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.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

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.     

A Cascade Strategy Enables a Total Synthesis of (−)‐Gephyrotoxin

A concise and efficient synthesis of (?)‐gephyrotoxin from L ‐pyroglutaminol has been realized. The key step in this approach is a diastereoselective intramolecular enamine/Michael cascade reaction that forms two rings and two stereocenters and generates a stable tricyclic iminium cation. A hydroxy‐directed reduction of this intermediate plays a key role in establishing the required cis‐decahydroquinoline ring system, enabling the total synthesis of (?)‐gephyrotoxin in nine steps and 14 % overall yield. The absolute configuration of the synthetic material was confirmed by single‐crystal X‐ray diffraction and is consistent with the structure originally proposed for material isolated from the natural source.     

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (?)‐stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (?)‐stenine, an asymmetric synthesis of 9a‐epi‐stenine was also executed. The C(9a) stereocenter in 9a‐epi‐stenine was installed by using a Staudinger/aza‐Wittig reaction of a keto–azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.     

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.     

Indole‐Diterpene Synthetic Studies: Total Synthesis of (−)‐21‐Isopentenylpaxilline

An efficient, stereocontrolled total synthesis of the complex indole‐diterpene alkaloid (?)‐21‐isopentenylpaxilline ( 1 ) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (?)‐ 68 , involving a highly efficient union of the eastern and western fragments (?)‐ 68 and 5 exploiting our 2‐substituted indole synthesis, application of the Negishi π cycloalkylation tactic as a new, potentially general protocol for the construction of ring C, and the fragmentation of a β,γ‐epoxy ketone to introduce the tertiary OH group at C(13) in the indole diterpene skeleton.     

Asymmetric Total Synthesis of Propindilactone G,Part 2: Enantioselective Construction of the Fully Functionalized BCDE Ring System

The enantioselective synthesis of the fully functionalized BCDE tetracyclic ring system of propindilactone G ( A ) is reported. Several synthetic methods were developed and applied to achieve this goal, including: 1) an asymmetric Diels–Alder reaction in the presence of Hayashi′s catalyst for the synthesis of optically pure key intermediate 3 ; 2) an intramolecular Pauson–Khand reaction (PKR) for the stereoselective synthesis of the BCDE ring with an all‐carbon chiral quaternary center at the C13 position by using the TMS‐substituted acetylene as the substrate; and 3) Pd‐catalyzed reductive hydrogenolysis for the stereoselective synthesis of the fully functionalized BCDE tetracyclic ring system. The chemistry developed herein provided a greater understanding of the total synthesis propindilactone G ( A ) and its analogues.     

Formal Synthesis of Sarain A: Intramolecular Cycloaddition of an Eight‐Membered Cyclic Nitrone to Construct the 2‐Azabicyclo[3.3.1]nonane Framework

An enantioselective route to the tetracyclic skeleton of sarain A has been developed. Asymmetric reduction of an ynone introduced a chiral center which was transferred to the contiguous tertiary stereogenic centers through an Ireland–Claisen rearrangement. The 2‐azabicyclo[3.3.1]nonane framework was constructed by an unprecedented intramolecular cycloaddition of an eight‐membered cyclic nitrone. Using the steric bias of the bicyclic system, the quaternary carbon atom was constructed by a stereoselective aldol reaction. Further ring formations were performed by ring‐closing metathesis for the 13‐membered ring and an iodoamidation reaction for the pyrrolidine ring. The present synthesis has successfully provided an alternative route to the late‐stage intermediate of Overman’s synthesis.     

Total Syntheses of Crinipellins Enabled by Cobalt‐Mediated and Palladium‐Catalyzed Intramolecular Pauson–Khand Reactions

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (?)‐crinipellin A and (?)‐crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium‐catalyzed Pauson–Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.     

Total Synthesis of (±)‐Waihoensene

The first total synthesis of waihoensene, a tetracyclic diterpene containing an angular triquinane and a six‐membered ring, with four contiguous quaternary carbon atoms, was achieved through the tandem cycloaddition reaction of an allenyl diazo substrate containing a six‐membered ring via trimethylenemethane (TMM) diyl intermediate.     

Asymmetric Chemoenzymatic Synthesis of (−)‐Podophyllotoxin and Related Aryltetralin Lignans

(?)‐Podophyllotoxin is one of the most potent microtubule depolymerizing agents and has served as an important lead compound in antineoplastic drug discovery. Reported here is a short chemoenzymatic total synthesis of (?)‐podophyllotoxin and related aryltetralin lignans. Vital to this approach is the use of an enzymatic oxidative C?C coupling reaction to construct the tetracyclic core of the natural product in a diastereoselective fashion. This strategy allows gram‐scale access to (?)‐deoxypodophyllotoxin and is readily adaptable to the preparation of related aryltetralin lignans.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

Formal Total Synthesis of (−)‐Taxol through Pd‐Catalyzed Eight‐Membered Carbocyclic Ring Formation

A formal total synthesis of (?)‐taxol by a convergent approach utilizing Pd‐catalyzed intramolecular alkenylation is described. Formation of the eight‐membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd‐catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd‐catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd‐catalyzed reaction.     

Total Synthesis,Stereochemical Reassignment,and Biological Evaluation of (−)‐Lyngbyaloside B

(?)‐Lyngbyaloside B is a 14‐membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co‐workers. The first total synthesis of (?)‐lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko–Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.     

Aza‐Quaternary Scaffolds from Selective Bond Cleavage of Bridgehead‐Substituted 7‐Azabicyclo[2.2.1]heptane: Total Synthesis of (+)‐Cylindricines C–E and (−)‐Lepadiformine A

A novel bridgehead‐substituted aza‐bicyclic framework has been designed and developed in both enantiomeric forms through an asymmetric desymmetrization reaction. Strategic exploitation of the ring strain in the aza‐bicyclic framework has been utilized for the construction of the chiral aza‐quaterenary scaffolds by selective bond fragmentation processes. Furthermore, a strategically designed precursor is employed for selective bond cleavage to initiate a cascade rearrangement for the total synthesis of the 1‐azaspirotricyclic marine alkaloids (+)‐cylindricines C, D, and E, as well as (?)‐lepadiformine A. An oxidation/retro‐aldol/aza‐Michael sequence generated three new chiral centers with the required configuration in one pot.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Catalytic Asymmetric Total Synthesis of (−)‐Galanthamine and (−)‐Lycoramine

The catalytic asymmetric total syntheses of (?)‐galanthamine ( 1 ) and (?)‐lycoramine ( 2 ) have been achieved by using a conceptually new strategy featuring two metal‐catalyzed reactions as the key steps. A new method for the construction of 3,4‐fused benzofurans has been developed through a palladium‐catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2 . To achieve the asymmetric synthesis of 1 and 2 , a Sc^III/N,N′‐dioxide complex was used to catalyze the enantioselective conjugate addition of 3‐alkyl‐substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.     

A Synthetic Approach for Constructing the 3/6/6/5‐Fused Tetracyclic Skeleton of Tenuipesine A

An efficient approach toward the 3/6/6/5‐fused tetracyclic skeleton of tenuipesine A has been accomplished. The strategy featured 1) a tandem Mitsunobu and 3,3‐rearrangement reaction yielding the key intermediate 7 with two adjacent all‐carbon quaternary centers with high d.r.; and 2) a tandem DBDMH‐mediated semipinacol rearrangement via a 1,2‐oxygen migration of an allylic hemiketal to construct the highly substituted tetrahydropyran ring.