Chiral initiators, enantioselective asymmetric

We describe highly enantioselective asymmetric autocatalysis with amplification of chirality and asymmetric autocatalysis initiated by chiral triggers. Asymmetric autocatalysis correlates between the origin of chirality and the homochirality of organic compounds. We also describe spontaneous absolute asymmetric synthesis in combination with asymmetric autocatalysis. 

When enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde 89 was examined, simple 2-butanol with low (ca 0.1%) induces a tiny chirality in the initially produced alkanol 81 and the value of the finally obtained alkanol becomes higher (73-76%) due to the asymmetric autocatalysis (Table 2). Note that the value can be further amplified by subsequent asymmetric autocatalysis, as described in the preceding section. Various chiral compounds have been proved to act as chiral initiators. 

Highly enantioselective asymmetric autocatalysis has recently been reported. In such reactions, a trace amount of chiral molecule automultiplies without the assistance of another chiral molecule. Moreover, asymmetric autocatalysis with an amplification of enantiopurity has been reported, that is, the enantiopurity of the initial chiral molecule increases from very low to very high during automultiplication. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

Then, we discovered that chiral 2-methyl-l-(5-pyrimidyl)propan-l-ol 8 serves as a highly enantioselective asymmetric autocatalyst for the addition of z-Pr2Zn to pyrimidine-5-carbaldehyde 7 (Scheme 4) [60]. In this compound, the formyl group is connected to the symmetric pyrimidine ring instead of the pyridine ring. When highly enantioenriched (S)-pyrimidyl alkanol 8 with 99% ee was employed as an asymmetric autocatalyst, (S)-8 with 95% ee composed of both the newly formed and the initially used 8 was obtained. The yield of the newly formed 8 was calculated to be 67% and the enantiomeric excess was 93% ee. 

The enantioselective asymmetric allylation of imines has been a synthetic challenge, the initial solutions of which required stoichiometric amounts of chiral allylbor on [87], allylsilane [88], allylzinc [89], or allylindium reagents [90]. Itsuno showed that a chiral B allyloxazaborolidine derived from norephedrine could add to the N trimethylsilyl imine prepared from benzaldehyde in high yield and enantiomeric excess (Scheme 1.22) [91]. Brown later reported that B allyldiisopinocamphenylbor ane is also very effective for the allylation of the same electrophiles, but the addition of a molar amount of water is necessary to obtain high yields [92]. The diastereo and... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of pharmacologically important molecules and natural products. The enantioselective synthesis of these compounds initially involved the chiral auxiUary-based asymmetric allylation of imines [41a, 4lb, 41c], and it is just recently that a few enantioselective variants have been reported. Although still in the regime of stoichiometric asymmetric synthesis, the first methods described below merit discussion for their synthetic utility and for establishing the groundwork for future development. 

Enantiopure benzylamines are important intermediates in the synthesis of pharmaceutically active compounds and chiral ligands for asymmetric transformations. Fernandez and co-workers ° reported that primary and secondary benzylamines could be obtained in moderate yields by converting the initially formed catecholboronate ester into a trialkylborane by reaction with either diethylzinc or methylmagnesium chloride, followed by treatment of the trialkylborane thus obtained with hydroxylamine-O-sulfonic acid, which yielded primary benzylamine 291. When the trialkylborane was treated with A-substituted chloramines, a secondary benzylamine, e.g., 292, was formed. A variety of vinylarenes gave the corresponding benzylamines in moderate to good yields and good-to-excellent enantioselectivity (78-98% ee). 

The reducing ability of NHC-borane complexes was later expanded to the use of chiral NHC-borane complexes in the asymmetric reduction of ketones carried out by Lindsay and McArthur [89]. They used borane complexes of the NHCs shown in Figure 15.19 to reduce acetophenone to chiral 1-phenylethanol. Though initially enantioselectivities were lower than would be desired, they then tested the effect of substitution around the boron center. A bulkier NHC coupled with a smaller Lewis acid additive (Bp3.0Et2) led to a 90% yield and 56% enantiomeric excess (ee) for acetophenone, with variations on these yields and enantioselectivities depending on the ketone. 

A reversal in enantioselectivity has been observed by the combination of a chiral diol and achiral alcohols as a chiral initiator in the asymmetric alkylation of a pyrimidine-5-carbaldehyde using diisopropylzinc. (25,35)-Butane-2,3-diol alone induced (R)-pyrimidyl alkanol, while a mixture of the chiral diol and phenol derivatives induced (5)-pyrimidyl alkanol (Scheme 5). 

The mechanism of the asymmetric alkylation of chiral oxazolines is believed to occur through initial metalation of the oxazoline to afford a rapidly interconverting mixture of 12 and 13 with the methoxy group forming a chelate with the lithium cation." Alkylation of the lithiooxazoline occurs on the less hindered face of the oxazoline 13 (opposite the bulky phenyl substituent) to provide 14 the alkylation may proceed via complexation of the halide to the lithium cation. The fact that decreased enantioselectivity is observed with chiral oxazoline derivatives bearing substituents smaller than the phenyl group of 3 is consistent with this hypothesis. Intermediate 13 is believed to react faster than 12 because the approach of the electrophile is impeded by the alkyl group in 12. 

Solladie-Cavallo s group used Eliel s oxathiane 1 (derived from pulegone) in asymmetric epoxidation (Scheme 1.3) [1]. This sulfide was initially benzylated to form a single diastereomer of the sulfonium salt 2. Epoxidation was then carried out at low temperature with the aid of sodium hydride to furnish diaryl epoxides 3 with high enantioselectivities, and with recovery of the chiral sulfide 1. 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

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