P—hydroxyketone

By the Fries reaction. This is a variant of the Friedel-Craft reaction it consists in the conversion of an ester of a phenol to the corresponding o- and p-hydroxyketone, or a mixture of both, by treatment with anhydrous aluminium chloride ... 

Sodium or tetramethylammonium triacetoxyborohydride has become the reagent of choice for diastereoselective reduction of P-hydroxyketones to antidiols. Trialkylborohydrides, eg, alkaH metal tri-j -butylborohydrides, show outstanding stereoselectivity in ketone reductions (39). 

P-Hydroxyketones are also subject to fragmentation. Lewis acids promote fragmentation of mixed aldol products derived from aromatic aldehydes.100... 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane, provides 9,ll-ethano-13,15-isoxazolinoprostanoids, PGH analogs, with alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (461). Chemical transformations of 9,11-ethano-13,15-isoxazolinoprostanoids furnish prostanoids with bifunctional fragments of P-hydroxyketone and a-aminoalcohol in the oo-chain. The reaction of P-hydroxy ketones with methanesulfonyl chloride gives rise to prostanoids with an enone component in the oo-chain. 9,ll-Ethano-16-thiaprostanoids have been prepared, for the first time, by nucleophilic addition of thiols to the polarized double bond in the oo-chain. The 1,3-dipolar addition to terminal alkenes of nitrile oxides, generated from nitromethylene derivatives of bicycloheptane provides 9,ll-ethano-13,15-isoxazolinoprostanoids with an alkyl, phenyl, or additional heterocyclic fragment in the oo-chain (462). 

According to these heuristic principles, a possible synthesis of prostaglandins that proceeds via an aldol condensation in the last step, would be in principle valid for synthesis of prostanoids of the A and the B series (26a or 26b). but not for those of the E series owing to the great unstability of the resulting aldol (P-hydroxyketone or 1,3-C system) under the reaction conditions [20] (Scheme 4.7). 

Fries rearrangement org chem The conversion of a phenolic ester into the corresponding 0- and p-hydroxyketone by treatment with catalysts of the type of aluminum chloride. frez re a ranj-mant)... 

Intramolecular cycloadditions of alkenyl-substituted nitrile oxides produce bicyclic isoxazolines. When monocyclic olehns are used, tricyclic structures are obtained. This approach was pioneered by both Kozikowski s and Curran s groups. A typical case involves the cycloaddition of nitro compound 191 [mixture of diastereomers derived from pentenose pyranoside 190], which produced a diaster-eomeric mixture of isoxazolines that contain cis-fused rings (i.e., 192) in near quantitative yield (326) (Scheme 6.85). Further elaboration of this mixture led to epoxycyclopentano-isoxazoline 193, which was then converted to the aldol product in the usual manner. The hydrogenation proceeded well only when rhodium on alumina was used as the catalyst, giving the required p-hydroxyketone 194. This... 

A related sequence was used by Kozikowski and Park (74) to prepare the ring skeleton of streptazolin (200), a compound that exhibits antibacterial and antifungal effects. In this approach, the tricyclic isoxazoline intermediate 198 was formed in the key cycloaddition step (Scheme 6.86). Thus, the reaction of oxime 197 (obtained from 4-piperidone) with sodium hypochlorite-triethylamine afforded tricyclic isoxazoline 198 in very good yield. This cycloadduct was converted to p-hydroxyketone 199 by reduction/hydrolysis using Raney Ni in the presence of acetic acid. Racemic streptazolin (200) was obtained from 199 in several additional steps (74). 

In a similar approach, Shishido et al. (241) used oxime 215 [derived from the monoterpene (+)-citronellal (214)] for the synthesis of (—)-mintlactone (218) and (+)-isomintlactone (219), sweet compounds isolated from some Mentha species (Scheme 6.89). Bicyclic isoxazoline 216 was obtained in good yield from the cycloaddition. As expected, the product possessing tra i-l,4-substimtion prevailed. Reductive hydrolysis of the major isomer of 216 using hydrogen-Raney Ni-trimethyl borate provided p-hydroxyketone 217. This compound was dehydrated to give an enone and this was followed by carbonyl reduction-lactonization to complete the synthesis of both lactones 218 and 219 (241). 

Aldol condensation reaction may be either acid or base catalysed. However, base catalysis is more common. The product of this reaction is called an aldol, i.e. aid from aldehyde and ol from alcohol. The product is either a P-hydroxyaldehyde or P-hydroxyketone, depending on the starting material. For example, two acetaldehyde (ethanal) molecules condense together in the presence of an aqueous base (NaOH), to produce 3-hydroxybutanal (a P-hydroxyaldehyde). 

The Evans-Tischenko Reaction generally requires a P-hydroxyketone (developed from an Aldol reaction) to react with an aldehyde. The resulting glycol monoester will be characterized as having high anti-selectivity. 

This was demonstrated by Fukumoto and co-workers in a synthesis of (+)-a bicanol (251), a sesquiterpene with potent fish antifeedant properties (272,273). Oxime 248 [prepared from the (+)-Wieland-Miescher ketone 247] was subjected to cycloaddition using sodium hypochlorite and gave isoxazoline 249 in very good yield (Scheme 6.95). Conversion of 249 into p-hydroxyketone 250 was again accomplished by the reductive hydrolysis sequence using Raney Ni and trimethyl... 

Experimental procedures are given in Expt 6.107 for o- and p-hydroxy-propiophenones (R = Et). The ortho-para ratio in the product is influenced by the nature of the alkyl residue, the temperature, the solvent and the amount of aluminium chloride used generally low temperatures favour the formation of p-hydroxyketones. It is usually possible to separate the two hydroxyketones by fractional distillation under reduced pressure through an efficient fractionating column or by steam distillation the ortho isomers, being chelated, are more steam volatile. It may be mentioned that Clemmensen reduction (cf. Sections 5.1.3, p. 476 and 6.1.1, p. 826) of the hydroxyketones affords an excellent route to alkyl phenols. 

Cerium chloride (CeCl3 7H20) in the presence of Nal catalyzes the diastereoselective dehydration of P hydroxyketones and esters such as 4.8 to the corresponding a, (3-unsaturated compound 4.9. 

A NMR analysis method has been developed that leads to the assignment of the stereochemistry of p-hydroxy ketones, by visual inspection of the ABX patterns for the (R)-methylene unit of the p-hydroxyketones. Since p-hydroxy ketones are derived from the aldol reaction (see p. 1339), this new method is particularly useful in organic synthesis. A method has also been developed that uses NMR to determine the relative stereochemistry of 2,3-dialkylpentenoic acids. 

Isoxazolines are used in organic synthesis because they mask a number of functionalities such as p-hydroxyketones or y- or P-amino alcohols. While they are not affected by the reaction conditions of many organic transformations, they can be easily unmasked in later steps of the synthesis. In fact, because of its wide applicability, this cycloaddition-reductive opening procedure has been termed the "isoxazoline route". 

Examination of A. qfficinarum by Itokawa and his group provided besides the known compound 6 (8) and the ketol 22 (25) two new enones, 28 and 29 (26). Circular dichroism studies revealed the interesting fact that, in contrast to the known components of Alms firma and A. sieboldiana, which contained (S)-6 and (5)-22, in Alpinia officinarum the same alcohols were present as the R enantiomers. On further investigation the same plant also yielded a total of eight new achiral or racemic diarylheptanoids 23, 24, 31 (27), 25, 26, and 30, (28), 33 (29), 27 and 32 (30). Since the highly susceptible P-hydroxyketones can readily undergo dehydration and subsequent addition of methanol, the enones 28, 29, and 30, as well as the P-methoxyketones 23, 25, and 26 may be artefacts. This assumption is also supported by the racemic nature of 23, 25, and 26. 

Diarylheptanoids from Zinziber officinale, the common ginger, the gingerones A, B, and C (49-51), as well as isogingerone B (52) were isolated by Endo and his coworkers in 1990 (42). Later Kikuzaki et al. isolated additional components, such as 53, the demethyl derivative of 49, further (5)-hexahydrocurcumin (42), from which 49 can be derived by dehydration (43). It is noteworthy that apart from the diastereomeric diols (S,S)-45 and (R,S)-4S, arising from the reduction of 42, the corresponding acetates, 54 and 55, could also be isolated (44). The same authors later described two more diarylheptanoid acetates (56, 60) and a series of racemic P-hydroxyketones (57-59) (45). Considering that P-hydr-oxyketones readily eliminate water, it cannot be excluded that the enones 49-53 are artefacts. 

Fries reaction. Titanium tetrachloride is useful as catalyst for the Fries rearrangement of phenol esters to o- or p-hydroxyketones. For example, p-cresyl acetate is rearranged in high yield in nitrobenzene solution. ... 

Scheme 8.13 SmI2-H20-Et3N-mediated selective reduction of P-hydroxyketones to the corresponding 1,3-diols.

Recently, Flowers and co-workers proposed the use of the Sml2-H20-Et3N system for the reduction of p-hydroxyketones to the corresponding 1,3-diols. In all cases, the reaction occurs without any by-product formation and with excellent diastereoselectivity with the syn-diol as the major isomer (Scheme 8.13).15... 

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