Asymmetric desymmetrization of meso-diols by C2-symmetric chiral 4-pyrrolidinopyridines

Article abstract of DOI:10.3762/bjoc.8.203

In this work we developed C₂-symmetric chiral nucleophilic catalysts which possess a pyrrolidinopyridine framework as a catalytic site. Some of these organocatalysts effectively promoted asymmetric desymmetrization of meso-diols via enantioselective acylation.

Full text of DOI:10.3762/bjoc.8.203

Asymmetric desymmetrization of meso-diols by
C2-symmetric chiral 4-pyrrolidinopyridines
Hartmut Schedel, Keizo Kan, Yoshihiro Ueda, Kenji Mishiro,
Keisuke Yoshida, Takumi Furuta and Takeo Kawabata*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1778–1787.
Institute for Chemical Research, Kyoto University, Uji, Kyoto
611-0011, Japan
doi:10.3762/bjoc.8.203
Received: 05 July 2012
Email:
Accepted: 06 September 2012
Published: 17 October 2012
Takeo Kawabata* - kawabata@scl.kyoto-u.ac.jp
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
acylation; desymmetrization; hydrogen bond; meso-diol; nucleophilic
catalyst; organocatalysis
© 2012 Schedel et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
In this work we developed C2-symmetric chiral nucleophilic catalysts which possess a pyrrolidinopyridine framework as a catalytic
site. Some of these organocatalysts effectively promoted asymmetric desymmetrization of meso-diols via enantioselective
acylation.
Introduction
Since the pioneering discovery of a catalyst for enantioselec- activity [19]. Catalyst 1 was demonstrated to be effective for the
tive acylation by Vedejs [1], numerous efforts have been kinetic resolution of racemic diols (s: up to 12) [8] and amino
devoted to the development of catalysts for enantioselective alcohol derivatives (s: up to 54) [9]. Catalyst 2, readily prepared
acylation [2,3]. We have focused on the development of chiral from L-proline, could be employed for the kinetic resolution of
nucleophilic catalysts possessing a pyrrolidinopyridine (PPY) amino alcohol derivatives (s: up to 11) [10]. Chiral PPY cata-
framework as a catalytic site because PPY has been known to lysts with dual functional side chains at C(2) and C(4) of the
be one of the most powerful catalysts for the acylation of alco- pyrrolidine ring such as 3 were prepared from trans-4-hydroxy-
hols [4-7]. The salient feature of our catalyst design is to intro- L-proline. These catalysts were found to be moderately effec-
duce chiral elements far from the catalytically active pyridine tive for the asymmetric desymmetrization of meso-diols [11].
nitrogen as shown in Figure 1 [8-18]. These catalysts are C2-Symmetric PPY-catalyst 4 was found to be effective for the
expected to show high catalytic activity because the introduc- chemo- and regioselective acylation of carbohydrates [12,14,16]
tion of substituents close to the pyridine nitrogen has been and the chemoselective monoacylation of linear diols [17].
known to result in the significant decrease of the catalytic Here, we report the asymmetric desymmtrization of meso-diols
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Figure 1: Chiral PPY catalysts.
by C2-symmetric PPY catalysts [20]. The effects of the func- of the pyrrolidine ring, catalyst 3 was found to be most effec-
tional side chains at C(2) and C(5) on the efficiency of the tive for the asymmetric desymmetrization (Scheme 1).
asymmetric desymmetrization are discussed. Some of the However, the enantioselectivity of the asymmetric desym-
results shown here have already been appeared in the patent metrization was far from being sufficient. Molecular modeling
JP2005132746.
of the related catalysts indicated that a C2-symmetric PPY cata-
lyst with functional side chains at C(2) and C(5) might be better
suited for this purpose [12,13]. Based on these background, we
have prepared various C2-symmetric chiral PPY-catalysts
according to Scheme 2 [12] and employed them for asymmetric
desymmetrization of meso-1,2-cyclohexanediol (5) [20].
Results and Discussion
Asymmetric desymmetrization of meso-1,2-
cyclohexanediol
The asymmetric desymmetrization of meso-diols via organocat-
alytic enantioselective acylation has been extensively studied
[1,21-38]. We have reported the asymmetric desymmetrization
of meso-1,2-cyclohexanediol (5) by catalytic enantioselective
acylation with catalyst 3 (Scheme 1) [11]. Among various chiral
PPY catalysts with dual functional side chains at C(2) and C(4)
We first examined chiral PPY catalyst 8a with an L-tryptophan
side chain, which was disclosed to be an excellent catalyst for
the regioselective acylation of glycopyranoses [12]. Reaction of
5 with isobutyric anhydride (1.3 equiv) in the presence of
5 mol % of 8a in chloroform at 20 °C gave monoacylate 6 in
73% ee and 85% yield with concomitant formation of 15% of
diacylate 7 (Table 1, entry 1). Catalyst 8b with a D-tryptophan
side chain gave a lower enantioselectivity (54% ee, Table 1,
entry 2). The hydroxy group at the (R)-chiral center was prefer-
entially acylated in both cases. Since both catalysts 8a with an
L-tryptophan side chain and 8b with a D-tryptophan side chain
gave (1R,2S)-6 [8] by asymmetric desymmetrization of 5, cata-
lysts with achiral side chains were then examined. The acyla-
tion of 5 with catalyst 9 which possesses a tryptamine moiety
Scheme 1: Asymmetric desymmetrization of 5 with catalyst 3.
Scheme 2: Preparation of a small library of chiral C2-symmetric PPY catalysts (reference, see [12]).
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
Table 1: Effects of the catalysts’ side chains on the asymmetric desymmetrization of meso-1,2-cyclohexanediol (5).a
Entry
Catalystb
6:7:Recovery of 5 (%)c
ee of 6 (%)d,e
1
2
3
4
5
6
7
8
9
8a
8b
9
85:15:0
70:18:12
74:16:10
72:19:9
75:23:3
70:25:5
77:14:9
76:18:6
75:20:5
73
54
72
71
87
74
83
54
81
10
11
12a
12b
13
14
aReactions were run at a substrate concentration of 0.2 M.
bStructures of catalysts:
.
cYields determined by 1H NMR with dibenzyl ether as an internal standard. dDetermined by GC analysis with a chiral stationary phase, beta-DEX 225.
e(1R,2S)-Isomer was obtained in each case.
gave 6 in 72% ee and 74% yield (Table 1, entry 3). Catalyst 10 substituents appears to have decisive effects on the stereochem-
with a glycine moiety gave 6 in 71% ee and 72% yield on treat- ical course of the asymmetric desymmetrization.
ment of 5 (Table 1, entry 4). Monoacylate 6 was also obtained
in 87% ee and 75% yield by acylation of 5 with catalyst 11 Since catalyst 12b showed relatively high enantioselectivity
which possesses a simple n-hexyl side chain (Table 1, entry 5). (83% ee) and mono/diacylation ratio (77:14), we next investi-
Catalysts with chiral side chains, 12a, 12b, 13, and 14, gated the solvent effects of the asymmetric desymmetrization of
possessing L-β-phenylalanine, D-β-phenylalanine, L-valine, or 5 with isobutyric anhydride in the presence of catalyst 12b
L-leucine moiety, respectively, also gave 6 in 54–83% ee and (Table 2, entries 1–5). A clear relationship between the enantio-
70–77% yields via acylative asymmetric desymmetrization of 5 selectivity and the solvent polarity was observed: The lower the
with isobutyric anhydride (Table 1, entries 6–9). In each case, polarity of the solvent, the higher the enantioselectivity. This
(1R,2S)-6 was preferentially obtained. These results indicate suggests that the hydrogen-bonding interaction between the
that the functionality and chirality of catalyst side chains do not catalyst and the substrate may be involved in the transition state
affect the absolute configuration of the monoacylate obtained of the enantioselective acylation (Figure 2 and Figure 3). The
by the asymmetric desymmetrization while they influence the temperature effects (lower temperature) of the asymmetric
extent of the enantioselectivity. Accordingly, the configuration desymmetrization employing catalysts 14 and 11 were exam-
of the stereocenters in C(2) and C(5) position bearing the amide ined because both of the catalysts show high solubility in chlo-
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
Table 2: Effects of solvents and temperature on the asymmetric desymmetrization of 5.a
Entry
Catalyst
Solvent
Temp. (°C)
6:7:recovery of 5 (%)b
ee of 6 (%)c,d
1
2
12b
12b
12b
12b
12b
14
CCl4
toluene
CHCl3
THF
20 °C
20 °C
20 °C
20 °C
20 °C
20 °C
−40 °C
20 °C
−40 °C
75:20:5
75:19:6
77:14:9
57:28:15
69:23:8
75:20:5
85:6:9
93
91
83
51
34
81
87
87
88
3
4
5
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
6
7e
8
14
11
75:23:2
92:5:3
9e
11
aReactions were run at a substrate concentration of 0.2 M. bYields determined by 1H NMR with dibenzyl ether as an internal standard. cDetermined
by GC analysis with a chiral stationary phase, beta-DEX 225. d(1R,2S)-Isomer was obtained in each case. eRun for 24 h.
roform at low temperatures (Table 2, entries 6–9). Both enantio- Further optimization of the asymmetric desymmetrization of 5
selectivity (87% ee) and mono/diacylation ratio (85:6) of the with catalyst 11 was examined at 20 °C (Table 3). The use of
acylation of 5 catalyzed by 14 at −40 °C were improved only 0.5 mol % of catalyst was found to be still effective in the
compared with those in the corresponding reaction at 20 °C asymmetric desymmetrization of 5 to give 6 in 90% ee and 76%
(Table 2, entry 6 vs entry 7). Similarly, the efficiency of the yield (Table 3, entry 2) [20]. Further decrease in the amount of
asymmetric desymmetrization of 5 catalyzed by 11 was impro- the catalyst to 0.05 mol % resulted in a lower enantioselectivity
ved by conducting the reaction at −40 °C (Table 2, entry 8 vs (74% ee) and in lower yield (66%) (Table 3, entry 3). The use
entry 9). Monoacylate 6 was obtained in 88% ee and 92% yield of a less amount (1.0 equiv) of the anhydride in the presence of
by treatment of 5 with isobutyric anhydride in the presence of 5 mol % of 11 improved the mono/diacylation ratio (84:7),
5 mol % of 11 at −40 °C.
while the enantioselectivity was decreased (81% ee, Table 3,
Table 3: Optimization of the asymmetric desymmetrization of 5 with catalyst 11.a
Entry
Mol % of 11
Equiv of (iPrCO)2O
6:7:Recovery of 5 (%)b
ee of 6 (%)c,d
1
2e
3
5
0.5
0.05
5
1.3
1.3
1.3
1.0
1.6
75:23:2
76:20:3
66:10:24
84: 7:4
87
90
74
81
98
4
5e,f
5
59:41:0
aReactions were run at a substrate concentration of 0.2 M. bYields determined by 1H NMR with dibenzyl ether as an internal standard. cDetermined
by GC analysis with a chiral stationary phase, beta-DEX 225. d(1R,2S)-Isomer was obtained in each case. eData quoted from reference [20].
f1.7 Equiv of collidine were used.
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
entry 1 vs entry 4). On the other hand, the use of an excess subunit among these chiral PPY catalysts. We chose catalyst 11,
amount (1.6 equiv) of the anhydride resulted in the highest which possesses the simplest n-hexyl amide side chain, and
enantioselectivity (98% ee) in compensation for the low yield examined the effect of the secondary amide linkage by
(59%) for monoacylation (Table 3, entry 5) [20]. The increase comparing the performance of the asymmetric desymmetriza-
in the amount of diacylate 7 is associated with the higher ee of tion with that shown by the analogous catalysts possessing the
monoacylate 6 (Table 3, entries 1, 4 and 5). This suggests that corresponding tertiary amide- or ester linkage, 15 or 16, res-
the ee of monoacylate 6 would be amplified by the second pectively (Table 4, entries 1–3). Much diminished enantio-
acylation step, i.e., acylative kinetic resolution of enantioen- selectivity (13% ee) was observed in the asymmetric desym-
riched monoacylate 6 produced by the asymmetric desym- metrization of 5 with isobutyric anhydride in the presence of
metrization of the meso-substrate (Scheme 3).
catalyst 15 with the tertiary amide linkage (Table 4, entry 2).
Similarly, catalyst 16 with the ester linkage was found to be far
less effective (13% ee) than 11 (Table 4, entry 3) in the asym-
metric acylation. These results indicate that the secondary
amide linkage in 11 is essential for the high efficiency of the
asymmetric acylation. The superior property of 11 compared to
16 as an asymmetric acylation catalyst could be ascribed to the
stronger Lewis basicity of the amide carbonyl group than that of
the ester carbonyl group (donor number of amides > donor
number of esters). However, the reasons for the poorer effi-
ciency of catalyst 15 with a tertiary amide linkage compared
with catalyst 11 with a secondary amide linkage are unclear (see
also Figure 3). We then examined the effects of the
C2-symmetric structure of catalysts 11 and 12a by comparing
the corresponding mono-functionalized chiral PPY catalysts 17
and 18 [10], respectively (Table 4, entry 4 and entry 5). Cata-
lyst 17 was found to be slightly less effective than 11 in the
asymmetric desymmetrization of 5 to give the monoacylate in
76% ee (Table 4, entry 4). Catalyst 18 gave monoacylate 6 in
Scheme 3: Amplification of enantiomeric purity of the major enan-
tiomer produced at the step of asymmetric desymmetrization of the
meso-substrate by the following kinetic resolution with the same cata-
lyst.
To confirm this issue, kinetic resolution of racemic-6 was diminished ee (41% ee) in the acylative desymmetrization of 5
performed with catalyst 12b because 12b is almost as effective (Table 4, entry 5 vs entry 6). The corresponding (1R,2S)-6 was
as 11 in the asymmetric desymmetrization of 5 (Table 1, entry 5 obtained in each case. These results imply that a C2-symmetric
and entry 7). Treatment of rac-6 with 0.7 equiv of isobutyric structure in catalysts is responsible for the higher efficiency in
anhydride in the presence of 5 mol % of 12b gave (1R,2S)-6 in the asymmetric acylation.
67% ee at 53% conversion (Scheme 4). This clearly indicates
Asymmetric desymmetrization of meso-1,3-
cyclohexanediol
that the (1S,2R)-isomer reacts faster than the (1R,2S)-isomer in
the acylation catalyzed by 12b.
We have reported that catalyst 3 promoted the acylative asym-
The results in Table 1 suggest that the amide carbonyl groups at metric desymmetrization of meso-1,3-cyclohexanediol (19) to
C(2) and C(5) of the pyrrolidine ring of the catalysts 8–14 give 20 in 52% ee and 48% yield [11]. Here, C2-symmetric
would play the key role in asymmetric acylation. This is due to chiral PPY catalysts were examined for this asymmetric trans-
the fact that the amide carbonyl group is the common structural formation (Table 5). Treatment of 19 with isobutyric anhydride
Scheme 4: Acylative kinetic resolution of racemic-6 with catalyst 12b.
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
Table 4: Effects of side chain linkage and C2-symmetric structure of catalysts on the asymmetric desymmetrization of 5.a
Entry
Catalystb
6:7:Recovery of 5c (%)
ee of 6 (%)d,e
1
2
3
4
5
6
11
15
75:23:3
79:15:6
65:24:11
70:26:4
61:34:5
70:25:5
87
13
13
76
41
74
16
17
18
12a
aReactions were run at a substrate concentration of 0.2 M.
bStructures of catalysts
.
cYields determined by 1H NMR with dibenzyl ether as an internal standard. dDetermined by GC analysis with a chiral stationary phase, beta-DEX 225.
e(1R,2S)-Isomer was obtained in each case.
in the presence of catalyst 4 at 0 °C gave monoacylate 20 in resulted in the formation of the monoacylate in 19–31% ee and
48% ee and 66% yield (Table 5, entry 1). The corresponding 48–69% yield (Table 5, entries 3, 5–7). Lowering the tempera-
reaction at −40 °C did not improve the enantioselectivity ture of acylation of 19 in the presence of 11 did not improve the
(Table 5, entry 2). The attempted asymmetric desymmetriza- enantioselectivity (Table 5, entry 3 vs entry 4). The lack of
tion of 19 at 20 °C promoted by catalysts 11, 12a, 12b, and 14 temperature effects may indicate that the hydrogen-bonding
Table 5: The asymmetric desymmetrization of meso-1,3-cyclohexanediol (19) with C2-symmetric chiral PPY catalysts.a
Entry
Catalyst
Temp. (°C)
Time (h)
20:21:Recovery of 19 (%)b
ee of 20 (%)c,d
1
2
3
4
5
6
7
4
4
0
12
48
4
66:15:17
26: 2:72
69:24:7
44:10:44
48:43:9
49:30:21
62:33:6
48
50
31
25
27
20
19
–40
20
11
11
12a
12b
14
–40
20
48
4
20
4
20
4
aReactions were run at a substrate concentration of 0.2 M. bYields determined by 1H NMR with dibenzyl ether as an internal standard. cDetermined
by GC analysis with a chiral stationary phase, beta-DEX 225. dThe absolute configuration of 20 was not determined.
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
interaction between the catalyst and the substrate may not effective in the asymmetric desymmetrization of 22a at 20 °C to
significantly be involved in the process of enantioselective give monoacylate 23a in 57–66% ee and 72–78% yield
acylation of 19 in the presence of catalysts 4 and 11.
(Table 6, entries 2, 3, 5, and 6). As observed in the asymmetric
desymmetrization of 5, the acylation of 22a at a lower tempera-
ture gave better selectivity. The catalytic enantioselective acyla-
tion of 22a with isobutyric anhydride in the presence of 11 or
Asymmetric desymmetrization of meso-2,3-
butanediol and meso-hydrobenzoin
The asymmetric desymmetrization of meso-2,3-butanediol 14 at −60 to −65 °C gave monoacylate 23a in 87% ee (72%
(22a) and meso-hydrobenzoin (22b) were examined (Table 6). yield) or 92% ee (61% yield), respectively (Table 6, entries 4
Treatment of 22a with isobutyric anhydride in the presence of and 8) [20] . The higher enantioselectivity was found to be asso-
5 mol % of catalyst 8a at 20 °C for 4 h gave monoacylate 23a in ciated with the higher mono/diacylation ratio in the asymmetric
53% ee and 78% yield (Table 6, entry 1). Catalysts 10, 11, 12b, acylation of 22a promoted by 14 (Table 6, entries 6–8). (Notice:
and 14 were also examined for asymmetric desymmetrization of Enantioenriched 23a gradually undergoes partial racemization
22a (Table 6, entries 2–8). These catalysts are almost equally when it is kept as a CHCl3 solution probably via intramolecular
Table 6: The asymmetric desymmetrization of meso-2,3-butanediol (22a), meso-hydrobenzoin (22b) and meso-1,2-cyclopentanediol (22c).a
Entry
Substrate
Catalystb
Temp. (°C)
Time (h)
23:24:Recovery of 22 (%)c
ee of 23 (%)
1
2
22a
22a
22a
22a
22a
22a
22a
22a
22b
22b
22b
22c
22c
22c
8a
10
11
11
12b
14
14
14
8a
8b
12b
4
20
20
4
4
78:11:11
77:16:7
78:13:9
72:7:21
72:6:22
73:18:9
82:4:14
61:<1:39
64:25:11
63:22:15
54:25:21
85:12:3
73:27:0
67:33:0
53d,e
62d,e
66d,e
87d,e
61d,e
57d,e
85d,e
92d,e
40g,h
23g,h
19g,h
~0i
3
20
4
4f
5
−60
20
24
4
6
20
24
24
24
4
7
−40
−65
20
8f
9
10
11
12
13
14j
20
4
20
4
−20
−20
−20
6
25
25
4
~0i
4
~0i
aReactions were run at a substrate concentration of 0.2 M.
bStructure of catalyst 25:
cYields determined by 1H NMR with dibenzyl ether as an internal standard. dEe was determined by GC analysis with a chiral stationary phase, beta-
DEX 225. e(2R,3S)-Isomer was obtained. fData quoted from reference [20]. gEe was determined by HPLC analysis with a chiral stationary phase,
Chiralcel OJ (iPrOH:hexane = 5:95, flow 0.5 mL min−1, tR = 35, 51 min). hThe absolute configuration was not determined. iEe of the corresponding
benzoate, which was determined by HPLC analysis with a chiral stationary phase, Chiralcel AS (iPrOH/hexane 1:99, flow 0.2 mL min−1,
tR = 43, 49 min). jRun in toluene.
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
acyl migration: e.g., from 88% ee to 71% ee after 168 h.) The Meso-1,2-cyclohexanediol (5) and meso-2,3-butanediol (22a)
asymmetric desymmetrization of meso-hydrobenzoin (22b) was (matched substrates) gave high enantioselectivity, while meso-
examined. Treatment of 22b with isobutyric anhydride in the 1,3-cyclohexanediol (19), meso-hydrobenzoin (22b), and meso-
presence of catalysts 8a, 8b, and 12b at 20 °C gave 23b in 1,2-cyclopentanediol (22c) (mismatched substrates) gave poor
19–40% ee in 54–64% yield (Table 6, entries 9–11). Signifi- enantioselectivity in the asymmetric desymmetrization. (2) A
cant amounts of the diacylate were also formed (22–25% yield) higher enantioselectivity was observed in the reactions of
together with the recovery of the unreacted material (11–21%). matched substrate 5 in the solvents of the lower polarity
In these transformations, the low enantioselectivity is asso- (Table 2, entries 1–5). (3) A higher enantioselectivity and a
ciated with the low mono/diacylation ratio, which was also higher mono/diacylation ratio were observed in the acylation of
observed in the asymmetric desymmetrization of meso-1,3- the matched substrates at the lower temperatures (Table 2,
cyclohexanediol (19, Table 5). The asymmetric desymmetriza- entries 6–9; Table 6, entries 3, 4, 6–8). These phenomena
tion of meso-1,2-cyclopentanediol (22c) was also examined suggest that the enantioselective acylation of the matched
using catalysts 4 and 25 [18], the corresponding octyl ester substrates proceeds in an accelerative manner via hydrogen-
analogues of 8a and 12a, respectively (Table 6, entries 12–14). bonding interaction between the catalyst and the substrate. A
The acylation of 22c with isobutyric anhydride in the presence possible model for the transition state assembly for the enantio-
of 4 in chloroform at −20 °C gave monoacylate 23c as a race- selective acylation of meso-1,2-cyclohexanediol (5) catalyzed
mate in 85% yield (Table 6, entry 12). Similarly, racemic 23c by 11 is shown in Figure 2. A chiral acylpyridinium ion gener-
was obtained by the reaction of 22c with isobutyric anhydride in ated from 11 and isobutyric anhydride is expected to be the
the presence of 25, either in chloroform or in toluene (Table 6, reactive intermediate which is responsible for the asymmetric
entries 13 and 14).
acylation. The most stable conformer A of the acylpyridinium
ion was generated by a molecular modeling search (AMBER*
force field with the GB/SA solvation model for chloroform
Mechanistic implication
Several characteristic phenomena were observed in the asym- using MacroModel V 9.0 (50,000 steps MCMM)) and shown in
metric desymmetrization of meso-diols promoted by Figure 2a and Figure 2b. Since the amide carbonyl groups at
C2-symmetric chiral PPY catalysts. (1) Substrate specificity: C(2) and C(5) seem to play the key role in the asymmetric
Figure 2: A hypothetical model for the transition-state assembly of the asymmetric acylation of 5 promoted by catalyst 11. Front view a) and side view
b) of the calculated structure of acylpyridinium ion A. Front view c) and side view d) of the possible modes for the substrate approach to A.
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Beilstein J. Org. Chem. 2012, 8, 1778–1787.
Figure 3: An alternative model for the transition state assembly of the asymmetric acylation of 5 promoted by catalyst 11. a) A possible mode of the
substrate approach to acylpyridinium ion A, and b) the calculated structure of A.
desymmetrization of 5 to give (1R,2S)-6 (Table 1 and Table 4), Conclusion
we assume that the amide carbonyl group would serve as a We have developed an organocatalytic method for the acylative
hydrogen-bond acceptor and the non-reacting OH of 5 as a asymmetric desymmetrization of meso-diols. Highly enantio-
hydrogen-bond donor. A possible approach of substrate 5 to A selective desymmetrization of meso-1,2-cyclohexanediol and
is shown in Figure 2c and Figure 2d. In the case where a meso-2,3-butanediol (matched substrates) was achieved while
hydrogen bond between the amide carbonyl group and an axial- low to moderate enantioselectivity was observed in the asym-
OH at the (S)-chiral center of 5 is formed, an equatorial-OH at metric desymmetrization of meso-1,3-cyclohexanediol,
the (R)-chiral center locates in the close proximity to the reac- meso-hydrobenzoin, and meso-1,2-cyclopentanediol
tive carbonyl group without any unfavorable steric interaction, (mismatched substrates). Organocatalytic enantioselective
resulting in the selective acylation of the hydroxy group at the acylation of the matched substrates was proposed to proceed via
(R)-chiral center to give (1R,2S)-6. On the other hand, there hydrogen-bonding interaction between the catalyst and the sub-
may be other possible modes of the approach of 5 to A. They strate.
involve hydrogen-bonding interaction between the amide car-
bonyl group of A and (1) an equatorial-OH at the (S)-chiral
Supporting Information
center of 5, (2) an axial-OH at the (R)-chiral center of 5, or (3)
an equatorial-OH at the (R)-chiral center of 5. The first one
Supporting Information File 1
would give (1R,2S)-6, while the latter two would give (1S,2R)-
6. In these cases, however, unfavorable steric interaction is
expected based on our molecular modeling study. It is also
anticipated that an axial-OH may be the better hydrogen-bond
donor than an equatorial-OH, according to the reported higher
acidity of the axial hydroxy groups of cyclohexane derivatives
[39]. An alternative model for the transition-state assembly is
shown in Figure 3 where the amide NH group of A serves as a
hydrogen-bond donor and the non-reacting OH of substrate 5 as
a hydrogen-bond acceptor. This model could explain the differ-
ence between effective catalyst 11 and ineffective catalysts 15
and 16 (Table 4, entry 1 vs entries 2 and 3). However, the calcu-
lated distance between the amide NH group and the reactive
amide carbonyl group of A seems too long (8.10 Å) for the
accommodation of the 1,2-diol substructure (calculated dis-
tance between two oxygen atoms of the hydroxy groups:
2.66 Å). It is also difficult to find the reasons for the preferable
acylation of the hydroxy group at the (R)-chiral center of 5 from
this model. We prefer the model shown in Figure 2, however,
the model in Figure 3 cannot be eliminated.
Experimental details and characterization data of new
compounds, copies of 1H NMR and 13C NMR.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-203-S1.pdf]
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research (A) and by Grant-in-Aid for JSPS Fellows to Y. U.
and K. M. from The Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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