Enantioselective Rhodium-Catalyzed Allylic Alkylation of Prochiral α,α-Disubstituted Aldehyde Enolates for the Construction of Acyclic Quaternary Stereogenic Centers

Article abstract of DOI:10.1021/jacs.6b10099

A highly enantioselective rhodium-catalyzed allylic alkylation of prochiral α,α-disubstituted aldehyde enolates with allyl benzoate is described. This protocol provides a novel approach for the synthesis of acyclic quaternary carbon stereogenic centers and it represents the first example of the direct enantioselective alkylation of an aldehyde enolate per se. The versatility of the α-quaternary aldehyde products is demonstrated through their conversion to a variety of useful motifs applicable to target-directed synthesis. Finally, mechanistic studies indicate that high levels of asymmetric induction are achieved from a mixture of prochiral (E)- and (Z)-enolates, which provides an exciting development for this type of transformation.

Full text of DOI:10.1021/jacs.6b10099

Communication
pubs.acs.org/JACS
Enantioselective Rhodium-Catalyzed Allylic Alkylation of Prochiral
α,α-Disubstituted Aldehyde Enolates for the Construction of Acyclic
Quaternary Stereogenic Centers
Timothy B. Wright and P. Andrew Evans*
Department of Chemistry Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
Scheme 1. Inspiration and Challenges with Previous
Approaches for the Enantioselective Alkylation of α-
Substituted Benzylic Aldehydes
ABSTRACT: A highly enantioselective rhodium-cata-
lyzed allylic alkylation of prochiral α,α-disubstituted
aldehyde enolates with allyl benzoate is described. This
protocol provides a novel approach for the synthesis of
acyclic quaternary carbon stereogenic centers and it
represents the first example of the direct enantioselective
alkylation of an aldehyde enolate per se. The versatility of
the α-quaternary aldehyde products is demonstrated
through their conversion to a variety of useful motifs
applicable to target-directed synthesis. Finally, mechanistic
studies indicate that high levels of asymmetric induction
are achieved from a mixture of prochiral (E)- and (Z)-
enolates, which provides an exciting development for this
type of transformation.
he asymmetric synthesis of acyclic α-quaternary function-
T
alized aldehydes is a very challenging endeavor for
modern synthetic chemistry.1,2 Although asymmetric enolate
alkylation provides a conceptually straightforward approach
toward accessing this motif,3 the propensity for aldehydes to
undergo competing reactions, such as aldol condensations,
makes them especially demanding substrates in this regard.
Furthermore, the enantioselective alkylation of enolates tends
to be optimal for geometrically defined systems,4 which are
particularly difficult to control in acyclic α,α-disubstituted
carbonyl derivatives.5 While recent advances in organocatalysis6
have resulted in several elegant methods for the asymmetric α-
alkylation of aldehydes to prepare ternary7 stereogenic centers,
there are relatively few methods that facilitate the construction
of the corresponding quaternary substituted derivatives
(Scheme 1A).8 Alternatively, the enantioselective formation of
α-quaternary aldehydes can also be accomplished via dual
organo- and transition metal catalysis (Scheme 1B).9 Although
recent reports have illustrated the success of these approaches
for the alkylation of α-methyl benzylic aldehydes, the ability to
extend these methodologies beyond substrates that contain a
simple methyl substituent has proven particularly challenging,
which thus limits their potential synthetic utility.10
using Wilkinson’s catalyst and a chiral monodentate phosphite
ligand.14 We anticipated a similar approach could be applied to
the asymmetric allylic alkylation of aldehydes, albeit controlling
the enolate geometry would be significantly more challenging
in the absence of chelation assistance. Herein, we now describe
the first direct and highly enantioselective rhodium-catalyzed
allylic alkylation of enolates derived from the α-alkyl benzylic
aldehydes 1 with allyl benzoate (2) to afford the chiral
nonracemic α-quaternary aldehydes 3 (Scheme 1C).
Table 1 outlines the preliminary studies for the development
of an enantioselective rhodium-catalyzed allylic alkylation
reaction using an aldehyde enolate. Treatment of allyl benzoate
(2) with the lithium enolate of 2-phenylbutanal (1a) in the
presence of the chiral complex derived from RhCl(PPh3)3 and
(R)-BINOL-MeOP at −10 °C afforded aldehyde 3a in 37%
yield and with excellent enantiomeric excess (entry 1). While
the level of enantioselectivity was very encouraging, we elected
We envisaged that the direct asymmetric allylic alkylation of
an aldehyde enolate would facilitate a significant expansion in
scope, while providing a straightforward solution to the
challenging aldehyde α-alkylation process. In a program
directed toward the development of rhodium-catalyzed allylic
substitution reactions,11−13 we recently reported the direct
enantioselective allylic alkylation of α-alkoxy ketone enolates
Received: September 26, 2016
© XXXX American Chemical Society
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DOI: 10.1021/jacs.6b10099
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Journal of the American Chemical Society
Communication
Table 1. Optimization of the Enantioselective Rhodium-
Catalyzed Allylic Alkylation Using 2-Phenylbutanal (1a)
Table 2. Scope of the Enantioselective Rhodium-Catalyzed
Allylic Alkylation of α-Alkyl Benzylic Aldehyde Enolates
a
a b c
, ,
b
c
entry
base
T (°C)
additive
yield of 3a (%)
ee (%)
1
2
3
4
5
6
7
8
9
LiHMDS
LDA
−10
”
−
−
−
−
37
34
32
23
27
55
45
54
51
93
14
34
22
80
84
87
90
92
92
LiTMP
”
d
LiDPA
”
e
LiHMDS
”
LiCl
e
”
”
12-crown-4
e
”
”
DMPU
”
0
”
”
”
RT
RT
f
g
10
LiHMDS
DMPU
77 (74)
a
All reactions were performed on a 0.25 mmol scale using 10 mol %
RhCl(PPh3)3, 40 mol % (R)-BINOL-MeOP, 2.0 equiv 1a, and 1.9
b
equiv of base in THF (2.5 mL) for ca. 16 h. GC yields of 3a.
c
Determined by chiral HPLC analysis on the corresponding alcohol.
d
e
f
DPA = diphenylamine. 1.9 equiv of additive. LiHMDS was added
g
dropwise over a period of 30 min. Isolated yield of 3a.
to investigate other lithium amide bases, which we envisioned
could impact the enolate reactivity. Remarkably, the lithium
enolates generated by deprotonation with LDA, LiTMP, and
LiDPA provided aldehyde 3a in similar yield but with
significantly reduced enantioselectivity (entries 2−4). Hence,
the silyl amide lithium base is a critical component for attaining
high levels of asymmetric induction in this reaction.15
Nevertheless, the poor yield prompted the examination of
deaggregating agents in an effort to enhance the reactivity of
the enolate. To this end, the addition of lithium chloride
reduced the efficiency and enantioselectivity, whereas 12-
crown-4 provided a significant improvement in yield (entries 5
vs 6). However, given the cost and toxicity of the crown ether,
we examined the impact of DMPU, which provided 3a in
similar yield and with slightly higher enantiomeric excess (entry
7 vs 6). In the next phase of this study, we elected to investigate
the effect of temperature, which afforded further improvement
in the selectivity of the reaction upon elevation from −10 °C to
room temperature (entries 7−9). Finally, in order to address
the rather modest yield, we examined dropwise addition of the
base using a syringe-pump to minimize the side-reactions
associated with aldehyde enolates. Gratifyingly, the dropwise
addition of base over 30 minutes provided 3a in an improved
74% isolated yield and with 92% enantiomeric excess (entry
10). Importantly, the ability to employ a commercially available
base and precatalyst with a readily available chiral ligand14 at
room temperature makes this a simple protocol for the
asymmetric construction of acyclic α-quaternary aldehydes.
Table 2 summarizes the application of the optimized reaction
conditions (Table 1, entry 10) to a variety of α-branched
benzylic aldehydes.16,17 Interestingly, the reaction is tolerant of
both electron-rich and electron-deficient aryl systems, albeit
with slightly lower enantioselectivity for aldehydes with
electron-withdrawing substituents (entries 1−5). An important
feature with this trend is its complementarity relative to our
previous work on the enantioselective rhodium-catalyzed allylic
alkylation of benzyl nitrile anions.18 For instance, the current
a
All reactions were performed on a 0.5 mmol scale using 10 mol %
RhCl(PPh3)3, 40 mol % (R)-BINOL-MeOP, 2.0 equiv of 1, 1.9 equiv
of LiHMDS, and 1.9 equiv of DMPU in THF (5 mL) for ca. 16 h.
b
c
Isolated yields. Enantiomeric excess was determined by chiral HPLC
d
analysis on the corresponding alcohol. 78% yield and 91% ee on a 10
mmol (1.6 g) scale using 5 mol % RhCl(PPh3)3 and 20 mol % (R)-
BINOL-MeOP.
work provides excellent enantioselectivity for aryl groups that
had proven challenging in the asymmetric alkylation of α-alkyl
benzyl nitriles. Furthermore, the ability to alkylate sterically
encumbered aldehydes offers a direct approach to products that
have not been accessible using the current organocatalytic
methods. For example, aldehydes with an α-isopropyl group
provided excellent levels of enantiomeric excess, despite a slight
reduction in efficiency for electron-rich aryl systems (entries 6−
10). Additionally, substrates bearing an α-cyclohexyl substituent
afforded comparable yields and selectivities to the isopropyl
series (entries 11−15). Finally, the reaction proceeds with
similar yield and enantioselectivity on gram-scale, which
highlights the utility of this process for target-directed synthesis
(entry 1). Overall, this work offers a convenient procedure for the
enantioselective construction of acyclic quaternary carbon stereo-
genic centers.
Scheme 2 outlines a series of transformations on the
enantioenriched α-quaternary aldehydes 3a and 3k to further
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DOI: 10.1021/jacs.6b10099
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Journal of the American Chemical Society
Communication
Scheme 2. Transformations of Enantiomerically Enriched
Aldehydes 3a and 3k
Scheme 3. Stereochemical Outcome of the (E)- and (Z)-
Enolate Isomers of Aldehyde 1b
illustrate the synthetic utility of these intermediates. For
example, Pinnick oxidation of aldehyde 3a provides efficient
access to the carboxylic acid 4a with excellent stereochemical
fidelity. Alternatively, condensation of aldehyde 3a with 4-
methoxybenzylamine under solvent-free conditions, followed
by reduction of the intermediary imine with lithium aluminum
hydride furnished the secondary amine 5a. Aldehyde 3a was
also converted to a nitrile with conservation of stereochemical
information by treatment with hydroxylamine hydrochloride to
afford the oxime, which upon heating with 1,1′-carbonyl-
diimidazole provides nitrile 6a. Hence, the interchangeable
nature of the aldehyde and nitrile groups permits access to
highly enantiomerically enriched quaternary benzylic stereo-
genic centers regardless of the electronic nature of the aryl
group (vide supra). In order to further illustrate the synthetic
utility of the homoallylic aldehyde adducts and to establish the
absolute configuration of the products, aldehyde 3k was
converted to the known γ-lactone 7k19 in 64% overall yield
(two steps). Overall, the ability to convert the aldehyde
products into an array of important intermediates with
retention of stereochemistry highlights the potential application
of this process to target-directed synthesis.
In order to delineate the origin of the excellent
enantioselectivity, we elected to probe the impact of enolate
geometry. In general, controlling the enolate geometry is a
critical component for attaining asymmetric induction,5,14,20
albeit the equilibration of a mixture of enolate isomers to
facilitate the stereoselective α-alkylation of carbonyls via a
dynamic kinetic resolution mechanism is also possible.21
Experiments probing the geometrical selectivity of enolate
formation under the optimized conditions (Table 1, entry 10)
indicates the presence of a mixture of (E)- and (Z)-enolates.22
Hence, in order to determine the impact of geometry on the
mechanism of asymmetric induction, we subjected stereo-
defined enolates to the optimized reaction conditions. To this
end, alkylation of the (E)-lithium enolate, generated by
treatment of the silyl enol ether (E)-8b with methyllithium,
furnished the aldehyde (R)-3b in 81% yield and with 71%
enantiomeric excess (Scheme 3A). Surprisingly, alkylation of
the lithium enolate derived from (Z)-8b proceeded with similar
yield and selectivity, providing aldehyde 3b with the same
absolute configuration (Scheme 3B). These results suggest that
both geometrical isomers are reactive under the optimized
conditions and that asymmetric induction occurs by alkylation
of the mixture of (E)- and (Z)-enolates to provide to same
enantiomer.23 Moreover, the level of stereocontrol is lower than
the observed value for the alkylation of aldehyde 1b, which
further highlights the importance of the silyl amide base that is
absent under these conditions.24 Additional studies are
currently ongoing to elucidate the origin of this interesting
phenomenon.
In conclusion, we have developed a direct and highly
enantioselective rhodium-catalyzed allylic alkylation of α-alkyl
benzylic aldehydes with allyl benzoate. This is a significant
development, given that it represents the first example of the
direct asymmetric alkylation of an α,α-disubstituted aldehyde
enolate to furnish an acyclic quaternary stereogenic center. The
reactive nature of the enolate nucleophile permits the alkylation
of more hindered α-alkyl benzylic aldehydes, to facilitate the
preparation of enantiomerically enriched α-quaternary alde-
hydes that have been previously inaccessible through related
methodologies. In addition, the conversion of the homoallylic
aldehydes to several functionalized derivatives illustrates the
utility of these intermediates for target-directed synthesis.
Finally, the study indicates that both the (E)- and (Z)-isomers
provide the same sense of asymmetric induction, which
circumvents the need to control the enolate geometry thereby
making this a simple and practical synthetic method. To the
best of our knowledge, this constitutes the first example of a
highly enantioselective alkylation of a geometrical mixture of
enolates that does not involve a dynamic kinetic resolution of
the enolate isomers.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b10099.
■
S
Experimental procedures, spectral data, and NMR
spectra for all compounds including pertinent NOEs,
GC and HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
*Andrew.Evans@chem.queensu.ca
■
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/jacs.6b10099
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(13) For a related example of the regio- and stereospecific rhodium-
catalyzed allylic substitution with achiral pronucleophiles, see: Evans,
P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(14) Evans, P. A.; Clizbe, E. A.; Lawler, M. J.; Oliver, S. Chem. Sci.
2012, 3, 1835.
(15) The use of LiDPTMDS (DPTMDS = 1,3-Diphenyl-1,1,3,3-
tetramethyldisilazane) under analogous conditions to Table 1, entries
1−4 afforded aldehyde 3a in 39% yield with 81% ee.
(16) α-Heteroaromatic aldehydes are also compatible substrates. For
example, the allylation of 3-methyl-2-(thiophen-2-yl)butanal (1p)
proceeds in 71% yield and with 93% ee.
ACKNOWLEDGMENTS
■
We sincerely thank the National Sciences and Engineering
Research Council (NSERC) for a Discovery Grant and Queen’s
University for generous financial support. NSERC is also
thanked for supporting a Tier 1 Canada Research Chair
(P.A.E.). We also acknowledge the Government of Ontario
for an Ontario Graduate Scholarship (T.B.W.).
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■
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1
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D
DOI: 10.1021/jacs.6b10099
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX