Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

Abstract

The studies reported here were motivated by the desire to probe the extent to which benzynes, one of the classical reactive intermediates in organic chemistry, would react in discriminating fashion with benzyne trapping reagents that contain multiple functional groups and, accordingly, possible modes and sites of reactivity. We deemed that natural products comprise a palette of potential multifunctional compounds with which to address this question. We show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a high preference for one among several potential pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products, some in as few as three steps, that enable subsequent and rapid access to structurally diverse, polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity—a trait perhaps not broadly appreciated.

Mechanistic Duality in Tertiary Amine Additions to Thermally Generated Hexadehydro-Diels–Alder Benzynes

“…The 1 H NMR spectrum of this reaction mixture (Figure 1a) shows the (i) formation of an equivalent of ethyl acetate, formed almost assuredly by dealkylation of 8 (A = AcO, Scheme 2a) by the acetate counterion and (ii) the overall cleanliness of the reaction. These results suggest the possibility of multicomponent coupling if a cyclic tertiary amine were to be used, a process known for both traditional 3r,t–w,10 a as well as HDDA-generated benzynes 10b .…”

“…Finally, when the tropane alkaloid 10b scopoline ( 27 ), the N- (β-hydroxyalkyl)amine of which exists nearly exclusively in a hydrogen bonded array, 16 was used (10 equiv), the 1:1 ether adduct 28 was cleanly formed. The use of only 1.5 equivalents of this more exotic aminoalcohol produced not only 28 but the 2:1 adduct 29 in a similarly clean overall reaction.…”

CuI‐Mediated Bromoalkynylation and Hydroalkynylation Reactions of Unsymmetrical Benzynes: Complementary Modes of Addition

“…In neither reaction was any of the product of the alternative constitution observed by NMR analysis of the crude product mixture.A dditional selectivity was seen when natural product derivatives were used as trapping agents. [19] Namely,t he hydroalkynylation products 25 m and 25 n were efficiently produced in the presence of CuCl when terminal alkynes derived from estradiol and cinchonidine (see the Supporting Information for details) were used as the trapping agents.T his is especially notable because these molecules contain additional potentially competing reactive moieties that include phenol, [8] alcohol, [18] tertiary amine, [19] ether, [20] alkene, [4e] cyclic alkane, [21] and quinoline sites. [22,23] Am echanistic proposal for the hydroalkynylation reaction is shown in Figure 5.…”

CuI‐Mediated Bromoalkynylation and Hydroalkynylation Reactions of Unsymmetrical Benzynes: Complementary Modes of Addition

“…In neither reaction was any of the product of the alternative constitution observed by NMR analysis of the crude product mixture. Additional selectivity was seen when natural product derivatives were used as trapping agents . Namely, the hydroalkynylation products 25 m and 25 n were efficiently produced in the presence of CuCl when terminal alkynes derived from estradiol and cinchonidine (see the Supporting Information for details) were used as the trapping agents.…”

“…Namely, the hydroalkynylation products 25 m and 25 n were efficiently produced in the presence of CuCl when terminal alkynes derived from estradiol and cinchonidine (see the Supporting Information for details) were used as the trapping agents. This is especially notable because these molecules contain additional potentially competing reactive moieties that include phenol, alcohol, tertiary amine, ether, alkene, cyclic alkane, and quinoline sites …”