Birch reduction Bromination

The superfluous bromine is then removed by reduction with zinc in acetic acid (26-1). The 20 ketone is next protected against the strongly reducing conditions in the subsequent step by conversion to the ethylene glycol acetal (26-2). Birch reduction with lithium in liquid ammonia in the presence of ethanol proceeds as usual to the dihydrobenzene (26-3). Treatment of this last product with mineral acid serves to hydrolyze both the enol ether at the 3 position and the acetal at the... 

DL-Dihydrostreptose and its ribo isomer were similarly obtained. Birch reduction of 2-methyl-3-furoic acid, followed by addition of methanol, bromination, and dehydrobromination, gave 402 as a mixture of the isomers. Hydroxylation of 402 with osmium tetraoxide-so-dium chlorate, and subsequent treatment with acetone-sulfuric acid afforded three isomeric acetals (403-405). The structures of these compounds were assigned on the basis of their H-n.m.r. spectra. In addition, the relationship between 403 and 404 was established by hydrolysis and reglycosidation. The methyl esters 403-405 were quantitatively reduced to the corresponding alcohols. The mixture of alcohols obtained from 403 and 404 was converted into crystalline 5-deoxy-3-C-(hydroxymethyl)-l,2-0-isopropylidene-a-DL-ribofuran-ose (406), which was compared directly with a sample prepared from D-xylose. Methyl 5-deox y-3-C-(hydroxy methyl)-2,3-O-isopropy lidene-/3-DL-lyxofuranoside (407), obtained by reduction of 405 with lithium aluminum hydride, was hydrolyzed with dilute hydrochloric acid, to give a,/3-DL-dihydrostreptose.2,ifi... 

Electrophilic Aromatic Bromination 673 Nitration of Benzene 675 Sulfonation of Benzene 676 Friedel-Crafts Alkylation 677 Friedel-Crafts Acylation 680 Benzylic Halogenation 701 Birch Reduction 710... 

The route commenced with the condensation of amine 229 and carboxylic acid 230 at 200 °C. Subsequent Bischler-Napieralski reaction and sodium borohydride reduction established the C/D ring system of morphine and delivered tetrahydroisoquinoline 231 in good yield. Next, Birch reduction and Af-formylation afforded enol ether 232, which was converted into the corresponding ketal before reaction with bromine allowed the isolation of the cyclization precursor. The halide in 233 serves to protect the para position in the aromatic ring in the subsequent acid-mediated electrophilic cyclization reaction—a common strategy that has also been applied by other research groups in their endeavors toward morphine and related alkaloids. 

Cheap and readily available cyclopentadecanone is alpha-brominated to (30) and ketalised with (29), and the resulting a-bromoketal (31) subjected to base induced elimination of HBr, giving (32). The key asymmetric step is now at hand. The Simmons-Smith cyclopropanation proceeds with very high facial selectivity, giving almost entirely the diastereomer of (33) shown. The result is rationalised on the basis of zinc chelation by the oxygens of the ketal. The synthesis is completed by acid hydrolysis of the ketal (the chiral diol may be recovered for reuse), reductive opening of the cyclopropane ring under Birch conditions, and re-oxidation of the alcohol back to the ketone. 

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