Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)‐Limaspermidine and (+)‐Kopsihainanine A

Enantioselective Pd‐catalyzed allylic alkylations of dihydropyrido[1,2‐a ]indolone (DHPI) substrates were used to construct the C20‐quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet–Spengler and Bischler–Napieralski cyclization/reduction cascades furnish the cis‐ and trans ‐fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)‐limaspermidine and (+)‐kopsihainanine A.     

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.     

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.     

Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A

A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A ( 1 ), which features a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps by making use of a late‐stage visible‐light‐mediated Schenck ene reaction of (?)‐1α,6α‐diacetoxyjungermannenone C ( 2 ). Along the way, a UV‐light‐induced bicyclo[3.2.1]octene ring rearrangement afforded (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one ( 4 ). These divergent photo‐induced skeletal rearrangements support a possible biogenetic relationship between (+)‐ 1 , (?)‐ 2 , and (+)‐ 4 .     

β‐Ketoesters as Mono‐ or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (−)‐Englerin A and B

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring‐group‐participating [4+3] cycloaddition, a novel one‐pot Heck coupling/regioselective 1,4‐hydrosilylation/Tamao–Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (?)‐englerin B.     

Asymmetric Total Synthesis of (+)‐Neooxazolomycin Using a Chirality‐Transfer Strategy

The total synthesis of (+)‐neooxazolomycin was achieved from the amino‐acid d ‐serine. The efficiency of this approach is derived from the use of principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of a serine derivative to build the densely functionalized lactam framework and to install three contiguous stereocenters. The key intermediate was readily elaborated to the target natural product.     

Total Synthesis of (−)‐Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction

Stereoselective total syntheses of (−)‐histrionicotoxin and (−)‐histrionicotoxin 235A are described. The 1‐azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation–cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (−)‐histrionicotoxin 235A through a one‐pot partial‐reduction–allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3‐amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (−)‐histrionicotoxin.     

Enantioselective Total Syntheses of (−)‐Rhazinilam, (−)‐Leucomidine B,and (+)‐Leuconodine F

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd‐catalyzed decarboxylative cross‐coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7 , respectively. The former was converted into (−)‐rhazinilam, while the latter was converted into (−)‐leucomidine B and (+)‐leuconodine F. A substrate‐directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self‐induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.     

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.     

Exploration of a Chiral Cobalt Catalyst for Visible‐Light‐Induced Enantioselective Radical Conjugate Addition

Chiral catalysts tolerating photochemical reactions are in great demand for the vast development of visible‐light‐induced asymmetric synthesis. Now, chiral octahedral complexes based on earth‐abundant metal and chiral N₄ ligands are reported. One well‐defined chiral Co^II‐complex is shown to be an efficient catalyst in the visible‐light‐induced conjugated addition of enones by alkyl and acyl radicals, providing synthetically valued chiral ketones and 1,4‐dicarbonyls in 47–>99 % yields with up to 97:3 e.r.