Electronic helix theory-guided rational design of kinetic resolutions by means of the Sharpless asymmetric dihydroxylation reactions

Article abstract of DOI:10.1016/j.tet.2012.06.102

Kinetic resolution represents a key chemical reaction strategy for asymmetric synthesis of optically enriched compounds, and it originates from a simple phenomenon that a pair of mirror images (enantiomers) of a racemate can react with different rates under a chiral environment. While highly efficient catalytic kinetic resolutions by means of the classical Sharpless asymmetric epoxidation (AE) reactions are well established in modern organic synthesis, such systems based on the arguably more versatile Sharpless asymmetric dihydroxylation (AD) processes, although long pursued and widely attempted, remain largely underexplored. With insights gained from a new electronic helix theory we recently developed for molecular chirality and chiral interactions, we were able to advance a proposal suggesting why this problem is challenging and how it might be solved. Guided by a new design concept aimed at identifying complimentary catalyst-substrate electronic interactions, we reported herein that not only can such elusive systems be generally feasible, but efficiencies well reach the highest levels known to date with chemical or enzymatic kinetic resolutions of any type.

Full text of DOI:10.1016/j.tet.2012.06.102

Tetrahedron 68 (2012) 7288e7294
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electronic helix theory-guided rational design of kinetic resolutions by means
of the Sharpless asymmetric dihydroxylation reactions
*
Xiangyou Xing, Yaohong Zhao, Chen Xu, Xinyang Zhao, David Zhigang Wang
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen University Town,
Shenzhen 518055, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Kinetic resolution represents a key chemical reaction strategy for asymmetric synthesis of optically
enriched compounds, and it originates from a simple phenomenon that a pair of mirror images (enan-
tiomers) of a racemate can react with different rates under a chiral environment. While highly efficient
catalytic kinetic resolutions by means of the classical Sharpless asymmetric epoxidation (AE) reactions
are well established in modern organic synthesis, such systems based on the arguably more versatile
Sharpless asymmetric dihydroxylation (AD) processes, although long pursued and widely attempted,
remain largely underexplored. With insights gained from a new electronic helix theory we recently
developed for molecular chirality and chiral interactions, we were able to advance a proposal suggesting
why this problem is challenging and how it might be solved. Guided by a new design concept aimed at
identifying complimentary catalystesubstrate electronic interactions, we reported herein that not only
can such elusive systems be generally feasible, but efficiencies well reach the highest levels known to
date with chemical or enzymatic kinetic resolutions of any type.
Received 18 April 2012
Received in revised form 7 June 2012
Accepted 26 June 2012
Available online 4 July 2012
Keywords:
Polarizability
Sharpless asymmetric dihydroxylation
Electronic helix theory
Stereochemistry
Kinetic resolution
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
alkene substrates, kinetic resolution by means of this fundamental
asymmetric catalysis technology has thus far only recorded very
The Sharpless asymmetric dihydroxylation (AD) and Sharpless
asymmetric epoxidation (AE) reactions are two fundamentally
important chemical transformations1 that stereoselectively oxidize
alkenes into optically enriched products of useful enantiomeric
excesses (ees). The enantioselections in these processes can in
principle be attained with two complementary scenarios,2e6 either
by converting achiral substrates enantioselectively into chiral
products (asymmetric induction) with the aid of an external chiral
catalyst, or by taking advantage of enantiomers of racemic sub-
strates or their derived products reacting with different rates under
a chiral environment generated by an external catalyst (kinetic
resolution). Strikingly, literature data accumulated from extensive
studies on both AE and AD in the past decades revealed a nearly
orthogonal stereochemical picture: while in asymmetric induction,
AE only works well on allylic alcohols it has been demonstrated to
be highly successful in kinetic resolutions of several classes of
substrate structures; by contrast, as visualized in Fig. 1, while
in asymmetric induction, with the aid of so-called commercial
limited success.2 The reasons for this have not yet been understood.
To date, only a few reports on scattered substrate structures were
known,2,7e23 and the uncovered kinetic resolution efficiencies were
relatively low. Consequently, there has been a growing belief that
realizing general and highly effective AD-based kinetic resolution
processes-if not impossible-can be rather difficult.2
Introduction to the electronic helix theory: a few years ago one of
us (DZW) had published a new electronic helix theory for
‘AD-mix-a or b’ reagent (bis-cinchona alkaloideOsO4 complex), AD
consistently yields high ees over an enormously broad spectrum of
Fig. 1. Stereochemical duality in the Sharpless asymmetric dihydroxylation reactions:
asymmetric induction versus kinetic resolution. (DHQD)2ePHAL stands for the
phthalazine (PHAL) adduct with dihydroquinidine (DHQD).
* Corresponding author. Tel.: þ86 755 26035307; fax: þ86 755 26032702; e-mail
addresses: dzw@pkusz.edu.cn, dzw@szpku.edu.cn (D.Z. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.102

X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
7289
molecular chirality and chiral interactions.23e28 That theory illus-
trated the following three major points: one, chirality is helicity,
and vice versa. Electronically they are just the same thing, thus
structurally diverse molecular chiralities can be generalized on the
basis of their inherent electronic helicities, being simply either
right- or left-handed (Fig. 2A).23,25 Such helicity could in turn be
analyzed and identified from molecular electronic polarizability
properties; two, within a pair of diastereomeric molecular in-
teractions, such as those encountered in competing diastereomeric
transition states in an asymmetric reaction, the interaction be-
tween molecules having the same helical handedness (i.e., homo-
helical interaction) is electronically always lower in energy than
that with opposite handedness (hetero-helical interaction). That is,
the principle underlying a chiral induction or recognition event is
suggested to be the conservation of molecular electronic hel-
icity;23,25 An illustration of this helicity conservation principle is
presented in Fig. 2B, in which the homohelical electronic inductions
in asymmetric hydrogenation of simple ketones executed by
a right-handed diphosphine diamine Ru catalyst all lead to chiral
alcohol products of the same indicated absolute stereochemistry.
What is notable in this exemplifying system is the demonstration of
substrate electronic polarizability-but not its size-as a critical factor
deciding the sense and magnitude of enantioselection. For B1 and
B2, conventional steric rationale would predict wrong stereo-
chemistry; and for B3 and B4, it is unclear how enantioselection
could originate from substrates featuring nearly isosteric sub-
stituents. By contrast,
a polarizability-based stereochemical
model23 has proven to be generally applicable and predictive as in
each of these cases the ketone substituent on the left (blue) is more
polarizable than that on the right (red), and for the first time it
helps explain why the foundation of current success in asymmetric
catalysis in general appears to be closely associated with substrates
characterized by significant
p-versus-s polarizability distinctions
(summarized as structure B5). Three, the homohelical-versus-
heterohelical energetic difference, thus accordingly the magni-
tude of enantioselection in an asymmetric reaction, could be
maximized when the interacting helices are energetically equal to
each other (which is the case of, for example, autocatalysis).24,26 As
a chiral molecule’s electronic helicity is closely derived from its
polarizability characteristics, this helix theory is in essence an ex-
tension of Pearson’s classical hard and soft acid and base (HSAB)
theory into the three dimensional chiral space.26 It is notable that
molecular chirality is conventionally thought to be a solely geo-
metrical property, and accordingly, chiral molecular interactions
are usually analyzed by considering steric effects, thus our work has
added useful electronic elements back to chiral systems. Indeed,
applying this theory to an extensive range of major experiments23
reported since the birth of asymmetric catalysis in 1960s showed
that it is powerfully predictive and also accommodates results that
conventional steric reasoning cannot.27,28
A
2. Results and discussion
Design concept for Sharpless AD-based kinetic resolutions: in-
trigued by the fascinating asymmetric induction-versus-kinetic
resolution stereochemical phenomenon highlighted in Fig. 1, we
initiated a program aimed at exploring the possibility of realizing
highly efficient kinetic resolution systems based on the AD re-
actions. In this context, our efforts were critically guided by insights
gained from electronic helix analysis on the AD systems,23,28 which,
as a conceptual reminiscence of an earlier stereochemical model29
originated by Lohray et al., points to the importance of the en-
B
gagement of electron-deficient hetero-aromatic linker unit (i.e.,
character phthalazine moiety, Fig. 1) in the bis-cinchona alkaloid
ligand towards stacking with an alkene substrate’s electron-
p-
pep
rich double bond. Within this context, we have recently been able
to advance successfully a new polarizability-based stereochemical
model for the Sharpless AD reactions.28 As visualized in Fig. 3A, the
AD-mix-
electronic helicity23 could be electronically represented by a simple
-chirality*-N-OsO4 diagram (in blue), thus in the illustrated cat-
b reagent (DHQD)2ePHALeOsO4 featuring a right-handed
p
alystesubstrate interaction mode (Fig. 3B) the alkene double bond
connects simultaneously with the catalyst through both complex-
ation to OsO4 and
pep stacking with its phthalazine (PHAL) ring.
While such a dual control mechanism on the substrate double bond
significantly facilitates enantio-facial control, as evidenced by the
remarkable success achieved across a broad range of alkenes in
classical AD reactions, it however electronically disregards a race-
mic substrate’s chirality, that is, positioned outside of the cata-
lystesubstrate interaction means, thus inevitably jeopardizing
chiral recognition efficiency requisite for high levels of catalytic
kinetic resolutions. A logical solution to this problem therefore
invites consideration on a new design scenario that takes advan-
Fig. 2. Background information on a new electronic helix theory for molecular chi-
rality and chiral interactions. A, Generalization of diverse molecular chiraltities on the
basis of their inherent electronic helicities. B, An illustration of homohelical electronic
induction in diphosphine diamine Ru complex-catalyzed asymmetric hydrogenation of
ketones: substituent polarizability plays more important role than its size in enan-
tage of an appropriately chosen
p-character R2 allylic substituent: it
is anticipated that an effectively operating
pep
stacking between
R2 and the catalyst PHAL ring should incorporate a substrate’s
chirality within the corresponding catalystesubstrate interaction
framework, thereby soliciting highly efficient chiral recognition and
subsequent kinetic resolutions (Fig. 3C). Indeed, a careful survey of
tioselection.
hetero-aromatics, ferrocenes, alkenes, or alkynes), and
PL: substituent of larger polarizability; PS: substituent of smaller polarizability.
p
denotes a
p-electron cloud-containing substituent (such as aromatics,
s
represents an alkyl group.

7290
X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
of participating on catalystesubstrate
actions. Our specific attention was placed on aryl rings flanked by
pep stacking in AD re-
A
both electron-donating and withdrawing substituents since their
p
-electronic clouds are considerably polarizable thus conducive for
soliciting
pep
stacking interactions.30 We reported herein that
execution of this design scenario has proven to be fruitful: not only
had we discovered that AD-based kinetic resolutions of such high-
value structural motifs as allylic unsaturated esters were generally
feasible, but also enantiomeric differentiation efficiencies in these
processes were found to reach the highest levels known to date for
chemical or even enzymatic kinetic resolution processes of any
reaction type.31
Kinetic resolutions of allylic unsaturated esters: our investigations
have chosen to focus on allylic unsaturated esters structured as 1 and
the corresponding results were compiled in Table
1 (see
Supplementary data for experimental details). Compound 1 contains
several synthetically attractive and readily editable functionalities in
B
C
its structure, including olefinic double bond, a,b-unsaturated ester,
allylic alcohol and its derived ester form. These recurring structural
motifs are well represented in a diverse range of biologically and
pharmaceutically meaningful natural products as well as their un-
natural analogues or mimics. Recently disclosed examples are
16-membered trilactone macrolides macrosphelides A and E,32 an-
tibacterial and antifungal agent botryolide E,33 P-glycoprotein in-
hibitor taxane derivative related to taxuspine X,34 anticancer agent
brefeldin A and its ester derivatives,35 and antibacterial cleistenolide
against notably Staphylococcus aureus and Bacillus anthracis.36 In
contrast to 1’s structural and functional significance, presently there
are no effective catalytic asymmetric reaction methods known that
could allow convenient access into these important chiral building
blocks.
D
The kinetic resolution efficiency is characterized by the pa-
rameter termed selectivity factor s, which numerically is the ratio of
(the rate of fast-reacting enantiomer)/(rate of slow-reacting enan-
tiomer), and its quantity is calculated on the basis of the known
equation s¼ln[(1ꢀc)(1ꢀee)]/ln[(1ꢀc)(1þee)], where ee is the en-
antiomeric excess of the recovered substrate and c denotes the
corresponding reaction conversion.37 As with standard AD re-
actions employing as little as 0.2% mol of pseudo-enantiomeric AD-
mix-a or b reagent for delivering high levels of asymmetric in-
duction,2 the experiments examined here also used this same low
catalyst loading and run at room temperature for the sake of
achieving reaction efficiency as well as operational practicality.
Furthermore, particular attention was given to determining the
selectivity factors associated with reaction conversions closely
around 50% as enantio-purities of the recovered substrate tend to
increase at the expense of higher reaction conversions, thus such s
values measured at w50% conversions are the more diagnostic
indicators for the corresponding catalystesubstrate enantio-
differentiation capacity thus the practical usefulness of the ki-
netic resolution process.37 Additionally, it merits a note here that,
although selectivity factor is a generally useful parameter for
evaluating kinetic resolution process, its accurate determination
depends on a detailed understanding of the rate laws of the re-
action under concern and in some cases may become less
straightforward.37 Therefore, in the experiments shown below a list
of ee deviations from the corresponding theoretical limit value at
the given reaction conversion were tabulated alongside with the
selectivity data to further aid the evaluation of kinetic resolution
efficiency. Under such considerations we have established that an
array of allylic unsaturated esters bearing different R2CO2 and R1
substitutions at the allylic carbons could be kinetically resolved
with extremely high selectivity factors and enantioselectivities.
As summarized in Table 1, racemate 1 substituted with a piper-
onylate and a cyclopropyl ring (entry 1) underwent catalytic kinetic
resolution with an extremely high selectivity factor of 213 under
Fig. 3. A, The electronic helix representation of Sharpless AD-mix-
b reagent, which
features a right-handed helicity,23
p
represent the hetero-aromatic phthalazine (PHAL)
ring. B, Inefficient catalystesubstrate chiral recognition in kinetic resolution by means
of the Sharpless asymmetric dihydroxylation reactions. C, A potential strategy for in-
corporating substrate chirality within catalystesubstrate interaction means through
exploring
pep stacking between catalyst PHAL ring and R2 allylic substituent. D,
Literature-reported substrates for AD-based kinetic resolutions that uniformly feature
a
p-character substituent (circled in green) adjacent to its reacting double bond. Star
represents a chiral element; R1eR4, R, R0, or R00 each denotes a substituent; for chiral Cn
fullerenes, n¼76, 78, 84.
those reported alkenes in AD-based kinetic resolutions uniformly
reveals the presence of a
p
-character group adjacent to its reacting
-character
double bond.2,7e23 As circled in green in Fig. 3D, such a
p
moiety could be an ester carbonyl (D1), an amide carbonyl (D2 and
D3), a benzene ring (D4), or a double bond (D5). Furthermore, in
complete agreement with predictions from electronic helix analy-
sis,23 in each of these systems the recovered substrate enantiomer
was the one that forms a homohelical recognition resting state with
the right-handed AD-mix-
Guided by the above analysis, we set out to explore some ra-
cemic alkenes containing a -character allylic substituent capable
b reagent.
p

X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
7291
Table 1
Kinetic resolution of allylic unsaturated esters by means of Sharpless asymmetric dihydroxylation (AD) reactions
Entry
1
R2
R1
s
ee of recovered substrate
Deviation to theor limita
194
213
194
73.7% ee (43.0% conv)
98.1% ee (50.6% conv)
99.9% ee (52.3% conv)
1.7% ee
1.9% ee
0.1% ee
2
3
4
166
45
88.7% ee (47.9% conv)
89.3% ee (50.5% conv)
3.2% ee
10.7% ee
21
25
77.9% ee (49.5% conv)
89.4% ee (53.3% conv)
20.1% ee
10.6% ee
5
6
39
24
83.6% ee (48.9% conv)
97.4% ee (58.1% conv)
12.1% ee
2.6% ee
301
213
198
261
170
>205
73.1% ee (42.6% conv)b
85.2% ee (46.6% conv)b
94.2% ee (49.4% conv)b
97.1% ee (50.1% conv)b
94.0% ee (49.5% conv)
>99.9% ee (51.8% conv)
1.1% ee
2.0% ee
3.4% ee
2.9% ee
4.0% ee
0.0% ee
7
138
87.3% ee (47.6% conv)
3.5% ee
8
75
101
86.7% ee (48.3% conv)
95.5% ee (50.7% conv)
6.7% ee
4.5% ee
9
55
68
80.4% ee (46.8% conv)
91.9% ee (50.3% conv)
7.6% ee
8.1% ee
10
11
12
13
14
15
32
28
78.3% ee (47.6% conv)
97.1% ee (56.5% conv)
12.5% ee
2.9% ee
41
47
90.1% ee (51.1% conv)
94.3% ee (52.3% conv)
9.9% ee
5.7% ee
156
114
79.0% ee (44.9% conv)
95.4% ee (50.5% conv)
2.5% ee
4.6% ee
407
139
96.8% ee (49.7% conv)
99.1% ee (51.7% conv)
2.0% ee
0.9% ee
53
76
83.1% ee (47.8% conv)
89.6% ee (49.3% conv)
8.5% ee
7.6% ee
78
79
87
84.3% ee (47.4% conv)
89.5% ee (49.1% conv)
93.9% ee (50.5% conv)
5.8% ee
7.0% ee
6.1% ee
(continued on next page)

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X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
Table 1 (continued )
Entry
R2
R1
s
ee of recovered substrate
Deviation to theor limita
16
22
28
21
68.8% ee (45.4% conv)
90.9% ee (53.2% conv)
97.0% ee (59.1% conv)
14.3% ee
9.1% ee
3.0% ee
17
31
70
62.8% ee (41.6% conv)
85.5% ee (48.1% conv)
8.4% ee
7.2% ee
a
The ee deviation to the theoretical limit value at the same conversion is calculated by [ee(experiment)ꢀee(theory)].
b
The catalyst here is AD-mix-a.
the action of 0.2 mol % of AD-mix-
b
reagent, yielding the recovered
within a comparable conversion range of 48e49%, but 85.5% ee of
the recovered substrate was still realized at 48.1% conversion. Evi-
dently, with such high levels of selectivity factors demonstrated in
Table 1, the examined allylic unsaturated esters could all be
obtained in enantio-pure form in the practically meaningful con-
version range of 45e55%.
substrate in 98.1% ee at 50.6% conversion. The selectivity factor was
194 with 73.7% ee being achieved at a conversion as low as 43.0%,
which corresponded to a merely 1.7% ee deviation from the theo-
retical limit value of 75.4% ee at this same conversion. The enan-
tioselection could be further improved to essentially 100% at 52.3%
conversion while maintaining the selectivity factor at 194. Replac-
ing the cyclopropyl ring with an isopropyl group resulted in a de-
creased selectivity factor at 166 (entry 2), but 88.7% ee was still
achieved at 47.9% conversion, which was again only 3.2% ee away
from the theoretical limit of 91.9% ee at this conversion. When R1
varied among isobutyl, n-propyl and ethyl groups, the selectivity
factors were in the range of 21e45 (entries 3e5). In marked con-
trast, when R1 is cyclopropyl, replacing the piperonylate moiety
with a 3,4-dimethoxybenzoate leaded to a significant increase of
selectivity factor to 301 (entry 6), which ranks among the very few
highest reported to date for kinetic resolution processes of any type,
chemical or enzymatic.37 This extreme catalystesubstrate chiral
discrimination efficiency readily ensured 97.1% ee to be achieved at
the practically significant 50.1% conversion. At 51.8% conversion,
a nearly perfect >99.9% ee was recorded, and the corresponding
selectivity factor became so large (>205) that it could not be cal-
culated. Retaining the 3,4-dimethoxybenzene ring in 1 while
changing the cyclopropyl to furan produced 87.3% ee at 47.6%
conversion, thus constituting a selectivity factor of 138 (entry 7).
From these results the important role of the R2 aryl ring in modu-
lating kinetic resolution efficacy clearly emerged, hence in entries
8e14 the R2CO2-moiety was replaced by six other aryl esters, in-
cluding 6-methoxy-2-naphthoate, 6,7-dimethoxy-2-naphthoate,
4-methoxybenzoate, 3-bromo-4-methoxybenzoate, 3-iodo-4-
methoxybenzoate and 2-methoxybenzoate. In each of these cases
excellent selectivity factors ranging from 28 to 407 were recorded,
demonstrating again the unique power of Sharpless AD reactions in
effecting such kinetic resolutions. It should be noted here that the
operation of electronic effects is transparent in these systems as
earlier experiments with R2 substituted with electron-withdrawing
groups or with aliphatic R2 all resulted in selectivity factors lower
than 10. A further evidence was appreciable from results in entries
11e13, where the introduction of an electronically increasingly soft
(i.e., more polarizable) bromo- and iodo-substituent, respectively,
onto 4-methoxybenzoate dramatically enhanced the selectivity
factors from 41 to 110 and then to 379 at about 50% conversions.
Next, with 3,4-dimethoxybenzoate with an optimal allylic sub-
stitution, racemates 1 with branched (entry 15) or linear (entry 16)
alkyl R1 group were examined, and the corresponding selectivity
factors, changing from 78e87 to 21e28, were found to respond
somewhat sensitively to the steric effect perturbations, but these
values remained to be practically significant and useful and high
ees were consistently obtained around 50% conversions. A more
pronounced steric effect was observed when a bulkier 3,4-dieth-
oxybenzoate was employed, a comparison on entry 6 to entry 17
showed a marked decrease of selectivity factor from 170 to 70
For kinetic resolutions reported in literature, it is rare that both
the recovered substrate and the corresponding kinetically derived
product could be obtained in high ees during the same reaction
course.37 In fact, none of the previously known AD-based kinetic
resolutions had achieved ees over 90% with diol products of any
type.2,7e23 Thus, to examine this issue in the present systems, the
stereoselections in the diol products 2 dihydroxylated from sub-
strate 1 of entry 1 of Table 1 were carefully analyzed at different
reaction conversions (Fig. 4A). Interestingly, at 35.5% conversion,
the enantio-purities of the two diastereomers in the ratio of 8.6:1
were found to reach 99.9% ee (minor isomer) and 91.4% ee (major
isomer), respectively. At 43.0% conversion, such high levels of ees
were essentially preserved. At an even larger conversion of 50.6%,
as might be well expected from the general kinetic resolution rate
laws, the ees of the product diastereomers decreased slightly (to
90.0% and 80.0%, respectively) as the reaction progressed further. To
the best of our knowledge, these findings represented the first
examples demonstrating that, when such processes were inter-
cepted at appropriate conversions, both recovered substrates and
their diol products could be purposefully furnished in excellent
enantio-purities.
Finally, the absolute stereochemical courses in these AD-based
kinetic resolutions were probed by X-ray crystallographic analy-
sis. To this end, we were able to grow single crystals of compounds
3 (R1¼isopropyl) and 4 (R1¼cyclopropyl) both prepared by deri-
vatizing the diol products of 1 (entries 15 and 14, respectively, Table
1) with the chiral auxiliary (1S)-camphanic chloride, establishing
unambiguously that the more reactive substrate enantiomer of 1 in
both cases has the (R)-configuration at its allylic carbon and the
produced major diol diastereomer has, in agreement with pre-
diction from the Sharpless mnemonic device,2 the expected (S,S)-
configuration (Fig. 4B and C). It should be pointed out here that
these stereochemical outcomes are again fully consistent with
predictions from the electronic helix theory-based rationale, which
was illustrated in Fig. 4D with 3 as a substrate. Because (S)-3 pos-
sesses right-handed electronic helicity (polarizability rankings
used for analyzing its helical handedness23 are C]C>O, and iPr>H)
while interacting with the right-handed catalyst, thus it charac-
terizes a homohelical recognition resting state with the AD-mix-
b
reagent and is recovered, and accordingly (R)-enantiomer is ki-
netically derived into a diol product.
3. Conclusion
In summary, with new stereochemical insight gained from
electronic helix theory as
a critical guiding force, we have

X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
7293
enrichments and at practically useful conversions, and further hints
at the possible applicability of this new catalysis scenario to other
types of important transformations, such as dynamic kinetic reso-
lutions and kinetic desymmetrizations of olefin-containing com-
pounds. Current efforts are thus directed at gaining a detailed
understanding of the stereochemical control principle underlying
these unusual kinetic reactivities and selectivities, as well as at
expanding its substrate scope and practicality to prepare other
high-value chiral substances.
A
B
4. Experimental
4.1. General experimental
Reagents were purchased at the highest commercial quality
from Acros and Aldrich and used without further purification un-
less otherwise noted. Silica gel (ZCX-II, 200e300 mesh) used for
flash column chromatography was purchased from Qing Dao Ocean
Chemical Industry Co. 1H and 13C NMR spectra were recorded on
a Bruker Avance III (300 MHz, 400 MHz or 500 MHz) spectrometers
and are internally referenced to residual solvent signals (note:
CDCl3 referenced at
d
7.26 ppm for 1H and
d
77.0 ppm for 13C). Data
parts per
for 1H NMR are reported as follows: chemical shift (
d
C
D
million), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
p¼pentet, dd¼doublet of doublets, ddd¼doublet of doublet of
doublets and m¼multiplet), integration, coupling constant (hertz)
and assignment. Data for 13C NMR are reported in terms of chemical
shift (d ppm). High resolution mass spectrometric (HRMS) data
were obtained using Bruker Apex IV RTMS. High performance liq-
uid chromatography (HPLC) was performed on a Shimadzu LC-20A
using Daicel ChiralcellÒ chiral columns (25 cm) and guard column
(5 cm) as noted for each compound. The room temperature
(294ꢁ1 K) single-crystal X-ray experiments were performed on
a
Bruker P4 diffractometer equipped with graphite mono-
chromatized Mo Ka radiation. Reagents were purchased at the
highest commercial quality and used without further purification,
unless otherwise stated. For full experimental details, including
procedures for all reactions and characterizations of all new com-
pounds (chiral HPLC analysis, 1H NMR, 13C NMR, mass spectrome-
try), X-ray single crystal structure analyses, see the Supplementary
data.
4.2. General procedure for kinetic resolutions of racemic 1 by
means of the Sharpless asymmetric dihydroxylation (AD)
reactions
Under a nitrogen atmosphere the olefin substrate (1 mmol) was
dissolved in 7.1 mL of t-BuOH and 7.1 mL of H2O (0.07 M),2 1.4 g AD-
mix-b (or AD-mix-a as indicated, 0.2 mol %) and 1 mmol meth-
Fig. 4. A, Enantiomeric enrichment in a diol product 2 from the AD-based kinetic
resolutions. B, Determination of the reaction absolute stereochemical course by X-ray
crystallographic analysis of a diol-derived structure 3. C, Determination of the reaction
absolute stereochemical course by X-ray crystallographic analysis of a diol-derived
structure 4. D, An electronic helix theory-derived stereochemical model23 for the ob-
served highly efficient kinetic resolution in racemic 3: right-handed (S)-substrate
anesulfonamide was added, respectively, the reaction mixture was
stirred at room temperature. Aliquots were removed at different
times and immediately quenched by adding saturated Na2SO3. The
resultant mixture was extracted three times with ethyl acetate. The
combined organic phase was washed with brine and then dried
over anhydrous Na2SO4 and concentrated to give a mixture con-
taining both the residual olefin and the corresponding diol product.
This mixture was analyzed directly by 1H NMR spectroscopy to
determine the conversion percentage. Then it was purified by col-
umn chromatography affording the recovered olefin and the diol
product, whose enantio-purities were subsequently ascertained by
chiral HPLC analysis (detailed HPLC conditions and results were
compiled in the online Supplementary data). For each case reported
in Table 1 multiple sampling and NMR/HPLC analysis were per-
formed to ensure data consistency and reproducibility, and the
enantiomer forms
a homohelical recognition resting state with the right-handed
AD-mix- catalyst thus is recovered, and accordingly (R)-enantiomer is kinetically
b
derived into a diol product.
demonstrated in these preliminary experiments that the long-
pursued highly stereoselective catalytic kinetic resolution pro-
cesses by means of the classical Sharpless asymmetric dihydrox-
ylation reactions were not only generally feasible, but also with
efficiencies up to the highest level known to date with chemical or
even enzymatic kinetic resolutions of any reaction type. The dis-
covery enables such versatile chiral building blocks as allylic un-
saturated esters to be readily accessed with excellent enantiomeric

7294
X. Xing et al. / Tetrahedron 68 (2012) 7288e7294
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Financial support was generously provided by the National Sci-
ence Foundation of China (grants20872004 and 20972008to D.Z.W.),
the National ‘973 Project’ from the State Ministry of Science and
Technology of China, the Shenzhen Bureau of Science, Technology
and Information, and the Shenzhen ‘Shuang Bai Project’. We also
thank Professor R.-J. Wang (Tsinghua University Chemistry De-
partment, X-Ray Diffraction Facility) and Professor T. Wang (Peking
University Shenzhen Graduate School, Structural Biology Unit) for
performing crystallographic analysis on 3 and 4, respectively.
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Supplementary data
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Detailed experimental procedures, single crystal X-ray struc-
tural analysis data, new compound characterization data, and
copies of 1H and 13C NMR spectra. Supplementary data related to
this article can be found online at http://dx.doi.org/10.1016/
j.tet.2012.06.102.
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