DOI: 10.1002/asia.200900331
Enantioselective Protonation of Itaconimides with Thiols and the Rotational
À
Kinetics of the Axially Chiral C N Bond
Shishi Lin, Dasheng Leow, Kuo-Wei Huang, and Choon-Hong Tan*[a]
Abstract: Bicyclic guanidines are able to catalyze the protonation reactions of 2-
phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The
protonation reaction of itaconimides with secondary phosphine oxides is also
known. Herein, the tandem conjugate addition–enantioselective protonation of N-
substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is inves-
Keywords: asymmetric catalysis ·
atropisomerism · guanidines · orga-
nocatalysis · protonation
À
tigated. The rotational barrier of the C N axis of N-2-tert-butyl phenylitaconimide
is also studied, both experimentally and computationally.
Introduction
of organocatalysis in enantioselective or diastereoselective
protonation reactions.[10]
À
The C S bond formation reaction is an important process in
synthetic chemistry.[1] Sulfur-containing natural amino acids
such as cysteine and methionine are found in many biologi-
cally active compounds and modified proteins.[2] Many chiral
sulfur-containing compounds have become useful as li-
gands,[3] organocatalysts,[4] and chiral reagents or auxilia-
ries.[5] A common approach for the preparation of optically
active sulfide is through the conjugate addition of thiols to
activated alkenes.[6] Although many enantioselective var-
iants have been developed, the majority of them result in
the chiral center being created at the b-position of an elec-
tron withdrawing group.[7]
Chiral guanidines have emerged as a class of powerful
and versatile asymmetric catalysts[11] by acting as strong
Brønsted bases. The use of this class of catalyst has been de-
veloped by several groups.[12] We have reported that chiral
bicyclic guanidines are excellent catalysts for Diels–Alder,
Michael, and alkyne isomerization reactions.[13] The ability
of a guanidine catalyst to participate in the dual hydrogen-
bonding mode of activation was also demonstrated.[13g–h] Re-
cently, we found that bicyclic guanidine 1 can catalyze the
protonation reactions of 2-phthalimidoacrylates with thiols
in excellent yields and enantioselectivities.[10c] In addition,
the protonation reactions of itaconimides with secondary
phosphine oxides was also reported (Scheme 1). N-substitut-
Sulfides bearing an a-carbonyl stereogenic center are
harder to access. A simple and direct strategy is through the
enantioselective protonation of an enolate, which is generat-
ed itaconimides provide
a useful 1,4-dicarbonyl motif.
Herein, we would like to expand the scope of the enantiose-
lective protonation of itaconimides to include thiols as
donors. These cyclic imides are capable of forming the tran-
sient Z enolates exclusively and should lead to high enantio-
selectivities.
Previously, we found that the positioning and electronic
properties of the substituents on the N-phenyl ring were cru-
cial in deciding the enantioselectivity and reactivity of the
reaction with secondary phosphine oxides. Thus, we pre-
pared various N-substituted itaconimides 3a–f (Table 1) and
subjected them to the protonation reaction using tert-butyl
thiol 2a as Michael donor. With the N-phenyl itaconamide
3a, an adduct was obtained with 62% ee (entry 1). Introduc-
tion of methyl groups at the 2, 4, and 6-positions witnessed
an increase in the ee value to 71% as well as an enhance-
ment in the reactivity (entry 2). Next we varied the electron-
ed from the conjugate addition with thiol nucleophiles.[8]
A
key issue to consider for this reaction is the control of the E
or Z enolate selectivity, as they will exhibit different enan-
tiofacial preferences. Metal-based catalysts have been tradi-
tionally employed in enantioselective protonation reac-
tions.[9] Recent research witnesses an increasing application
[a] S. Lin,+ D. Leow,+ Prof. Dr. K.-W. Huang, Prof. Dr. C.-H. Tan
Department of Chemistry
National University of Singapore (NUS)
3 Science Drive 3 (Singapore)
Fax : (+65)6779-1691
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
Chem. Asian J. 2009, 4, 1741 – 1744
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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