Bromination asymmetric

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

The influence of 1,2-asymmctric induction on the exchange of diastereotopic bromine atoms has also been investigated22,23. Thus, treatment of the / -silyloxydibromo compound 15 with butyllithium at — 110°C in the presence of 2-methylpropana led to products 17-19 after the reaction mixture was warmed to 20 °C. The distribution of the products indicates that the diastereomeric lithium compounds 16 A and 16B were formed in a ratio of 84 16, with 16A being kinetically favored by 1,2-asymmetric induction. Formation of the m-configurated epoxide (cis,anti-18) was slowed to such an extent that its formation was incomplete and a substantial amount of the parent bromohydrin 17 remained. The analogous m.yyn-configurat-ed epoxide was not observed. Presumably for sterie reasons, the parent bromohydrin did not cyclize to the epoxide but instead led to the ketone 1923. 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

The deleterious effects of catalyst poisoning when carrying out asymmetric hydrogenations at low catalyst loading caimot be overemphasised. In order to eliminate the possibility that the substrate synthesis introduced inhibitory impurities, an alternative synthetic protocol was examined (Scheme 7.4). The use of a brominating agent and an expensive palladium catalysed step in the initial route could limit the development of this as an economically favourable process and this was further motivation to examine alternative routes to the hydrogenation substrate. 

Although the process as it stands is still not enantioselective in nature, the high yield and mild reaction conditions may attract further search for an asymmetric version of this reaction using proper chiral bromine-comtaining compounds as the catalyst. 

Asymmetric synthesis of amino acids.1 These lactones can serve as an optically active form of glycine for synthesis of either D- or L-amino acids. Thus (+ )-1 (or (—)-l) on radical bromination is converted into a single monobromide (2), which can be coupled with nucleophilic organometallic reagents, by either an SN1... 

The addition of electrophilic reagents to chiral a,/3-unsaturated sulfoxides is also accompanied by asymmetric induction. Stirling and Abbott (318,322) found that the addition of bromine to the optically active (.R)-vinyl-p-tolyl sulfoxide 319 yields a mixture of diastereo-meric a,/3-dibromosulfoxides 320. Oxidation of this mixture gives the optically active sulfone 321, with a center of chirality at the a-carbon atom only. The optical purity (32%) of this sulfone was estimated by comparing its specific rotation with that obtained as a result of oxidation of diastereomerically pure sulfoxide (/ )-320. The assignment of configuration at the a-carbon atom was based on the analysis of the polarizabilities of substituents. 

The D-fructose-derived, chiral, nonracemic l,3-oxazin-2-one derivative 260 exerted smooth stereocontrol, resulting in high levels of asymmetric induction and good chemical yields in various synthetic transformations. The chiral fragments 256 and 261 formed in the aldol or a-bromination reactions of the A -propionyl derivative 257 could easily be removed from the parent auxiliary by mild hydrolysis (Scheme 48). The Diels-Alder cyloadditions of the A -acryloyl and A -cinnamoyl derivatives of 260 were also characterized by excellent diasterofacial selectivity <1998T9765>. 

The key step in their-approach was asymmetric photoisomerization of the a, 3-unsaturated (Z)-ketone precursor 103b in diethyl ( + )-Lg-tartrate. The bromide 103a obtained by N-bromo-succinimide bromination of the (Z)[8.8] precursor 64b, was converted into the a,P-unsaturated (Z)-ketone 103b by the routine synthetic procedures. Irradiation in a hexane solution with a medium pressure Hg lamp effected the photoisomerization of the (Z)-precursor 103b to afford a 1 5.5 mixture of (Z)-( )[8.8] ketones. After these preliminary experiments, a neat solution of 103 b in diethyl ( + )-Lg-tartrate was irradiated for 3 h. Preparative GLC of the resulting 1 7 mixture of (Z) and ( )[8.8] ketones produced a 38 % yield of ( )[8.8] ketone 104 enriched in the (—)-enantiomer, [a]n4 —13° (hexane). 

The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11, the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol in > 96 4... 

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