Synthetic Studies Toward Tetrodecamycin: An Efficient Approach to the Core Structure of the Antibiotic

Abstract

An efficient synthetic pathway to the core structure 5 of the polyketide antibiotic tetrodecamycin (1a) has been developed. Our approach features the acid-catalyzed cyclization of a tert-butyldimethylsilyl protected methyl α-(γ-hydroxyacyl) tetronate, leading to the novel tricyclic ring skeleton exhibited by 5. An insight into the mechanism of this key ring closure step has been gained. Furthermore an alternative pathway to this ring skeleton, based on a fluoride ion induced desilylation-cyclization sequence, has been disclosed.

tetrodecamycin - antibiotics - tetronic acid - cyclizations - dihydroxylations

References

1a Isolation and biological evaluation: Tsuchida T. Iinuma H. Nishida C. Kinoshita N. Sawa T. Hamada M. Takeuchi T. J. Antibiot.  1995,  48:  1104 

1b Structure determination: Tsuchida T. Iinuma H. Sawa R. Takahashi Y. Nakamura H. Nakamura KT. Sawa T. Naganawa H. Takeuchi T. J. Antibiot.  1995,  48:  1110 

For references to representative members of this class of natural products, see:

2a Alvi KA. Nair BG. Rabenstein J. Davis G. Baker DD. J. Antibiot.  2000,  53:  110 

2b Arai K. Miyajima H. Mushiroda T. Yamamoto Y. Chem. Pharm. Bull.  1989,  37:  3229 

2c Jacobsen JP. Reffstrup T. Cox RE. Holker JSE. Boll PM. Tetrahedron Lett.  1978,  1081 ; and references therein

3 Paintner FF. Bauschke G. Kestel M. Tetrahedron Lett.  2000,  41:  9977 

4 For a previous attempt to access the 3,4-dihydro-2H,8H-furo[3,4-b]oxepine-5,6-dione ring system, see: Gelin S. Pollet P. Synth. Commun.  1980,  10:  805 

5 Shing TKM. Tam EKW. Tai VW.-F. Chung IHF. Jiang Q. Chem.-Eur. J.  1996,  2:  50 

6 Paintner FF. Allmendinger L. Bauschke G. Synthesis  2001,  2113 

7

(1 RS ,9 RS )-9-Methyl-2,5-dioxa-tricyclo[7.3.1.0 [3] [7] ] tridec-3(7),11-dien-6,8-dione(12). Colorless crystals (EtOAc); mp 144 °C; IR (KBr): 3061, 2928, 1776, 1611 cm^-1; MS (CI, CH₅ ⁺): m/z (%) = 221(100) [M + H⁺]; ¹H NMR (CDCl₃): δ = 1.22 [s, 3 H, CH₃-(C-9)], 1.97 (d, J = 17.9 Hz, 1 H, 10-H), 2.11 (dd, J = 16.1/6.5 Hz, 1 H, 13-H), 2.46 (d, J = 16.1 Hz, 1 H, 13-H), 2.73 (dd, J = 17.9/6.0 Hz, 1 H, 10-H), 4.52 (d, J = 16.7 Hz, 1 H, 4-H), 4.63 (d, J = 16.7 Hz, 1 H, 4-H), 5.31 (m, 1 H, 1-H) 5.73 (m, 1 H, 12-H), 6.18 (m, 1 H, 11-H); ¹³C NMR (CDCl₃): δ = 25.9 [CH₃-(C-9)], 34.4 (C-13), 37.3 (C-10), 44.7 (C-9), 65.4 (C-4), 76.6 (C-1), 102.7 (C-7), 121.4 (C-12), 135.2 (C-11), 168.8 (C-6), 176.8 (C-3), 198.2 (C-8); Anal. Calcd for C₁₂H₁₂O₄ (220.23): C, 65.45; H, 5.64; Found: C, 65.68; H, 5.64.

8

Crystallographic data for structure 12 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 182759. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: [phone] or e-mail: [e-mail].

9

E-Z isomers were assigned on the basis of 2D NMR according to Boll and co-workers: ref. 2c.

Acyl tetronic acids are known to exist in four monoenolic tautomeric forms. Only exo-enol tautomer 15 is depicted in Scheme 4 for reasons of clarity. For a discussion of this tautomeric equilibria, see:

10a Jacobsen JP. Reffstrup T. Boll PM. Acta Chem. Scand., Ser. B  1977,  31:  756 

10b Gelin S. Pollet P. Tetrahedron Lett.  1980,  21:  4491 

10c Eckert-Maksic M. Maksimovic L. J. Mol. Struct. Theochem  1987,  153:  121 

10d Broughton HB. Woodward PR. J. Comput.-Aided Mol. Des.  1990,  4:  147 ; and references therein

11 Bassindale AR. Stout T. J. Organomet. Chem.  1984,  271:  C1 

12 Schraml J. Kvicalovi M. Blechta V. Cermak J. Magn. Reson. Chem.  1997,  35:  659 

13

Attempts to achieve fluoride ion induced cyclization of acyl tetronate 7 [TBAF·3H₂O (1.0 equiv), THF, r.t.] were unsuccessful, due to preferential cleavage of the activated enol ether thus affording tetrabutylammonium salt i (Figure [3] ) on aqueous work up.

14 Clemo NG. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1985,  2407 

15 Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 

16 Pollet P. Gelin S. Tetrahedron  1978,  34:  1453 

17

Treatment of 24 with osmium tetroxide (2 mol%) and N-methylmorpholine N-oxide (1.0 equiv) as co-oxidant (acetone, t-BuOH, H₂O, r.t.) gave ii (34%) and iii (12%) (Figure [4] ) along with recovered starting material (36%).

The facile oxidation of sulfides to sulfones in the presence of C-C double bonds using catalytic osmium tetroxide and N-methylmorpholine-N-oxide or trimethylamine-N-oxide as co-oxidant has been reported:

18a Kaldor SW. Hammond M. Tetrahedron Lett.  1991,  32:  5043 

18b Priebe W. Grynkiewicz G. Tetrahedron Lett.  1991,  32:  7353 

On the other hand, sulfides are known to be essentially inert to oxidation by osmium tetroxide under stoichiometric conditions:

19a Stork G. van Tamelen EE. Friedman LJ. Burgstahler AW. J. Am. Chem. Soc.  1953,  75:  384 

19b Djerassi C. Engle RR. J. Am. Chem. Soc.  1953,  75:  3838 

19c Henbest HB. Khan SA. J. Chem. Soc., Chem. Commun.  1968,  1036 

19d For chemoselective oxidations of C-C double bonds in the presence of sulfides with catalytic OsO₄ and K₃Fe(CN)₆ as co-oxidant, see: Walsh PJ. Ho PT. King B. Sharpless KB. Tetrahedron Lett.  1994,  35:  5129 

20 Yamada T. Hagiwara H. Uda H. J. Chem. Soc., Chem. Commun.  1980,  838 

21

tert-Butyldimethylsilyl ether 27 was prepared to enable chromatographic purification of the intermediate sulfoxides, which were hardly soluble in appropriate organic solvents when derived from 26.

22

(1 RS ,9 RS ,11 RS ,12 RS )-11,12-Dihydroxy-9-methyl-4-methylene-2,5-dioxatricyclo-[7.3.1.0 [3] [7] ]tridec-3(7)-ene-6,8-dione(5). Colorless crystals (MeCN); mp > 370 °C; IR (KBr): 3460, 2924, 1786, 1588 cm^-1; MS (CI, CH₅ ⁺): m/z (%) = 267(100) [M + H⁺]; ¹H NMR (d ₆-DMSO): δ = 1.07 [s, 3 H, CH₃-(C-9)], 1.58 (dd, J = 12.4/3.7 Hz, 1 H, 10-H_eq), 1.72 (t, J = 12.4 Hz, 1 H, 10-H_ax), 1.99 (dd, J = 16.4/4.5 Hz, 1 H, 13-H), 2.31 (d, J = 16.4 Hz, 1 H, 13-H), 3.39 (d, J = 12.4 Hz, 1 H, 11-H), 3.89 (m, 1 H, 12-H), 4.80 (d, J = 5.6 Hz, 1 H, OH), 4.98 (m, 1 H, 1-H), 5.39 [d, J = 2.8 Hz, 1 H, (C-4) =CH₂], 5.41 [d, J = 2.8 Hz, 1 H, (C-4) =CH₂], 5.43 (d, J = 4.5 Hz, 1 H, OH); ¹³C NMR (d ₆-DMSO): δ = 26.3 [CH₃-(C-9)], 28.4 (C-13), 39.2 (C-10), 47.7 (C-9), 64.7 (C-11), 72.3 (C-12), 84.2 (C-1), 96.7 [(C-4) =CH₂], 101.5 (C-7), 147.6 (C-4), 163.4 (C-6), 165.6 (C-3), 198.3 (C-8); HRMS: m/z Calcd for C₁₃H₁₄O₆ (M⁺): 266.0790; Found: 266.0762.