Asymmetric Total Synthesis of Heronamides A–C: Stereochemical Confirmation and Impact of Long‐Range Stereochemical Communication on the Biological Activity

Heronamides are biosynthetically related metabolites isolated from marine‐derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as‐yet‐unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure–activity relationship of synthetic and natural heronamides revealed the importance of both long‐range stereochemical communication and the 20‐membered macrolactam ring for the biological activity of these compounds.     

Asymmetric catalytic synthesis of the proposed structure of trocheliophorolide B

A concise catalytic asymmetric synthesis of the proposed structure of trocheliophorolide B is reported. The synthetic sequence notably features an asymmetric acetaldehyde alkynylation, a Ru-catalyzed alder-ene reaction, and a Zn-ProPhenol ynone aldol condensation. Comparison with the reported data suggests a misassignment of the natural product structure.     

Asymmetric Total Synthesis of Propindilactone G,Part 3: The Final Phase and Completion of the Synthesis

Two independent synthetic approaches were evaluated for the final phase of the asymmetric total synthesis of propindilactone G ( 1 ). The key steps that led to the completion of the asymmetric total synthesis included: 1) an intermolecular oxidative heterocoupling reaction of enolsilanes to link the core structure to the side chain; 2) an intermolecular Wittig reaction for the formation of the α,β,γ,δ‐unsaturated ester; and 3) a regio‐ and stereoselective OsO₄‐catalyzed dihydroxylation of an α,β,γ,δ‐unsaturated enone, followed by an intramolecular lactonization reaction to afford the final product. These reactions enabled the synthesis of (+)‐propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)‐propindilactone G has been revised. Furthermore, the direct oxidative coupling strategy for ligation of the core of propindilactone G with its side chain may find application in the syntheses of other natural products and complex molecules.     

Total synthesis of the proposed structure of xylarolide

A total synthesis of a proposed structure of xylarolide is described. The key features of the synthesis include Sharpless asymmetric reaction, Wittig olefination, Sharpless asymmetric dihydroxylation, Still-Gennari olefination and Yamaguchi lactonization. The differences in the spectroscopic data of the synthetic and natural product indicate a revision of the assigned structure.     

Total synthesis of the proposed structure of aldingenin B

The first enantioselective total synthesis of the proposed structure of aldingenin B is reported in 16 steps from known compounds. The stereochemistry at C5 and C6 were established by an asymmetric acetal aldol. Following a ring-closing metathesis, a selective, substrate-controlled hydrogen bond-mediated dihydroxylation provided control of the C2 and C3 stereocenters. Discrepancies in the spectroscopic data of the synthetic and natural material led to the conclusion that the structure of the natural sample was misassigned.     

Stereoselective synthesis of the published structure of feigrisolide A. Structural revision of feigrisolides A and B

The total synthesis of the proposed structure of feigrisolide A is reported. Ethyl (S)-3-hydroxybutyrate was the chiral starting material. A Brown asymmetric allylation and an Evans aldol reaction were key steps of the synthesis. The NMR data of the synthetic product are different from those of the natural product. The published structure of feigrisolide A is therefore erroneous. A subsequent comparison of spectral data strongly suggests that feigrisolides A and B are identical with (-)-nonactic acid and (+)-homononactic acid, respectively.     

Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (−)‐Chaetominine and Its Biosynthetic Implications

The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (?)‐chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio‐inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.     

Synthesis of the putative structure of eupomatilone-6

[reaction: see text] The synthesis of eupomatilone-6 (1) has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular Horner-Wadsworth-Emmons reactions. The spectroscopic studies carried out on synthetic eupomatilone-6 do not agree with those reported for the natural product, and therefore revision of the assigned structure is warranted.     

Total Syntheses of (−)‐Huperzine Q and (+)‐Lycopladines B and C

Utilizing a late‐stage enamine bromofunctionalization strategy, the twelve‐step total synthesis of (?)‐huperzine Q was accomplished. Furthermore, the first total syntheses of (+)‐lycopladines B and C are described. An unprecedented X‐ray crystal structure of an unusual epoxyamine intermediate is also reported, and the synthetic application of this intermediate in natural product synthesis is demonstrated.     

A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)‐Norleucosceptroid A, (−)‐Norleucosceptroid B,and (−)‐Leucosceptroid K

The first asymmetric total synthesis of the antifeedant terpenoids (+)‐norleucosceptroid A, (−)‐norleucosceptroid B, and (−)‐leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser–Kraus‐type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol‐type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.     

Efficient Enantioselective Syntheses of Chiral Natural Products Facilitated by Ligand Design

The employment of enantioselective transition‐metal‐catalyzed transformations as key steps in asymmetric natural product syntheses have attracted considerable attention in recent years owing to their versatile synthetic utilities, mild conditions and high efficiency in chirality generation. The chiral catalysts or supporting ligands are believed to be crucial for the requisite reactivity and enantioselectivity. Therefore, the rational design of chiral ligands is at the heart of developing new asymmetric transition‐metal catalyzed reactions and provides an avenue to the asymmetric synthesis of natural products. Our group has been engaged in the development of transition‐metal‐catalyzed enantioselective cross‐coupling, cyclization and other related reactions and the application of these methodologies to natural product syntheses. In this account, we summarized our recent synthetic efforts towards the efficient total syntheses of several different types of natural products including terpenes, alkaloids and polyketides facilitated by the design of a series of versatile P‐chiral phosphorous ligands.     

A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)‐Norleucosceptroid A, (−)‐Norleucosceptroid B,and (−)‐Leucosceptroid K

The first asymmetric total synthesis of the antifeedant terpenoids (+)‐norleucosceptroid A, (?)‐norleucosceptroid B, and (?)‐leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser–Kraus‐type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol‐type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.     

A Stereoselective Switch: Enantiodivergent Approach to the Synthesis of Isoflavanones

A modular six‐step asymmetric synthesis of two naturally occurring and three non‐natural isoflavanones containing tertiary α‐aryl carbonyls is reported. This synthetic route, utilising a Pd‐catalyzed decarboxylative asymmetric protonation, produces isoflavanones in excellent enantioselectivities from 76–97 %. A switch in the sense of stereoinduction was observed when different H⁺ sources were employed, showing the first example of dual stereocontrol in an asymmetric protonation reaction. The first enantioselective synthesis of the naturally occurring isoflavanones sativanone and 3‐o‐methylviolanone has been accomplished.     

Total Synthesis of the Proposed Structure of Ardimerin,and Proposal for its Structural Revision

We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.     

Total Synthesis of Rubriflordilactone B

Taking advantage of a 6π electrocyclization–aromatization strategy, we accomplished the first and asymmetric total synthesis of rubriflordilactone B, a heptacyclic Schisandraceae bisnortriterpenoid featuring a tetrasubstituted arene moiety. The left‐hand fragment was accessed through a chiral‐pool‐based route, and linked to the right‐hand fragment by a Sonogashira coupling. The cis geometry of the electrocyclization substrates was established by hydrogenation or hydrosilylation of the alkyne. An electrocyclization–aromatization sequence finally built the multisubstituted arene. The hydrosilylation approach was of significant advantage in terms of reaction scale, reproducibility, and intermediate stability. The structure of synthetic rubriflordilactone B was validated by X‐ray crystallographic analysis, and found to be consistent with that reported for the authentic natural product based on an independent X‐ray crystallographic analysis. However, obvious differences in the NMR spectra of the synthetic and authentic samples suggest that the authentic samples subjected to X‐ray crystallography and NMR spectroscopy were two different compounds.     

Catalytic asymmetric reactions in alkaloid and terpenoid syntheses

Catalytic asymmetric induction is one of the most important methods in current synthetic organic chemistry for designing efficient and attractive synthetic routes. The efficient total synthesis of a natural product can be achieved through the identification of appropriate method and strategy. This Letter introduces the catalytic asymmetric syntheses of alkaloids and terpenoids based on an overview of four recently reported types of asymmetric reaction: (1) asymmetric decarboxylative allylation, (2) organocatalytic cascade reaction, (3) polyene cyclization, and (4) asymmetric [2+2]-photocycloaddition catalyzed by a chiral Lewis acid.     

Enantioselective Biomimetic Total Syntheses of Kuwanons I and J and Brosimones A and B

The first enantioselective total syntheses of prenylflavonoid Diels–Alder natural products (?)‐kuwanon I, (+)‐kuwanon J, (?)‐brosimone A, and (?)‐brosimone B have been accomplished from a common intermediate based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis‐inspired asymmetric Diels–Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable tandem inter‐/intramolecular asymmetric Diels–Alder cycloaddition process was applied for the synthesis of (?)‐brosimone A.     

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

The Friedel‐Crafts alkylation (F‐CA) reaction is a special kind of carbon?carbon bond formations, which is frequently being used for the formation of such bond in some aromatic rings in organic synthesis. Its asymmetric variant gives enantiorich products. Commonly, an in situ organocatalyzed asymmetric Friedel‐Crafts alkylation (AF‐CA) proceeds via generation of an enamine as an intermediate. The organocatalyzed‐AF‐CA was discovered and established in the mid‐1980s and reviewed comprehensively in 2010. In this report, we are trying to update the applications of novel organocatalysts in the AF‐CA as a versatile synthetic strategy, which is frequently used in the effective asymmetric synthesis of complex molecules, pharmaceutically important compounds and most importantly in the total synthesis of biologically active natural products.     

Short,Enantioselective Total Synthesis of Chatancin

An enantioselective total synthesis of the polycyclic diterpene (+)‐chatancin, a potent PAF antagonist, is reported. Proceeding in seven steps from dihydrofarnesal, this synthetic route was designed to circumvent macrocyclization‐based strategies to complex, cyclized cembranoids. The described synthesis requires only six chromatographic purifications, is high yielding, and avoids protecting‐group manipulations. An X‐ray crystal structure of this fragile marine natural product was obtained.     

Short,Enantioselective Total Synthesis of Chatancin

An enantioselective total synthesis of the polycyclic diterpene (+)‐chatancin, a potent PAF antagonist, is reported. Proceeding in seven steps from dihydrofarnesal, this synthetic route was designed to circumvent macrocyclization‐based strategies to complex, cyclized cembranoids. The described synthesis requires only six chromatographic purifications, is high yielding, and avoids protecting‐group manipulations. An X‐ray crystal structure of this fragile marine natural product was obtained.