Development of (trimethylsilyl)ethyl ester protected enolates and applications in palladium-catalyzed enantioselective allylic alkylation: Intermolecular cross-coupling of functionalized electrophiles

Article abstract of DOI:10.1021/ol500355z

The development of (trimethylsilyl)ethyl ester protected enolates is reported. The application of this class of compounds in palladium-catalyzed asymmetric allylic alkylation is explored, yielding a variety of α-quaternary six- and seven-membered ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to traditional β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of (trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Full text of DOI:10.1021/ol500355z

Letter
pubs.acs.org/OrgLett
Development of (Trimethylsilyl)ethyl Ester Protected Enolates and
Applications in Palladium-Catalyzed Enantioselective Allylic
Alkylation: Intermolecular Cross-Coupling of Functionalized
Electrophiles
Corey M. Reeves, Douglas C. Behenna, and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United
States
S
* Supporting Information
ABSTRACT: The development of (trimethylsilyl)ethyl ester
protected enolates is reported. The application of this class of
compounds in palladium-catalyzed asymmetric allylic alkyla-
tion is explored, yielding a variety of α-quaternary six- and
seven-membered ketones and lactams. Independent coupling
partner synthesis engenders enhanced allyl substrate scope
relative to traditional β-ketoester substrates; highly function-
alized α-quaternary ketones generated by the union of
(trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this
method for complex fragment coupling.
atent or protected enolates such as silyl enol ethers, silyl
Lketene acetals, allyl enol carbonates, allyl β-keto esters, and
others have found broad use in organic synthesis owing to their
mild release and ease of use.1 Perhaps the most well studied
class of protected enolates employ oxygen-bound protecting
groups (i.e., silyl enol ethers). Unfortunately, the utility of this
class of compounds is often limited by poor regioselectivity
when forming fully substituted enol derivatives.2 Although
much effort has been devoted to the identification of conditions
that allow for selective generation of so-called “thermodynamic”
enolate isomers, selectivity often drops precipitously when
sterically demanding α-substitution is introduced.3 This
problem would be solved, ideally, by the development of
enolate precursors that are readily prepared and, when
Figure 1. New substrate design enables broader functional group (R2)
scope in allylic alkylation reactions.
triggered, release the “thermodynamic” enolate under kinetic
control.
In the context of allylic alkylation reactions, carboxylate-
protected enolates (i.e., allyl β-ketoesters, e.g., I, Figure 1A)
represent a significant advance toward such a solution. Allyl β-
ketoesters enjoy relatively uncomplicated, selective synthesis4
and mild deprotection, resulting in enolate formation following
decarboxylation.5 Despite these advantages, facile nucleophilic
attack of the incipient enolate at the transition metal-allyl
species generated during deprotection often precludes
applications that do not involve allylic alkylation.6 Moreover,
with traditional carboxylate-protected enolates any functionality
borne by the allyl fragment (R2, Figure 1A) must be compatible
with the conditions required for substrate synthesis (i.e., strong
base and reactive electrophiles, Figure 1A). Tunge and co-
workers have demonstrated the utility of acyl-protected
enolates, which may undergo deprotection via a retro Claisen
condensation to reveal fully substituted enolates that participate
in catalysis.7 However, these reactions often require the use of
elevated temperatures and alkoxide base to proceed.
In a recent communication,8 we disclosed a novel class of
substrates for enolate alkylation chemistry,9 (trimethylsilyl)-
ethyl β-ketoesters (TMSE β-ketoester), that undergo mild
deprotection upon treatment with a fluoride source, and we
demonstrated their use in the diastereoselective allylic
alkylation of cyclic β-ketoesters. The TMSE β-ketoester
Received: February 3, 2014
Published: April 11, 2014
© 2014 American Chemical Society
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Table 1. Optimization of Reaction Parameters11
substrate class (i.e., II, Figure 1B) boasts similar ease of
preparation as compared with allyl β-ketoesters but is not
susceptible to transition metal-mediated deprotection, a benefit
that enabled sequential transition metal-catalyzed allylic
alkylation events in our previous work.8 We hypothesized
that use of TMSE β-ketoesters may enhance the breadth of
functional group tolerance at the allyl coupling partner in
asymmetric allylic alkylations, relative to allyl β-ketoesters, by
virtue of the fact that the allyl fragment is not subjected to the
conditions of substrate synthesis (Figure 1B). In this report, we
describe the preparation and development of this substrate class
and the evaluation thereof in the enantioselective palladium-
catalyzed allylic alkylation of six- and seven-membered ketone
and lactam scaffolds. Furthermore, we go on to show how the
use of these substrates can enable the union of complex
fragments bearing functionality that would be incompatible
with incorporation into traditional allyl β-ketoester substrates.
In considering novel carboxylate protected enolates, our
design criteria called for a substrate that could be synthesized
efficiently and deprotected under mild conditions and facilitate
the convergent union of complex fragments in a synthetic
setting. To address these concerns we chose to explore 2-
(trimethylsilyl)ethyl 1-alkyl-2-oxocyclohexane-1-carboxylates or
TMSE β-ketoesters. We were pleased to find that α-methyl
TMSE β-ketoester (3a) could be prepared in a single synthetic
operation from commercially available cyclohexanone (1), 2-
(trimethylsilyl)ethyl chloroformate (2), and methyl iodide
(MeI) in good overall yield (Scheme 1).
a
Yield determined by comparison to tridecane internal standard.
b
Percent ee determined by chiral GC analysis of the crude reaction
Scheme 1. Synthesis of TMSE β-Ketoester
c
mixture. Reaction performed at 25 °C.
substitutions, such as α-benzyl substituted β-ketoester 3b (R1 =
Bn, X = Y = CH2, n = 1, Figure 2), functioned consistently well
in the chemistry; the desired benzyl substituted α-quaternary
ketone 4b was obtained in high yield and enantioselectivity. In
addition to simple α-alkyl substrates (i.e., compounds 3a and
3b), heteroatom-substituted substrate 3c (R1 = F, X = Y = CH2,
n = 1) proved to be a viable coupling partner and provided the
corresponding α-fluoro-allylic alkylation product 4c in good
yield and excellent ee. Subjecting methyl ester bearing substrate
3d (R1 = CH2CH2CO2Me, X = Y = CH2, n = 1) to our
optimized conditions resulted in an efficient and selective
reaction, furnishing enantioenriched ketone 4d in 93% yield
and 89% ee. Substrates constituted from seven-membered
rings, including ketone 3e (R1 = Me, X = Y = CH2, n = 2) and
vinylogous ester 3f (R1 = Me, X = CH, Y = CO(i-Bu), n = 2),
were shown to be suitable coupling partners, affording α-
quaternary ketone 4e and α-quaternary vinylogous ester 4f
products in 95% and 89% yield and 87% and 92% ee,
respectively. Finally, six- and seven-membered lactams were
investigated. We were pleased to find that under slightly
modified reaction conditions (40 °C), the desired α-function-
alized lactam products 4g and 4h were obtained in good to
excellent yields and excellent ee’s.
With TMSE β-ketoester 3a in hand, our investigation into
this substrate class commenced in the context of palladium-
catalyzed allylic alkylation. We were pleased to find that
exposure of β-ketoester 3a to allyl bromide, tetrabutylammo-
nium difluorotriphenylsilicate (TBAT), [Pd2(dba)3], and (S)-t-
Bu-PHOX10 in toluene at 40 °C generated the desired α-
quaternary ketone 4a in modest yield and good enantiose-
lectivity (entry 1, Table 1). We next explored the scope of allyl
sources that could be used in the reaction and found that a
variety of diverse allyl sources were competent in the chemistry,
including allyl sulfonates, allyl acetates, and allyl carbonates
(entries 2−5). Allyl methyl carbonate proved to be the most
efficient, selective, and prudent allyl source, in particular with
respect to the number of the allyl equivalents required for
optimal reactivity (entry 6). Reaction parameters including
relative stoichiometry (entries 7−9), solvent (entries 10−13),
and temperature (entry 14) were all subsequently explored and,
ultimately, we found that a slight excess of mixed carbonate in
THF at 25 °C proved optimal, delivering the desired ketone in
81% yield and 86% enantioselectivity (entry 14).
Having surveyed the scope of reaction with respect to
nucleophile α-substitution and scaffold type, we next probed
the reaction with respect to substitution at the 2-allyl position.
We were pleased to find that a variety of functional groups
could be introduced through the use of variously substituted
allyl carbonates (5, R2 ≠ H, Figure 2). Simple alkyl substitution
at the internal allyl position was well tolerated as 2-methylallyl
ketone 4i was obtained in 89% yield and 89% ee. 2-Chloroallyl
Having identified optimal reaction conditions, we turned our
attention to exploring reaction scope, beginning with tolerance
of variability with respect to the nucleophile’s α-substitution,
ring size, and carbonyl functionality (Figure 2). Simple α-alkyl
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Figure 3. Complex allyl architectures.
which was synthesized by allylic oxidation of (S)-carvone, also
bears functionality that would be unstable to the conditions
required for standard allyl β-ketoester substrate synthesis. In
particular, we envisioned that attempts to acylate a ketone
enolate with an allyl chloro- or allyl cyanoformate bearing
enone 7 would be complicated by undesired conjugate addition
and enolate chemistries (e.g., aldol reaction, Michael addition,
etc.). In both cases, our new TMSE β-ketoester chemistry
allows for the independent preparation and, thus, physical
separation of nucleophilic and electrophilic components until
the enantioselective fragment coupling stage.
Subjecting allyl carbonate 6 and TMSE β-ketoester 3b (R1 =
Bn, X = Y = CH2, n = 1, Figure 2) to our fluoride-modified
allylic alkylation conditions with achiral ligand L1 revealed
modest substrate-controlled diastereoselection of 1.7:1 (entry
1, Table 2A). Use of (S)-t-Bu-PHOX (L2) resulted in a highly
Table 2. Union of Complex Fragments by Asymmetric
a
Allylic Alkylation
Figure 2. Exploration of functional group and scaffold diversity in the
fluoride-triggered palladium-catalyzed allylic alkylation reaction. Notes:
(a) Reaction conditions: 3 (1.0 equiv), 5 (1.1 equiv), [Pd2(dba)3] (5
mol %), (S)-t-Bu-PHOX (12.5 mol %), and TBAT (1.25 equiv) in
THF (0.033 M) at 25 °C for 12−48 h. (b) Reaction performed on
substrates 3k and 3l at 40 °C. (c) All reported yields are for isolated
products.
methyl carbonate (5, R2 = Cl) also participated well in the
chemistry, furnishing the corresponding α-quaternary ketone 4j
in 72% yield and 96% ee. Allyl fragments bearing electron-
neutral and electron-deficient aryl groups also functioned well
in the reaction, delivering the desired products 4k and 4l,
respectively, in excellent yields and ee’s.
While the new fluoride-triggered chemistry described thus far
permits alternative access to structures previously available by
allylic alkylation, a distinct advantage offered by TMSE β-
ketoesters in allylic alkylation chemistry is the ability to
introduce allyl-coupling partners that would be unstable to the
conditions of allyl β-ketoester substrate synthesis. To illustrate
this feature of the new chemistry, we synthesized mixed
carbonates 6 and 7 as coupling partners for palladium-catalyzed
allylic alkylation (Figure 3). Allyl carbonate 6, derived from
leucine, bears an epimerizable stereocenter that is racemized
upon treatment with strong base.12 Because strong base (i.e.,
LDA, LHMDS, etc.) is typically required for enolization and
acylation in the preparation of standard allyl β-ketoesters,
employing electrophiles bearing base-labile functionality has
not been previously possible. Alternatively, allyl carbonate 7,
a
Reaction conditions: 3b (1.0 equiv), 6 or 9 (1.1 equiv), [Pd2(dba)3]
(5 mol %), ligand (12.5 mol %), and TBAT (1.25 equiv) in THF
(0.033 M) at the indicated temperature for 24−48 h. Diaster-
eoselectivity determined by H NMR analysis of the crude reaction
b
1
c
mixture. Yields are reported for the combined diastereomeric mixture.
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T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto,
efficient and diastereoselective reaction giving the desired
amino ester 8 in 95% yield and greater than 25:1 dr, with no
detectable epimerization at the amino ester side chain (entry
2). The inherent diastereoselectivity could be completely
reversed under catalyst control by using (R)-t-Bu-PHOX
(L3), without significant loss in selectivity or reactivity (entry
3). Likewise, upon exposing carbonate 7 and ketoester 3b to
slightly modified allylic alkylation conditions (40 °C) with an
achiral ligand, we again observed an efficient reaction and slight
inherent diastereoselectivity (entry 4, Table 2B). This bias
could be enhanced by using ligand L2 to obtain α-quaternary
ketone 10 in 6:1 dr and 87% yield or overturned by use of L3
to obtain 11 in 5:1 dr and 77% yield (entries 5 and 6).
In conclusion, we have developed a new class of substrates
for enolate alkylation chemistry that benefit from ease of
preparation and mild deprotection conditions that are
orthogonal to those used with traditional allyl β-ketoesters.
We examined the application of these compounds in palladium-
catalyzed asymmetric allylic alkylation chemistry and found that
a wide range of functional groups and substrate scaffolds are
well tolerated, including six- and seven-membered ketones and
lactams. We have further demonstrated the value of these
compounds for uniting complex coupling partners that would
be incompatible to preparation via standard allyl β-ketoester
based allylic alkylation. We envision this technology will also
enable the convergent cross-coupling of synthetically challeng-
ing fragments for complex molecule synthesis. Further studies
exploring the application of TMSE β-ketoesters in diverse
reaction methodologies and complex natural product synthesis
are ongoing in our laboratory.
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ASSOCIATED CONTENT
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■
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This material is available free of charge via the Internet at
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T. F. Beilstein J. Org. Chem. 2013, 9, 1533.
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Chem. Soc. Rev. 2014, 43, 819.
(11) Catalyst loading was reduced to 2.5 mol % Pd2(dba)3, without
loss of ee; however, conversion of 71% was observed in this case.
(12) Williams, P.; Albericio, F.; Giralt, E. Chemical Approaches to the
Synthesis of Peptides and Proteins; CRC Press: Boca Raton, 1997;
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Stoltz@caltech.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank NIH-NIGMS (R01GM080269),
Amgen, the Gordon and Betty Moore Foundation, the Caltech
Center for Catalysis and Chemical Synthesis, and Caltech for
financial support. C.M.R. thanks the Rose Hills Foundation for
a predoctoral fellowship. The authors thank Scott Virgil
(Caltech) for helpful discussions and instrumentation assis-
tance. Rob Craig (Caltech) and Dr. Allen Hong (Caltech) are
thanked for helpful discussion.
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