STEREOSELECTIVE SYNTHESIS OF DIHYDROBENZOPYRAN

Universita’ degli Studi di Milano: Dipartimento di Chimica Organica e Industriale e Centro CNR- Via Venezian, 21-20133 Milano (Italy)

In a preceding paper we have reported the stereoselective synthesis of a b-lactam tricyclic structure exploiting the chirality induced by ortho substituted chromiumarenes as well as its activation to the nucleophylic aromatic substitution, according the following Scheme:

The scope was the extension of the above reaction to nitrogen containing products; therefore we have synthetised the b-lactam 1, first in racemic and then in enantiomeric pure form, by [2+2] cycloaddition starting from tricarbonyl[N-(2-fluorobenzylidene)-4-methoxyaniline]chromium and phthalimidoacetyl chloride in the presence of Et₃N as a base:

From the phthalimido protecting group, the 3-amino-b-lactam can be obtained normally with treatment by hydrazine or by reduction with NaBH₄ followed by the acidic hydrolysis. In this case, the treatment with hydrazine was completely unsuccesful, while NaBH₄in iso-propanol gave rise only to product 2 in 65% yield to which we assigned a dihydrobenzopyran structure on the basis of spectroscopic and analytical data.

The dihydrobenzopyran ring should arise from an unusual reductive ring opening of azetidinone followed by the nucleophylic aromatic substitution of the fluorine atom by the new formed hydroxy group.

This reaction, made possible only by the presence of Cr(CO)₃ group, represents an interesting method to transform the b-lactam ring in dihydrobenzopyran compounds in stereoselective manner.

Experimental data:

Product 1: Yield 94%; mp 198 °C (from petroleum ether); IR (nujol) cm^-1 1972, 1903, 1869, 1762, 1723. ¹⁹F NMR d-141.6. ¹H NMR d 3.8 (s, 3H); 4.7 (dt, 1H, J=6.2, 1.9 Hz); 5.1 (t, 1H, J=5.7 Hz); 5.3 (dt, 1H, J=6.5, 2.8 Hz); 5.6 (m, 2H); 5.8 (d, 1H, J=5.5 Hz); /.0-7.7 (AB systhem, 4H); 7.8 (m, 4H). [a]_D=-25.5 (c 0.114 CHCl₃).

Product 2: Yield 65%; mp 105/6 °C (from petroleum ether); IR (nujol) cm^-13336, 1959, 1871, 1640. ¹H NMR d 3.8 (s, 3H); 3.85 (m, 2H, OH and NH); 4.2 (dd, 1H+NH, J=11.6 and 4.2 Hz); 4.4 (dd+d, 2H, J=7.5, 11.6 and 2.0 Hz); 5.0 (t, 1H, J=6.2 Hz); 5.3 (d, 1H, J=6.8Hz); 5.5 (t, 1H, J=6.7 Hz); 5.6 (d, 1H, J=6.2 Hz); 6.8-7.0 (AB systhem, 4H, J=8.9, 6.5 Hz); 7.4-7.6 (m, 4H). ¹³C NMR d 47.16, 53.1, 56.19, 65.16, 66.42, 81.29, 87.93, 92.65, 94.12, 94.46, 115.12, 115.72, 128.53, 128.65, 131.23, 132.18, 134.7, 138.18, 140.05, 140.66, 153.76, 170.57, 232.82. [a]_D=+161.8 (c 0.092 CHCl₃).

Product 3: Yield 94%; mp 75 °C (from petroleum ether); IR (nujol) cm^-1 3367, 1635. ¹H NMR d 1.6 (m, 1H, NH); 3.7 (m, 1H, NH); 3.8 (s, 3H); 3.9 (t, 1H, OH, J=6.3 Hz); 4.3 (dt, 1H, J=11.5, 2.5 and 4.6 Hz); 4.5-4.65 (m, 4H); 4.7 (dq, 1H, J=2.6, 4.2 and 7.8 Hz); 7.0 (m, 4H); 7.5 (m, 8H). ¹³C NMR d 46.14, 52.45, 56.25, 64.61, 65.1, 114.55, 114.75, 114.79, 115.45, 115.65, 115.53, 122.34, 128.50, 128.66, 130.12, 131.30, 131.81, 132.14, 112.57, 135.64, 139.88, 140.73, 153.08, 154.06, 170.25. [a]_D=-156.1(c 0.132 CHCl₃).

[1] Davies, S. G. in Comprehensive Organometallic Chemistry II, Vol. 12, E. W. Abel, F. G. A. Stone and G. Wilkinson; Ed. Pergamon Press, 1995, 1039.

[2] Semmelhack, M. F. in Comprehensive Organometallic Chemistry II, Vol. 12, E. W. Abel, F. G. A. Stone and G. Wilkinson; Ed. Pergamon Press, 1995, 979.