Aromatic spiroketal

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

The synthesis of the bisbenzannelated spiroketal core of the y-rubromycins was achieved by the research team of C.B. de Koning." The key step was the Nef reaction of a nitroolefin, which was prepared by the Henry reaction between an aromatic aldehyde and a nitroalkane. The nitroolefin was a mixture of two stereoisomers, and it was subjected to catalytic hydrogenation in the presence of hydrochloric acid. The hydrogenation accomplished two different tasks it first converted the nitroalkene to the corresponding oxime and removed the benzyl protecting groups. The oxime intermediate was hydrolyzed to a ketone that underwent spontaneous spirocyclization to afford the desired spiroketal product. 

Milbemycin P3 (383) is a 16-membered macrocyclic lactone isolated from the fermentation broth of Streptomyces B-41-146 and is the simplest member of a family of compounds structurally related to the avermectins. Milbemycin P3 has been demonstrated to have marked insecticidal as well as limited antibiotic activity. Structurally, 383 is a 16-membered lactone fused to an aromatic ting. Although nearly devoid of asymmetric centers on the cyclic framework, it does contain the rather unusual spiroketal moiety. 

Conversely, cephalostatins 5 and 6 (5, 6), in which ring C of the left hand steroid unit is aromatized, exhibited reduced activity in the PS system (10 2-10 3 pgmL 1) suggesting the importance of C - D ring junction and possibly C-22 spiroketal structural integrity to the cytostatic properties of the cephalostatins [19]. 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

In order to form the final carbon-carbon bond, functionalizatimi of the aromatic nucleus was required. Attempted iodination with iV-iodosuccinimide at 0 °C furnished a mixture of products that was difficult to analyze by NMR. However, lowering of the temperature to 20 °C, followed by quenching at this temperature after 3 h provided an inseparable mixture of C-6 and C-8 iodination products 41/42 in 47% yield together with 30% recovered spiroketal 39. 

Although spiroketal 42 contains the iodine atom in the undesired C-8 position, we reasoned that successful carbonylation, followed by acid-catalyzed equilibration of the spiroketal might allow rotation of the aromatic core, facilitating interchange between the two regioisomeric carbonylation products... 

A novel intramolecular alkylation using a spiroketal (14) with BFj.OEt, in THF at reflux forms the benzene-fused 8-oxabicyclo[3.2.1]octane ring system (15) in satisfactory yield. IV-Tosylpipecolinic acid (16) in the presence of sulfuric acid in benzene forms the unexpected aromatized derivative (17) in 18% yield and the mechanism is suggested to involve the reaction of intermediate (18) with benzene to form (19). Cumyl and r-butyl hydroperoxides have been used for the electrophilic alkylation of activated aromatic substrates, mainly phenols and phenol ethers.The hydroperoxides behave differently as far as catalysis and regioselectivity are concerned. The latter is believed to be explicable by steric and reactivity/selectivity considerations. Electrophilic r-butylation may be followed by radical reactions due to the r-butyl... 

The efficiency of a series of rhodium and iridium complexes as catalysts for the cyclization of terminal and nonterminal alkynes to give 0,0-acetals and spiroketals was tested using [Ir(PyP)(CO)2]BPh4 and [Rh(bim)(CO)2]BPh4 (bim = bis (N-methylimidazol-2-yl)-methane [32-34]. The iridium complex was more efficient than rhodium in promoting the reactions of aliphatic alkyne diols. The rhodium was more effective for promoting the reactions of aromatic substrates (Scheme 15). 

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