Highly efficient kinetic resolution of 2-cyclohexenyl acetate in Pd- catalyzed allylic alkylation

Article abstract of DOI:10.1016/S0040-4039(00)00844-3

A new phosphine ligand has been synthesized and employed in the Pd- catalyzed alkylation of 2-cyclohexenyl esters. A very efficient resolution of 2-cyclohexenyl acetate was observed during alkylation. In addition, the reactivity and enantioselectivity showed a strong dependence on the acetate salt with the BSA/MOAc (M = alkali metal) base system during alkyation of cyclohexenyl carbonate. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00844-3

Tetrahedron Letters 41 (2000) 5435±5439
Highly ecient kinetic resolution of 2-cyclohexenyl acetate in
Pd-catalyzed allylic alkylation
James M. Longmire, Bin Wang and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 16 May 2000; accepted 25 May 2000
Abstract
A new phosphine ligand has been synthesized and employed in the Pd-catalyzed alkylation of 2-cyclo-
hexenyl esters. A very ecient resolution of 2-cyclohexenyl acetate was observed during alkylation. In
addition, the reactivity and enantioselectivity showed a strong dependence on the acetate salt with the
BSA/MOAc (M=alkali metal) base system during alkyation of cyclohexenyl carbonate. # 2000 Published
by Elsevier Science Ltd.
The design and synthesis of new chiral ligands remains an important area of research with
respect to developing highly enantioselective transition metal-catalyzed reactions. A successful
ligand should therefore be readily accessible, stable, and highly tunable since modi®cation of the
steric and electronic properties are often necessary for achieving high asymmetric induction.
We have begun to develop ligand families derived from e€ective chiral synthons with the aim of
meeting the above-mentioned requirements. One such synthon, 3, as shown in Scheme 1, is
1
derived from the well-known chiral phosphinoferrocenyloxazoline (1). Hydrolysis of the oxazoline
2
ring in 1 using tri¯ic acid followed by acylation gives the amide-ester 2. Compound 2 is then
3
converted in high yield to the desired acid 3 upon treatment with t-BuOK. The bene®ts of 3 are
that it is readily available in large quantities and is air-stable. Ligand modi®cations can then be
easily realized by appending various units to the carboxylate functionality. Furthermore, the planar
chirality of ferrocene, usually in conjunction with additional sources of chirality, has proven to be
4
quite an e€ective framework for providing high asymmetric induction. Herein we wish to report
our ®ndings for the Pd-catalyzed allylic alkylation reaction employing ligands 4 and 5. These
ligands are easily obtained by coupling acid 3 with (1S,2S) and (1R,2R)-diaminocyclohexane as
outlined in Scheme 1.5
*
Corresponding author. Tel: (814) 865-4221; fax: (814) 863-8403; e-mail: xumu@chem.psu.edu
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00844-3

5
436
ꢀ
2
O/THF, 0 C to rt, 24 h; (b) acetic anhydride, pyridine,
Scheme 1. Reagents: (i) (a) tri¯uoroacetic acid, Na
2
SO
4
, H
O, 0 C to rt, 24 h; (iii) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-
HCl, 4-(dimethylamino)pyridine, CH Cl , 24 h, rt
ꢀ
ꢀ
CH Cl , 0 C to rt, 24 h; (ii) t-BuOK, Et O, H
2 2 2 2
2
2
The Pd-catalyzed allylic alkylation reaction has become the standard test reaction for gauging
the e€ectiveness of new ligands. Speci®cally, (E)-1,3-diphenylprop-2-enyl acetate has been the
substrate most often used and numerous ligands have been successfully applied to the enantio-
6
selective alkylation of this compound. As for the more challenging cycloalkenyl ester substrates,
7
far fewer successful ligands have been reported. Employing ligands 4 and 5 we sought to ®nd
conditions to alkylate cyclohexenyl acetate 6 with high enantioselectivity.
Using dimethyl malonate as nucleophile and ligand 4, the reaction conditions were optimized
as outlined in Table 1. The highest enantioselectivity was obtained using THF as solvent and BSA/
3
KOAc as base. Under these conditions, there was very little di€erence between [(Z -allyl)PdCl]2
and Pd (dba) CHCl (entry 10 versus 11, Table 1). Furthermore, under the conditions in entries
1
2
3
3
0 and 11, ligand 5 gave much lower enantioselectivity (37% and 30% ee, respectively, of (R)-7).
It is clear from the results that the (S)-planar chirality and the (S) con®guration of the diamine
backbone work in a cooperative sense. However, despite the conditions employed, the reaction
conversion remained only moderate. Conveniently, GC could be used to monitor the progress of
the reaction. Using a chiral capillary column, conditions were found which allowed determination
of both the product and unreacted starting material enantioselectivity. As Table 2 shows, a very
8
ecient kinetic resolution of 6 is occurring. After 54% conversion unreacted 6 has an ee of 99%
and the alkylation product 7 an ee of 92%. This equates to an S-factor of 61 illustrating the
9
remarkable eciency of this resolution. Furthermore, the results in Table 2 also illustrate how
the reaction slows considerably after 54% conversion is reached. An additional 20 hours of
reaction time results only in a further 20% reaction conversion. Based on the optical rotations of
10
isolated 7 and unreacted 6, it is (R)-6, which proceeds rapidly to product. On the other hand,
S)-6 proceeds slowly to product and may inhibit, in some way, catalyst turnover since the reaction
never reaches 100% conversion. These results indicate that the stereochemistry of the allylic
(

5
437
Table 1
Optimization for alkylation of 6a
Table 2
Kinetic resolution of 6a
substrate 6 has an in¯uence over the intermediate p-allyl/Pd complex formed prior to nucleophilic
attack. This so-called memory e€ect has been the topic of recent reports in the area of Pd-catalyzed
1
1
allylic alkylation.

5
438
Interestingly, by changing the leaving group in 6 from acetate to the methyl carbonate 8,
complete reaction conversion could be achieved. The reaction reached complete conversion
without slowing signi®cantly or ceasing as with acetate 6. What is most interesting is the e€ect of
the acetate salt.12 As Table 3 illustrates, both the reactivity and enantioselectivity increase as the
size of the alkali metal increases, reaching a maximum with Cs.13 Such a trend was not observed
with substrate 6.
Table 3
E€ect of acetate salt on alkylation of 8
In conclusion, we have developed a very selective ligand that can that can di€erentiate quite
e€ectively between the R and S enantiomers of acetate 6. This selectivity results in a very ecient
kinetic resolution of acetate 6 during alkylation. Currently, we are investigating a variety of tran-
sition metal-catalyzed reactions as well as synthesizing additional ligands derived from synthon 3.
The results of this work will be reported in due course.
Acknowledgements
NIH (1R01 GM58832-01A1) and a Camille and Henry Dreyfus Teacher Scholar Award sup-
ported this work. We thank Supelco for a generous gift of a b-Dex 120 chiral capillary column.
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