COMMUNICATION
Enantioselective construction of stereogenic quaternary centres via
Rh-catalyzed asymmetric addition of alkenylboronic acids to
a,b-unsaturated pyridylsulfones{
Pablo Mauleo´n and Juan C. Carretero*
Received (in Cambridge, UK) 14th June 2005, Accepted 5th August 2005
First published as an Advance Article on the web 8th September 2005
DOI: 10.1039/b508142d
hindered nucleophile, such as alkenylboronic acids, the sluggish
character of trisubstituted substrates could be overcome.
The highly enantioselective construction of all-carbon quater-
nary stereogenic centres via Rh-catalyzed Chiraphos-mediated
conjugate addition of alkenylboronic acids to b,b-disubstituted
a,b-unsaturated 2-pyridylsulfones is described.
To test this hypothesis the vinyl sulfones 1a,b were readily
prepared in satisfactory overall yields by addition of the carbanion
of pyridyl methyl sulfone to the corresponding acetophenone and
further stereoselective dehydration (Scheme 1).
Although much progress has been achieved in recent years, the
highly efficient enantioselective formation of all-carbon quaternary
stereogenic centres by asymmetric catalytic methods remains a
great challenge in organic synthesis.1,2 Considering the broad scope
and excellent enantioselectivities described in the last decade in the
construction of tertiary stereogenic carbon centres by catalytic
asymmetric conjugate addition (ACA) reactions to a,b-unsatu-
rated carbonyls and related compounds,3 a seemingly straight-
forward alternative to the enantioselective formation of
quaternary stereogenic centers would be the catalytic ACA to
b,b-disubstituted Michael acceptors. However, this approach
must overcome a serious difficulty: the well-known reluctance of
these substituted Michael substrates to undergo intermolecular
conjugate addition due to steric reasons.
Unlike the behaviour of disubstituted 2-pyridylsulfones, no
reaction or very low conversions (, 20%) were observed after
treatment of the trisubstituted alkene 1a with p-fluorophenyl-
boronic acid in the presence of Rh(acac)(C2H4)2 as catalyst and a
variety of chiral ligands in dioxane–H2O at 100 uC.7 However,
to our delight, a smooth and clean reaction was observed
when (E)-styrylboronic acid was used as nucleophile and
(S,S)-Chiraphos as ligand (5 mol%), reaching 65% conversion
after 24 h and providing the addition product 2a in 94% ee
(HPLC, Daicel Chiralcel OD column). At that point, we
confirmed that both the pyridylsulfonyl group and Chiraphos
ligand were essential to the success of the conjugate addition. For
instance, no reaction at all occurred either after treatment of 1a
with styrylboronic acid in the presence of Binap as ligand or after
heating the phenylsulfone analogue of 1a with styrylboronic acid
under the same Rh(acac)(C2H4)2/Chiraphos mediated reaction
conditions, suggesting the participation of a key Rh-chelation
effect in the case of the pyridylsulfone substrate.
In fact, only very recently, in 2005, the first two catalytic
enantioselective procedures based on this type of ACA process
have been described, both involving Cu-mediated reactions. Thus,
Hoveyda et al. have described the highly enantioselective addition
of dialkylzinc reagents to b-aryl b-alkyl nitroalkenes,4 while
Alexakis et al. have reported the highly enantioselective addition
of trialkylalanes to trialkyl-substituted cyclohexenones.5 These
very recent publications have prompted us to report our
concomitant results in this arena. In particular, we describe herein
that the Rh-catalyzed Chiraphos-mediated addition of alkenyl-
boronic acids to b-aryl b-alkyl substituted vinyl pyridylsulfones
takes place with very high enantioselectivity (88–. 99% ee). In
addition, the versatile reactivity of the sulfonyl group offers wide
possibilities for its further transformation into a variety of carbon
functional groups having a close quaternary stereocenter.
We next briefly studied the scope of this enantioselective
conjugate addition by using some commercially available alkenyl-
boronic acids. The results obtained are shown in Table 1.
All the reactions were performed under the same conditions:
Rh(acac)(C2H4)2 (5 mol%), (S,S)-Chiraphos (5 mol%), a mixture
of dioxane : H2O (10 : 1), and 100 uC for 24 h.{ Conversions
between 45 and 77% were observed in all cases. Unfortunately, the
use of a great excess of boronic acid or longer reaction times
provided similar results, most likely due to the progressive
decomposition of the catalyst in the harsh reaction conditions.8
However, as the process occurs without formation of side
products, both the remaining vinyl pyridylsulfone and the final
conjugate addition product can be readily separated by standard
As a starting point, taking into account our previous results on
the Rh-catalyzed addition of arylboronic acids to differently
substituted vinyl sulfones,6 we reasoned that using the combination
of the potentially rhodium coordinating 2-pyridylsulfonyl group at
the Michael acceptor (chelation-assisted effect) and a sterically low
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad
Auto´noma de Madrid, Cantoblanco 28049 Madrid, Spain.
E-mail: juancarlos.carretero@uam.es; Fax: 91 497 3966; Tel: 91 497 3925
{ Electronic supplementary information (ESI) available: experimental
details and spectral data for new compounds, and X-ray data for
Scheme 1 Synthesis of b-aryl b-alkyl pyridylsulfones.
Chem. Commun., 2005, 4961–4963 | 4961
This journal is ß The Royal Society of Chemistry 2005