Migratory Hydroamination: A Facile Enantioselective Synthesis of Benzomorphans

We describe a highly efficient, general strategy for the enantioselective synthesis of benzomorphans (45−46% overall yield from commercially available material). The new synthesis demonstrates the effectiveness of an unprecedented diastereoselective cycloisomerization via migratory hydroamination and the power of palladium-catalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates in the context of complex synthesis. The strategy outlined here for the enantioselective synthesis of three contiguous stereogenic centers and the novel cycloisomerization should have many applications in alkaloid synthesis

Synthesis of Functionalized Cyclohexenone Core of Welwitindolinones via Rhodium-Catalyzed [5 + 1] Cycloaddition

The cyclohexenone core of welwitindolinones was synthesized by a Rh(I)-catalyzed [5 + 1]-cycloaddition of an allenylcyclopropane with CO. A pentasubstituted cyclopropane was prepared successfully by a Rh(II)-catalyzed intramolecular cyclopropanation of alkenes with chlorodiazoacetates

Enantioselective Synthesis of (−)-Codeine and (−)-Morphine

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons−Wadsworth−Horner phosphate reagent. This intermediate requires only two steps to convert to (−)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine

Stereoselective Total Synthesis of (−)-Kumausallene

A stereoselective total synthesis of (−)-kumausallene was completed in 12 steps from acetylacetone. The hidden symmetry of (−)-kumausallene was recognized, and its skeleton was constructed efficiently from a C2-symmetric diol by a palladium-catalyzed cascade reaction. High diastereoselectivity was observed for the DMF-promoted biomimetic 1,4-bromocyclization of a conjugated enyne

An Enantioselective Strategy to Macrocyclic Bisindolylmaleimides. An Efficient Formal Synthesis of LY 333531

The ability to employ a bromo alcohol as a nucleophile in a palladium-catalyzed dynamic kinetic asymmetric transformation leads to an efficient synthesis of a selective PKC inhibitor under clinical development

General Strategy for the Synthesis of Rare Sugars via Ru(II)-Catalyzed and Boron-Mediated Selective Epimerization of 1,2-<i>trans</i>-Diols to 1,2-<i>cis</i>-Diols

Human glycans are primarily composed of nine common sugar building blocks. On the other hand, several hundred monosaccharides have been discovered in bacteria and most of them are not readily available. The ability to access these rare sugars and the corresponding glycoconjugates can facilitate the studies of various fundamentally important biological processes in bacteria, including interactions between microbiota and the human host. Many rare sugars also exist in a variety of natural products and pharmaceutical reagents with significant biological activities. Although several methods have been developed for the synthesis of rare monosaccharides, most of them involve lengthy steps. Herein, we report an efficient and general strategy that can provide access to rare sugars from commercially available common monosaccharides via a one-step Ru­(II)-catalyzed and boron-mediated selective epimerization of 1,2-trans-diols to 1,2-cis-diols. The formation of boronate esters drives the equilibrium toward 1,2-cis-diol products, which can be immediately used for further selective functionalization and glycosylation. The utility of this strategy was demonstrated by the efficient construction of glycoside skeletons in natural products or bioactive compounds

Base-Catalyzed Intramolecular Hydroamination of Conjugated Enynes

A de novo intramolecular hydroamination of conjugated enynes was developed using commercially available n-BuLi as a precatalyst. This hydroamination reaction successfully afforded allenyl-substituted pyrrolidines with up to 95% yield. One of the resulting allenyl pyrrolidines was converted to the natural products irniine and irnidine in three steps

Rhodium-Catalyzed Tandem Annulation and (5 + 1) Cycloaddition: 3‑Hydroxy-1,4-enyne as the 5‑Carbon Component

A Rh-catalyzed tandem annulation and (5 + 1) cycloaddition was realized. 3-Hydroxy-1,4-enyne served as the new 5-carbon component for the (5 + 1) cycloaddition. Substituted carbazoles, dibenzofurans, and tricyclic compounds containing a cyclohexadienone moiety could be prepared efficiently. The identification of a byproduct suggests that metal carbene and ketene intermediates may be involved in the (5 + 1) cycloaddition

Divergent Enantioselective Synthesis of (−)-Galanthamine and (−)-Morphine

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (−)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine

Stereoselective Total Synthesis of Hainanolidol and Harringtonolide via Oxidopyrylium-Based [5 + 2] Cycloaddition

The tetracyclic carbon skeleton of hainanolidol and harringtonolide was efficiently constructed by an intramolecular oxidopyrylium-based [5 + 2] cycloaddition. An anionic ring-opening strategy was developed for the cleavage of the ether bridge in 8-oxabicyclo[3.2.1]­octenes derived from the [5 + 2] cycloaddition. Conversion of cycloheptadiene to tropone was realized by a sequential [4 + 2] cycloaddition, Kornblum–DeLaMare rearrangement, and double elimination. The biomimetic synthesis of harringtonolide from hainanolidol was also confirmed