Tandem jump: A novel copper‐catalyzed tandem trifluoromethylation/semipinacol rearrangement reaction of allylic alcohols has been achieved under mild conditions. This reaction is valuable for the ...difunctionalization of alkenes through simultaneous construction of a C sp 3CF3 bond and a quaternary carbon center, and could provide a straightforward strategy for the preparation of α‐quaternary β‐trifluoromethyl ketone derivatives.
(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular ...architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.
Quaternary carbon stereocenters are found in a broad range of organic compounds, including important bioactive natural products and medicinal agents. Given their ubiquity and the significant ...synthetic challenges they present, quaternary carbon stereocenters have long attracted great interest from synthetic organic chemists. Numerous efforts have been devoted to their construction, leading to a spectrum of strategies for creating stereogenic quaternary carbon centers. In this context, the semipinacol rearrangement has proven successful. In this extension of the pinacol rearrangement, the 1,2-carbon-to-carbon migration in a 1,2-diol has been expanded to include leaving groups other than the hydroxyl group. Over the past decade, our laboratory has explored the semipinacol rearrangement strategy for the stereoselective construction of quaternary carbon stereocenters. We have investigated various substrates, including 2,3-epoxy alcohols (also termed α-hydroxy epoxides), 2,3-aziridino alcohols, and allylic alcohols. Several promoters that effect the semipinacol rearrangement have been identified, including Lewis acids based on Al, Sm, B, Zn, and Ti for the rearrangement of α-hydroxy epoxides and 2,3-aziridino alcohols; cationic halogen species for the rearrangement of allylic alcohols; and cinchona alkaloids and chiral phosphoric acid for the asymmetric semipinacol rearrangement. Our research efforts have led to a series of valuable synthetic methods, including (1) a tandem semipinacol rearrangement and Meerwein–Ponndorf–Verley reduction, (2) a tandem semipinacol rearrangement and Tishchenko reaction, (3) a tandem semipinacol rearrangement with either an allylation or a propargylation, (4) a tandem semipinacol rearrangement and Schmidt reaction, (5) a semipinacol rearrangement of 2,3-aziridino alcohols, (6) a semipinacol rearrangement of allylic alcohols induced by halogen cation, (7) a tandem aziridination and semipinacol rearrangement of allylic alcohols, and (8) asymmetric semipinacol rearrangements with chiral organic catalysts. One hallmark of these reactions is the creation of stereogenic quaternary carbon centers with high levels of stereocontrol. In this Account, we describe the development of these synthetically useful methodologies and their successful application to the total syntheses of natural products. Our results demonstrate that the semipinacol rearrangement of carefully designed substrates constitutes an efficient approach to the stereoselective construction of quaternary carbon centers. These reactions have produced a broad array of useful compounds that lend themselves to further elaboration. Furthermore, the total synthesis of a series of alkaloids, with significant bioactivity and intriguing molecular architecture, was achieved through these semipinacol rearrangement strategies, highlighting their synthetic value.
A challenging direct asymmetric catalytic aerobic oxidative cross‐coupling of 2‐naphthylamine and 2‐naphthol, using a novel CuI/SPDO system, has been successfully developed for the first time. ...Enantioenriched 3,3′‐disubstituted NOBINs were achieved and could be readily derived to divergent chiral ligands and catalysts. This reaction features high enantioselectivities (up to 96 % ee) and good yields (up to 80 %). The DFT calculations suggest that the F–H interactions between CF3 of L17 and H‐1,8 of 2‐naphthol, and the π–π stacking between the two coupling partners could play vital roles in the enantiocontrol of this cross‐coupling reaction.
We describe a challenging and straightforward asymmetric catalytic aerobic oxidative cross‐coupling of 2‐naphthylamine and 2‐naphthol by using a CuI/SPDO/air system. Optically pure 3,3′‐disubstituted NOBINs were achieved that could be readily derived to divergent chiral ligands/catalysts. Mechanistic studies and DFT calculations give a comprehensive understanding of the high enantioselectivity and good chemoselectivity.
A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling ...enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (−)-chimonanthidine has been achieved.
A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables ...efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C1‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C1‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.
Enabler: An asymmetric aerobic oxidative cross‐coupling of 2‐naphthols, enabled by a novel Cu/SPDO system, generates a series of chiral C1‐symmetric BINOLs bearing 3,3′‐substituents. This method features high enantioselectivity, good chemoselectivity, and a broad substrate scope. The prepared C1‐symmetric BINOL organocatalysts gave better enantioselectivity than the previously reported catalyst for the asymmetric α‐alkylation of amino esters.
1,2-Carbon atom rearrangement has been broadly applied as a guiding strategy in complex molecule assembly. As it entails the carbon-carbon or carbon-heteroatom bond migration between two vicinal ...atoms, this type of reaction is capable of generating structural complexity through a molecular skeletal reorganization. This review will focus on recent employment of this strategy in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors.
An enantioselective sulfenylation/semipinacol rearrangement of 1,1‐disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as ...cocatalysts, generating various β‐arylthio ketones bearing an all‐carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid. Additionally, the synthetic utility of this method was exemplified by an enantioselective total synthesis of (−)‐herbertene and a one‐pot synthesis of a chiral sulfoxide and sulfone.
An enantioselective sulfenylation/semipinacol rearrangement of 1,1‐disubstituted and trisubstituted allylic alcohols was accomplished by chiral Lewis base/chiral Brønsted acid co‐catalysis. Various β‐arylthio ketones bearing all‐carbon quaternary centers were generated in moderate to excellent yields and excellent enantioselectivities.
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