Yong-Qiang Tu

Direct Sp3 α-C–H activation and functionalization of alcohol and ether

Seven kinds of sp(3)α-C-H activation/C-C formation reactions of alcohols and ethers have been reviewed in this tutorial review, from the viewpoint of both methodology and synthetic application, towards the efficiency, chemo-, regio- and stereoselectivity, catalytic system, substrate scope and mechanistic study. Section 2 describes radical-mediated α-C-H activation and addition/elimination of ethers with unsaturated (C=C and C[triple bond]C) species. Sections 3-8 discuss the α-C-H activation and additions of alcohols and/or ethers with unsaturated (C=C, C[triple bond]C, C=O and C=N) compounds, which involve the key processes of radical mediation, carbenoid insertion, 1,5-H-migration, oxidative dehydrogenation coupling, transfer hydrogenative coupling, and metal-mediated C=C insertion into the C-H bond.

Stereoselective Construction of Quaternary Carbon Stereocenters via a Semipinacol Rearrangement Strategy

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.

Semipinacol Rearrangement in Natural Product Synthesis

[Song, Zhen-Lei] Sichuan Univ, Key Lab Drug Targeting, Educ Minist, Dept Med Chem,W China Sch Pharm, Chengdu 610041, Peoples R China

Organocatalytic asymmetric halogenation/semipinacol rearrangement: highly efficient synthesis of chiral α-oxa-quaternary β-haloketones.

A novel asymmetric halogenation/semipinacol rearrangement reaction catalyzed by cinchona alkaloid derivatives was developed. Two types of β-haloketones (X = Br, Cl) were obtained with up to 95% yield and 99% enantiomeric excess. The desired (+) and (-) enantiomers of the β-haloketones were readily obtained.

Organocatalytic Asymmetric Vinylogous α-Ketol Rearrangement: Enantioselective Construction of Chiral All-Carbon Quaternary Stereocenters in Spirocyclic Diketones via Semipinacol-Type 1,2-Carbon Migration

The catalytic enantioselective synthesis of all-carbon quaternary stereogenic centers in spirocyclic diketones has been achieved for the first time by an unprecedented asymmetric vinylogous alpha-ketol rearrangement in which an enantiocontrolled semipinacol-type 1,2-carbon migration was realized using multifunctional cinchona-modified primary amine catalysis.

Iron(III)‐Catalyzed and Air‐Mediated Tandem Reaction of Aldehydes, Alkynes and Amines: An Efficient Approach to Substituted Quinolines

Economic and practical advantages are offered by the iron(III)-catalyzed and air-mediated tandem coupling/hydroarylation/dehydrogenation of simple readily available aldehydes, alkynes, and amines for the synthesis of 2, 4-disubstituted quinolines (see scheme).

Organocatalytic Asymmetric Direct C sp 3H Functionalization of Ethers: A Highly Efficient Approach to Chiral Spiroethers

and pharmaceuticals, is an important endeavor in organic synthesis. Tremendous efforts have been made during the past few years toward developing methods for the synthesis of spiroethers, although of the methods developed, many involve multiple steps and only a few are enantioselective. Therefore, the development of methods that are highly efficient, catalytic, and enantioselective is still required. The direct and selective functionalization of inactive Csp3 H bonds is not only a significant and actively studied subject in fundamental organic chemistry, it is also becoming a practical method for organic synthesis because of its atomand step economy. Among the reported transformations, intramolecular redox processes for the direct functionalization of Csp3 H bonds that are a to heteroatoms are important for the synthesis of structurally diverse amine and ether derivatives. Furthermore, since the pioneering work of Kim and co-workers, there have many good results reported in the area of intramolecular redox processes for the direct enantioselective Csp3 H functionalization at positions a to nitrogen atoms. However, examples of the corresponding enantioselective reaction of ethers are scarce. In 2005, Sames and co-workers. reported that Sc(OTf)3 or BF3·Et2O could initiate a direct functionalization of Csp3 H bonds of cyclic ethers 1 to give racemic spiroethers 2’ (Scheme 1). This

Enantioselective bromination/semipinacol rearrangement for the synthesis of β-bromoketones containing an all-α-carbon quaternary center

A bromination/semipinacol rearrangement reaction catalyzed by cinchona alkaloid derivatives was developed. With 5 mol% (DHQD)2PYDZ, β-bromoketones containing an all-α-carbon quaternary center, which were synthetically useful but challenging to construct, were obtained in up to 97% yield and 93% ee.

Development of the intramolecular Prins cyclization/Schmidt reaction for the construction of the azaspiro[4,4]nonane: application to the formal synthesis of (±)-stemonamine.

A TiCl(4)-promoted tandem intramolecular Prins cyclization/Schmidt reaction has been designed and developed to be an efficient method for the construction of the azaspiro[4,4]nonane. The present tandem protocol has been employed to construct the tricyclic azaquaternary skeleton (ring A, B, and C) of stemonamine.

Total Synthesis of (±)‐Alopecuridine and Its Biomimetic Transformation into (±)‐Sieboldine A

cholinesterase (AChE) significantly (IC50 = 2.0 mm) and is cytotoxic against murine lymphoma L1210 cells (IC50 = 5.1 mgmL ). Both molecules contain two contiguous quarternary stereocenters and sieboldine A even possesses an unprecedented skeleton with an Nhydroxyazacyclononane ring bridged to a tetrahydrofuran ring. Despite their unique structures and significant biological activity, few reports on their total synthesis have appeared. Recently, the Overman research group disclosed an elegant total synthesis of (+)-sieboldine A in 20 steps, in which an efficient gold(I)-catalyzed cyclization/pinacol sequence was used to construct the important cis-hydrindanone intermediate. However, the total synthesis of alopecuridine and its biomimetic conversion into sieboldine A have not been achieved to date. Herein, we report the first total synthesis of ( )-alopecuridine and its biomimetic transformation into ( )-sieboldine A. Our retrosynthetic analysis is presented in Scheme 1. Inspired by Kobayashi s proposed biogenetic pathway, we expected that a two-step oxidation of alopecuridine (2) would introduce the N-hydroxy group and construct the tetrahydrofuran ring in sieboldine A (1). Alopecuridine may exist in either a carbinolamine form 2 or an aminoketone form 2’. Unlike most of the synthesis performed on fawcettimine-type alkaloids, our strategy to obtain the tricyclic core of 2’ leaves the formation of the five-membered B ring until a late stage. A SmI2-mediated pinacol coupling [5] of compound 4 might form ring B and simultaneously establish the oxa-quarternary stereocenter at C4. We further envisioned that the other allcarbon quarternary center at C12 and the aza-cyclononane ring could be constructed through a challenging semipinacol ring expansion of an eight-membered nitrogen-containing ring from hydroxy epoxide 5. The precursor 5 could be readily prepared from iodoalkene 6 and carbamate 7 by coupling and epoxidation. As depicted in Scheme 2, we began our synthesis by the preparation of fragment 6. Luche reduction of known iodide 8 7] afforded cis-allylic alcohol 9 quantitatively (d.r.> 20:1). After transforming the hydroxy group of 9 into its acetyl ester 10, we attempted to introduce the allyl group by iodine-catalyzed allylation. However, this method failed to generate iodoalkene 6 ; only a small amount of iodosubstituted products were isolated and large quantities of starting materials were recovered. To solve this problem, we attempted to replace the iodine with a Lewis acid. FortuScheme 1. Retrosynthetic analysis. Boc= tert-butoxycarbonyl.