An enantioselective, intermolecular α-arylation of ester enolates to form tertiary stereocenters

Article abstract of DOI:10.1021/ja2066829

In transition-metal catalyzed, asymmetric α-arylation of carbonyl compounds, formation of tertiary centers with high enantioselectivity is a longstanding problem, due to easy enolization of the monoarylation products. Herein, we report such examples using a palladium catalyst supported by a new, (R)-H₈-BINOL-derived monophosphine. Silyl ketene acetals, together with a weakly basic activator, were used as equivalents of ester anions, and they reacted smoothly with aryl triflates in excellent enantiomeric excess (ee). The usefulness of the reaction was demonstrated in a gram-scale synthesis of (S)-Naproxen in 92% ee.

Full text of DOI:10.1021/ja2066829

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An Enantioselective, Intermolecular α-Arylation of Ester Enolates
To Form Tertiary Stereocenters
Zhiyan Huang, Zheng Liu, and Jianrong (Steve) Zhou*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S Supporting Information
b
α-arylation of ester anions to produce tertiary centers with
high ee.
ABSTRACT: In transition-metal catalyzed, asymmetric
α-arylation of carbonyl compounds, formation of tertiary
centers with high enantioselectivity is a longstanding pro-
blem, due to easy enolization of the monoarylation pro-
ducts. Herein, we report such examples using a palladium
catalyst supported by a new, (R)-H8-BINOL-derived mono-
phosphine. Silyl ketene acetals, together with a weakly basic
activator, were used as equivalents of ester anions, and they
reacted smoothly with aryl triflates in excellent enantiomeric
excess (ee). The usefulness of the reaction was demon-
strated in a gram-scale synthesis of (S)-Naproxen in 92% ee.
hiral α-arylalkanoic acids and derivatives are core structures
C
in many drug molecules. For example, the Profen family of
nonsteroidal anti-inflammatory drugs are all α-arylpropionic
acids, including blockbusters such as Ibuprofen, Naproxen, and
Ketoprofen.1 Their enantiomers are known to display substan-
tially different pharmacological profiles and Naproxen is sold in
its optically pure (S)-form. To achieve convergent and efficient
synthesis, aryl groups are best introduced with concomitant
establishment of chirality. However, asymmetric α-arylation of
esters using either aryl-metal reagents or aryl electrophiles has
met only with limited success. One example was reported by Fu
et al. recently, in which arylsilanes were used as equivalent of
“aryl-metal” reagents.2 They underwent Ni-catalyzed coupling
with racemic α-bromoester to give products containing tertiary
centers in high enantiomeric excess (ee) (eq 1). A more
straightforward disconnection would involve CꢀC bond forma-
tion between aryl halides/sulfonates and enolate anions.3 Suc-
cessful examples of this kind with excellent ee were surprisingly
scarce. In the work by Buchwald and co-workers, aryl chlorides
were used to couple with enolates generated in situ from
γ-butyrolactone and a strong base (eq 2).4 Although a high level
of ee was achieved, the method was limited to the formation of
quaternary stereocenters. In fact, all of metal-catalyzed, enantio-
selective arylations of carbonyl compounds (including ketones,5
aldehydes,6 oxindoles,7 and α-methylacetoacetates8) suffered
from the same limitation.9 The challenge to produce tertiary
centers lies in that the monoarylation products contain more
acidic α-hydrogens than the starting material, and they can be
readily deprotonated under basic conditions. The deprotonation
can eventually lead to racemization and, in some cases, double
arylation. In this communication, we report an efficient
Silyl ketene acetals in combination with activators have been
studied as equivalent of ester anions in diastereoselective
arylations.10 We reason that if the activators are not basic enough
to deprotonate α-arylesters, asymmetric arylation to form ter-
tiary centers is plausible with catalyst control of stereochemistry.
Indeed in our model arylation of 1-naphthyl triflate (eq 3), the use
of LiOAc activator allowed efficient coupling of an O-trimethylsilyl
ketene acetal, which was derived from tert-butyl propionate. In
presence of a palladium catalyst supported by phosphine ligand L6,
90% ee was realized. The reaction was devoid of racemization and
double arylation and the ee of the monoarylation product remained
constant during the course of the reaction. Other activators
such as NaOAc, KOAc, CsOAc and CsF were much less effective
(for details, see Supporting Information).
Among some common palladium complexes, PdMe2(TMEDA)
turned out to be superior in the model reaction. When it was
replaced by Pd(dba)2, the coupling became slower, probably due
to competitive binding of dba to the active catalyst LPd(0).
Inclusion of 0.2 equiv of ZnF2 as coactivator can bring back the
activity and afforded the coupling product in 99% yield and 92%
ee after 24 h at 50 °C (see Supporting Information).
From our extensive screening of chiral ligands, a series of
(R)-H8-BINOL-derived monophosphines L1ꢀ6 emerged to be
most promising (Table 1). Finetuning of the ligand O-alkyl R0
group revealed that 2-naphthylmethyl in L6 was optimal in terms
of both reactivity and stereoinduction (entry 6). Similar (R)-
BINOL-derived ligands L7 and L8 were not as selective
Received: July 18, 2011
Published: September 13, 2011
r
2011 American Chemical Society
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Table 1. Effect of Chiral Phosphine Ligands (Same Condi-
tions as in eq 3)
entry
ligand
yield (%)
ee (%)
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
55
63
37
71
40
99
76
46
62
2
68
81
72
86
85
90
67
70
12
26
3
4
5
6
7
8
9
10
Figure 2. Substrate scope.
Notably, the structure of silyl ketene acteals has a large influence
on the outcome of the asymmetric coupling (Table 2). First, the
size of R groups in the (E)-O-TMS ketene acetals affects the ee
significantly (entries 1ꢀ5). For instance, <10% ee was observed
if R was methyl or ethyl (entries 1ꢀ2), while 90% ee was
achieved when R was t-butyl (entry 4). Second, the geometry
of the O-TMS ketene acetals is very important, to our surprise.
The (E)-isomer afforded 90% ee, while the (Z)-isomer only gave
modest 50% ee (entry 4 versus 6). This result indicates that no
lithium enolate is produced from the silyl ketene acetal and
LiOAc, since geometric isomers of the former can quickly
equilibrate. The result also contradicts with common belief that
after transmetalation, enantiomeric (C)-bound Pd-enolates can
undergo fast equilibration via the (O)-bound form before
reductive elimination.11 Thus, under our condition, equilibration
of (C)-bound enolates is slower than reductive elimination.
Third, the corresponding C-trimethylsilyl enolate did not react
at all. Fourth, the corresponding (E)-O-t-butyldimethylsilyl
ketene acetal was completely unreactive.
Figure 1. Synthesis of ligand L6.
Table 2. Effect of Silyl Ketene Acetals
entry
R
yield (%)
ee (%)
1
2
3
4
5
6
Me
99
99
99
99
99
95
5
5
Et
Cy
67
90
52
50
t-Bu
2-Naph
t-Bua
a (Z)-O-TMS ketene acetal.
The Pd/L6 catalyst can be applied to couplings of various aryl
triflates, as shown in Figure 2. In all cases, full conversion was
achieved with only 2 mol % PdMe2(TMEDA) or Pd(dba)2 and
2.4 mol % ligand L6. In some cases, inclusion of 0.2 equiv of ZnF2
additive was beneficial to reaction rates. Both electron-donating
and -withdrawing groups can be present. These groups can be
(entries 7ꢀ8). KenPhos L9 containing an NMe2 group and
MOP L10 were much less satisfactory (entries 9ꢀ10). All the
ligands can be easily assembled and a typical synthesis of L6 is
shown in Figure 1. Ligands L1ꢀ6 are octahydro analogues of
BINOL-derived ligands used in Buchwald’s previous study.5c
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Judged from the X-ray structure of L6 shown in Figure 4b, the right
side of the ligand is more hindered due to specific orientation of
the P-cyclohexyl group and/or conformational flexibility of the
O-CH2Ar0 group. Thus, the enolate is expected to transfer to Pd
from the left side. Furthermore, (E)- and (Z)-silyl enolates were
shown to give very different ee in the product, indicating that a
cyclic, closed transition state is operating during transmetalation
instead of an open one. In the acetate-bridged transition state, both
(E)-geometry and bulky OR group of the silyl enolate ensure
enolate delivery from its Re face. Transfer from the Si face will
require the OR and methyl groups of the enolate to point toward the
bottom ring of L6, and result in unfavorable steric repulsion. A
similar analysis can be used to understand why (Z)-ketene acetals
gave low ee. Transfer from either face of the (Z)-ketene acetals will
always place one of OR and methyl groups close to the bottom ring.
In summary, we have achieved the first examples of α-arylation
of esters to form tertiary centers with high ee. The combination
of silyl ketene acetals and a mild activator made it possible to
avoid racemization and/or double arylation of the monoarylation
products. The method is applicable to a gram-scale synthesis of
(S)-Naproxen in 92% ee. Extension of the new method to
asymmetric coupling of ketone enolates is ongoing.
Figure 3. A proposed catalytic cycle.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
the synthesis of reactants and chiral phosphine ligands, asym-
metric coupling and characterization of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 4. (a) Transmetalation assembly with ligand L6 colored in blue
and (b) ORTEP of ligand L6.
’ AUTHOR INFORMATION
Corresponding Author
jrzhou@ntu.edu.sg
located on not only para and meta positions of the aromatic rings,
but also the more hindered ortho sites. The condition is
compatible with sensitive functional groups such as nitro, nitrile,
ester and ketone. Two examples of heteroaryl triflates are
included to illustrate the generality of the method. Moreover,
three more examples of silyl ketene acetals with α-alkyl substit-
uents can couple efficiently with high ee.12 It is worth pointing
out that all of the O-TMS ketene acetals (except Y = Bn) can be
easily prepared in good yield and excellent (E):(Z) ratio (99:1).
Following a reported procedure, t-butyl esters were first treated
with LDA at 0 °C in a mixed solvent of cyclohexane/cyclopentyl
methyl ether, followed by TMSCl quenching.13
The reaction can be easily scaled up to produce 1.2 g of
(S)-Naproxen, after acidic hydrolysis of the ester (eq 6). The pro-
duct ee can be improved from 92% to 99% after a simple crystal-
lization. The configuration of the new stereocenter was assigned
to be (S) by comparison with reported optical rotation.14
We propose a catalytic cycle (Figure 3) that starts from
oxidative addition of ArOTf to form cationic LPdAr species.
Binding of acetate anion facilitates the transfer (transmetalation)
of the enolate from silicon to palladium via an acetate-bridged
structure. Subsequent CꢀC reductive elimination directly leads
to the arylation product. Equilibration of the (C)-enolate to its
epimer via the (O)-enolate intermediate is probably much slower
than reductive elimination in this case.
’ ACKNOWLEDGMENT
We thank Singapore National Research Foundation
(NRF-RF2008-10) and Nanyang Technological University for finan-
cial support. We thank Dr. Bo Zhu for help in some experiments.
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