18-Dihydro compounds, aldehyde group

The 18-dihydro compounds showed significantly reduced antibacterial activity. It is suggested that the aldehyde group at C-18 is one of the functional groups essential for the biological activity of the macrolide. 

Macrolides containing only neutral sugars were obtained from a platenomycin-producing organism (217,218). Four demycarosyl derivatives of platenomycins were isolated from biosyntheticaHy blocked mutants of S. platensis, two of these possessed a methyl group rather than an aldehyde (219). A pair of novel compounds related to carbomycin were isolated in which one contained an unusual 10,ll-dihydro-12,13-diol moiety, the other a 14-hydroxy-epoxyenone moiety (220). 

The benzoylphenylketene generated from 321 displayed a pronounced tendency to form chemospecific [2+4] Diels-Alder adducts with the C=N group of keto-imines. When compounds 328, derived from />-aminoacetophe-none and aromatic aldehydes, were reacted with a-diazo-/3-diketone 321, 2,3-dihydro-4//-l,3-oxazin-4-ones 329 were obtained via the addition of benzoylphenylketene to the C=N bond, and no formation of the corresponding C=0 adducts, 477-l,3-dioxin-4-ones, was observed (Equation 31) <2001J(P1)2266>. 

Dihydro-l,4-benzoxazin-3-ones and -benzothiazin-3-ones are synthesized by the reductive cyclodehydration of 2-nitrophenoxyacetic acids or their thioxy equivalents and as these heterocycles have an active methylene group it is a simple matter to prepare 2-substituted derivatives by condensation reactions with aldehydes and other carbonyl compounds (Scheme 123) (79AP302). 

Saturated 1,4-dicarbonyl compounds give 1,4-dihydro-pyridazines or -pyridazinones, etc., which are easily oxidized. 1,2-Diketone monohydrazones 124 and esters 125 containing a reactive CH2 group give 3-pyridazinones 126 (Scheme 64) . A popular modification of this approach is the Ugi four-component condensation of diarylethane-l,2-dione monohydrazones 127 with isocyanides, aldehydes, and methylene active acids leading to the corresponding substituted pyridazin-3(2//)-ones 128 (Scheme 65) The intermediate Ugi condensation products have never been observed because of their tendency to cyclize <2003S691>. 

This result was confirmed by cleavage of the double bond in XXIV to give the aldehyde XXV, in which the aldehydic hydrogen atom shows a 1 2 1 triplet at 9.83 S and therefore lies adjacent to a methylene group in position 6. Furthermore, isomerization of the methine XXIV with hydrochloric acid moves the double bond to the 6,7 position (XXVI) as shown by the appearance of an allylic methyl group in the NMR-spectrum (1.68 S, doublet, J = 2.6 c/sec), and in this compound (XXVI) there are two vinyl protons (multiplet at 5.47 S). The transformation of XXIV to XXVI does not involve rearrangement because both compounds on reduction yield the same dihydro derivative, XXVII. 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

Only two reactions involving the replacement of substituents at position 5 of 3,4-dihydro-2H-l,4-thiazines have been described. Thus, in the presence of sodium ethoxide, the chlorine atom of the derivative 56 was replaced by an ethoxy group, and, when heated at 140°-150°C, compound I64a underwent decarboxylation to give I64b. There are a number of examples in which modification of the S-substituent occurs. For example, when treated with lithium aluminum hydride, the acid 164a was reduced to the aldehyde 164c. ... 

The aza Diels-Alder reactions of a, ff-unsaturated sulfinimines (140) represent a very efficient approach to enantiopure dihydro- and tetrahydropyridines (141) (Scheme 8.34, Table 8.11) for a reasonable reaction rate the 1-aza-l,3-butadiene moiety 140 must carry an electron-withdrawing group at the 3-position [65]. The compounds are accessible in only three steps starting from commercially available substrates. Thus, the enantiopure 1-aza-l,3-butadiene can be prepared from the enantiopure menthyl sulfinate with lithium hexamethyldisilazide followed by addition of acetic acid and an a, -unsaturated aldehyde. The cycloadditions of sulfinimines such as 140 run under mild conditions with high yields and excellent endo-selectivity in most cases when high pressure is applied. In these reactions two endo and two exo transition structures namely syn and anti to the sulfoxide moiety should be discussed. The cycloaddition of 140 and t-butyl vinyl ether was performed under various pressures ranging from 0.2 to 1.2 GPa. 

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. 

As imido esters, dihydro-1,3-oxazines of type 14 display reactivity similar to 2-oxazolines (see p 135). The a-C-H bonds of the 2-alkyl group are CH-acidic. They are metalated by reaction with butyllithium and then undergo C-C forming reactions with electrophiles such as haloalkanes, oxiranes or carbonyl compounds. The dihydro-1,3-oxazines 16, which are obtained from 15 by a-metalation and alkylation, undergo reduction with NaBH4 forming 17. Acid hydrolysis cleaves the cyclic aminal function of 17 yielding aldehydes 18 ... 

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