Alcohols, chiral from acetylenic ketones

Cabarrocas G, Ventura M, Maestro M, Mahia J, Villalgordo JM (2001) Synthesis of novel optically pure quinolyl-P-amino alcohol derivatives from 2-amino thiophenol and chiral a-acetylenic ketones and their IBX-mediated oxidative cleavage to IV-Boc quinolyl carboxamides. Tetrahedron Asymmetry 12 1851-1863... 

Brinkmeyer and Kapoor (101) reported that the chiral hydride complex formed from LAH and (+ )-90 (Darvon alcohol) gave high enantiomeric ratios of chiral propargylic carbinols in the reduction of acetylenic ketones (Table 10, entries... 

Reduction of a, -acetylenic ketones with chiral borane NB-Enanthrane prepared by addition of 9-borabicyclo[3.3.1]nonane to the benzyl ether of nopol yielded optically active acetylenic alcohols in 74-84% yields and 91-96% enantiomeric excess [770]. Another way to optically active acetylenic alcohols is reduction with a reagent prepared from lithium aluminum hydride and (2S, 3R)-( -I- )-4-dimethylamino-3-methy 1-1,2-dipheny 1-2-butanol. At —78° mainly R alcohols were obtained in 62-99% yield and 34-90% enantiomeric excesses [893]. 

Asymmetric reduction of a,f -acetylenic ketones. This borane can be used to reduce 1-deulerio aldehydes to chiral (S)-l-deulerio primary alcohols in 90% optical yields. It also reduces a,/ -acctylcnic ketones to (R)-propargylic alcohols with enantiomeric purity of 73-100%. The ee value is increased by an increase in the size of the group attached to the carbonyl group. The value is also higher in reductions of terminal ynones. Alcohols of the opposite configuration can be obtained with the reagent prepared from (— )-a-pinene. 

R)-Propargylic alcohols have also been produced, this time in 73—100% e.e., by asymmetric reduction of a,/3-acetylenic ketones with the chiral borane prepared from (+)-a-pinene and 9-borabicyclo[3.3.1]nonane (9-BBN) (Scheme 10), a system already known to reduce aldehydes to chiral alcohols cf. 2,115). These results compare favourably with those from the LiAlH4- Darvon complex above, and the availability of both (+)-and (-)-o -pinene means that either (R)-or (5)-propargylic alcohols may be produced. 

The reaction of diphenyl methylphosphonate with lithium alkoxides gives phenyl alkyl methylphosphonates even with hindered alcohols and, in the case of chiral alcohols, with high diastereoselectivity at phosphorus. [Hydroxy(pho-sphoryloxy)X, iodo]benzenes 289, prepared from reactions of iodosobenzene with phosphonic or phosphinic acids react with ketones, esters or phenyl acetylene to give esters 290. Racemic l-hydroxy-4-(3-phenoxyphenyl)butylphosphonate diethyl ester undergoes stereoselective acetylation in the presence of a lipase to... 

The synthesis of (5S,15S)-diHETE is shown in Scheme 4.16 and makes use of Pd-Cu coupling of a terminal acetylene to trans vinyl bromides (48 + 50 —> 51 and 51 + 49 — 52) to obtain eneynes. The acetylenes are reduced by catalytic hydrogenation to give the requisite cis-trans dienes. Acetylenes 46 and 47 bear the suitable optically active secondary alcohols for the (5S)and (155)-alcohol functions in the natural product and are derived from chiral reductions of the corresponding ketones. ... 

It was already known that amino alcohols of the kind we have just used 78 were good at this kind of asymmetric addition but this particular combination of an acetylenic nucleophile and an aryl trifluoromethyl ketone was uncharted territory. After some exploration, stoichiometric pyrrolidine alcohol 88 prepared by alkylation of norephedrine 87 from the chiral pool (chapter 23) proved the best and the ketone 85 had to be used as its V-4-methoxybenzyl derivative18 89. 

Compound 11 is, however, unexpectedly unreactive with Wittig-Horner reagents. Upon heating with the carbanion of ester phosphonates an addition across the allenic bond occurs [14]. In contrast, a slow normal 1,2-addition takes place [14] with the ylide from cyano-methylphosphonate but, unexpectedly, this proceeds with concomitant inversion at the chiral axis as shown in Scheme 3, to give a mixture of 6R or 6S, and (9E)- or (9Z)-isomers 12-15. However, a fast and very clean 1,2-addition occurs with the ethynyl ketone 18 to yield the esters 19 and 20 (Scheme 4). DIB AH reduction of the separated stereoisomers gives the allenic alcohols 21 and 22 in high yield. Mild oxidation to the aldehydes 23 and 24, followed by their condensation with the acetylenic Cio-bis-ylide 25, leads to the stereoisomeric 15,15 -didehydromimulaxanthins 26 and 28, respectively (Schemes 5 and 6). The optically active. 

There have been significant discoveries of methods that enable the enantioselective addition of an alkyne to an aldehyde or a ketone [182]. The resulting chiral propargyl alcohols are amenable to a wide variety of subsequent structural modifications and function as useful, versatile chemical building blocks. In 1994, Corey reported the enantioselective addition reactions of boryl acetylides such as 292, prepared from the corresponding stannyl acetylenes (e.g., 291) in the presence of the oxazaborolidine 293 as the chiral catalyst (Scheme 2.36) [183]. Both aliphatic and aromatic aldehydes were demonstrated to participate in these addition reactions, which proceeded in high yields and with impressive enantioselectivity. The proposed transition state model 295 is believed to involve dual activation both of the nucleophile (acetylide) and of the electrophile (aldehyde). The model bears a resemblance to the constructs previously proposed for alkylzinc addition reactions (Noyori, 153) and borane reductions (Corey. 188). 

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