A Facile Synthesis of (n+3) and (n+4) Ring-Enlarged Lactones as well as of Spiroketolactones from n-Membered Cycloalkanones

Abstract

We report detailed studies of the facile synthesis of functionalized 8-, 9-, 10-, 11-, and 15-membered-ring lactones from simple ethyl 1-allyl-2-oxocycloalkanecarboxylates, resulting from a three-atom ring enlargement. Similarly, four-atom ring enlargements of a 5- to 9- and 6- to 10-membered-ring lactones were achieved. Alkoxy radical fragmentation (ARF) with hypervalent iodine was used as the key step for these ring expansions. The ring enlargement proceeds via an unstable hemiketal intermediate, which was isolable in some cases. Where hemiketals were not isolated, molecular modeling calculations are consistent with the relative stability of hydroxy ketones vs. hemiketals. The same substrates can be diverted in an ionic pathway on reaction with iodine or bromine to afford spirolactones. The formation of spirolactones occurs in a highly stereoselective manner, apparently involving participation of the ester carbonyl group.

Keywords

spiro compounds - ring expansion - radical reaction - dia­stereoselectivity - lactone

References

• 1 Larock RC. Comprehensive Organic Transformations   2nd ed.:  John Wiley; New York: 1999. 
• See, for example:
• 2a Masamune S. Bates GS. Corcoran JW. Angew. Chem., Int. Ed. Engl.  1977,  16:  585 
• 2b Bertinoto EP. Sorensen J. Meng D. Danishefsky SJ. J. Org. Chem.  1996,  61:  8000 
• 2c Nicolaou KC. Ninkovic S. Sarabia F. Vourloumis V. He Y. Vallberg H. Finlay MRV. Yang Z. J. Am. Chem. Soc.  1997,  119:  7974 
• 2d Kobayashi J. Kubota T. J. Nat. Prod.  2007,  70:  451 
• 3a Beckwith AL. Kazlauskas JR. Syner-Lyons MR. J. Org. Chem.  1983,  48:  4718 
• 3b Suginome H. Yamada S. Tetrahedron  1987,  43:  3371 
• 3c Hesse M. Ring Enlargements in Organic Chemistry   VCH; Weinheim: 1991. 
• 3d Dowd P. Zhang W. Chem. Rev.  1993,  93:  2091 
• 3e Zhang W. Dowd P. Tetrahedron Lett.  1996,  37:  957 
• 3f Arencibia MT. Freire R. Perales A. Rodriguez MS. Suarez E. J. Chem. Soc., Perkin Trans. 1  1991,  3349 
• 4a Hatcher MA. Borstnik K. Posner GH. Tetrahedron Lett.  2003,  44:  5407 
• 4b Posner GH. Hatcher MA. Maio WA. Org. Lett.  2005,  7:  4301 
• 4c Ramesh NG. Hassner A. Eur. J. Org. Chem.  2005,  1892 
• 4d Pradhan TK. Hassner A. Synlett  2007,  1071 
• 5 Hassner A. Pradhan TK. Tetrahedron Lett.  2006,  47:  5511 
• 6a Freire R. Marrero JJ. Rodriquez MS. Suarez E. Tetrahedron Lett.  1986,  27:  383 
• 6b Courtneidge JL. Lusztyk J. Page D. Tetrahedron Lett.  1994,  35:  1003 
• 6c Gonzalez CC. Leon EI. Riesco-Fagundo C. Suarez E. Tetrahedron Lett.  2003,  44:  6347 
• 6d Gonzalez CC. Kennedy AR. Leon EI. Riesco-Fagundo C. Suarez E. Angew. Chem. Int. Ed.  2001,  40:  2326 
• 6e Suarez E. Rodriguez MS. In Radicals in Organic Synthesis   Vol. 2:  Renaud P. Sibi MP. Wiley-VCH; Weinheim: 2001.  p.441 
• 7a Paquette LA. Efremov I. J. Am. Chem. Soc.  2001,  123:  4492 
• 7b Cuzzupe AN. Di Florio R. Rizzacasa MA. J. Org. Chem.  2002,  67:  4392 
• 7c Anjaneyulu ASR. Venugopal MJRV. Sarada P. Clardy J. Lobkovsky E. Tetrahedron Lett.  1998,  39:  139 
• 7d Yamaki M. Bai L. Kato T. Inoue K. Takagi S. Yamagata Y. Tomita D. Phytochemistry  1993,  33:  1497 
• 7e Orduna A. Zepeda LG. Tamariz J. Synthesis  1993,  375 
• 7f Brocksom TJ. Coelho F. Depres JP. Greene AE. Freire de Lima ME. Hamelin O. Hartmann B. Kanazawa AM. Wang Y. J. Am. Chem. Soc.  2002,  124:  15313 
• 8 Chitkul B. Pinyopronpanich Y. Thebtaranonth C. Thebtaranonth Y. Tetrahedron Lett.  1994,  35:  1099 
• 9 Fraga CAM. Teixeira LHP. Menezes CMS. Sant’Anna CMR. Ramos MCKV. de Aquino Neto FR. Barreiro EJ. Tetrahedron  2004,  60:  2745 
• 10 Moloney MG. Nettleton E. Smithies K. Tetrahedron Lett.  2002,  43:  907 
• 11 Cole BM. Han L. Snider BB. J. Org. Chem.  1996,  61:  7832 
• 12 Tsuji J. Yamada T. Shimizu I. J. Org. Chem.  1980,  45:  5209 
• 13a Rabeyrin C. Sinou D. Tetrahedron: Asymmetry  2003,  14:  3891 
• 13b Park EJ. Kim MH. Kim DY. J. Org. Chem.  2004,  69:  6897 
• 14 Compare with: Hartung J. Daniel DK. Rummey C. Bringmann G. Org. Biomol. Chem.  2006,  4:  4089 
• 16a Belotti J. Cossy JP. Portella PC. J. Org. Chem.  1986,  51:  4196 
• 16b Nagumo S. Suemuen H. Sakai K. Tetrahedron  1992,  48:  8667 
• 17 Westermann B. Gedrath I. Synlett  1996,  665 
• 18 Iodolactonization of esters is well precedented; Bartlett PA. Barstow JF. J. Org. Chem.  1982,  47:  3933 

15

MM2 calculations, performed by CS Chem3D Pro version 5.0, Cambridge Soft Corporation, 100 Cambridge Park Drive, Cambridge, MA 02140.D, showed that bicyclic γ-hydroxy ketones intermediates 5, derived from 5-, 7-, 8-, and 12-membered rings, are more stable by 10, 9, 12, 8, kcal/mol respectively than their corresponding hemiketals of type 2, while in the 6-membered ring case the difference is approx 4 kcal. Similarly, δ-hydroxy ketones 10a and 10c are more stable by about 7 and 12 kcal/mol respectively than their corresponding hemiketals. Though these are only simple gas phase calculations they provide relative energies for isomer pairs.

19

These results are consistent with ab initio calculations by A. M. Belostotskii, to be reported separately.