Stereocontrolled synthesis of (±)-12a-deoxytetracycline

Journal of the American Chemical Society

Volumn 118, Issue 22, 1996, Pages 5304-5305

  Stork, Gilbert ^a   La Clair, James J ^a,b   Spargo, Peter ^a,c   Nargund, Ravi P ^a,d   Totah, Nancy ^a,e  

^a Och Spine at New York Presbyterian Hospitals   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^d MERCK RESEARCH LABORATORIES   (United States)

^e UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

12A DEOXYTETRACYCLINE; TETRACYCLINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CYCLIZATION; DRUG CONFORMATION; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

EID: 0030003196     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja960434n     Document Type: Article

References (36)

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18. Among the numerous methods which have been used to oxidize 1,5-naphthalenediol to 5-hydroxy-1,4-naphthoquinone, we selected the periodate method of Pinto, A. V.; Ferreira, V. F.; Pinto, M. do C. Synth. Commun. 1985, 15, 1177. It was modified to make it suitable for ∼50 g scale preparation by reducing the amount of periodate to 2.2 equiv and using aqueous THF as solvent rather than DMF. This gave the quinone, also known as juglone, in 83% yield, after purification.
19. This selectivity is, obviously, due to conjugative deactivation of the C4 carbonyl; cf.: Shemyakin, M. M.; Kolosov, M. N.; Karapetyan, M. G.; Chaman, E. S. Dokl. Akad. Nauk SSSR 1957, 112, 669.
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22. Methoxycarbonyl lactone 11 was produced in the same manner as used for 10, using the monomethyl ester of malonic acid.
23. We thank Dr. Michael Chiang for this determination.
24. Isoxazole 14 can be prepared from trimethylorthoacetate and dimethyl malonate, as detailed in the supporting information. It was first prepared several years ago, by a different route, by Dr. M. Mansuri.
25. Jeffrey, P. D.; McCombie, S. W. J. Org. Chem. 1982, 47, 587. The alkoxycarbonyl group is required to enhance nucleophilicity of the conjugated lactone because attempted conjugate addition in its absence gave no adduct, presumably because the seven-membered unsaturated lactone does not readily achieve planarity, so that the conjugated ester external to the lactone becomes essential.
26. Kahne, D. Ph.D. Thesis, Columbia University, New York, NY, 1986.
27. The extreme moisture sensitivity of compound 18 made its isolation difficult. Attempts to chromatograph it on a variety of adsorbents destroyed the silyl hemiacetal. Its structure was established by CI-MS, NMR, and IR spectroscopy.
28. The material was purified on MN Polyamid SC6 eluting with a gradient of acetonitrile (with 0.1% TFA) to methanol/acetonitrile (1:1 with 0.1% TFA). Trace amounts of additional impurities were removed by triturating the solid chromatographed product in refluxing anhydrous methanol.
29. 254) of both synthetic and natural 2 matched when eluted with methanol, water, acetic acid (3:10:1) and acetonitrile, water, TFA (100:100:1).
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32. 20 for the stereospecific 12a-oxidation of 2. We are not aware, however, that a reproducible method for the oxidation of 2 to 1 is available. We were unable to duplicate the platinum-oxygen reaction of ref 20b which gave us a mixture of 12 different products, none of which had an HPLC retention time consonant with that of tetracycline. (We thank Dr. P. E. Sum of Wyeth-Ayerst Research for this determination). It appears that the best that has been reported for the 12a oxidation of a tetracycline relative bearing a dimethylamino group at C4 (but lacking substituents at C6) is the 6.5% obtained in ref 20c.
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