoroactic anhy-
dride. All other reagents were obtained from commercial sources
and used as received. Column chromatography was done on silica
1.34, CHCl3).
4.2.4. 2-{[(9-epi-Aminoquinidin-9-yl)imino]methyl}-4-methylphenol
(9). Yellow solid; mp 83e85 ꢁC; 1H NMR (CDCl3, 300 MHz)
gel 60 (40e63
m
m) from Merck as stationary phase. TLC was
d 0.99e1.06 (m, 1H), 1.16e1.28 (m, 1H), 1.49e1.58 (m, 2H),
performed using precoated aluminum plates (Merck silica gel 60
F254). Detection was done either using UV light (254 nm) or
KMnO4 stain. NMR spectra were recorded on a Varian Inova 400
(400 MHz) or Mercury 300 (300 MHz) instrument. Chemical
1.60e1.67 (m, 1H), 2.24 (s, 3H), 2.26e1.34 (m, 1H), 2.82e3.10 (m,
4H), 3.44 (q, J¼9.4 Hz, 1H), 4.01 (s, 3H), 4.92 (d, J¼9.7 Hz, 1H),
5.05 (dt, J¼5.7, 1.5 Hz, 1H), 5.08e5.12 (m, 1H), 5.82e5.95 (m, 1H),
6.82 (d, J¼8.2 Hz, 1H), 7.00e7.10 (m, 2H), 7.40 (dd, J¼9.2, 2.7 Hz,
1H), 7.49 (d, J¼4.5 Hz, 1H), 7.57 (d, J¼2.5 Hz, 1H), 8.03 (d,
J¼9.2 Hz, 1H), 8.33 (s, 1H), 8.76 (d, J¼4.5 Hz, 1H), 13.07 (br s, 1H);
shifts are given in parts per million relative to TMS (
d
¼0 ppm) or
solvent residual peaks as internal standards. Mass spectra were
recorded on a Finnigan SSQ 7000 system (EI, 70 eV). Elemental
analyses were measured on an Elementar Vario EL instrument. IR
spectra were recorded on a PerkinElmer Spectrum 100 FT-IR
13C NMR (CDCl3, 75 MHz)
d
20.3, 24.9, 26.5, 27.8, 39.5, 47.6, 49.6,
55.6, 61.0, 70.5, 101.6, 114.6, 116.6, 118.5, 121.2, 121.8, 127.7, 131.8,
132.1, 133.2, 140.5, 144.5, 145.0, 147.7, 157.9, 158.7, 165.5; IR (KBr)
n
spectrometer. Optical rotations were measured on
a
Per-
2934, 2108, 1626, 1493, 1221, 1029, 914, 821, 714, 666 cmꢀ1
;
kineElmer Model P241 instrument using a light frequency of
589 nm. Concentration c is listed in g/100 mL. Melting points
were determined on a Büchi B-450 apparatus in open capillaries
and are uncorrected.
HRMS calcd for C28H31N3O2 ([Mþ]) 441.2411. Found: 441.2424;
21
[
a
]
þ137.7 (c 1.10, CHCl3).
D
4.2.5. N-[(1S,2S)-2-(Piperidin-1-yl)cyclohexyl]3,5-bis(trifluoro-
methyl)benzenesulfonamide (10a). White solid; mp 110e111 ꢁC; 1H
4.2. Preparation of catalysts
NMR (CDCl3, 400 MHz) d 1.00e1.27 (m, 4H), 1.28e1.56 (m, 6H),
1.62e1.70 (m, 1H), 1.73e1.86 (m, 2H), 2.10e2.36 (m, 6H), 2.75e2.86
Aminoalcohols 5ae5e,11 5f,23 7,11 and thioureas 11c and 11d16
were prepared according to the literature procedures. Com-
pounds 6a and 6b were obtained by alkylations of the commercial
available (S,S)-(ꢀ)-2-amino-1,2-diphenylethanol. All enantiopure
cyclohexane-based diamine derivatives, imines 8,14a sulfonamides
10,10a thioureas 11, and squareamide 1219 were prepared from the
corresponding enantiopure 1,2-cyclohexane diamine.14 Imine 924
was obtained from 9-epi-aminoquinidine following literature
procedures.
(m, 1H), 6.20 (br s, 1H), 8.05 (s, 1H), 8.34 (s, 2H); 13C NMR (CDCl3,
100 MHz)
d 22.9, 24.2, 24.5, 25.3, 26.5, 32.6, 49.2, 53.9, 67.3, 122.5
(q, J¼272.8 Hz), 125.9, 127.3, 132.7 (q, J¼34.3 Hz), 143.3; IR (KBr)
n
3149, 2933, 1740, 1452, 1354, 1278, 1136, 964, 900, 843, 680 cmꢀ1
;
MS (EI, 70 eV) m/z 459 ([MþH]þ, 9%), 439 (9%), 213 (18%), 181
(100%), 164 (13%), 96 (11%), 84 (13). Anal. Calcd for C19H24F6N2O22S2:
C, 49.78; H, 5.25; N, 6.11. Found: C, 49.66; H, 5.23; N, 6.06; [a]
D
þ60.1 (c 1.39, CHCl3).
4.2.6. N-[(1R,2R)-2-(Dimethylamino)cyclohexyl]3,5-bis(tri-
4.2.1. (1S,2S)-trans-2-(Piperidin-10-yl)-cyclopentanol
solid; mp 49e51 ꢁC; 1H NMR (CDCl3, 400 MHz)
1.38e1.49 (m, 3H),
1.49e1.72 (m, 7H), 1.78e1.95 (m, 2H), 2.41e2.54 (m, 5H), 2.84 (br s,
1H), 4.07e4.14 (m, 1H); 13C NMR (CDCl3, 100 MHz)
21.8, 24.6, 26.1,
3140, 2930, 2083, 1448, 1332,
(7). White
fluoromethyl)benzenesulfonamide (10b). White solid; mp 80e81 ꢁC;
d
1H NMR (CDCl3, 400 MHz)
d 0.95e1.24 (m, 4H), 1.60e1.67 (m, 1H),
1.71e1.80 (m, 2H), 1.98 (s, 6H), 2.13e2.21 (m, 1H), 2.21e2.28 (m,
d
1H), 2.69e2.78 (m, 1H), 8.03 (s, 1H), 8.32 (s, 2H); 13C NMR (CDCl3,
27.1, 34.4, 52.4, 74.9, 75.5; IR (KBr)
n
100 MHz)
d
21.2, 24.2, 25.0, 39.7, 54.5, 66.3, 122.5 (q, J¼272.9 Hz),
1255, 1175, 1108, 1038, 987, 903, 872, 805, 739, 661 cmꢀ1; MS (EI,
70 eV) m/z 169 ([Mþ], 24%), 124 (100%), 110 (44%), 98 (22%). Anal.
Calcd for C10H19NO: C, 70.96; H, 11.31; N, 8.28. Found: C, 71.32; H,
125.8, 127.5, 132.6 (q, J¼34.3 Hz), 143.5; IR (KBr)
n 3095, 2945, 1739,
1454, 1353, 1274, 1109, 970, 900, 844, 729, 680 cmꢀ1; MS (EI, 70 eV)
m/z 418 ([M], 9%), 399 (16%), 213 (40%), 141 (100%), 124 (55%), 96
(52%), 84 (21%), 70 (22%). Anal. Calcd for C16H20F6N2O2S: C, 45.93;
11.66; N, 8.27; [
a
]
D
21 þ43.3 (c 2.95, CHCl3).
H, 4.82; N, 6.70. Found: C, 46.18; H, 4.73; N, 6.77; [
CHCl3).
a
]
D
22 ꢀ65.9 (c 1.28,
4.2.2. 4-Methyl-2-({[(1R,2R)-2-(piperidin-1-yl)cyclohexyl]imino}
methyl)phenol (8a). Yellow solid; mp 76e77 ꢁC; 1H NMR (CDCl3,
400 MHz)
d
1.20e1.48 (m, 9H), 1.54e1.67 (m, 1H), 1.69e1.95 (m,
4.2.7. 1-[3,5-Bis(trifluoromethyl)phenyl-3-[(1S,2S)-2-(piperidin-1-
yl)cyclohexyl]thiourea (11a). White solid; mp 79e81 ꢁC; 1H NMR
4H), 2.29 (s, 3H), 2.34e2.45 (m, 3H), 3.17 (dt, J¼10.4, 4.4 Hz, 1H),
6.86 (d, J¼8.5 Hz, 1H), 7.03 (d, J¼1.6 Hz, 1H), 7.09 (dd, J¼8.5, 2.2 Hz,
(CDCl3, 300 MHz)
2.27e2.40 (m, 3H), 2.53e2.65 (m, 3H), 3.68e3.82 (m, 1H), 7.70 (s,
1H), 7.84 (s, 2H); 13C NMR (CDCl3, 75 MHz)
23.4, 24.3, 24.5, 25.3,
26.3, 32.6, 49.6, 56.2, 68.9, 119.1, 122.9 (q, J¼273.4 Hz), 124.7, 132.8
d 1.07e1.42 (m, 10H), 1.68e1.96 (m, 3H),
1H), 8.16 (s, 1H), 13.75 (br s, 1H); 13C NMR (CDCl3, 75 MHz)
d 20.4,
24.6, 24.8, 25.0, 25.5, 26.7, 34.3, 50.0, 67.9, 67.9, 116.7, 118.4, 126.8,
d
130.8, 132.4, 159.5, 163.2; IR (KBr)
n 2931, 2850, 2792, 1626, 1589,
1494, 1445, 1282, 1157, 828, 774, 671, 575 cmꢀ1; MS (EI, 70 eV) m/z
300 ([Mþ], 35%), 217 (100%), 165 (30%), 150 (89%), 136 (26%), 124
(46%), 98 (29%), 84 (53%). Anal. Calcd for C19H28N2O: C, 75.96; H,
(q, J¼33.5 Hz), 139.8, 187.1; IR (KBr)
n 3249, 2935, 1533, 1471, 1381,
1274, 1172, 1128, 967, 884, 702, 680 cmꢀ1; MS (EI, 70 eV) m/z 453
([Mþ], 23%), 165 (100%), 124 (51%), 86 (52%). Anal. Calcd for
C20H25F62N13S: C, 52.97; H, 5.56; N, 9.27. Found: C, 52.99; H, 5.53; N,
9.39; N, 9.32. Found: C, 76.10; H, 9.43; N, 9.64; [
CHCl3).
a]
21 ꢀ157.7 (c 3.02,
D
9.09; [
a
]
D
þ13.4 (c 0.96, CHCl3).
4.2.3. 2-({[(1R,2R)-2-(Dimethylamino)cyclohexyl]imino}methyl)-4-
4.2.8. 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-morpholino-
cyclohexyl]thiourea (11b). White solid; mp 176e177 ꢁC; 1H NMR
methylphenol (8b). Yellow oil; 1H NMR (CDCl3, 400 MHz)
d
1.20e1.39 (m, 3H), 1.52e1.68 (m, 1H), 1.68e1.92 (m, 4H), 2.26 (s,
(CDCl3, 400 MHz) d 1.05e1.42 (m, 4H), 1.69e1.99 (m, 3H), 2.30e2.41
6H), 2.28 (s, 3H), 2.50e2.62 (m, 1H), 3.20 (dt, J¼10.2, 4.2 Hz, 1H),
6.85 (d, J¼8.2 Hz, 1H), 7.02 (d, J¼2.2 Hz, 1H), 7.09 (dd, J¼8.4,
2.2 Hz, 1H), 8.24 (s, 1H), 13.55 (br s, 1H); 13C NMR (CDCl3,
(m, 3H), 2.61e2.74 (m, 3H), 3.47e3.60 (m, 4H), 3.95e4.07 (m, 1H),
6.71 (br s, 1H), 7.72 (s, 1H), 7.81 (s, 2H), 8.71 (br s, 1H); 13C NMR
(CDCl3, 75 MHz)
122.7 (q, J¼272.6 Hz), 123.6, 133.2 (q, J¼33.8 Hz), 138.9, 179.9; IR
(KBr) 3247, 2939, 1740, 1542, 1462, 1381, 1272, 1218, 1171, 1130,
1017, 971, 894, 849, 704, 681 cmꢀ1; MS (EI, 70 eV) m/z 455 ([Mþ],
d 23.3, 24.6, 25.3, 32.5, 48.5, 55.8, 67.4, 68.0, 119.1,
75 MHz)
118.7, 127.2, 131.1, 132.7, 159.4, 163.0; IR (capillary)
1493, 1278, 1157, 1033, 947, 819, 673 cmꢀ1; HRMS calcd for
d
20.2, 20.3, 23.9, 24.6, 25.2, 34.7, 40.8, 66.9, 69.3, 116.8,
n
2929, 1634,
n

6356
E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
15%), 368 (56%), 167 (100%), 126 (69%), 88 (43%). Anal. Calcd for
C19H23F6N3OS: C, 50.10; H, 5.09; N, 9.23. Found: C, 50.09; H, 4.96; N,
210 nm, 95/5 heptane/i-PrOH, 1.0 mL/min): tR1¼17.8 min (major),
tR2¼19.0 min.
9.22; [
a
]
D
21 ꢀ66.7 (c 1.00, CHCl3).
Acknowledgements
4.3. General procedure for the enantioselective methanolysis
of meso-anhydrides
We are grateful to the Fonds der Chemischen Industrie and the
Deutsche Forschunggemeinschaft (DFG) within the SPP 1179
(‘Organocatalysis’) for financial support. E.S. thanks Dr. Toni Ran-
tanen for guiding her in this project and Thomas Eschemann,
Christian Borkner, Oliver Schmidt, Ludger Lautenschütz and Janine
Broda for experimental contributions. I.S. is thankful to Professor
Hille Perl for fruitful discussions.
Anhydride (0.5 mmol) and thiourea 11d (13.9 mg, 0.05 mmol)
were dissolved in dry diethyl ether (40 mL) under Ar. The reaction
was started by addition of methanol (203 mL, 5.0 mmol), and the
reaction mixture was stirred at room temperature for 24 h. The
solvent was evaporated in vacuum (to dryness), and the resulting
residue was dissolved in ethyl acetate. The solution was extracted
with a saturated solution of sodium carbonate (3ꢂ3 mL). The
combined aqueous phases were acidified with concd HCl, extracted
with ethyl acetate, and the organic phase was dried over MgSO4,
filtered, and concentrated providing the corresponding hemiester
without any further purification.
References and notes
1. For reviews, see: (a) Chen, Y.-G.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103,
2965e2983; (b) Tian, S.-K.; Chen, Y.-G.; Hang, J.; Tang, L.; McDaid, P.; Deng, L.
Acc. Chem. Res. 2004, 37, 621e631; (c) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem.
Rev. 2007, 107, 5683e5712.
The analytic data for 2ae2j were in agreement with those
reported in literature.
2. (a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem. Commun. 1985,
1717e1718; (b) Hiratake, J.; Inagaki, M.; Yamamoto, Y.; Oda, J. J. Chem. Soc.,
Perkin Trans. 1 1987, 1053e1058.
3. (a) Aitken, R. A.; Gopal, J.; Hirst, J. A. J. Chem. Soc., Chem. Commun. 1988,
632e633; (b) Aitken, R. A.; Gopal, J. Tetrahedron: Asymmetry 1990, 1, 517e520.
4. (a)Bolm, C.;Gerlach, A.;Dinter, C.L. Synlett 1999,195e196; (b)Bolm, C.;Schiffers, I.;
Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984e6991; (c) Bolm, C.; Schiffers, I.;
Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron: Asymmetry 2003, 14, 3455e3467;
(d) Bolm, C.; Atodiresei, I.; Schiffers, I. Org. Synth. 2005, 82, 120e125.
5. (a) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542e9543; Pat-
ents: (b) Deng, L.; Chen, Y.; Tian, S. PCT Int. Appl. WO 2001074741 A2, 2001;
Chem. Abstr. 2001, 135, 288345; (c) Deng, L.; Chen, Y.; Tian, S. U.S. Patent
20,040,082,809 A1, 2004; Chem. Abstr. 2004, 140, 374734.
6. (a) Rho, H. S.; Oh, S. H.; Lee, J. W.; Chin, J.; Song, C. E. Chem. Commun. 2008,
1208e1210; (b) Peschiulli, A.; Gun’k, Y.; Connon, S. J. J. Org. Chem. 2008, 73,
2454e2457.
The ee of the hemiester was determined either by GC analysis
using a chiral column after conversion into the corresponding lac-
tone (for 2ae2e)4b or HPLC analysis using a chiral column after
conversion to the corresponding thioester with benzyl mercaptan
(for 2fe2j). The absolute product configurations were determined
comparing the measured optical rotations to literature values.
4.4. General procedure for the enantioselective thiolysis
of meso-anhydrides
7. Sang, H. O.; Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew.
Chem., Int. Ed. 2008, 47, 7872e7875.
Anhydride (1.0 mmol) and thiourea 11b (22.8 mg, 0.05 mmol)
were dissolved in dry diethyl ether (10 mL) under Ar. The reaction
was started by addition of benzyl mercaptan (0.141 mL, 1.2 mmol),
and the mixture was then stirred at room temperature for 24 h.
Next, methanol (1 mL) and a solution of TMSCHN2 (2.0 M in hexane,
1 mL, 2.0 mmol) was added and stirring for 15 min was followed by
addition of 2 M HCl and extraction with diethyl ether. The organic
phase was dried over MgSO4, filtered, and concentrated providing
the corresponding product, which was purified by column
chromatography.
8. (a) Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli, F. Tetrahedron: Asymmetry
1999, 10, 3403e3407; (b) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 8793e8794; (c) Bernardi, A.; Arosio, D.; Manzoni, L.; Micheli, F.;
Pasquarello, A.; Seneci, P. J. Org. Chem. 2001, 66, 6209e6216; (d) Tanyeli, C.;
Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167e1170; (e) Keen, S. P.;
Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.; Davies, A. J.; Dolling, U. H.; Lie-
berman, D. R.; Stewart, G. W. J. Org. Chem. 2005, 70, 1771e1779; (f) Yue, T.-Y.;
McLeod, D. D.; Albertson, K. B.; Beck, S. R.; Deerberg, J.; Fortunak, J. M.; Nugent,
W. A.; Radesca, L. A.; Tang, L.; Xiang, C. D. Org. Process Res. Dev. 2006, 10,
262e271; (g) Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asymmetry
2007, 18, 1095e1098; (h) Freire, F.; Fisk, J. D.; Peoples, A. J.; Ivancic, M.; Guzei, I.
A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 7839e7841; (i) Ruebsam, F.; Tran,
C. V.; Li, L.-S.; Kim, S. H.; Xiang, A. X.; Zhou, Y.; Blazel, J. K.; Sun, Z.; Dragovich, P.
S.; Zhao, J.; McGuire, H. M.; Murphy, D. E.; Tran, M. T.; Stankovic, N.; Ellis, D. A.;
Gobbi, A.; Showalter, R. E.; Webber, S. E.; Shah, A. M.; Tsan, M.; Patel, R. A.;
LeBrun, L. A.; Hou, H. J.; Kamran, R.; Sergeeva, M. V.; Bartkowski, D. M.; Nolan,
T. G.; Norris, D. A.; Kirkovsky, L. Bioorg. Med. Chem. Lett. 2009, 19, 451e458; (j)
Kong, N.-C.; Zhang, Y.; Gao, S.; Lu, Y.; Zheng, Q.-T.; Sun, Q.-Y.; Yang, F.-M.; Di, Y.-
T.; Hao, X.-J. Tetrahedron Lett. 2009, 50, 957e959; (k) Campbell, C. L.; Hassler, C.;
Ko, S. S.; Voss, M. E.; Guaciaro, M. A.; Carter, P. H.; Cherney, R. J. J. Org. Chem.
2009, 74, 6368e6370; (l) Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett.
2009, 11, 5354e5356; (m) Ruebsam, F.; Murphy, D. E.; Tran, C. V.; Li, L.-S.; Zhao,
J.; Dragovich, P. S.; McGuire, H. M.; Xiang, A. X.; Sun, Z.; Ayida, B. K.; Blazel, J. K.;
Kim, S. H.; Zhou, Y.; Han, Q.; Kissinger, C. R.; Webber, S. E.; Showalter, R. E.;
Shah, A. M.; Tsan, M.; Patel, R. A.; Thompson, P. A.; LeBrun, L. A.; Hou, H. J.;
Kamran, R.; Sergeeva, M. V.; Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.;
Khandurina, J.; Brooks, J.; Okamoto, E.; Kirkovsky, L. Bioorg. Med. Chem. Lett.
2009, 19, 6404e6412; (n) Archambaud, S.; Legrand, F.; Aphecetche-Julienne, K.;
Collet, S.; Guingant, A.; Evain, M. Eur. J. Org. Chem. 2010, 1364e1380.
9. (a) Uozumi, Y.; Yasoshima, K.; Miyachib, T.; Nagai, S. Tetrahedron Lett. 2001, 42,
411e414; (b) Okamatsu, T.; Irie, R.; Katsuki, T. Synlett 2007, 1569e1572; (c)
Wang, S.-X.; Chen, F.-E. Adv. Synth. Catal. 2009, 351, 547e552; (d) Honjo, T.;
Tsumura, T.; Sano, S.; Nagao, Y.; Yamaguchi, K.; Sei, Y. Synlett 2009, 3279e3282;
For a recent example of a diastereoselective alcoholysis, see: (e) Evans, A. C.;
The analytic data for 13ce13h were in agreement with those
reported in literature.
4.4.1. (1R,3S)-Methyl-3-[(benzylthio)carbonyl]cyclopen-
tanecarboxylate (13i). Colorless oil; 89% ee; 1H NMR (CDCl3,
400 MHz)
1H), 2.90e3.01 (m, 1H), 3.60 (s, 3H), 4.05 (s, 2H), 7.13e7.26 (m, 5H);
13C NMR (CDCl3, 100 MHz)
29.2, 29.8, 33.3, 33.8, 43.9, 51.9, 52.7,
d 1.82e1.98 (m, 4H), 2.01e2.22 (m, 2H), 2.68e2.78 (m,
d
127.2, 128.6, 128.8, 137.5, 171.2, 200.5; IR (capillary)
n 2951, 1734,
1685, 1451, 1205, 999, 918, 878, 770, 703 cmꢀ1; MS (EI, 70 eV) m/z
278 ([Mþ], 5%), 247 (8%), 155 (100%), 127 (23%), 95 (33%), 91 (31%),
67 (31%). Anal. Calcd for C15H18O3S: C, 64.72; H, 6.52. Found: C,
21
64.78; H, 6.52; [
a
]
ꢀ8.6 (c 1.16, CHCl3); HPLC (Chiralcel AD-H,
D
20 ꢁC, 210 nm, 99/1 heptane/i-PrOH, 0.5 mL/min): tR1¼47.9 min,
tR2¼51.4 min (major).
4.4.2. (2S,5R)-Methyl-5-[(benzylthio)carbonyl]tetrahydrofuran-2-
carboxylate (13j). Colorless oil; 49% ee; 1H NMR (CDCl3, 300 MHz)
ꢀ
Longbottom, D. A.; Matsuoka, M.; Davies, J. E.; Turner, R.; Franckevicius, V.; Ley,
S. V. Org. Biomol. Chem. 2009, 7, 747e760.
d
2.05e2.33 (m, 4H), 3.69 (s, 3H), 3.98e4.12 (m, 2H), 4.49e4.59 (m,
2H), 7.15e7.26 (m, 5H); 13C NMR (CDCl3, 75 MHz)
d
29.1, 30.3, 32.7,
10. (a) Honjo, T.; Sano, S.; Shiro, M.; Nagao, Y. Angew. Chem., Int. Ed. 2005, 44,
5838e5841; (b) Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Y. K.; Connon, S. J.
J. Org. Chem. 2008, 73, 6409e6412.
11. For straightforward syntheses of such compounds including their resolutions,
see: (a) Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmanns, W.; Zani, L.; Bolm, C.
J. Org. Chem. 2006, 7, 2320e2331; (b) Schiffers, I.; Bolm, C. Org. Synth. 2008, 85,
106e117; (c) Ogawa, R.; Fujino, T.; Hirayama, N.; Sakai, K. Tetrahedron: Asym-
metry 2008, 19, 2458e2461.
52.1, 78.8, 84.8, 127.2, 128.5, 128.9,137.4, 171.6, 200.9; IR (capillary)
n
2952, 1741, 1679, 1450, 1287, 1212, 1090, 923, 706 cmꢀ1; MS (EI,
70 eV) m/z 280 ([Mþ], 37%), 129 (44%), 101 (100%), 91 (44%), 69
(30%). Anal. Calcd for C14H16O4S: C, 60.08; H, 5.78. Found: C, 59.98;
H, 5.75; [
21
a]
þ18.63 (c 1.01, CHCl3); HPLC (Chiralcel AD-H, 20 ꢁC,
D

E. Schmitt et al. / Tetrahedron 66 (2010) 6349e6357
6357
12. cis-Aminoalcohols were less effective than their trans-counterparts. For ex-
ample, under standard conditions (1R,2S)-5b led to ent-2a with 28% ee: Ran-
tanen, T. Dissertation at RWTH Aachen University, 2007.
13. Basic extraction of the product followed by acidification and organic extraction
yielded in pure product.
14. (a) Dimethyl-substituted diamine: Mitchell, J. M.; Finney, N. S. Tetrahedron Lett.
2000, 41, 8431e8434; (b) Enantiopure piperidinyl- and morpholinyl-
substituted diamines were prepared by resolution with mandelic acid. For the
synthesis of the racemate and an alternative method for the resolution, see:
Gonzalez-Sabin, J.; Gotor, V.; Rebolledo, F. Chem.dEur. J. 2004, 10, 5788e5794.
15. A solvent screening in the asymmetric methanolysis of 2a with catalyst 5b
(10 mol %) under standard conditions led to the following results: toluene: 72%
ee; Et2O, dioxane: 70% ee; THF: 60% ee; CH2Cl2: 45% ee; MeCN: 14% ee.
16. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672e12673.
17. When benzylalcohol or ethanol was used instead of methanol similar enan-
tioselectivities were observed, but the reaction rates decreased.
18. For preparations of 2h, 2i, and 2j by enzyme-catalyzed hydrolyses of meso-
dimethylesters, see: (a) Boaz, N. W. Tetrahedron: Asymmetry 1999, 10, 813e816;
(b) Chênevert, R.; Martin, R. Tetrahedron: Asymmetry 1992, 3, 199e200; (c)
Chênevert, R.; Lavoie, M.; Courchesne, G.; Martin, R. Chem. Lett. 1994, 93e96;
(d) Jones, J. B.; Hinks, R. S.; Hultin, P. G. Can. J. Chem. 1985, 63, 452e456.
19. Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153e156.
20. Ivesic, T.; Hamersak, Z. Tetrahedron: Asymmetry 2009, 20, 1095e1098.
21. In contrast, this behavior was not observed in quinine-accelerated opening of
succinic anhydrides. There, the enantioselectivity increased when more catalyst
was used.
22. A solvent screening with catalyst 10a (10 mol %) under standard conditions led
to the following results: Et2O: 64% ee; THF: 51% ee; toluene: 46% ee; CH2Cl2:
13% ee.
23. Steiner, D.; Sethofer, S. G.; Goralski, C. T.; Singaram, B. Tetrahedron: Asymmetry
2002, 13, 1477e1483.
24. Brunner, H.; Bügler, J. Bull. Soc. Chim. Belg. 1997, 106, 77e84.