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Collective Syntheses and Biological Evaluation of Akuammiline Indole Alkaloids

Final Report Summary - STRICTSYN (Collective Syntheses and Biological Evaluation of Akuammiline Indole Alkaloids)

1,3-Dipolar cycloadditions of hydrazones or azomethine imines are robust methods for the assembly of five-membered nitrogen-containing heterocycles. In recent years, catalytic enantioselective 1,3-dipolar cycloadditions of hydrazones or azomethine imines have been developed, that provided efficient accesses to enantio-enriched pyrazolidine analogues. Among them, normal-electron-demand 1,3-dipolar cycloadditions of azomethine imines with electron-deficient alkenes are well established. In contrast, inverse-electron-demand 1,3-dipolar cycloadditions between azomethine imines and electron-rich alkenes are far less developed. In molecular orbital terms, the frontier molecular orbital of electron-rich alkene has higher energy than that of 1,3-dipole, and the dominant interaction in inverse-electron-demand 1,3-dipolar cycloadditions is HOMO of alkene and LUMO of 1,3-dipole, which is quite opposite to that of normal-electron-demand 1,3-dipolar cycloadditions. Consequently, developing catalytic asymmetric dipole-LUMO/dipolarophile-HOMO controlled 1,3-dipolar cycloadditions is highly desirable and full of challenge.
Enol ethers and thioethers are the main dipolarphiles used in inverse-electron-demand 1,3-dipolar cycloadditions. Curiously, enamides are rarely employed for this purpose. Indeed, it was reported that tertiary enamides failed to react with hydrazones, while secondary enamide afforded the cycloadducts without noticeable enantioselectivity. In connection with our interest in developing asymmetric transformations of enamides, we decided to use enencarbamate as dipolarphile in inverse-electron-demand 1,3-dipolar cycloaddition.
We first examined the reaction between hydrazone and enecarbamate. However, no desired product was obtained. Assuming that the activation mode of azomethine imine might be different from that of hydrazone, we thought that secondary enecarbamate would be an ideal reaction partner for azomethine imine in the presence of bifunctional chiral phosphoric acid. After catalyst screening, SPINOL-derived chiral phosphoric acid was found to be the most promising catalyst. Under optimized conditions, a broad range of azomethine imines with electron-withdrawing or electron-donating substituents at different positions of the aromatic ring participated in the reaction with secondary enecarbamate to afford the corresponding isoquinoline-fused pyrazolidines in excellent yields with excellent regio-, diastereo- and enantioselectivities. The absolute configuration of the cycloadduct was determined by X-ray analysis. We note here that pyrazoline derivatives display a broad spectrum of biological activities including antibacterial, antidepressant, antidiabetic, antiepileptic, antihypotensive, anti-inflammatory, antimalarial, antimicrobial antipyretic-analgesic, antituberculotic, antitumor, immunosuppression, insecticidal, muscle relaxant, psycho analeptic, and tranquilizing activities.
1,2-Disubstituted alkenes are generally considered as poor dipolarphiles for the aforementioned cycloaddition reaction. We found that (Z)-enecarbamates underwent readily dipolar cycloaddition with a wide range of azomethine imines in the presence of H8-BINOL-based chiral phosphoric acid. Under optimized conditions, the corresponding cycloadducts were isolated in excellent yields with excellent regio-, diastereo- and enantioselectivities. The absolute configuration of the cycloadduct was determined by X-ray analysis. To the best of our knowledge, this represented the first example of inverse-electron-demand 1,3-dipolar cycloaddition between azomethine imine and electron-rich internal double bond. We then found that increasing the size of β-substituent of enecarbamate decelerated the reaction. However, adding molecular sieves restored the enantioselectivity. The fact that the reaction of (E)-enecarbamate afforded lower yield and enantioselectivity excluded the possibility of the isomerization of (E)-enecarbamate to (Z)-enecarbamate prior to the cycloaddition process. In addition, re-submitting the cycloadduct to the standard conditions did not cause the epimerization. Therefore, the trans-relationship between β-substituent and NHCbz indicated that the cycloaddition proceeded through stepwise process.
While pyrazolidine motif is of self-importance as it is found in a myriad of natural products and biologically active compounds, we increased the skeleton diversity by conducting a series of highly diastereoselective post-transformations. SmI2 mediated reductive cleavage of N–N bond gave chiral aminal in excellent yield. Acyclic N-protected chiral aminals are useful building blocks for the synthesis of retro-inverso pesudopeptides. Lewis acid-mediated diastereoselective cyanation of our cycloadducts afforded chiral α-amino nitriles, which are versatile intermediates en route to α-amino acid, vicinal diamine and vicinal amino alcohol etc. Using allyltrimethylsilane as nucleophile, homoallylamine was similarly prepared in good yields and diastereoselectivity. Subsequent SmI2-mediated reductive N–N bond cleavage provided C1-substituted tetrahydroisoquinoline. Tetrahydroisoquinoline bearing a stereogenic center at the C1 position is a pharmacophore that is widely present in biologically active compounds. Finally, a sequence of standard transformations converted cycloadduct to aminobenzo[a]quinolizidine, a tricyclic compound used in the development of selective α2-adrenoceptor antagonist and DDP-IV inhibitor for the treatment of type II diabetes.