A Short Scalable Route to (−)‐α‐Kainic Acid Using Pt‐Catalyzed Direct Allylic Amination

An increased supply of scarce or inaccessible natural products is essential for the development of more sophisticated pharmaceutical agents and biological tools, and thus the development of atom‐economical, step‐economical and scalable processes to access these natural products is in high demand. Herein we report the development of a short, scalable total synthesis of (?)‐α‐kainic acid, a useful compound in neuropharmacology that is, however, limited in supply from natural resources. The synthesis features sequential platinum‐catalyzed direct allylic aminations and thermal ene‐cyclization, enabling the gram‐scale synthesis of (?)‐α‐kainic acid in six steps and 34 % overall yield.     

Total Syntheses of (−)‐Isoschizogamine and (−)‐2‐Hydroxyisoschizogamine

Total syntheses of (?)‐isoschizogamine and (?)‐2‐hydroxyisoschizogamine are described. The synthesis employs two asymmetric Michael additions to establish chiral centers at C7 and the quaternary carbon C20. Regioselective reduction of the methylthioiminium cation rather than the enamine generates an isoschizogamine‐type pentacyclic skeleton. Acidic hydrolysis of the isoschizogamine‐type intermediate in the absence of oxygen provides natural (?)‐isoschizogamine. Conducting the reaction in the presence of oxygen leads to a multistep oxidative hydrolysis cascade that affords unnatural (?)‐2‐hydroxyisoschizogamine.     

The Use of (−)‐Sparteine/Organolithium Reagents for the Enantioselective Lithiation of 7,8‐Dipropyltetrathia[7]helicene: Single and Double Kinetic Resolution Procedures

The effect of organolithium reagent (RLi: R=nBu, iPr, sBu, tBu), solvent (diethyl ether, diethyl ether/THF and MTBE), and stoichiometry on the (?)‐sparteine‐mediated silylation of 7,8‐dipropyltetrathia[7]helicene shows that, unusually, substantially more than 0.5 equivalent of RLi (R=iPr, sBu, tBu) and a large excess of (?)‐sparteine (R=nBu, sBu) is often needed to achieve substantial conversions and good ee values. With nBuLi, however, just one equivalent of the organolithium reagent is sufficient to obtain high conversions. Our best results were obtained using the convenient tBuLi/(?)‐sparteine adduct with which the need for a high (?)‐sparteine/RLi ratio can be avoided. Single‐ and double‐kinetic resolution (KR) procedures give enantiopure samples of 2‐trimethylsilyl‐ and 2,13‐di(trimethylsilyl)‐7,8‐dipropyltetrathia[7]helicene and two‐step double‐KR combining (?)‐sparteine/sBuLi and chiral formamides affords the synthetically valuable 2‐formyl‐7,8‐dipropyltetrathia[7]helicene. This is the first use of (?)‐sparteine for the enantioselective lithiation of helicenes and the first report of tBuLi outperforming sBuLi in a (?)‐sparteine‐mediated procedure.     

Divergent Total Syntheses of Enmein‐Type Natural Products: (−)‐Enmein, (−)‐Isodocarpin,and (−)‐Sculponin R

Divergent total syntheses of the enmein‐type natural products (?)‐enmein, (?)‐isodocarpin, and (?)‐sculponin R have been achieved in a concise fashion. Key features of the strategy include 1) an efficient early‐stage cage formation to control succeeding diastereoselectivity, 2) a one‐pot acylation/akylation/lactonization to construct the C‐ring and C8 quarternary center, 3) a reductive alkenylation approach to construct the enmain D/E rings and 4) a flexible route to allow divergent syntheses of three natural products.     

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.     

Enantiocontrolled Total Synthesis of (−)‐Mersicarpine

A racemic synthesis of mersicarpine ( 1 ) was achieved by the Mizoroki–Heck reaction and a DIBALH‐mediated reductive ring‐expansion reaction. Based on a first‐generation synthesis, a second‐generation enantiocontrolled total synthesis of (?)‐mersicarpine ( 1 ) was achieved by an 8‐pot/11‐step sequence in 21 % overall yield from commercially available 2‐ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d’Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six‐membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH‐mediated reductive ring‐expansion reaction, gradually increasing the reaction temperature and in situ‐protection of the nitrogen in an oxygen‐sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high‐yielding process. With these methodologies, the short‐step and efficient synthesis of (?)‐mersicarpine was accomplished. Several synthetic efforts are also described.     

(−)‐Sparteine copper(II) diacetate

The chiral nitrogen‐chelating alkaloid (?)‐sparteine acts as a bidentate ligand, reacting with copper(II) acetate in ethanol to form the title complex, [Cu(CH₃COO)₂(C₁₅H₂₆N₂)], with the two acetate groups occupying the remaining coordination sites in a monodentate fashion to produce a distorted four‐coordinate tetrahedral structure. The dihedral angle between the N—Cu—N and O—Cu—O planes is 45.8 (3)°.     

Concise Syntheses of bis‐Strychnos Alkaloids (−)‐Sungucine, (−)‐Isosungucine,and (−)‐Strychnogucine B from (−)‐Strychnine

The first chemical syntheses of complex, bis‐Strychnos alkaloids (?)‐sungucine ( 1 ), (?)‐isosungucine ( 2 ), and (?)‐strychnogucine B ( 3 ) from (?)‐strychnine ( 4 ) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N‐oxide; (2) a biomimetic Mannich coupling to forge the signature C23?C5′ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH₃CN‐mediated reduction to fashion the ethylidene moieties in 1 – 3 . DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.     

Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)‐Epiglobulol and (−)‐4β,7α‐ and (−)‐4α,7α‐Aromadendranediols

Three natural aromadendrane sesquiterpenes, (?)‐epiglobulol, (?)‐4β,7α‐aromadendranediol, and (?)‐4α,7α‐aromadendranediol, have been synthesized in only seven steps in 12, 15, and 17 % overall yields, respectively, from (E,E)‐farnesol by a stereodivergent gold(I)‐catalyzed cascade reaction which forms the tricyclic aromadendrane core in a single step. These are the shortest total syntheses of these natural compounds.     

Efficient Enantioselective Total Synthesis of (−)‐Horsfiline

A new efficient and concise enantioselective synthetic method for (?)‐horsfiline is reported. (?)‐Horsfiline could be obtained from diphenylmethyl tert‐butyl malonate in 9 steps (32 %,>99 % ee) by using the enantioselective phase‐transfer catalytic allylation (91 % ee) as the key step. This approach can be applied as a practical route for the large‐scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed.     

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.     

Total Syntheses of (−)‐Minovincine and (−)‐Aspidofractinine through a Sequence of Cascade Reactions

We report 8‐step syntheses of (?)‐minovincine and (?)‐aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta‐ and hexacyclic frameworks. These cascade transformations included organocatalytic Michael‐aldol condensation, a multistep anionic Michael‐S_N2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo‐ and regioselective transformations.     

Total Syntheses of (−)‐Strictosidine and Related Indole Alkaloid Glycosides

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α‐cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (?)‐strictosidine, which is an important intermediate in biosynthesis. This two‐step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (?)‐strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (?)‐strictosamide, (?)‐neonaucleoside A, (?)‐cymoside, and (?)‐3α‐dihydrocadambine.     

Catalytic Asymmetric Construction of α‐Quaternary Cyclopentanones and Its Application to the Syntheses of (−)‐1,14‐Herbertenediol and (−)‐Aphanorphine

A novel and efficient strategy to build α‐benzylic quaternary cyclopentanones with excellent enantioselectivities (up to 96 % ee) and high yields (up to 99 % yield) has been developed, and its application demonstrated by the first catalytic asymmetric total synthesis of (?)‐1,14‐herbertenediol and the formal synthesis of (?)‐aphanorphine.     

Total Synthesis of (−)‐Lithospermoside

The total synthesis of the naturally occurring noncyanogenic cyanoglucoside (?)‐lithospermoside ( 1 ) was achieved starting from optically pure oxatrinorbornenone (+)‐ 2 in 12 steps and 10% overall yield. The key step of the synthesis, the glycosidation, turned out to be very sensitive to steric hindrance, and we had, therefore, to optimize the choice of the protection used for the two other OH functions of the aglycone. Finally, the desired β‐D ‐glucoside 15 was obtained in a very good yield (72%) under Koenigs–Knorr‐glycosidation conditions, closely related to those used for the total synthesis of (?)‐bauhinin.     

Asymmetric [3+2] Annulation Approach to 3‐Pyrrolines: Concise Total Syntheses of (−)‐Supinidine, (−)‐Isoretronecanol,and (+)‐Elacomine

An asymmetric [3+2] annulation reaction to form 3‐pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4‐bromocrotonate is deprotonated and trapped with Ellman imines selectively at the α‐position to yield enantiopure 3‐pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (?)‐supinidine, (?)‐isoretronecanol, and (+)‐elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5‐dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza‐Darzens reaction can be realized.     

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.     

Scalable Enantioselective Total Synthesis of (−)‐Goniomitine

A scalable enantioselective total synthesis of (?)‐goniomitine has been developed by using an iridium‐catalyzed asymmetric hydrogenation of an exocyclic enone ester to control the configuration of the molecule. The synthesis begins from commercially available starting materials, and proceeds through an integrated asymmetric ketone hydrogenation, Johnson–Claisen rearrangement, and one‐pot oxidation/deprotection/cyclization process. With this highly efficient and scalable strategy, (?)‐goniomitine was synthesized in eleven steps with 27 % overall yield, and formal enantioselective syntheses of (+)‐1,2‐dehydroaspidospermidine, (+)‐aspidospermidine, and (+)‐vincadifformine were also achieved.     

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.     

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.