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Tetracycline (1) 1 has been one of the major antibiotics for almost half a century. The difficult problems implied by its sensitive functionality and demanding stereochemistry have, predictably, attracted the attention of chemists for several decades. 2 Muxfeldt's construction of terramycin, 2a 5a-hydroxytetracycline, wassand issan impressive achievement in total synthesis. It, nevertheless, did not control the introduction of the center at C4a and would not, in any case, be easily extended to tetracycline itself. A remarkable reconstruction of tetracycline has been achieved recently 3 from anhydrotetracycline. If the 12a-hydroxylation 4 of synthetically available 2c 12a-deoxyanhydrotetracycline could be verified, this would constitute a formal, if indirect, total synthesis of tetracycline.We describe here a stereospecific total synthesis of (()-12adeoxytetracycline (2) which solves the longstanding problem of establishing the proper relative stereochemistry of the C5a and C4a centers.

The C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide, was found to react with a range of 3-oxidopyridinium betaines (bearing different substituents on nitrogen) in high yield and with total diastereoselectivity. A 2.3:1 mixture of regioisomers was formed with all of the 3-oxidopyridinium betaines but the ratio was found to change over prolonged periods of time due to reversibility of the minor regioisomer. 3-Oxidopyridinium betaines bearing methyl substituents at either the 2- or 6-position were also tested in the cycloaddition process. Improved regioselectivity (8:1) and again high diastereoselectivity were observed with the betaine having an additional substituent at the 2-position, but with betaines having a substituent in the 6-position although high regioselectivity was observed (9.9:1), the major isomer was formed with low diastereoselectivity (5.5:4.4). The origin of the regio- and diastereo-selectivity with all the betaines is discussed. Finally, the C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide was reacted with an oxidopyrylium betaine in moderate yield. Good regioselectivity and moderate diastereoselectivity were observed.

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