Hydroxyketone dehydration

A closely related oxygenated heterocyclic system devoid of acidic groups interestingly shows quite different biological activity. Thus, condensation of the benzofuran hydroxyketone 66 with ethyl thiomethyl acetate (67) probably proceeds initially by formation of the acylation product 68. Intramolecular dehydration leads to formation of a pyran ring. There is thus obtained the hypo-cholesterolemic agent timefurone (69) [14],... 

It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50). Reaction of anthra-quinone (45) with the Grignard reagent from 3-chloro-N,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46. This is then converted to oxime 47 in a straightforward manner. Treatment of that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of... 

Synthesis of 31 by Method I (107,108) and its conversion to the related anti and syn diol epoxide derivatives (32,33) has been reported (108). The isomeric trans-1,lOb-dihydrodiot 37) and the corresponding anti and syn diol epoxide isomers (38,39) have also been prepared (108) (Figure 19). Synthesis of 37 from 2,3-dihydro-fluoranthene (109) could not be accomplished by Prevost oxidation. An alternative route involving conversion of 2,3-dihydrofluoranthene to the i8-tetrahydrodiol (3-J) with OsO followed by dehydration, silylation, and oxidation with peracid gave the Ot-hydroxyketone 35. The trimethylsilyl ether derivative of the latter underwent stereoselective phenylselenylation to yield 36. Reduction of 3 with LiAlH, followed by oxidative elimination of the selenide function afforded 3J. Epoxidation of 37 with t-BuOOH/VO(acac) and de-silylation gave 38, while epoxidation of the acetate of JJ and deacetylation furnished 39. 

For instance, the marked lack of stability of prostaglandins of the E series (26). [20] in acid as well as in basic medium, is due to the presence of a 3-hydroxyketone system in the structure which, under these conditions, is dehydrated to give in the first place the secondary prostaglandins of the A series (26a) and later on, under more drastic conditions, the prostaglandins of the B series (26b) (Scheme 4.6). 

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). 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

A very short and elegant synthesis of the 16-rtiembered dilactone ( )-pyrenophorin (515) has been accomplished by the dipolar cycloaddition reaction of a trialkylsilyl nitronate (81TL735). Nitromethane was added to 3-buten-2-one and the carbonyl group of the product reduced with sodium borohydride. The nitro alcohol (511) was converted to the acrylate (512) which was then subjected to a dimerization-cyclization reaction by treatment with chlorotrimethylsilane and triethylamine in dry benzene. Hydrogenation of the mixture of isoxazoline products (513) over palladium on charcoal followed by double dehydration of the intermediate bis-/3-hydroxyketone (514) led to ( )- and meso-pyrenophorin (Scheme... 

The forward synthetic reaction is a base-catalysed condensation reaction between two carbonyl compounds, the aldol condensation leading to -hydroxy-aldehydes or / -hydroxyketones followed by dehydration. This sequence is one of the most important carbon-carbon bond forming reactions, and aldol-type condensation reactions are considered in a number of other sections of the text, for example, the Doebner reaction (Section 5.18.3, p. 805), the Knoevenagel reaction (Section 5.11.6, p. 681), the Perkin reaction (Section 6.12.3, p. 1036) and the Robinson annelation reaction (Section 7.2). 

The first step is a condensation of the aldol type (see Section 5.18.2, p. 799) involving the nucleophilic addition of the carbanion derived from the methyl ketone to the carbonyl-carbon of the aromatic aldehyde. Dehydration of the hydroxyketone to form the conjugated unsaturated carbonyl compound occurs spontaneously. 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

The aldol reaction is often combined with dehydration of the initial aldol product, forming a conjugated double bond (an enone). Thus, (3-hydroxyaldehyde and (3-hydroxyketone undergo dehydration to produce a, 3-unsaturated aldehyde and a, -unsaturated ketone, respectively. In fact, it is difficult to isolate (3-hydroxyaldehydes and (3-hydroxyketones because they are very prone to dehydration. 

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. 

The reaction of an aldehyde with a ketone employing sodium hydroxide as the base is an example of a mixed aldol condensation reaction, the Claisen-Schmidt reaction. Dibenzalacetone is readily prepared by condensation of acetone with two equivalents of benzaldehyde. The aldehyde carbonyl is more reactive than that of the ketone and therefore reacts rapidly with the anion of the ketone to give a /3-hydroxyketone, which easily undergoes base-catalyzed dehydration. Depending on the relative quantities of the reactants, the reaction can give either mono- or dibenzalacetone. 

The ]9-hydroxyaldehydes and j9-hydroxyketones obtained from aldol condensations are very easily dehydrated the major products have the carbon-carbon double bond between the a- and j9-carbon atoms. For example ... 

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. 

An anion may be formed from a symmetrical acid anhydride by using the carboxylate anion of the corresponding acid as the base. This anion may then be reacted with an aldehyde, such as benzaldehyde, to yield as the initial product a mixed anhydride. Dehydration and hydrolysis often follow to result in an a, P-un saturated acid. This is the Perkin reaction. In the benzoin condensation, benzaldehyde is treated with cyanide ion to form an anion, which then attacks another benzaldehyde molecule to form, after the elimination of the original cyanide ion, a 2-hydroxyketone. 

Carbanions of type (2) or type (4) also react readily with 1,2-oxides to form 1,3-dithiane derivatives of /3-hydroxyaldehydcs (from type 2) or /J-hydroxyketones (from type 4). For example, the carbanion (7) reacts with styrene oxide to give (8) in 70% yield on hydrolysis and dehydration (8) is converted into benzylideneacetone... 

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. 

Most antibody-catalyzed reactions are hydrolytic processes, which are highly exergonic in aqueous environment. / -Elimination of /J-hydroxyketones to form a,/ -unsaturated ketones is a rare case of a dehydration reaction proceeding exothermically in aqueous environment. Catalytic antibodies promoting -elimination of /1-hydroxy and /1-halo-carbonyl compounds have been described [52]. The most interesting from a synthetic viewpoint concerns compound 30, which can be dehydrofluorinated to Z-olefin 32 using catalytic antibody 1D4 raised against hapten 29, while the uncatalyzed reaction exclusively yields the more stable E-olefin 31 (Scheme 11) [53]. Dehydratase activity also arises in aldolase antibodies and will be discussed below in that context. 

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