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 Scheme 1. Diastereoselective nucleoside formation via an iron-stabilized cationic intermediate. Scheme 2. a) TDSCl, pyridine, RT, 16 h (98 %); b) DEAD, PPh 3 , benzene, 80 8C, 4 h (81 %); c) LiBr, tetramethylurea, toluene, reflux, 2.5 h (68 %) d) H 2 C = PPh 3 , THF, À78 8C !RT (86 %); or Ph 3 P = C(H)CO 2 Et, THF, reflux, 1 h (95 %); e) [Fe 2 (CO) 9 ] Et 2 O, reflux, 18 h (for R = H, 72 %, 10:11 = 3.3:1) or 3 h (for R = CO 2 Et, 77 %, 12:13 = 4.3:1); DEAD = diethylazodicarboxylate.