Enantioselectivity deprotonation

Configurational stability has also been confirmed for various metalated carbamates by Hoppe and coworkers. Remarkably, carbamate-protected alcohols such as 20 are deprotonated enantioselectively, when treated with i-butyllithium in the presence of (—)-sparteine. The lithium carbenoids like 21 (R = alkyl) thus generated turn out to retain their configuration (equation 11). Similar results have been obtained for a-lithiated amines and carbamate protected amines " . As a rule, dipole stabilization of the organolithium compounds in general also enhances the configurational stability of a-oxygen-substituted lithium carbenoids. 

A second s-BuLi-(-)-sparteine deprotonation amplifies the enantiomeric excess of the product 388. The sequence below gives the 2,5-dimethylpyrrolidine derivative 391 in >99% ee.67 A phosphorus analogue 392 is also deprotonated enantioselectively.171... 

The piperidines 393 are deprotonated enantioselectively, but the organolithiums have significantly lower levels of configurational stability, and high enantiomeric excesses result only if the electrophilic quench is a fast, intramolecular reaction, as in the formation of 394. 

Carbamates containing unsaturated substituents may undergo enantioselective anionic cyclisations (see also section 7.2.4) for example, 421 is deprotonated enantioselectively by s-BuLi-(-)-sparteine and gives the cyclopentane 422.180... 

Interestingly, asparagin acid derivative 14 is deprotonated enantioselectively by s BuLi-(-)-3 in ether (-78 °C, 5 h) furnishing after carbonylation and subsequent methy-lation the ester 15 in 90% yield (Eq. 8). [17]... 

In all examples of enantioselective deprotonation of meso-epoxides with organo-... 

Metzner and co-workers reported a one-pot epoxidation reaction in which a chiral sulfide, an allyl halide, and an aromatic aldehyde were allowed to react to give a trons-vinylepoxide (Scheme 9.16c) [77]. This is an efficient approach, as the sulfonium salt is formed in situ and deprotonated to afford the corresponding ylide, and then reacts with the aldehyde. The sulfide was still required in stoichiometric amounts, however, as the catalytic process was too slow for synthetic purposes. The yields were good and the transxis ratios were high when Ri H, but the enantioselectivities were lower than with the sulfur ylides discussed above. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

Alkyldimethylphosphine-boranes 74 underwent enantioselective deprotonation employing (-)-sparteine/s-BuLi, followed by oxidation with molecular oxygen [91, 92] in the presence of triethyl phosphite (Scheme 12) to afford moderate yields of enantiomerically enriched alkyl(hydroxymethyl)methylphosphine-bo-ranes 76, with 91-93% ee in the case of a bulky alkyl group and 75-81% ee in the case of cyclohexyl or phenyl groups [93]. Except for the adamantyl derivative (in which the ee increased to 99%), no major improvement in the ee was observed after recrystallization. 

We further synthesized unsymmetrical MiniPHOS derivatives 13b (Scheme 13) [30]. Thus, enantioselective deprotonation of l-adamantyl(dimethyl)phos-phine-borane (74, R = 1 -Ad), followed by treatment with ferf-butyldichlorophos-phine or 1-adamantyldichlorophosphine, methylmagnesium bromide and bo-rane-THF complex afforded the optically active diphosphine-boranes 82b as a mixture with the corresponding raeso-diastereomer. Enantiomerically pure unsymmetrical MiniPHOS-boranes 82b were obtained by column chromatography on silica gel or separation by recycling preparative HPLC. 

An elegant enantioselective [2,3] sigmatropic rearrangement ofbisalkynyl ethers such as 75 was reported by Manabe in 1997 [20]. The deprotonation... 

Asymmetric deprotonation of prochiral cychc ketones (Scheme 50) was performed with chiral ureas in the presence of butylhthium. Yields were good (85-88%) with high enantioselectivities (83-87%). Moderate enantioselectiv-ity is obtained with the cyclopentyl-containing urea (Scheme 50 37% ee with R = Ph 7% ee with R = Me) [ 168,169]. 

Improvement in the catalyst activities and enantioselectivities was realised by the development of the chiral, bidentate alkoxy-functionalised imidazolium and imidazolidinium pro-ligands (134 and 136). 134, after deprotonation, was used to prepare the well-defined complex 135. Both 136 in the presence of BuLi and Cu(OTf)2 or 135 without any additional co-reagents were efficient catalysts in the asymmetric 1,4 addition of dialky Izincs and Grignards to cyclohexen-2-one giving higher ee (83% at rt and 51% at -30°C, respectively) [107, 108]. 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric hydrogens and the chiral base, resulting from differences in diastere-omeric TSs.27 For example, transition structure E has been proposed for deprotonation of 4-substituted cyclohexanones by base D.28 This structure includes a chloride generated from trimethylsilyl chloride. 

Analogous rearrangement occurs under much milder conditions when the reactant is a zwitterion generated by deprotonation of an acylammonium ion. Substituted pyrrolidines were used as the chiral auxiliary, with the highest enantioselectivity being achieved with a 2-TBDMS derivative.267... 

The consistent observation of the arylated products with 92% ee confirms that the enantioselectivity of the asymmetric deprotonation was preserved during the transmetalation with ZnCl2 and retained during the Pd-catalyzed coupling. In fact, the Negishi coupling with 3-bromopyridine (entry 16) was performed at 60 °C, and still provided 26m in 92% ee, which constitutes a formal total synthesis of (R)-nicotine [27]. 

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