Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 6 141Entry Substrate R Time h Product Yield e.e.%1 (±)-58a H 4.0 (±)-27g 91.0 -2 (-)-(R)-58a H 4.0 (+)-(S)-27g 90.0 97.53 (±)-58b 4Me 4.0 (±)-63a 89.5 -4 (+)-(S)-58b 4Me 4.0 (-)-(R)-63a 89.9 99.05 (±)-58c 4F 2.5 (±)27l 78.0 -6 (+)-(S)-58c 4F 2.5 (-)-(R)-27l 79.7 97.77 (±)-58e 4CN 8.0 (±)-27h 0.0 -8 (±)-58h 3Me 3.0 (±)-63b 92.0 -9 (+)-(S)-58h 3Me 3.0 (-)-(R)-63b 93.0 98.110 (±)-58i 3F 5.0 (±)-63c 85.0 -11 (+)-(S)-58i 3F 5.0 (-)-(R)-63c 82.8 98.512 (±)-58l 2Me 8.0 (±)-63d 89.5 -13 (+)-(S)-58l 2Me 8.0 (-)-(R)-63d 82.8 93.3Table 6.5: Times, yields and e.e. of Aryl-benzo[b]furane methanols 27-g,l,h and 63ad.obtainedby heteroannulation of 1-Aryl-2-propyn-1-ols 58-a-c,e,h-l.Unfortunately, there was one exception (entry 7; Table 6.5). Allattempts to cyclize racemic 1-[4cyanophenyl]-2-propyn-1-ole (±)-58e tothe corresponding benzo[b]furane, the most active Menarini anticancerdrug, failed. The reaction gave a large number of products among whichthe desired product was not detectable.The present work, to our knowledge, is the first application ofpalladium catalysis for the synthesis of enantiopure aryl-benzo[b]furanemethanols 27-g,l,h and 63-a-d, derived from enantiopurearylpropynols. Attempts to synthesize the same products by asymmetricreduction of the corresponding prochiral ketones failed (chapter 2), andup to now no chemical chiral synthesis or enzymatic resolution of theracemic alcohols is reported.6.4 Cyclization of racemic and enantiopure 1-aryl-2-propyn-1-ols 58-a-c,e,h-l to racemic and enantiopure aryl-2-(Nmesyl)indolylmethanols 64-a-g.An obvious expansion of the procedure for the synthesis ofenantiopure arylbenzo[b]furan methanols 27-g,l,h and 63-a-d described