than the reported n-pentane/CH
evaporation.
2
Cl
2
extraction, drying, and
Key features of the modified procedure were the follow-
ing:
Modification 3: Efficient Recovery of the Chiral
Auxiliary D-Pantolactone (5). D-Pantolactone, the cost driver
of the whole synthesis, has been widely used as an efficient
chiral auxiliary in asymmetric syntheses.6,7 However, few
literature references actually mention the recovery of D-
pantolactone, except for one dated 1940, where D-panto-
lactone was obtained from a liver extract by a complicated
(i) D-Pantolactone, which is quite water soluble, was
recovered in a yield of up to 85% by extracting with ethyl
acetate four times. Additional extraction time can increase
the amount of recovered product. Furthermore, if a continu-
ous extraction apparatus were used in manufacturing, the
recovery yield could be even higher. In consideration of the
whole procedure, 0.53 g of D-pantolactone can be recovered
8
10
procedure.
if 1 g of D-pantolactone is used in the formation of acrylate.
Since, in Poll’s method, the D-pantolactone fragment was
hydrolyzed to the ring-opened, water-soluble D-pantoic acid
(ii) Detailed HPLC and optical rotation analyses (see
Experimental Section) indicated that no racemization had
occurred during this process, and D-pantolactone could,
therefore, be recycled repeatedly without reducing its optical
purity.
(iii) Lactonization was also possible at room temperature
overnight, indicating that the reaction proceeded easily. It
will be significant to do further experiments and to apply
this room-temperature lactonization to plant operation.
(
4), several methods were tried in our laboratory to keep
the pantolactone portion intact during the removal of the
chiral auxiliary from the substrate. Mild hydrolysis with K
CO /CH OH at room temperature or in an ice bath and trans-
2
-
3
3
9
esterification did not succeed. This indicated that the
carbonyl carbon of the lactone was attacked preferentially.
Therefore, an attempt to close the ring of D-pantoic acid
(
4) to a five-membered lactone ring by simple heating of
We noted that, in d
posed quickly to form D-pantoic acid (4). The H NMR of
compound 5 recorded in d -DMSO actually reflected the
structure of D-pantoic acid (4) (see Experimental Section).
The commercial D-pantolactone behaves in the exact same
way.
6
-DMSO, D-pantolactone (5) decom-
1
the acidified mixture was tried, and this proved to be
successful. The lactonization is an intramolecular nucleo-
philic attack by the γ-hydroxy group on the protonated
carboxylic acid, which should not cause racemization.
Using modified reaction conditions as shown in Scheme
6
2, the Diels-Alder adduct 2a was hydrolyzed to give, after
acidification to pH 2-3, (-)-(1S,2S)-5-norbornene-2-car-
boxylic acid (3) and D-pantoic acid (4). The product 3 was
collected by filtration as described in modification 2. The
filtrate containing the D-pantoic acid was then heated at 90-
Conclusions
A convenient, cost-effective procedure to prepare (-)-
1S,2S)-5-norbornene-2-carboxylic acid (3) has been devel-
(
oped and successfully scaled up to kilogram scale in a pilot
plant. The efficient method presented above to recycle
D-pantolactone may be applicable to other reactions where
D-pantolactone is used as a chiral auxiliary.
9
5 °C for 2-3 h to complete the lactonization, and after
cooling, sodium bicarbonate was added to bring the pH to
.5-8. Under these slightly basic conditions, a small amount
7
of (-)-(1S,2S)-5-norbornene-2-carboxylic acid (3) was re-
tained in the aqueous phase as a salt without mixing with
the subsequent D-pantolactone extract. Strongly basic condi-
tions would have decomposed the D-pantolactone molecule
and were, therefore, avoided. After this turbid, slightly basic
mixture was filtered, the filtrate was extracted with ethyl
acetate. Subsequent drying and concentration produced
recycled D-pantolactone (5) as a pure white crystalline solid
in a high recovery of 85%. For convenient plant operation,
after two-thirds of the ethyl acetate was removed, the product
D-pantolactone (5) can be precipitated as crystals by addition
of heptane and can, therefore, be collected by filtration. The
optical purity of D-pantolactone can be increased by recrys-
tallization from methyl tert-butyl ether/heptane. Nevertheless,
it is wise to use a solution of D-pantolactone extract directly
in acrylate formation, and it is worthwhile to do further
investigation.
Experimental Section
Melting points were determined on an Electrothermal
digital melting point apparatus (IA9300). NMR spectra were
measured on a Bruker spectrometer (300 MHz). Elemental
analysis was performed by QTI, Whitehouse, NJ. Optical
rotations were obtained on a Perkin-Elmer polarimeter 241.
HPLC analyses were performed on an Alliance Waters 2690
separations module system with a Waters 996 photodiode
array detector. The chemical purity of (-)-(1S,2S)-5-nor-
bornene-2-carboxylic acid (3) and D-pantolactone (5) was
measured by reversed-phase HPLC using a Keystone BDS
Hypersil C8 column (150 × 2.0 mm, 5 µm). The chiral purity
of (-)-(1S,2S)-5-norbornene-2-carboxylic acid (3) and D-
pantolactone (5) was measured by normal-phase HPLC using
a Chiralcel OD column (250 × 4.6 mm, 10 µm).
Preparation of (-)-(1S,2S)-5-Norbornene-2-carboxylic
Acid (3). To a stirred solution of Diels-Alder adduct 2a
All analytical data for the recycled D-pantolactone con-
formed to the theoretical data or were identical to those of
commercially available D-pantolactone.
(275.7 g, 1.1 mol) in THF (1100 mL) and MeOH (550 mL)
was added 5 N NaOH (1100 mL) dropwise. The resulting
colorless mixture was stirred at room temperature for 1 h,
and the mixture was concentrated in vacuo in a water bath
set at 35-45 °C to remove organic solvents. The residue
(
(
(
(
6) Poll, T.; Abdel Hady, A. F.; Karge, R.; Linz, G.; Weetman, J.; Helmchen,
G. Tetrahedron Lett. 1989, 30, 5595.
7) Linz, G.; Weetman, J.; Abdel Hady, A. F.; Helmchen, G. Tetrahedron Lett.
1
989, 30, 5599-5602.
8) Stiller, E. T.; Keresztesy, J. C.; Finkelstein, J. J. Am. Chem. Soc. 1940, 62,
779.
9) This experiment was carried out by Chemical Research Lab., Biogen.
1
(10) Calculated as 80% yield for acrylate formation, 79% yield for Diels-Alder
reaction, and 85% yield for D-pantolactone recovery from compound 2a.
290
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Vol. 3, No. 4, 1999 / Organic Process Research & Development