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R. Chinchilla et al. / Tetrahedron: Asymmetry 10 (1999) 821–825
The cycloaddition reaction was also carried out using cyclohexa-1,3-diene (20 equiv.), but then heating
at 90°C during 8 h was necessary to get complete reaction (TLC). Analysis of the crude (1H NMR, 300
MHz) showed again a major diastereomer 13 (88% 13+12% other diastereomers) which was isolated by
flash chromatography in 49% yield (Scheme 2). The stereochemistry of this major compound 13 was
determined from the final amino acid (see below) as a thermodynamic exo cycloadduct derived from the
diene following again the less hindered face of the double bond in derivative 7.
Cycloadducts 12 and 1316 were subjected to the same hydrolytic protocol in order to achieve
the desired final bicyclic amino acids (Scheme 2). Thus, acid hydrolysis of the imine moiety with
2 N HCl in THF, followed by catalytic hydrogenation at normal pressure of the double bond and
subsequent hydrolysis of the ester function with 6 N HCl at 150°C (pressure tube) yielded amino acid
hydrochlorides. Final treatment with propylene oxide in refluxing ethanol allowed the isolation of the
free enantiomerically pure (−)-(1R,2R,4S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid17 (−)-endo-
1 and (−)-(1R,2R,4S)-2-aminobicyclo[2.2.2]octane-2-carboxylic acid17 (−)-2 in 85% and 75% overall
yields, respectively. The NMR and specific rotation data of amino acid (−)-2 confirmed the proposed
stereochemistry for adduct 13.
3. Conclusion
In conclusion, we have found that chiral cyclic DDAA derivative 7 is an appropriate reactive dien-
ophile for achieving highly diastereoselective Diels–Alder cycloaddition reactions for the synthesis of
enantiomerically pure bicyclic α-amino acids (−)-endo-1 and 2. Further studies on the synthetic uses of
these new DDAA derivatives in other cycloaddition reactions are now underway.
Acknowledgements
We thank the Dirección General de Investigación Científica y Técnica (DGICYT) of the Spanish
Ministerio de Educación y Cultura (MEC) (PB94-1515 and PB95-0792) for financial support. N. G.
thanks MEC for a grant.
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