An Experimentally Derived Model for Stereoselectivity in the Aerobic Oxidative Kinetic Resolution of Secondary Alcohols by (Sparteine)PdCl 2

Article abstract of DOI:10.1021/ja039551q

A model for asymmetric induction in palladium-catalyzed aerobic oxidative kinetic resolution is described. The model is based on coordination complexes and general reactivity trends of the parent (sp)PdCl₂ catalyst. The first example of a nonracemic chiral palladium alkoxide complex is presented, and exhibits the subtle steric influences of the C₁symmetric ligand sparteine. Copyright

Full text of DOI:10.1021/ja039551q

Published on Web 03/18/2004
An Experimentally Derived Model for Stereoselectivity in the Aerobic
Oxidative Kinetic Resolution of Secondary Alcohols by (Sparteine)PdCl
2
Raissa M. Trend and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received November 11, 2003; E-mail: stoltz@caltech.edu
Palladium-catalyzed aerobic oxidation of alcohols has a rich
history that began with the first example by Schwartz in 1977.1
Recently, enantioselective aerobic oxidation of secondary alcohols
by Pd and (-)-sparteine (sp) has emerged as a powerful method
for the preparation of enantioenriched alcohols by kinetic
resolution.3 While numerous improvements to oxidative kinetic
,2
-5
3b,c
resolution (OKR) have been made and the mechanism has been
6
analyzed using kinetics, there have been no reports detailing a
structural model for asymmetric induction by sp in these reactions.
Herein, we describe experiments that probe the origins of stereo-
selectivity in the oxidation and present a nonintuitive model for
the absolute stereochemical outcome. This model is based on the
II
reactivity and solid-state structures of (sp)Pd complexes, including
Figure 1.7 Three perspectives of (-)-sparteine, (-)-R-isosparteine, and
sp)PdCl2 showing the C1- and C2 symmetry of these ligands and the
quaternization effect around the metal center.
the first reported structure of a chiral Pd(II) alkoxide relevant to
this problem.
(
The oxidation of alcohols to carbonyl compounds most likely
involves associative alcohol substitution on Pd, deprotonation of
the resulting Pd‚ROH complex by base to form a Pd alkoxide, and
Scheme 1
8
â-hydride elimination to the carbonyl. For the kinetic resolution
2 2
of 2° alcohols by (sp)PdCl , sp, and O , Sigman has shown that
â-hydride elimination is rate determining and that the observed
enantioselectivity results from a combination of the energy barriers
for the elimination and the thermodynamic stability of the alkoxide
6
Scheme 2 7
complexes. In this analysis sp was treated as if it mimicked a C
2
9
2
symmetric ligand. It is well accepted that C symmetric ligands
quaternize the space around a transition metal to achieve asymmetric
induction via equivalent hemispheres in the catalyst framework
(
Figure 1),10 but the hemispheres of (sp)-ligated Pd are clearly
1
2
nonequivalent (e.g., Cl vs Cl in 1, Figure 1). Thus, to probe the
structural origin of stereoselection in the OKR, we chose to address
the extent to which the C
bound to PdCl
To experimentally test whether the C
behaved as such (i.e., not as a C mimic), complex 1 was treated
with AgSbF in the presence of pyridine. It was anticipated that if
sp mimicked a C symmetric ligand, two cationic pyridyl complexes
2 and 3) would be isolated (Scheme 1). In the event, one major
1 2
symmetric sp exhibits C symmetry when
2
.
1
symmetric sp ligand
2
6
2
(
have been characterized, but few bear â-hydrogens.11 A meaningful
1
13
complex was observed by H and C NMR. Analysis of a single
crystal by X-ray diffraction revealed complex 2.11
steric model for the prototypical OKR substrate 1-phenylethanol
12a,b
is R-(trifluoromethyl)benzyl alcohol 5,
in particular (+)-5, which
Intrigued by this observation, we turned to 2-mesityl pyridine
to probe the steric environment of the other quadrants. Under
identical conditions, we again observed one major product out of
four possible, indicating that not only had substitution occurred on
a single site of the Pd, but that there was also an atropisomeric
preference about the Pd-pyridyl bond. X-ray crystallographic
analysis showed that Cl had been substituted as in 2 and that the
mesityl group resided exclusively in quadrant IV (4, Scheme 2).
These ligand substitution experiments provide convincing evidence
corresponds to the more reactive enantiomer in the resolution.
Treatment of complex 1 with the sodium alkoxide of (+)-5
produced a major product that was crystallized and shown to be
alkoxide complex 6 by X-ray analysis (Scheme 3). A single isomer
1
is observed, and again substitution of Cl occurs. The phenyl moiety
is located in quadrant IV in an orientation similar to that of the
mesityl group of complex 4. Moreover, alkoxide 6 contains a
distorted square plane in which the benzylic C-H bond points
toward the Pd center and the chloride is displaced toward open
quadrant II (15.4° out of plane).1
1
3,14
2
that sparteine does not mimic a C symmetric ligand when bound
to PdCl
2
.
2
On the basis of the reactivity of (sp)PdCl (1) and the structures
To better understand the early stages of the OKR, we set out to
synthesize a relevant alkoxide complex. Numerous Pd alkoxides
of 2, 4, and 6, we propose a general model for asymmetric induction
in the Pd-catalyzed OKR of secondary alcohols. Upon reaction of
4482
9
J. AM. CHEM. SOC. 2004, 126, 4482-4483
10.1021/ja039551q CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Scheme 3 7
In conclusion, we have developed a model for the stereoselec-
tivity in the Pd-catalyzed aerobic oxidative kinetic resolution. The
model is based on coordination complexes and general reactivity
2
trends of (sp)PdCl . The first solid-state structure of a nonracemic
chiral palladium alkoxide is presented and further exhibits the subtle
steric influences of the ligand sparteine. Utilization of this model
to develop new ligands for the asymmetric oxidation of organic
substrates as well as investigation of complex 6 and derivatives to
further probe the mechanism is currently underway. Finally, our
findings may have general implications on the role of sparteine in
other processes.
Acknowledgment. We are grateful to Caltech and the A. P.
Sloan Foundation for financial support. We are indebted to Dr. M.
W. Day and Mr. L. M. Henling for X-ray crystallographic expertise
as well as to Professors J. E. Bercaw, R. H. Grubbs, H. B. Gray,
and J. C. Peters and their groups for assistance and helpful
discussions.
1
complex 1 with a racemic alcohol, Cl is substituted preferentially
2
over Cl to form two diastereomeric Pd alkoxides (Figure 2, 7 and
8
), which could reprotonate and dissociate or undergo â-hydride
elimination. The unsaturated moiety (R ) resides in open quadrant
IV. The position of R in quadrant IV of reacting diastereomer 8
situates the benzylic C-H bond opposite the oblique Pd-Cl bond,
as observed in structure 6. The same orientation of R in quadrant
L
Supporting Information Available: Experimental details and
characterization data for all new compounds. X-ray crystallographic
files in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
L
L
IV of the less reactive diastereomer 7 requires that the C-H bond
point away from Pd. The transition state for â-hydride elimination
References
(
i.e., 9) is expected to involve a cationic Pd species with four-
(1) Schwartz, J.; Blackburn, T. F. J. Chem. Soc., Chem. Commun. 1977, 157.
(2) For recent Pd(II) aerobic alcohol oxidations, see: (a) Peterson, K. P.;
Larock, R. C. J. Org. Chem. 1998, 63, 3185. (b) Nishimura, T.; Onoue,
T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750. (c) Brink, G.-J.;
Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636. (d) For a
review, see: Muzart, J. Tetrahedron 2003, 59, 5798.
15
coordinate square planar geometry, although calculations have
shown that Cl remains closely associated below the square plane.
In structure 6, and 8 by analogy, the reactive C-H bond is poised
to achieve the conformation for elimination via 9 after displacement
of Cl into quadrant II. This sequence of events minimizes potential
steric interactions en route to ketone. In contrast, achievement of a
similar conformation by diastereomer 7 would entail destabilizing
interactions between R
quadrant I (Figure 2). A closely associated Cl could further
disfavor the diastereomeric transition state (arising from 7) by steric
-
16
(
3) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725. (b)
2
Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5, 835.
(c) Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 353.
(
4) (a) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001,
123, 7475. (b) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M.
S. J. Org. Chem. 2003, 68, 4600 and references therein. (c) Mandal, S.
K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535.
2
L
and quadrant III or between Cl and
-
(
5) For other direct dioxygen coupled palladium-catalyzed reactions, see: (a)
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892. (b) Ferreira, E. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 9578 and references therein.
crowding with R
protolytically dissociates to result in the observed enantiomer of
resolved alcohol. This model predicts the absolute stereochemical
outcome of every (sp)PdCl -catalyzed OKR performed to date.
On the basis of this model, we wondered about the behavior of
the C
symmetric ligand (-)-R-isosparteine (isosp) (Figure 1).17
Both anionic Cl ligands of (isosp)PdCl are in an environment
Attempted resolutions of
led to a value for krel of only
Unlike many asymmetric reactions in which a
symmetric ligand leads to a more selective process,10 these results
symmetric ligand can be
better for the OKR.20 Further, the poor selectivity and low reactivity
of (isosp)PdCl provide additional support for the relevance of this
L
. Thus, diastereomer 8 reacts to form ketone, while
7
(6) (a) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005. (b)
Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002,
124, 8202.
2
(
7) Molecular structures of 1, 4, and 6 are shown with 50% probability
ellipsoids. Hydrogens from the sp framework in all front views and the
anion from 4 have been removed for clarity. Stereoviews and crystal-
lographic data for all structures are in the Supporting Information.
2
2
(8) (a) Steinhoff, B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179. (b) Stahl, S. S.;
2
18
Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001,
2
identical to that of Cl in (sp)PdCl .
123, 7188 and references therein.
1
4
C
-phenylethanol with (isosp)PdCl
2
(
9) For another example that uses similar logic, see: Li, X.; Schenkel, L. B.;
19,11
Kozlowski, M. C. Org. Lett. 2000, 2, 875.
.7 after 72 h.
(
(
(
10) Whitesell, J. K. Chem. ReV. 1989, 89, 1581.
11) See Supporting Information for details.
2
support the unusual conclusion that a C
1
12) (a) Under our kinetic resolution conditions, (()-5 does not react. (b) A
racemic Pd(II) alkoxide complex of (()-5 has been reported: [(PMe ) -
3
2
3
Pd(Me)(OR)] where R ) PhCH(CF ). See: Kim, Y.-J.; Osakada, K.;
2
Takenaka, A.; Yamamoto, A. J. Am. Chem. Soc. 1990, 112, 1096.
(13) Similar out-of-plane distortions are observed in complexes 1, 2, and 4.
1
model to the OKR (i.e., reactivity only at Cl ).
(
6 2 2
14) Treatment of 6 with AgSbF (1.5 equiv) in CD Cl at 23 °C leads to
immediate production of the corresponding ketone (92% yield).
15) (a) Bryndza, H. E.; Tam, W. Chem. ReV. 1988, 88, 1163. (b) Zhao, J.;
Hesslink, H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 7220. (c) For
an alternative with Pt, see: Bryndza, H. E.; Calabrese, J. C.; Marsi, M.;
Roe, D. C.; Tam, W.; Bercaw, J. E. J. Am. Chem. Soc. 1986, 108, 4805.
16) High level calculations (B3LYP DFT) agree with this model. The Cl- is
not fully bound. Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W.
A. J. Am. Chem. Soc. Submitted for publication, 2004.
(
(
(
17) Prepared by the method of Leonard, see: Leonard, N. J.; Beyler, R. E. J.
Am. Chem. Soc. 1950, 72, 1316.
(
(
(
18) See Supporting Information for X-ray crystallographic structure.
19) (sp)PdCl provides krel ) 17.3 in 24 h.
2
20) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien P. J. Am.
Chem. Soc. 2002, 124, 11870. (b) Hermet, J.-P. R.; Porter, D. W.; Dearden,
M. J.; Harrison. J. R.; Koplin, T.; O’Brien, P.; Parmene, J.; Tyurin, V.;
Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1,
3977.
Figure 2. Model for stereoselectivity in the Pd-catalyzed aerobic oxidative
kinetic resolution using (sp)PdCl2.
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J. AM. CHEM. SOC.
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