Cinchona alkaloids resolution

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

There is little doubt in my mind that the versatility that the cinchona alkaloids have exhibited in catalyzing such a diverse range of reactions is due to molecular interactions that to some extent mirror those of importance in resolutions (5). 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

WO3-3O % H2O2-CINCHONA ALKALOIDS A NEW HETEROGENEOUS CATALYTIC SYSTEM FOR ASYMMETRIC OXIDATION OF SULFIDES AND KINETIC RESOLUTION... 

Chiral sulfoxides have emerged as versatile building blocks and chiral auxiliaries in the asymmetric synthesis of pharmaceutical products. The asymmetric oxidation of prochiral sulfides with chiral metal complexes has become one of the most effective routes to obtain these chiral sulfoxides.We have recently developed a new heterogeneous catalytic system (WO3-30% H2O2) which efficiently catalyzes both the asymmetric oxidation of a variety of thioethers (1) and the kinetic resolution of racemic sulfoxides (3), when used in the presence of cinchona alkaloids such as hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQD)2-PYR], Optically active sulfoxides (2) are produced in high yields and with good enantioselectivities (Figure 9.3). ... 

TABLE 1 Chiral Resolution of Amino Acid Derivatives on Cinchona Alkaloid-Based CSPs... 

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

No examples of simple organocatalytic kinetic resolution of dicarboxylic acid anhydrides, e.g. by alcoholysis (Scheme 13.1, middle, X = CR2) seem to have been reported. This type of transformation requires that one anhydride enantiomer remains unchanged while the other is transformed to a mono-ester. Nucleophilic catalysts such as cinchona alkaloids have been shown to effect parallel kinetic resolution, that is, the two enantiomers of the anhydride are converted to regioiso-meric esters. This type of transformation is therefore discussed in Section 13.1.3. 

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. 

Corey, E. J., Noe, M. C., Guzman-Perez, A. Kinetic Resolution by Enantioselective Dihydroxylation of Secondary Allylic 4-Methoxybenzoate Esters Using a Mechanistically Designed Cinchona Alkaloid Catalyst. J. Am. Chem. Soc. 1995, 117, 10817-10824. 

Bauer and Untz analyzed a series of cinchona alkaloids by means of straight-phase HPLC (Fig.5.15). They found that the addition of 2.65 ml of water to 1 liter of the mobile phase (chloroform - isopropanol - diethylamine(940 57 l)), which corresponds to about 75% saturation, gave optimum separation, as regards resolution versus time of analysis. To obtain the correct percentage of water in the mobile phase, the water content present in the mixture was deter-ined by the Karl Fischer method, and water was then added to obtain a final concentration of 2.65 ml/1. 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

Resolution of Racemates and Enantioselective Analytics by Cinchona Alkaloids and Their Derivatives... 

Interestingly, besides the well-known classical resolutions, a significant progress in the field of cinchona-based enantioseparation and their use as enantioselective analytical tools has been made in the last two decades only. This chapter reviews and summarizes analytical applications of the cinchona alkaloids and their derivatives, with the emphasis on modern enantioselective chromatographic techniques. 

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