Sha-Hua Huang

Stereodivergent Synthesis of Functionalized Tetrahydropyrans Accelerated by Mechanism‐Based Allylboration and Bioinspired Oxa‐Michael Cyclization

A stereodivergent strategy enabled by bioinspired oxa-Michael cyclization was developed for the synthesis of functionalized tetrahydropyrans on the basis of the inherent symmetry in 1,3-diols, the symmetries of which were tunable by stereoselective hydroboration of an allene with a variety of alkylborane reagents and subsequent allylation of an aldehyde. The mechanism-based utilization of monoalkyl borane in the hydroboration and allylation cascade is unprecedented.

Total synthesis of strictamine: a tutorial for novel and efficient synthesis

When teaching synthetic design in the classroom, the novelty and efficiency of the overall synthetic route are the key values being imparted to the younger generation of synthetic chemists. The creative synthetic design is of great interest to graduate students who are entering into this exciting field for the first time. Strictamine, an akuammiline alkaloid, bears a congested cage-like structure and has interesting biological activities. Numerous attempts have been made toward the total synthesis of this compound since its discovery five decades ago. The synthesis was not completed until last year when synthetic chemists began to apply novel ring construction strategies. In 2016, two research groups reported the total syntheses of strictamine and four reported the formal syntheses. In this Highlight, the synthesis of strictamine is used as a tutorial case to illustrate novelty and efficiency in total synthesis.

Construction of Morphan Derivatives by Nitroso–Ene Cyclization: Mechanistic Insight and Total Synthesis of (±)‐Kopsone

A type II nitroso-ene cyclization was developed for the construction of morphan derivatives with good functional-group tolerance. DFT calculations revealed that the nitroso-ene reaction proceeds in a stepwise manner involving diradical or zwitterionic intermediates. The rate-determining step is C-N bond formation, followed by a rapid hydrogen-transfer step with a chair-conformation transition state. The current approach was also successfully applied in the first total synthesis of (±)-kopsone, a highly strained yet simple morphan-type alkaloid isolated from Kopsia macrophylla.

Catalytic Aza-Wacker Annulation: Tuning Mechanism by the Activation Mode of Amide and Enantioselective Syntheses of Melinonine-E and Strychnoxanthine

An unprecedented N-substituent of the amide was found to be crucial for the successful annulation to establish 2-azabicyclo[3.3.1]nonane and other ring skeletons in good yield. The novel catalytic aza-Wacker annulation methodology was further illustrated in the concise syntheses and the absolute configuration determinations of melinonine-E and strychnoxanthine.

Chemoenzymatic construction of chiral alkenyl acetylenic alcohol, a key building block to access diastereoisomers of polyacetylenes

BackgroundEnzymatic kinetic resolution is proved as an efficient strategy of accessing chiral secondary alcohols in organic synthesis. Although several synthetic methods have been developed for the preparation of chiral acetylenic alcohol, biotransformation remains as a direct approach in the synthesis of polyacetylene lipids, which represent an intriguing class of marine natural products featuring interesting biological profiles.ResultsNovozym 435, a commercial lipase immobilized on macroporous acrylic resin, is utilized in the kinetic resolution of 1-yn-3-ol-4-(E)-ene (alkenyl acetylenic alcohol), which exists as terminus in recently isolated isofulvinol (1) both from the mollusk Peltodoris atromaculata and the sponge Haliclona fulva. The kinetic resolution enabled by Novozym 435 resulted in acetylenic alcohol and the corresponding acetate both in excellent enantiomeric excess and high isolated yield. The optimized reaction conditions allow us to realize the reaction at room temperature in toluene. The reaction is readily scaled up for synthetic use.ConclusionsThe current investigation builds up a platform for future exploration on stereoisomers of isofulvinol, synthetic intermediates with different chain length, and natural product analogs.

Pinacol coupling going in a photocatalytic asymmetric manner: construction of chiral vicinal amino alcohols

Vicinal amino alcohols are a class of important motifs in pharmaceuticals, natural products as well as wide application in asymmetric catalysis (Scheme 1(a)). It is no doubt that development of efficient methods to access them has been a prominent research topic in the past decades. A particularly interesting approach to build such important motifs is directly forming the carbon-carbon bond between two carbonhetereoatom bonds in a high enantioselective manner. However, this approach would inquire a well-defined preorganization before the ultimate bond formation, either through a chelation or open-transition state. In an early report, Xu and Lin et al. [1] realized a reductive coupling between an aryl aldimine bearing the pre-installed chirality on N and a variety of alkyl aldehydes to generate vicinal amino alcohols in excellent diastereoselectivity (Scheme 1 (b)). After removal of the chiral sulfinyl group, the corresponding anti-amino alcohols are suitable for application in the synthesis of bioactive compounds. Such chiral auxiliary process requiring a stoichiometric amount of chirality resource and reducing reagent (e.g. 2 equiv. of Kagan’s reagent, SmI2) challenge the development of a catalytic variant in the succeeding research. Recently, Zhang, Lu, and Huang et al. [2] disclosed a breaking solution to address this challenge exemplified in the coupling of nitrone and aldehyde (Scheme 1(c)). The aforementioned SmI2-mediated single-electron-transfer (SET) process can be surrogated by a photocatalytic protocol. To chelate two oxygens from nitrone and aldehyde, an oxophilic Lewis acid, rare earth metal cation, was optimized. The density functional theory (DFT) calculation indeed supported that a pre-coordinated complex is readily reduced to generate the ketyl radical complex (Scheme 1(d)). The reducing potential of the coordinated aldehyde with Sc(OTf)3 was ‒0.62 V (vs. SCE, saturated calomel reference electrode), which was much higher than that of Ru(bpy) (E1/2 II/