Keto acids lactonization

PdCb, and the allylated lactone 232 is formed. Regeneration ofPdCl2 as shown by 231 makes the reaction catalytic. In this reaction, use of the Li salt 227 of 4-pentynoic acid (223) is recommended. Reaction of lithium 3-octynoate (233) with allyl chloride affords the unsaturated lactone 234, which is converted into the 7-keto acid 235 by hydrolysis[126]. 

Sorm" " found that when cholesterol acetate (67) is oxidized by chromic acid in acetic acid-water at 55°, crystalline keto seco-acid (69) is obtained in 25-30 % yield from the mother liquors after removal of successive crops of 7-ketocholesterol acetate (68). Reaction of keto acid (69) with benzoyl chloride in pyridine gives a dehydration product, shown" to be the )5-lactone... 

P-Acetoxy-5-hydroxy-B-mrcholestan-6-carboxylic Acid 5,6-Lactone (TO)."" A solution of 5 g (0.011 mole) of keto acid (69), 4.4 g of benzoyl chloride and 10 ml of anhydrous pyridine is allowed to stand for 3 days at room temperature. After a short period the mixture turns red-brown and at the end of the reaction the dark semi-solid mass is poured into 200 ml of water and extracted with two 100 ml portions of ether. The ethereal extracts are washed twice with equal portions of 5 % sodium hydroxide and water, dried and the ether evaporated. The red sirupy residue is mixed with 10 ml of methanol and a brown solid separates immediately. After standing for 1 hr the solid is removed by filtration and washed with methanol. A second crop is obtained upon concentration of the filtrate. The combined crops are recrystallized twice from methanol to give (70) as white needles mp 124-125° yield 2.8 g (58 %). 

In a typical Knof procedure, 3jS-hydroxyandrost-5-en-17-one acetate is epoxidized with perbenzoic acid (or m-chloroperbenzoic acid ) to a mixture of 5a,6a- and 5)5,6)5-epoxides (75) in 99 % yield. Subsequent oxidation with aqueous chromium trioxide in methyl ethyl ketone affords the 5a-hydroxy-6-ketone (76) in 89% yield. Baeyer-Villiger oxidation of the hydroxy ketone (76) with perbenzoic acid (or w-chloroperbenzoic acid ) gives keto acid (77) in 96% yield as a complex with benzoic acid. The benzoic acid can be removed by sublimation or, more conveniently, by treating the complex with benzoyl chloride and pyridine to give the easily isolated )5-lactone (70) in 40% yield. As described in section III-A, pyrolysis of j5-lactone (70) affords A -B-norsteroid (71). Knof used this reaction sequence to prepare 3)5-hydroxy-B-norandrost-5-en-17-one acetate, B-noran-... 

Acetoxy-D-homo-androst-5-en-17a-one, 64 3 -Acetoxy-5/3-hydroxy-17-keto-B-noran-drostan-6/3-carboxylic acid lactone, 435 3/3-Acetoxy-5-hydroxy-B-norcholestan-6-carboxylic acid 5,6-lactone, 431... 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Disconnecting the lactone gives hydroxyacid (48), With succinic anhydride In mind as an available 1,4-dl-carbonyl starting material, we can write keto acid (49) as an intermediate and the orientation is then correct for a Frledel-Crafts disconnection as both MeO and He activate this position. 

This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the Af-methylphth-alideisoquinolinium salts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type jft-elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo adds may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type 85,86), which seem to be the final products of the metabolism of phthalideiso-quinoline alkaloids. 

Parent phthalideisoquinoline alkaloid Configuration Enol lactone Configuration Keto acid Diketo acid Ene lactam Configuration... 

Enol lactones can also be obtained from keto acids by enolization-dehydration. Adlumidiceine (103) as well as N-methylhydrasteine (104) when heated in toluene with acetic anhydride or p-toluenosulfonic acid were transformed to enol lactones 97 (97) and 98 (5,102), respectively. Narceine (106) under the influence of PC13 yielded 101 (87,100). 

In a hydrolytic environment enol lactones can be easily hydrolyzed to the corresponding keto acids. Both Ai-methylhydrastines (98 and 99) when allowed to stand in aqueous acetone gave rise to N-methylhydrasteine (104) (5). 

Secophthalideisoquinoline keto acids are postulated to be biosynthesized from phthalideisoquinoline metho salts via enol lactones. Such transformations occur easily in laboratory experiments (Section III,B,1). There are... 

Steric hindrances may also be the reason why quaternary salts of 8-alkylnarcotoline (130) were transformed during Hofmann degradation to analogous keto acids (131) (111,112) and not to the enol lactones (Scheme 24). In some cases (5,87) the keto acids and their esters have been synthesized from the corresponding enol lactones by hydration (Section III,A,2). Nornarceine (107) was prepared from JV-benzyl-(—)-a-narcotinium bromide (139, X = Br) by Hofmann degradation followed by N-debenzylation and ester hydrolysis (109). 

Keto acids can be dehydrated to enol lactones (Section III,A,1). They may also undergo esterification with alcohols e.g., /V-methylhydrasteine (104) in methanol at room temperature gave the expected keto ester 126 (R + R = CH2, R1 = CH3) (5,87). Sodium borohydride reduction of keto acid 104 supplies the saturated y-lactone 132 identical with that obtained from enol lactone 98 (5). 

It has been postulated that secophthalideisoquinoline ene lactams and hydroxy lactams are most probably artifacts of isolation resulting from the reaction of enol lactones or keto acids with ammonia during the extraction process. The hydroxy lactams are probably formed initially and then undergo dehydration to give ene lactams (5,8). For this reason, this section covers the hydroxy lactams in addition to the ene lactams. The hydroxy lactams are... 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

Simultaneous lactonization and isomerization of 2-keto acids or esters. 

Reductive Esterification. Organosilane reductions of y- or 5-keto acids and esters provide the corresponding lactones as the final products (Eqs. 226 and 227).69,79,402... 

Dunitz, in his review (82), describes also studies on other systems. It should be mentioned that in the O - - C=0 interaction the correlation is poorer than inN C=0, presumably because the interaction is weaker and more sensitive to perturbation. However, compounds 39 and 40 of this series are worthy of note. The keto acid 39a and the isomeric lactone alcohol 39b are in dynamic equilibrium in solution at room temperature, and are present in similar concentrations. This substance has been obtained in only one crystal modification, corresponding to die closed form, 39b. However, the pattern of bond lengths... 

There are many reports describing the preparation of various butyrolac-tones from AAs. When r-butyl 2-dibenzylaminoacetate in the form of its Li-enolate was treated with (5)-0-benzyllactic aldehyde, a mixture of four diastereoisomeric hydroxy-AAs was obtained. After separation and further treatment, three lactones were obtained (Scheme 17) (87T2317). Similar compounds were obtained from a-acylamino-y-keto acids after cycliza-tion (75CC905). 

The cyclization method of Ochiai et al (85CPB989), used for reduced furans 94, affords a mixture of six-membered lactone 243 and the rearranged y-keto acid 244 when acid 242 is the substrate. 

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],... 

Typical examples are listed in Table 2.1. A few oxidations are effected by RuO but in general it is too powerful an oxidant for this purpose. The system RuCyaq. NaCl-CCy Pt anode oxidised benzyl alcohol to benzaldehyde and benzoic acid and p-anisaldehyde to p-anisic acid [24], and a wide range of primary alcohols and aldehydes were converted to carboxylic acids, secondary alcohols to ketones, l, -diols to lactones and keto acids from RuOj/aq. NaCl pH 4/Na(H3PO )/Pt electrodes (Tables 2.1-2.4). The system [RuO ] "/aq. K3(S303)/Adogen /CH3Cl3 oxidised benzyhc alcohols to aldehydes [30]. The oxidation catalyst TPAP (( Pr N)[RuO ]) (cf. 1.3.4) is extremely useful as an oxidant of primary alcohols to aldehydes and secondary alcohols to ketones without... 

When male F-344 rats were injected with NNN-2 -14c, 75-95% of the dose was excreted in the 48 hr urine. In one experiment, the urine was collected in vessels containing DNP reagent. However, the DNPs of 4-hydroxy-l-(3-pyridyl)-l-butanone and 4-hy-droxy-4-C3-pyridy1)butanal were not detected. Since this was likely due to further oxidation in vivo, methods were developed for isolation of their probable oxidation products. This resulted in identification of the lactone, 5- C3-pyridyl)—tetrahydrofuran-2-one (1-2%), the keto acid, 4-(3-pyridyl).-4-oxobutyric acid (1-2%) and the hydroxy acid, 4-(3-pyridyl)-4-hydroxybutyric acid (26-40%) as urinary metabolites. These metabolites resulted. 

The reaction takes place in a two-phase medium. Secondary alcohols form ketones (90%), primary alcohols and aldehydes are oxidized to carboxylic acids (60-77%), 1,2-diols are cleaved to carboxylic acids (75%), 1,4- and 1,5-diols are transformed to lactones and keto acids (75 %). 

Ketones of the form RCOCH3 and RCOCH2R can be carboxylated indirectly by treatment with magnesium methyl carbonate 52.613 Because formation of the chelate 53 provides the driving force of the reaction, carboxylation cannot be achieved at a disubstituted a position. The reaction has also been performed on CH3N02 and compounds of the form RCH2N02614 and on certain lactones.61s Direct carboxylation has been reported in a number of instances. Ketones have been carboxylated in the a position to give (3-keto acids.616 The base here was lithium 4-methyl-2,6-di-f-butylphenoxide. 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

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