The Journal of Antibiotics (2013) 66, 107–129 & 2013 Japan Antibiotics Research Association All rights reserved 0021-8820/13 www.nature.com/ja REVIEW ARTICLE Total synthesis of the big four antibiotics and related antibiotics Kuniaki Tatsuta The first total syntheses of a variety of antibiotics have been accomplished by using carbohydrates as a chiral source. The key target molecules were members of the ‘Big Four’ classes of antibiotics (macrolides, aminoglycosides, b-lactams and tetracyclines), naphthoquinone antibiotics and their related antibiotics. The Journal of Antibiotics (2013) 66, 107–129; doi:10.1038/ja.2012.126 Keywords: antibiotics; carbohydrates; enantiospecific synthesis; natural products; total synthesis INTRODUCTION In the present paper, the author introduces the dynamic as well as ‘Antibiotic’ was one of the greatest scientific discoveries in the 20th elegant parts of his total synthesis of big four antibiotics and related century and the masterpiece of the total synthesis of antibiotics and compounds, focusing not only on ‘art’ but also on the significance bioactive natural products is a display of beauty, achieving a status of of the total syntheses, and featuring his concept of ‘all begins from ‘art’ in organic chemistry. total synthesis’. Anybody can draw a picture, but pictures painted by famous painters such as van Gogh, Monet and Picasso are praised as ‘art’. At TOTAL SYNTHESIS OF MACROLIDE ANTIBIOTICS AND THE the present time, many chemists are able to synthesize natural RELATED MACROLACTONE ANTIBIOTICS products, even those having complicated structure, using advanced When a stone is thrown into a pond, several ripples are produced in organic chemistry. However, not all such synthesis is above the succession, gradually radiating outward from the point of entry until mundane and can thus be raised to the level of ‘art’. The author is of they finally cover the whole pond. The ‘stone’ in macrolide synthesis the opinion that ‘art’ is a sublimate of originality, and has inherent was the news that R B Woodward had begun the total synthesis of special characteristics, and, even in the 21st century, it should be erythromycin A (2) in 1973. His group including the author recognized as such. accomplished the total synthesis in 1981. Some ripples from this Among bioactive natural products, several antibiotics, termed as the point of origin are represented by Masamune’s methymycin synthesis ‘BigFour’,weretheforemostsubjectofresearchatthetimetheauthor in 1977, Corey’s erythronolide synthesis in 1978 and our syntheses of 1 1–6 started his study of antibiotic synthesis. As shown in Figure 1, they carbomycin B, leucomycin A3 (3) and tylosin (4) in 1977 and 1981. were the macrolides (oleandomycin (1), erythromycin A (2), leuco- mycin A3 (3), tylosin (4)), aminoglycosides (kanamycin A (5), The first total synthesis of 16-membered macrolide antibiotics apramycin (6)), b-lactams (thienamycin (7)) and tetracyclines (tetra- The first total syntheses of the 16-membered macrolide anti- 7 8,9 cycline (8)). The author’s group has fortunately succeeded in complet- biotics, A26771B (1980), carbomycin B (1980), leucomycin A3 ing the total syntheses of 102 diverse bioactive natural products, (josamycin, 1980),8,9 and tylosin (1982)10,11 were accomplished in our including the above-mentioned representatives of the big four anti- laboratories.1–6 These syntheses were based on the stereoselective biotics, and 95 of them represented the first total synthesis of the construction of the carbon skeletons from D-glucose as shown in respective compounds.2–6 It is noteworthy that most of optically active Figure 2. compounds have been synthesized efficiently using carbohydrates as The first total synthesis of tylosin (4) was accomplished by chiral sources, to help determine the absolute structure and to clarify coupling of the C1-C10 (13) and C11-C15 (14) segments derived their structure-activity relationships. The methodologies devised are from D-glucose, and the stereo- and regio-selective introduction of now established as the usual way in the natural product synthesis.2–6 the three sugar moieties (17, 19 and 22) (Figure 3).10,11 The The first total synthesis requires the creation of original synthesis C-methyl compound 9, derived from D-glucose, was converted into concepts and methodologies, including the definition of the absolute the unsaturated ester 10, which was transformed to the methyl structure of the bioactive natural products, as well as the verification ketone 13 through a Michael addition with lithiated methyl of their biological activities. methylthiomethyl sulfoxide to give the branched ester 12. This Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Correspondence: Professor K Tatsuta, Research Institute for Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan. E-mail: [email protected] Received 5 October 2012; revised 15 October 2012; accepted 24 October 2012 Total synthesis of big four antibiotics and related antibiotics K Tatsuta 108 O O O NH Me Me Me 2 HO O HO Me Me Me Me OH Me HO NH OH OH HO 2 N Me Me N Me Me Me OH O HO HO HO NH2 Me O O O Me O O O Me HO O Me H2N O O O O OMe HO O Me Me OMe Me Kanamycin A (5) O OH O OH OH Me Me O Me Oleandomycin (1) Erythromycin A (2) H2N OH HO HN HO OH O O Me O CHO NH H N 2 Me 2 O HO NH N Me 2 MeO HO HO O O O O OH Me Apramycin (6) Me Me O OAc Aminoglycoside Antibiotics O O Me Me Leucomycin A3 (3) O Me O Me Me Me CHO HO Me OH N H H H H Me Me OH Me N Me Me NH2 O Me HO S HO O O O O O OH N O Me O OMe Me OH OMe O OH CO2H OH O OH O NH O OH 2 Me Tylosin (4) Me Thienamycin (7) Tetracycline (8) Macrolide Antibiotics -Lactam Antibiotic Tetracycline Antibiotic Figure 1 Representatives of big four antibiotics. 1 O C O C O C HO 6 HO AcO AcO HO HO OMe OMe 4 Me OH Sug O Sug O Sug O O HO Me 6 OH 1 CHO 9 CHO O OHC OHC OHC Me 12 Me OH OH Me Me Me Me N Me O Me HO 1 O HO O 9 HO HO O O 4 O O MeO OH OH OMe Me 1 CHO OMe O 1 OH D-Glucose O OH Me Me OH Me 12 HO O Sug 4: Tylosin OH OH O O 15 O 6 OH Me Me Me Carbomycin Leucomycin A3 Tylosin Figure 2 Total synthesis of 16-membered macrolide antibiotics from D-glucose. addition of the lithiated reagent to the correct position from the aldehyde group. The ethylene acetal 16 was submitted to initial desired side was effectively assisted by the metal chelation between glycosylation with D-mycaminosyl bromide 17, yielding the the isopropylidene oxygen and the carboxyl oxygen of the transition b-glycoside 18 after methanolysis. The second glycosylation, state 11, to give only the natural configuration at C6, as expected. accomplished by our particular method,8,13 using the glycal of This step was the first key component in completion of the synthesis. mycarose 19 and 1,3-dibromo-5,5-dimethylhydantoin, to give the The aldehyde 14 was also derived from D-glucose through the 2-bromo-2-deoxy-a-glycoside 20 followed by deprotection and branched alcohol. Aldol condensation of 13 with 14 gave the debromination to afford de-mycinosyl tylosin (21). This product unsaturated keto-ester 15, which was transformed to the seco-acid, was also isolated from the natural sources.14 The third glycosylation, followed by lactonization according to Corey’s procedure12 to give a using the mycinosyl bromide 22 under Koenigs ÀKnorr conditions, tylonolide derivative 16, following formation of the acetal of the followed by deprotection, completed the total synthesis of tylosin (4). The Journal of Antibiotics Total synthesis of big four antibiotics and related antibiotics K Tatsuta 109 The first total synthesis of 14-membered macrolide antibiotics then cyclization by intramolecular Horner ÀEmmons reaction after The author’s group accomplished the first total synthesis of a esterification of the C1-C7 and C8-C14 segments, 27 and 28,which 14-membered macrolide antibiotic, oleandomycin (1)(Figure4).15,16 were derived from the enantiomeric intermediates 25 and 26.Thesugar As mentioned above, this is also based on the construction of the moieties 30 and 31 were regio- and stereoselectively introduced on the skeleton from carbohydrates, L-andD-rhamnosides, (23)and(24), and aglycone, oleandolide (29), to give oleandomycin (1). CO Me O 2 H H OH OBn Me H MeS CO Me O BnO OMe 2 O 5 OH OH Me O MeS Me OH O O OOLi O 1 Me Me Me HO 3 C O OH BnO O MeS S S OH 2 Me H Me D-Glucose 9 MeS BnO O n-BuLi 10 11 12 O O O Me 10 Me 10 MeO Me Me O 10 Me OH 11 Me 615 6 OMe + Me OMe 6 Me Me Me O O TrO H TrO O Tr O O OH 15 3 3 11 15 3 MeO 1 OH O OH OH O OH Me CO2Me 13 14 1 Me 15 16 O O Me O O N Br Me Me Me N CHO O Br O Me Me Me Me N Me N Me Me HO Me HO Me Tr O O O OH AcO O OH O Me HO 14 O O O Me O O β Me 3 α NMe OH Me 2 O OH O OH OH Br O AcO 17 Me Me 19 Me Me AcO X (Mycarose 20: X = Br (Mycaminose 18 21: X = H Moiety) Moiety) O Me CHO Me Me Me N Me O β Me HO Me HO O O O O O OH O Me OMe Me Br OMe O OH OH O AcO 22 Me Me MeO OMe (Mycinose 4: Tylosin Moiety) Figure 3 Total synthesis of tylosin.