Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones

Article abstract of DOI:10.1021/acs.orglett.5b02376

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF₃)₃-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.

Full text of DOI:10.1021/acs.orglett.5b02376

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Enantioselective Decarboxylative Allylic
Alkylation of Cyclopentanones
Robert A. Craig, II,† Steven A. Loskot,† Justin T. Mohr, Douglas C. Behenna, Andrew M. Harned,
and Brian M. Stoltz*
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering Division of Chemistry and Chemical
Engineering, California Institute of Technology, MC 101-20, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: The first general method for the enantioselec-
tive construction of all-carbon quaternary centers on cyclo-
pentanones by enantioselective palladium-catalyzed decarbox-
ylative allylic alkylation is described. Employing the electroni-
cally modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary
cyclopentanones were isolated in yields up to >99% with ee’s
up to 94%. Additionally, in order to facilitate large-scale
application of this method, a low catalyst loading protocol was
employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.
Scheme 1. Cyclic Ketone Substrates in Transition-Metal-
Catalyzed Enantioselective Decarboxylative Allylic Alkylation
he efficient construction of all-carbon quaternary centers
T(Cq’s) remains a challenge for the modern synthetic
chemist.1 The difficulty associated with forming Cq’s arises from
the inherent steric congestion during the C−C bond-forming
event. Toward this end, our laboratory disclosed the first
palladium-catalyzed enantioselective decarboxylative allylic
alkylation for the construction of Cq’s.2 Over the past decade,
we have continued to explore the breadth of our reaction
manifold,3 including the development of new ligands based on
the original phosphinooxazoline (PHOX) scaffold.4 Cyclic
ketones generally represent the most explored class of substrates,
from the initially reported cyclohexanones (Scheme 1A),2,5
cycloheptanones,2,3d,5b,c and cyclooctanones2,3d,5b to the more
recently disclosed and highly strained cyclobutanones (Scheme
1B).6
Contrastingly, cyclopentanones have typically performed
worse than the corresponding 6-membered substrates, often
furnishing the α-Cq ketone products in comparatively reduced
yields and enantiomeric excess (ee).3d Only a few examples with
limited substrate scope exist for the formation of α-Cq
cyclopentanones by transition-metal-catalyzed enantioselective
allylic alkylation.7 However, cyclopentanes containing enan-
tioenriched Cq’s characterize a number of biologically pertinent
and chemically fascinating natural products, including polycyclic
terpenoids 7,8 8,9 and 910 as well as alkaloids 10,11 11,11 and 1212
(Figure 1). As part of our continued efforts to extend the utility of
our reaction methodology, we revisited the problematic
cyclopentanone substrate class, striving to develop the first
general method for the construction of α-Cq cyclopentanones
and 5-membered cyclic ketone substrates by transition metal-
catalyzed enantioselective decarboxylative allylic alkylation
(Scheme 1C).
toluene in the presence of a chiral PHOX ligand, affording
enantioenriched α-Cq cyclopentanone 14a (Table 1).13,14 Using
the classic (S)-t-BuPHOX ligand ((S)-L1), cyclopentanone (S)-
14a was provided in 87% ee (entry 1). Switching to the electron-
deficient (S)-(p-CF3)3-t-BuPHOX ((S)-L2) furnished product
(S)-14a in an improved 89% ee (entry 2). The recently disclosed,
cost-effective alternative to L2, (R)-(p-CF3)3-i-PrPHOXMe2
((R)-L3), provided cyclic ketone (R)-14a in a decreased 83%
ee (entry 3).4a Similarly to (R)-L3, geminally disubstituted
Initial reaction development employed p-Me-benzyl-substi-
Received: August 17, 2015
tuted β-ketoester 13a, using catalytic Pd2(dba)3 at 20 °C in
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02376
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Organic Letters
Letter
reaction conditions from our ligand screen, using toluene as the
solvent, we isolated α-Cq cyclopentanone (S)-14b in 91% ee,
achieving complete consumption of starting material 13b in 8.0 h
(entry 1). Switching to the less polar solvent mixture 2:1
hexanes/toluene, which has previously provided increased ee’s
for other α-Cq cyclic ketones constructed through palladium-
catalyzed enantioselective decarboxylative allylic alkylation,15 did
not affect the reaction time but furnished ketone (S)-14b in a
diminished 88% ee (entry 2). Changing to ethereal solvents
(entries 3 and 4) drastically decreased the reaction time,
facilitating the full consumption of β-ketoester 13b in 1.0 h.
While the use of MTBE (entry 3) afforded cyclopentanone (S)-
14b in nearly identical ee to the mixed nonpolar solvent system
(entry 2), switching to THF (entry 4) proved deleterious.
Ultimately, the use of Pd2(dba)3 (2.75 mol %) with (S)-(p-
CF3)3-t-BuPHOX ((S)-L2, 6.00 mol %) in toluene (0.033 M in
β-ketoester 13b) at 20 °C proved optimal.
Figure 1. Natural products characterized by cyclopentane rings
containing chiral all-carbon quaternary centers (Cq’s).
a
Table 1. PHOX Ligand Screen
Subsequently, we explored the substrate scope of the
enantioselective allylic alkylation of cyclopentanones. We
found that our reaction manifold was tolerant of a variety of
substitution at the α-position of the cyclopentanone (Scheme
2).16 Alkyl-substituted α-Cq cyclopentanones (S)-14c, (S)-14d,
Scheme 2. Substrate Scope of Cyclopentanone Substitution in
a
Enantioselective Allylic Alkylation
a
Conditions: β-ketoester 13 (0.19 mmol), Pd2(dba)3 (2.75 mol %),
b
ligand (6.00 mol %), toluene (5.8 mL). Measured by analytical chiral
SFC.
valine-derived (S)-(p-CF3)2-i-PrPHOXPh2 ((S)-L4) afforded
ketone (S)-14a with nearly equivalent ee (82%, entry 4).
Switching to ester-substituted β-ketoester 13b, we confirmed
(S)-(p-CF3)3-t-BuPHOX ((S)-L2) was indeed the optimal
ligand for the desired enantioselective decarboxylative allylic
alkylation, providing enantioenriched α-Cq cyclopentanone (S)-
14b in 91% ee (entry 6). The remaining PHOX ligands (S)-L1,
(R)-L3, and (S)-L4 furnished the desired product (14b) in
reduced ee’s, ranging between 80% and 82% (entries 5, 7, and 8,
respectively).
a
Unless otherwise noted, all reported yields are isolated yields.
Enantiomeric excess (ee) was determined by either analytical chiral
SFC or HPLC. Conditions: β-ketoester 13 (0.19 mmol), Pd2(dba)3
Having identified the optimal ligand for the enantioselective
decarboxylative allylic alkylation, we next examined the solvent
effect using β-ketoester 13b (Table 2). Employing identical
a
(2.75 mol %), (S)-L2 (6.00 mol %), toluene (5.8 mL).
b
Cyclopentanone product was volatile, resulting in a reduced isolated
c
yield compared to other substrates. Reaction performed at 0 °C.
Table 2. Solvent Effect on Enantiomeric Excess of
d
Yield reported based on recovered β-ketoester starting material.
a
Cyclopentanone Product (S)-14b
Isolated yield was 56%.
and (S)-14e were each produced over reaction times greater than
30 h with ee’s ranging from 86% to 88%, providing the more
sterically congested cyclopentanone (S)-14e over a slightly
longer reaction time.13 Along with ester-substituted cyclo-
pentanone (S)-14b, nitrile (S)-14f and phthalamide (S)-14g
were both produced quite rapidly at 20 °C in excellent yield with
good ee (2.5 h, 97% yield, 87% ee and 3.0 h, 93% yield, 88% ee,
respectively). We found that we could increase the ee of these
two products significantly by lowering the temperature without
any deleterious effect on the yield, providing cyclopentanones
(S)-14f and (S)-14g in an improved 90% ee and 93% ee,
respectively, at 0 °C over 23.0 h. This result represents a dramatic
b
entry
solvent
toluene
time (h)
ee (%)
1
2
3
4
8.0
8.0
1.0
1.0
91
88
87
81
2:1 hexane/toluene
MTBE
THF
a
Conditions: β-ketoester 13b (0.19 mmol), Pd2(dba)3 (2.75 mol %),
(S)-L2 (6.00 mol %), toluene (5.8 mL). Measured by analytical chiral
b
SFC.
B
DOI: 10.1021/acs.orglett.5b02376
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Letter
improvement in the formation of (S)-14g compared to our
previously reported system, employing THF as the solvent with
(S)-L1 as the ligand, which provided (S)-14g in only 67% yield
with 48% ee.3d Comparatively, benzyl-substituted cyclopenta-
nones proved to have a correlation between the electronics of the
aryl substituent and the overall reaction time. Electron rich p-
OMe-benzyl cyclopentanone (S)-14h was furnished in only 8.0
h, while the electron-neutral benzyl and p-Me-benzyl products
((S)-14i and (S)-14a) were each provided over a slightly
extended reaction time (13.0 h). Contrastingly, the reaction
producing electron poor p-CF3-benzyl-substitued (S)-14j failed
to proceed to full conversion over 96.0 h, affording the product in
a reduced 56% overall yield (83% yield based on recovered β-
ketoester). Interestingly, despite the variable reaction times, the
ee of the benzyl-substituted cyclopentanone products was largely
consistent (88%−89% ee), with a slight boost for the electron-
rich p-OMe-benzyl product ((S)-14h) to 92% ee.
similar ee’s in slightly reduced yield. Interestingly, each of the
alkyl-substituted cyclopentanone products possessing a 2-
substituted allyl fragment were produced over a shorter reaction
time than the same substrates containing an unsubstituted allyl
fragment (see Scheme 2).
Lastly, we examined the potential to apply our recently
disclosed palladium(II) low catalyst loading protocol for
enantioselective decarboxylative allylic alkylation to this new
substrate class.17 We discovered that on a small scale, ester-
substituted cyclopentanone (S)-14b was provided in an identical
91% ee and an improved 98% yield at 20 °C using only 0.15 mol
% palladium catalyst (Scheme 5) compared to our palladium(0)-
Scheme 5. Low Catalyst Loading Palladium(II)-Mediated
a
Enantioselective Allylic Alkylation
Additionally, we found that indanones were competent
substrates within our reaction manifold (Scheme 3).3d,5a,d,7g
Scheme 3. Enantioselective Allylic Alkylation of Indanone
Substrates
a
All reported yields are isolated yields. Enantiomeric excess (ee) was
b
determined by analytical chiral SFC. Pd(OAc)2 (0.15 mol %), (S)-L2
(1.50 mol %) used.
mediated reaction conditions, which employ 5.50 mol %
palladium (vide supra). Increasing the scale of the reaction
slightly (0.22 mmol) as well as the temperature (28 °C) and
catalyst loading (0.30 mol % Pd) furnished (S)-14b over a
reduced 18 h in 96% yield with 89% ee. Using these reaction
conditions and increasing the scale 17 times (3.73 mmol)
provided (S)-14b with identical 89% ee, although in a slightly
diminished 82% yield.
In conclusion, we have disclosed the first general method for
the construction of α-Cq cyclopentanones by enantioselective
palladium-catalyzed decarboxylative allylic alkylation. The
reaction manifold proved optimal when electron-deficient (S)-
(p-CF3)3-t-BuPHOX ((S)-L2) was employed, providing a
variety of substituted cyclopentanone products in up to near-
quantitative yield and with up to 94% ee. Additionally, the
enantioselective allylic alkylation was found to be tolerant of allyl
fragments substituted at the 2-position. Use of low-catalyst
loading, palladium(II)-mediated reaction conditions was suc-
cessfully accomplished, facilitating the synthesis of α-Cq
cyclopentanones on increased scale in a cost-effective manner.
Currently, our laboratory is pursuing further development of this
technology through substrate scope extension and application in
natural product synthesis.
Methyl-substituted indanone product (S)-16a was furnished
over a greatly shortened 4.5 h compared to the methyl-
substituted cyclopentanone product ((S)-14c, see Scheme 2).
Additionally, bicycle (S)-16a was provided in 94% yield with 84%
ee. Comparatively, the fluorinated analog (S)-16b was produced
in an improved >99% yield and 87% ee, albeit over a longer
reaction time (13.0 h).
Having investigated the tolerance of our reaction manifold to a
variety of substitutions on the cyclopentanone ring, we next
evaluated the potential to use 2-substituted allyl fragments in the
enantioselective allylic alkylation of cyclopentanones (Scheme
4). Methyl- and ethyl-substituted cyclopentanone products (S)-
6a and (S)-6b containing a 2-phenylallyl fragment were both
produced in excellent yield and with 90% and 94% ee,
respectively. Comparatively, cyclopentanones (S)-6c and (S)-
6d, each containing a 2-chloroallyl fragment, were produced with
Scheme 4. Enantioselective Allylic Alkylation of
Cyclopentanone Substrates with 2-Substituted Allyl
a
Fragments.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02376.
Experimental details, characterization data, and NMR and
IR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
a
All reported yields are isolated yields. Enantiomeric excess (ee) was
*E-mail: stoltz@caltech.edu.
a
determined by analytical chiral SFC. Conditions: β-ketoester 5 (0.19
Author Contributions
†R.A.C. and S.A.L. contributed equally.
mmol), Pd2(dba)3 (2.75 mol %), (S)-L2 (6.00 mol %), toluene (5.8
mL).
C
DOI: 10.1021/acs.orglett.5b02376
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi,
N. Tetrahedron Lett. 2002, 43, 8307−8311.
Notes
The authors declare no competing financial interest.
(12) Oh, H.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F.
Tetrahedron Lett. 1998, 39, 7633−7636.
ACKNOWLEDGMENTS
(13) Absolute configuration of cyclopentanone (S)-19 was determined
by comparison of the optical rotation of the methyl ketone Wacker
■
We thank the NIH-NIGMS (R01GM080269 and postdoctoral
fellowship F32GM073332 to A.M.H.), Amgen, the Gordon and
Betty Moore Foundation, and Caltech for financial support.
R.A.C. gratefully acknowledges the support of this work provided
by a predoctoral fellowship from the National Cancer Institute of
the National Institutes of Health under Award No. F31A17435.
Additionally, we thank Eli Lilly (predoctoral fellowship to
J.T.M.) and the Fannie and John Hertz Foundation (predoctoral
fellowship to D.C.B.).
product to the known literature value; see: Thominiaux, C.; Rousse,
́
S.;
Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10,
̈
2015−2021. The absolute configuration of all other products generated
herein was assigned by analogy to the absolute configuration of (S)-19.
For full details, see the Supporting Information.
(14) Additionally, silyl enol ether derivatives of cyclopentanones were
found to be suitable enolate precursors for the formation of α-Cq
cyclopentanones under similar reaction conditions with an external allyl
electrophile. See the Supporting Information.
(15) McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett 2010, 11,
1712−1716.
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(16) Additionally, α′,α′-disubstituted cyclopentanones were suitable
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the α-Cq cyclopentanone products in reduced yields and with slightly
diminished ee. β,β-disubstituted cyclopentanones were not suitable
substrates under the optimized conditions. See the Supporting
Information for full details.
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