Dihydro ozonolysis

Ozonolysis of 5,8,9-trihydroxy-2,3-dihydro-l//-pyrimido[l, 2-n]quinoline-3-carboxylic acid (420), obtained from isopyoverdin isolated from Pseudomonas putida BTPl by acidic hydrolysis, gave l-2,4-diaminobutyric acid, which confirmed the hypothesis that heterocyclic chromophores 1 and 4 of pyoverdin and isopyoverdin, respectively, could have the same precursor, and the configuration at C(3) should be 5 (97ZN(C)549). 

Much effort this year has been expended on chrysanthemic acid syntheses. Aratani et al. have extended earlier work on asymmetric synthesis (Vol. 6, p. 21) by decomposing various alkyl diazoacetates in 2,5-dimethylhexa-2,4-diene in the presence of chiral copper complexes to yield up to 92% of rrans-chrysanthemic acid in 88% dextrorotatory enantiomeric excess. Mitra has used ozonolysis of (+)-a-pinene to obtain, stereospecifically, the bromo-ketone (104) which undergoes Favorskii rearrangement to yield the anticipated ester (105) from which (+)-trans-chrysanthemic acid is readily obtained a second paper reports another route from (+)-car-3-ene initially to methyl (—)-c/s-chrysanthemate or to (—)-dihydro-chrysanthemolactone (106), both of which are convertible into (+)-rra s-chrysan-... 

It is also possible to intercept the chiral sulfoxide intermediate and convert this species to an a-amino ester. Thus, the Grignard addition to dihydro-l,2-thiazine 1-oxides 131a and 131b followed by NH4CI workup and subsequent ozonolysis of 132a and 132b affords amino ester 133 with excellent retention of the absolute stereochemistry (Scheme 17) <2004JOC7198>. 

Ozonolysis of 3,5-dihydroxy-3,5-di-(w-buten-3-yl)pyrrolizidine (167c) resulted in the formation of pyrrolizidine-3,5-dihydro xy-3,5-bis(3 -propionic acid) monolactone (170). Similar treatment of 3,5-dihydro xy-3,5-bis(phenylethynyl)pyrrolizidine (167b) afforded stereoisomeric 3,5-dihydroxypyrrolizidine-3,5-dicarboxylic acids (171a and 171b). 

Dihydro-4//-pyrans are oxidized by several reagents as shown in Scheme 34. The hydroperoxide obtained by ozonolysis may be converted into the ester or aldehyde (62JOC4498). 

In the synthesis of the monocyclic bisabolene-type sesquiterpenoids (-f)-curcuquinone and (—)-curcuhydro-quinone, 1,3-diol 107 was obtained by ozonolysis of 4,5-dihydro-l,3-dioxepin 106 (obtained by Heck reaction, see Section 13.11.10) and reductive workup (Scheme 25) <2003ARK232>. 

The enol acetate 77 of 3,4-dihydro-7-methoxy-5-methyl-l-(2l/)-naphthalenone was converted to the acid 78 by ozonolysis and hydrolysis and this by a Wittig reaction with a-methoxyethyltriphenyl-phosphonium chloride gave 79. Compound 79 was converted into 80 by a series of reactions, five in number, which in turn was converted into 81 by reaction with potassium in -butanol. The methyl ester of compound 81, one isomer of which was recognized as that having the correct stereo structure, was converted to 82 by heating with acetic anhydride and 10-camphorsulfonic acid. Subsequent steps involved ozonization, reaction with V,iV -carbonyldiimidazole, lactam formation, reaction with pyridinium bromide perbromide, reaction with sodium hydride, and a further series in which (+ )-oxodendrobine (83) was ultimately obtained. Reduction of the latter to ( )-dendrobine... 

A hetero-Diels-Alder reaction has been used to prepare racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran (9). This ester 9 was resolved by Bacillus lentus protease to provide the R-isomer. Reduction, protection, and ozonolysis provided the bis-mesylate 10 (Scheme 26.9), a key intermediate in the synthesis of the PKC (protein kinase C) inhibitor LY333531 (ll).278 This resolution approach was used because it was more efficient than an asymmetric Diels-Alder reaction. 

Acetyl-8,9-dimethoxy-5,6-dihydro-4/7-benzo[iie][l,6]naphthyridine (159) underwent ozonolysis to afford methyl l-acetyl-4-methoxycarbonylmethylene-l,2,3,4-tetrahydro-l,6-naphthyridine-5-carboxylate (160) (or tautomer) (substrate, MeOH, 03, —78°C, 1 h Me2S, 20°C %).1143... 

The 3-chloro-l,7-dimethylpyridazino[3,4-(7][l,3]oxazine-4,5-dione (149) was prepared in a four-step synthesis starting with (Z)-methyl-3-(3,6-dichloro-l-methyl-4-oxo-l,4-dihydropyridazin-5-yl)-2-methylacrylate (146) which is converted with sodium azide into the 6-azido compound (147). Heating in o-dichlorobenzene at 150°C results in cyclization to methyl 3-chloro-l,6-dimethyl-4-oxo-1,4-dihydro(7//)pyrrolo[2,3-c]pyridazine-5-carboxylate (148) via a nitrene intermediate. Ozonolysis effects ring-enlargement of the pyrrole ring into the 3-chloro-l,7-dimethylpyridazino[3,4-d][l,3]oxazine-4,5-dione (149) (Scheme 26) <79JHC1213>. 

Among compounds related to uleine that have been isolated from A. dasycarpon are X-noruleine (CCLVII-B), dasycarpidone (CCLVII-A), the corresponding alcohol, dasycarpidol, X-nordasycarpidone, and 1,1 -dihydro-l -hydroxyuleine. Dasycarpidone may be obtained from uleine by ozonolysis, or from dasycarpidol by oxidation with chromium trioxide in pyridine. l,l -Dihydro-l -hydroxyuleine has been synthesized from uleine by hydroboration (143b). Apparicine, an alkaloid of novel skeleton present in A. dasycarpon and several other species, has been shown to have the structure CCLVII-U (37). 

It has been found that the C-11,12 double bond in paclitaxel was resistant to many reaction conditions, including catalytic hydrogenation and ozonolysis. Harriman et al. reasoned that C-10 acetate may hamper the epoxidation from the p-face and the cupshaped core structure prevents the epoxidation from the ot-face. By removal of 10-acetate in paclitaxel, the 11,12-p-epoxide was formed quantitatively. The 11,12-epoxidized taxoid 27 was only one third as cytotoxic as paclitaxel against B16 melanoma cells. The 11,12 double bond in baccatin was reducible by zinc in acidic conditions. Since treatment of 11,12-dihydro baccatin 28b with base only yielded 13-acetyl-4-... 

Ozonolysis op Dihydrocodeine Methine Rupture of the aromatic nucleus with production of an aldehydo-ester, 7 8-dihydrocodizal-3-methyl ester methine [lxix], occurs when dihydrocodeine methine [x] is treated with ozonized oxygen in aqueous acid solution. The hydroxyl group of [x] presumably remains intact, as an acetyl ester of [lxix] can be prepared, and oxidation with chromic acid leads to 6-keto-7 8-dihydrocodizonal-3-methyl ester methine [lxx] which no longer yields an acetyl derivative, [lxix] can be hydrogenated to a dihydro-derivative [87]. It is surprising that in the ozonolysis of dihydrocodeine methine rupture of the aromatic nucleus at the 2 3 bond occurs, whereas with dihydrocodeine rupture occurs at the 3 4 bond (see Chap. IV). 

A cost effective and easily scaled-up process has been developed for the synthesis of (S)-3-[2- (methylsulfonyl)oxy ethoxy]-4-(triphenylmethoxy)-1 -butanol methanesulfonate, a key intermediate used in the synthesis of a protein kinase C inhibitor drug through a combination of hetero-Diels-Alder and biocatalytic reactions. The Diels-Alder reaction between ethyl glyoxylate and butadiene was used to make racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran. Treatment of the racemic ester with Bacillus lentus protease resulted in the selective hydrolysis of the (R)-enantiomer and yielded (S)-2-ethoxycarbonyl-3,6-dihydro-2H-pyran in excellent optical purity, which was reduced to (S)-3,6-dihydro-2H-pyran-2-yl methanol. Tritylation of this alcohol, followed by reductive ozonolysis and mesylation afforded the product in 10-15% overall yield with excellent optical and chemical purity. Details of the process development work done on each step are given. 

Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base " ) or by ozonolysis of a cyclopentene precursor. They react with ammonia, with loss of two mole equivalents of water to produce cychc bis-enamines, i.e. 1,4-dihydro-pyridines, which are generally unstable, but can be easily and efficiently dehydrogenated to the aromatic heterocycle. 

Yellow deoxyvomicine is formed by the direct action of HI on vomicine but is readily converted to the stable isomer with bases, zinc chloride, or heat. Accordingly, with benzaldehyde and base they both yield the same benzal derivative. Furthermore, the yellow isomer forms a yellow metho-salt which also undergoes ready transition with base to the metho-salt of the colorless species, and both salts as a result yield the same Emde product with sodium amalgam. That the allylic double bond remains at the C21-22 position is shown by ozonolysis of both the deoxyvomicines (and the dihydro derivative of the yellow isomer) to significant yields of acetaldehyde (337, 339c). Thus yellow deoxyvomicine has been formulated as CCLI (337, 340), the isomerization to... 

A mixture of americine, C31H39O4N5 (mp 136° and 142°-182° [ ]d 198°) and its homologue, homoamericine, was difficult to separate but served for the purpose of structure investigations. In addition to UV, IR, and NMR spectroscopy which identified many structural features, the use of mass spectroscopy and complete hydrolysis of americine and its dihydro derivative resulted in the elucidation of its structure as XXXIIa 48). Further study of ceanothamine-B has resulted in a revised structure XXXIIb, based on exhaustive physical methods and upon ozonolysis and hydrolysis 49, 50). It is identical with adouetine-X and ceanothamine-A is identical with frangulanine 49, 50). 

An ingenious approach to racemic estrone has used two reactions in a combined tandem Cope-Claisen rearrangement (ref. 130). 1-Bromomethyi-3,4-dihydro-6-methoxynaphthalene is used to alkylate 1-methoxycarbonyl-2-methylcyclopent-2-ene and the ester group in the product converted to a vinyloxymethyl substituent. Thermolysis afforded a mixture of diastereoisomeric aldehydes (2 1) containing a majority of the trans compound. Ozonolysis and epimerisation at the 8-position succeeded by McMurry coupling gave the required tetracyclic structure from which racemic estrone methyl ether was obtained. 

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