Dimeric cinchona alkaloids

The development of dimeric cinchona alkaloids as very efficient and practical catalysts for asymmetric alkylation of the N-protected glycine ester 18 was reported... 

The highest enantioselectivity (up to >99%) yet achieved in the addition of S-nucleophiles to enones was reported in 2002 by Deng et al. [59]. By systematic screening of monomeric and dimeric cinchona alkaloid derivatives they identified the dihydroquinidine-pyrimidine conjugate (DHQD PYR (72, Scheme 4.35) as the most effective catalyst. This material is frequently used in the Sharpless asymmetric dihydroxylation and is commercially available. Screening of several aromatic thiols resulted in the identification of 2-thionaphthol as the nucleophile giving best yields and enantioselectivity. Examples for the (DHQD PYR-catalyzed addition of 2-thionaphthol to enones are summarized in Scheme 4.35. 

Deng et al. later found that dimeric cinchona alkaloids such as (DHQ AQN (8, Scheme 6.6) and (DHQD PHAL (9, Scheme 6.7) - both well known as ligands in the Sharpless asymmetric dihydroxylation and commercially available - also catalyze the highly enantioselective cyanosilylation of acetal ketones with TMSCN... 

Deng and Tang reported in 2002 that the 5-alkyl l,3-dioxolane-2,4-diones roc-15 shown in Scheme 13.8 undergo kinetic resolution in the presence of alcohols and dimeric cinchona alkaloids such as (DHQD)2AQN 11 [19]. In a first step, the racemic a-hydroxy carboxylic acids roc-14 were reacted with diphosgene to afford the... 

Deng et al. reported in 2001 that a wide variety of N-urethane-protected N-carboxy anhydrides such as, for example, rac-18 shown in Scheme 13.9 undergo kinetic resolution when treated at low temperature with alcohols in the presence of dimeric cinchona alkaloids such as (DHDQ)2AQN, 11 [20], The N-carboxy anhydrides rac-18 were prepared from the racemic amino acids rac-17 by a two-step procedure involving cyclization with diphosgene and subsequent N-protection with, e.g., Cbz or Fmoc. The kinetic resolution of rac-18 proceeded with excellent... 

Scheme 13.8 summarized kinetic resolution of the 5-oIfcyI-l,3-dixolane-2,4-diones roc-15 by alcoholysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Tang and Deng [19]. These authors observed that the related 5-oryl-l,3-dioxolane-2,4-diones 29 (Scheme 13.12) underwent rapid rac-emization under the reaction conditions used, thus enabling dynamic kinetic resolution. This difference in reactivity was attributed to the higher acidity of the a-CH... 

Scheme 13.9 summarized kinetic resolution of N-urethane protected N-carboxy anhydrides rac-18 by methanolysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Deng et al. [20]. These kinetic resolutions were typically conducted at low temperature - from —78 to —60 °C. Deng et al. later observed that if the reaction temperature was increased racemization of the starting aryl N-carboxy anhydrides rac-18 becomes sufficiently rapid to enable a dynamic kinetic resolution [21]. Configurational stability of the product esters... 

Quite remarkable progress has also been achieved in enantioselective transformation of cyclic anhydrides derived from a-hydroxy and a-amino carboxylic acids. By careful choice of the reaction conditions, dynamic kinetic resolution by alcoholysis has become reality for a broad range of substrates. Again, the above mentioned dimeric cinchona alkaloids were the catalysts of choice. In other words, organoca-talytic methods are now available for high-yielding conversion of racemic a-hydroxy and a-amino acids to their enantiomerically pure esters. If desired, the latter esters can be converted back to the parent - but enantiomerically pure - acids by subsequent ester cleavage. 

Soon after, the same research group found that dimeric cinchona alkaloids such as (DHQ)2AQN (125) and (DHQD)2PHAL (33) can also be used as highly enantioselective organic Lewis base catalysts for the cyanosilylation of acetal ketones (131,... 

As depicted in Scheme 11.31, the authors proposed a general base catalysis mechanism in which dimeric cinchona alkaloids such as (DHQD)2AQN (11) act as a dual activator (i.e., (i) the racemization of UNCA by a-deprotonation and (ii) the activation of the nucleophile (R OH)). 

The condensation reaction of (3-dicarbonyl compounds with a-haloketones to generate hydroxydihydrofuran is known as an interrupted Feist-Benary reaction. Calter et al. reported an enantioselective version of this reaction [26]. The aldol reaction of diketone with a-bromo-a-ketoester followed by cyclization proceeded in the presence of dimeric cinchona alkaloid catalyst to give cyclized product in high yield with high ee... 

Dimeric Cinchona alkaloid ammonium salts have also been evaluated in LL-PTC alkylation of A -(diphenylmethylene)glycine tcrt-butyl ester (Scheme 15). meta-Dimer 18 generates a-alkyl derivative 11 in excellent yield and ees, whereas ortho and para dimers afford lower and scarce enantioselective alkylations, respectively [68],... 

An enantioselective dichlorination of allylic alcohols using (dichloroiodo)arenes as chlorine sources in the presence of catalytic amounts of a dimeric cinchona alkaloid derivative (DHQ)2PHAL has been developed [57]. For example, the dichlorination of frans-cinnamyl alcohols 71 with 4-Ph(C6H4)ICl2 catalyzed by (DHQ)2PHAL affords products 72 in good yields and enantioselectivities (Scheme 3.24). 

Figure 6.1 Two examples of dimeric cinchona alkaloid-based Bronsted base catalysts.

More detailed structure-selectivity studies and study of in j/tw-formed CBPTC were reported by Lygo et al. [12]. Shortly afterward based on the above-mentioned findings, other more efficient CBPT catalysts were developed and studied. In 2001, Jew et al. [13] prepared the dimeric Cinchona alkaloid ammonium salts III-V (Scheme 8.1) to enhance catalytic efficiency by the dimerization effect. The highest catalytic activity in the alkylation of 1 was observed with the mcto-dimeric catalyst derived from xylene IV when the corresponding alkylated products were obtained with excellent enantiomeric excess (90-99% ee). 

Enantioselective dichlorination of cinnamyl alcohols ArCH=CHCH20H, catalysed by dimeric cinchona alkaloid derivatives and employing ArICl2 as a chlorine source, has been reported. This new hot area has also been reviewed as a highlight. ... 

Scheme 2.97 Dimeric cinchona alkaloid-catalysed DKR azlaetone.

Despite tremendous advances in the development of chiral methods, asymmetric alkene dichlorination remains one of the challenges. This reaction was successfully achieved for frans-cinnamyl alcohols as substrates using (dichloroiodo)arenes in combination with dimeric cinchona alkaloid derivatives 41 leading to products with up to 85% ee (Scheme 19) [64]. Chiral iodine(V) reagent 42 in combination with pyridine hydrobromide led to the dibromination of p-methylstyrene in only 3% ee [65]. 

Scheme 1.28 Michael additions of dicyanoalkylidenes to quinones catalysed by dimeric cinchona alkaloid.

Squaramide-based dimeric cinchona alkaloid organocatalysts have also been described [92] and shown to be highly suitable for the dynamic kinetic resolution of racemic azlactones (Scheme 6.43). The dimeric squaramide derivatives were free from self-association, as indicated by the observation that the enantioselectivity was not influenced to any significant extent by the concentration of the dimeric squaramide, in contrast to the monomeric species that showed a decline in ee upon an increase in concentration. 

The desymmetrization method was applied for the asymmetric synthesis of (+)-biotin [78] and the y-amino acid baclofen [79]. Furthermore, Deng et al. reported the kinetic resolution of cyclic anhydrides of p,y-unsaturated a-amino acids in the presence of the dimeric cinchona alkaloid catalyst (DHQD)jAQN 68a (10 mol%)... 

Inspired by the positive effect of dimeric cinchona alkaloid ligands in the Sharpless asymmetric dihydroxylation [55], Jew, Park, and coworkers developed a new family of dimeric cinchona-derived catalysts. The authors first prepared a series of dimeric cinchonidinium salts 24, 25a, and 26 using a phenyl spacer (Figure 12.7)... 

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