Terminal Cyclopropylsilyl Alcohols as Useful Key Units to Access 2,3,4,6-Tetrasubstituted Tetrahydropyran Scaffolds by Stereocontrolled Prins Cyclization.

In this study, the use of terminal cyclopropylsilyl alcohols in Prins cyclization is reported as a very efficient methodology for the preparation of polysubstituted tetrahydropyrans, in which three new stereogenic centers have been created in a single pot. The reaction is general for a wide variety of aldehydes (alkylic, vinylic, aromatic, or dialdehydes), different types of alcohols, and halogenation agents providing high yields and excellent diastereoselectivity 2,3,4,6-tetrasubstituted tetrahydropyranyl frameworks. Interestingly, diastereomeric alcohols provide the same tetrahydropyranyl derivatives, showing that the reaction mechanism proceeds through common intermediates.

Towards an efficient methodology for the synthesis of functionalized dihydropyrans by silyl-Prins cyclization: access to truncated natural products.

We herein present a selective methodology for the synthesis of disubstituted dihydropyrans by silyl-Prins cyclization of -vinylsilyl alcohols mediated by trimethylsilyl trifluoromethanesulfonate (TMSOTf). The reaction features broad substrate scope, short reaction times and ease of process scale-up. Moreover, to showcase the applicability of the proposed method, we also report a facile and linear synthesis of analogues of rhopaloic acid and natural doremox fragrance.

Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs.

In this perspective, we showcase the benefits of continuous flow chemistry and photochemistry and how these valuable tools have contributed to the synthesis of organic scaffolds from the marine environment. These technologies have not only facilitated previously described synthetic pathways, but also opened new opportunities in the preparation of novel organic molecules with remarkable pharmacological properties which can be used in drug discovery programs.

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer's Disease and Parkinson's Disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders.

Changing the Reaction Pathway of Silyl-Prins Cyclization by Switching the Lewis Acid: Application to the Synthesis of an Antinociceptive Compound.

Developing new procedures for the synthesis of tetrahydropyrans in a very stereoselective manner is of great importance for the synthesis of THP-containing natural products. Here, we report an interesting protocol for the synthesis of polysubstituted halogenated tetrahydropyrans by silyl-Prins cyclization of vinylsilyl alcohols, in which the nature of the Lewis acid determines the outcome of the process. The methodology has been applied to the synthesis of a known antinociceptive.

Diastereoselective Synthesis of -2,6-Disubstituted Dihydropyrane Derivatives through a Competitive Silyl-Prins Cyclization versus Alternative Reaction Pathways.

A convenient regioselective synthesis of allyl- and vinylsilyl alcohols, from a common precursor, was described, by selecting the appropriate reaction conditions. Allyl- and vinylsilyl alcohols were tested in silyl-Prins cyclizations for the preparation of disubstituted oxygenated heterocycles in a one-pot sequential reaction. The methodology was sensitive to the structure of the starting alkenylsilyl alcohol and reaction conditions, with competitive pathways observed (particularly for allylsilyl alcohols), such as Peterson elimination and oxonia-Cope reactions.

The Tetrahydrofuran Motif in Marine Lipids and Terpenes.

Heterocycles are particularly common moieties within marine natural products. Specifically, tetrahydrofuranyl rings are present in a variety of compounds which present complex structures and interesting biological activities. Focusing on terpenoids, a high number of tetrahydrofuran-containing metabolites have been isolated during the last decades.

The Tetrahydrofuran Motif in Polyketide Marine Drugs.

Oxygen heterocycles are units that are abundant in a great number of marine natural products. Among them, marine polyketides containing tetrahydrofuran rings have attracted great attention within the scientific community due to their challenging structures and promising biological activities. An overview of the most important marine tetrahydrofuran polyketides, with a focused discussion on their isolation, structure determination, approaches to their total synthesis, and biological studies is provided.

Influence of the Substituents on the Opening of Silylepoxy Alcohols: 5--Cyclization towards Tetrahydrofurans vs. Unexpected Side Reaction Leading to Tetrahydropyrans.

The regioselective ring opening of epoxy alcohols is an effective method for the synthesis of different types of oxacycles. The 5- opening being preferred vs. the 6- mode, according to Baldwin rules, the use of silyl-substituted oxiranes has been reported as a possible method to favor the 6- cyclization.

Unexpected Domino Silyl-Prins/Aryl Migration Process from Geminal Vinylsilyl Alcohols.

The silyl-Prins cyclization of geminal vinylsilyl alcohols and aldehydes, promoted by TMSOTf, provides access to polysubstituted tetrahydropyrans in which the silyl group remains in the molecule and an aryl group has migrated from silicon to carbon. This domino silyl-Prins/aryl migration process is general and high-yielding for aryl, vinyl, or alkyl aldehydes. Moreover, cyclization proceeds with very high stereocontrol in a one-pot reaction in which both quaternary and tertiary stereogenic centers have been created.

Marine Heterocyclic Compounds That Modulate Intracellular Calcium Signals: Chemistry and Synthesis Approaches.

Intracellular Ca plays a pivotal role in the control of a large series of cell functions in all types of cells, from neurotransmitter release and muscle contraction to gene expression, cell proliferation and cell death. Ca is transported through specific channels and transporters in the plasma membrane and subcellular organelles such as the endoplasmic reticulum and mitochondria. Therefore, dysregulation of intracellular Ca homeostasis may lead to cell dysfunction and disease.

Synthesis of Polysubstituted Tetrahydropyrans by Stereoselective Hydroalkoxylation of Silyl Alkenols: En Route to Tetrahydropyranyl Marine Analogues.

Tetrahydropyrans are abundantly found in marine natural products. The interesting biological properties of these compounds and their analogues make necessary the development of convenient procedures for their synthesis. In this paper, an atom economy access to tetrahydropyrans by intramolecular acid-mediated cyclization of silylated alkenols is described.

The Oxepane Motif in Marine Drugs.

Oceans have shown to be a remarkable source of natural products. The biological properties of many of these compounds have helped to produce great advances in medicinal chemistry. Within them, marine natural products containing an oxepanyl ring are present in a great variety of algae, sponges, fungus and corals and show very important biological activities, many of them possessing remarkable cytotoxic properties against a wide range of cancer cell lines.

Synthesis of Azepane Derivatives by Silyl-aza-Prins Cyclization of Allylsilyl Amines: Influence of the Catalyst in the Outcome of the Reaction.

The synthesis of seven-membered nitrogen heterocycles by silyl-aza-Prins cyclization is described. The process provides trans-azepanes in high yields and good to excellent diastereoselectivities. Moreover, the reaction outcome is dependent on the Lewis acid employed.

From Silylated Trishomoallylic Alcohols to Dioxaspiroundecanes or Oxocanes: Catalyst and Substitution Influence.

A versatile method for the synthesis of dioxaspiroundecanes through a tandem Sakurai-Prins cyclization of allylsilyl alcohols in the presence of TMSOTf is described. The process is general and highly stereoselective with total control in the creation of three new stereogenic centers in a single step. Moreover, a very interesting chemoselectivity has been observed depending on the nature of the catalyst used or the substitution of the trishomoallylic alcohol, since the same reaction under BF3·OEt2 catalysis or using alcohols with allylic substituents provides exclusively the corresponding oxocanes, by a direct silyl-Prins cyclization.

Competitive silyl-Prins cyclization versus tandem Sakurai-Prins cyclization: an interesting substitution effect.

Two different mechanism pathways are observed for the reaction of allylsilyl alcohols 1 and aldehydes in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). In the case of allylsilyl alcohols without allylic substituents, the reaction gives dioxaspirodecanes, which are the products of a tandem Sakurai-Prins cyclization. In contrast, allylsilyl alcohols with an allylic substituent (R(2)≠H) selectively provide oxepanes, thus corresponding to a direct silyl-Prins cyclization.

Multicomponent prins cyclization from allylsilyl alcohols leading to dioxaspirodecanes.

A multicomponent reaction for the preparation of dioxaspirodecanes starting from allylsilyl alcohols was achieved. The one-pot sequence involves the sequential acid-catalyzed reaction of an allylsilyl alcohol with an aldehyde to afford an alkenediol. The subsequent Prins cyclization of the homoallylic alcohol moiety generates a tetrahydropyranyl carbocation which is intramolecularly trapped by the second hydroxyl group.

Seven-membered ring formation from cyclopropanated oxo- and epoxyallylsilanes.

A useful strategy for cycloheptane annulations from oxo- and epoxyallylsilanes, prepared by silylcupration of allenes, has been developed, and their application to the stereoselective synthesis of 4-methylenecycloheptan-1-ols is of great potential in the construction of seven-membered ring natural products presented.

One-pot multicoupling reaction of silylcopper reagents, organolithium compounds and α,β-unsaturated nitriles.

The silylcupration of allene using a lower order silylcopper species gives an allylsilane-vinyl copper intermediate 2 which, in conjunction with an organolithium reagent, is able to participate in a one-pot multicoupling reaction with α,β-unsaturated nitriles. The scope of this tandem reaction is studied and a possible mechanism pathway is outlined.

Allylsilanes in the synthesis of three to seven membered rings: the silylcuprate strategy.

Addition of low order phenyldimethylsilylcyanocuprates to allenes followed by "in situ" reaction of the intermediate silylcuprate with electrophiles ("the silylcuprate strategy") provides new routes for the synthesis of functionalised allylsilanes, which undergo highly stereocontrolled silicon-assisted intramolecular cyclizations leading to three to seven membered ring-formation.

Peterson olefination from alpha-silyl aldehydes.

A procedure for the stereoselective synthesis of substituted alkenes from alpha-silyl aldehydes, via the Peterson reaction, is described. The protocol for the preparation of alpha-silyl aldehydes is also included. Organometallic addition to the alpha-silyl aldehyde gives erythro-beta-hydroxysilanes in high yields (85-90%), which undergo elimination on treatment with potassium hydride (KH) or boron trifluoride to afford respectively Z- o E-alkenes (87-90%).

Intramolecular ene reaction of epoxyallylsilanes: synthesis of allyl- and vinylsilane-functionalized cyclohexanols.

[reaction: see text] Epoxyallylsilanes bearing the bulky tert-butyldiphenylsilyl group undergo an uncommon tandem rearrangement-cyclization process upon treatment with Lewis acids. Two pathways for the carbonyl ene reaction are observed: one leading to allylsilane-cyclohexanols when the epoxyallylsilane (28-31) is nonsubstituted, 2-, or 4-monosubstituted and other leading to vinylsilane-cyclohexanols when the epoxyallylsilane (24-27) is 2,4-disubstituted or trisubstituted. An explanation for the observed regio- and stereoselectivity is advanced and a reliable mechanism proposed.

Allylstannanes and vinylstannanes from stannylcupration of C-C multiple bonds. Recent advances and applications in organic synthesis.

The stannylcupration of allenes and alkynes has emerged as a powerful tool for the synthesis of allyl- and vinylorganostannanes. The regio- and stereoselectivity of this reaction depends upon the nature of the cuprate, the temperature and the structure of the allene or alkyne. The versatility and synthetic scope of the tin-synthons thus obtained is very wide.

Silylcuprates from allene and their reaction with alpha,beta-unsaturatedd nitriles and imines. Synthesis of silylated oxo compounds leading to cyclopentane and cycloheptane ring formation.

The silylcupration of allenes and the subsequent capture of the intermediate cuprate with alpha,beta-unsaturated nitriles is reported. The influence of the substitution of the nitrile, the nature of the silylcopper species, and the temperature on the selectivity of the reaction is studied. An interesting diaddition process was observed (1,2-addition and 1,4-addition), leading to oxo compounds which simultaneously have an allylsilane and a vinylsilane group.

Spiro-cyclopropanation from oxoallylsilanes.

A novel highly stereoselective spiro-cyclopropanation reaction from oxoallylsilanes is described. Oxoallylsilanes are readily obtained by silylcupration of allene followed by conjugate addition to enones. The former oxoallylsilanes undergo a tandem cyclization-cyclopropanation reaction when treated with CH2I2/Me3Al, leading to hydroxylated polycyclic systems bearing the spiro-cyclopropane moiety.