N,N-Dimethylaminobenzoates enable highly enantioselective Sharpless dihydroxylations of 1,1-disubstituted alkenes

Article abstract of DOI:10.1039/c4ob00621f

A design scenario aimed at exploring beneficial catalyst-substrate π-π stacking electronic interactions in the classical Sharpless asymmetric dihydroxylations (SAD) leads to the identification of highly polarizable allylic N,N-dimethylaminobenzoate as a remarkably efficient auxiliary for inducing high levels of enantioselectivities (up to 99% ee) in the traditionally challenging substrate class of 1,1-disubstituted aliphatic alkenes. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00621f

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N,N-Dimethylaminobenzoates enable highly
enantioselective Sharpless dihydroxylations of
1,1-disubstituted alkenes†
Cite this: Org. Biomol. Chem., 2014,
12, 4314
Received 23rd March 2014,
Accepted 9th April 2014
Yaohong Zhao,‡ Xiangyou Xing,‡ Shaolong Zhang and David Zhigang Wang*
DOI: 10.1039/c4ob00621f
www.rsc.org/obc
A design scenario aimed at exploring beneficial catalyst–substrate
π–π stacking electronic interactions in the classical Sharpless
asymmetric dihydroxylations (SAD) leads to the identification of
highly polarizable allylic N,N-dimethylaminobenzoate as a remark-
ably efficient auxiliary for inducing high levels of enantioselectivi-
ties (up to 99% ee) in the traditionally challenging substrate class
of 1,1-disubstituted aliphatic alkenes.
The Sharpless asymmetric dihydroxylation (SAD) reactions of
alkenes serve as one of the cornerstone technologies of
modern asymmetric catalysis and have found widespread
applications in organic synthesis.1 The unusually broad utility
of SAD constitutes a continuous driving force for its further
advancements in tackling some of the outstanding problems
that remain to be solved. Such problems2 include, but are not
limited to, experimental realizations of efficient kinetic resolu-
tion3 of chiral substances by means of SAD and of highly
enantioselective dihydroxylations of traditionally challenging
substrate classes of alkenes, notably purely aliphatic gem-1,1-
disubstituted alkenes.1 Asymmetric inductions on such com-
pounds typically yield only low-to-mediocre enantiomeric
excesses (ees). Recently, guided by new stereochemical insights
gained through mechanistic analysis3 of SAD by means of our
electronic helix theory4 for molecular chirality and chiral inter-
actions, we were able to identify critical yet long-overlooked
substrate–catalyst π–π stacking electronic interactions which in
turn help explain why kinetic resolutions by means of SAD are
usually difficult and how this might be solved. Specifically, as
summarized in Scheme 1, we have previously demonstrated
that, simply by employing an electronically polarizable allylic
benzoate (highlighted in blue color, where the R2 substituent
denotes an electron-donating group) moiety capable of com-
Scheme 1 Explorations on substrate–catalyst π–π stacking interactions
in the Sharpless asymmetric dihydroxylation leading to extremely
efficient kinetic resolutions.
peting with the corresponding alkene double bond towards
π–π stacking with the electron-deficient heterocyclic pyrada-
zine π-cloud in the bis-cinchona alkaloid ligand of the so-
called Sharpless AD-mix-β catalyst,3 we were able to achieve
extremely high selectivity factors (up to 400) and enantio-
selectivities (up to >99.9% ee) in the SAD-based kinetic resolu-
tion of a range of allylic unsaturated esters. In many cases,
such racemic substrates were kinetically resolved with chiral
recognition efficiencies close to the theoretical limits at their
corresponding reaction conversions, yielding recovered sub-
strate enantiomers and kinetic dihydroxylation products both
in high enantiopurities. These achievements directly prompted
us to further investigate the function of these π-stacking
scaffolds in tackling the SAD reaction on aliphatic 1,1-disubsti-
tuted alkenes where high ees are typically difficult to attain
with established protocols. We are delighted to report herein
that the same design strategy enables continued successes in
stereochemical control that transcends from the context of
kinetic resolution to that of asymmetric induction.
Key Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen University
Town, Shenzhen, China 518055. E-mail: dzw@szpku.edu.cn
†Electronic supplementary information (ESI) available: Detailed experimental
Thus, as shown in Table 1 with 1a–f as the substrate
probes, by slightly optimizing and identifying a conducive
π-stacking moiety Rπ positioned allylic to the substrate double
procedures, X-ray crystallographic structural analysis, NMR spectra, and chiral
HPLC data are provided. See DOI: 10.1039/c4ob00621f
‡These two authors contributed equally to this work.
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Table 1 Investigations of Rπ substituents on the Sharpless asymmetric
dihydroxylation of 1,1-disubstituted alkenesa
Table 2 Survey on reaction scope: highly enantioselective Sharpless
asymmetric dihydroxylations of a series of 1,1-disubstituted aliphatic
alkenesa
Entry
1
Rπ
Yieldb
68%
eec
42%
2
3
67%
83%
76%
64%
4
5
6
76%
88%
92%
68%
85%
96%
a Reaction conditions: 1 (0.1 mmol), Sharpless AD-mix-β reagent (2.0 g
mmol−1), tBuOH–H2O (1 mL, v/v = 1 : 1), 0 °C. b Isolated yield.
c Determined by chiral HPLC analysis.
bond, we arrived at para-N,N-dimethylamino-benzoate 1f as
the auxiliary of choice in terms of both isolated yield and high
enantio-control (96% ee of diol 2f) over 5 h.5 The preparation
of diol 2f by this new protocol could be readily scaled up to
one-gram without compromising either the reaction yield or
enantioselectivity (92% and 97% ee as compared to data in
entry 6 of Table 1), thus demonstrating a high level of practi-
cality and usefulness. It merits attention that at least in this
case acyl transfer to the primary alcohol in 2f, which appar-
ently would be deleterious to its enantiopurity, was absent.
The ability to achieve high enantiopurity on such multi-
hydroxylated substances is of significant synthetic merit as it
allows similar functionalities to be readily differentiated
towards further needed structural elaborations.6–12 Within this
a Reaction conditions: 1f (0.1 mmol), Sharpless AD-mix-β (1.4
g
mmol−1), tBuOH–H2O (1 mL, v/v = 1 : 1), 0 °C. b Isolated yield.
c Determined by chiral HPLC analysis. d AD-mix-α was used as the
reagent.
context it should be noted that the use of allylic 4-methoxy- double bond moiety with the electron-deficient heterocyclic
benzoates as efficient substrates for SAD had been pioneered pyradazine π-cloud in the bis-cinchona alkaloid ligand of the
by Corey and co-workers.5 Important distinctions between the Sharpless AD-mix-β catalyst, but not π–π stacking between an
present work and that of Corey et al. are three-fold: one, the alkene substrate’s aryl substituent with the ligand quinoline
present work derived the finding of para-N,N-dimethylamino- ring; and three, the present work employs the commercially
benzoate conceptually from stereochemical insights enabled available AD-mix-β or α catalyst, but not any purposefully
by electronic polarizability analysis and electronic helix theory designed Os complexes of other bis-cinchona-type alkaloids.
previously developed and published by us,3,4 rather than from
As shown in Table 2, a range of substrates with the N,N-di-
the known “U-shaped” binding theory where steric effects are methylamino benzoates 3a–19a were conveniently prepared
dominant;5 two, the present work emphasizes the critical from their corresponding 1,1-disubstituted aliphatic allylic
significance of π–π stacking2,3 between an alkene substrate’s alcohols, and subsequently subjected to the Sharpless AD-mix-
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β catalyst, except in the case of 1f where its pseudo-enantio-
meric AD-mix-α catalyst was employed. The ee of 2f′ thus
obtained (94%) was virtually identical to that of entry 6 of
Table 1 (96%). The absolute configuration of 2f was deter-
mined by comparing its optical rotation sign with the litera-
ture value,1p and those of other diols 3b–18b were assigned by
analogy. The size of the aliphatic side chain R in 3b–7b seems
to have a negative influence on the reaction stereochemical
control, as the product ee gradually decreases from 90% (R =
ethyl or propyl) to 83% (R = butyl), 82% (R = pentyl), and
further to 72% (R = hexyl), but these values remain substantial
when compared to relevant literature reports.1 Remarkably,
some of the bulkiest allylic silyl ether protecting groups, such
as TBS, TBDPS, TIPS, were surprisingly well tolerated, and the
diols 8b–10b were furnished in 98%, 96% and 96% ee, respect-
ively. Allylic alkoxy groups were also compatible, and 95–96%
ees were obtained in the cases of 11b–13b. Moreover, homo-
allylic substituents, being structurally either alkoxy or silyl
ethers, demonstrated again excellent ees (96–99% in 14b–16b).
It is synthetically remarkable to access such highly oxygenated
structural motifs as 8b–16b in practically enantiopure forms
and with chemically well-differentiated functionalities.
Homo-allylic chloro or fluoro-substituents present some-
what lower ees, but respectable 88% ees were nevertheless
recorded. The above results collectively help showcase the
dominant role of π–π stacking N,N-dimethyl-aminobenzoate in
overriding stereoelectronic fluctuations incurred by other sub-
stituents, thereby yielding a new protocol with broad applica-
bilities. Finally, the reactions do not appear to be able to
accommodate aromatic substituents, as a low ee (43%) was
recorded when R = phenyl (diol 19b). It should be added that,
when an amide linkage was employed in placement of the
ester in 1f, asymmetric dihydroxylation only proceeded in 68%
ee at 80% yield under otherwise identical reaction conditions.
In conclusion, by following the design concept of identify-
ing appropriate π-stacking scaffolds capable of soliciting
efficient catalyst–substrate electronic interactions, we report
herein that para-N,N-dimethyl aminobenzoate, when tethered
to various 1,1-disubstituted aliphatic alkenes, serves as an un-
usually efficient auxiliary for inducing high levels of enantio-
control, yielding high-value multi-hydroxylated substances
with stereochemical differentiation that are otherwise difficult
or impossible to access. The protocol established in this
work helped solve chiral induction problems in a challenging
class of alkene substrates and should find uses in organic
synthesis.
Notes and references
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Acknowledgements
We thank the NSFC (grants 20872004, 20972008, and
21290180 to DZW), the national “973 Project” of the State Min-
istry of Science and Technology (grants 2012CB722602 and
2013CB911500 to DZW), the Shenzhen Bureau of Science and
Technology and the Shenzhen “Shuang Bai Project” for finan-
cial support.
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