Modular, Enantioselective Entry into Polysubstituted Shapeshifting Molecules.

Dynamic, shapeshifting hydrocarbons have emerged as enabling frameworks across drug discovery, materials science, and catalysis. Their employment, however, is often hampered by a lack of efficient synthetic methods for their preparation. Herein, we report a unified, concise, and modular synthesis of enantioenriched shapeshifting hydrocarbons (barbaralones and bullvalones) and multisubstituted bullvalenes, leveraging mild photochemical and base-induced rearrangements.

Indole C5-Selective Bromination of Indolo[2,3-a]quinolizidine Alkaloids via In Situ-Generated Indoline Intermediate.

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5-selective bromination of indolo[2,3-a]quinolizidine alkaloids by adding nearly equimolar amounts of Br3 ⋅ PyH and HCl in MeOH. The resulting reaction plausibly proceeds through an indoline intermediate by the nucleophilic addition of MeOH to the C3-brominated indolenine intermediate. Data support the intermediacy of a C3-, C5-dibrominated indolenine intermediate as a brominating agent. These conditions demonstrate excellent selectivity for indole C5 bromination of natural products and their derivatives. Thus, these simple, mild, and metal-free conditions allow for selective, late-stage bromination followed by further chemical modifications. The utility of the brominated product prepared from naturally occurring yohimbine was demonstrated through various derivatizations, including a bioinspired heterodimerization reaction.

Total Syntheses of (+)-Villocarine A, (-)-Apogeissoschizine, and (+)-Geissoschizine.

Total syntheses of geissoschizine-type monoterpenoid indole alkaloids (MTIAs) are reported. An intramolecular Pictet-Spengler cyclization was developed for the selective construction of the 3R stereocenter. The first total synthesis of (+)-villocarine A was then achieved. Furthermore, the first total synthesis of the highly strained (-)-apogeissoschizine was also accomplished in an aza-Michael cyclization/E1cB elimination/stereoselective olefin isomerization sequence. Finally, (+)-geissoschizine, a common biosynthetic intermediate of MTIAs, was obtained from apogeissoschizine through ring-opening along with a release of ring strain.

Bioinspired Transformations Using Strictosidine Aglycones: Divergent Total Syntheses of Monoterpenoid Indole Alkaloids in the Early Stage of Biosynthesis.

A series of bioinspired transformations that are applied to convert strictosidine aglycones into monoterpenoid indole alkaloids is reported. The highly reactive key intermediates, strictosidine aglycones, were prepared in situ by simple removal of a silyl protecting group from the silyl ether derivatives, and converted selectively via bioinspired transformations under substrate control into heteroyohimbine- and corynantheine-type, and akagerine and naucleaoral related alkaloids. Thus, concise, divergent total syntheses of 13 monoterpenoid indole alkaloids, (-)-cathenamine, (-)-tetrahydroalstonine, (+)-dihydrocorynantheine, (-)-corynantheidine, (-)-akagerine, (-)-dihydrocycloakagerine, (-)-naucleaoral B, (+)-naucleidinal, (-)-naucleofficines D and III, (-)-nauclefiline, and (-)-naucleamides A and E, were accomplished in fewer than 13 steps.

Asymmetric Total Syntheses of Mitragynine, Speciogynine, and 7-Hydroxymitragynine.

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in >11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.

Secorubenine, a Monoterpenoid Indole Alkaloid Glycoside from Adina rubescens: Isolation, Structure Elucidation, and Enantioselective Total Synthesis.

A new pentacyclic monoterpenoid indole alkaloid glycoside named secorubenine (1) was isolated from the heartwood of Adina rubescens, collected in Indonesia. The structure was elucidated by spectroscopic analysis and chemical modification of isolated secorubenine (1). The bioinspired enantioselective total synthesis of 1 was accomplished in 12 steps, whereafter its structure was determined and the absolute stereochemistry was confirmed.

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.

Total Syntheses of (-)-Secologanin, (-)-5-Carboxystrictosidine, and (-)-Rubenine.

The first enantioselective total syntheses of (-)-secologanin (1), (-)-5-carboxystrictosidine (2), and (-)-rubenine (3) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate (16), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram-scale in seven steps. The total syntheses of 2 and 3, which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet-Spengler reaction, a site- and stereoselective epoxidation, and a site-selective epoxide ring-opening followed by a lactonization reaction.

Divergent Total Syntheses of Hetero-Oligomeric Iridoid Glycosides.

Divergent total syntheses of the hetero-oligomeric iridoid glycosides mainly found in Dipsacus asper were achieved. Thus, loganin (1), which is important as a monomer unit, was efficiently synthesized by stereoselective reductive cyclization using secologanin (2) as a substrate. Sequential condensation reactions of derivatives of 1 and 2 as monomer units led to the first enantioselective total syntheses of the heterooligomers cantleyoside, (E)-aldosecologanin, dipsaperine, (3R, 5S)-5-carboxyvincosidic acid 22-loganin ester, and dipsanoside A.