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Angewandte
Communications
Herein we report the results of a mass spectrometric study
of this reaction, which clearly shows that the catalytic cycle
proceeds via an enamine intermediate. Moreover, we dem-
onstrate for peptidic catalysts of type 1, bearing a proton
Both 2 and ent-2’ were obtained with the same enantiomeric
excess of 97% using the catalyst 1a and its enantiomer,
respectively, thus confirming that the mass labels do not affect
the stereoselectivity of the reaction.
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donor on the side chain, that C C bond formation between
In the ESI-MS screening of the back reaction, starting
from an equimolar mixture of 2 and ent-2’, we monitored the
signals of the two mass-spectrometrically distinguishable
enamines En and En’ which were formed upon reaction
with 1a.[14] The En/En’ ratio, determined from the relative
signal intensities, is equivalent to the ratio of the rates by
which 2 and ent-2’ are converted into the corresponding
enamines En and En’ via the iminium ions Im and Im’
(Scheme 3). If the reaction of the enamine with the nitroolefin
is rate-determining in the forward reaction, the stereoselec-
tivity 2/ent-2’ (= k1/k2) is determined by the energy difference
DDG° of the transition states of this step leading to Im and
Im’. In this case, according to the principle of microscopic
reversibility, the same transition states would also control the
stereoselectivity of the back reaction, which is characterized
by a pre-equilibrium between Im and Im’ and a slow rate-
the enamine and the nitroolefin is the stereoselectivity-
determining step, whereas with catalysts lacking an acidic
group the stereoselectivity is determined in a different step.
ESI-MS back-reaction screening using equimolar mix-
tures of mass-labeled quasienantiomeric substrates is a val-
uable tool for the rapid determination of the enantioselectiv-
ity of chiral catalysts and catalyst mixtures.[12] In contrast to
ESI-MS-based mechanistic investigations that solely rely on
the detection of reaction intermediates,[5,13] this methodology
also provides information on the enantioselectivity-determin-
ing step and the intermediates involved therein. It has been
successfully used for screening a variety of reactions including
palladium-catalyzed allylic substitutions,[12a–e] metal- and
organocatalyzed Diels–Alder reactions,[12e,f] and Michael
additions.[12g]
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We envisioned this method to be ideally suited to examine
whether conjugate addition reactions between aldehydes and
nitroolefins proceed via an enamine intermediate and
determining C C bond cleavage (Curtin–Hammett condi-
tions). Thus, the En/En’ ratio measured in the back reaction
by ESI-MS should be identical to the stereoselectivity
determined for the preparative reaction in the forward
direction.
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whether the C C bond-forming reaction between this puta-
tive enamine and the nitroolefin is the stereoselectivity-
determining step. For the back-reaction screening we
required a pair of mass-labeled quasienantiomeric conjugate
addition products (Scheme 3). Thus, we prepared the sub-
strates (2S,3R)-2 and (2R,3S)-2’ (ent-2’) bearing an ethyl and
a methyl label, respectively, in the para-position of the phenyl
ring derived from the aldehyde used in the forward reaction.
Accordingly, a close match between the enantiomeric
ratios in the forward reaction and En/En’ measured for the
back reaction would provide strong evidence for the involve-
ment of an enamine and not an enol in the stereoselectivity-
determining step. In contrast, a En/En’ ratio that deviates
from the stereoselectivity of the preparative reaction would
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not rule out an enamine mechanism but show that C C bond
formation is not the stereoselectivity-determining step.
We started our investigations by reacting an equimolar
mixture of the two quasienantiomeric substrates 2 and ent-2’
with 1a in the protic solvent mixture CHCl3/iPrOH as well as
the aprotic solvent DMSO, and analyzed the reaction mixture
by ESI-MS.[15] CHCl3/iPrOH was chosen since it had been
found in previous experiments to provide optimum stereose-
lectivity and reactivity. DMSO was used since enamines are
known to be significantly more stable in aprotic compared to
protic solvents.[4d,e,16] In addition, the enantioselectivity of 1a
is significantly lower in DMSO (46% ee) compared to that in
CHCl3/iPrOH (97% ee). Thus, the signal corresponding to the
minor enantiomer of the putative enamines 1a-En and 1a-En’
was expected to be more easily detectable in DMSO. In both
solvents intense ESI-MS signals corresponding to the iminium
ions 1a-Im and 1a-Im’ were readily observed (Figure 1a, and
see the Supporting Information). Whereas in the protic
solvent CHCl3/iPrOH the only other visible signals corre-
sponded to the catalyst (see the Supporting Information),
signals corresponding to the enamines 1a-En and 1a-En’ were
clearly identified in DMSO (Figure 1a).[17] The relative
intensities of these signals were 73:27, a ratio which correlates
perfectly with the enantiomeric ratio observed for the
preparative forward reaction. Thus, the intrinsic selectivity
of the attack of the enamine onto the nitroolefin determined
by ESI-MS matches the stereoselectivity of the preparative
reaction.
Scheme 3. Concept of the back-reaction ESI-MS screening using mass-
labeled quasienantiomeric conjugate addition products.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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