Possible origin of electronic effects in Rh(I)-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1021/ja903089f

(Chemical Equation Presented) Reducing the electron density of ligands switches the regioselectivity of Rh(I)-catalyzed hydrometalation. A reversal of the sense of chiral induction was also observed when chiral ligands are electronically tuned in the same

Full text of DOI:10.1021/ja903089f

Published on Web 06/25/2009
Possible Origin of Electronic Effects in Rh(I)-Catalyzed Enantioselective
Hydrogenation
Hai-Chen Wu,† Shafida Abd Hamid,† Jin-Quan Yu,*,†,‡ and Jonathan B. Spencer†
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge, U. K. CB2 1EW, and Department
of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received September 23, 2008; E-mail: yu200@scripps.edu
Enantioselective hydrogenation of olefins is one of the most reliable
and practical asymmetric methods for introducing chiral centers,1 yet
synthetic chemists are often puzzled by poor enantioselectivity obtained
with a particular substrate. Notably, asymmetric hydrogenation of
olefins lacking attached chelating groups had remained an unsolved
problem until recent remarkable progress reported by Pfaltz.2 Evidently,
further efforts are needed to understand how chiral induction occurs
in asymmetric hydrogenation to provide guidance in designing more
general and effective catalysts.3
Figure 1. Electronic effects observed by RajanBabu and Ayers.
The isolation of the first metal-alkyl intermediates of the hydro-
metalation step by Halpern and Brown paved the way for mechanistic
investigation into asymmetric hydrogenation.4 Halpern’s kinetic studies
with MAC3a showed that oxidative addition of H2 onto the diastere-
omeric olefin-bound Rh(I) catalysts is the rate-determining and
enantioselection step; the isolation of the dihydride intermediate by a
parahydrogen-induced polarization (PHIP) technique,5 as well as a
theoretical study,5b however, suggest the hydrometalation step could
also be the rate-determining step that affects the chiral induction. To
date, rationalization of chiral induction and design of improved chiral
ligands for hydrogenation are often based on steric arguments. On the
other hand, electronic effects with respect to both substrates and ligands
are less thoroughly understood. The most unambiguous evidence of
electronic effects in asymmetric hydrogenation was obtained by
RajanBabu and Ayers by investigating Rh(I) catalyzed hydrogenation
of the extensively studied substrates dehydroamino acids.6,7 In this
case, a drastic decrease of ee was observed when electron-deficient
ligands were employed (Figure 1). The origin of this effect is attributed
to the alteration of the relative rates of oxidative addition of H2 to the
diastereomeric L2Rh(I)-olefin complexes.
Herein we disclose our findings in support of a new model
rationalizing the electronic effects in enantioselective hydrogenation:
electronic properties of the catalysts and substrates affect the regiose-
lectivity of hydrometalation and hence the enantioselectivity. This
model, in conjunction with Knowles’ “four quadrant steric analysis”1a
for the asymmetric reduction of a pro-chiral alkene, explains how
electronic effects could determine to which face of the olefin the metal
hydride adds. Since the chiral ligands are attached to the metal, we
argue that the switch in the regioselectivity of hydrometalation from
pathway A to B will position the chiral ligand at the different end of
the double bond, which will inevitably affect enantioselection of the
re-face and si-face of the olefins based on Knowles’ four quadrant
model (Figure 2). Importantly, if the sense of chiral induction in path
A and B are opposite, their simultaneous participation in the same
reaction could result in erosion of enantioselectivity. This is also
consistent with the high enantioselectivity often obtained with func-
tionalized substrates where regioselective hydrometalation assisted by
σ-chelation is made possible.4,7
Figure 2. Effects of regioselectivity on enantioselection.
As the first key step to verify this model, we sought to determine
how electronic properties of catalysts influence the regioselectivity of
the hydrometalation step. A convenient method for determining
regioselectivity of hydrometalation has been previously developed by
Spencer using the location of deuterium incorporation into cis-ꢀ-
methoxystyrene 1 as a reporter (Table 1; for the measurement and
calculation of D-incorporation see SI).8 Notably, other deuterium
labeling strategies have been widely used in hydrogenation.9 Our
experimental efforts began with the preparation of catalysts with
systematically tuned electronic properties following a literature pro-
cedure10 (Table 1). Remarkably, deuteration of cis-ꢀ-methoxystyrene
1 using these catalysts under 1 atm of D2 showed, for the first time,
that reduction of the electronic density of the ligands can switch the
regioselectivity of hydrometalation from mode a to mode b (Table 1)
consistently.
This result encouraged us to electronically tune the most broadly
used BINAP ligands1b in the same manner and test how this could
influence the enantioselectivity. Based on analysis depicted in Figure
2, we anticipate a drastic change in ee values including a possible
switch of the sense of chiral induction by tuning the electronic
properties of BINAP ligands. Thus a range of ligands with different
electronic properties are prepared using methods developed in our
laboratory (Table 2).11
The most extensively studied substrate dehydrocinnamic acid 3 and
its derivatives were selected for the investigation. The enantioselectivity
of asymmetric hydrogenation of substrates 3 and 4 suffered a drastic
drop from 88% and 90% ee (Table 2, entries 1, 2) to 45% and 13%
ee, respectively, when electron-deficient catalyst 2c was used (entries
9, 10). Following the trend of regioselectivity observed in Table 1, a
† University of Cambridge.
‡ The Scripps Research Institute.
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9604 J. AM. CHEM. SOC. 2009, 131, 9604–9605
10.1021/ja903089f CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Electronic Effects on the Regioselectivity of
that in mode a; therefore, the operation of mode a and mode b
simultaneously will decrease ee.
Hydrometalationa
Further experiments are carried out to to gain insights into the sense
of chiral induction in the mode b pathway. According to our previous
studies, electron-donating groups attached to the aryl rings of substrates
further enhance mode b hydrometalation as a result of the polarity of
the double bonds.8 If mode b hydrometalation can be further promoted
to operate as a predominant pathway by using these types of substrates,
the sense of chiral induction of mode b can then be revealed. As
anticipated, the hydrogenation of 5 and 6 using electron-deficient
catalyst 2c afforded enantioselectivity in favor of (R)-configuration,
suggesting a reversal of the sense of chiral induction. The relatively
low ee is most likely due to the simultaneous operation of the mode
a pathway giving the opposite chiral induction. While we cannot rule
out the possibility that the weakened coordination of catalyst 2c could
lead to background reaction7 and result in the decrease of ee, the
reversed sense of chiral induction is more consistent with our
mechanistic model. At this stage, these analyses are not conclusive
partially due to the lack of experimental tools to determine regiose-
lectivity and enantioselectivity using the same set of olefin substrates
and chiral ligands.
In summary, we have shown that the electronic density of Wilkin-
son-type catalysts strongly influences the regioselectivity of the
hydrometalation step. Tuning electronic properties of BINAP type
chiral ligands in asymmetric hydrogenation result in a drastic decrease
or even reversal in chiral induction. These two observations, being
consistent with each other, point to a new direction to seek the origin
of electronic effects in asymmetric hydrogenation.
a Reaction conditions: (Ar3P)3RhCl (0.025 mmol), cis-ꢀ-methoxystyrene
(0.5 mol), 1 atm of D2, in benzene at 24 °C, 0.5-5 h.
Table 2. Reversing the Enantioselectivity via Electronic Tuning
Acknowledgment. We thank GlaxoSmithKline and Cambridge
Overseas Trust (to H.-C.W.) and Cambridge Commonwealth Trust
and Universiti Sains Malaysia for studentships (to S.A.H.). This
manuscript is written in memory of our mentor J. B. Spencer who
passed away on April 6, 2008.
Supporting Information Available: Experimental procedure and
characterization of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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shift of the hydrometalation regioselectivity from predominantly mode
a to a mixture of mode a and mode b is expected. This shift could
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the chiral induction in mode b is less effective based on a steric
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