Asymmetric Synthesis of 3,3-Diarylpropanals with Chiral Diene-Rhodium Catalysts

Article abstract of DOI:10.1021/ja053270w

A general route to enantioenriched 3,3-diarylpropanals is presented. These useful building blocks are prepared via an asymmetric rhodium-catalyzed conjugate addition of arylboronic acids to cinnamaldehyde derivatives in the presence of chiral dienes. The

Full text of DOI:10.1021/ja053270w

Published on Web 07/14/2005
Asymmetric Synthesis of 3,3-Diarylpropanals with Chiral Diene-Rhodium Catalysts
Jean-Franc¸ois Paquin, Christian Defieber, Corey R. J. Stephenson, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg, CH-8093 Zu¨rich, Switzerland
Received May 19, 2005; E-mail: carreira@org.chem.ethz.ch
Compounds incorporating diarylmethine stereogenic centers are
found in natural products1 and a number of notable pharmaceuticals,
such as tolterodine and sertraline.2 However, the stereoselective
preparation of building blocks leading to these is challenging,
particularly when little differentiates the two arenes electronically
or sterically. This is especially problematic in cases where the only
differentiation occurs at the para position of the aromatic groups.
The current state of the art for the preparation of nonracemic 3,3-
diarylpropanals is the amine-catalyzed addition of aromatic nu-
cleophiles to 3-substituted acrolein derivatives (74-92% ee).3 While
this approach performs well with electron-rich nucleophiles,
electron-poor aromatics do not furnish 1,4-addition products because
they are insufficiently reactive. The Rh(I)-catalyzed conjugate
addition of arylboronic acids4 offers the promise of a general
solution for the synthesis of this important class of compounds5
and is less sensitive to the electronic nature of the arene nucleophile.
We envisioned that the 1,4-addition to cinnamaldehydes with both
electron-rich and -poor arylboronic acids would provide facile
access to valuable intermediates, such as 3 (eq 1). Herein, we
Figure 1. Possible reaction pathways.
Table 1. Ligand Screening and Reaction Optimization
entry
ligand
solvent
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
6
7
8
9
9
9
dioxane/H2O (10:1)
dioxane/H2O (10:1)
dioxane/H2O (10:1)
dioxane/H2O (10:1)
EtOH/H2O (10:1)
MeOH/H2O (10:1)
MeOH/H2O (10:1)
MeOH/H2O (10:1)
43
45
50
43
68
80
19
33
47
60
83
92
92
92
56
-89
document the asymmetric addition of arylboronic acids to cinna-
maldehyde derivatives to give optically active 3,3-diaryl-substituted
aldehydes. The method is noteworthy on a number of grounds: it
provides access to building blocks that are otherwise not readily
accessible; the process is both chemo- and regioselective wherein
conjugate addition is preferred over 1,2-addition, and in doing so,
expands the use of chiral dienes as ligands for transition metals.6
The use of chiral dienes as ligands has recently been applied to
the asymmetric conjugate addition of arylboronic acids to a selection
of electron-poor olefins.7,8 This follows in the footsteps of the
excellent work involving conjugate addition reactions of boronic
acids to unsaturated esters, ketones, and lactones using Rh(I)-
phosphine complexes.4 The general, reliable conjugate addition to
unsaturated aldehydes is notably absent from this listing. In fact,
there have been only two reports of additions of arylboronic acids
to unsaturated aldehydes by Miyaura; however, the products are
either achiral9 or obtained in modest yield (3-alkyl-3-arylpropanal).10
In contrast, the Rh(I)-catalyzed 1,2-addition of arylboronic acids
to aldehydes to give benzylic alcohols has been studied exten-
sively.9,11,12 This precedence indicates that a serious complication
could arise in developing a general conjugate addition reaction to
unsaturated aldehydes (Figure 1). Any effort could be thwarted by
1,2-addition either in competition with 1,4-addition (a vs b) or after
the formation of 3 (a then c) to give 5.
phosphoramiditec
(R)-BINAP
a Isolated yield after chromatography on SiO2. b Determined by chiral
HPLC after reduction of the aldehyde (see SI for details). c O,O′-(R)-(1,1′-
Dinaphthyl-2,2′-diyl)-N,N-di-i-propylphosphoramidite.
isolated in 43% yield and 47% ee along with <5% of the product
resulting from 1,2-addition (path b) (Table 1, entry 1). A modest
increase to 60% ee was observed with Bn-substituted ligand 7 (entry
2). When phenyl was replaced with isobutyl, a significant ampli-
fication in the enantioselectivity to 83% ee was observed with ligand
8 (entry 3). The use of ligand 9,13 a hybrid of 7 and 8, afforded the
desired product in 92% ee. In each case (entries 1-4), we were
able to recover approximately 10% of cinnamaldehyde along with
20-25% of the corresponding double addition product (a then c).
This observation is consistent with the greater propensity of the
system to undergo conjugate addition than 1,2-addition. It also
provided us with further impetus to study the reaction with the aim
of precluding 1,2-addition to 10.
In further investigations to optimize yield which had at this point
been in the range of 43-50%, we observed that the use of alcohol
solvents had a dramatic influence on the outcome of the reaction.
Thus, in a mixture of 10:1 MeOH/H2O when the reaction was
conducted with ligand 9, the desired aldehyde 10 could be isolated
in 80% yield and 92% ee (entry 6).14 It is worthy of note that
phosphorus-based ligands such as a phosphoramidite15 and BINAP
The addition of 4-methoxybenzeneboronic acid to cinnamalde-
hyde was used as a test reaction to optimize enantioselectivity via
systematic variation of the pseudo-C2 symmetric ligand scaffold
(Table 1).7a In the presence of the parent ligand 6, adduct 10 was
9
10850
J. AM. CHEM. SOC. 2005, 127, 10850-10851
10.1021/ja053270w CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Conjugate Addition Reactions Catalyzed by Rh(I)‚9
90% yield and 89-93% ee from readily available arylboronic acids
and substituted cinnamaldehydes. The successful fine-tuning of the
enantioselectivity in this process was made possible by our modular
synthesis of bicyclo[2.2.2]octadiene ligands beginning with natural
carvone. In addition, this approach offers a tactical advantage over
existing methodology in that electron-poor nucleophiles function
with efficiency equal to that of their electron-rich counterparts. In
a broader sense, the study demonstrates the ability to tune reaction
parameters such as chemo- (unsaturated versus saturated aldehyde)
and regioselectivity (1,4 versus 1,2) by diene ligands in conjunction
with reaction media, which may have additional wide applications
in other processes involving this novel class of catalysts.
Acknowledgment. This research is supported by a Swiss
National Science Foundation Grant and by the ETHZ. J.-F.P. is
grateful to the National Sciences and Engineering Research Council
of Canada (NSERC) for a postdoctoral fellowship.
Supporting Information Available: General experimental proce-
dures, specific details for representative reactions, and isolation and
spectroscopic information for the new compounds prepared. This
material is available free of charge via the Internet at http://pubs.acs.org.
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a Isolated yield after chromatography on SiO2. b Determined by chiral
HPLC after reduction of the aldehyde. c The absolute configuration was
assigned by correlation to earlier work with related acceptors. In entry 9,
the adduct of conjugate addition was converted to the known TBDMS
O-silyl ether3 of the corresponding primary alcohol, accessed by reduction
of the aldehyde (NaBH4) and silylation (TBDMSCl) (see SI for details).
d Rxn t (time) ) 2 h. e Rxn t ) 22 h. f Rxn t ) 2.5 h. g Rxn t ) 4 h.
furnished adduct 10 in 19% yield/56% ee and 33% yield/89% ee,
respectively.
While examining the scope of this transformation, the addition
of both electron-rich (entry 1) as well as electron-poor boronic acids
(Table 2, entries 2-6) proceeded smoothly with various enals in
63-90% yield with insignificant variation in the enantioselectivity
(89-93% ee). Both enantiomers of a given building block can be
obtained by varying the donor and acceptor (cf. Table 2, entries 1
and 7, and entries 2 and 8) for a single enantiomer of the ligand.
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subsequently in the diversity-oriented synthesis of pharmaceutically
interesting libraries.
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In summary, the application of Rh(I)-diene complexes provides
access to valuable, optically enriched 3,3-diarylpropanals in 63-
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J. AM. CHEM. SOC. VOL. 127, NO. 31, 2005 10851