J . Org. Chem. 1996, 61, 1875-1876
1875
Sch em e 1
P r a ctica l Syn th esis of (R,R)- a n d
(S,S)-Bis[2,6-bis(1-eth oxyeth yl)p h en yl]
Diselen id e
Robert De´ziel,* Eric Malenfant, and Guillaume Be´langer
Bio-Me´ga/ Boehringer Ingelheim Research Inc.,
2100 Cunard Street, Laval (Que´bec), Canada, H7S 2G5
Received October 27, 1995
We recently reported the synthesis of a new chiral C2
symmetrical organoselenium reagent, 1a , and showed its
usefulness in the asymmetric selenomethoxylation of
olefins1a and in the preparation of enantiomerically
enriched heterocycles via asymmetric ring closure
reactions.1b However, in order for this new reagent to
be more synthetically useful, a facile and economical
access to both enantiomers was highly desirable. Al-
though our original synthesis was highly enantioselec-
tive, it was, nevertheless, lengthy, and the chiral reagents
involved were somewhat expensive. We now report a
more practical enantioselective synthesis of (R,R)- and
(S,S)-1 featuring a dual asymmetric reduction of the
diketone intermediate 3 (Scheme 1).
Our original synthesis involved the sequential conver-
sion of each carboxylic acid in 2 to the desired chiral
ethoxyethyl moiety. Clearly, it would be more efficient
if we could convert both carboxylic acids simultaneously.
However, attempts to prepare the diketone 3 by adding
methyl organometallic reagents to activated acyl deriva-
tives of the bromophthalic acid 2 turned out to be
problematic. Loss of the bromine atom was a major side
reaction, and the separation of 3 from the resultant
complex mixture was difficult. We have now found that
condensation of the diacyl chloride of 2 with the sodium
salt of dimethyl malonate followed by hydrolysis and
decarboxylation2 afforded the desired diketone 3 in 75%
yield after distillation. In our original synthesis, we
achieved the stepwise enantioselective reduction of the
two carbonyls via the oxazaborolidine-catalyzed borane
reaction.3 We thus attempted to use this reagent for the
dual asymmetric reduction of 3 to give 4. However, in
our hands, this method gave irreproducible yields and
enantioselectivities. We obtained more reproducible
results including high enantioselectivities using com-
mercially available (+)- or (-)-B-chlorodiisopinocamphey-
lborane (DIP-chloride).4 Thus treating 3 with 2.2 equiv
of (+)-DIP-chloride in THF at -25 °C afforded the desired
R,R diol 4a in 81% yield and with an enantiomeric purity
>99% (measured by chiral HPLC).5 The S,S diol 4b
(>99% ee) was similarly obtained from (-)-DIP-chloride
in 82% yield. It should be noted that both (+)- and (-)-
DIP-chloride, even used in stoichiometric amounts, are
less expensive than the R,R-diphenyl-2-pyrrolidinemetha-
nol used in the oxazaborolidine-catalyzed borane reduc-
tion. Treatment of the diols 4a ,b with ethyl iodide and
sodium hydride gave the diethyl ethers 5a ,b in 83% yield.
As previously described, the diselenides 1a ,b were pre-
pared by lithiation of 5a ,b with 2 equiv of tert-BuLi in
THF at low temperature followed by the addition of
elemental selenium. Air oxidation of the crude product
in the presence of a catalytic amount of sodium hydroxide
and crystallization from methanol afforded the desired
diselenide 1a ,b in 70-76% yield with an enantiomeric
purity >99%.
In summary we have developed a short and highly
enantioselective synthesis of the C2 symmetrical R,R and
S,S diselenides 1. This new synthetic route relies on the
efficient and reproducible asymmetric reduction of the
diketone 3 with (+)- or (-)-B-chlorodiisopinocamphey-
lborane.
Exp er im en ta l Section
2,6-Dia cetylbr om oben zen e (3). The diacid 26 (24.3 g,
0.0989 mol) was refluxed in 30 mL of thionyl chloride overnight.
The reaction mixture was concentrated in vacuo, and the residue
was kept under vacuum overnight to give the diacyl chloride
derivative of 2 as an off-white solid (27.9 g) which was used as
such for the next step. Dimethyl malonate (28.2 mL, 0.247 mol)
was added dropwise to a 0 °C cooled suspension of sodium
hydride (60% dispersion in mineral oil, 19.8 g, 0.495 mol) in THF
(220 mL). The mixture was heated to reflux, and then a THF
(130 mL) solution of the diacyl chloride (27.9 g, 0.0989 mol) was
slowly added. After 15 h of reflux, the mixture was cooled and
10% sulfuric acid (200 mL) was slowly added. The THF was
removed under vacuum, and the resultant mixture was extracted
with ether (3×). The combined organic layers were concentrated
under vacuum. The crude tetraester was then refluxed for 24
h in a mixture of water (44 mL), concentrated sulfuric acid (8.6
mL), and acetic acid (67 mL). The reaction mixture was diluted
with water (100 mL) and extracted with EtOAc (2×). The
combined organic layers were washed with brine, dried over K2-
(1) (a) De´ziel, R.; Goulet, S.; Grenier, L.; Bordeleau, J .; Bernier, J .
J . Org. Chem. 1993, 58, 3619. (b) De´ziel, R.; Malenfant, E. J . Org.
Chem. 1995, 60, 4660.
(2) Protocol based on a similar transformation: McKinnon, D. M.;
Wong, J . Y. Can. J . Chem. 1971, 49, 2018.
(3) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987,
109, 5551. Corey, E. J .; Shibata, S.; Bakshi, R. K. J . Org. Chem. 1988,
53, 2861. Corey, E. J .; Link, J . O. Tetrahedron Lett. 1992, 33, 4141
and references cited therein.
(4) Purchased from Aldrich Chemial Co. Inc. For a good review on
this reagent see: Dhar, R. K. Aldrichim. Acta 1994, 27, 43.
(5) We also obtained some of the R,S (meso) isomer (6.5%) which
was easily separated by column chromatography on silica gel.
(6) Prepared according to: Coulson, E. A. J Chem. Soc. 1937, 1298.
0022-3263/96/1961-1875$12.00/0 © 1996 American Chemical Society