28 HIVインテグラーゼ阻害物質OteromycinおよびCYP3A4阻害物質Diaporthichalasinの全合成(口頭発表の部)

抄録

Recently, natural biologically-active a-acyl-y-hydoroxylactams with decalin skeletons and their alkoxyaminal-type analogues have been reported. The series of compounds attract much attention for their various and interesting biological activity. Each of these compounds shows the different biological activity owing to the structural variation in the decalin skeleton and the substituents on the γ-position of lactam rings. However, their activity spectra and mode of actions have not yet been declared. Therefore, we started synthetic study for this type of compounds in order to elucidate the above mentioned undefined points. We would like to report here the first total synthesis and structure determination of H1V-integrase inhibitor Oteromycin (1) based on a novel synthetic strategy for the α-acyl-γ-hydroxylactams. In the course of this study, intramolecular Diels-Alder (IMDA) reaction of 1 was found to be applicable for the synthesis of CYP3A4 inhibitor Diaporthichalasin (2). Therefore, we also would like to describe the first total synthesis of 2 as an extension of our developed synthetic strategy. First, total synthesis of 1 was investigated. Chiral vinyl iodide and trienyl borane were respectively prepared from (+)-citronellal and trans-2-methyl-2-butenal. These compounds were then coupled by Suzuki-Miyaura reaction, and the following two step reactions gave the corresponding pentaenal-type cyclization precursor. IMDA reaction of this precursor proceeded stereoselectively to afford the desired decalin fragment. On the other hand, N-Teoc-protected y-benzyl-y-methoxylactam was also prepared as another important fragment. Aldol reaction between these fragments proceeded smoothly, and the following several transformations gave the desired precursor of 1. However, hydrolysis of the methoxyaminal moiety gave the undesired pentacyclic compound because of the exclusively occured IMDA reaction between diene-type side chain on the decalin skeleton and the α,β-unsaturated lactam moiety. Therefore, we tried to develop the second synthetic strategy which is not through the hydrolysis step. An interesting model synthesis of α-acyl-γ-hydroxylactams utilizing the epoxidation of the enol form of α-acyl-α,β-unsaturated lactam was reported by Snider's group in 2004. However, this method has not been applied to the total synthesis of natural products. It is probably due to the unsatisfactory stability of the intermediate α-acyl-α,β-unsaturated lactam under the basic condition. Therefore, we developed novel synthetic pathway via the in situ preparation of α-acyl-α,β-unsaturated lactam starting from the corresponding saturated-type one. That is, saturated-type α-acyllactam was synthesized and subjected to the phenylselenenylation to give the corresponding a-selenolactam. The obtained a-selenolactam was then treated with two equivalents of MMPP (magnesium monoperoxyphthalate hexahydrate). In this reaction condition, oxidative elimination of phenylselenenyl group, enolization of the resulting α,β-unsaturated lactam, epoxidation at β-γ position and ring opening to the desired γ-hydoroxylactam subsequently proceeded in one pot. Thus, the first total synthesis of 1 was successfully achieved. The absolute configuration of 1 was assigned by comparison of the optical rotation with reported data. However, the configuration of C24-position could not be determined from all of the spectral data. Therefore, IMDA reaction between diene side chain on the decalin skeleton and the a,13-unsaturated lactam moiety was carried out to observe the cross-peaks in the NOE spectrum of the resulting pentacyclic compound. As a result, the absolute configuration of C24-position was defined as 5, and the chemical structure of 1 was entirely determined. Surprisingly, the carbon skeleton and the relative configulation of the obtained pentacyclic compound were the same as that reported as 2. Therefore, we also studied the

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