Radical cyclisation routes to terpenes and furans

Abstract

The thesis entitled “Radical Cyclisation Routes to Terpenes and Furans” consists of three chapters.

Chapter I This chapter describes various aspects of radical cyclisation reactions (eq. 1) along with examples of their application in natural product synthesis.

Chapter II This chapter presents the total syntheses of (+)-laurenes (2) and (3), and the formal total syntheses of (+)-cuparenones (4) and (5), along with two unsuccessful approaches to cuparene (1), based on radical cyclisation reactions.

Two approaches to cuparene (1), via cyclisation of radicals 6 (Path a) and 7 (Path b), were attempted:

Path a: The radical precursor bromo olefin 8 was prepared starting from isobutyrophenone 9, via ketone 10, tertiary alcohol 11, diol 12, and enomesylate 13. Radical cyclisation (n-Bu?SnH, AIBN, C?H?, 0.02 M) of bromide 8 furnished exclusively the 6-endo-trig cyclised product 14.

Path b: The radical precursor hexenyl bromide 15 was synthesized starting from propiophenone 16 via esters 17 and 18, tertiary alcohol 19, diol 20, and enomesylate 21. Radical cyclisation of bromide 15 also furnished exclusively the 6-endo-trig cyclised product 22.

Total synthesis of laurenes (2) and (3) was achieved via ester cyclisation of the acetylenic radical 23. Intermediate 18 was converted into the key acetylenic acetal 24 via aldehyde 25, eneacetal 26, and aldehyde 27. Acetal 24 was transformed into xanthate 28, the radical precursor, via aldehyde 29 and alcohol 30. Radical cyclisation of xanthate 28 provided a 1:1 mixture of laurene (2) and epilaurene (3). In contrast, radical cyclisation of vinyl radical 31, generated from enyne 32 (obtained from aldehyde 29), furnished exclusively the 6-endo cyclised product 33.

Synthesis of enone 34, an immediate precursor to 3-cuparenone (5), was developed via cyclisation of radical 35. The radical precursor bromo acetate 36 was synthesized starting from aldehyde 25 via enyne 37. Radical cyclisation of bromo acetate 36 furnished a 1:3:1.5 mixture of stannylated product 38, 5-exo-dig cyclised product 39, and rearranged acetate 40. The major product, cyclised acetate 39, was converted into enone 34 via alcohol 41.

A short route to ?-cuparenone (4) was developed via a combination of Claisen rearrangement and radical cyclisation. Mercuric acetate–catalyzed one-pot Claisen rearrangement of cinnamyl alcohol 42 (obtained from 4-methylacetophenone) furnished pentenal 43, which was homologated to hexenal 44 via a Wittig reaction. Cyclisation of radical anion 45, derived from hexenal 44, followed by oxidation of the resultant alcohol, furnished a 1:6 mixture of cyclopentanone 46, an immediate precursor to ?-cuparenone (4).

Chapter III This chapter describes the syntheses of various substituted furans 47 (3-substituted, 2,3-disubstituted, 2,3,5-trisubstituted, and 2,3,4,5-tetrasubstituted), including two naturally occurring furanoterpenes, perillene (48) and dendrolasin (49), based on radical cyclisation reactions.

N-Bromosuccinimide (NBS) bromination of vinyl ethers 50 in the presence of propargyl alcohols 51 furnished radical precursors, bromoacetals 52. The 5-exo-dig cyclisation of radicals derived from bromoacetal 52, using in situ generated catalytic n-Bu?SnH (from n-Bu?SnCl, NaBH?CN, t-BuOH) in the presence of catalytic AIBN, generated 3-alkylidenetetrahydrofurans 53. Acid-catalyzed (PTSA) aromatisation of cyclised products 53 furnished the furans 47.