The Total Synthesis of (−)‐Nitidasin

Nitidasin is a pentacyclic sesterterpenoid with a rare 5‐8‐6‐5 carbon skeleton that was isolated from the Peruvian folk medicine “Hercampuri”. It belongs to a small class of sesterterpenoids that feature an isopropyl trans‐hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans‐hydrindanone, followed by chemoselective epoxidation, ring‐closing olefin metathesis, and redox adjustment.     

Enantioselective Total Synthesis of (−)‐Hosieine A

The first total synthesis of (?)‐hosieine A was accomplished and features an unprecedented nitroso–ene cyclization to construct the 2‐azabicyclo[3.2.1]octane ring system. Phosphine‐enabled stereoselective bromohydrination provided interesting mechanistic insights into the anti‐Markovnikov process. Also noteworthy is the retention of stereochemistry at C9 in the facile radical debromination initiated by Et₃B/air.     

Total Synthesis and Biological Evaluation of (+)‐Neopeltolide and Its Analogues

The stereocontrolled total synthesis of the originally proposed ( 1 ) and correct ( 2 ) structures of (+)‐neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki–Miyaura coupling/ring‐closing metathesis strategy. Alkylborate 44 , which was generated in situ from iodide 34 , was coupled with enol phosphate 8 by a Suzuki–Miyaura coupling. Ring‐closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34 . Our convergent strategy enabled us to construct the 14‐membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure–activity relationships of 2 , led to the discovery of a structurally simple yet potent cytotoxic analogue, 9‐demethylneopeltolide ( 54 ).     

Total Syntheses and In Vivo Quantitation of Novel Neurofuran and Dihomo‐isofuran Derived from Docosahexaenoic Acid and Adrenic Acid

Neurofurans (NeuroFs) and dihomo‐isofurans (dihomo‐IsoFs) are produced in vivo by non‐enzymatic free‐radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo‐isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo‐IsoFs in biological samples was attainable.     

Oxidative Decarboxylation of Short‐Chain Fatty Acids to 1‐Alkenes

The enzymatic oxidative decarboxylation of linear short‐chain fatty acids (C4:0–C9:0) employing the P450 monooxygenase OleT, O₂ as the oxidant, and NAD(P)H as the electron donor gave the corresponding terminal C₃ to C₈ alkenes with product titers of up to 0.93 g L^?1 and TTNs of >2000. Key to this process was the construction of an efficient electron‐transfer chain employing putidaredoxin CamAB in combination with NAD(P)H recycling at the expense of glucose, formate, or phosphite. This system allows for the biocatalytic production of industrially important 1‐alkenes, such as propene and 1‐octene, from renewable resources for the first time.     

Practical Route to the Left Wing of CTX1B and Total Syntheses of CTX1B and 54‐deoxyCTX1B

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant‐sensitive bisallylic ether moiety, by a 6‐exo radical cyclization/ring‐closing metathesis strategy. This new route enabled us to achieve the second‐generation total synthesis of CTX1B and the first synthesis of 54‐deoxyCTX1B.     

Asymmetric Total Synthesis of (−)‐Cladospolide B

An enantioselective total synthesis of (?)‐cladospolide B was described. The key steps in this synthesis include(a) a Sharpless asymmetric dihydroxylation to elaborate syn diol at C‐4 and C‐5 positions; (b) a Mitsunobu esterification to reverse the configuration at C‐11 from (S) to (R); and (c) a ring‐closing metathesis to access the 12‐membered macrocyclic ring.     

An Unexpected Transannular [4+2] Cycloaddition during the Total Synthesis of (+)‐Norcembrene 5

We report a concise and versatile total synthesis of the diterpenoid (+)‐norcembrene 5 from simple building blocks. Ring‐closing metathesis and an auxiliary‐directed 1,4‐addition are the key steps of our synthetic route. During the synthesis, an unprecedented, highly oxidized pentacyclic structural motif was established from a furanocembranoid through transannular [4+2] cycloaddition.     

Enantiospecific Total Synthesis of (−)‐Bengamide E

Total synthesis of the polyhydroxy caprolactam amide natural product, bengamide E, is accomplished starting from tartaric acid. Key reactions in the synthesis include desymmetrization of the bis(dimethylamide) unit of tartaric acid, Zn(BH₄)₂‐mediated anti‐selective reduction, and a Horner–Wadsworth–Emmons olefination.     

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

The asymmetric synthesis of dragmacidin D ( 1 ) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C₂‐symmetric tetramine and lithium N‐(trimethylsilyl)‐tert‐butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.