Cinchona scaffolds

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

Michael addition of (3-ketoester to enone (Table 9.9). With the aid of an ethereal-derived catalyst from the cinchona scaffold, the reaction gave excellent enantioselectivity, dia-stereoselectivity, and product yield. In this system, the catalyst could handle not only a wide variety of a-substituted (3-ketoesters but also a wide spectrum of vinyl enones. 

Small chiral molecules. These CSPs were introduced by Pirkle about two decades ago [31, 32]. The original brush -phases included selectors that contained a chiral amino acid moiety carrying aromatic 7t-electron acceptor or tt-electron donor functionality attached to porous silica beads. In addition to the amino acids, a large variety of other chiral scaffolds such as 1,2-disubstituted cyclohexanes [33] and cinchona alkaloids [34] have also been used for the preparation of various brush CSPs. 

Keywords Asymmetric organocatalysis Bifunctional catalyst Brpnsted base Chiral scaffold Cinchona akaloid Cyclohexane-diamine Guanidine... 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

The development of predictive transition state models for the interpretation of selectivity data pertaining to the use of cinchona alkaloid derivatives in all the processes described above is challenging due to the complex conformational behaviour of these natural scaffolds (for example, it is well known that 0-acylated quinidines undergo major conformational changes upon protonation) [223]. Consequently, hypotheses regarding the details of chirality transfer in these systems are notably absent. 

As yet, the l-azabicyclo[3.2.2]nonane scaffold has been encountered in nature only rarely, for example, in tronoharine, vincathicine, and communesin B, in contrast to the l-azabicyclo[2.2.2]octane moiety of cinchona alkaloids. A short and simple access to this particular bicyclic system is thus ofhigh interest for exploring its biological and chemical properties. 

In the development of another enantioselective reaction, it was found that cinchona alkaloids 266 perform as efficient phase-transfer catalysts to forge quaternary centers on oxindole scaffolds. It was also found that these catalysts increase the reaction rate and allow for mild conditions and very low catalyst loadings down to 0.3%. It was envisioned that this method could be used to prepare scaffolds of drug-like molecules to treat migraine headaches (14AG(I)8375). 

In the next few years, the use of isobutyraldehyde as the nucleophile in conjugate additions to aromatic nitroalkenes received a lot of attention. He and coworkers reported a chiral thiourea that could efficiently catalyse this transformation, while Chen and coworkers employed a catalyst combining the 1,2-diaminocyclohexane moiety with the privileged Cinchona alkaloid scaffold. A more sustainable protocol was provided by Ma and coworkers, where catalyst 40, based on a beyerane skeleton, was found to promote the same transformation both in organic solvents (up to 92% yield and 98%... 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

Chiral Br0nsted base catalysis began with the recognition of a natural product class of compounds in the cinchona alkaloid family [2]. Cinchona alkaloids are templates for Br0nsted bases when their quinuclidine nitrogen is protonated by nucleophilic substrates, resulting in a stabilized chiral intermediate for stereochemical attack of an electrophile. Systematic evaluahon of structural variants to the scaffold... 

Ever since Dolling s impressive work at Merck with cinchona alkaloid-mediated enolate alkylations (Chapter 10, Section 10.4) [178], the identification of new phase-transfer catalysts for applications in various other processes has captured the imaginations of chemists. There have been a number of key advances in this area that impact aldol addition chemistry. A particularly interesting series of investigations by Maruoka involve the use of designed chiral ammonium ions derived from spiro-fused bis-BlNOL scaffolds [179, 180], As shown in Equation 33, a chiral phase-transfer catalyst of this type, compound 352, mediated aldol additions of enolates prepared in situ from the corresponding enol silane 351 [179]. 

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