We have previously demonstrated that h 4 -butadiene-Fe(CO) 3 complexes of type 1 undergo highly selective substitution reactions at the acetal center via Fe(CO) 3 -stabilized cationic intermediates of type 2.[1] As an example, the SnCl 4 -catalyzed reaction of complex 1 (R = H) with a silylated uracil derivative [2] afforded the nucleoside analog 3 with greater 95 % diastereoselectivity in high yield (Scheme 1).Encouraged by the high efficiency of this transformation and the growing importance of bio-organometallic chemistry, [3] we felt challenged to apply this methodology to the stereoselective synthesis of iron-containing nucleoside analogs of type 4 or 5 (NB = nucleobase) also possessing a 5'-CH 2 OR' substituent. Such compounds could exhibit useful biological activities, since nucleoside analogs in general have a great pharmacological potential (e.g. as anti-viral and antitumoral drugs) [4] and transition-metal carbonyl complexes offer some unique new opportunities for drug development.[5]Herein, we disclose the discovery of new iron-containing nucleoside analogs, which surprisingly exhibit strong apoptosis-inducing properties.[6] The synthesis of complexes 10 and 12 (Scheme 2) as precursors for nucleoside analogs of type 4 started with commercial a-methylglucopyranoside (6), which was first converted into the aldehyde 7 by silylation of the primary hydroxyl group (TDS = thexyldimethylsilyl), Mitsunobu epoxide formation, and subsequent LiBr-induced rearrangement/ring contraction. [7] Complexation of the dienes 8 and 9, obtained from 7 by Wittig olefination, with [Fe 2 (CO) 9 ] in refluxing Et 2 O proceeded with significant diastereoselectivity [8] to preferentially give the endo-complexes 10 and 12, respectively. While chromatographic separation of the mixtures (10/11 and 12/13) was possible only by preparative HPLC, the corresponding primary alcohols, obtained by

The isolation from the marine sponge Leiosella cf. arenifibrosa and structural elucidation of halipeptin D (5), a relative of the previously isolated halipeptins A-C (1-3), is described along with the total synthesis of a number of oxazoline analogues (7 a-d and epi-7 c-d). The developed synthetic strategy provides a flexible entry into the various isomers of the polyketide domain of the halipeptins and improvises for a late stage construction of the oxazoline ring after a macrolactamization process which secures the required macrocycle.

The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d. The synthesized halipeptins, together with the previously constructed oxazoline analogues 5d and 6d, were subjected to biological evaluation revealing anti-inflammatory properties for 1a, 1d, and 6d while being noncytotoxic against human colon cancer cells (HCT-116).

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