Origin of high e -selectivity in 4-pyrrolidinopyridine-catalyzed tetrasubstituted α,α′-alkenediol: A computational and experimental study

Article abstract of DOI:10.1021/jo5029453

We have developed 4-pyrrolidinopyridine catalysts for the geometry-selective (E-selective) acylation of tetrasubstituted α,α′-alkenediols. To elucidate the major factors of the high geometry selectivity, experimental and computational studies were carried out. The control experiments with respect to the substituent of the substrate indicated the fundamental hydrogen bonding of the acidic hydrogen of NHNs and the Z-OH in the substrate. Comparison between C₂- and C₁-symmetric catalysts exhibited the necessity of the C₂-symmetric catalyst structure. The computationally proposed transition state (TS) model well explained the experimental results. Whereas the fundamental NH/amide-CO and the two-point free-OH/acetate anion hydrogen bonds stabilize the transition state (TS), affording the E-product, the steric repulsion between the N-protecting group and the amide side chain destabilizes TS, affording the Z-product. The role of the two amide side chains of the catalyst in a C₂-symmetric fashion is the enhancement of the molecular recognition ability through the additional hydrogen bond in a cooperative manner.

Full text of DOI:10.1021/jo5029453

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Article
Origin of High E-Selectivity in 4-Pyrrolidinopyridine-
Catalyzed Tetrasubstituted alpha,alpha’-Alkenediol:
A Computational and Experimental Study
Masahiro Yamanaka, Urara Yoshida, Makoto Sato, Takashi
Shigeta, Keisuke Yoshida, Takumi Furuta, and Takeo Kawabata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5029453 • Publication Date (Web): 12 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Origin of High E-Selectivity in 4-Pyrrolidinopyridine-Catalyzed Tetrasubstituted
α,α’-Alkenediol: A Computational and Experimental Study
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Masahiro Yamanaka,* † Urara Yoshida,† Makoto Sato,† Takashi Shigeta,‡ Keisuke Yoshida,‡ Takumi
Furuta,‡ Takeo Kawabata*‡
†Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo
University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
‡Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Eꢀmail: myamanak@rikkyo.ac.jp, kawabata@scl.kyotoꢀu.ac.jp
Abstract
We have developed 4ꢀpyrrolidinopyridine catalyst for the geometryꢀselective (Eꢀselective)
acylation of tetrasubstituted α,α’ꢀalkenediols. To elucidate the major factors of the high geometry
selectivity, experimental and computational studies were carried out. The control experiments with
respect to the substituent of the substrate indicated the fundamental hydrogen bonding of the acidic
hydrogen of NHNs and the ZꢀOH in the substrate. Comparison between C2ꢀ and C1ꢀsymmetric
catalysts exhibited the necessity of the C2ꢀsymmetric catalyst structure. The computationally
proposed transition state (TS) model well explained the experimental results. Whereas the
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fundamental NH/amideꢀCO and the twoꢀpoint freeꢀOH/acetate anion hydrogen bonds stabilizes the
transition state (TS) affording to the Eꢀproduct, the steric repulsion between the Nꢀprotecting group
and the amide side chain destabilizes TS affording to the Zꢀproduct. The role of the two amide side
chains of the catalyst in a C2ꢀsymmetric fashion is enhancement of the molecular recognition ability
through the additional hydrogen bond in a cooperative manner.
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Introduction
The selective manipulation of multiple hydroxy groups of polyol compounds is a
fundamental challenge in current organic synthesis.1,2 We have developed numerous selective
reactions, including the chemoꢀ and regioselective acylation of glycopyranoses,3 the chemoselective
monoacylation of linear diols,4 the chemoselective acylation of a secondary alcohol in the presence
of a primary alcohol,5 and the geometryꢀselective acylation of tetrasubstituted α,α’ꢀalkenediols6 by
organocatalysis. In those reactions, the multiple hydrogen bonds between the C2ꢀsymmetric
4ꢀpyrrolidinopyridine catalysts (1 and 2) and the substrates play key roles in the molecular
recognition depending on the substrate structure (Figure 1). In particular, the discrimination of the
two hydroxy groups having intrinsically similar reactivity has been a difficult task.7 Whereas the
geometryꢀselective acylation of various unsymmetrically trisubstituted 2ꢀalkylideneꢀ1,3ꢀpropanediols
and the deacylation of the corresponding diesters have been achieved by enzymatic methods,8 the
corresponding nonꢀenzymatic method has been scarcely reported. We have reported the highly
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geometryꢀselective (Eꢀselective) acylation of triꢀ and tetrasubstituted 2ꢀalkylideneꢀ1,3ꢀpropanediols 3
and 4 using 2 as the catalyst (Figure 2).6 To the best of our knowledge, this is the only example of
the highly geometryꢀselective acylation of tetrasubstituted 2ꢀalkylideneꢀ1,3ꢀpropanediols among
enzymatic and nonꢀenzymatic methods.
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Figure 1. C2ꢀ and C1ꢀsymmetric 4ꢀpyrrolidinopyridine catalysts
Figure 2. Triꢀ and tetrasubstituted 2ꢀalkylideneꢀ1,3ꢀpropanediols
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We herein clarify the origin of the unprecedentedly high geometry selectivity and the role of
the two amide side chains at C(2) and C(5) of 2 by experimental and computational studies.
Focusing on the molecular recognition process through hydrogenꢀbonding interactions between 2 and
tetrasubstituted alkenediols, the substituent effects of 4, 5, and 6 were investigated in detail (Figure
2). In addition, the molecular recognition ability of 2 and 2‘ was experimentally and
computationally compared to identify the necessity of the C2ꢀsymmetric catalyst structure. The
computationally proposed transition state (TS) model well explained the experimental results.
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Results and Discussion
Selected data for the catalytic acylation of various tetrasubstituted alkenediols 4 from
our previous report6 and additional new data (entries 8 and 12) are shown in Table 1. Remarkable
differences in geometry selectivity depending on substituent R were observed in the present
2ꢀcatalyzed acylation of 4. Highly Eꢀselective (96~>99:4~<1) acylation (93ꢀ98%) was noted for
4aꢀ4g (entries 1ꢀ7). In contrast, nonꢀselective acylation was observed in the catalytic acylation of
phenyl–substituted alkenediol 4h (Eꢀ7:Zꢀ7 = 50:50, entry 8). The high geometry selectivity in the
acylation of 4bꢀ4f was associated with the high yield of the monoacylation (entries 2ꢀ6).9 This
indicates that the first acylation to give the monoacylate proceeded in an accelerative manner.4,10,11
The high selectivity (98:2) was maintained even when the reaction was conducted in CHCl3/DMF =
4:1 instead of CHCl3, but the chemical yield was decreased (69%, entry 4 vs. entry 9). On the other
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hand, use of pure DMF hampered the geometry selectivity (entry 4 vs. entry 10). The experimental
results suggest that the hydrogenꢀbonding interactions between 2 and 4 play a key role in the
geometryꢀselective acylation and the smooth monoacylation through molecular recognition. To
obtain the mechanistic insights with respect to the hydrogenꢀbonding network between 2 and 4,
substituent effects on the coordination sites of 4 were investigated. The use of NMeNs (Ns =
2ꢀnitrobenzenesulfonyl) derivative 5 resulted in a significant decrease of the geometry selectivity and
a diminished yield of the monoacylation (entry 11 vs. entry 4). The relative acylation rate between
4d and 5 (k4d/k5) was found to be 26 based on the competitive acylation reaction between them.6 In
addition, the acylation of 4d was 89 times faster than that of corresponding ZꢀOMe derivative 6 in
the presence of 2 (k4d/k6 = 89).6 Those substituent effects indicate that the acidic hydrogen of
NHNs and the ZꢀOH in 4d, which potentially act as hydrogen bond donors, are responsible for the
Eꢀselective acylation as well as the accelerative monoacylation of E-OH. The reaction of 4d using
corresponding C1ꢀsymmetric catalyst 2' showed slightly lower selectivity than C2ꢀsymmetric one, but
yet showed significantly high selectivity (Eꢀ7:Zꢀ7 = 93:7, 97% yield of the monoacylation, entry 12).
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Table 1. Catalytic acylation of tetrasubstituted alkenediols 4 in the presence of 2
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Entry
1
R
7 [%]
52
Eꢀ7 : Z-7[b]
>99 : <1
98 : 2
8 [%] / Recovery [%]
24 / 24
1 / 2
4
Me
Et
4a
4b
4c
4d
2
93
3
Pr
96
98 : 2
~0 / 3
4
C7H15
98
98 : 2
~0 / 1
5
H2CH2CH=CH2 4e
97
98 : 2
~0 / 3
6
CH2Ph
Br
98
98 : 2
~0 / 1
4f
7[a]
8
73
96 : 4[b]
50 : 50
98 : 2
15 / 12
15 / 15
8 / 6
4g
4h
4d
4d
5
Ph
55
9[c]
10[d]
11[e]
12[h]
C7H15
C7H15
C7H15
C7H15
69
41
50 : 50
64 : 36[g]
93 : 7
14 / 36
64[f]
97
4d
[a] Run in CHCl3/THF (10:1).
[b] Eꢀ7g and Zꢀ7g (R=Br) indicate that NHNs and OAc are in Eꢀ and Zꢀgeometry to each other,
respectively, although this does not follow the nomenclature.
[c] Run in CHCl3/DMF (4:1).
[d] Run in DMF.
[e] The corresponding NMeNs derivative was used.
[f] The yield of the corresponding NMeNs derivatives.
[g] The ratio of the corresponding NMeNs derivatives.
[h] Catalyst 2’ was used instead of 2.
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Chemical Model and Computational Method
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According to Zipse’s computationally predicted mechanism12 and our previously proposed
mechanism,6 the TS model of the nucleophilic attack of 4 on the Nꢀacetylpyridinium ion of 2 was
computationally investigated (Figure 3a). As the geometry selectivity was determined in the
nucleophilic addition step, the diastereomeric TS models of this step (TS-E and TS-Z) leading to the
Eꢀ and Zꢀacylation were compared. To obtain a mechanistic insight into the roles of the two amide
side chains derived from αꢀaminoꢀ2ꢀnaphthalenepropanoic acid in a C2ꢀsymmetric fashion, cat1 (C1
symmetry) and cat2 (C2 symmetry) were used as the chemical models of 2 (Figure 3b). In the
chemical models of cat1 and cat2, methyl ester was employed instead of octyl ester in the original
catalyst structure to reduce computational cost, respectively. Focusing on the primary interactions
(highlighted in yellow, Figure 3a) between the catalyst and the substrate for both cat1 and cat2, the
benzenesulfonyl group on the nitrogen substituent was initially employed instead of the Ns group in
sub1 to identify the most favored TS structure for geometry selectivity control. Based on the ideal
TS structure, a more realistic chemical model of sub2 bearing the NHNs group was also used to
clarify the secondary effect of the NO2 group in TS. All calculations were performed with the
Gaussian 09 package.13 Geometries were fully optimized and characterized by frequency
calculation at the B3LYP/6ꢀ31G* level.14,15 Gibbs free energies were also computed for the
gas phase by single-point energy calculations at the same level.
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Figure 3. (a) Proposed TS models and (b) computational chemical models.
There are a wide variety of conformational isomers for both the catalyst and the substrate
because of their flexible linear structures (red curved arrows in Figure 4). To identify the
fundamental interactions between the catalyst and the substrate, various diastereomeric TS models
(TS1) using cat1 and sub1 were explored. As a preliminary conformational analysis, the relative
Gibbs free energies of possible TS models having various types of hydrogenꢀbonding networks were
compared to determine the energetically most favored TS structure. Using the totally optimized 31
TS models (TS1-E: 16 models, TS1-Z: 15 models, see Supporting Information) as local minimum
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structures, diastereomeric TSs (series a – d) constructed by the typical hydrogenꢀbonding network
are shown in Figures 5 (TS1-E) and 6 (TS1-Z).
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Figure 4. Conformational analysis of various TS models using cat1.
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Figure 5. Schematic and 3D structures of typical diastereomeric TSs for TS1-E. Relative Gibbs
free energies are shown in kcal/mol. Bond lengths are shown in Å.
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Figure 6. Schematic and 3D structures of typical diastereomeric TSs for TS1-Z. Relative Gibbs
free energies are shown in kcal/mol. Bond lengths are shown in Å.
On the basis of Zipse’s computationally predicted TS model,12 the nucleophilic OH
group of sub1 attacks the N-acylpyridinium ion while maintaining the interaction
between the functional groups of cat1 and the remaining OH group, and simultaneously
the acetate anion abstracts the proton of the nucleophilic OH group. The hydrogen
bond between the NH group of sub1 and the amide carbonyl (amide-CO) of cat1 plays a
key role in the TS stabilization. It is supposed that the acidic NH group on the Nꢀprotecting
phenylsulfonyl group of sub1 forms an NH/amide-CO hydrogen bond as a fundamental
interaction between sub1 and N-acylpyridinium ion. In addition to this fundamental
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hydrogen bond, other hydrogen bonds formed between the remaining OH (free-OH) of
sub1 and the negatively charged sites of N-acylpyridinium ion (e.g., acyl and ester
carbonyl groups) or acetate anion also affect the stabilization of TS (highlighted in
yellow, Figures 5 and 6).16 The most stable TS1-E-a has a strong NH/amide-CO
hydrogen bond (1.935 Å) and two-point hydrogen bonds between the two OH groups of
sub1 and the acetate anion (1.235 Å, 1.920 Å). The two-point hydrogen bonds formed
between the two OH groups and the anionic site enhance the stability of TS1-E-a
(Figure 5). In contrast, free-OH interacts with amide-CO (2.063 Å) while keeping the
strong NH/amide-CO hydrogen bond (1.975 Å) in TS1-E-b. However, TS1-E-b is
4.5-kcal/mol less stable than TS1-E-a due to the relatively weak hydrogen bond formed
between free-OH and neutral amide-CO. Although TS1-E-c is our previously proposed
TS model where the ester group of cat1 (ester-CO) interacts with free-OH, it is
4.8-kcal/mol less stable than TS1-E-a. The ester-CO/free-OH hydrogen bond (1.998 Å)
geometrically induces the intramolecular NH/free-OH hydrogen bond (2.279 Å) to
significantly weaken the NH/amide-CO hydrogen bond (2.531 Å) in TS1-E-c. Such
changes in the internal hydrogen-bonding network between sub1 and cat1 destabilize
TS1-E-c. The other scenario involving the hydrogen bonding of free-OH stabilizes the
developing negative charge of the N-acylpyridinium carbonyl group (acyl-CO) in TS
(TS1-E-d). However, TS1-E-d is 7.7-kcal/mol higher in energy than TS1-E-a and an
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energetically disfavored TS. Whereas TS1-Z also has the fundamental NH/amide-CO
hydrogen bond in a manner similar to TS1-E, only two series (a and d) of the
hydrogenꢀbonding network enable to be constructed due to the geometrical requirement of
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the
Z-selective acylation in TS1-Z (Figure 6). In both TS1-Z-a and TS1-Z-d, the
N-protecting phenylsulfonyl group is located close to the sterically demanding amide
side chain of cat1 to induce a large steric repulsion. TS1-Z-a having the two-point
hydrogen bonds between the two OH groups of sub1 and the acetate anion (1.237 Å,
1.869 Å) is energetically more favored than TS1-Z-d having the free-OH/acyl-CO
hydrogen bond (1.916 Å). The relative Gibbs free energy difference between the most
stable TS1-E and TS1-Z (e.g., TS1-E-a and TS1-Z-a) is qualitatively consistent with the
experimental results in an
E-selective manner.
After exploring TS1 using cat1 and sub1, the ideal TS structures were found to
be TS1-E-a and TS1-Z-a, where the NH group and the freeꢀOH of sub1 interact with
amide-CO and acetate anion, respectively, and the 2-naphthyl group is located far from
sub1 as the stable conformation of the amide side chain. On the basis of these
promising TS structures, more realistic TS models (TS2) using C2ꢀsymmetric cat2 were
investigated to elucidate the role of the two amide side chains. In addition, a more realistic
chemical model of sub2 bearing the NHNs group was also studied to identify the secondary effect of
the NO2 group in TS (TS3). By expanding TS1-E-a and TS1-Z-a, the realistic TS models
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(TS2-E-a, TS2-Z-a, TS3-E-a, and TS3-Z-a) were geometrically optimized, respectively (Figure 7).
The relative Gibbs free energies between TS-E and TS-Z were significantly increased for TS2 (7.1
kcal/mol) and TS3 (6.9 kcal/mol) compared to TS1 (4.9 kcal/mol). This is qualitatively good
agreement with the experimental results where C2ꢀsymmetric 2 achieved higher Eꢀselectivity (E:Z =
98:2) than C1ꢀsymmetric 2’ (E:Z = 93:7). The gross structure and the hydrogenꢀbonding network
in the rightꢀhand part of TS2-E-a and TS2-Z-a are almost the same as those of TS1-E-a and
TS1-Z-a, respectively (Figure 7). Both TS2-E-a and TS2-Z-a also have the NH/amideꢀCO
hydrogen bond and the twoꢀpoint freeꢀOH/acetate anion hydrogen bonds as fundamental interactions
stabilizing TS (highlighted in yellow). As for TS2-E-a, it is noted that the NH group of the
additional amide side chain (amideꢀNH, leftꢀhand part in TS2-E-a) interacts with the sulfonyl group
of sub1 (SO2) to enhance the stabilization of TS (highlighted in yellow). This indicates that cat2
possesses the dual function of the two amide side chains albeit in a C2ꢀsymmetric fashion. The
inducedꢀfitꢀtype structural change of cat2 caused by the multiple hydrogenꢀbonding interactions
enables geometrical recognition. In contrast, the C2ꢀsymmetric structure of cat2 has no impact on
the stability of TS2-Z-a because no additional interaction exists other than the fundamental
interactions in cat1 (Figure 7). Therefore, the additional SO2/amideꢀNH hydrogen bond
significantly stabilizes TS2-E-a and increases the relative Gibbs free energy difference between
TS2-E-a and TS2-Z-a to achieve higher Eꢀselectivity for 2 than 2’. Focusing on the structural
feature of TS2, the Me group of sub1 in TS2-E-a (highlighted in blue) is located close to the
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additional amide side chain (highlighted in green, Figure 7). It is clear that the sterically demanding
substituent (e.g., Ph) of the substrate induces a large steric repulsion with the additional amide side
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chain.
In fact, phenyl–substituted alkenediol 4h showed no geometry selectivity (E:Z = 50:50 in
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Table 1). The introduction of the N-protecting Ns group (TS3-E-a and TS3-Z-a) has little
influence on the gross structures, the hydrogenꢀbonding network, and the relative Gibbs
free energies of both TS2-E-a and TS2-Z-a. As the secondary effect of the NO2 group in TS3,
fundamental hydrogen bonds tend to be enhanced in comparison with TS2.
O
O
O
H
H
O
X = H
a: 1.969
b: 1.949
c: 2.491
X = H
a: 2.107
b: 1.852
a
a
O
N
NH
O
NH
O
O
H
H
X
S
N
S
N
H
O
X
X = NO2
a: 1.886
b: 1.874
O
H
b
N
O
H
H
H
X = NO2
O
O
c
H
N
H
N
a: 1.965
b: 1.926
c: 2.406
O
O
O
O
N
N
O
O
H
O
O
H
O
O
H
H
H
O
b O
O
TS2-E-a (X = H: 0.0)
TS2-Z-a (X = H: +7.1)
TS3-E-a (X = NO2: 0.0)
TS3-Z-a' (X = NO2: +6.3)
X = H
front view
X = H
front view
1.969
1.251
1.211
side view
side view
1.251
1.906
1.941
Figure 7. Schematic and 3D structures of diastereomeric TSs for cat2. Relative Gibbs free
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energies are shown in kcal/mol. Bond lengths are shown in Å.
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Conclusion
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Experimental and DFT studies of the 4ꢀpyrrolidinopyridineꢀcatalyzed geometryꢀselective
acylation of tetrasubstituted α,α’ꢀalkenediols were carried out to reveal the major factors affecting
Eꢀselectivity, particularly the role of the two amide side chains of the catalyst in a C2ꢀsymmetric
fashion. Experiments comparing C1ꢀsymmetric and C2ꢀsymmetric catalysts showed that the
geometry selectivity was sufficiently achieved even by the C1ꢀsymmetric unit of the catalyst, and the
additional amide side chain of the C2ꢀsymmetric unit enhanced the stereocontrol ability.
A
mechanistic insight into the role played by the two amide side chains of the catalyst was obtained by
DFT calculations. The fundamental NH/amideꢀCO and the twoꢀpoint freeꢀOH/acetate anion
hydrogen bonds as well as the steric repulsion between the N-protecting group and the amide
side chain mainly contribute to the Eꢀselective acylation. The other amide side chain of the
catalyst acts cooperatively to further stabilize TS of the Eꢀselective acylation through the additional
hydrogen bond, thereby achieving higher Eꢀselectivity. The dual function of the amide side
chains is responsible for the molecular recognition process. Each of them participates
independently and in a cooperative manner in the events to achieve high geometry
selectivity in the tetrasubstituted α,α’ꢀalkenediols.
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General Remarks. 1H and 13C NMR spectra were obtained at 400 and 600 MHz, respectively, with
chemical shifts being given in ppm units (tetramethylsilane as internal standards, indicating 0). IR
spectra were recorded on a FTꢀIR spectrometer. Specific rotation was measured with an automatic
digital polarimeter. MS spectra were recorded by FAB mass spectrometer. TLC analysis and
preparative TLC were performed on commercial glass plates bearing a 0.25 mm layer or 0.5 mm
layer of silica gel. Silica gel chromatography was performed with 150ꢀ325 mesh silica gel. Dry
solvents (dichloromethane, and chloroform; <50 ppm water contents) obtained from commercial
suppliers were used without further purification.
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Synthesis
of
Octyl
(S)-3-(naphthalen-2-yl)-2-((S)-1-(pyridin-4-yl)pyrrolidine-2-carboxamido)propanoate (2’). To a
solution of octyl (S)ꢀ2ꢀaminoꢀ3ꢀ(naphthalenꢀ2ꢀyl)propanoate hydrochloride (406 µL, 0.57 mmol),
Nꢀ(4ꢀpyridyl)ꢀL
ꢀproline17 (189mg, 0.38 mmol) in CH2Cl2 (5 mL) were added EDCI (109 mg, 0.57
mmol), HOBt (78 mg, 0.57 mmol) and NMM (115 mg, 1.14 mmol). After being stirred for 24 h, the
mixture was diluted with EtOAc and washed with sat. aq. NaHCO3, brine, dried over MgSO4,
filtered and evaporated in vacuo. The residue was purified by column chromatography to afford
PPYꢀcatalyst 2’ in 34% (142 mg) as a colorless powder.
Octyl (S)-3-(naphthalen-2-yl)-2-((S)-1-(pyridin-4-yl)pyrrolidine-2-carboxamido)propanoate (2’):
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D
1
M.p. 60–61 °C. [α]
= –132 (c 0.32, CHCl3). H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz,
20
3H), 1.22–1.29 (m, 9H), 1.50–1.58 (m, 3H), 1.79–1.85 (m, 1H), 2.06–2.18 (m, 3H), 3.08–3.15 (m,
1H), 3.20 (dd, J = 7.1, 14.0 Hz, 1H), 3.32 (t, J = 8.5 Hz, 1H), 3.39 (dd, J = 5.7, 14.0 Hz, 1H), 4.01
(dd, J = 2.8, 8.2 Hz, 1H), 4.06 (t, J = 6.9 Hz, 2H), 4.88 (q, J = 6.9 Hz, 1H), 6.31–6.33 (m, 2H), 6.55
(d, J = 7.3 Hz, 1H), 7.20 (dd, J = 1.6, 8.5 Hz, 1H), 7.44–7.50 (m, 3H), 7.71–7.75 (m, 2H), 7.79–7.82
(m, 1H), 8.14–8.15 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 14.1, 22.6, 23.3, 25.7, 28.4, 29.1, 31.0,
31.7, 37.7, 48.4, 52.8, 63.1, 65.9, 108.0, 125.9, 126.4, 126.9, 127.3, 127.7, 127.9, 128.4, 132.4, 133.2,
133.3, 149.8, 151.7, 170.9, 172.0. IR (KBr) 3331, 2954, 2927, 1753, 1657, 1601, 1541, 1515 cmꢀ1.
MS (FAB) m/z 502 (M+H)+. HRMS (FAB) m/z calcd for C31H40O3N3 (M+H)+ 502.3070, found
502.3069.
Procedure for Competitive Acylation Reaction between 4d/4h. According to our previous report
7, the reaction was carried out as written below.
To a solution of Nꢀ(2ꢀ(1,3ꢀDihydroxypropanꢀ2ꢀylidene)nonyl)ꢀ2ꢀnitrobenzenesulfonamide (11.7 mg,
1.0 equiv.) and Nꢀ(4ꢀhydroxyꢀ3ꢀ(hydroxymethyl)ꢀ2ꢀphenylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ2ꢀnitrobenzenesulfonamide
(11 mg, 1.0 equiv.), catalyst (1.5 mg, 10 mol%) and 2,4,6ꢀcollidine (6.6 ꢁL, 1.7 equiv.) in CHCl3 (2.9
ml, concentration of the substrate: 0.01 M) was added acid anhydride (0.53M solution in CHCl3)(58
ꢁL, 1.05 equiv.) at – 60 °C. The resulting mixture was stirred at the same temperature for 24 h. The
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reaction was quenched with MeOH (1 mL), and the solvent was evaporated. The residue was
dissolved in EtOAc, washed with 1N HCl, brine, dried over MgSO4, filtered and concentrated in
vacuo. The crude compound was purified by preparative TLC (SiO2, hexane : EtOAc = 1 : 3) to
afford monoacylates 7h in 20% (2.5 mg, E : Z = 57 : 43) and 7d in 76% (9.8 mg, E : Z = 95 : 5). E/Z
ratio of monoacylate 7h was determined by the integration of 1H NMR. Spectral data for compounds
7d and 8d were reported in our previous report.6
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(E)-2-(Hydroxymethyl)-4-((2-nitrophenyl)sulfonamido)-3-phenylbut-2-en-1-yl acetate) (E-7h):
1
Colorless oil. H NMR (400 MHz, CDCl3) δ 2.04 (s, 3H), 2.25 (t, J = 5.5 Hz, 1H), 4.24 (d, J = 6.4
Hz, 2H), 4.39 (d, J = 5.5 Hz, 2H), 4.49 (s, 1H), 5.61 (t, J = 5.7 Hz, 1H), 6.88–6.90 (m, 2H), 7.20–
7.24 (m, 3H), 7.67–7.74 (m, 2H), 7.81–7.84 (m, 1H), 8.02–8.04 (m, 1H). 13C NMR (150 MHz,
CDCl3) δ 20.9, 45.9, 59.6, 63.6, 125.4, 128.2, 128.2, 128.6, 130.8, 132.9, 133.4, 134.1, 134.6, 137.6,
139.9, 170.9. IR (KBr) 3610, 3375, 3031, 2927, 1736, 1543 cmꢀ1. MS (FAB) m/z 443 (M+Na)+.
HRMS (FAB) m/z calcd for C19H20O7N2SNa (M+Na)+ 443.0889, found 443.0886.
(E)ꢀStereochemistry was determined by NOESY spectrums as shown below.
(Z)-2-(Hydroxymethyl)-4-((2-nitrophenyl)sulfonamido)-3-phenylbut-2-en-1-yl acetate) (Z-7h):
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Colorless oil. H NMR (600 MHz, CDCl3) δ 1.90 (t, J = 5.9 Hz, 1H), 2.17 (s, 3H), 3.95 (d, J = 5.5
Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 4.95 (s, 2H), 5.54 (t, J = 5.9 Hz, 1H), 6.89–6.91 (m, 2H), 7.16–
7.22 (m, 3H), 7.64–7.70 (m, 2H), 7.80 (dd, J = 7.6 Hz, J = 1.4 Hz, 1H), 7.95 (dd, J = 1.4, 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 21.1, 45.9, 61.1, 61.5, 125.4, 125.4, 128.2, 128.5, 130.7, 132.9, 133.3,
134.2, 134.7, 137.4, 139.3, 1731.4. IR (KBr) 3617, 3371, 2960, 2925, 1730, 1714, 1543, 1412 cmꢀ1.
MS (FAB) m/z 443 (M+Na)+. HRMS (FAB) m/z calcd for C19H20O7N2SNa (M+Na)+ 443.0889,
found 443.0887.
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2-(2-((2-Nitrophenyl)sulfonamido)-1-phenylethylidene)propane-1,3-diyl diacetate (8h):
Colorless powder. M.p. 97–99 °C. 1 H NMR (400 MHz, CDCl3) δ 2.02 (s, 3H), 2.13 (s, 3H), 4.27 (d,
J = 6.0 Hz, 2H), 4.40 (s, 2H), 4.85 (s, 2H), 5.58 (t, J = 5.5 Hz, 1H), 6.88 (dd, J = 1.6, 8.0 Hz, 2H),
7.16–7.26 (m, 3H), 7.63–7.72 (m, 2H), 7.81 (dd, J = 1.4, 7.8 Hz, 1H), 7.96 (dd, J = 1.6, 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 20.8, 20.9, 45.9, 60.6, 62.9, 125.4, 128.1, 128.4, 128.6, 130.2, 130.7,
132.9, 133.3, 134.2, 137.1, 141.8, 147.6, 170.5, 170.9. IR (KBr) 1730, 1539, 1339, 1250 cmꢀ1. MS
(FAB) m/z 485 (M+Na)+. HRMS (FAB) m/z calcd for C21H22O8N2SNa (M+Na)+ 485.0995, found
485.0992.
N-(4-Hydroxy-3-(hydroxymethyl)-2-phenylbut-2-en-1-yl)-2-nitrobenzenesulfonamide (4h):
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Colorless powder. M.p. 115–116 °C. H NMR (400 MHz, CDCl3) δ 1.97 (s, 1H), 2.44 (s, 1H), 4.08
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(s, 2H), 4.21 (d, J = 6.0 Hz, 2H), 4.56 (s, 2H), 5.60 (t, J = 5.5 Hz, 1H), 6.88ꢀ6.90 (m, 2H), 7.18–7.23
(m, 3H), 7.69–7.75 (m, 2H), 7.81–7.83 (m, 1H), 8.05ꢀ8.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ
45.7, 61.4, 63.3, 125.5, 128.1, 128.4, 128.6, 131.0, 133.1, 133.5, 134.2, 136.4, 137.9, 138.0. IR
(KBr) 2362, 1539, 1404, 1363 cmꢀ1. MS (FAB) m/z 401 (M+Na)+. HRMS calcd for C17H18O6N2SNa
(M+Na)+ 401.0783, found 401.0783.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H and 13C spectra and computational details (cartesian coordinates and absolute energies for
stationary points). This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT. This work was supported by a GrantꢀinꢀAid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan, MEXTꢀSupported Program for the
Strategic Research Foundation at Private Universities, and Collaborative Research Program of
Institute for Chemical Research, Kyoto University (No. 2014ꢀ82).
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References
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(1) For nonenzymatic approaches to the regioselective acylation of carbohydrates, see: (a)
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Kurahashi, T.; Mizutani, T.; Yoshida, J. Tetrahedron 2002, 58, 8669–8677; (c) Griswold, K. S.;
Miller, S. J. Tetrahedron 2003, 59, 8869ꢀ8875; (d) Kattnig, E.; Albert, M. Org. Lett. 2004, 6,
945–948; (e) Demizu, Y. Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.;
Onomura, O. Org. Lett. 2008, 10, 5075–5077.
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(2) The regioselective acylation of polyol derivatives via a molecular recognition process by
peptideꢀbased catalysts has been reported. For examples, see: (a) reference 1c; (b) Lewis, C. A.;
Miller, S. J.; Angew. Chem. Int. Ed. 2006, 45, 5616ꢀ5619; (c) Lewis, C. A.; Longcore, K. E.;
Miller, S. J.; Wender, P. A. J. Nat. Prod. 2009, 72, 1864ꢀ1869.
(3) (a) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem. Soc. 2007,
129, 12890–12895; (b) Ueda, Y.; Muramatsu, W.; Mishiro, K.; Furuta, T.; Kawabata, T. J. Org.
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(4) Yoshida, K.; Furuta, T.; Kawabata, T. Angew. Chem. Int. Ed. 2011, 50, 4888ꢀ4892.
(5) Yoshida, K.; Shigeta, T.; Furuta, T.; Kawabata, T. Chem. Commun. 2012, 48, 6981ꢀ6983.
(6) Yoshida, K.; Mishiro, K.; Ueda, Y.; Shigeta, T.; Furuta, T.; Kawabata, T. Adv. Syn. Catal. 2012,
354, 3291ꢀ3298.
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(7) For an example of the discrimination of prochiral primary diols by peptideꢀbased catalysts, see:
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6
7
Lewis, C. A.; Sculimbrene, B. R.; Xu, Y.; Miller, S. J. Org. Lett. 2005, 7, 3021ꢀ3023.
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(8) (a) Schirmeister, T.; Otto, HꢀH. J. Org. Chem. 1993, 58, 4819ꢀ4822; (b) Takabe, K.; Mase, N.;
Hisano, T.; Yoda, H. Tetrahedon Lett. 2003, 44, 3267ꢀ3269; (c) Hisano, T.; Onodera, K.;
Toyabe, Y.; Mase, N.; Yoda, H.; Takabe, K. Tetrahedron Lett. 2005, 46, 6293ꢀ6295; (d) Miura,
T.; Kawashima, Y.; Umetsu, S.; Kanamori, D.; Tsuyama, N; Jyo, Y; Murakami, Y.; Imai, N.
Chem. Lett. 2007, 36, 814ꢀ815; (e) Miura, T.; Kawashima, Y.; Takahashi, M.; Murakami, Y.;
Imai, N. Synth. Commun. 2007, 37, 3105ꢀ3109; (f) Miura, T.; Okazaki, K.; Ogawa, K.; Otomo,
E.; Umetsu, S.; Takahashi, M.; Kawashima, Y.; Jyo, Y.; Koyata, N.; Murakami, Y.; Imai, N.
Synthesis 2008, 2695ꢀ2700; (g) Miura, T.; Umetsu, S.; Kanamori, D.; Tsuyama, N.; Jyo, Y.;
Kawashima, Y.; Koyata, N.; Murakami, Y.; Imai, N. Tetrahedon 2008, 64, 9305ꢀ9308.
(9) Among substrates 4aꢀ4g that underwent highly E-selective acylation, 4a (R=Me) and 4g (R=Br)
gave monoacylates in moderate yields together with significant amounts of diacylates. This was
assumed to be a result of the relatively poor solubility of those substrates in CHCl3 at low
temperature.
(10) The importance of the accelerative nature in the selective acylation and sulfonylation reactions
has been noted. See: (a) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496ꢀ6502;
(b) Fiori, K. W.; Puchlopek, A. L. A. : Miller, S. J. Nature Chem. 2009, 1, 630ꢀ634.
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(11) The relative rate of acylation between 4d and 4h was determined to be k4d/k4h = 6.4. by the
competitive acyaltion (see Supporting Information). This suggests that selective substrates
undergo acylation faster than non-selective substares.
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(12) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem. Eur. J. 2005, 11,
4751ꢀ4757.
(13) Frisch, M. J. et al. Gaussian 09, Revision D.01.; Gaussian, Inc.:Wallingford, CT, 2013.
(14) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648ꢀ5652; (b) Lee, C.; Yang, W.; Parr, R. G. Phys.
Rev. B 1988, 37, 785ꢀ789.
(15) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio Molecular Orbital Theory;
John Wiley: New York, 1986. References cited therein.
(16) Hydrogen bonding networks affect the stabilization of TS even though some hydrogen bonds
have slightly longer distance than the usual one. See: (a) Steiner, T. Angew. Chem. Int. Ed. 2002,
41, 48-76; (b) Scheiner, S. Hydrogen Bonding: A Theoretical Perspective; New York: Oxford
University Press, 1997.
(17) Edward J. D.; Leigh E. W.; Irving M. K. J. Am. Chem. Soc., 1982, 104, 799–807.
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