An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF 3 ·Et 2 O promoted stereospecific addition of Me 2 CuLi toα,β-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (6 steps, 40% overall yield) and the stereospecific NaBH 4 reduction of 2 to give cermizine C (1) (7 steps, 40% overall yield).Kobayashi recently reported the isolation of the lycopodium alkaloid cermizine C (1) from the club moss Lycopodium cernuum and the related alkaloid senepodine G (2) from the club moss Lycopodium chinense (see Scheme 1). 1,2,3 The structures were elucidated by 1D and 2D NMR spectroscopic methods. Senepodine G (2) is cytotoxic to murine lymphoma L1210 cells with an IC 50 of 7.8 μg/mL. The absolute configuration of other co-occurring more complex natural products were assigned by modified Mosher's method suggesting that the absolute configurations of 1 and 2 are as drawn.We set out to synthesize these novel alkaloids as a means of developing chemistry that might be useful for more complex members of these families. We thought that it should be possible to prepare cermizine C (1) from senepodine G (2) by reduction of the iminium cation with NaBH 4 . Although similar reductions are known, 2b,4 the stereoselectivity of this reduction is uncertain because steric interactions with the methyl group should direct hydride attack from the bottom face, whereas steric interactions with the right hand ring should direction hydride attack from the top face. Iminium cation 2 can be prepared by addition of MeMgBr to lactam 3 followed by treatment with HCl. We conceived of two approaches to lactam 3. We hoped that it might be possible to carry out a directed conjugate reduction of unsaturated Meldrum's acid derivative 4 to give 5, which would cyclize to form lactam 3. Alternatively, it might be possible to add methylcuprate stereospecifically to unsaturated lactam 6.Knoevenagel condensations between a ketone and a β-dicarbonyl compound are typically carried out using an ammonium acetate catalyst. Since (±)-pelletierine (7) 5 contains a secondary amine we treated it with 1 equiv of AcOH to form the acetate salt. Heating this salt with 2.4 equiv of Meldrum's acid in EtOH required 2 days at 60 °C for the complete consumption of the pelletierine. To our surprise, we did not isolate 4, but rather the β,γ-unsaturated lactam 11 in 68% yield. Equilibration of 11 with K 2 CO 3 in MeOH for 1 day afforded a 3:1 mixture of α,β-unsaturated lactam 13 and β,γ, -unsaturated lactam 11. Treatment of pure 13 afforded the identical 3:1 mixture indicating that equilibrium had been reached. Although α,β-unsaturated carbonyl compounds are usually much more stable than their β,γ, -unsaturated isomer, there are examples of unsaturated amides in which significant amounts of both isomers are present at equilibrium. 6 Ban prepared 13 by treatment of N-acetylpelletierine with triethyloxonium tetrafluoroborate in CH 2 Cl 2 and then ...
Crisscross cycloaddition of citronellal azine (6) with 2 equiv. of TFA and powdered 3 Å molecular sieves in CH2Cl2 at reflux for 22 h afforded 37% of the desired C2-symmetric hydrazine 7 and 5%–10% of diastereomer 8 in which one of the 6–5 ring fusions is cis. Methylation of the hydrazine of 7 and reduction of the resulting salt (9) with Li in NH3 cleaved the N—N bond to give secondary tertiary amine 10 in 97% yield. Eschweiler–Clarke methylation afforded the C2-symmetric bis tertiary amine 11 in 69% yield. Racemic products were obtained in initial attempts at asymmetric catalysis using 7 or 11 as asymmetric bases, using bistertiary amine 11 as a ligand analogous to sparteine for alkyllithiums, or using the lithium amide from secondary tertiary amine 10 as an asymmetric base. Apparently, the proton is buried in the core of 11, leaving a hydrophobic surface; the free counterion is not an asymmetric catalyst. Diamine 11 may be too hindered to complex to s-BuLi. Tertiary amine 11 (pKa1 = 24.7) is more basic than DBU (pKa = 24.3) in CH3CN, in good agreement with theory.Key words: crisscross cycloaddition, azine, dipolar cycloaddition, calculation of pKa.
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