Stereopopulation control. III. Facilitation of intramolecular conjugate addition of the carboxyl group

Abstract

The alkylated benzoquinonepropionic acid 3, 3-(3',6'-dioxo-2',4',5'-trimethylcyclohexa-l',4'-diene)-3,3-dimethylpropionic acid, while stable in anhydrous solvents, cyclizes in the presence of water to a spirolactone 5, 4,4,7,8,10-pentamethyl-l-oxaspiro[4.5]dec-7-ene-2,6,9-trione. The pH-dependent equilibrium mixture contains 87% spirolactone at pH 4 and 1 Kinetic analysis (at 30") shows the ring-opening elimination step to be subject to catalysis by buffer base, proton transfer from 5 to the buffer being the rate-limiting step in the range studied. Conjugate addition involves, at low buffer concentration, a rate-limiting proton transfer from buffer acid to the carbanion of 5, the cyclic counterpart of the anion of 3. At moderate buffer concentrations, the ratelimiting dependence on buffer acid disappears as proton transfer becomes faster than the initial addition step. At still higher concentrations of buffer, the rate of lactone formation falls again, for reasons still undetermined. Although the existence of a carbanion species could not be shown by deuterium exchange, the change in ratedetermining step makes it a mandatory intermediate in the reaction. The analogous brominated quinonepropionic acid 11, 3-(3',6'-dioxo-2',4'-dibromo-5'-methylcyclohexa-l',4'-diene)-3,J-dimethylpropionic acid, cyclizes to the spirolactone 12, 8,10-dibromo-4,4-dimethyl-l-oxaspiro[4.5]dec-7-ene-2,6,9-trione, so rapidly it could not be isolated or even detected under the reaction conditions. Unless 4,4,5-trisubstitution (the trialkyl lock) is present, no conjugate addition can be detected. The unique reactions of 3 and 11 are attributed to the severe conformationrestricting ability of the "lock" and to secondary phenomena resulting therefrom. This reaction provides a useful model for enzyme-catalyzed conjugate addition and elimination.at pH 8. n preceding papers of this series2 we have shown how (20) J. Miller, "Aromatic Nucleophilic Substitution," Elsevier, New York, N. Y., 1968, p 303. (21) Compound 17 is also unstable above pH 8.

Structural Analysis of a Facile Lactonization System Facilitated by a “Trimethyl Lock”

“…The situation is similar with the dihydroquinone system 1c (6). The facilitation of other cyclization reactions by such a trimethyl lock system has also been observed (3,(7)(8)(9)(10)(11)(12)(13). The mechanism through which such a trimethyl lock and gem-dialkyl substitution facilitate certain cyclization reactions and its relevancy to SCHEME I enzymatic reactions have been a subject of continued interest (14 ).…”

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

“…Dr. Cohen, a highly respected physical-organic chemist, had recently published the initial paper 5 in his series "Stereopopulation Control", in which he pointed out that an ingenious arrangement of three methyl groups, the "trimethyl lock," could immobilize certain internal motions of the parent compound, very much related to what Ron had accomplished in a different way in the work reported in his doctoral dissertation (1970) and published three Journal of Medicinal Chemistry papers [2][3][4] in 1971 and 1972 . Ron held his NIH appointment from 1969 until 1971 and during that time carried out synthetic and kinetic studies on the "trimethyl-lock" approach that were published in five Journal of the American Chemical Society papers [6][7][8][9][10] that appeared in 1972 and 1973. That Ron's and Dr. Cohen's "trimethyl-lock" publications were truly pioneering is beautifully articulated in a Perspective article published recently by Michael Levine and Ronald Raines.…”

“…After moving to KU to become a faculty member, Ron and his graduate student Kent Amsberry took advantage of Ron's findings as a postdoctoral fellow at the NIH related to the lactonization rate acceleration by a "trimethyl lock" [6][7][8][9][10] and applied them to prodrug design. Specifically, they compared prodrugs of p-methoxyphenyl amine, model compound, using 3-(2'-(benzyloxy)-4',6'-dimethylphenyl)-3,3-dimethylpropionic acid (3-BDPA) and 2'-hydroxyhydrocinnamic acid (2'-HHCA) promoieties to prove that this "trimethyl lock" group affected the rate of release of the amine.…”

Synthesis of a new long-wavelength latent fluorimetric indicator for analytes determination in the DT-Diaphorase coupling dehydrogenase assay system

“…The UV detector was set at a wavelength of 250 nm and identification of the HPLC peaks were determined by their retention times and standards. The standard, lactone (5), was prepared according to the published procedure (Borchardt and Cohen, 1972).…”

“…The latent fluorophore BQC (1) was constructed from three major components, the quinone acid (6) (Borchardt and Cohen, 1972), mono-Boc-protected amine (7) (de Groot et al, 2000) and coumarin (3) (Scheme 1). The synthesis of BQC (1) was completed in four steps with an overall yield of 42% from (6).…”