Pd-catalyzed asymmetric β-hydride elimination en route to chiral allenes

Article abstract of DOI:10.1021/ja401606e

We wish to report our preliminary results on the discovery and development of a catalytic, asymmetric β-hydride elimination from vinyl Pd(II)-complexes derived from enol triflates to access chiral allenes. To achieve this, we developed a class of chiral p

Full text of DOI:10.1021/ja401606e

Communication
pubs.acs.org/JACS
Pd-Catalyzed Asymmetric β‑Hydride Elimination en Route to Chiral
Allenes
Ian T. Crouch, Robynne K. Neff, and Doug E. Frantz*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
Table 1. Selected Optimization Data for the Pd-Catalyzed
Asymmetric β-Hydride Elimination of Enol Triflates to
Chiral Allenes
ABSTRACT: We wish to report our preliminary results
on the discovery and development of a catalytic,
asymmetric β-hydride elimination from vinyl Pd(II)-
complexes derived from enol triflates to access chiral
allenes. To achieve this, we developed a class of chiral
phosphite ligands that demonstrate high enantioselectivity,
allow access of either allene enantiomer, and are readily
synthesized. The methodology is demonstrated on over 20
substrates, and application to the formal asymmetric total
synthesis of the natural product, (+)-epibatidine, is also
provided.
rganic chemists are on a perpetual path of discovery to
Oidentify new methods for asymmetric synthesis. Histor-
Scheme 1. Pd-Catalyzed Pathways to 1,3-Dienes or Allenes
from Enol Triflates
a
Enantiomeric excesses (ee) and yields reported were determined by
b
quantitative chiral HPLC analysis. Reaction performed in THF.
c
d
Reaction performed in i-PrOAc. Reaction performed at 35 °C.
Reaction performed at rt. 2 equiv of base. 4 equiv of base. Reaction
e
f
g
h
performed using ligand based on (S)-BINOL instead of (R)-BINOL
yielding the opposite enantiomer of 2.
exploited as substrates in a multitude of synthetic method-
ologies,1 as chiral ligands in asymmetric catalysis,2 and exist as
structural motifs in ∼150 natural products (usually in
enantioenriched form),3 robust methods to synthesize chiral
ically, much of this effort has focused on the generation and
control of point chirality (i.e., stereogenic centers), and as a
result, approaches to engender axial chirality have not been as
forthcoming. A perfect example of this unbalanced dichotomy
is in the synthesis of chiral allenes. While allenes continue to be
Received: February 13, 2013
Published: March 14, 2013
© 2013 American Chemical Society
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Scheme 2. Synthesis of Ligands 4 and 5
Scheme 3. Known Limitations of the Methodology
reaction conditions to allow the allene to be isolated as the
terminal product in these reactions.
More importantly, we envisioned that this pathway might
lead to a viable approach to access enantioenriched allenes
using chiral ligands associated with the Pd-catalyst via an
asymmetric β-hydride elimination, a reaction that has no
precedence in the literature as far as we are aware.13
Our initial experiments began with (E)-enol triflate 1 as our
model substrate and Pd2dba3 as our preferred source of
palladium (eq 1). A preliminary survey of ∼60 commercially
available chiral phosphorus-based ligands to promote the
asymmetric β-hydride elimination en route to chiral allene 2
provided only partial success with respect to enantioselectivity.
Fortuitously, however, we were able to determine that several
of these ligands were in fact able to induce moderate
enantioselectively initially but competing racemization over
the course of the reaction was responsible for the observed low
enantioselectivity at higher conversions.14 Upon closer
inspection, a general trend was noticed in the fact that therate
allenes directly from prochiral substrates with high stereo-
chemical fidelity are few and far between.4−9
Our own interest in this area was sparked by our ability to
exploit stereodefined enol triflates as pluripotent substrates in
organic synthesis.10,11 In previous work, we reported the
catalytic elimination/isomerization of enol triflates to 1,3-dienes
using Pd(P(tBu)3)2 as the ideal catalyst.12 A viable mechanism
for this reaction involves an initial β-hydride elimination from a
cationic vinyl Pd(II)-complex generating the corresponding
allene intermediate that subsequently isomerizes to the 1,3-
diene product (Scheme 1). We believed that it might be
possible to interrupt this catalytic cycle under attenuated
a b
,
Table 2. Preliminary Scope of the Pd-Catalyzed, Asymmetric β-Hydride Elimination en Route to Chiral Allenes
a
b
Reported are isolated yields with enantiomeric excess (ee) or diastereomeric excess (de) determined by chiral HPLC analysis. Absolute
configuration assignments are based on the observed optical rotation and application of the rules developed by both Brewster and Lowe for chiral
c
allenes (see ref 16). Reaction performed with the enantiomer of ligand 4 provided (+)-6 in equal yield and ee (87% yield, 95% ee).
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Communication
There are several limitations of this methodology that we
would like to disclose (Scheme 3). First, the corresponding
(Z)-enol triflates do not participate in this reaction. Based on
our previous work, we believe this lack of reactivity can be
attributed to the internal chelation of the carbonyl group after
stereospecific oxidative addition that attenuates the agostic
interaction with the β-hydrogens in these cationic Pd(II)-
complexes.12 Even the addition of Lewis acids (i.e., TMSOTf)
did not recover the reactivity of (Z)-enol triflates as had been
observed previously.12 Second, fully substituted (E)-enol
triflates such as 28 that would provide trisubstituted chiral
allenes are poor substrates for this methodology. In this
particular example, we were only able to observe ∼30%
conversion to the chiral allene 29 in 20% ee. While we view
these as significant limitations that warrant disclosure, we are
confident that further optimization will ultimately provide a
solution for these substrates.
Scheme 4. Formal Total Synthesis of (+)-Epibatidine
The application of this methodology to the formal
asymmetric total synthesis of (+)-epibatidine is shown in
Scheme 4.17 Originally discovered in 1976 from the skin extract
of the Ecaudorian poison frog, Epipedobates tricolor, interest in
epibatidine did not peak until its structure was reported in 1992
along with its exquisite biological activity as a powerful
analgesic (∼200× over morphine).18 It is now known that
epibatidine is a highly potent agonist at multiple neuronal
nicotinic acetylcholine receptor (nAChR) subtypes.19 However,
the lack of receptor specificity and dose-limiting toxicity have
led to significant efforts to identify analogs that overcome these
limitations that still continue today.20
of racemization was slower with phosphite-based ligands than
phosphine-based ligands. Thus, we turned our attention to the
design of our own chiral phosphite ligands. After an extensive
screen of ∼50 novel phosphite ligands, we found ligands based
on the BINOL scaffold in combination with menthol-derived
alcohols proved most effective. A highly condensed summary of
our optimization studies with a selected set of these ligands is
provided in Table 1.15
Our approach to (+)-epibatidine began with enol triflate (E)-
30 readily available from the corresponding acetoacetate
derivative.10 Catalytic, asymmetric β-hydride elimination using
ligand 5 gave(+)-(S)-19 in 75% yield and 96% ee on a 3 mmol
scale. A Lewis acid catalyzed Diels−Alder reaction with excess
N-Boc pyrrole gave the corresponding endo-product 31 in 57%
yield.21 Low-pressure chemoselective hydrogenation followed
by ozonolysis yielded β-keto ester 32 in 65% overall yield.
Subsequent decarboxylation followed by reprotection gave
ketone 33 in 70% yield and 89% ee. Previously, Merck has
shown the conversion of racemic 33 to both enantiomers of
epibatidine that completes the formal asymmetric total
synthesis.22
With two chiral phosphite ligands capable of providing either
allene enantiomer in high excess (Table 1, entries 5 and 6), we
turned our attention to the robust synthesis of these ligands
that would facilitate their utility in asymmetric β-hydride
eliminations. Their respective syntheses are outlined in Scheme
2. Both routes developed are easily scalable providing
multigram quantities of 4 and 5 in 80% and 23% overall
yield (respectively) from commercially available starting
materials.
The applicability of this methodology to a broad range of
disubstituted (E)-enol triflates is shown in Table 2. The
preferred reaction conditions include using isopropyl acetate as
the solvent (0.2 M), 5 mol % Pd2dba3, 10 mol % chiral ligand,
In summary, we have discovered a Pd-catalyzed, asymmetric
β-hydride elimination from enol triflates to access chiral allenes
using two optimized phosphite ligands that provide a
complementary substrate scope. Extension of this methodology
to the formal total synthesis of (+)-epibatidine is also described.
Further optimization and application of this catalytic system to
additional substrates is currently underway.
and Hunig’s base (4 equiv) and performing the reaction at
̈
room temperature. Under these conditions, the catalytic system
tolerates multiple functionalities providing good yields of the
corresponding chiral allenes in moderate to excellent
enantioselectivities. Absolute configuration assignments in
Table 2 are based on the observed optical rotation and
application of the rules developed by both Brewster and Lowe
for chiral allenes.16
During the course of these studies we did observe differences
with respect to substrate specificity between ligands 4 and 5
that we wish to highlight. In general, higher enantioselectivities
are obtained using ligand 4 with enol triflates that contain bulky
carbonyl groups (compare 6 and 7 for both ligands). In
contrast, higher enantioselectivities are observed with ligand 5
with less hindered carbonyl groups (Table 1, entry 5 vs 6). We
cannot yet formulate a stereochemical model for these reactions
that would rationalize the apparent substrate preferences
between the two ligands. Nonetheless, we believe the
identification of two highly selective, complementary ligands
is an advantage that broadens the scope of viable substrates at
this early stage of development.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Detailed experimental procedures and ligand screen, H and
13C NMR spectra, and chiral HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
doug.frantz@utsa.edu
Notes
The authors declare no competing financial interest.
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Anderson, D. J.; Campbell, J. E.; Kuntzweiler, T. A.; Donnelly-Roberts,
D. L.; Piattoni-Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J.
Med. Chem. 1998, 41, 407.
(20) Liu, J.; Eaton, B.; Caldarone, B.; Lukas, R. J.; Kozikowski, A. P. J.
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(21) Kimura, H.; Fujiwara, T.; Katoh, T.; Nishide, K.; Kajimoto, T.;
Node, M. Chem. Pharm. Bull. 2006, 54, 399.
(22) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Herbert, R. H.;
Hobbs, S. C.; Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J.
Org. Chem. 1994, 59, 1771.
ACKNOWLEDGMENTS
■
We like to thank the Welch Foundation (AX-1735) for
supporting this work. We also thank Dr. Stephen Bach and Dr.
David Black for high-resolution mass spectral data (supported
by a grant from the National Institute on Minority Health and
Health Disparities (G12MD007591) from the National
Institutes of Health).
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