Stereodivergent α-allylation of linear aldehydes with dual iridium and amine catalysis

Article abstract of DOI:10.1021/ja5003247

We describe the fully stereodivergent, dual catalytic α-allylation of linear aldehydes. The reaction proceeds via direct iridium-catalyzed substitution of racemic allylic alcohols with enamines generated in situ. The use of an Ir(P,olefin) complex and a diarylsilyl prolinol ether as catalysts in the presence of dimethylhydrogen phosphate as the promoter proved to be crucial for achieving high enantio- and diastereoselectivity (>99% ee, up to >20:1 dr). The utility of the method is demonstrated in a concise enantioselective synthesis of the antidepressant (-)-paroxetine.

Full text of DOI:10.1021/ja5003247

Communication
pubs.acs.org/JACS
Stereodivergent α‑Allylation of Linear Aldehydes with Dual Iridium
and Amine Catalysis
Simon Krautwald, Michael A. Schafroth, David Sarlah, and Erick M. Carreira*
Eidgenossische Technische Hochschule Zurich, 8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
starting materials and under identical conditions simply by the
use of the four available catalyst permutations in a pairwise
fashion (Scheme 1b). The utility of the method is showcased in a
concise synthesis of the antidepressant (−)-paroxetine.
ABSTRACT: We describe the fully stereodivergent, dual
catalytic α-allylation of linear aldehydes. The reaction
proceeds via direct iridium-catalyzed substitution of
racemic allylic alcohols with enamines generated in situ.
The use of an Ir(P,olefin) complex and a diarylsilyl
prolinol ether as catalysts in the presence of dimethylhy-
drogen phosphate as the promoter proved to be crucial for
achieving high enantio- and diastereoselectivity (>99% ee,
up to >20:1 dr). The utility of the method is demonstrated
in a concise enantioselective synthesis of the antidepres-
sant (−)-paroxetine.
Since the initial report by Tsuji on the Pd-catalyzed reaction of
allyl acetates with stoichiometric amounts of enamines,5 the
method has been developed further to provide enantioselectively
allylated ketones and aldehydes.6 In addition, there are a number
of reports describing transition metal catalyzed enantioselective
intermolecular allylation of linear aldehydes that are also catalytic
in amine.7,8 However, these methods exert control over just one
stereogenic center. By contrast, catalytic enantio- and diaster-
eoselective methods providing access to γ,δ-unsaturated carbon-
yls in a single step with control of configuration of two vicinal
stereogenic centers are rare and limited to variants of the
asymmetric Claisen rearrangement.9
espite impressive advances in the field of asymmetric
D
synthesis,1 the development of processes that enable at will
the generation of any stereoisomer of a molecule bearing
multiple stereogenic centers remains a challenge.2 We recently
introduced the concept of stereodivergent dual catalysis, which
entails the simultaneous use of two distinct chiral catalysts to
furnish products with full control over the configuration of two
stereogenic centers (Scheme 1a).3 The concept was successfully
A notable difficulty associated with the stereoselective α-
functionalization of linear aldehydes is that the products bear an
enolizable stereogenic center, rendering them prone to
epimerization (Scheme 2). This is especially the case for adducts
Scheme 2. Antecedents and Challenges in Reaction
Development for Stereodivergent Dual Catalysis
Scheme 1. Stereodivergent Dual Catalytic Allylation of Linear
Aldehydes
generated under the reaction conditions developed to date in the
context of stereodivergent, dual catalytic allylations for which
acidic promoters and amine catalysts are prescribed.3 Our earlier
report involving the allylation of branched aldehydes circum-
vented this critical stereochemical issue because products were
generated incorporating Cα quaternary stereocenters (Scheme
2). Additionally, the more hindered starting materials and
products are considerably less prone to participate in side
reactions, such as self-condensation, which take place at the
expense of product yield. Filling this gap in the method was
deemed important toward the development of fully stereo-
divergent allylation reactions of linear aldehydes. More
applied in the α-allylation of branched aldehydes catalyzed by a
chiral Ir(P,olefin) complex and a chiral cinchona-alkaloid derived
primary amine.4 Herein, we report the development of enantio-
and diastereodivergent α-allylation of linear aldehydes, which
considerably expands the implementation of stereodivergent
dual catalysis conceptually and preparatively. The full comple-
ment of product stereoisomers is prepared from the same set of
Received: January 12, 2014
Published: February 9, 2014
© 2014 American Chemical Society
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significantly, it would underline and expand the generality of
stereodivergent dual catalysis as a concept. In addition, the
allylation of unbranched aldehydes would constitute an enantio-
and diastereodivergent equivalent to the venerable Ireland−
Claisen rearrangement in which independent control of two
stereogenic centers can be effected by the selection of enolate
geometry (E versus Z) and alcohol configuration.
dropped to 2:1 (entry 5). The use of dimethylhydrogen
phosphate (pKa = 1.29 in H2O), by contrast, gave 3a in 90%
1
yield by H NMR analysis (85% isolated yield), >99% ee, and
20:1 dr (entry 6).14 Although the reaction was complete after 6 h,
it is noteworthy that when it is stirred for an additional 12 h only a
modest drop in diastereoselectivity to 14:1 is observed. This
indicates that epimerization under these conditions post C−C
bond formation is slow relative to the time scale of the reaction.
This is significant because at the outset of our studies when
stronger acids, such as p-TsOH (pKa = −2.8 in H2O) or TFA
(pKa = 0.23 in H2O), were employed we observed substantial
epimerization at Cα following C−C bond formation. Additional
investigations revealed that the anti diastereomer of 3a could be
produced in good yield and stereoselectivity (>99% ee, 7:1 dr) by
employing the enantiomeric amine catalyst (R)-A (entry 7). This
switch in the sense of diastereoselectivity indicates that the two
chiral catalysts are capable of independent control over the
configuration of the two stereocenters, the defining feature of
stereodivergent, dual catalysis. A number of other amine catalysts
were also employed in the presence of dimethylhydrogen
phosphate as the promoter but gave inferior results in terms of
diastereoselectivity (entries 8 and 9) and the extent of the
diastereochemical switch (see Supporting Information (SI) for
details).
In line with our earlier studies, initial experiments were focused
on intercepting reactive π-allyliridium intermediates10−12 with
enamines derived from Cα monosubstituted acetaldehydes. In
contrast to the work involving branched aldehydes, which
necessitated the use of a primary amine organocatalyst, we
examined the use of secondary amines such as (S)-A (Scheme 1),
which has been shown to enable the highly enantioselective α-
functionalization of aldehydes via enamine catalysis.13 In the
initial prospecting experiments, the reaction of phenyl vinyl
carbinol 1a and hexanal 2a in the presence of acetic acid as the
promoter along with (S)-A and [Ir/(R)-L] as catalysts afforded
1
the desired product 3a in 26% H NMR yield and >20:1 dr
(Table 1, entry 1). The use of benzoic acid improved the
a
Table 1. Variation of Reaction Parameters
With a suitable set of conditions in hand, we went on to
establish that all four stereoisomers of γ,δ-unsaturated aldehyde
3a can be prepared (Scheme 3). From the same set of starting
Scheme 3. Synthesis of All Stereoisomers of 3a
a
Reactions run on 0.25 mmol scale under the standard conditions (see
b
1
SI). dr determined by H NMR analysis of crude reaction mixture.
c
ee of the corresponding primary alcohol determined by SFC on a
materials 1a and 2a and under identical reaction conditions, all
four products are obtained in good yields, excellent enantiose-
lectivity (>99% ee), and good diastereoselectivity (7:1 to 20:1
dr) by simply selecting from the various pairwise catalyst
combinations.
We then set out to explore the scope of the α-allylation with
regard to the allylic alcohol component (Table 2). A range of
allylic alcohols substituted with arenes bearing alkyl and electron-
donating substituents furnish products (3b−3d) in good yields,
7:1 to >20:1 dr, and >99% ee. In addition, an allylic alcohol
incorporating a thiophene (3e) proved to be a good substrate for
the reaction. Allylic alcohols incorporating arenes with halogen
or electron-withdrawing substituents also participated in the
reaction, but they required the use of a stronger promoter such as
trichloroacetic acid (3f and 3g) to give good yields.15
chiral stationary phase; for entries 1−3, ee not determined; for entries
4−9, ee >99%; absolute configuration determination described in SI.
d
Yields determined by 1H NMR with 1,4-(NO2)2C6H4 as internal
e
standard. 50 mol %.
outcome only slightly (entry 2). In both cases, the reactions did
not go to completion and were plagued by self-aldol
condensation of the aldehyde starting material.
Stronger acids such as p-toluenesulfonic acid led to product
formation, albeit with a drop in diastereoselectivity and equally
poor yield due to further reactions of the product (entry 3). The
use of dibutylhydrogen phosphate gave the desired product with
good stereoselectivity (>99% ee, 13:1 dr) but in low yield (25%).
Careful analysis of the reaction mixture revealed that no aldol
byproduct had been formed (entry 4). Consequently, we turned
our attention to the use of phosphoric acid diesters as
coactivators. While diphenylhydrogen phosphate gave clean
and full conversion to the desired product, the observed dr
We then turned our attention to investigating the scope of the
reaction with regard to the aldehyde component (Table 3). A
range of unfunctionalized linear aldehydes give the desired
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a b c
, ,
a
Table 2. Allylic Alcohol Scope of the Allylation
Scheme 4. Concise Synthesis of (−)-Paroxetine
a
Reagents and conditions: (a) 3 mol % [Ir(cod)Cl]2, 12 mol % (S)-L,
10 mol % (S)-A, 50 mol % Cl3CCO2H, DCE, rt, 16 h, 64%, >99% ee,
6:1 dr. (b) NaBH4, CH2Cl2/MeOH (2/1), −78 °C, 20 min, 73%
(single diastereomer). (c) DEAD, PPh3, sesamol, THF/toluene (6/1),
reflux, 10 h, 74%. (d) 9-BBN, THF, rt, 2 h; then NaBO3, 1 h, 67%. (e)
N2H4·H2O, EtOH, reflux, 30 min, 79%. (f) PPh3, DIAD, 0 °C to rt, 2.5
h, 71%. (g) 3 mol % [Ir(cod)Cl]2, 12 mol % (S)-L, 10 mol % (R)-A,
50 mol % Cl3CCO2H, DCE, rt, 18 h, 78%, >99% ee, 8:1 dr.
a
All reactions were run on 0.25 mmol scale under the standard
b
conditions. Yields of isolated products (diastereomeric mixture) after
purification by flash chromatography. ee of the corresponding primary
c
which was then displaced to give the corresponding aryl ether.
Hydroboration/oxidation of the terminal olefin furnished 5.
Cleavage of the phthalimide followed by cyclization then
afforded (−)-paroxetine 6.16 It is noteworthy that stereoisomer
(R,R)-4 could also be prepared in enantiomerically pure form
and in a single step from the same starting materials 1m and 2k,
thus enabling the synthesis of the diastereomer of (−)-parox-
etine. We anticipate that this feature of stereodivergent dual
catalytic methods will make them highly attractive for use in
medicinal chemistry in establishing structure−activity relation-
ships.
alcohol determined by SFC on a chiral stationary phase; dr (shown in
parentheses) determined by 1H NMR analysis of crude reaction
d
mixture. Absolute stereochemistry determined by analogy. 50 mol %
of trichloroacetic acid instead of dimethyl hydrogen phosphate.
a b c
, ,
Table 3. Aldehyde Scope of the Allylation
In summary, we have disclosed a stereodivergent dual catalytic
α-allylation of linear aldehydes that relies on the combination of
iridium and amine catalysis. The method enables the preparation
of a range of γ,δ-unsaturated aldehydes bearing two vicinal
stereogenic centers. The appropriate combination of chiral
catalysts provides any given product stereoisomer from the same
set of starting materials under identical conditions. The synthetic
utility of the method was showcased in a concise synthesis of
(−)-paroxetine. Studies to further establish the concept of
stereodivergent dual catalysis are ongoing and will be reported in
due course.
a
Reactions were run on 0.25 mmol scale under the standard
b
conditions. Yields of isolated products (diastereomeric mixture)
c
after purification by flash chromatography. ee determined by SFC on
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all
a chiral stationary phase; dr (shown in parentheses) determined by 1H
■
S
NMR analysis of crude reaction mixture. Absolute configuration
determined by analogy. 100 mol % dimethyl hydrogen phosphate.
d
1
reactions and products, including H and 13C NMR spectra as
well as SFC traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
products (3a, 3h−3j) in good yields and 3.5 to >20:1
diastereoselectivity. In addition, common functional groups
such as a phthalimide and an ester were tolerated (3k, 3l).
Finally, in an effort to demonstrate the practicality and utility
of this stereodivergent dual catalytic process, we examined the
application to the synthesis of a high-profile target. (−)-Parox-
etine, a selective serotonin reuptake inhibitor, is commonly used
in the treatment of depression, obsessive compulsive disorders,
and panic disorders.15 Ir((S)-L)/(S)-A catalyzed allylation of
aldehyde 2k with 4-fluorophenyl vinyl carbinol 1m afforded γ,δ-
unsaturated aldehyde (S,R)-4 in 64% yield, >99% ee, and 6:1 dr
(gram scale, Scheme 4). Separation of the diastereomers was
achieved after reduction to the corresponding primary alcohol,
AUTHOR INFORMATION
Corresponding Author
carreira@org.chem.ethz.ch
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
S.K. thanks the Fonds der Chemischen Industrie for support
(Chemiefonds-Stipendium). We thank Dr. Steffen Muller for
insightful discussions.
■
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