Total Synthesis of (−)‐Salinosporamide A via a Late Stage C−H Insertion

The synthesis of (?)‐salinosporamide A, a proteasome inhibitor, is described. The synthesis highlights the assembly of a densely decorated pyrrolidinone core via an aza‐Payne/hydroamination sequence. Central to the success of the synthesis is a late‐stage C?H insertion reaction to functionalize a sterically encumbered secondary carbon. The latter functionalization leads to an enabling transformation where most of the prototypical strategies failed.     

A Concise Enantioselective Total Synthesis of (−)‐Virosaine A

The total synthesis of (−)‐virosaine A ( 1 ) was achieved in ten steps starting from furan and 2‐bromoacrolein. A one‐pot Diels–Alder cycloaddition/organolithium addition initiated an efficient sequence to access a key oxime/epoxide intermediate. Heating this intermediate in acetic acid resulted in an intramolecular epoxide opening/nitrone [3+2] cycloaddition cascade to construct the caged core of 1 in a single step. Several methods of C−H functionalization were assessed on the cascade product, and ultimately, a directed lithiation/bromination effected selective C14 functionalization, enabling the synthesis of 1 .     

Total Synthesis of (−)‐Himeradine A

(?)‐Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)‐fastigiatine. A 2,4,6‐trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst‐controlled Overman rearrangement. The piperidine segment was coupled in a B‐alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)‐fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one‐pot procedure. (?)‐Himeradine A was prepared in 17 steps in the longest linear sequence.     

Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

Total Synthesis of (−)‐Indoxamycins A and B

The concise total syntheses of (?)‐indoxamycins A and B is reported. The chemistry features a seven‐step preparation of a highly congested [5.5.6] tricyclic advanced common intermediate from a readily available R‐carvone derivative. Key steps involve a Pauson–Khand reaction for the rapid construction of a basic scaffold bearing a quaternary carbon, a copper‐catalyzed Michael addition for the introduction of another adjacent all‐carbon quaternary stereocenter, and a tandem retro‐oxa‐Michael addition/1,2‐addition/oxa‐Michael addition for the installation of a trisubstituted olefin side chain. This synthetic strategy allows for easy access to both enantiomers of this family of natural products and their analogues from cost‐effective starting material through straightforward chemical transformations.     

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

The bioactive Kopsia alkaloids lundurines A–D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (?)‐lundurine A has previously been achieved through a Simmons–Smith cyclopropanation strategy. Here, the total synthesis of (?)‐lundurine A was carried out using a metal‐catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of α‐diazo‐ carboxylates or cyanides, a one‐pot, copper‐catalyzed Bamford–Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.     

Enantioselective Total Synthesis of (−)‐Deoxoapodine

The first enantioselective total synthesis of (−)‐deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum‐catalyzed enantioselective ring‐closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5‐quaternary stereocenter. After C21‐oxygenation, the pentacyclic core was accessed by electrophilic C19‐amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6‐etherification reaction proved highly effective to secure the F‐ring and the fourth contiguous stereocenter of (−)‐deoxoapodine with complete stereochemical control.     

Total Synthesis of (±)‐Hippolachnin A

The first total synthesis of the marine polyketide (±)‐hippolachnin A has been achieved in nine linear steps and an overall yield of 9 %. Rapid access to the oxacyclobutapentalene core structure was secured by strategic application of an ene cyclization.     

Total Synthesis of Lactacystin and Salinosporamide A

Lactacystin and salinosporamide A are fascinating molecules with regard to both their chemical structures and biological activities. These naturally occurring compounds are potent and selective proteasome inhibitors. The molecular structures are characterized by their densely functionalized γ‐lactam cores. The structure and biological properties of these two compounds are attracting the attention of many chemists as challenging synthetic targets. We discuss their synthetic strategies in this review.     

Total Synthesis of (−)‐Salvinorin A

Salvinorin A ( 1 ) is natural hallucinogen that binds the human κ‐opioid receptor. A total synthesis has been developed that parlays the stereochemistry of l ‐(+)‐tartaric acid into that of (?)‐ 1 via an unprecedented allylic dithiane intramolecular Diels–Alder reaction to obtain the trans‐decalin scaffold. Tsuji allylation set the C9 quaternary center and a late‐stage stereoselective chiral ligand‐assisted addition of a 3‐titanium furan upon a C12 aldehyde/C17 methyl ester established the furanyl lactone moiety. The tartrate diol was finally converted into the C1,C2 keto‐acetate.