Cascade radical-mediated cyclisations with conjugated ynone electrophores. An approach to the synthesis of steroids and other novel ring-fused polycyclic carbocycles

A cascade radical-mediated Diels-Alder reaction with the iododienynone 16b produced the tricyclic ketone 17 (22%). By contrast, treatment of the substituted furans 36 and 47 with Bu(3)SnH-AIBN, instead led to the tetracycles 44 and 58 respectively, rather than the anticipated oestranes, i.e. 38 and 48. In a separate study, attempted cascade radical-mediated cyclisations from the ortho-aryl substituted iododienynones 72 and 73, leading to the ring-D aromatic steroid 7, instead gave the macrocyclic ketone 76 or the novel bridged tricycles 77/82, respectively, depending on whether benzene or heptane was used as solvent in the reactions.     

Biomimetic syntheses of ineleganolide and sinulochmodin C from 5-episinuleptolide via sequences of transannular Michael reactions

Treatment of a solution of the macrocyclic norcembranoid 7 with lithium hexamethyldisilazide in THF at −78 °C to 0 °C, leads to the polycyclic norcembranoids ineleganolide 1 and sinulochmodin C (2) (65%), which are found in the corals Sinularia inelegans and Sinularia lochmodes, respectively. The conversions are believed to be biomimetic, and occur by successive transannular Michael reactions in 7. Under different temperature conditions the novel polycycle 30 is the main product, alongside small quantities of 1 and 2. The polycycle 30 is possibly produced from ineleganolide 1, following a reverse oxy-Michael reaction and two successive aldol reactions. The significance of the synthesis of ineleganolide 1, sinulochmodin C (2) and the structure 30 from 5-episinuleptolide 7, to the likely biosynthesis of the related norcembranoids scabrolide A (3), scabrolide B (4) and horiolide 31 found in Sinularia sp. is discussed.     

Novel polyoxazole-based cyclopeptides from Streptomyces sp. Total synthesis of the cyclopeptide YM-216391 and synthetic studies towards telomestatin

A convergent, complementary, synthetic approach to the contiguously linked tris-oxazole units 10, 11 and 12 in telomestatin (1) and YM-216391 (2) is described. The route involves coupling reactions between oxazole 4-carboxylic acids, viz 16a, 16c, 16d and oxazole 2-substituted methylamines, viz 16b, 16e, 17, leading to the amides 18 and 21, followed by cyclodehydrations to the corresponding bis-oxazole oxazolines, e.g. 19, and oxidations of the latter using well-established protocols. The tris-oxazoles 11 and 12 were next converted stepwise into the hexa-oxazole bis-macrolactams 33. Although the bis-macrolactams 33 (cf. 28) could be converted into the corresponding oxazoline-hexa-oxazoles 34 and to the enamides 35, neither of these intermediates could be elaborated to the hepta-oxazole 30en route to telomestatin 1. Likewise, neither the hexa-oxazole 47 or application of an intramolecular Hantzsch oxazole ring-forming reaction from 44b allowed access to the advanced polyoxazole-macrolactam intermediates 48 and 30a, respectively, towards telomestatin. Combination of the tris-oxazole based methylamine 70 with the dipeptide carboxylic acid 71 derived from D-valine and L-isoleucine, leads to the corresponding amide which, in two straightforward steps, is converted into the -amino acid 78. Macrolactamisation of 78, using HATU, next produces the cyclopeptide 79 which is then elaborated to the thiazole and oxazole based cyclopeptide YM-216391 (2). The synthetic cyclopeptide 2 is shown to be the enantiomer of the natural product isolated from Streptomyces nobilis.     

A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure alpha-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones

Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.