Highly tunable arylated cinchona alkaloids as bifunctional catalysts

Abstract

We report the design and evaluation of a library of chiral bifunctional organocatalysts in which the distance between the catalytically active units can be systematically varied.The inexpensive cinchona alkaloids quinine (1) and quinidine (2) have been intensely studied as structural templates upon which bifunctional hydrogen-bond donating organocatalysts can be constructed.1 For instance, C-9 substituted (thio)urea-, sulfonamide-, and more recently squaramide derivatives (e.g. 3,2,3 4 4 and 5 5 respectively) together with C-6 0 demethylated cupreine-derived materials (e.g. 6-8 1,6 ) have been developed (inter alia) with the goal of controlling the encounter of two reacting components in a chiral environment via interaction between the substrates and the hydrogen bond donating (blue)/Brønsted basic (red) catalyst functionality. 1While undoubtedly broad in scope, there is an inherent inflexibility associated with these materials which frustrates the ambition of designing catalysts genuinely tuned to meet the demands of any given process. For example, the relative positioning of the nucleophile-and electrophile-activating components is key to successful bifunctional catalyst design ( Fig. 1). An examination of 3-8 reveals that the practitioner is offered two options: hydrogen bond donating functionality at either C-9 or C-6 0 . 7 Therefore if the stereoelectronic demands of a particular general acid/base catalysed process do not correlate well with the spatial relationship between the catalyst's C-9/C-6 0 substituted bifunctional components, it is unlikely that any modification of the catalytically relevant functionality will improve efficacy.More desirable and potentially useful would be the identification of a stable structural template, the chemical space around which could be easily modified in such a way that the relative positioning (and relative orientation) of the catalytically critical groups could be systematically modified.With this in mind, we noted a recent report from Skarżewski et al. detailing the synthesis of 9-phenyl-9-deoxyquinine (9, Fig. 2) and its quinidine counterpart, 8 together with a number of derivatives. We were intrigued as to the catalytic potential of such templates, as they seem to represent a potential (partial) solution to the questions posed above: they are stable, easily synthesised 8 materials, the conformation of 9 (i.e. 9a, Fig. 2) in both the solid state and solution is known 8 and would seem to be conducive to bifunctional catalysis if a phenolic hydrogen bond donor were installed (due to its relative proximity to the quinuclidine base). However, no catalytic applications of this class of materials have been reported thus far. We reasoned that we would be able to design a small library of catalysts based on this motif (i.e. 10, Fig. 2) which would be tunable to an unprecedented extent: for example: (a) the C-9 position would be devoid of a heteroatom, thus one would expect the basicity of the quinuclidine nitrogen atom to be augmented relative to traditional catalyst struc...

C‐5′‐Substituted Cinchona Alkaloid Derivatives Catalyse the First Highly Enantioselective Dynamic Kinetic Resolutions of Azlactones by Thiolysis

“…This was quite a surprise, because we have significant experience with this particular reaction and both related azlactone DKR reactions15,16,17 and other catalytic methodologies involving thioester intermediates/products30 and had never encountered hydrolysis as a problem when standard precautions to eliminate adventitious water were taken. In an attempt to circumvent this, we carried out the reaction (under unoptimised conditions) in the presence and absence of 3 Å molecular sieves.…”

“…However, in the thiol‐based variant of this process (by using primary thiol nucleophile 5 ) catalysis was efficient but relatively unselective (Scheme , B). Recently,16 we reported the synthesis of C‐9 arylated cinchona alkaloid 7 17 (Scheme , C), which proved capable of catalysing the thiolysis of furyl‐substituted azlactone 8 with 73 % product ee . This catalyst could operate at room temperature and accepted a range of azlactone substrates derived from unhindered amino acids, however both activity and selectivity were markedly diminished in the presence of a valine‐derived substrate.…”

Cinchona Alkaloids from Cinchona succirubra and Cinchona ledgeriana

“…Pharmacological investigations on these alkaloids and their derivatives demonstrated cytotoxic [8], antimalarial [9,10], antiarrhythmic [11], antibacterial [12,13], antifebrile, and MAO-inhibitory activities [14]. Over the last thirty years, cinchona alkaloids have become increasingly popular in organic chemistry, being used as chiral catalysts, ligands, and NMR discriminating agents, among others [15][16][17][18]. The barks of several species of Cinchona and Remijia (Rubiaceae) trees have been proven to be good sources of cinchona alkaloids [1,3,4,14,[19][20][21][22].…”

“…As a result, seven new cinchona alkaloids, including three quinoline alkaloids (1-3) and four indole alkaloids (4-7), together with 29 known compounds were isolated. The new alkaloids were elucidated by means of spectroscopic methods, while the known alkaloids were identified as cinchoninone (8) [26,34], cinchotoxine (9) [14], remijinine (10) [20], cinchonamine (11) [3], quinamine (12) [3], liriodenine (13) [35], lyscamine (14) [36], cinchophylline (15) [4], quinidinone (16) [37], quininone (17) [37], cinchonidinone (18) [38], quinine (19) [39], quinidine (20) [38], cinchonine (21) [5,19] [42], and alkaloid 376 (36) [43], by comparison with data in the literature. All compounds were evaluated for their cytotoxicity against five human cancer cell lines.…”

Organocatalytic asymmetric approach to spirocyclic tetrahydrothiophenes containing either a butenolide or an azlactone structural motif

“…Subsequent, intramolecular aldol reaction enables the construction of a five-membered tetrahydrothiophene scaffold bearing three contiguous stereogenic centers with one being quaternary at the spiro carbon atom (for related examples of thio-Michael/aldol reaction sequences realized under organocatalytic conditions see refs [32][33][34][35][36]. It was expected that the reaction should be possible to realize under basic conditions (for selected reviews on the enantioselective Brønsted base catalysis see refs [37][38][39][40][41][42] and the use of chiral catalyst should enable the synthesis of enantiomerically enriched products 7 and 8. Notably, the devised strategy can be categorized as a cascade reactivity (for selected reviews on organocatalytic cascade reactivities see refs [43][44][45][46] where more than one-bond is being formed in a single operation what further increases the attractiveness of the approach.…”