Concise Total Synthesis of (+)-Lyconadin A Speaker: Chia-Fu Chang J. Am. Chem. Soc. Takuya Nishimura, Aditya K. Unni, Satoshi Yokoshima, Tohru Fukuyama* J. Am. Chem. Soc Postdoctoral Study Harvard University (Professor Y. Kishi) 1979 Assistant Professor, Rice University 1988 Full Professor, Rice University 1995 Professor of Pharmaceutical Sciences University of Tokyo

Selected congener of the Lycopodium alkaloid family isolated by Bödeker in 1881 and the structural elucidation by Wiesner in 1957 elucidation by Wiesner in 1957

significance in pharmaceutics Murine lymphoma L1210 cells Modest cytotoxicity against ＋ Human epidermoid carcinoma KB cells Enhanced mRNA expression Nerve growth factor (NGF) in 1321N1 human astrocytoma

Past attempt to lyconadin A

Retrosynthetic analysis of (+)-Lycondain and (-)- Lyconadin B by Amos B. Smith, Ⅲ

Construction of tricyclic 35 under diluted acidic condition in DMSO

Stereochemical Analysis of the Strategy-Level Conjugate Addition by using Gaussian package, B3LYP/6-31G ** level of theory Note: 1. The observed products were resulted from both thermodynamic and kinetic processes operating at different points along the reaction sequence. 2. Formation of the C(6)-C(7) bond is irreversible. Stereoelectronically preferred product, axial protonation (kinetic control) Kinetic control Thermodynamic control

Correction of the Stereogenicity at C(12)

Accomplishment of tetracyclic core structure of Lyconadin A by iodioamination.

(+)-Lyconadin A was achieved via one-pot protocol involving condensation and decarboxylation Entry 1: polymerization Entry 2: 20% cyanide substitute compound Entry 3: conversion not good

Synthetic analysis of (+)-Lyconadin A and related compounds via oxidative C-N bond formation by Richmond Sarpong

To obtain cycloheptadiene 14 by sequent reactions, Michael reaction, Grubbs-Hoveyda, Heck reaction

Generation four chiral centers by sequent stereo- control reduction reaction to obtain precursor 8 Corey-Bakshi-Shibta (CBS) reduction Saegusa-Ito reaction

Total synthesis of (+)-Lyconadin A via oxidative C- N bond formation

Retrosynthetic Aanalysis

α, β-unsturated cyclohexone as allyl cation precursors in the Ionic Diels-Alder Reaction Advantages: 1. Avoiding the ease of polymerization caused by adding the Lewis acid or under high pressure 2. higher yield than traditional Lewis-acid-promoted Diels Alder reaction 3. it can occurs readily below 0 ℃ ; steric control

Preparation of tricyclic 8 by aza-Prins reaction Mechanism of aza-Prins reaction

Construction of cyclic amine by Mannich-type and Pris-type ring closure

To finish tetracyclic 11 by inducing ring expansion and formation of a C-N bond Mechanism

To afford enone 2 by Pummerer rearrangement Mechanism:

To afford enone 2 by formation and isomerization of nitrosoalkene 15, and following hydrolysis of oxime 16

To obtain lyconadin A via michael addition, cyclization, and desulfination to form pyridone ring

Summary AuthorJournal Key steps Steps Total yield A. B. Smith III ; D. C. Beshore J. Am. Chem. Soc. 2008, 130, J. Am. Chem. Soc. 2007, 129, endo-trig cyclization unber diluted acidic condition diluted acidic condition 2. Aminoiodination reaction 3. Accomplish pyridone by Mulzer’s method method272.2% R. Sarpong; S. P. West; A. Bisai J. Am. Chem. Soc. 2008, 130, J. Am. Chem. Soc. 2007, 129, Heck reaction 2. C-N bond formation promoted with dianion with Iodine dianion with Iodine188% Tohru Fukuyama J. Am. Chem. Soc. 1. aza-Prins reaction 2. Ring expansion 11 or % or 11.6 %

Conclusion 1. The synthesis of Fukuyama features the facile construction of the highly fused tetracyclic compound 11 throught a combination of highly fused tetracyclic compound 11 throught a combination of aza-Prins reaction and electoncyclic ring opening aza-Prins reaction and electoncyclic ring opening 2. The pyridone could be formed either from vinylgolous Pummerer rearrangement or formation and subsequent isomerization of rearrangement or formation and subsequent isomerization of nitrosoalkene. nitrosoalkene. Thanks for your attendance

Conditions examined to affect formation of (-)- Lyconadin B The conversion of 63 and 64 to 2 proved unsuccessful. (treated with acid)