Nineteen-step total synthesis

of (+)-phorbol

报告人: 高翔

检查: 严忠

日期: 2016/05/31

Baran, P. S. et al.

Nature 2016, 532, 90-93. Phil S. Baran

The Scripps Research Institute

Introduction

Asymmetric formal synthesis by Wender

Nineteen-step total synthesis by Baran

Summary

Contents

Introduction

Isolated in 1934 as the hydrolysis product of croton oil, which is derived

from the seeds of croton tiglium

Structural complexity: 8 consecutive stereocenters, 7-membered ring

and 3-membered ring

Phorbol 12-myristate-13-acetate, currently in phase II clinical trials for

treatment of acute myeloid leukaemia

Phorbol (1) Croton tiglium

Asymmetric formal synthesis by Wender

Retrosynthetic Analysis of Phorbol

Wender, P. A. et al. J. Am. Chem. Soc. 1997, 119, 7897.

Asymmetric formal synthesis by Wender

Oxidopyrylium-alkene

cycloaddition

Asymmetric formal synthesis by Wender

Zr(IV)-mediated enyne cyclization

Asymmetric formal synthesis by Wender

Asymmetric formal synthesis by Wender

Asymmetric formal synthesis by Wender

Asymmetric formal synthesis by Wender

Nineteen-step total synthesis by Baran

Baran, P. S. et al. Science 2013, 341, 878.

Baran, P. S. et al. Nature 2016, 532, 90.

Nineteen-step total synthesis by Baran

Nineteen-step total synthesis by Baran

Site-selective

Oxidation of C-H

Mukaiyama

hydration

Nineteen-step total synthesis by Baran

Nineteen-step total synthesis by Baran

Nineteen-step total synthesis by Baran

Nineteen-step total synthesis by Baran

Nineteen-step total synthesis by Baran

Summary

Phorbol, the flagship member of the tigliane diterpene family, has

been known for over 80 years and has attracted attention from

many chemists and biologists owing to its intriguing chemical

structure and the medicinal potential of phorbol esters. Access to

useful quantities of phorbol and related analogues has relied on

isolation from natural sources and semisynthesis. Despite efforts

spanning 40 years, chemical synthesis has been unable to compete

with these strategies, owing to its complexity and unusual

placement of oxygen atoms. Purely synthetic enantiopure phorbol

has remained elusive, and biological synthesis has not led to even

the simplest members of this terpene family.

Recently, the chemical syntheses of eudesmanes, germacrenes,

taxanes and ingenanes have all benefited from a strategy inspired

by the logic of two-phase terpene biosynthesis in which powerful C–

C bond constructions and C–H bond oxidations go hand in hand.

Here we implement a two-phase terpene synthesis strategy to

achieve enantiospecific total synthesis of (+)-phorbol in only 19

steps from the abundant monoterpene (+)-3-carene. The purpose of

this synthesis route is not to displace isolation or semisynthesis as

a means of generating the natural product, but rather to enable

access to analogues containing unique placements of oxygen

atoms that are otherwise inaccessible.

Oxidopyrylium-alkene cycloaddition

Oxidative ring expension

Lefebvre, Y. et al. Tetrahedron Lett. 1972, 133.

Zr(IV)-mediated enyne cyclization

RajanBabu. T. V. et al. J. Am. Chem. Soc. 1988, 110, 7128.

Pauson-Khand cyclization

Brummond, K. M. et al. Org. Lett. 2002, 4, 1931.

Allenic Pauson-Khand-type reaction

Origin of site-selectivity

Martin sulfurane

Martin. J. C. et al. J. Am. Chem. Soc. 1972, 94, 5003.

Mukaiyama hydration

Mukaiyama, T. et al. Chem. Lett. 1989, 515.