Palladium-mediated regiodivergent kinetic resolution

Article abstract of DOI:10.1021/ol016633f

(metrix presented) racemic substrate optically active regioisomers of opposite configuration The allylic substitution of racemic 5-vinyloxazolidinones with phthalimide and a chiral palladium catalyst afforded optically enriched regioisomeric products. Optimal divergence was found by employing chiral DIOP ligands in toluene. These results demonstrate the influence of chiral ligand/chiral substrate matching on the regioselectivity in a novel resolution strategy.

Full text of DOI:10.1021/ol016633f

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3531-3533
Palladium-Mediated Regiodivergent
Kinetic Resolution
Gregory R. Cook* and S. Sankaranarayanan
Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
gregory.cook@ndsu.nodak.edu
Received August 22, 2001
ABSTRACT
The allylic substitution of racemic 5-vinyloxazolidinones with phthalimide and a chiral palladium catalyst afforded optically enriched regioisomeric
products. Optimal divergence was found by employing chiral DIOP ligands in toluene. These results demonstrate the influence of chiral
ligand/chiral substrate matching on the regioselectivity in a novel resolution strategy.
Since the first report of the kinetic resolution of enantiomers
by Pasteur nearly 150 years ago,1 many novel and interesting
resolution processes have been developed.2 In a traditional
resolution, enantiomers are separated by the selective reaction
of one enantiomer with a chiral reagent leading to a
maximum 50% yield of an enantioenriched product or
recovered starting material. Recently, processes in which both
enantiomers react in a divergent sense to form two different
optically enriched products have been investigated. Parallel
kinetic resolution (PKR), where two different chiral reagents
react with a racemic substrate to form two different products,
has been examined.3
Figure 1. Divergent kinetic resolution of enantiomers by the
formation of regiosomeric products of opposite configuration.
Conceptually similar to PKR is a process wherein a single
chiral catalyst or reagent may react with a racemic substrate
to form regioisomers of opposite configuration (Figure 1).
The theoretical aspects of regiodivergent resolution were
recently described by Kagan.4 In practice, there are only a
few examples to demonstrate the concept. The enzymatic
or copper-catalyzed asymmetric Bayer-Villiger oxidation
of racemic cycloalkanones led to the formation of regioiso-
meric lactones of opposite configuration with high enantio-
meric excess.5 Asymmetric copper-catalyzed alkylation of
(1) Pasteur, L. C. R. Hebd. Se´ance Acad. Sci. Paris 1858, 46, 615-618.
(2) For recent reviews, see: (a) Cook, G. R. Curr. Org. Chem. 2000, 4,
869-885. (b) Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2,
489-526. (c) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475-1490.
(d) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36-55. (e) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 395-409. (f) Brown, J. M. Chem
Ber. 1989, 25, 276-280. (g) Finn, M. G.; Sharpless, K. B. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1985; pp 247-
308.
(3) (a) For a recent review, see: Eames, J. Angew. Chem., Int. Ed. 2000,
39, 885-888. See also: (b) Vedejs, E.; Rozners, E. J. Am. Chem. Soc.
2001, 123, 2428-2429. (c) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997,
119, 2584-2585. (d) Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein,
T.; Tanner, D.; Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535-538. (e)
Cardona, F.; Valenza, S.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 1999,
1319-1323. (f) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D.
A.; Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117,
11021-11022.
(4) Kagan, H. Croat. Chem. Acta 1996, 69, 669-680.
10.1021/ol016633f CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

diamine 4 and 1,4-diamine 5. When chiral ligands were
employed in this reaction, the regioselectivity was found to
be highly dependent on the matching of the ligand chirality
and the substrate chirality. (R)-BINAP afforded a 20:1
regioselectivity, whereas (S)-BINAP gave a reduced 3:1
regioselectivity. Interestingly, diastereoselectivity was com-
pletely controlled by the substrate and the chiral ligand did
not exert any influence.
Scheme 1. Chiral Ligand Dependent Regioselectivity in the
Pd-Catalyzed Allylic Substitution of 5-Vinyloxazolidinonesa
As the regioselectivity of the allylic substitution of 1 was
dependent on the asymmetric matching of the ligand and
substrate, we anticipated that reaction of rac-1 with phthal-
imide in the presence of a chiral catalyst would afford
optically active regiodivergent products. Herein we present
the results of our investigation of the regiodivergent kinetic
resolution of rac-1.
As shown in Scheme 2, the allylic substitution of rac-1 is
complicated by the presence of equilibrating diastereomers.
Reaction of enantiomer (S)-1 will lead to diastereomeric
complexes (S)-2 and (S)-3, while reaction of (R)-1 will give
(R)-2 and (R)-3. The vicinal diamine products (S,S)- and
(R,R)-4 can only be derived from (S)-2 and (R)-2, respec-
tively. However, the 1,4-diamine products (S)-5 could arise
from either (S)-2 or (S)-3. Likewise, either (R)-2 or (R)-3
could give (R)-5. Fortunately, as we have previously shown,8
the chiral ligand matching with the substrate has no influence
on the diastereoselectivity and the syn-isomers of 4 should
be produced from either set of equilibrating intermediates.
Thus, this system would not be complicated by the presence
of anti-4.
a (a) cat. [C3H5PdCl]2/chiral ligand, phthalimide, cat. K-phthal-
imide, THF, rt.
racemic vinylepoxides with dialkyl zinc reagents afforded
optically enriched regioisomeric alcohols via a SN2 or SN2′
mechanism.6 Also, Pfaltz has recently demonstrated a variant
of this concept in the Pd-catalyzed allylic substitution reaction
where the regiodivergent products stemmed from the con-
figuration of starting substrates.7
As part of our program to develop new methods for the
stereoselective preparation of vicinal diamines, we have
investigated the Pd-catalyzed allylic substitution of 5-vinyl-
oxazolidinones with phthalimide nucleophile (Scheme 1).8
Reaction of diastereomeric mixtures of 1 with a Pd(0) catalyst
resulted in the formation of equilibrating diastereomeric
complexes 2 and 3. Addition of phthalimide to the allyl
complexes led to the stereoselective formation of vicinal
The results of the enantioselective regiodivergent kinetic
resolution9 are summarized in Table 1. Ideally, for optimal
regiodivergence, the chirality match and mismatch should
be opposite (e.g., 100:0 vs 0:100). As the reaction of (S)-1
with (R)- or (S)-BINAP was found to afford the same major
Scheme 2. Regiodivergent Kinetic Resolution
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Org. Lett., Vol. 3, No. 22, 2001

Table 1. Regiodivergent Kinetic Resolution of 5-Vinyloxazolidinonesa
% eed (config)
yielde
entry
ligandb
solvent
regioselectivityc (4:5)
4
5f
4
5
1
2
3
4
5
6
7
8
9
(R)-BINAP
(S)-BINAP
(R)-BINAP
(S)-BINAP
(R)-BINAP
(S)-BINAP
(R,S)-J OSIPHOS
(S,R)-J OSIPHOS
(R,R)-DIOP
(S,S)-DIOP
(R,R)-DIOP
(S,S)-DIOP
THF
THF
5:1
5:1
1:1
1:1
1:2.4
1:2.4
2:1
14 (S,S)
9 (R,R)
62 (R)
57 (S)
29 (R)
36 (S)
17 (R)
13 (S)
22 (S)
22 (R)
38 (S)
37 (R)
48 (S)
46 (R)
73
69
35
34
24
24
53
54
26
23
33
35
11
16
37
36
47
47
25
25
44
47
39
41
CH2Cl2
CH2Cl2
CH3CN
CH3CN
THF
THF
THF
THF
toluene
toluene
33 (S,S)
35 (R,R)
36 (S,S)
37 (R,R)
11 (R,R)
11 (S,S)
45 (R,R)
44 (S,S)
52 (R,R)
50 (S,S)
2:1
1:1.8
1:1.8
1:1.2
1:1.2
10
11
12
a 1 mol % [(C3H5)PdCl]2, 4 mol % ligand, 10 mol % potassium phthalimide, 1.1 equiv phthalimide. b (R)-BINAP ) (R)-2,2′-bis(dihpenylphosphino)-
1,1′-binaphthyl, (R,S)-JOSIPHOS ) (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine, (R,R)-DIOP ) (4R,5R)-O-isopropylidene-2,3-
dihydroxy-1,4-bis(diphenylphosphino)butane. c Regioselectivity was determined by 1H NMR analysis of the crude reaction mixture. d Enantiomeric excess
was determined by chiral HPLC (Chiracel OD or Chiralpak AS) analysis after chromatographic separation of the regioisomers. e Isolated yield. f The ee of
5 was measured after hydrogenation of the double bond.
regioisomer but with different levels of selectivity (20:1 vs
3:1, respectively), it is not surprising that BINAP ligands
employed under our original conditions with rac-1 would
not provide very high selectivity. Indeed, this was the case,
as shown in entries 1 and 2. The vicinal diamine was formed
as the major regioisomer (5:1) with a low 10% ee. The minor
regioisomer was, however, significantly enhanced in optical
purity (∼60% ee). The use of other solvents that provide a
more equal mixture of regiosomers provided proof of concept
for regiodivergent resolution (entries 3 and 4). Although
optical purity was not high, both regioisomers were obtained
with nearly the same level and opposite configurations. The
use of acetonitrile as the solvent led to an increased amount
of 5. Again, the major regioisomer was obtained with lower
ee than the minor (entries 5 and 6). Other commercially
available bisphosphine ligands were briefly investigated.
JOSIPHOS provided low levels of enantiomeric excess
(entries 7 and 8), whereas DIOP ligands afforded the highest
ee for both regioisomers in a single reaction (entries 9-12).
In conclusion, we have established the asymmetric re-
giodivergent kinetic resolution of 5-vinyloxazolidinones by
a Pd-catalyzed allylic substitution with phthalimide. Optimal
divergence was found by employing chiral DIOP ligands in
toluene. While the ee’s are only modest, these results
demonstrate the influence of chiral ligand/chiral substrate
matching to command, not stereochemistry, but regioselec-
tivity in a novel resolution strategy. Currently we are
investigating the utility of chiral nucleophiles in this regio-
divergent kinetic resolution and our results will be reported
in due course.
(5) (a) Petit, F.; Furstoss, R. Tetrahedron: Asymmetry 1993, 4, 1341-
1352. (b) Bolm, C.; Schlingloff, C.; Schlingloff, G. J. Chem. Soc., Chem.
Commun. 1995, 1247-1248.
(6) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L.
Angew. Chem. Int. Ed. 2001, 40, 930-932.
Acknowledgment. We are grateful to the National
Institutes of Health (GM58470-01, RR15566-01), the Na-
tional Science Foundation (CHE9875013), and NDSU for
generous support of or programs. NMR instrumentation was
made available through funds from the National Science
Foundation (CHE9871223).
(7) Loiseleur, O.; Elliott, M. C.; von Matt, P.; Pfaltz, A. HelV. Chim.
Acta 2000, 83, 2287-2294.
(8) Cook, G. R.; Shanker, P. S.; Pararajasingham, K. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 110-112.
(9) General Procedure. A 10-mL Schlenk flask was charged with
5-vinyloxazolidinone 1 (77 mg, 0.25 mmol), phthalimide (41 mg, 0.27
mmol), potassium phthalimide (9.3 mg, 0.05 mmol), [(π-C3H5)PdCl]2 (0.9
mg, 1 mol %), and ligand (4 mol %) and sealed with a rubber septum. The
flask was evacuated and flushed with nitrogen three times. Solvent (2 mL)
was added, and the reaction was stirred at ambient temperature until TLC
indicated complete consumption of starting material. The regioisomers were
separated on silica gel (200-400 mesh) using 10-35% v/v ethyl acetate/
hexane as eluent to afford pure 4 and 5. The 1,4-products 5 were
hydrogenated under 1 atm H2 with 5% Pd/C in ethyl acetate for 2 h prior
to HPLC analysis.
Supporting Information Available: Characterization
data and NMR spectra for 4, 5 and hydrogenated 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016633F
Org. Lett., Vol. 3, No. 22, 2001
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