6394
J . Org. Chem. 1997, 62, 6394-6396
Notes
dissymmetrization, asymmetric synthesis) to give an
A Str a tegy for th e Tr a n sfor m a tion of a
enantiomerically enriched compound and (ii) derivatiza-
tion of the chiral compound with the bifunctional non-
chiral material which will allow, after crystallization and
hydrolysis, for completion of the enantiomers separation.
This methodology has not been applied in our knowledge
to multifunctional compounds. We reasoned that the
second part of the process (derivatization and hydrolysis)
will not result in an additional step when multifunctional
compounds are used, if the derivatization (necessary for
diastereoisomers formation) acts at the same time also
as a functional group protection and the bifunctional
molecule enriched in one enantiomer thus obtained is
used in a bi-directional synthesis not requiring terminus
differentiation. The principles of this sequence are better
explained in Figure 1: the nonracemic compound (en-
riched in the R-enantiomer) when treated with the
bifunctional nonchiral reagent as in step a gives three
stereoisomers in the ratio expected from simple calcula-
tions.2 If the meso stereoisomer can be separated by
crystallization, the enantiomeric purity of the R,R form
can be raised up to one single enantiomer in favorable
conditions. The compound obtained from step b is a
protected form of the enantiomerically enriched starting
material and can be further transformed (step c) and
finally deprotected (step d) to give the required product,
allowing the recovery of the bifunctional auxiliary.
Mu ltifu n ction a l Ch ir a l Syn th on of
Mod er a te ee in to a n En a n tiom er ica lly P u r e
Syn th etic In ter m ed ia te
Paola D’Arrigo, Luca Feliciotti,
Giuseppe Pedrocchi-Fantoni, and Stefano Servi*
CNR Centro di Studio sulle Sostanze Organiche Naturali,
Dipartimento di Chimica, Politecnico, Via Mancinelli, 7,
20131 Milano, Italy
Received March 21, 1997
In tr od u ction
The preparation of chiral compounds in enantiomeri-
cally pure form is an argument of increasing interest in
the preparation of fine chemicals. The various tech-
niques which can be applied to the production of chirality
have been considered.1 Among them, the possibility of
obtaining pure enantiomers using crystallization as a key
step is still the most successful way to reach the goal.2
While the crystallization of diastereoisomeric salts is
more often employed,3 the direct crystallization of enan-
tiomers from a racemic mixture is sometimes possible.
Horeau showed that by linking a chiral compound with
a bifunctional nonchiral molecule the starting material
itself can act as a chiral auxiliary forming diastereoiso-
meric couples which can be separated or recognized by
physical or chemical means, thus allowing the analysis
of the enantiomeric purity of the starting material or
separation of diastereoisomer and then recovery of the
enantiomers in enriched form.4 This method has been
widely used in determining the enantiomeric excess of a
mixture. For example a nonracemic chiral alcohol de-
rivatized with a bicarboxylic acid will give rise to two
enantiomeric esters and a meso form. Their ratio will
tell the enantiomeric purity of the starting material.
While this technique has been often considered for
analytical purposes,5 only seldom it has been applied to
the preparative enrichment of a nonracemic mixture.
Fleming recently used the diester obtained from oxalyl
chloride and a methylcarbinol to prepare, after crystal-
lization of the diastereoisomeric mixture and hydrolysis,
the starting alcohol in enantiomerically pure form.6
We here report the application of the former sequence
using as starting materials 2,3-O-isopropylidene glycerol
1 as a chiral educt, the terephthaloyl group 2 as achiral
linker, and the amino diol 3, intermediate in the syn-
thesis of optically active timolol,7 as the synthetic target
(Figure 2). We used as starting materials 2,3-O-isopro-
pylidene glycerol 1 of (S) or (R)-absolute configuration8-10
of 80% ee as resulting from uncomplete resolution of the
racemic mixtures.11 Their esters with terephthalic acid
were easily and quantitatively obtained via esterification
with terephthaloyl dichloride (2a ) or methyl terephtha-
late (2b) in standard conditions. Functionalized tereph-
thalic acids are among the least expensive bicarboxylic
acid derivatives; they often give crystalline esters which
are easily cleaved via basic transesterification in alcoholic
medium at room temperature. They are otherwise stable
in acid conditions allowing the series of manipulation
successively described. Terephthalates are therefore
Resu lts a n d Discu ssion
The application of the above technique in the synthetic
sequence requires (i) generation of chirality (resolution,
(1) (a) Collins, A. N., Sheldrake, G. N.,Crosby, J ., Eds. Chirality in
Industry; J ohn Wiley & Sons: New York, 1992. (b) Sheldon, R. A.
Chirotechnology; Marcel Dekker Inc., New York, 1993.
(2) Wilen, H. S.; Collet, A.; J acques, J . Tetrahedron 1977, 33, 2725.
(3) Kozma, D.; Acs, M.; Fogassy, E. Tetrahedron 1994, 50, 6907.
(4) Vigneron, J . P.; Dhaenens, M.; Horeau, A. Tetrahedron 1973,
29, 1055.
(5) Feringa, B. L.; Smaardijk, A. A.; Wynberg, H.; Strijtveen, B.;
Kellog, R. M. Tetrahedron Lett. 1986, 27, 997. Feringa, B. L.; Strijtveen,
B.; Kellog, R. M. J . Org. Chem. 1986, 51, 5486. Strijtveen, B.; Feringa,
B. L.; Kellog, R. M. Tetrahedron 1987, 43, 1987. Chan, T. H.; Peng,
Q.-J .; Wang, D.; Guo, J . A. J . Chem. Soc., Chem. Commun. 1987, 325.
Leitich, J . Tetrahedron Lett. 1978, 19, 997. Pasquier, M. L.; Marty,
W. Angew. Chem., Int. Ed. Engl. 1985, 24, 315. Heumann, A.; Loufti,
A.; Ortiz, B. Tetrahedron: Asymmetry 1995, 6, 1073. Grotjahn, D. B.;
J oubran, C. Tetrahedron: Asymmetry 1995, 6, 745.
(7) Weinstock, L. M.; Mulvey, D. M.; Tull, R. J . Org. Chem. 1976,
41, 3121.
(8) Baer, E.; Mourukas, J .; Russel, M. J . J . Am. Chem. Soc. 1952,
74, 152. Nelson, W. L.; Burke, T. J . Org. Chem. 1978, 43, 3641. Hirth,
G.; Walker, W. Helv. Chim. Acta 1985, 68, 1863. J urczak, J .; Bauer,
T. Tetrahedron 1986, 42, 447. Bhatia, S. K.; Hajdu, J . Tetrahedron
Lett. 1987, 28, 1729. Peters, U.; Bankova, W.; Welzel, P. Tetrahedron
1987, 43, 3803.
(9) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. J . Org. Chem.
1994, 59, 1751. Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O.
Tetrahedron: Asymmetry 1994, 5, 5. Sih, C. J . U.S. Patent 4,931,399,
1990. Aragozzini, F.; Maconi, E.; Potenza, D.; Scolastico, C. Synthesis
1989, 225.
(10) Francalanci, F.; Cesti, P.; Cabri, W.; Bianchi, D.; Martinengo,
T.; Foa`, M. J . Org. Chem. 1987, 52, 5079. Bianchi, D.; Bosetti, A.; Cesti,
P.; Golini, P.; Pina, C. Eur. Pat. Appl. 93200395.7.
(6) Fleming, I.; Ghosh, S. K. J . Chem. Soc., Chem. Commun. 1994,
99.
(11) Fuganti, C.; Grasselli, P.; Servi, S.; Lazzarini, A.; Casati, P. J .
Chem. Soc., Chem. Commun. 1987, 538.
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