Lactams, olefinic, reduction

It was also of interest to apply such lOOC reactions to formation of carbocyclic rings. Oxime olefins 230 a-e, formed in good yield via reaction of 229 with 0-silyl-a-bromoaldoximes 228 in the presence of F ions, cyclized in a sealed tube at 190 °C to provide 231 a-e (Eq. 24, Table 22) [63]. Reduction of 231a provided amino alcohol 232 a in 68% yield. Amino alcohol 232 e was converted stereo-specifically to the fused -lactam 233. 

The asymmetric synthesis of (+)-Codeine 432 devised by White and colleagues included a Beckmann rearrangement to introduce the nitrogen atom in the carbocyclic structure (equation 182). Even though two isomeric lactams 430 and 431 were obtained as a result of the rearrangement, the preferential migration of the bridgehead carbon atom produced 430 as the predominant isomer. The synthesis of the non-natural enantiomer of Codeine was completed after oxidation, olefin formation and reduction. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

An alternative route to chiral p-lactams was provided by reactions of electron-deficient isocyanates with chiral nucleophilic alkenes such as vinyl ethers or vinyl acetates. Chlorosulfonyl isocyanate (CSI), a commonly used reactive isocyanate [34], undergoes stereospecific 5-yn-addition to alkenes. The chlorosulfonyl group can subsequently be reductively removed from the nitrogen atom. It has been shown that reactions between CSI and (Z)- and ( )-alkenyl ethers stereoselectively give cA-3,4-disubstituted azetidinones from (Z)-olefins and tmns-3,4-... 

The required chain extension of 12 was accomplished via deprotonation with NaH and condensation with aldehyde 7 to afford the Diels-Alder precursor 13 in 50% yield. Thermolysis of triene 13 and lactam 3 in xylene at 170 C for four days resulted in the desired cycloaddition to 14. Chromatographic purification permitted isolation of pure 14 in addition to a small amount of an exo isomer (>4 1 ratio). Acid treatment induced cleavage of both the silyl ether and acetonide. Reprotection of the diol and selective epoxidation of the A olefin produced 15 in 64% yield from 12. Epoxide 12 was then transformed to the isomeric allylic alcohol 16 by conversion of the alcohol to the bromide followed by reductive elimination. Protecting-group manipulation and subsequent oxidation the gave aldehyde 17, which was homologated and hydrolyzed to give seco acid 18 in 32% overall yield from 16. 

Diene condensation of 3,4-methylenedioxy-j8-nitrostyrene and methyl hexa-3,5-dienoate afforded the adduct (XXI). Catalytic reduction of the olefinic and nitro groups occurred with spontaneous formation of the lactam (XXII). Lithium aluminum hydride reduction of XXII followed by Pictet-Spengler cyclization afforded ( + )-a-lycorane, identical in its IR-spectrum with (— )-a-lycorane. 

The isomeric 4-ep/-statine (834) is also readily accessible from 825 by alkylation at C-5 with methallyltrimethylsilane in the presence of boron trifluoride etherate via an A -acylimi-nium ion intermediate. The resulting lactam 832 is produced as an 11 1 mixture of trans and cis isomers which is readily separable by crystallization. Reduction of the olefin and protective group manipulation furnishes 833, an intermediate that intersects with a previous synthesis of 834. 

With 41 in hand, a two-step nitro reduction and protection, followed by partial reduction of the lactam and resulting cyclization furnished aminal 42. Further treatment with cyanogen azide generated Wcyanoamidine 43. Hydrolysis and amide protection followed by alkylation with allyl iodide yielded olefin 44 as a single diastereomer. Conversion of 44 to aldehyde 45 was the followed reaction of the mesylate with azide, a cross-aldol reaction with acetone, lactam reprotection with Boc, and trimethylphosphine-mediated reductive rearrangement to provide spiro-y-lactam 46. Methyllithium addition to lactam 46 and similar chemistry as reported by Qin et al. gave communesin F (17) (Scheme 6). 

An additional example (Scheme 4), on the utility of CSI in the synthesis of p-lactam building blocks has also been shown by Favara and coworkers [22] in the synthesis of both PS-5 and 6-epi PS-5 carbapenem antibiotics. They found that [2 + 2] cycloaddition of excess of CSI to the conjugated olefin 25 followed by reductive hydrolysis produced a four isomer mixture of P-lactams 26 in about 50% yield. The cis isomer 27 was easily crystallized from diisopropyl ether and transformed into the acid 28. Completion of the synthesis of 6-epi PS-5 was achieved according to established procedures [5f, 7]. 

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