1
1
the first case the reaction occurs via the S
N
2′ mechanism
metrization of methylidene cycloalkene oxides, the allylic
1
2
with retention (the nucleophile attacks from the same side
alkylation of cinnamyl derivatives, and the rhodium-
3
13
of the allylic leaving group), in the second case the allylic
catalyzed addition of arylboronic acids.
4
displacement reaction takes place with inversion. Piarulli,
In this paper we report a highly enantioselective desym-
metrization of meso-4-cyclopentene-1,3-bisdiethyl phosphate
(2a), meso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), and
meso-2-cycloheptene-1,4-bisdiethyl phosphate (2c) with di-
ethylzinc catalyzed by copper(I) complexes of phosphora-
midite ligands 5 (Figure 1).
Gennari, and co-workers have recently disclosed a new
highly regio-, diastereo-, and enantioselective desymmetri-
zation of meso-cyclic allylic bisdiethyl phosphates with
5
organozinc reagents catalyzed by copper(I) complexes of
6
chiral Schiff base ligands 1 (Scheme 1). In the case of meso-
Scheme 1. Desymmetrization of meso-Cyclic Allylic
Bisdiethyl Phosphates with Organozinc Reagents Catalyzed by
Copper(I) Complexes of Chiral Schiff Base Ligands 1
Figure 1. Structure of the phosphoramidite ligands 5.
Copper complexes of ligands 5a-f were obtained in situ
I
by stirring Cu OTf with 2 equiv of the appropriate ligand in
toluene (45 min, rt). Reaction of meso-4-cyclopentene-1,3-
bisdiethyl phosphate (2a), readily obtained from com-
14
mercially available meso-4-cyclopentene-1,3-diol, with 2.0
equiv of Et Zn in the presence of 10 mol % of the copper-
2
phosphoramidite complexes afforded the product arising from
allylic displacement with inversion (3a, R ) Et) in variable
yields and enantiomeric excesses (Table 1). In particular,
the screening of the ligands revealed that good yields and
enantiomeric excesses were obtained when phosphoramidite
ligands with bulkier secondary amine substituents were used
4
-cyclopentene-1,3-bisdiethyl phosphate (2a), only the prod-
uct arising from the allylic displacement (S 2′) mechanism
N
with inversion (3a) was obtained with excellent yield and
enantiomeric excess (ee) up to 88% after screening a library
of 125 Schiff-base ligands 1. Reaction of diethylzinc with
meso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), on the
contrary, gave the allylic displacement products originating
from either inversion (3b) or retention (4b) with good
diastereoselectivity (81:19-4:96), depending on the solvent
and the ligand used. However, very low ees were obtained.
The reaction of meso-2-cycloheptene-1,4-bisdiethyl phos-
phate (2c) afforded only the product arising from the allylic
displacement with inversion (3c), albeit with modest ee (up
to 56%).
(entries 2-4). Varying the temperature with the best ligand
(5b) increased the enantiomeric excess to 87% at -40 °C
(entry 7). Dimethylzinc was considerably less reactive than
diethylzinc; the reaction had to be run at 0 °C to obtain 3a
(
R ) Me) with a fair conversion (54%), still associated with
15
a good ee (87%, Table 1, entry 10).
meso-2-Cyclohexene-1,4-bisdiethyl phosphate (2b) was
obtained starting from cyclohexadiene via a palladium-
(8) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374-2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,
L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997,
The Groningen group has demonstrated that phosphora-
midites of general structure 5 serve as very effective ligands
in a number of catalytic asymmetric carbon-carbon bond-
forming reactions. These include the already mentioned
copper-catalyzed ring opening of oxabicyclic alkenes, the
3
6, 2620-2622. (c) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa,
B. L. Org. Lett. 1999, 1, 623-626.
9) (a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedon 2002,
(
5
8, 5773-5778. (b) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.
7
Chem. Soc. 2003, 125, 3700-3701.
(10) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L.
Angew. Chem., Int. Ed. 2001, 40, 930-932.
4
8
conjugate addition of dialkylzincs to enones and nitro
alkenes, the ring opening of vinyl epoxides, the desym-
(11) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
9
10
Feringa, B. L. Org. Lett. 2000, 2, 933-936.
(12) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett.
2
001, 3, 1169-1171.
(
5) Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew.
Chem., Int. Ed. 2003, 42, 234-236.
6) (a) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew.
(13) Boiteau, J. G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.
2003, 5, 682-685 and 1385.
(
(14) cis-4-Cyclopentene-1,3-diol was transformed into the corresponding
bisdiethyl phosphate (2) by deprotonation with n-BuLi and reaction with
diethylchlorophosphate in THF/TMEDA (4/1); see: Yu, K. L.; Ko, K. Y.;
Fraser-Reid, B. Synth. Commun. 1988, 465-468.
Chem., Int. Ed. 2000, 39, 916-918. (b) Ongeri, S.; Piarulli, U.; Jackson,
R. F. W.; Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (c) Chataigner,
I.; Gennari, C.; Ongeri, S.; Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001,
7
, 2628-2634.
(15) Reactions at -40 or -20 °C showed poor conversions (15-20%)
associated with slightly better ees (90-93%).
(7) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.
4494
Org. Lett., Vol. 5, No. 23, 2003