Hydrogen Bonding-Assisted Enhancement of the Reaction Rate and Selectivity in the Kinetic Resolution of d,l-1,2-Diols with Chiral Nucleophilic Catalysts

Article abstract of DOI:10.1002/adsc.201700057

An extremely efficient acylative kinetic resolution of d,l-1,2-diols in the presence of only 0.5 mol% of binaphthyl-based chiral N,N-4-dimethylaminopyridine was developed (selectivity factor of up to 180). Several key experiments revealed that hydrogen bonding between the tert-alcohol unit(s) of the catalyst and the 1,2-diol unit of the substrate is critical for accelerating the rate of monoacylation and achieving high enantioselectivity. This catalytic system can be applied to a wide range of substrates involving racemic acyclic and cyclic 1,2-diols with high selectivity factors. The kinetic resolution of d,l-hydrobenzoin and trans-1,2-cyclohexanediol on a multigram scale (10 g) also proceeded with high selectivity and under moderate reaction conditions: (i) very low catalyst loading (0.1 mol%); (ii) an easily achievable low reaction temperature (0 °C); (iii) high substrate concentration (1.0 M); and (iv) short reaction time (30 min). (Figure presented.).

Full text of DOI:10.1002/adsc.201700057

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DOI: 10.1002/adsc.201700057
Very Important Publication
Hydrogen Bonding-Assisted Enhancement of the Reaction Rate
and Selectivity in the Kinetic Resolution of d,l-1,2-Diols with
Chiral Nucleophilic Catalysts
Kazuki Fujii,a Koichi Mitsudo,a Hiroki Mandai,a,* and Seiji Sugaa,*
a
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1
Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
E-mail: mandai@cc.okayama-u.ac.jp or suga@cc.okayama-u.ac.jp
Received: January 16, 2017; Revised: February 27, 2017; Published online: && &&, 0000
Supporting information for this article is available under http://dx.doi.org/10.1002/adsc.201700057.
Abstract: An extremely efficient acylative kinetic hydrobenzoin and trans-1,2-cyclohexanediol on
resolution of d,l-1,2-diols in the presence of only a multigram scale (10 g) also proceeded with high se-
0.5 mol% of binaphthyl-based chiral N,N-4-dimethyl- lectivity and under moderate reaction conditions: (i)
ACHTUNGTRENNUNGaminopyridine was developed (selectivity factor of very low catalyst loading (0.1 mol%); (ii) an easily
up to 180). Several key experiments revealed that achievable low reaction temperature (08C); (iii) high
hydrogen bonding between the tert-alcohol unit(s) of substrate concentration (1.0M); and (iv) short reac-
the catalyst and the 1,2-diol unit of the substrate is tion time (30 min).
critical for accelerating the rate of monoacylation
and achieving high enantioselectivity. This catalytic
system can be applied to a wide range of substrates Keywords: acylation; chiral nucleophilic catalyst;
involving racemic acyclic and cyclic 1,2-diols with N,N-4-dimethylaminopyridine; d,l-1,2-diols; kinetic
high selectivity factors. The kinetic resolution of d,l- resolution
Introduction
dinary ring strain, except for an eight-membered
ring). The most satisfactory results with an enantiose-
The establishment of a general method for obtaining lective pinacol coupling (Scheme 1b) were reported
a pure enantiomer with two or more adjacent chiral by Yamamoto,[7d] which also showed high diastereose-
carbons is a challenging topic in organic synthesis.[1] lectivity and enantioselectivity for a variety of hydro-
An enantiomerically pure 1,2-diol moiety which has benzoin-type 1,2-diols, while cyclic and dialkyl-substi-
two contiguous chiral carbon centers is often found in tuted 1,2-diols have not been fully studied (except for
biologically important molecules,[2] chiral ligands for 1,2-diol derivatives obtained from cyclohexyl alde-
metal catalysis,[3] auxiliaries,[4] and organocatalysts.[5] hyde). There have been only a few reports on the
A variety of enantioselective methods has been devel- enantioselective reduction of a-hydroxy ketones or
oped to obtain such enantiomerically pure 1,2-diols, 1,2-diketones to deliver enantiopure 1,2-diols
including enantioselective Sharpless dihydroxyla- (Scheme 1c), since most metal-catalyzed reductions
tion,[6] pinacol coupling,[7] reduction of a-hydroxy ke- give the meso-isomer as a major product by substrate
tones or 1,2-diketones,[8] and Jacobsen hydrolysis of control.[10] An alternative method for obtaining enan-
epoxides[9] (Scheme 1). The enantioselective Sharpless tiopure 1,2-diol is the enantioselective hydrolysis of
dihydroxylation (Scheme 1a) is a splendid synthetic a meso-epoxide (Scheme 1d).[9a–f] This reaction is
method that has been frequently used to synthesize a nearly ideal catalytic enantioselective reaction for
chiral building blocks and natural products. However, obtaining 1,2-diols and offers several advantages (dia-
it has several drawbacks: (i) it requires the use of poi- stereospecific and highly enantioselective, low cost,
sonous osmium(VIII) oxide; (ii) trans-alkenes are pre- air- and water-stable, and recyclable catalyst). Howev-
pared because the reaction proceeds via syn-addition er, the reaction has mainly been shown to be effective
(when a cis-alkene is used as a substrate, the reaction when terminal epoxides are used as substrates (there
gives only meso-diol); and (iii) trans-1,2-cyclic diols has been no report of an enantioselective hydrolysis
cannot be obtained (trans-cycloalkenes have extraor- for cis-stilbene oxide).[9f] Thus, it cannot cover all the
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Scheme 1. Various enantioselective syntheses for 1,2-diols.
various structures of 1,2-diols. On the other hand, rac-
Recently, we have developed two classes of chiral
emic acyclic or cyclic 1,2-diols were much easier to N,N-4-dimethylaminopyridine (DMAP) derivatives.[18]
access than in the enantioselective variant.[11] Against Among them, binaphthyl-based DMAP derivatives 1a
this background, we were interested in the enantiose- with hydrogen-bonding substituents at the 3,3’-posi-
lective separation of d,l-1,2-diol using a chiral catalyst tions remarkably accelerated the rate of the reaction
(i.e., kinetic resolution, Scheme 1e), but substrate lim- and showed high enantioselectivity in the Steglich re-
itations and over-reactions (e.g., diacylation) some- arrangement of O-acylated oxindole derivatives [Eq.
times became problematic. Lewis acid-catalyzed acy- (1)].[18d] According to extensive mechanistic studies
lative kinetic resolutions of diols often proceed with
good enantioselectivity, but these reactions needed
high catalyst loading (1–5 mol%) and showed unsatis-
factory substrate scope (high selectivities were only
observed with the use of d,l-hydrobenzoin series).[12]
Fujimoto,[13] Schreiner,[14] and Yamada[15] have previ-
ously reported the efficient kinetic resolution of d,l-
1,2-diols with organocatalysts. These catalytic systems
showed excellent selectivity factors (s factors)[16] for
a limited number of substrates. For example, Fujimo-
toꢁs method could be applied to acyclic d,l-1,2-diols
(d,l-hydrobenzoin series), but the use of cyclic and
acyclic d,l-1,2-diols resulted in moderate s factors (s=
11–20). In contrast, Schreinerꢁs and Yamadaꢁs meth-
ods were particularly effective with cyclic trans-1,2-
diols, but the efficacy of their application to acyclic
d,l-1,2-diols is unclear. Oriyama reported an organo- on the Steglich rearrangement, the reaction system ef-
catalyzed enantioselective acylation of diols with fectively used hydrogen bonding between the catalyst
a proline-derived diamine catalyst. It was applicable and the counteranion of the N-acylpyridinium ion to
to the desymmetrization of meso-diols with high stabilize the transition state (oxyanion stabilization)[19]
enantioselectivity, and suppressed undesired over-acy- to in turn enhance the catalytic activity and enantiose-
lation (required a very low reaction temperature); lectivity. In this paper, we report the details of the
however, this system was not applied to the kinetic acylative kinetic resolution of acyclic and cyclic d,l-
resolution of d,l-diols.[17] Accordingly, the develop- 1,2-diols using chiral DMAP derivative 1b, and reveal
ment of a general and reliable synthetic method for that hydrogen bonding between 1b and d,l-1,2-diols
accessing an array of enantiopure 1,2-diols would be plays a key role due to enhancement of the reaction
extremely valuable.
rate, enantioselectivity, and mono/di selectivity.
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Results and Discussion
to be an ideal enantioselective reaction system
(Scheme 2b and c).[18d] In particular, the acylative ki-
In our previous paper, we described the acylative ki- netic resolution of d,l-1,2-diols gave not only excellent
netic resolution of racemic carbinols with our cata- s factors, but also prevented undesired over-acylation
lysts as an example of an intermolecular acyl-transfer (mono:di=99:1). These features make this approach
reaction (Scheme 2a).[18d,e] The reaction proceeded advantageous for application at a practical scale.
faster than that with the use of DMAP and in moder-
When a diol is subjected to monoacylation, sup-
ate to high selectivity, which was achieved by hydro- pression of the diacylated product (over-acylation) be-
gen bonding between the catalyst and substrate. How- comes a significant issue. In the ideal kinetic resolu-
ever, this reaction cannot be applied to compounds tion of diols, the monoacylated product should show
other than benzylic carbinols (the use of cyclic or high selectivity regardless of the d,l-1,2-diol structure.
propargylic alcohols gives quite a low selectivity and In other words, the reaction rate of the first acylation
reaction efficiency), and requires rigorous reaction step should be much faster than that of the second
conditions (high catalyst loading, very low reaction acylation step. Our catalyst can evidently recognize
temperature, low substrate concentration). These limi- the 1,2-diol moiety and accelerate the first monoacy-
tations might be serious problems for kinetic resolu- lation step. We performed a competitive experiment
tions on a practical scale.
with (S,S)-2a and (S)-5 (the fast-reacting enantiomer
In contrast, our previously reported enantioselec- in the kinetic resolution of racemic alcohol 2a or 5
tive monoacylation of d,l- and meso-1,2-hydroben- with 1b)[18e] in the presence of 0.5 mol% catalyst 1b,
zoins showed excellent results and has the potential 1.0 equiv. of isobutyric anhydride, and 1.0 equiv. of
N,N,N ꢀ,N ꢀ-tetramethylethylenediamine (TMEDA) in
THF (0.2M) at À788C for 5 h (Scheme 3a). Although
a hydroxy group of (S,S)-2a was thought to be more
sterically hindered than that of (S)-5, only the selec-
tive monoacylation of (S,S)-2a proceeded to afford
(S,S)-3a, and (S)-6 was not detected. For comparison,
we performed the same reaction with 5 mol% of
DMAP.[20] Acylation of (S,S)-2a and (S)-5 proceeded
to give a mixture of (S,S)-3a (14% yield) and (S)-6
(29% yield). Furthermore, a significant amount of di-
acylate (S,S)-4a was obtained (25% yield). This con-
trol experiment strongly suggested that monoacyla-
tion of 1,2-diol using 1b proceeded much faster than
that of a monool. Surprisingly, catalyst 1b can ade-
quately recognize not only a diol unit but also its dia-
stereomers (Scheme 3b). Although the acylation of
two diastereomers, d,l-2a and meso-2a (d,l:meso=
1:1), with 5 mol% of DMAP under slightly modified
reaction conditions [1.0 equiv. of isobutyric anhydride,
1.0 equiv. of TMEDA in Et2O (0.2M)[21] for 5 h] gave
almost the same ratio of two diastereomers of monoa-
cylate (3a and 3a’) in quite low yields and a considera-
ble amount of diacylates 4a, the use of 1b only gave
3a (30% yield) with high enantioselectivity (s=20) as
a sole product. It is quite difficult to separate a 1:1
mixture of d,l- and meso-1,2-diols. Nevertheless, this
catalytic process with 1b allows the reaction with d,l-
diol selectively in the presence of structurally similar
meso-1,2-diol.
We also investigated the subsequent kinetic resolu-
tion step[22] (Scheme 4). Under the optimized reaction
conditions for the kinetic resolution of d,l-1,2-diols
(see the Supporting Information, Tables S1–5), race-
mic monoacylate 3a was barely converted to (R,R)-4a
with very low s factor (10% conversion, s=3.7). As
a result, the minor enantiomer in the first acylative ki-
Scheme 2. Enantioselective acylations of various alcohols by
our group.
netic resolution step [(R,R)-3a] was consumed in the
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Scheme 3. Catalytic accelerating effect of d,l-1,2-diol over monool and meso-diol. The reactions were performed on
a 0.15 mmol scale under an argon atmosphere. Conversions (Æ2%) and mono/di ratios were determined by analysis of the
1
1H NMR spectra of the unpurified mixtures. Product yields were determined by H NMR spectroscopy using 2-methoxy-
naphthalene as an internal standard. The er values (Æ1%) were determined by chiral HPLC analysis of the unpurified mix-
tures. The s factors were calculated using Kaganꢁs equation.[16]
for various control substrates (Scheme 5). These ex-
periments clearly indicated that racemic substrates re-
quire two adjacent free hydroxy groups to achieve
a high s factor and conversion. For example, the use
of racemic monomethyl-capped 1,2-diol 7, benzyl
phenyl carbinol 8, and benzoin 9 as substrates gave
quite low s factors (s=1.0–2.6) and conversions (8–
38% conv.) under the optimal reaction conditions. We
presumed that the catalyst 1b recognizes two adjacent
hydroxy groups on the substrate to accelerate the re-
action and discriminate between the two enantiomers
Scheme 4. Investigation of the subsequent kinetic resolution
of the substrate.
step. The reaction was performed on a 0.070 mmol scale
under an argon atmosphere. Conversions (Æ2%) were de-
1
termined by analysis of the H NMR spectra of the unpuri-
fied mixtures. The er values (Æ1%) were determined by
chiral HPLC analysis of the unpurified mixtures. The s fac-
tors were calculated using Kaganꢁs equation.[16]
second acylation step. This result showed that the
enantiomeric ratio of monoacylate 3a was slightly am-
plified by the second acylation step, but this subse-
quent reaction proceeded very slowly. This control ex-
periment clearly showed that the enantiomeric ratio
of monoacylate 3a was determined by the first acyla-
tion step, and catalyst 1b accelerated the rate of the
first acylation (i.e., monoacylation of diol 2a vs. acyla-
tion of monool 3a, Scheme 2b vs. Scheme 4). This ob-
servation supports the notion that catalyst 1b only
Scheme 5. Control experiments with various substrates. The
gives a monoacylate with high selectivity.
reactions were performed on a 0.3 mmol scale under an
We next investigated in more detail the effect of
hydrogen bonding between the hydroxy groups of the
catalyst and two hydroxy groups of the substrate by
several control experiments. We focused on the struc-
argon atmosphere. Conversions (Æ2%) were determined by
1
analysis of the H NMR spectra of the unpurified mixtures.
The er values (Æ1%) were determined by chiral HPLC
analysis of the unpurified mixtures. The s factors were calcu-
ture of the substrate, and performed kinetic resolution lated using Kaganꢁs equation.[16]
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Next, we considered the catalyst structure cellent s factor and selectivity of monoacylation,
(Scheme 6). The acylative kinetic resolution of 2a was whereas catalyst 1b’ gave quite a low s factor (s=
carried out using four catalyst analogues, including 125.1 with 1b vs. s=1.1 with 1b’). Similarly, the use of
the optimal catalyst 1b, methyl ether analogue 1b’, catalyst 1c resulted in a low s factor and a significant
C1-symmetrical analogue 1c, and analogue 1d without amount of diacylate was obtained (s=1.9 and
tert-alcohol units. The use of catalyst 1b gave an ex- mono:di=80:20). To our great surprise, catalyst 1d
gave the lowest catalytic activity and almost no enan-
tioselectivity (s=1.1). These results indicate that the
catalyst must have two hydroxy units, and is effective
in the enantioselective monoacylation of the d,l-1,2-
diol series.
To examine the enhancement of the reaction rate
by catalyst 1b, we next examined the catalytic activity
of this reaction system by comparison with commer-
cially available pyridine-based nucleophilic catalysts
(Scheme 7). With the use of 0.5 mol% of catalyst 1b,
the monoacylation of (S,S)-2a, which is the fast-react-
ing enantiomer (if we exclude the process of kinetic
resolution), proceeded in 79% conversion after 5 h
and perfectly suppressed over-acylation. The use of
0.5 mol% of DMAP and PPY gave low conversions
(24% and 32%, respectively) with a considerable
amount of diacylate (S,S)-4a under the identical reac-
tion conditions. Despite the stoichiometric reaction
conditions [1.0 equiv. of (i-PrCO)2O], a large amount
of undesirable diacylate was obtained by the use of 9-
azajulolidine, which is known to be a highly active
pyridine-based nucleophilic catalyst[23] (60% conv.,
mono:di=60:40). These results clearly showed that
catalyst 1b selectively accelerated the monoacylation
step.
The results of several control experiments regard-
Scheme 6. Control experiments focused on hydroxy groups
ing the effect of hydrogen bonding (Scheme 4,
on the catalyst. The reactions were performed on a 0.3 or
Scheme 5, and Scheme 6) strongly support the notion
0.6 mmol scale under an argon atmosphere. Conversions (Æ
that hydroxy groups on 1b and two hydroxy groups
2%) and mono/di ratios were determined by analysis of the
1H NMR spectra of the unpurified mixtures. The er values
(Æ1%) were determined by chiral HPLC analysis of the un-
purified mixtures. The s factors were calculated using
Kaganꢁs equation.[16]
on the substrate play an important role in the rate ac-
celeration and high enantioselectivity. Furthermore,
in our previous paper,[18e] we stated that the leaving
group of an acylating reagent strongly affected the
Scheme 7. Comparison of various nucleophilic catalysts in the monoacylation of (S,S)-2a. The reactions were performed on
a 0.30 mmol scale under an argon atmosphere. Conversions (Æ2%) and mono/di ratios were determined by analysis of the
1H NMR spectra of the unpurified mixtures.
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enantioselectivity in the acylative kinetic resolution of catalyst, and thus another hydroxy group is acylated
a secondary carbinol. We also investigated the bene- to give (S,S)-3a. In the disfavored transition state,
fits of this acylating reagent in this reaction steric repulsion between the phenyl group (Ph drawn
(Scheme 8). The use of 0.75 equiv. of isobutyric chlo- as blue in Figure 1) and the isopropyl group of acylat-
ride instead of isobutyric anhydride under otherwise ing agent would be dominant. These transition states
optimal reaction conditions resulted in almost no con- may explain all of the observations obtained in the
version with a very low enantioselectivity[24] (<2% control experiments at the present stage. Although
conv.). This implies that the leaving group of acylating computational calculations to elucidate the reaction
reagents (ÀOCO-i-Pr vs. ÀCl), which comprise the mechanism and the high selectivity in the transforma-
counteranion of N-acylpyridinium ion in the transi- tions are currently conducted, the enormous numbers
tion state, strongly affects the reactivity and enantio- of possibilities of the alignments prevent us from
selectivity in this kinetic resolution process.[18e,25]
drawing a conclusion. These results will be reported
elsewhere. The hydrogen bonding interactions in acy-
lative kinetic resolution were already studied in detail
by Miller (H-bonds between a peptide-based imida-
zole catalyst and a vicinal amino alcohol[29] or carbi-
nol[30]) and Seidel (H-bonds between a chiral thiour-
ea-DMAP combination catalyst and
a
vicinal
amine).[31] The present study also clearly demonstrates
the utility of the hydrogen bonding network in design-
ing enantioselective acyl-transfer reactions.
Scheme 8. Investigation of the effect of an acylating reagent.
The reactions were performed on a 0.300 mmol scale under
an argon atmosphere. Conversions (Æ2%) were determined
The kinetic resolution of various 1,2-diols including
acyclic and cyclic variants was examined under the
optimal reaction conditions (Scheme 9). We initially
focused on hydrobenzoin derivatives 2a–j as a sub-
strate (Scheme 9a). The reactions of 2a–j proceeded
with good conversions and excellent s factors (32–
55% conv., s=54.0–180.3, except for 2b). In all cases,
1
by analysis of the H NMR spectra of the unpurified mix-
tures.
To summarize these observations, and after consid- the monoacylated product was obtained with high se-
ering the explanations offered by Spivey,[26] Zipse,[27] lectivity (mono:di= >96:4, except for 2b). Diol 2b,
and Kawabata,[28] we speculated that the transition which contained 2-naphthyl groups, showed a some-
state involves several hydrogen bonding networks what low selectivity of monoacylation and a low
among the tert-alcohol unit of the catalyst, the ortho- s factor (mono:di=82:12, s=6.7). In contrast, struc-
hydrogen of the pyridine moiety, the carboxylate turally similar diol 2c, which contains 1-naphthyl
anion, and
a hydroxy group of the substrate groups, showed an excellent ratio of monoacylation
(Figure 1). After formation of the appropriate hydro- and an excellent s factor (mono:di=99:1, s=180.3).
gen bonding networks in the favored transition state, This catalytic system could also achieve the separa-
the more acidic proton of the hydroxy group (activat- tion of enantiomers from para-substituted hydroben-
ed by a neighboring hydroxy group through intramo- zoin derivatives 2d–g with excellent s factors even
lecular hydrogen bonding) of the substrate is depro- though these molecules have diverse substituents such
tonated by the closest carboxylate anion fixed by the as electron-donating groups, electron-withdrawing
Figure 1. Postulated transition states.
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Scheme 9. Substrate scope. The reactions were performed on a 0.30 or 0.60 mmol scale under an argon atmosphere (see the
1
Supporting Information for details). Conversions (Æ2%) and mono/di ratios were determined by analysis of the H NMR
spectra of the unpurified mixtures. The er values (Æ1%) were determined by chiral HPLC analysis of the unpurified mix-
tures. The s factors were calculated using Kaganꢁs equation.[16]
groups, or hydrogen bond-accepting groups (s=74.9– hexane-1,2-diol 2k and its structurally similar variants
139.3). Also, ortho- or meta-substituted hydrobenzoin 2l and 2m showed high to excellent s factors under
derivatives 2h–j could be resolved with high s factors the optimal reaction conditions (s 146.1, 48.7, and
(s=54.0–146.0).
20.1, respectively). Diols containing seven-membered
Additionally, this kinetic resolution could be ap- 2n and eight-membered rings 2o could also be re-
plied to cyclic 1,2-diols in good conversions and with solved with high s factors (s=27.7 and 74.7, respec-
high s factors (Scheme 9b). Remarkably, trans-cyclo- tively). Unfortunately, this catalytic system could not
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Table 1. Exploration of the conditions for a practical scale
be applied to a five-membered ring system (2p: s=
3.0, 2q: s=6.4).
reaction.[a,b]
Notably, acyclic diols with alkyl, vinyl, or allyl sub-
stituents 2r–t could be resolved under these catalytic
systems with moderate to excellent s factors (s=9.7–
36.3, Scheme 9c). It was difficult to resolve these sub-
strates under the kinetic resolution conditions, per-
haps because the conformationally flexible nature of
acyclic d,l-1,2-diol would result in undesirable confor-
mations in the transition state. Thus, there have been
only a few reports on the acylative kinetic resolution
of acyclic d,l-1,2-diols with alkyl substituents with
moderate s factors.[13,14c] On the other hand, the reac-
tions of acyclic diols 2u and 2v with neighboring func-
tional groups resulted in low s factors and poor selec-
tivity of monoacylation. While there are no clear ex-
planations for these results, we considered that neigh-
boring functional groups might inhibit the hydrogen
bonding between the catalyst and the substrate
(Figure 1). To the best of our knowledge, this is the
first example of a case where a very small amount of
DMAP-based chiral nucleophilic catalyst (0.5 mol%
of 1b) can be applied to various d,l-1,2-diols involving
acyclic and cyclic substrates with good to excellent
s factors.
Entry
X
Conc.
Conv.
[%][c]
er of
er of
s[e]
[mol%] [M]
3a[d]
2a[d]
1
2
3
4
0.5
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.5
1.0
1.0
56
47
41
58
56
52
88:12
91:9
91.5:8.5 84:16
85:15
86:14
88:12
99:1
91:9
31.9
26.3
21.6
25.9
21.6
21.0
99:1
97:3
93:7
5
6[f]
[a]
Performed on a 0.1–0.4 mmol scale under an argon at-
mosphere.
[b]
[c]
Mono/di ratios were >98:2 in all cases.
Conversions (Æ2%) and mono/di ratios were determined
1
by analysis of the H NMR spectra of the unpurified mix-
tures.
[d]
The er values (Æ1%) were determined by chiral HPLC
analysis of the unpurified mixtures.
The s factors were calculated using Kaganꢁs equation.[16]
Stirred for 0.5 h.
[e]
[f]
In principle, a practical scale reaction should offer
a very low catalyst loading, a higher substrate concen-
tration (to reduce the amount of solvent needed),
a high s factor (s>20),[32] and an easily achievable low
With the optimized reaction conditions for a practi-
reaction temperature. As previously mentioned, cata- cal scale reaction in hand, we carried out the kinetic
lyst 1b combined high catalytic activity and excellent resolution of two different substrates on a multigram
chiral recognition for d,l-1,2-diols [0.5 mol% of 1b, scale (Scheme 10a and b). The use of 10 grams of rac-
THF (0.2M), À788C, 9 h, Scheme 9]. Hence, we reex- emic hydrobenzoin 2a under the practical scale condi-
amined the reaction conditions for a practical scale tions (only 0.1 mol% of 1b=34.4 mg was used) gave
reaction with maintenance of a synthetically useful s- the monoacylate 3a in 52% yield with 88.5:11.5 er
factor (s> 20).[32] We began by reducing the catalyst along with the recovery of 2a in 47% yield with 93:7
loading in THF (0.1M) at 08C for 3 h (Table 1, en- er (purified by column chromatography on silica gel).
tries 1–3). The results with 0.1 mol% of catalyst 1b Recrystallization of recovered 2a improved the enan-
showed good conversion and a good s factor (47% tiomeric ratio (>99:1 er) in 39% yield. Furthermore,
conv.; s=26.3; entry 2), and the reaction with catalyst 1b was recovered in 97% yield. We also con-
0.05 mol% of catalyst 1b also proceeded smoothly ducted a 10 gram-scale reaction with trans-cyclohex-
while maintaining a satisfactory s factor (41% conv.; ane-1,2-diol 2k to give monoacylate 3k in 59% yield
s=21.6; entry 3). Since the use of 0.1 mol% of 1b was with 86:14 er along with the recovery of 2k in 34%
thought to be optimal with respect to both conversion yield with >99:1 er (after chromatographic separation
and s factor, we next performed screening reactions and recrystallization), and recovered catalyst 1b in
regarding the substrate concentration and reaction 96% yield. Both reactions clearly demonstrated the
time (entries 4–6). A higher substrate concentration near-perfect selectivity of monoacylation (mono:di=
(0.5 and 1.0M) did not significantly affect the s factor >99:1) and synthetically acceptable s factors[32] (s=
(entries 4 and 5). Finally, the reaction within a shorter 20.6 and 19.1, respectively) even when the reaction
time (0.5 h) under otherwise identical conditions gave was carried out on a multigram scale reaction. Fur-
monoacylate 3a and unreacted enantio-enriched 2a in thermore, the recyclability of 1b was confirmed by
52% conversion with a high s factor (s=21.0, performing the kinetic resolution of racemic hydro-
entry 6). For a practical scale reaction, the optimized benzoin 2a (0.3 mmol scale) under the optimal reac-
reaction conditions were determined to be 0.1 mol% tion conditions, which showed almost the same
of catalyst 1b, 0.75 equiv. of isobutyric anhydride, s factor (s=157.8), selectivity of the monoacylate, and
0.75 equiv. of TMEDA in THF (1.0M) at 08C for conversion (Scheme 10c vs. Scheme 9).
0.5 h.
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Scheme 10. Kinetic resolution on a multigram scale and recyclability. The yields (Æ2%) refer to isolated material after silica
gel chromatography. The er values (Æ1%) were determined by chiral HPLC analysis of the unpurified mixtures. The s factors
were calculated using Kaganꢁs equation.[16]
Conclusions
chemistry for pharmaceutical production. Further ap-
plications of this approach for the syntheses of biolog-
We have developed a highly accelerated kinetic reso- ically important molecules are now in progress.
lution of diverse d,l-1,2-diols with a small amount of
high-performance chiral DMAP derivatives (0.1–
0.5 mol%). Several key experiments revealed that
such transformations were due to a hydrogen bonding
Experimental Section
network among tert-alcohol units and the ortho-hy-
drogen of a pyridine moiety of the catalyst, the car-
boxylate anion generated by the acylating reagent,
and the 1,2-diol moiety of the substrate. The current
catalytic system allows the use of hydrobenzoin deriv-
atives with various functional groups, trans-1,2-cyclic
diols, and acyclic dialkyl-substituted 1,2-diols with an
excellent selectivity of monoacylation and high s fac-
tors (up to s=180.3, 22 examples). The multigram
General Procedure for Acylative Kinetic Resolution
with 1b
In a dry screw-top test tube, to a solution of substrate
(1.0 equiv.), TMEDA (0.75 equiv.), and stock solution of 1b
(0.5 mol%) in THF (0.200M) was added (i-PrCO)2O
(0.75 equiv.) at À788C. The reaction mixture was stirred for
9 h at À788C, and then MeOH (5 mL) was added to the re-
action vessel at À788C. The resulting solution was warmed
up to room temperature and stirred for 15 min at room tem-
scale reaction using less than 0.1 mol% of the catalyst perature. After stirring for 15 min, the resulting solution was
transferred to another flask using Et2O to wash the reaction
vessel and concentrated under vacuum. The residue was
passed through a short pad of silica gel [eluent: hexane/
EtOAc or hexane/Et2O adjusted Rf =0.5 (unreacted sub-
strate)] to give the crude mixture. The conversion and ratio
under the milder reaction conditions also proceeded
smoothly with an excellent selectivity of monoacyla-
tion and synthetically acceptable s factors (2a: s=20.6
and 2k: 19.1, respectively) under reoptimized condi-
tions for the practical scale. Furthermore, the catalyst
could be easily recovered in >96% yield and recycled
without a loss of catalytic activity or enantioselectivi-
ty. We believe that the present method to access
highly enantio-enriched 1,2-diols with catalyst 1b is
1
of mono/diacylate were determined by H NMR analysis of
the crude mixture. The enantiomeric ratios of monoacylate
and recovered substrate were determined by chiral HPLC
analysis of the crude mixture. In the case of using a substrate
without chromophores, benzoylation of the isolated monoa-
extremely valuable from a viewpoint of process cylate and recovered substrate was conducted. The mono-
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benzoate and dibenzoate were used to determine of the
enantiomeric ratios by chiral HPLC analysis.
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Acknowledgements
This research was partially supported by the Naito Founda-
tion, Okayama Foundation for Science and Technology, and
a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts”
and “Middle molecular strategy” from MEXT (Japan). The
authors thank the Division of Instrumental Analysis, Depart-
ment of Instrumental Analysis & Cryogenics, Advanced Sci-
ence Research Center, Okayama University for the NMR and
high-resolution mass spectrometry measurements (FAB, EI,
and ESI). The authors are grateful to Dr. Toshinobu Korena-
ga (Iwate University) for the fruitful discussions.
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12 Hydrogen Bonding-Assisted Enhancement of the Reaction
Rate and Selectivity in the Kinetic Resolution of d,l-1,2-
Diols with Chiral Nucleophilic Catalysts
Adv. Synth. Catal. 2017, 359, 1 – 12
Kazuki Fujii, Koichi Mitsudo, Hiroki Mandai,* Seiji Suga*
Adv. Synth. Catal. 0000, 000, 0 – 0
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