ChemInform Abstract: Synthesis of 10,11‐Didehydro Cinchona Alkaloids and Key Derivatives.

Abstract

A series of 10,11-didehydro Cinchona alkaloids containing an ethynyl group at C(3) were prepared efficiently in two steps from the naturally occurring Cinchona alkaloids (Scheme 1). 10,11-Didehydroquinine (4c) and 10,11-didehydroquinidine (4a) belong to a significantly new class of semi-natural Cinchona alkaloids. They are more polar and basic than the natural compounds and serve as versatile building blocks for further functionalization; they were transformed into the corresponding 11-halo and 11-pseudohalo derivatives and (Z)-vinyl halides (Schemes 2 and 3). The conformation of the alkaloids was elucidated by NOE and X-ray crystal diffraction analysis of 4a (Fig.), and the cytostatic activity of selected didehydroquinidine derivatives was evaluated ( Table 5).Introduction. ± The Cinchona alkaloids are commercially the most important alkaloid family. They are used in various pharmaceuticals and soft drinks and are produced worldwide at an estimated 700 t per annum. They are also versatile chiral auxiliaries for the separation of enantiomers via formation of diastereoisomeric salts, for asymmetric syntheses, e.g. as chiral ligands in the Sharpless asymmetric dihydroxylation [1] or as chiral phase-transfer catalysts [2]. Cinchona alkaloids have been known and studied for over 350 years, and a great deal of literature in diverse scientific journals and also in numerous patents has appeared. Christensen has reported one of the title alkaloids (10,11-didehydroquinine (4c)) at the beginning of this century [3], but to our surprise, no further work on this potentially interesting and useful class of compounds has come forward since then. Substituted alkynes can be found in various pharmacologically interesting natural products and lead structures [4]. Enynes [5] (brasilenyne, gephyrotoxin, histrionicotoxin) and enediyne antibiotics [6] (dynemicin A, calicheamicin g 1 ) are two prominent classes of natural products containing alkyne units. Moreover, halogenated acetylenes are crucial intermediates for the synthesis of increasingly complex structures, especially in total synthesis, as they can easily be subjected to Pd-and Nicatalyzed cross-coupling reactions. Cyclic enediyne cores of enediyne antibiotics have been formed via intramolecular Nozaki-type coupling of an iodoalkyne moiety or directly via a terminal alkyne [7]. Iodoalkynes have also been hydrogenated to (Z)-vinyl iodides, which have been elaborated further, e.g., to pheromones [8].In the course of our work on acetylenic Cinchona alkaloids, we have now prepared the four alkyne derivatives 4a ± d and their 9-O-protected analogs 4e ± g (Scheme 1, Tables 1 and 2). Quinidine-and quinine-based alkynes 4a and 4c have also been transformed into key derivatives 5a ± k ad 6a ± d via halogenation, cis-hydrogenation, propynol formation, cyanation, and isomerization.

Dimeric Cinchona alkaloids

“…The vinyl group in the alkaloids can also be converted to a terminal alkyne by bromine addition followed by two HBr elimination reactions [ 139 , 140 ]. The alkynes QN-11 and QD-11 (didehydroalkaloids) were then directly coupled in a Sonogashira-type oxidation reaction.…”

An improved synthesis of 10,11‐didehydro Cinchona alkaloids

“…As compared with the reported strategy, 22 the described procedure offers the advantages of robustness, scalability, operational simplicity, use of as-received solvents, and chromatography-free work-up. We are confident that with the now ready access of didehydro Cinchona alkaloids, these versatile scaffolds will see frequent future use in the fields of asymmetric synthesis and chiral recognition.…”

“…Considerable efforts to establish a double dehydrobromination procedure were also described by Hoffmann's group, who screened different types of bases in a range of solvents and at various temperatures. 22 However, the yields of the chromatographically isolated didehydro Cinchona alkaloids did generally not exceed 50%, with increasing temperature and extended reaction times further compromising product recovery because of decomposition. From these observations, we concluded that successful double dehydrobromination demands a set of carefully matched reaction condi- Scheme 2 tions, including relatively mild bases and low temperatures.…”

“…In 2000, Hoffmann reinvestigated the synthesis of didehydro Cinchona alkaloids, and reported their use for various metal-catalyzed cross coupling reactions, such as Sonogashira-, Heck-, and homocoupling protocols. 22,23 In recent years, these derivatives are receiving increasing attention from the asymmetric synthesis community. Thus, 10,11-Didehydrocinchonidine (4c) was utilized by Soó s and coworkers to create fluorous-tagged Cinchona reagents.…”

“…To access these compounds, we attempted to reproduce the three-step procedure recently published by Hoffmann's group. 22 This strategy involved the bromination of the Cinchona vinyl group to form a diastereoisomeric mixture of dibromides 2a-d, followed by a triethylamine-mediated elimination to the corresponding bromovinyl compounds 3a-d. Consecutive treatment of the chromatographically purified 3a-d with KOH in presence of a phase transfer catalyst was claimed to give, after an additional chromatographic purification step, the corresponding didehydro alkaloids 4a-d in overall yields up to 74%.…”