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This minireview focuses on recent advances in the synthesis of seven‐membered ring oxacycles, whether saturated, unsaturated, fused or isolated. We cover a remarkable variety of strategies and methods developed during the past two decades, based mainly on cyclizations, ring‐closing metathesis, conjugate additions, and ring expansions. The cyclizations can be generated directly or triggered through an oxocarbenium ion, carbocation or iminium‐type species. Also discussed are ring‐closing metatheses and conjugate additions, in which the precursor has the functionalities and correct stereochemistry of the final seven‐membered ring oxacycle. Finally, examples of ring expansions are described, predominantly involving cyclopropanes and epoxides. These cases include reactions governed by the intermediate species and others, where the precursor holds the stereochemical information for the final oxacycle., This research was supported by the Ministerio de Ciencia, Innovación y Universidades (MCIU), la Agencia Estatal de Investigación (AEI), Fondo Europeo de Desarrollo Regional (FEDER) and ACIISI (Gobierno de Canarias) (PGC2018‐094503‐B–C22 and ProID2017010118). V. S. thanks the Spanish MCIU for an F.P.U. fellowship. D. A. C. thanks the Cabildo de Tenerife for a postdoctoral Agustín de Betancourt contract. The manuscript was edited by Guido Jones, also funded currently by Cabildo de Tenerife under the TFinnova Program, supported by MEDI and FDCAN.

Several l-idose and l-iduronic acid glycosyl donors (mostly thioglycosides but also halides and trichloroacetimidates) with acyl protecting groups at the C-2 position were prepared and evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide syntheses in the literature, the presence of C-2 acyl protecting groups in l-ido-configured glycosyl donors generally results in exclusive formation of 1,2-trans glycosidic linkages, a finding that has typically been attributed to neighbouring-group participation. However, glycosylations of simple alcohols with l-ido-configured donors (particularly thioglycosides), reported here, generally displayed incomplete stereocontrol and gave mixtures of the 1,2-trans and 1,2-cis products, suggesting that neighbouring-group participation has lesser importance in these reactions. Glycosyl donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for the desired α-l-anomer (1,2-trans) as the major product. Interestingly, glycosylations under the same reaction conditions with more complex monosaccharide acceptors gave exclusively the expected 1,2-trans products. The role of neighbouring-group participation in these glycosylations was explored with density functional theory (DFT) calculations, which revealed that the non-stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.

A new 1,2-trans-selective glycosylation reaction is described. Glucosyl donors protected cyclically at the C-2 and C-3 hydroxy groups as six- (butane diacetal), seven- (tetraisopropyldisiloxanylidene), or eight- (2,3-o-xylylene) membered fused rings were synthesized in a straightforward manner. The glycosylation reactions of the glucosyl donors with various acceptors mainly generated β-glycosides under conventional reaction conditions. The results show that the o-xylylene group is a suitable 1,2-trans-directing group from the points of view of stereoselectivity and chemical stability. A conformational study of the oxocarbenium ion of an o-xylylene-protected glucose derivative by NMR spectroscopy and computational simulation was carried out. The results imply that the oxocarbenium ion mainly adopts a 4H3 conformation owing to the rigid trans-fused ring at C-2 and C-3, while a noncyclically protected derivative might fluctuate between conformations. These results suggest that an eclipsing interaction between the pseudoequatorial xyloxy group at C-2 and the incoming nucleophile hampers 1,2-cis attack.

Prins cyclization has emerged as one of the most valuable methods for the construction of heterocycles. It proceeds through intramolecular addition of a π-nucleophile to an oxocarbenium or related ion. The use of electron-rich alkenes, such as allylsilanes (so-called silyl-Prins cyclization) offers the benefit of allowing more selective reactions. The regio- and stereochemical outcomes of these transformations are explained by well-stablished transition states. This review presents the most important contributions involving silyl-Prins cyclization to the stereoselective preparation of oxygen and nitrogen heterocycles. The influence of different structural variants in the selectivity of the cyclization is discussed. These reactions have frequently been used as key steps in the synthesis of a wide variety of natural products.

Metal-free halogen, chalcogen, or oxocarbenium ion mediated yne-carbonyl or yne-thioxo transformations of a range of N- and O-propargylic compounds have been studied. This investigation has led to the development of a mild, economic, and effective method for the synthesis of functionalized 4H-1,3-oxazines, 4H-1,3-thiazines, 4,5-dihydrothiazoles, and α-substituted enones. The structure of the propargylic substrate and the nature of electrophile influence both the outcome and regioselectivity of processes.

The cyanation of acetals and orthoesters by using a sterically congested α-cyanoamine as a cyanating reagent was investigated. The α-cyanoamine effectively facilitated cyanation in the presence of trichlorosilyl triflate to produce a variety of cyanated adducts in excellent yields. Analysis of the reaction mixture by 1H NMR spectroscopy revealed that trichlorosilyl triflate produced an oxocarbenium cation species as an intermediate.

A novel Bronsted acid/Lewis acid dual catalyst system has been developed to promote an efficient C-C bond formation between a range of oxocarbenium precursors derived from chromene acetals and ethyl diazoacetate. The reaction proceeds under mild conditions and is tolerant of common functionalized 2H-chromene and isochromene acetals. In addition, an asymmetric variant of diazoacetate addition towards 2H-chromene acetal is described. Continued investigations include the further optimization of asymmetric induction towards the formation of diazo ester substituted 2H-chromene.

A modular enantioselective synthesis of spiroketals, spiroethers, and oxabicycles, each containing a dihydropyran subunit, is described. It is based on the 2,2-spiro- and 2,6-bicycloannulation of sulfoximine-substituted 2-hydroxy-dihydropyrans. Key steps of the spiroannulations are the ring-closing metathesis of the corresponding 2,2-oxadienyl and 2,6-dienyl dihydropyrans and Prins cyclization of 2-alkenyl 2-hydroxy-dihydropyrans. Ring-closing metathesis of the corresponding 2,6-dienyl dihydropyrans gave oxabicycles with oxabicyclo[4.3.1]decane skeletons. These routes were extended to the synthesis of spiroketals and spiroethers incorporating additional annulated six-membered rings. Diastereoselective Prins cyclization of mono- and bicyclic 2-alkenyl-2-hydroxy-dihydropyrans was highly selective and afforded chloro-substituted spirocycles. Substituted 2-hydroxy-dihydropyrans were obtained through cyclization of δ-hydroxy ketones, which were synthesized from enantiomerically pure sulfoximine-substituted homoallylic alcohols through lithiation and trapping of the α-lithioalkenylsulfoximines with unsaturated aldehydes, followed by allylic oxidation. Inter- and intramolecular glycosidations of the 2-hydroxy-dihydropyrans with O- and C-nucleophiles proceeded with high stereoselectivities and furnished 2,6-trans-configured glycosides. Dihydropyran oxocarbenium ions are most likely intermediates in the glycosidations. According to ab initio calculations, sulfoximine- and trimethyl-substituted dihydropyran oxocarbenium ions adopt a half-chair-like conformation. The energy difference between the oxocarbenium ion with pseudoaxial and the one with pseudoequatorial methyl groups is very small. A transition state model for their reactions with nucleophiles is proposed. It features a half-chair-like conformation, a pseudoequatorial C6 substituent, and an anti-addition of the nucleophile along an axial trajectory to C2 that produces an anti-periplanar lone pair at the O atom. A similar transition state model allows a general explanation for the trans stereoselectivity of the reactions between C6-substituted dihydropyran oxocarbenium ions and nucleophiles.

Prins-type cyclization reactions proceed through the intramolecular addition of a π-nucleophile to an oxocarbenium ion or related species to generate a ring through carbon–carbon bond formation, often with excellent and predictable stereocontrol. The widespread presence of naturally occurring oxygen-containing heterocycles has made these reactions exceedingly valuable for total synthesis efforts. This microreview covers several common variations of Prins-type cyclizations and highlights their applicability to the total synthesis of natural products and analogs.

The reactivity and stereoselectivity of a galacturonic acid 3,6-lactone thioglycosyl donor, previously described as a highly reactive glycosylating agent, has been investigated by using a series of competition experiments and condensation reactions with different thiophilic activator systems. It is revealed that the relative reactivity of the thioglycosides depends on the activator system used and that p-nitrophenylsulfenyl triflate shows overall attenuated reactivity differences with respect to the commonly used N-iodosuccinimide/triflic acid promoter system. With respect to the stereoselectivity of the studied galacturonic acid 3,6-lactone thioglycosyl donor, it is revealed that a preactivation-based glycosylation system gives rise to α-selective glycosylation, whereas an in situ activation protocol leads to the formation of the β-product with good selectivity. It is hypothesized that these opposingstereoselectivities are the result of different product-forming intermediates. Where preactivation of the donor leads to the formation of an intermediate β-triflate, which is substituted in a concerted fashion to provide the α-product, a 3H4 oxocarbenium ion like species is substituted in the in situ activation experiment to provide the β-linked product.

A powerful approach for controlling the stereochemistry of glycosylation reactions involves using a directing group at an adjacent carbon to influence the stereochemistry of nucleophilic attack. The use of substituents such as I, PhS, and PhSe has proven to be especially valuable because it enables the preparation of 2-deoxysugars after reductive removal of the directing group. The mechanisms of these reactions are generally considered to involve nucleophilic opening of bridged onium ions and to proceed with inversion. Onium ions, however, equilibrate with open cations, and these open forms can be favored when the cation is highly stabilized. Although the selectivities of reactions of carbohydrate-derived cations are consistent with the intermediacy of onium ions, the reactions of acyclic cations are not. Instead, consideration of the preferred conformations of the oxocarbenium ions and stereoelectronically favored additions to these intermediates provides a predictive model to explain the diastereoselectivities observed in reactions of oxocarbenium ions bearing proximal heteroatoms.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A set of C-disaccharide analogs was designed to probe the recognition of a known O-disaccharide mimetic of sialyl Lewis X, to P-selectin. The synthesis of the C-glycosides centered on the de novo construction of the galactose residue via an oxocarbenium ion/enol ether cyclization. Conformational analysis was performed by a combination of NMR spectroscopy and molecular mechanics (MM) and molecular dynamics (MD) calculations. The inhibition of P-selectin binding was evaluated in a P-selectin Biacore assay. At 12 mM, the O-glycoside showed 48 % inhibition of binding, while the C-glycoside analogs exhibited between 25–31 % inhibition. This data is discussed within the context of the active conformation of sLex and the conformational behavior of these ligands. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Monosubstituted γ-lactols 1a−1c, 3a−3c and 4a−4c, as well as disubstituted γ-lactol 5 and the γ-hydroxy-substituted γ-lactone 6, were transformed into disubstituted tetrahydrofuran derivatives by treatment with allyl- and propargylsilanes in the presence of Lewis acids. The diastereoselectivities were moderate to excellent and are interpreted by application of the Felkin−Anh model to cyclic oxocarbenium ions. The effects of the equilibria between conformers of the intermediates are discussed. The surprisingly high diastereoselectivity of 4-substituted γ-lactols 3 can be explained on this basis.

ZnCl2-triggered lactonization reactions of γ,δ-epoxy-β-silyloxy esters with remote alkoxy groups (CH2)nOR (n = 2, 3), producing five- and/or six-membered ring lactones, have been investigated. Under such conditions, the regiochemistry of the reaction is governed by the cis or trans nature of the starting epoxy ester and also by its C(3) stereochemistry. An X-ray crystallographic structure of a γ-lactone (compound 24′) and a 13C NMR correlation for the C(4) carbon chemical shifts of all γ-lactones were obtained and used to determine the regioselectivity of the epoxide ring-opening. A mechanistic hypothesis, involving an oxocarbenium ion as a common intermediate, is presented in interpretation of the results.