Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Acyclic α- N-Pyrrolyl/Indolyl Ketones

Article abstract of DOI:10.1021/acs.orglett.0c01303

The synthesis of fully substituted α-N-pyrrolyl and indolyl ketones via enantioselective palladium-catalyzed allylic alkylation is described. The acyclic ketones are alkylated in high yields with high enantioselectivities through the use of an electron-deficient phosphinooxazoline ligand, furnishing a highly congested and synthetically challenging stereocenter. The obtained alkylation products contain multiple reactive sites poised for additional functionalizations and diversification.

Full text of DOI:10.1021/acs.orglett.0c01303

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Letter
Palladium-Catalyzed Enantioselective Decarboxylative Allylic
Alkylation of Acyclic α‑N‑Pyrrolyl/Indolyl Ketones
Remi Lavernhe, Eric J. Alexy, Haiming Zhang, and Brian M. Stoltz*
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ABSTRACT: The synthesis of fully substituted α-N-pyrrolyl and indolyl ketones via
enantioselective palladium-catalyzed allylic alkylation is described. The acyclic ketones
are alkylated in high yields with high enantioselectivities through the use of an
electron-deficient phosphinooxazoline ligand, furnishing a highly congested and
synthetically challenging stereocenter. The obtained alkylation products contain
multiple reactive sites poised for additional functionalizations and diversification.
romatic nitrogen heterocycles, such as indoles and
enantioselective synthesis of fully substituted N-stereocenters,
Apyrroles, are high-value motifs found in a wide range of a motif that is found in a number of bioactive compounds
(Scheme 1A).5 Furthermore, to the best of our knowledge,
there is no report of the asymmetric synthesis of fully
substituted α-N-pyrrolyl ketones, which is in sharp contrast
with the wide utility of pyrrole in medicinal chemistry. In
2016, the Peters and Fu groups disclosed a photoinduced
copper-catalyzed method for coupling racemic tertiary alkyl
chloride electrophiles with carbazole and C3-protected indole
derivatives to generate fully substituted N-stereocenters with
high enantioselectivity (Scheme 1B).6 Because of the
importance of these heterocycles, and in continuation of
ongoing research from our group regarding the synthesis and
utility of fully substituted acyclic enolates in palladium-
catalyzed allylic alkylation,7 we sought to target this
challenging structural motif by ultimate C−C bond
formation, not C−N bond construction (Scheme 1C).
We began by investigating the synthesis of fully substituted
acyclic ketone enolates bearing an α-N-pyrrole substituent.
Utilizing the recently reported conditions,8 a highly selective
enolization could be performed and, following enolate
trapping with allyl chloroformate, provide a fully substituted
enol carbonate poised to undergo a subsequent palladium-
catalyzed allylic alkylation (eq 1). This robust and opera-
tionally simple process relies on the combination of LiHMDS
and dimethylethylamine (2 equiv each) and proceeds
smoothly at ambient temperature.
natural products, agrochemicals, and pharmaceuticals.1 In
fact, indole is one of the most common heterocycles in FDA-
approved drugs.2 Whereas extensive efforts toward the
functionalization of indole (or pyrrole) C2 and C3 positions
have been described in the literature,3 functionalization of the
N−H can be challenging due to the attenuated nucleophil-
icity of this position. This drawback led to N−H
functionalization of such heterocycles being overlooked in
the past. Recently, progress has been made in the
intermolecular enantioselective N-alkylation of indoles.4
However, few methods have been reported for the
Scheme 1. Significance and Foundational Research
With access to a stereodefined α-N-pyrrolyl enolate
derivative established, we next sought to examine a
subsequent palladium-catalyzed allylic alkylation to establish
Received: April 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01303
© XXXX American Chemical Society
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A

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Letter
electron-deficient ligands, such as L4 (entry 4). Continuing
with PHOX ligand L3, a screen of solvents and conditions
revealed that a 2:1 hexane/toluene mixture was indeed the
optimal solvent for this transformation, and that the catalyst
loading could be significantly lowered to 0.25 mol %
Pd2(dba)3 and 0.6 mol % L3. With these conditions, the
alkylation product is obtained with a high 86% ee and in an
excellent 96% isolated yield (entry 7).
the desired tetrasubstituted stereocenter. Initially, a variety of
ligands commonly utilized in the literature for this trans-
formation were examined, with a representative set of these
provided in Table 1. Use of the Trost-type bis-phosphine
Having identified optimized reaction conditions, we next
examined the scope of the transformation. A variety of
substrates containing different α-alkyl and ketone aryl groups
were synthesized and subjected to the optimized reaction
conditions (Scheme 2). All enol carbonate substrates were
prepared with excellent E/Z selectivity (>98:2). Substrates
bearing simple α-alkyl groups such as ethyl (2b) and methyl
(2f) provided the alkylation products in excellent 98% yield
with 90% ee in both cases. Notably, alkylation product 2f was
prepared on a gram scale with no significant change in either
yield or ee. Substrate 2c bearing an n-pentyl chain and 2d
bearing a branching isobutyl substituent both proceeded well,
with the alkylation products being afforded with 91 and 94%
ee, respectively, both in excellent yields. A slightly decreased
84% ee was obtained with the α-benzyl substrate (2e).
Examining the electronic effects of the ketone aryl substituent
revealed that both donating and withdrawing groups were
tolerated (2g−l). Notably, alkylation product 2k with a p-Br
phenyl group was obtained in 90% yield with an excellent
97% ee and contains multiple reactive functionality that may
be utilized for subsequent synthetic manipulations. We were
pleased to find that sterically demanding substrate 2m
bearing an o-tolyl substituent performed well in the
transformation, with the product obtained in 85% yield
with a high 90% ee. Additionally, substitution at the two-
position of the α-N-pyrrole was tolerated, forging an
exceedingly hindered tetrasubstituted stereocenter with a
high 90% ee (i.e., 2n). From this result, we were inspired to
investigate additional, bulkier α-N-indole-containing sub-
strates (2o−r) and found that these performed well,
providing the alkylation products with excellent 90−95% ee.
With a scope of the transformation established, we next
sought to examine the importance of enolate geometry on the
selectivity of the transformation (eq 2). Enol carbonate
Table 1. Optimization of Palladium-Catalyzed Allylic
a b
,
Alkylation
c
entry
ligand
solvent
%ee (yield)
1
2
3
4
5
6
L1
L2
L1
L4
L3
L3
L3
2:1 hexane/PhMe
2:1 hexane/PhMe
2:1 hexane/PhMe
2:1 hexane/PhMe
benzene
−51
34
85
84
80
methylcyclohexane
2:1 hexane/PhMe
81
86 (96)
d
7
a
Conditions: 0.1 mmol 1a, 2.5 mol % Pd2(dba)3, 6 mol % ligand, and
b
2.0 mL of solvent. Conversion over 95% if no yield from isolated
substrate 1f was prepared as a 61:39 E/Z mixture via a
nonselective enolization and subjected to the optimized allylic
alkylation conditions. The resultant alkylation product was
obtained in an excellent 94% yield but with a diminished 65%
ee, highlighting the importance of synthesizing the starting
enol carbonate as a single geometric isomer. This result runs
contrary to the alkylation of acyclic ketones bearing all-
carbon substituents, in which we found that the starting
enolate geometry of acyclic ketones was inconsequential for
obtaining a high selectivity.7b This divergence in reactivity
may be due to the electron-rich nature of the α-N-
hetereocyclic substrates used herein, which may facilitate a
faster reductive elimination and outcompete the enolate
c
d
product is stated. Determined by chiral SFC analysis. Reaction
performed with 0.2 mmol 1a, 0.25 mol % Pd2(dba)3, 0.6 mol %
ligand, and 2.0 mL of solvent.
ligand L1 in a 2:1 hexane/toluene solvent mixture led to the
formation of the desired product with a promising 51% ee
(entry 1). Switching to the phosphinooxazoline (PHOX)
ligand L2, the ee slightly decreased to 34% (entry 2). We
were pleased to find, however, that the use of the electron-
deficient PHOX ligand L3 provided the desired product with
an improved 85% ee. However, no further increase in
selectivity was observed through the use of even more
B
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Scheme 2. Substrate Scope of Palladium-Catalyzed Allylic
Alkylation
Scheme 3. Derivatization of Alkylation Products 2f
a
providing tertiary-amine-containing product 5 in an excellent
93% yield.
In conclusion, we have developed a general method to
access fully substituted α-N-pyrrolyl and indolyl ketones.
Both the use of the electron-deficient phosphinooxazoline
ligand L3 and the preparation of the starting enol carbonates
as single geometric isomers are crucial for obtaining a high
enantioselectivity. The transformation proceeds efficiently
with only 0.25 mol % of Pd2(dba)3 and 0.6 mol % ligand,
and the resulting alkylated products could be selectively
functionalized at different reactive sites in high yields.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01303.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1996295 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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a
Reactions performed on a 0.2 mmol scale unless stated otherwise.
b
c
Yield of isolated product. Determined by chiral SFC analysis.
d
Absolute configuration of 2e is determined by single-crystal X-ray
e
diffraction; all other compounds are assigned by analogy. Reaction
performed on a 0.1 mmol scale. Reaction performed on a 0.107
mmol scale.
f
AUTHOR INFORMATION
■
Corresponding Author
Brian M. Stoltz − Warren and Katharine Schlinger Laboratory
for Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125, United States;
orcid.org/0000-0001-9837-1528; Email: stoltz@
caltech.edu
equilibration of an intermediate Pd enolate, thereby reacting
to form the C−C bond through both geometries with only
moderate observable enantioselectivity.
Lastly, we turned toward examining product derivatizations
(Scheme 3). The divergent functionalizations of the ketone,
terminal olefin, and pyrrole are all possible. Treatment of the
alkylation product 2f with cross-metathesis conditions using
methyl acrylate and a Hoveyda-Grubbs second-generation
catalyst provided unsaturated ester 3 in an excellent 95%
isolated yield. Substituted styrene 4 could be obtained in 84%
yield via a Wittig olefination. Functionalization of the pyrrole
could be realized by treatment with Eschenmoser’s salt,
Authors
Remi Lavernhe − Warren and Katharine Schlinger Laboratory
for Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125, United States
Eric J. Alexy − Warren and Katharine Schlinger Laboratory
for Chemistry and Chemical Engineering, Division of
C
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Crespo, A.; Wiltsie, J.; Clemas, J.; Gibson, J.; Contino, L.; Lisnock,
J.; Zhou, G.; Garcia-Calvo, M.; Jochnowitz, N.; Ma, X.; Pan, Y.;
Brown, P.; Zamlynny, B.; Bateman, T.; Leung, D.; Xu, L.; Tong, X.;
Liu, K.; Crook, M.; Sinclair, P. Bioorg. Med. Chem. Lett. 2016, 26,
2866−2869.
Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125, United States
Haiming Zhang − Small Molecule Process Chemistry,
Genentech, Inc., South San Francisco, California 94080,
United States; orcid.org/0000-0002-2139-2598
(6) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.;
Peters, J. C.; Fu, G. C. Science 2016, 351, 681−684.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01303
(7) (a) Starkov, P.; Moore, J. T.; Duquette, D. C.; Stoltz, B. M.;
Marek, I. J. Am. Chem. Soc. 2017, 139, 9615−9620. (b) Alexy, E. J.;
Zhang, H.; Stoltz, B. M. J. Am. Chem. Soc. 2018, 140, 10109−10112.
(c) Alexy, E. J.; Fulton, T. J.; Zhang, H.; Stoltz, B. M. Chem. Sci.
2019, 10, 5996−6000. (d) Lavernhe, R.; Alexy, E.; Zhang, H.;
Stoltz, B. M. Adv. Synth. Catal. 2020, 362, 344−347. (e) Fulton, T.
J.; Wu, B.; Alexy, E. J.; Zhang, H.; Stoltz, B. M. Tetrahedron 2019,
75, 4104−4109.
(8) (a) Mack, K. A.; McClory, A.; Zhang, H.; Gosselin, F.; Collum,
D. B. J. Am. Chem. Soc. 2017, 139, 12182−12189. (b) Li, B. X.; Le,
D. N.; Mack, K. A.; McClory, A.; Lim, N. K.; Cravillion, T.; Savage,
S.; Han, C.; Collum, D. B.; Zhang, H.; Gosselin, F. J. Am. Chem.
Soc. 2017, 139, 10777−10783.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH-NIGMS (R01GM080269), the Gordon
and Betty Moore Foundation, and Caltech for financial
support. E.J.A. thanks the National Science Foundation for a
predoctoral fellowship. We thank Dr. David VanderVelde
(Caltech) for NMR expertise. Dr. Scott Virgil (Caltech
Center for Catalysis and Chemical Synthesis) is thanked for
instrumentation and SFC assistance. Dr. Michael Takase
(Caltech) and Lawrence Henling (Caltech) are acknowledged
for X-ray analysis.
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