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.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin,and (−)‐Pavidolide B: A Divergent Approach

A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (?)‐3‐oxochatancin, and (?)‐pavidolide B, has been developed, and it also led to the structural revision of (?)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.     

Total Synthesis of (−)‐Caprazamycin A

Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features a) the scalable preparation of the syn‐β‐hydroxy amino acid with a thiourea‐catalyzed diastereoselective aldol reaction, b) construction of a diazepanone with an unstable fatty‐acid side chain, and c) global deprotection with hydrogenation. This report provides a route for the synthesis of related liponucleoside antibiotics with fatty‐acid side chains.     

Enantioselective Total Synthesis of (−)‐Lansai B and (+)‐Nocardioazines A and B

The concise total syntheses of the bis(pyrroloindolines) (?)‐lansai B and (+)‐ nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)‐nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation.     

Total Synthesis of (−)‐Amphidinolide K

Macrolide magic : An enyne cross‐metathesis reaction of an alkynyl boronate with an alkene derivative as well as a radical cyclization reaction of a homopropargylic β‐alkoxyacrylate are the key transformations in the total synthesis of the cytotoxic macrolide (?)‐amphidinolide K.

     

Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (−)‐Nitidasin

Astellatol and nitidasin belong to a subset of sesterterpenoids that share a sterically encumbered trans‐hydrindane motif with an isopropyl substituent. In addition, these natural products feature intriguing polycyclic ring systems, posing significant challenges for chemical synthesis. Herein, the evolution of our stereoselective strategy for isopropyl trans‐hydrindane sesterterpenoids is detailed. These endeavors included the synthesis of several building blocks, enabling studies toward all molecules of this terpenoid subclass, and of advanced intermediates of our initial route toward a biomimetic synthesis of astellatol. These findings provided the basis for a second‐generation and a third‐generation approach toward astellatol that eventually culminated in the enantioselective total synthesis of (?)‐nitidasin. In particular, a series of substrate‐controlled transformations to install the ten stereogenic centers of the target molecule was orchestrated and the carbocyclic backbone was forged in a convergent fashion. Furthermore, the progress toward the synthesis of astellatol is disclosed and insights into some observed yet unexpected diastereoselectivities by detailed quantum‐mechanical calculations are provided.     

Total Synthesis of (−)‐Enigmazole A

Total synthesis of (?)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone.     

Bioinspired Total Syntheses of Isospongian‐type Diterpenoids (−)‐Kravanhins A and C

The first bioinspired total syntheses of (?) kravanhins A and C were accomplished from a labdane diterpenoid derivative. The key reactions involve a photooxidation and a one‐pot sequential aldol cyclization and lactonization, which provide a new plausible biosynthetic pathway for the kravanhins and other symbiotic members.     

Protecting‐Group‐Free Enantioselective Synthesis of (−)‐Pallavicinin and (+)‐Neopallavicinin

The first enantioselective synthesis of (?)‐pallavicinin and (+)‐neopallavicinin has been achieved in 15 steps. The described synthesis avoids protecting‐group manipulations by synthesis designs predicated on highly chemo‐ and stereoselective transformations. Highlights of the synthesis include a palladium‐catalyzed enantioselective decarboxylative allylation to form the chiral all‐carbon quaternary stereocenter, a palladium‐catalyzed oxidative cyclization to assemble the [3.2.1]‐bicyclic moiety, and an unprecedented LiBHEt₃‐induced fragmentation/protonation of an α‐hydroxy epoxide to form the α‐furan ketone with the desired configuration.     

Total Synthesis of (−)‐Nakadomarin A

A highly efficient 12‐step synthesis of the marine alkaloid (?)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (?)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.     

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.     

Organocatalytic,Asymmetric Total Synthesis of (−)‐Haliclonin A

The first total synthesis of the alkaloid (?)‐haliclonin A is reported. The asymmetric synthesis relied on a novel organocatalytic asymmetric conjugate addition of nitromethane with 3‐alkenyl cyclohex‐2‐enone to set the stereochemistry of the all‐carbon quaternary stereogenic center. The synthesis also features a Pd‐promoted cyclization to form the 3‐azabicyclo[3,3,1]nonane core, a SmI₂‐mediated intermolecular reductive coupling of enone with aldehyde to form the requisite secondary chiral alcohol, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocyclic ring systems, and an unprecedented direct transformation of enol into enone.     

Biomimetic Total Syntheses of (−)‐Leucoridines A and C through the Dimerization of (−)‐Dihydrovalparicine

Concise biomimetic syntheses of the Strychnos‐Strychnos‐type bis‐indole alkaloids (?)‐leucoridine A ( 1 ) and C ( 2 ) were accomplished through the biomimetic dimerization of (?)‐dihydrovalparicine ( 3 ). En route to 3 , the known alkaloids (+)‐geissoschizoline ( 8 ) and (?)‐dehydrogeissoschizoline ( 10 ) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza‐Michael/spirocyclization sequence over the alternate hetero‐Diels–Alder cycloaddition reaction.     

Asymmetric Total Synthesis of (−)‐Kravanhin B

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)‐(?)‐carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis‐fused decalin skeleton and an acid‐catalyzed dehydration and olefin isomerization to install the γ‐butenolide ring.     

Total Synthesis of (+)‐ and (±)‐Hosieine A

Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold‐catalyzed Rautenstrauch reaction.