Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.
By using commercially available 1,4-pentadiene
as a pronucleophile,
a copper(I)-catalyzed regioselective asymmetric allylation of ketones
is achieved. A variety of chiral tertiary alcohols bearing a terminal
(Z)-1,3-diene unit are generated in high (Z)/(E) ratio and high enantioselectivity.
Both aromatic ketones and aliphatic ketones serve as suitable substrates.
Furthermore, the reactions with (E)-C1(alkyl)-1,4-dienes proceed in moderate yields with acceptable enantioselectivity
but with low (Z,E)/others ratio,
which demonstrates the partial isomerization of (E)-allylcopper(I) species to (Z)-allylcopper(I) species
through 1,3-migration. Subsequent Heck reaction and olefin metathesis
compensate for the low efficiency with C1-1,4-dienes. The
synthetic utility of the product is further demonstrated by a copper(I)-catalyzed
regioselective borylation of the 1,3-diene group.
By using copper(I) homoenolates as nucleophiles, which are generated through the ring‐opening of 1‐substituted cyclopropane‐1‐ols, a catalytic asymmetric allylic substitution with allyl phosphates is achieved in high to excellent yields with high enantioselectivity. Both 1‐substituted cyclopropane‐1‐ols and allylic phosphates enjoy broad substrate scopes. Remarkably, various functional groups, such as ether, ester, tosylate, imide, alcohol, nitro, and carbamate are well tolerated. Moreover, the present method is nicely extended to the asymmetric construction of quaternary carbon centers. Some control experiments argue against a radical‐based reaction mechanism and a catalytic cycle based on a two‐electron process is proposed. Finally, the synthetic utilities of the product are showcased by means of the transformations of the terminal olefin group and the ketone group.
Reported is a modular one‐step three‐component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza‐Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2‐alkyl‐ and 2‐aryl‐substituted aziridines to access 1,3‐cis‐substituted and 1,4‐cis‐substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.
Monoterpenoids are the main components of plant essential oils and the active components of some traditional Chinese medicinal herbs like Mentha haplocalyx Briq., Nepeta tenuifolia Briq., Perilla frutescens (L.) Britt and Pogostemin cablin (Blanco) Benth. Pulegone reductase is the key enzyme in the biosynthesis of menthol and is required for the stereoselective reduction of the Δ2,8 double bond of pulegone to produce the major intermediate menthone, thus determining the stereochemistry of menthol. However, the structural basis and mechanism underlying the stereoselectivity of pulegone reductase remain poorly understood. In this study, we characterized a novel (−)-pulegone reductase from Nepeta tenuifolia (NtPR), which can catalyze (−)-pulegone to (+)-menthone and (−)-isomenthone through our RNA-seq, bioinformatic analysis in combination with in vitro enzyme activity assay, and determined the structure of (+)-pulegone reductase from M. piperita (MpPR) by using X-ray crystallography, molecular modeling and docking, site-directed mutagenesis, molecular dynamics simulations, and biochemical analysis. We identified and validated the critical residues in the crystal structure of MpPR involved in the binding of the substrate pulegone. We also further identified that residues Leu56, Val282, and Val284 determine the stereoselectivity of the substrate pulegone, and mainly contributes to the product stereoselectivity. This work not only provides a starting point for the understanding of stereoselectivity of pulegone reductases, but also offers a basis for the engineering of menthone/menthol biosynthetic enzymes to achieve high-titer, industrial-scale production of enantiomerically pure products.
A cooperative catalytic system involving a Pd/XPhos complex and inexpensive 5-norbornene-2-carbonitrile that enables the use of alkyl tosylates as alkylating reagents in the Catellani reaction has been developed. This mild, scalable protocol is compatible with a range of readily available functionalized aryl iodides and alkyl tosylates, as well as terminating olefins (45 examples, up to 97% yield).
By using copper(I) homoenolates as nucleophiles, which are generated through the ring‐opening of 1‐substituted cyclopropane‐1‐ols, a catalytic asymmetric allylic substitution with allyl phosphates is achieved in high to excellent yields with high enantioselectivity. Both 1‐substituted cyclopropane‐1‐ols and allylic phosphates enjoy broad substrate scopes. Remarkably, various functional groups, such as ether, ester, tosylate, imide, alcohol, nitro, and carbamate are well tolerated. Moreover, the present method is nicely extended to the asymmetric construction of quaternary carbon centers. Some control experiments argue against a radical‐based reaction mechanism and a catalytic cycle based on a two‐electron process is proposed. Finally, the synthetic utilities of the product are showcased by means of the transformations of the terminal olefin group and the ketone group.
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