A-benzyloxy ketones

L-Selectride reduction of a-dibenzylamino ketones. Interestingly, a-benzyloxy ketones give anri-l,2-diol monobenzyl ethers with low isomer ratios (e.g, anti syn =6 1) which can be increased dramatically by changing the reducing agent to lithium tri-n-butylborohydride (>99 1). ... 

Enantiomer separation of a-benzyloxy ketones can be accomplished via lipase-catalyzed enantiomer-differentiating hydrolysis of the corresponding enol esters with formation of a mixture of the resulting ketone and the unchanged enol ester (94a,b). 

These tri(alkoxy)titanium enolates, which have low Lewis acidity, are known to react chemoselective-ly with an aldehyde group in the presence of a ketone (equation 4). Other uses described by Reetz et al. include the diastereofacially selective additions of ketone and ester enolates to chiral a-alkoxy aldehydes with nonchelation control. - For example, aldol addition of the tri(isopropoxy)titanium enolate of pro-piophenone to the aldehyde (24) leads to only the two syn diastereomers, with the nonchelation adduct (25) favored (equation 5) i.e. Felkin-Anh selectivity is operating. In the case of aldol addition of t-butyl propionate to the same aldehyde (equation 6), highest stereoselectivity for the isomer (26) is obtained using the tri(diethylamino)titanium enolate. Very high levels of nonchelation stereoselectivity can also be obtained in the aldol addition to chiral a-siloxy or a-benzyloxy ketones if a titanium enolate of low Lewis acidity is employed, as in equation (7). ... 

Located at an "ofif-template" site, we expected the Cl 4 center to be more difficxilt to establish and verify. We were going to have to rely on precedents of acyclic stereoselection, and based on Kishi s empirical observations (ref. 30), hydroxylation of olefin 32b should have given the R epimer 33, preferentially. On the other hand. Cram chelate addition (ref. 31), as elaborated by Still (ref. 32), to the a-benzyloxy ketone 32a, should give the allyl alcohol 34 from which the S-epimer 35 could be derived. Indeed, both processes were entirely stereoselective, and we were able to prepare the two possible products, each as a single isomer. 

It was anticipated that two of the three stereochemical relationships required for intermediate 12 could be created through reaction of the boron enolate derived from imide 21 with a-(benzyloxy)ace-taldehyde 24. After conversion of the syn aldol adduct into enone 23, a substrate-stereocontrolled 1,2-reduction of the C-5 ketone car-... 

A 3 -benzyloxy ketone gives preferential 2,2 -syn stereochemistry through a chelated TS for several titanium enolates. The best results were obtained using isopropoxytitanium trichloride.112 The corresponding /(-boron enolate gives the 2,2 -anti-2,3-anti isomer as the main product through a nonchelated TS.110... 

Phenyl methyl ketone 1 was brominated to give l-phenyl-2-bromoethanone 2. Compound 2 was treated with methylsulfonic acid to yield the corresponding methylsulfonate 3. Etherification of 3 gave the a-benzyloxy derivative 4 and compound 4 was then chlorinated to give the 2,4-dichlorinated derivatives in both aromatic ring systems 5. Compound 5 reacted with imidazole in dimethylformamide to give miconazole 6 [7], which is converted to miconazole nitrate. 

The a-chiral ketone from Figure 10.18—the a-substituent is a benzyloxy group—is reduced to the Cram chelate product by Zn(BH4)2, a Lewis acidic reducing agent. The Zn2 ion first bonds the benzyl and the carbonyl oxygen to a chelate. Only this species is subsequently reduced by the BH 4 ion because a Zn2 -complexed C=0 group is a better elec-... 

Enders and Bhushan reported the preparation of a-benzyloxy aldehydes and a-acetoxy ketones 6 of high enantiomeric purity and in good overall yield by oxygenation of the azaenolates of chiral hydrazone 4 with 3-phenyl-2-(phenylsulfonyl)oxaziridine 282. The chiral auxiliary was removed without racemization by ozonolysis of the a-hydroxy hydrazone 5 at — 78 °C. 

Williams has reported that orr/io-lithiated anisole may be acylated with the A -methoxy-A/ -methylamide of 2-(benzyloxy)acetic acid (equation 13) in higher yield than previously demonstrated with organocad-mium reagents (90% versus 40%). The ketone (23) is an early intermediate in an approach to quinocar-cin. Acylation of lithium 3-lithiopropoxide, generated from the stannane, afforded a hydroxy ketone without racemization at the a-position (equation 14). ... 

The reduction of tert-butyl 2-methoxy-3-oxo esters has also been investigated. These behave in a manner reminiscent of the a-alkoxy ketones 3-benzyloxy-4-methyl-4-hexen-2-one and 2-methoxy-l,2-diphenylethanone (see p 3994) in that, even with sodium borohydride in 2-propanol, they appear to react under chelation control, giving non-products54. Unfortunately, the analogous 2-/< rt-butoxy-3-oxo esters, which would be more versatile as intermediates, react with rather less selectivity. 

The method was also successful with an a-benzoyloxy ketone, but was unsuccessful with 2-dimethylamino-l-phenylpropanone, which failed to react, and with 2-benzyloxy-l-phenyl-propanone, which reacted with negligible stereoselectivity2,... 

The aldol reaction using chiral a-oxygenated ketones proceeds in a diastereose-lective manner (Scheme 3) (Z)-boron enolate 28 derived from benzyloxy ketone 27 afforded sy -aldol 29 via chelation control, while benzoyloxy ketone 30 afforded anft-aldol 32 via ( )-enolate 31 through a nonchelation transition state [9]. 

Stereoselective aldol addition to the lithium enolates themselves has been achieved by reaction of the deprotonated benzyloxy-substituted iron complex 66b and subsequent reaction with symmetrical ketones. The enolate involved in this procedure is assumed to exist as a chelated species 67b. The aldol 68 is obtained in a diastereomeric ratio higher than 99 1. The reaction is, nevertheless, plagued by low chemical yield, because of deprotonation of acetone. Because a symmetric ketone is used as an electrophile, the reaction leads to the formation of just one new stereogenic center [117, 118]. 

The Grignard reagent attacks from the side opposite to that of the bulky benzyloxy group resulting in predominant formation of the trans isomer. For a discussion of the stereochemistry of addition of organometallics to a-alkoxy ketones, see D. J. Cram and D. R. Wilson, J. Amer. Chem. Soc., 85, 1245 (1963). 

V. -(l-Carbobemoxy-4 -piperidyl)propionyl chloride. /3-(iV-carbo-benzyloxy-4-piporidyl)ethyl 3-indolyl ketone (208) was obtained similarly by the condensation of ]3-(A -carbobenzoxy-4-piperidyl)-propionyl chloride with indole magnesium bromide in ether. ... 

It is not clear whether the silyl iodide causes activation of only one of the benzyloxy groups, or if a substitution by iodine takes place before reductive metalation. These reagents exhibit a high preference for aldehyde over ketone addition13. 

A combination of substrate-induced and auxiliary-induced stereoselectivity is provided by the diisopinocampheylborinates 11a and lib derived from the chiral ketone (S)-l-benzyloxy-2-mcthyl-3-pentanone52. Whereas this ketone provides no significant diastereoselectivity when converted into the dibutylboron enolate and, subsequently, added to aldehydes, use of the diisopinocampheyl reagents 11a and lib leads to the jS-hydroxy ketones 12 and 13 in a stereoselective manner. The chiral information which is located in the carbon chain of the starting ketone 10 is incorporated into the products ... 

A jy -diastereoselective aldol reaction based on titanium enolates from (A)-l-benzyloxy-2-methyl-3-pentanone was developed by Solsona et al. (Equation (12)).64 The titanium enolate of this chiral ketone afforded the corresponding syn-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes. 

Sinou and coworkers evaluated a range of enantiopure amino alcohols derived from tartaric acid for the ATH reduction of prochiral ketones. Various (2R,iR)-i-amino- and (alkylamino)-l,4-bis(benzyloxy)butan-2-ol were obtained from readily available (-I-)-diethyl tartrate. These enantiopure amino alcohols have been used with Ru(p-cymene)Cl2 or Ir(l) precursors as ligands in the hydrogen transfer reduction of various aryl alkyl ketones ee-values of up to 80% have been obtained using the ruthenium complex [93]. Using (2R,3R)-3-amino-l,4-bis(benzyloxy)butan-2-ol and (2R,3R)-3-(benzylamino)-l,4-bis(benzyloxy)butan-2-ol with [lr(cod)Cl]2 as precursor, the ATH of acetophenone resulted in a maximum yield of 72%, 30% ee, 3h, 25 °C in PrOH/KOH with the former, and 88% yield, 28% ee, 120 h with the latter. 

Ketones containing triple bonds in the a,)3-positions are reduced to the corresponding unsaturated alcohols with sodium cyanoborohydride or tetra-butylammonium cyanoborohydride in 64-89% yields [780]. Thus 4-phenyl-3-butyn-2-one gave 4-phenyl-3-butyn-2-ol [780]. If the same ketone was converted to its p-toluenesulfonylhydrazone and this was reduced with bis benzyloxy)borane, 1-phenyl-1,2-butadiene was obtained in 21% yield [786]. 

Nakata showed that stoich. RuOyCCl oxidised steroidal diols to the corresponding ketones [237] electrogenerated RuO from RuO /aq. NaCl/Na(H3PO ) pH 4/ Pt electrodes converted diols to lactones and keto acids (Tables 2.1-2.4) [267] and RuCyaq. 10(0H)3/CC1 -CH3CN oxidised 3-(benzyloxy)-l,2-octanediol to the acid (Tables 3.4, 3.5) [107]. A diol was converted to a lactone by stoicheio-metric oxidation with RuOyCCl as part of the total synthesis of the quassinoid ( )-amarolide [82],... 

The original racemic patents described the use of resolution to give a chiral oxirane, such as 25, as an intermediate or the use of a chiral auxiliary (20) to produce the salmeterol enantiomers. Alkylation of chiral amine 20 with 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester, followed by diastereoselective reduction of the ketone with lithium borohydride furnished intermediate 21 after chromatographic separation of the diasteromers. Removal of the benzyl group and the chiral auxiliary was... 

Cardenolides.1 Digitoxigenin (7) has been synthesized by reaction of a 3/J-benzyloxy a./3-unsaturated 17-ketone (2) with 1, followed by further transformations as shown. Allylic rearrangement of the initial product 3 results in 4. After reduction... 

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