Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

Abstract

An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the synthesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium catalyst, an optically active phosphoramidite ligand, K 3 PO 4 and Ag 3 PO 4 . The obtained piperidone was converted to epieburnamonine.Key words enantioselective reaction; total synthesis; terpenoid indole alkaloid Chem. Pharm. Bull. 56(11) 1567-1574 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: takemoto@pharm.kyoto-u.ac.jp under normal conditions (entries 1-3). However, lactam 9 was isolated in 60% yield when Ag 3 PO 4 was added to the reaction (entry 4). The combination of Pd 2 (dba) 3 and BINAP was also able to promote the cyclization in the presence of Ag 3 PO 4 (entry 5). Nolan's NHC catalyst was not effective (entry 6).With these results in hand, syntheses of each cis-trans isomer of alkenyl chloroformamide 2 were performed. Alkene (E)-4 was synthesized through hydroalumination as a key step (Fig. 5). 4-Pentyn-1-ol (10) was transformed into alcohol 11 through oxidation, acetalization, and hydroxymethylation using benzotriazolylmethanol (BtCH 2 OH). 22) Alcohol 11 was then subjected to the hydroalumination-iodination sequence 23,24) to give (Z)-iodo alkene 12, whose configuration was confirmed by NOE experiment. Ethylation by Suzuki coupling, followed by benzylation gave the desired alkene (E)-4.Change of the starting material afforded the alternative stereoisomer (Fig. 6). (Z)-Iodoalkene 14 was synthesized from 2-pentyn-1-ol (13) through hydroalumination and iodination. Since benzylation of the hydroxy group under either basic or acidic conditions competed with decomposition of the starting material, protection by THP group was carried out. The resultant THP ether 15 underwent Negishi coupling with 3,3-(dimethoxy)propylzinc chloride 16. 25) Selective hydrolysis of the THP ether and benzylation afforded the desired alkene (Z)-4.Alkenyl acetals (E)-4 and (Z)-4 were coupled with tryptamine 3 26) through hydrolysis and reductive amination to give amines (E)-17 and (Z)-17, respectively (Fig. 7). These compounds were converted to the corresponding chloroformamides (E)-2 and (Z)-2 by treating with triphosgene and Et 3 N.Before the enantioselective Heck-type reaction, a racemic reaction was attempted to find out a suitable palladium source ( Table 2). The cyclized product 1 was isolated after hydrolysis of the resultant enol ether. At the early stage, poor reproducibility was a serious problem. After several attempts, it was found that the activity of the catalyst is highly associated with the conditions used to mix palladium sources and ligands prior to the addition of chloroformamide 2. When [Pd(h 3 -C 3 H 5 )Cl] 2 was premixed with (p-tol) 3 P at 30°C for 30 min, the disappearance of 2 was slow and the yield was 30% after 24 h (entry 1). In contrast, the starting material disappeared in 3 h and yield reached 49% when premixing was performed at 40°C...

Asymmetric Total Synthesis of (+)-21-epi-Eburnamonine Via a Photocatalytic Radical Cascade Reaction

“…The delivered pentacycle 23 was then subjected to catalytic hydrogenation in which the vinyl group was reduced to afford the target molecule in 89% yield. Notably, the NMR data of 8 had identical NMR data to (−)-20-epi-eburnamonine reported in the literature [66] but opposite optical rotation, which again confirmed the In summary, we have disclosed an efficient approach to the asymmetric total synthesis of (+)-21-epi-eburnamonine with trans D/E ring fusion. From a strategical perspective, the synthesis features a photocatalytic intra-intramolecular radical cascade reaction to assemble the A/B/C/D ring system and a highly diastereoselecive Johnson-Claisen rearrangement to forge the C20 all-carbon quaternary stereocenter.…”

“…Yuan Huang and Fanglin Xue contributed equally to this work. asymmetric total synthesis of 2, see: [54][55][56][57][58][59][60][61][62]), the asymmetric synthesis of the above molecules (i.e., 6-8) with trans D/E ring fusion remains limited [63][64][65][66][67]. Among the numerous strategies developed to access eburanamine-vincamine alkaloids, stereoselective construction of the C20 and C21 stereocenters has always been the most difficult point.…”

Palladium(0)-Catalyzed Benzylic C(<i>sp</i>³)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

“…57) We previously developed a novel method for the construction of oxindole skeletons from carbamoyl chlorides, as well as a spirooxindole synthesis that proceeded via the bismetallation of 1,3-dienes. [58][59][60][61] Furthermore, this method was subsequently applied to a formal synthesis of elacomine. 60) Although these synthetic methods represent efficient strategies for the construction of spirooxindole moieties, their application has been limited by their requirement for the preparation of the carbamoyl chloride precursors.…”

A Concise and Versatile Double‐Cyclization Strategy for the Highly Stereoselective Synthesis and Arylative Dimerization of Aspidosperma Alkaloids

“…The ability to employ an unactivated C3 À C4 olefin as the nucleophile in the second cyclization is likely a result of the enhanced electrophilicity at C2 of intermediate 6 imparted by the chlorine atom, [19] together with a high resilience of 6 toward an undesired Pictet-Spengler rearrangement. [20,21] Consistent with the sensitivity of this doublecyclization step, the use of less-basic 2-chloropyridine or more-nucleophilic pyridine as the additive gave the desired diiminium ion 5 with reduced efficiency as evidenced by the presence of singly cyclized side products, recovered starting material, and significant decomposition. [22] The synthetic versatility of diiminium ion 5 is illustrated by its conversion into alkaloids (À)-1, (+)-2, and (À)-17 (Scheme 3).…”