Ketones, -y-hydroxy

Schreiber found that the monoalkylation of the lithium enolate of cyclonona-none with propene oxide could be cleanly effected by addition of AlMe3 to give the y-hydroxy ketone 145, a key intermediate for the synthesis of recifeiolide [69a]. 

The cyclization of y -hydroxy ketones is useful for the formation of pyrans,306,403 both directly and via rearrangement, as illustrated in Eq. 231.153 As with their acyclic counterparts, these cyclizations also occur with the silyl ethers of the hydroxy ketones where Et3SiH/BiBr3 is used with the TBS and TES ethers.342,404 A methyl thiomethyl ether is also capable of undergoing the reductive cyclization 405 In like manner, 1,4-diols and e-hydroxy ketones provide oxepanes, with I ds Si H or PhMe2SiH/TMSOTf being especially effective (Eqs. 232 and 233).336,406 The trimethylsilyl ether of the alcohol also provides the oxepane.306... 

Fig. 11.22. Mechanisms postulated for cyclodehydration of a) linear y-hydroxy ketones (11.170) as metabolites of alkanes and alkanones to form 2,5-dialkyl-2,3-dihydrofurans (11.171), and b) piroxicam (11.172) to form its cyclodehydrated metabolite 11.173...

Rats exposed to a fteptone-containing atmosphere excreted a variety of metabolites resulting from oxidative pathways [176]. The major metabolites were isomeric mono-alcohols and ketones, but small amounts of 2-ethyl-5-methyl-2,3-dihydrofuran (11.171, R = Et, R = Me, Fig. 11.22,a) and 5-ethyl-2-methyl-2,3-dihydrofuran (11.171, R = Me, R = Et) were also detected. These metabolites are believed to arise from 6-hydroxyheptan-3-one (11.170, R = Et, R = Me) and 5-hydroxyheptan-2-one (11.170, R = Me, R = Et). The postulated mechanism of formation of 2,3-dihydrofurans involves their equilibrium with the corresponding linear y-hydroxy ketones, as shown in Fig. 11.22,a. Such a reaction has been documented for linear y-hydroxy aldehydes [177],... 

Cyclopropyl ketones 1 can be made by cyclisation of some derivative of the y-hydroxy-ketone 2. Notice that we proposing to make a three-membered carbocyclic ring from an easily made three-membered Tetracyclic ring. 

Glycosides made from y-hydroxy ketones undergo photoelimination to give O-vinyl glycosides, which can undergo a Claisen rearrangement in certain deoxy sugars [68]. 

Yttrium triflate catalyzes the reaction of lithium enolates with epoxides to form y-hydroxy ketones. 

Stereoselective reduction of a y-hydroxy ketone. Reaction of the y-liydroxy ketone 1 with LiAIHj. ZnBHi. or NaBHj yields about equal amounts of the two possible diols. However, reduction 4 ith Li(C,H,),BH (2 cquiv.) yields only one product (2) in yield. The high stereoi-icicctivity is attributed to formation of a chelated boron intermediate that favors attack by the hydride from the (3-facc. The diol (2) is converted by TsCI into ancistrofuran (3), a ddfensive secretion of certain termites. 

Dehydration of a y-hydroxy ketone. The synthesis of the antibiotic nonactin (1) presents an unusual problem in that the subunit, nonactic acid, occurs as both optical antipodes. In a recent synthesis, this problem was simplifed by synthesis of both antipodes... 

Addition of lithium enolates derived from esters and ketones to epoxides has been the object of some consideration, because it offers a direct route for the synthesis of y -hydroxy esters and y-hydroxy ketones, very useful for difunctionahzed organic compounds" . In fact, more complex molecules can be synthesized by using these compounds as synthons... 

Examples of asymmetric induction from more remote hydroxy groups in the reduction of hydroxy ketones are rare. However the correct choice of reducing agent allowed complete diastereoselectivity to be achieved in the reduction of "y-hydroxy ketone (43) in a synthesis of ancistrofuran. 2 equiv. of LiEtsBH in THE, one presumably coordinating the "y-hydroxy ketone in a fixed conformation, gave the diol (44) as the sole product in 88% yield (equation II). 

A good way to prepare p-diketones consists of heating a,p-epoxy ketones at 80-140°C in toluene with small amounts of (Ph3P)4Pd and l,2-bis(diphenyl-phosphino)ethane. ° Epoxides are converted to 1,2-diketones with Bi, DMSO, O2, and a catalytic amounts of Cu(OTf)2 at 100°C. a,p-Epoxy ketones are also converted to 1,2-diketones with a ruthenium catalyst or an iron catalyst. Epoxides with an a-hydroxyalkyl substituent give a pinacol rearrangement product in the presence of a ZnBr2 " or Tb(OTf)3 catalyst to give a y-hydroxy ketone. 

The reactions with esters of stabilized anions (32) and (38) give a-phenylthio ketones in yields of 75-82% (equation 37). Acylations with succinic anhydride and butyrolactone to give y-keto acids and y-hydroxy ketones respectively, also proceed in good yields. ... 

Chiral y-hydroxy ketones meyo-1,4-Bis(siloxy)-2-alkenes undergo regioselective isomerization on treatment with a BINAP-Rh complex. On exposure to Bu NF the enol ether moiety of the products is hydrolyzed (a TBS group can be retained). 

Hydroxycodeinone was first represented as an a-hydroxy-ketone, but such a formulation was rejected by Gulland and Robinson [9] on account of the stability of the base towards alkaline silver and cupric solutions, and, moreover, the base does not behave as an allylamine in its reaction with cyanogen bromide [4, 13-16]. A /3-hydroxy-ketone structure was never seriously considered and is in any case at variance with the observed difficulty of dehydrating 14-hydroxycodeinone and its derivatives, but a y-hydroxy-ketone formulation is compatible with all the experimental facts. 14 Hydroxycodeinone does not show the properties of a methylene-ketone, but its dihydro-compound does, facts best explained by postulating the presence of the system —GO—0—C—C—OH in the former [9]. 

Cyclopropanols undergo facile reaction with photoexcited aryl ketones such as benzophenone and fluorenone. Irradiation of fluorenone (14) and 1-phenylcyclopropanol gives a 78% yield of the coupling product 15. Spiro product 16, obtained from 1,2,2-trimethylcyclopropanol, may be derived from the y-hydroxy ketone by a further intramolecular cyclization reaction of this initial coupling adduct. 

Not only 1,2-di-functionalized substrates with heteroatoms but also tertiary alcohols and hemiketals undergo oxidative C-C bond cleavage at the a position on treatment with lead tetraacetate. For example, a y-hydroxy ketone and the corresponding hemiketal have been fragmented by lead tetraacetate into a 9-membered olefinic lactone (Scheme 13.57) [76]. 

Intramolecular dehydration of y-hydroxyketones.2 When y-hydroxy ketones are heated to about 150° with DCC, water is eliminated with formation of a cyclopropane ring. For example, 5-hydroxy-2-pentanone (1) is transformed into (3) in 80% yield. In the suggested mechanism, (2) is proposed as an intermediate. The reaction is noteworthy because dehydration is accompanied by formation of a carbon-carbon bond. 

The cleavage of strained heterocyclic rings can also be achieved by PET (Scheme 25). Cleavage of the epoxide ring of an a-epoxy ketone leads to a y-hydroxy ketone... 

A wide repertoire of cleavage reactions demonstrates the synthetic potential of the pseudoephedrine amides, providing access to chiral a-branched carboxylic acids, aldehydes, ketones or primary alcohols with recovery of the auxiliary (Scheme 2). Moreover, efficient alkylation reactions utilizing epoxides and epoxide-derived electrophiles open up a route to chiral y-lactones and y-hydroxy ketones. [7]... 

The oxime 7, prepared from salicyl aldehyde, is converted with iV-chlorosuccinimide into the hydrox-amic acid chloride 8. From this, the nitrile oxide is obtained with KHCO3, which reacts regioselec-tively with styrene to give the 3,5-diaryl-4,5-dihydroisoxazole 9. Catalytic hydrogenation leads to the y -hydroxy ketone 10, which on acid-catalysed cyclodehydration gives the flavanone 11. 

The product isolated after the nucleophilic attack of the enol is an a,3 unsaturated ketone and not the intermediate y hydroxy ketone because the alcohol will spontaneously dehydrate in the acid media to form the conjugated system. The product here is particularly stable because the subsequently formed double bond is conjugated to the benzene ring as well as the carbonyl group. 

Alkylations. The alkylation of pseudoephedrine amides with epoxides is a practical method for gaining access to chiral y-lactones. Reaction of the alkylation products with alkyllithiums leads to y-hydroxy ketones. 

Decarbonylation. Aromat Sc(OTf)j in methanol (forming electron-releasing substituents facil AUylation. The catalyzed illyltrimethylsilane, and a similar it room temperature or below. Hon Aldol reactions. The reactio A ith aldehydes and imines - give -elease 1,3-diols and amino alcohol y-Hydroxy ketones. The op f Sc(OTf)3 is effective (5 example... 

Diketones. The reagent (1) reacts with Grignard reagents to form y-hydroxy ketones, which can be oxidized directly with Jones reagent to give 1,4-diketones. ... 

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