Coriolin B

The first applications of the squarate ester cascade to natural products synthesis have been realized. Only 10 laboratory steps mediate the conversion of diisopropyl squarate to (+/-)-hypnophilin (8). Key reactions include a combination of chlorination, reduction, dehydration, and oxidation maneuvers in the proper sequence. A penultimate precursor to 8 has previously been converted into coriolin (9), thereby allowing a formal synthesis of racemic 9 also to be claimed. A rather different strategy was employed to arrive at (+/-)-ceratopicanol (10). Of the seven steps involved, three consisted of the use of lithium in liquid ammonia. The three divergent synthetic objectives realized in these experiments involved (a) generation of an extended enolate anion and its regioselective C-methylation at the gamma-carbon; (b) unprecedented reductive cleavage of a beta-isopropoxy group in a 2,3-diisopropoxy-2-cyclopentenone setting; and (c) conventional conversion of an alpha-alkoxy ketone to the parent carbonyl system. Thus, the appreciable enhancement in structural complexity offered by the squarate cascade holds considerable potential for the concise synthesis of constitutionally intricate targets.

This paper describes the application of chiral oxazaborolidinium cations of type 2 to various enantioselective Diels-Alder reactions that have served as early key steps for the syntheses of complex natural products. In the original syntheses these Diels-Alder reactions produced racemic adducts and led to racemic target molecules unless a separation of enantiomers by classical resolution was employed. By use of chiral catalysts of type 2, chiral products were obtained directly from Diels-Alder reactions of achiral components in excellent yield and enantioselectivity and with the mechanistically predicted absolute configuration. As a result, a number of classical syntheses could be converted to enantioselective versions, including (1) cortisone/cortisol (Merck/Sarett), (2) dendrobine (Kende), (3) vitamin B(12) (Eschenmoser), (4) myrocin C (Chu-Moyer/Danishefsky), (5) coriolin and hirsutene (Mehta), (6) dendrobatid 251F (Aube), (7) silphinene (Ito), and (8) nicandrenone core (Stoltz/Corey).

Hydrolysis of 5,8-di-O-tetrahydropyranyl-5-deoxo-5-hydroxycoriolin which was prepared from coriolin B, followed by oxidation of the hydroxy groups at C-5, or C-1 and C-5, or C-1, C-5 and C-8 afforded coriolin (2), 1-deoxy-1-ketocoriolin (3) and 1,8-dideoxy-1,8-diketocoriolin (4). All three ketones were found to have antitumor activity, whereas antibacterial activity was observed in 2 and 3 but not in 4.