Khellin synthesis

Khellin is a natural product closely related to the psoralens in which a chromone ring has been substituted for the cou-marin. The plant material has been used since ancient times as a folk remedy modern pharmacologic work has confirmed the bronchio-dilating and antispasmodic activity of khellin. The synthesis outlined below, it should be noted, is selected from a half-dozen or so reported within the last quarter century. 

A plausible pathway is that the aromatisation of the cyclohexadienone 92 by a proton shift is accelerated in the presence of Ac20 under formation of acetate 93. The simultaneously generated acetic acid then cleaves the acetate to form the free phenol 94 (Scheme 44). This effect was observed for the first time during studies towards the total synthesis of the lipid-alternating and anti-atherosclerotic furochromone khellin 99 [64].The furanyl carbene chromium complex 96 was supposed to react with alkoxyalkyne 95 in a benzannulation reaction to give the densely substituted benzofuran derivative 97 (Scheme 45). Upon warming the reaction mixture in tetrahydrofuran to 65 °C the reaction was completed in 4 h, but only a dimerisation product could be isolated. This... 

Initial observations on khellin (32), a furochromone-type compound from Ammi visnaga L., showed a mast-cell stabilizing effect. This led to the synthesis of many derivatives of this lead for the potential treatment of allergy and asthma, most notably the approved preventive antiasthma drug, cromolyn sodium (33). The precise molecular mechanism of this class of drugs is not yet clearly imderstood. ... 

This method is suited to the synthesis of natural benzofuran derivatives karanjin (111, R = R = H) (a furoflavone) and pongapin (111, RR = 0-CH2-0) have been prepared in this way,201 as well as khellin (26).315 From the chromone acetaldehyde (112), visnagin (113) (4-methoxy-7-methyl-5//-furo[3,2-g][l]benzopyran-5-one) was synthesized.310... 

A similar approach has been used in the synthesis of khellin analogues. The acid chloride derived from khellin (457) yields the chromone (458) through reaction with piperidinocyc-loalkenes and subsequent hydrolysis with acid. Some demethylation is observed and the amide (459) is formed in small amounts (Scheme 164) <78JCS(Pi)726). 

KHELLIN Khellin is extracted from the schizocarp (Ammeos visnagae fructus) of Ammi visna a-, L. (Lam.), family Apiaceae (see COID), and has a vasodilating effect. It is an ingredient in asthma preparations. Some side-effects have limited its clinical nse. It served as a model compound for the synthesis of sodium cromoglycate. 

The total synthesis of Khellin has been achieved by this method. 

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