Dimeric kinetic resolution

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

The asymmetric ring opening (ARO) of racemic terminal epoxides with H2O via hydrolytic kinetic resolution provides an efficient synthetic route to prepare optically pure terminal epoxides. The dimeric type chiral Co(salen)AlX3 complex has great potential to catalyze HKR of terminal epoxides in a highly reactive and enantioselective manner in comparison to their monomeric analogy. 

The hydrolytic kinetic resolution of terminal epoxides catalyzed by the monomer la and dimer lb... 

Kureshy, R. I. Singh, S. Khan, N. H. Abdi, S. H. R. Ahmad, I. Bhatt, A. Jasra R. V. (2005) Improved catalytic activity of homochiral dimeric cobalt salen complex in hydrolytie kinetic resolution of terminal racemic epoxides.. Chirality, 17 590-594. 

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. 

An easily synthesized dimeric chiral (salen)Co bearing aluminium catalyst29 dramatically improves the kinetic resolution of racemic terminal epoxides. The new catalyst gives enantiomerically enriched terminal epoxides with >99% ee. 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

In order to obtain levoglucosenone 1 in both enantiomeric forms by employing lipase-mediated kinetic resolution, we used acrolein dimer 2 as the starting material.4 2 was first transformed to the bicyclic ketone ( )-6 by sequential four steps of reactions via 3-5. Racemic levoglucosenone ( )-l was obtained from 6 via the silyl ether 7 by employing the Saegusa reaction. To carry out lipase-mediated resolution, ( )-l was transformed into the e/wfo-alcohol ( )-8 and the acetate ( )-9 (Scheme 1). 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Table 2 Use of Pd(II) dimers in oxidative kinetic resolution of secondary alcohols...

The occurrence of chiral amplification in this case is explained by the mechanism of Figure 8.31. When chiral amplification is observed one always finds—as is the case here—that two molecules of the chiral auxiliary become linked to each other, albeit indirectly (i.e., via another component of the reaction mixture). In other words, a derivative of the dimer of the chiral auxiliary is formed. When chiral amplification occurs, this derivative of the dimer exists in the form of only two of its three conceivable stereoisomers. The reason for this is a mutual kinetic resolution (cf. Section 3.4.3). 

When using (rac)-vinylcyclohexane epoxide as a standard substrate (Scheme 4.24), the dendrimer catalysts exhibited significantly higher catalytic activities in the hydrolytic kinetic resolution of terminal epoxides as compared to the monomer or the dimer catalysts. Among the dendrimer catalysts, the first-generation dendrimer catalyst gave the best results and the efficiency of the catalyst on a per-metal basis was in the following order 4-Co(salen)-PAMAM > 8-Co(salen)-PAMAM > 16-Co(salen)-PAMAM. This dendrimer effect was considered to arise from the restricted conformation imposed by the dendrimer structure, which enhanced the... 

The separation of the products from the IL catalytic mixture can be performed in various cases by simple decanting and phase separation or by product distillation. In this respect, a continuous-flow process using toluene as extractant has been appHed for the selective Pd-catalyzed dimerization of methyl acrylate in ILs [136]. However, in cases where the products are retained in the IL phase, extraction with supercritical carbon dioxide can be used instead of classical liquid-liquid extractions that necessitate the use of organic solvents, which may result in cross-contamination of products. This process was successfully used in catalyst recycling and product separation for the hydroformylation of olefins employing a continuous-flow process in supercritical carbon dioxide-IL mixtures [137]. Similarly, free and immobilized Candida antarctica lipase B dispersed in ILs were used as catalyst for the continuous kinetic resolution of rac-l-phenylethanol in supercritical carbon dioxide at 120°C and 150°C and 10 Mpa with excellent catalytic activity, enzyme stability and enantioselectivity levels (Fig. 3.5-11). 

It can be summarised that the different methods of kinetic resolution and the synthetic correlations have led to the determination of stereochemistry at the biaryl linkage of atrivirin and flavomannin derivatives. Because the position and shape of the CD couplet around 275 nm is not much influenced by substituents present in the two halves of the dimers (refs. 3, 23), several other pigments can now be correlated. It will however need the development of further methods to elucidate the stereochemistry of the phlegmacin group and to determine the configuration of the chiral centers located in the alicyclic rings of the dimers. 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

Recently Iwabuchi et al. reported the first total synthesis of (—)-idesolide (650) (559), an efficient inhibitor of nitric oxide production induced by lipopolysaccharide in BV2 microglial cells, isolated firom the deciduous tree Idesia polycarpa (560). As idesolide may originate from dimerization of the precursor 651, two major challenges had to be addressed in this investigation. The first was installation of the required absolute configuration in 651 and the second, identifying useful dimerization conditions for this monomeric precursor. Synthesis of 651 could be achieved successfully by carrying out an oxidative kinetic resolution on the easily synthesized racemic... 

The allylation of cyclic acetates such as cyclopentenyl or cyclo-hexenyl and cycloheptenyl derivatives also has been widely studied. For exart ile, the allyl palladium chloride dimer (1) is a useful catalyst precursor in the kinetic resolution of 2-cyclohexenyl acetate using Trost s chiral ligands pockets in conjunction to the planar chirality of ferrocene (eq 46). 1 The conversion was stopped at 54%, which allowed high enantiomeric excess for both the alkylated derivative and the chiral allylic acetate. 

Milller and co-workers recently developed an enantioselective benzoin dimerization using purified enzymes from Pseudomonas. The thiamine diphosphate (ThDP) dependent enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BED) were found to catalyze the reversible benzoin condensation of aromatic aldehydes. The reaction is driven in the forward direction by the poor solubility of the benzoin products in aqueous media. A wide variety of aromatic aldehydes are accepted by BAL, and products of the (/ )-configuration are produced in excellent yield and enantiomeric purity. The (S)-enantiomer of benzoin is also available in high enantiomeric purity from a BAL-catalyzed kinetic resolution of rac-benzoin. In the presence of excess acetaldehyde, BAL selectively converts (i )-benzoin into (/ )-2-hydroxy-l-phenylpropanone, while the (iS)-benzoin enantiomer is not a substrate for the enzyme. At 49% conversion, (5)-benzoin is resolved to > 99% ee. BED can produce (i )-benzoin from benzaldehyde in comparable yield and enantiomeric purity with respect to BAL, but the substrate scope appears more limited. ... 

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