Enantioselective Sequential Conjugate Addition−Allylation Reactions: A Concise Total Synthesis of (+)-Podophyllotoxin

Abstract

A highly flexible and concise total synthesis of (+)-podophyllotoxin featured with an enantioselective sequential conjugate addition-allylation reaction was reported. Starting from commercially available 3,4,5-trimethoxycinnamic acid, this new route leads to (+)-podophyllotoxin 1 in only eight steps with 29% overall yield.

Manipulating Micellar Environments for Enhancing Transition Metal-Catalyzed Cross-Couplings in Water at Room Temperature

“…1 H NMR (400 MHz, CDCl 3 ):δ 7.50 (d, J = 16.0 Hz, 1H), 6.74 (s, 2H), 6.28 (d, J = 16.0 Hz, 1H), 3.89 (s, 9H), 1.54 (s, 9H). 37 …”

Investigation and Expression of the Secoisolariciresinol Dehydrogenase Gene Involved in Podophyllotoxin Biosynthesis

“…One of these sources is the rhizomes of the plant Podophyllum peltatum [6]. Due to a combination of the slow growth-rate of the plant and increasing demand for PPT [7][8][9], various other approaches for the chemical synthesis and in vitro production of PPT have been explored [1,[10][11][12][13][14]. These methods have so far proven to be inadequate for the commercial production of PPT due to low yields and high costs.…”

Biomimetic Synthesis of Lignans

“…While many synthetic strategies have been developed to circumvent the growing demand on the plant resource, few are truly biomimetic. Indeed, most synthetic routes toward 15 rely on tandem conjugate addition approaches [22][23][24], Diels-Alder approaches [25][26][27], or, more recently, enantioselective sequential conjugate addition-allylation reactions [28]. It is well established that 15 is biosynthesized by the oxidative cyclization of the dibenzylbutyrolactone yatein (33), itself a lignan derived from 8-8 heterocoupling [29].…”

“…Under hypervalent iodine or ruthenium catalysis, an unexpected eight-membered ring (35) forms exclusively [30]. Thus, with the proper metal catalysis, a biomimetic approach to podophyllotoxin is possible, but other routes have proven more direct and, importantly, enantioselective [28]. …”