fication conditions in the presence of a lipase of Pseudo-
monas sp. However, the fate of the unreacted starting material
was not mentioned at all. We therefore reinvestigated the
lipase-mediated resolution more extensively so as to improve
the optical yield of the acetate (-)-4 and to know the fate
of the other enantiomer in the racemic starting material (()-
2. Among the lipases examined, it was found that clear-cut
resolution occurred under transesterification conditions in the
presence of an immobilized lipase-on-Celite, Lipase AK
(Pseudomonas fluorescens, Amano). Thus, when the racemic
alcohol (()-2 was stirred with vinyl acetate in dichloro-
methane at room temperature for 2 days in the presence of
Lipase AK, the highly enantiomerically enriched7 (99% ee)
acetate (-)-4, mp 85.0-86.0 °C, [R]25D -8.8 (c 0.6, CHCl3),
was obtained in 49% yield, leaving the enantiopure7 (>99%
(c 0.5, CHCl3). The secondary carbamate of (+)-6 was next
alkylated to give the tertiary prenyl carbamate (-)-7, [R]30
D
-18.4 (c 0.6, CHCl3), after desilylation, which was next
transformed into the key xanthate ester (+)-8, [R]D31 +30.5
(c 0.8, CHCl3), under standard conditions (NaH, CS2, THF,
then MeI, -30 °C). Overall yield of (+)-8 from (+)-2 was
58% in six steps (Scheme 3).
Scheme 3
ee) alcohol (-)-2, mp 79-83 °C, [R]27 -60.6 (c 0.5,
D
CHCl3), in 45% recovery yield.8 The acetate (-)-4 gave the
alcohol (+)-2, mp 79-82 °C, [R]D30+60.9 (c 0.4, CHCl3),
on alkaline methanolysis (Scheme 2).
Scheme 2
To initiate concurrent Chugaev syn-elimination and intra-
molecular ene reaction, (+)-8 was heated in refluxing
diphenyl ether in the presence of sodium hydrogen carbon-
ate.11,12 Gratifyingly, the expected concurrent reaction did
take place to give the tricyclic product (-)-10, [R]31D -8.0
(c 1.0, CHCl3), bearing the trisubstituted pyrrolidine frame-
work in 72% yield as a single diastereomer presumably via
the transient 1,6-diene intermediate 9 in this single operation.
At this point, though the product (-)-10 could not be
distinguished unambiguously from its diastereomer 11 owing
to its presence as the carbamate rotamers, significant NOEs
between C2-H and C3-H, C2-H and C4-H, and C3-H
and C4-H were observed to support diastereospecific
generation of the former product having all-cis-configuration
(Figure 1). The assigned stereochemistry was consistent with
To explore further utilization of the resolved products, we
examined the conversion of (+)-alcohol (+)-2 into (-)-kainic
acid (1) by concurrent Chugaev syn-elimination9 and intra-
molecular ene reaction10 as the key step, though such a
combination of reactions in thermolysis conditions has not
been reported so far. To install C2-carboxy and C3-
carboxymethyl functionalities of (-)-kainic acid (1) without
difficulty in the later stage, the compound (+)-2 was
transformed to (+)-5, [R]29 +7.0 (c 0.7, CHCl3) (TBSCl,
D
imidazole, DMF), and the olefin functionality was dihy-
droxylated and protected as the acetonide (+)-6, [R]31D +19.8
(7) Optical purity of the products was determined by HPLC using a
column with a chiral stationary phase (CHIRALCEL OD, elution with
i-PrOH/hexane 20:80 v/v for 4 and i-PrOH/hexane 10:90 v/v for 2).
(8) Typical Procedure for the Lipase-Mediated Transesterification.
A suspension of (()-2 (503 mg, 2.16 mmol), vinyl acetate (0.2 mL, 2.16
mmol), and Lipase AK (100 mg) in dichloromethane (10 mL) was stirred
at room temperature for 48 h. After filtration through a Celite pad, the filtrate
was evaporated under reduced pressure and chromatographed (silica gel,
elution with AcOEt/hexane, 1:4 to 1:1 v/v) to give (-)-4 (293 mg, 49%)
and (-)-2 (225 mg, 45%).
Figure 1.
the preference of the exo-transition state 9a over the endo-
transition state 9b as has been observed in some precedents10
(Scheme 4).
To confirm the assigned stereochemistry of (-)-10 and
to convert (-)-10 into (-)-kainic acid (1), it was transformed
first into the known all-cis-diester13 (+)-12 on the basis of
(9) Nace, H. R. Org. React. 1962, 12, 57.
(10) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978,
17, 476. (b) Curruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990; pp 252-264.
3182
Org. Lett., Vol. 2, No. 20, 2000