Metric-Based Analysis of Convergence in Complex Molecule Synthesis

Abstract

Conspectus Convergent syntheses are characterized by the coupling of two or more synthetic intermediates of similar complexity, often late in a pathway. At its limit, a fully convergent synthesis is achieved when commercial or otherwise readily available intermediates are coupled to form the final target in a single step. Of course, in all but exceptional circumstances this level of convergence is purely hypothetical; in practice, additional steps are typically required to progress from fragment coupling to the target. Additionally, the length of the sequence required to access each target is a primary consideration in synthetic design. In this Account, we provide an overview of alkaloid, polyketide, and diterpene metabolites synthesized in our laboratory and present parameters that may be used to put the degree of convergence of each synthesis on quantitative footing. We begin with our syntheses of the antiproliferative, antimicrobial bacterial metabolite (−)-kinamycin F (1) and related dimeric structure (−)-lomaiviticin aglycon (2). These synthetic routes featured a three-step sequence to construct a complex diazo­cyclo­pentadiene found in both targets and an oxidative dimerization to unite the two halves of (−)-lomaiviticin aglycon (2). We then follow with our synthesis of the anti­neuro­degenerative alkaloid (−)-huperzine A (3). Our route to (−)-huperzine A (3) employed a diastereoselective three-component coupling reaction, followed by the intramolecular α-arylation of a β-ketonitrile intermediate, to form the carbon skeleton of the target. We then present our syntheses of the hasubanan alkaloids (−)-hasubanonine (4), (−)-delavayine (5), (−)-runanine (6), (+)-periglaucine B (7), and (−)-acutumine (8). These alkaloids bear a 7-azatricyclo­[4.3.3.01,6]­dodecane (propellane) core and a highly oxidized cyclohexenone ring. The propellane structure was assembled by the addition of an aryl acetylide to a complex iminium ion, followed by intramolecular 1,4-addition. We then present our synthesis of the guanidinium alkaloid (+)-batzelladine B (9), which contains two complex polycyclic guanidine residues united by an ester linkage. This target was logically disconnected by an esterification to allow for the independent synthesis of each guanidine residue. A carefully orchestrated cascade reaction provided (+)-batzelladine B (9) in a single step following fragment coupling by esterification. We then discuss our synthesis of the diterpene fungal metabolite (+)-pleuromutilin (10). The synthesis of (+)-pleuromutilin (10) proceeded via a fragment coupling involving two neopentylic reagents and employed a nickel-catalyzed reductive cyclization reaction to close the eight-membered ring, ultimately providing access to (+)-pleuromutilin (10), (+)-12-epi-pleuromutilin (11), and (+)-12-epi-mutilin (12). Finally, we discuss our synthesis of (−)-myrocin G (13), a tricyclic pimarane diterpene that was assembled by a convergent annulation. In the final section of this Account, we present several paramaters to analyze and quantitativ...

Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites**

“…Although the installation of the two stereocenters was not fully diastereoselective, we anticipated that the forward reaction conditions would concomitantly epimerize those C2 and C3 stereocenters to the desired configurations. At least two important features of this cascade relay were noteworthy: i) Our imine formation/alkylation tactic enabled the facile synthesis of cyclic imines, which usually requires extensive redox and protecting‐group manipulations; [39] and ii) the overall cascade sequence enabled rapid complexity generation and good convergence, as four bonds, two rings and two stereocenters were formed from two comparatively complex building blocks [40] …”

Syntheses and structural plasticity of kratom pseudoindoxyl metabolites

“…At least two important features of this cascade relay were noteworthy: i) Our imine formation/alkylation tactic enabled the facile synthesis of cyclic imines, which usually requires extensive redox and protecting group manipulations; 35 and ii) The overall cascade sequence enabled rapid complexity generation and good convergence, as 4 bonds, 2 rings and 2 stereocenters were formed from two comparably complex building blocks. 36 With the pentacyclic core of mitragynine pseudoindoxyl (3), two seemingly straightforward tasks remained: the installation of the methyl enol ether moiety onto the acetyl side chain and stereoselective reduction of the alkene. To this end, an -formylation protocol was adapted to our substrate; this protocol does not require preventive but only transient protection of the pseudoindoxyl NH.…”

Total Synthesis of (−)-Exiguolide, a Potent Anticancer Marine Macrolide

“…From a holistic point of view, it should be recalled that the longest linear sequence of a given synthesis can be considered as a function of multiple variables including the number of steps required to prepare each fragment and the number of steps necessitated after the point of convergence. 86 While all previous syntheses of exiguolide were based on convergent synthesis planning, most of them involved assembly of two fragments of largely different complexity for the construction of the macrocyclic skeleton and hence required a relatively longer linear sequence to access the fragment of greater complexity. Further advances in synthetic method development for short synthesis and straightforward assembly of polyketide fragments are of great importance in the field of macrolide synthesis.…”