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Traceless chirality transfer from a norbornene b-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-( )-(1R,2S,3R,4S)-3aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [( )-1] was successfully transfered to heterocycles (+)9a, (+)-10a, ( )-9b, ( )-10b and ( )-10c. 2017 Published by Elsevier Ltd.


Introduction
Several pyrimido [2,1-a]isoindoles are well known for their potential biological and pharmacological properties such as prolactin-inhibition, 1 antidepressant and diuretic, 2 anxiolytic, 3 vasorelaxant, 4 antiplasmodial 5 and antifungal 6 activity. In contrast to these findings, derivatives of these heterocyles are still insufficiently studied, even less their enantiomers. To our best knowledge so far, as single enantiomers, 1N-Me, 7 -OMe, 8 and -OBn 8 substituted pyrimidoisoindole derivatives have been synthetized. Compounds were prepared by the application of retro Diels-Alder (rDA) reaction. 9

Results and discussion
In an earlier paper, 7 we described an enantioselective synthesis of pyrimido [2,1-a]isoindoles by microwave-induced retro Diels-Alder 10 reaction. diexo-(À)-3-Amino-norbornene-2-carboxylic acid readily available through an enzymatic resolution was used as a starting chiral source. 11 The goal of the present work was to explore further extensions of the above methodology that includes (i) the introduction of diendo-(À)-ethyl-3-aminonorbornene-2-carboxylate as a chiral source, (ii) the use of 2-formyl-, 2-acetyl-and 2-(4-methylbenzoyl)-benzoic acid for the preparation of isoindoloquinazolinone intermediates, (iii) the investigation of the steric effect of the 2-formyl and 2-acyl groups on the diastereoselectivity of the ring-closure reaction, (iv) separation of diastereomers, and (v) removal of cyclopentadiene in a retro Diels-Alder reaction to obtain pyrimido[2,1-a]isoindole racemates and enantiomers.
It should be noted that all spectroscopic data of the enantiopure compounds were identical with those of the racemic samples.

General
Melting points were determined on a Kofler apparatus and are uncorrected. 1 H NMR (400 Hz) and 13 C NMR (100 MHz) spectra were recorded on a Bruker Avance DRX 400 spectrometer, with TMS as internal reference and DMSO-d 6 or CDCl 3 as solvent. FTIR spectra were recorded on a Perkin-Elmer 100 FT-IR spectrometer. Elemental analyses were carried out on a Perkin-Elmer 2400 elemental analyser. Microwave-promoted reactions were performed in sealed reaction vials (10 mL) by means of a CEM, Discover microwave reactor. Optical rotations were measured on a Perkin-Elmer 341 polarimeter. Mass spectra were recorded on a Finnigan MAT 95S spectrometer.
The ee values of (+)-10a and (À)-10b were determined on a Chiralpak IA column

X-ray structure determination
The crystals of 2a, 2b, 3a, and 3b were immersed in cryo-oil, mounted in a MiTeGen loop, and measured at 120-170 K on a Rigaku Oxford Diffraction Supernova or on a Bruker Kappa Apex II diffractometer using Cu Ka (k = 1.54184 Å) or Mo Ka (k = 0.71073) radiation. The CrysAlisPro 18 or Denzo-Scalepack 19 program packages were used for cell refinements and data reductions. Multi-scan absorption corrections (CrysAlisPro 18 or SADABS 20 ) were applied to the intensities before structure solution. The structures were solved by charge flipping method using the SUPERFLIP 21 software. Structural refinements were carried out using SHELXL-2014. 22 The high R-values and residual densities in 3a are due to the low data quality and possible twinning. However, not satisfactory twin model could be found and therefore no twin model was used in the final refinement. In 2b and 3b the NH hydrogen atoms were located from the difference Fourier map and refined isotropically. Other hydrogen atoms were positioned geometrically and constrained to ride on their parent   Table XS1.