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A new route to the rigidified cyclic β-amino acids such as cispentacin has been developed by sulfanyl radical addition-cyclization of the alkenyl-tethered-oxime ethers and hydrazones.The β-amino acids 1 have attracted considerable interest because they are useful tools in the synthesis of modified peptides with increased activity and in vivo stability. Although much less abundant than their α-analogs, β-amino acids are also present in nature. They are found, for instance, in the anticancer agent taxol, macrocyclic peptides, and antibiotics (β-lactam, cispentacin, etc.). Recently, Seebach's 2,3 and Gellman's 2,4 groups found that peptide analogs from β-amino acids fold into defined three-dimensional structures (helical structures) similar to those of natural peptides and they were much more resistant than the corresponding α-peptide to cleavage by pepsin and peptidase enzymes. We report a concise synthesis of the rigidified (cyclic) β-amino acids employing the newly developed sulfanyl radical addition-cyclization 5 of the alkenyl-tethered-oxime ethers and hydrazones. Carbocyclization of radicals onto C=N bonds has been most studied in halogeno-6 , carbonyl6q,7 , alkynyl-6d,8 , and allenic 9 -tethered-oxime ethers and hydrazones. In contrast, little is known 10 about radical cyclization of the alkenyltethered-oxime ethers and hydrazones. Our approach is shown in Scheme 1. Sulfanyl radical would attack the terminal alkenyl group in the substrates 1 to provide the alkyl radical species A which is expected to form to the substituted cyclic amines 2, as a result of 5-exo-trig cyclization. Subsequent conversion of the phenylsulfanylmethyl group into the carboxyl group would furnish the desired β-amino acids 3. Scheme 1We first investigated the radical cyclization of the readily available oxime ethers 4a-d (Table 1). The oxime ether 4a was treated with thiophenol (1 equiv.) and AIBN (0.5 equiv.) in refluxing benzene. The reaction proceeded smoothly to give a mixture of the cis-and transcyclopentylamines 5a 11 and 6a 11 in good yield, although with modest cis/trans selectivity (entry 1). Under the same reaction conditions, sulfanyl radical addition-cyclization of the simple substrate 4b gave a mixture of the desired products 5b 11 and 6b 11 in 49 % combined yield (entry 2). Sulfanyl radical addition-cyclization of the oxime ethers 4c and 4d having the hetero atoms (X=NTs, O) as a X group, proceeded smoothly to give the cyclized products 5c 11 and 6c 11 , and 5d 11 and 6d 11 in 88 and 72 % yields, respectively (entries 3 and 4).After successful cyclization of the oxime ethers 4a-d, we then extended the sulfanyl radical addition-cyclization to the hydrazones 4e-g. Cyclization of the hydrazone 4e gave 5e 11 and 6e 11 in 73% combined yield (entry 5). This represented a much more efficient cyclization than that of the oxime ether 4a. Similar results were achieved for heterocyclic systems, although stereoselectivities were lower (entries 6 and 7). The sulfanyl radical addition-cyclization of the alkenyl-tetheredoxime ethers and...

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A Concise Synthesis of Rigidified β-Amino Acids via Sulfanyl Radical Addition-Cyclization of Oxime Ethers and Hydrazones.-Sulfanyl radical cyclization of alkenyl-tethered oxime ethers and hydrazones (I) provides cis/trans mixtures of the cyclized products (III) and (IV). The cyclopentylamines (IIIb)/(IVb) are useful precursors for the synthesis of the antifungal antibiotic cispentacin (V). -(MIYATA, O.; MUROYA, K.; KOIDE, J.; NAITO, T.; Synlett (1998) 3, 271-272; Kobe Pharm. Univ., Higashinada, Kobe 658, Japan; EN)