Stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans: Brønsted acid-catalyzed intramolecular oxa-conjugate cyclization of α,β-unsaturated ester surrogates

Intramolecular oxa-conjugate cyclization (IOCC) of α,β-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure of substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Br?nsted acid-catalyzed IOCC of α,β-unsaturated ester surrogates (e.g., α,β-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These α,β-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Br?nsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.     

Nickel-catalyzed diastereoselective alkyl-alkyl kumada coupling reactions

A nickel pincer complex is found to catalyze alkyl-alkyl Kumada coupling reactions of 1,3- and 1,4-substituted cyclohexyl halides and tetrahydropyrans with an excellent diastereoselectivity. The mechanistic investigation of the coupling reactions provides evidence that the activation of alkyl halides is reversible.     

Enantioselective route to 3-vinylidene tetrahydropyrans and 3-vinylidene oxepanes based on a silyl-Prins cyclization

A general method has been developed for the asymmetric synthesis of 3-vinylidene tetrahydropyrans and 3-vinylidene oxepanes based on the Lewis acid-catalyzed intramolecular reactions of oxocarbenium ions with propargylsilanes. The observed excellent diastereoselectivity and a high asymmetric induction offer a new synthetic method with a wide scope and generality.     

Organocatalytic approach to polysubstituted piperidines and tetrahydropyrans

Polysubstituted piperidines and tetrahydropyrans are synthesized from aldehydes and two classes of trisubstituted nitroolefins via an O-TMS protected diphenylprolinol catalyzed domino Michael addition/aminalization (or acetalization) process. This approach allows formation of four contiguous stereocenters in the piperidine or tetrahydropyran ring in one step with excellent enantioselectivity.     

Biosynthesis-inspired intramolecular oxa-conjugate cyclization of α,β-unsaturated thioesters: stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans

Intramolecular oxa-conjugate cyclization of α,β-unsaturated thioesters under Br?nsted acid catalysis, inspired by biosynthesis of polyketide natural products, provides a variety of 2,6-cis-substituted tetrahydropyran derivatives with excellent diastereoselectivities. An added bonus of this methodology is that the product tetrahydropyrans could be readily elaborated to various derivatives by exploiting the unique reactivity of the thioester group.     

An Efficient Prins Cyclization for Stereoselective Synthesis of Tetrahydropyran from Imines and Homoallyl Alcohols

An unprecedented protocol has been developed for the efficient synthesis of substituted tetrahydropyrans via a bismuth‐promoted Prins cyclization of imines with homoallyl alcohols. In the presence of 40 mol% BiCl₃, a wide variety of imines react smoothly with homoallyl alcohols at room temperature to give the corresponding 4‐chlorotetrahydropyran derivatives in good to excellent yields.     

Chirality transfer in Au-catalyzed cyclization reactions of monoallylic diols: selective access to specific enantiomers based on olefin geometry

The gold(I)-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is shown to be highly stereoselective when chiral allylic alcohols are employed. Substrates that differ only in olefin geometry provide enantiomeric products from formal S(N)2' reactions in high yields with excellent chirality transfer. The allylic alcohol stereochemistry also efficiently controls the facial selectivity when the substrates include additional stereocenters.     

四氯化锡诱导的Prins环化法高选择性地合成四氢吡喃衍生物

本文通过预先将醛和四氯化锡进行配位形成高活性的醛中间体,同时采用滴加高烯丙醇的方法高收率和高选择性地合成了2,4,6-三取代四氢吡喃.     

A Sakurai-Prins-Ritter sequence for the three-component diastereoselective synthesis of 4-amino tetrahydropyrans

A simple one-pot procedure for the Sakurai-Prins-Ritter sequence allows rapid assembly of 4-acylamino-2,6-substituted tetrahydropyrans in high yields and with excellent diastereoselectivity from readily available 4-acetoxy-1,3-dioxanes, allylsilanes, and nitriles. A variety of nitriles have been shown to participate. Diastereoselectivities are uniformly high and observed stereochemistry of cation trapping proceeds according to Alder's model of the 4-tetrahydropyranyl cation.     

Chemoselective oxygen-centered radical cyclizations onto silyl enol ethers

A new oxygen-centered radical cyclization onto silyl enol ethers has been developed and utilized for the synthesis of versatile siloxy-substituted tetrahydrofurans. The reactions display excellent chemoselectivity for cyclization onto the electron-rich silyl enol ether when competing terminal alkene cyclization, 1,5-hydrogen abstraction, and beta-fragmentation pathways are present. The increased chemoselectivity also allows for the synthesis of tetrahydropyrans, a challenging substrate class to access using oxygen-centered radical alkene cyclizations due to competing 1,5-hydrogen abstractions.     

Multi-component regio- and diastereoselective cobalt-catalyzed hydrovinylation/allylboration reaction sequence

The combination of a regioselective cobalt-catalyzed 1,4-hydrovinylation and the diastereoselective allylboronation reaction leads to a wide scope of functionalized hydroxydienyl esters in a one-pot reaction in excellent yields. With catalytic amounts of base, these products are easily converted either into α,β,γ,δ-unsaturated hydroxyl esters or complex tetrasubstituted tetrahydropyrans in chemo- and diastereoselective fashions. In addition, a high-yielding four-component one-pot reaction involving an acrylate, two different and unsymmetrical 1,3-dienes, and an unsaturated aldehyde is presented.     

Acid-catalyzed regioselective sulfetherification of alkenols and stereoselective rearrangement of tetrahydrofuran to tetrahydropyran

An efficient acid-catalyzed sulfetherification of various unsaturated alcohols with sulfenamides to form tetrahydrofurans and tetrahydropyrans regioselectively is described. Mechanistic studies have shown that the tetrahydrofurans can stereoselectively rearrange to the corresponding tetrahydropyrans.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

The "aqueous" Prins reaction

[reaction: see text] In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic alpha,beta-unsaturated acetals are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles in water, demonstrating that colloidal suspensions can protect highly electrophilic intermediates from hydrolysis. Reactions are experimentally facile and useful in the preparation of a variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol.     

Practical and Highly Selective CH Functionalization of Structurally Diverse Ethers

A trityl ion mediated C? H functionalization of ethers with a wide range of nucleophiles at ambient temperature has been developed. The reaction displays high chemoselectivity and good functional group tolerance. The protocol also exhibits excellent regio‐ and diastereoselectivities for the unsymmetric ethers, thus stereoselectively generating highly functionalized disubstituted 2,5‐trans tetrahydrofurans (THF), 2,6‐trans tetrahydropyrans (THP), 2,6‐trans dihydropyrans (DHP), and 1,3‐trans isochromans, and highlighting the capacity of the protocol in complex molecule synthesis.     

Practical and Highly Selective C?H Functionalization of Structurally Diverse Ethers

A trityl ion mediated C H functionalization of ethers with a wide range of nucleophiles at ambient temperature has been developed. The reaction displays high chemoselectivity and good functional group tolerance. The protocol also exhibits excellent regio‐ and diastereoselectivities for the unsymmetric ethers, thus stereoselectively generating highly functionalized disubstituted 2,5‐trans tetrahydrofurans (THF), 2,6‐trans tetrahydropyrans (THP), 2,6‐trans dihydropyrans (DHP), and 1,3‐trans isochromans, and highlighting the capacity of the protocol in complex molecule synthesis.     

Substituent effects on regioselective intramolecular oxidation of unactivated C-H bonds: stereoselective synthesis of substituted tetrahydropyrans

Our previously reported intramolecular delta-selective C-H bond oxidation by dioxiranes, generated in situ from activated ketones, offers a novel approach to the synthesis of tetrahydropyrans. To synthesize substituted tetrahydropyrans in a stereoselective manner, we examined the effects of alkyl, nitrogen, and oxygen substituents at the alpha-, beta-, and gamma-sites of ketones on the stereoselectivities of intramolecular C-H bond oxidation reactions. Ketones 1-4 with a methyl group at the alpha-, beta-, or gamma-site showed the diastereoselectivities that agreed with the trans/cis ratio predicted by considering steric interactions in the transition states. Furthermore, ketones 5 and 6 carrying a bulky phthalimido group at the alpha- and the beta-sites, respectively, exhibited excellent stereoselectivity, each affording only one diastereomer. However, ketones 9 and 10 bearing beta-oxygen substituents gave reversed stereoselectivity as compared to those with beta-alkyl or nitrogen substituents, possibly because of the hydrogen bonding interaction in the transition state. For ketones 12 and 13, both bearing methyl and silyloxy groups, the hydrogen bonding interaction was probably more important than the steric effect on the diastereoselectivity of intramolecular oxidation of C-H bonds.     

Stereoselective synthesis of 4-hydroxy-2,3,6-trisubstituted tetrahydropyrans

[reaction: see text] Reaction of homoallylic alcohols with aldehydes in the presence of TFA gives, after hydrolysis of the ester, 4-hydroxy-2,3,6-trisubstituted tetrahydropyrans with the creation of three new stereocenters in a single-pot process. By varying the aldehyde component, a variety of functionalized side chains are installed at C-2. The utility of this approach is extended to the enantioselective synthesis of tetrahydropyrans with >99% ee.     

CeCl3·7H2O/AcCl-catalyzed Prins-Ritter reaction sequence: a novel synthesis of 4-amido tetrahydropyran derivatives

Homoallylic alcohols, carbonyl compounds and nitriles undergo a smooth tandem Prins-Ritter type cyclization in the presence of CeCl₃·7H₂O/AcCl at ambient temperature to produce 4-amido tetrahydropyrans in high yields with all cis-selectivity. Spirocyclic 4-amido tetrahydropyrans are obtained in the case of cyclic ketones.