Asymmetric a-methylation

Styrene, a-ethyl-asymmetric hydroformylation catalysts, platinum complexes, 6, 266 asymmetric hydrogenation catalysts, rhodium complexes, 6, 250 Styrene, a-methyl-asymmetric carbonylation catalysis by palladium complexes, 6, 293 carbonylation... 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Anilino vinyl derivatives of thiazolium (30, R = H) or acetanilido (30, R = C0CH3), as well as formyl methylene 30b (methods E-G), give asymmetrical dyes when condensed with a methyl reactive group of another species (Scheme 42). Mesosubstituted symmetrical or unsymmet-rical thiazolocyanines are obtainable via /S-alkylmercaptovinyl thiazolium derivatives (32) (methods H and I) (Scheme 43). a or /S carbon atoms of the trimethine chain can be substituted by acetyl when a dye is treated with acetic anhydride (method L). The hydrolysis of neocyanines lead to trimethine cyanine by fractional elimination of a composant chain (method K). 

Z)-l-Methyl-2-butenylboronate 7 undergoes an exceptionally enantioselective reaction with benzaldehyde (99% ee), propanal (79%. 98% ee), 2-methyl-2-propenal (85%, 99% ee), and ( )-2-methyl-2-pentenal (81 %, 99% ee)10 38. Excellent enantioselectivity is also realized in reactions of the analogous chiral a-methyl-) y-disubstituted allylboronate27 40. Whether the l,2-dicyclohexyl-l,2-ethanediol auxiliary plays a beneficial role in this reaction, as suggested above for the asymmetric allylboration reactions of 6, has not yet been determined. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Allyl p-tolyl sulphoxide 535 reacts with sodium methoxide in methanol by initial prototropic isomerization and subsequent addition of methanol to give 536 (equation 333). Protic solvents are photochemically incorporated by the open chain olefinic bond of trans methyl )S-styryl sulphoxide 537 in a Markovnikov regiospecificity (equation 334). Mercaptanes and thiophenols add to vinyl sulphoxides in a similar manner (compare also Reference 604 and Section IV.B.3) to give fi-alkylthio(arylthio)ethyl sulphoxides 538 (equation 335). Addition of deuteriated thio-phenol (PhSD) to optically active p-tolyl vinyl sulphoxide is accompanied by a low asymmetric a-induction not exceeding 10% (equation 336) . Addition of amines to vinyl sulphoxides proceeds in the same way giving )S-aminoethyl sulphoxides in good to quantitative yields depending on the substituents at the vinyl moiety When optically active p-tolyl vinyl sulphoxides are used in this reaction, diastereoisomeric mixtures are always formed and asymmetric induction at the p- and a-carbon atoms is 80 20 (R = H, R = Me) and 1.8 1 (R = Me, R = H), respectively (equation 337) ... 

The method has been used for a short asymmetric synthesis of (-)-prostaglandin Ej methyl ester (PGEj) (2-58) starting from 2-47, 2-55 and 2-56 (Scheme 2.12) [17]. The domino reaction provided 2-57 in 60 % yield as mixture of two diastereomers in reasonable stereoselectivity (trans-threo trans-erythro ratio 83 17). Further transformations led to 2-58 in an overall yield of 7% and 94% ee in seven steps. 

Node and coworkers have used this aromatization strategy for the synthesis of (-) aphanor-phine.27 The Diels-Alder reaction of chiral nitroalkene, prepared by the asymmetric nitroolefi-nation reaction of a-methyl-8-valerolactone, with the Danishefsky s diene followed by aromatization is used as a key step for this total synthesis, as shown in Scheme 8.6. 

Node and Fuji have developed a new chiral synthesis of various alkaloids using chiral nitroalkene, (S)-(-)-2-methyl-2-(2 -nitrovinyl)-S-valerolactone. Scheme 8.11 shows a total synthesis of (-)-physostigmine, a principal alkaloid of the Calabar bean.53 The key nitroalkene is prepared by asymmetric nitroolefination of a-methyl-8-lactone using a chiral enamine (see... 

UV radiation hypothetical, but so is the transport of molecules from outer space to Earth. Recent analyses of the Murchison meteorite by two scientists from the University of Arizona, Tucson (Cronin and Pizzarello, 1997 Cronin, 1998) have shown it to contain the four stereoisomeric amino acids DL-a-methylisoleucine and DL-a-methylalloisoleucine. In both cases, the L-enantiomer is present in a clear excess (7.0 and 9.1%). Similar results were obtained for two other a-methyl amino acids, isovaline and a-methylvaline. Contamination by terrestrial proteins can be ruled out, since these amino acids are either not found in nature or are present in only very small amounts. Since the carbonaceous chondrites are thought to have been formed around 4.5 billion years ago (see Sect. 3.3.2), the amino acids referred to above must have been subject to one or more asymmetric effects prior to biogenesis. 

Asymmetric syntheses of (3- amino acids result from the addition of chiral enolates (399) to nitrone (400) via A-acyloxyiminium ion formation (642, 643). Regioselective convergence is obtained in the reactions of chiral boron- and titanium- enolates (399a,b), (401), and (402). This methodology was used in preparing four stereoisomers of a-methyl- 3-phenylalanine (403) in enantiomeric pure form (Scheme 2.179) (644). 

Mikami and co-workers16-19 have done extensive work for developing catalysts for the asymmetric carbonyl-ene reaction. Excellent enantioselectivites are accessible with the binol-titanium catalyst 17 (Equation (10)) for the condensation of 2-methyl butadiene (R1 = vinyl) and glyoxalates (binol = l,T-binaphthalene-2,2 -diol).16 The products were further manipulated toward the total synthesis of (i )-(-)-ipsdienol. The oxo-titanium species 18 also provides excellent enantioselectivity in the coupling of a-methyl styrene with methyl glyoxalate.17 Reasonable yields and good enantioselectivites are also obtained when the catalyst 19 is formed in situ from titanium isopropoxide and the binol and biphenol derivatives.18... 

Perfect stereochemical control in the synthesis of sy -a-methyl-/ -hydroxy thioesters has been achieved by asymmetric aldol reaction between the silyl enol ether of. S -ethyl propanethioate (1-trimethylsiloxy-l-ethylthiopropene) and aldehydes using a stoichiometric amount of chiral diamine-coordinated tin(II)... 

Linz et al.6 report the synthesis of enantiomerically pure cyclosarkomycin 6, a stable crystalline precursor of sarkomycin 5. As described in Scheme 5-3, 6 can be obtained from 8, an asymmetric Diels-Alder adduct of (E )-bromoacry-late. (E)-3-bromoacrylate 9a [the acrylate of (R)-pentolactone 11] and 9b [the acrylate of ( S )-A-methyl hydroxyl succinimide 12] undergo TiCL-mediated Diels-Alder reactions giving 10a or 10b, the endo-product, with high diaster-eoselectivity (Scheme 5-4). With the key intermediate 10a in hand, synthesis of compound 6 is accomplished by following the reaction sequence shown in Scheme 5-5. 

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

If the hydrogen of the hydroxyl on the asymmetric carbon is replaced by a methyl group which would be not expected to migrate readily, the optical rotation with changing concentration becomes negligible. 

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