Palladium mediated cycloisomerization of sugar alkynols: synthesis of cyclic enol-ethers and spiroketals

Functionalized bicyclic enol-ethers and spiroketals are prepared by Pd catalyzed cycloisomerization of 3-C-alkynylfuranosyl derivatives. Cycloisomerization of differently substituted alkyne derivatives revealed a preference for 6-endo-dig cyclization over 5-exo-dig if the substituent is not sufficiently electron withdrawing. The scope of these cycloisomerizations has been further extended by integrating with conjugate addition.     

Asymmetric synthesis of naturally occurring spiroketals

Spiroketals are widely found as substructures of many naturally occurring compounds from diverse sources including plants, animals as well as microbes. Naturally occurring spiroketals are biologically active and most of them are chiral molecules. This article aims at reviewing the asymmetric synthesis of biologically active spiroketals for last 10 years (1998-2007).     

CeCl3-mediated addition of acetylenic bis-lithium salts to aldehydes and ketones: An efficient route to bis-substituted alkyne diols

An efficient, chemoselective protocol to access propargylic diols via a CeCl₃-mediated addition reaction is reported. Propargylic alcohols were transformed into the corresponding acetylenic bis-lithium salt intermediates, which react with aldehydes and ketones in the presence of dry CeCl₃ to furnish the corresponding bis-substituted alkyne diols. This protocol does not involve protection-deprotection or transmetallation steps, and allows the use of poorly reactive or highly enolizable substrates.     

Furanyl spiroketals as stereochemical relays in the synthesis of 1,9-anti diols: synthesis of insect pheromones

A suite of spiroketal insect pheromones (15 and 17a-d) has been synthesised in good yield and with very high levels of diastereoselectivity via furanyl spiroketals. Remote asymmetric induction is achieved under thermodynamic control. The use of furanyl spiroketals as temporary scaffolds in the synthesis of 1,9-anti diols has been demonstrated with the synthesis of the swede midge pheromone (2S,10S)-2,10-diacetoxyundecane 1. The enzymatic resolution of a C₂ symmetric 1,9-anti diol was used as a confirmation of diastereomeric purity.     

Synthesis and elaboration of functionalised carbohydrate-derived spiroketals

The scope of a stereoselective three-step approach for the synthesis of sugar derived spiroketals is presented. The methodology consists of Grignard addition of vinyl- or allylmagnesium bromide to a carbohydrate lactone, followed by K-10 clay mediated glycosidation with a terminal alkenol and subsequent ring-closing metathesis of the resulting diene. The generality of this procedure is demonstrated by the synthesis of various pyranose- and furanose-derived spiroketals, as well as more advanced tricyclic spiroketal derivatives. It is shown that functionalisation of the double bond in the resulting spiroketals leads to fused polycyclic ethers.     

Ruthenium-catalyzed propargylic substitution reaction of propargylic alcohols with thiols: a general synthetic route to propargylic sulfides

A novel cationic methanethiolate-bridged diruthenium complex [Cp*RuCl(mu2-SMe)2RuCp*(OH2)]OTf (1e) has been disclosed to promote the catalytic propargylic substitution reaction of propargylic alcohols bearing not only terminal alkyne group but also internal alkyne group with thiols. It is noteworthy that neutral thiolate-bridged diruthenium complexes (1a-1c), which were known to promote the propargylic substitution reactions of propargylic alcohols bearing a terminal alkyne group with various heteroatom- and carbon-centered nucleophiles, did not work at all. The catalytic reaction described here provides a general and environmentally friendly preparative method for propargylic sulfides, which are quite useful intermediates in organic synthesis, directly from the corresponding propargylic alcohols and thiols.     

A Julia olefination approach to the synthesis of functionalized enol ethers and their transformation into carbohydrate-derived spiroketals

A synthesis of spiroketals from carbohydrate lactones is reported. A modified Julia olefination is used to synthesize trisubstituted and highly functionalized exo-glycals, which were subsequently transformed into spiroketals under acidic conditions.     

Brønsted Acid‐Catalyzed Cascade Reactions Involving 1,2‐Indole Migration

A cascade reaction of indoles with propargylic diols involving an unprecedented metal‐free 1,2‐indole migration onto an alkyne was carried out. DFT calculations support a mechanism consisting of a concerted nucleophilic attack of the indole nucleus with loss of water, followed by the 1,2‐migration and subsequent Nazarov cyclization. This Brønsted acid‐catalyzed protocol affords indole‐functionalized benzofulvene derivatives in high yields.     

Synthesis of electron deficient 5,6-aryloxy spiroketals

[reaction: see text] A strategy for the construction of electron deficient 5,6-aryloxy spiroketal is reported. The process should prove useful for the synthesis of natural products containing similar spiroketals. The strategy uncovers an unexpected rearrangement between ortho and para quinone spiroketals.     

Efficient protocol for ring opening of spiroketals using trifluoroacetyl trifluoromethanesulfonate (TFAT)

[reaction: see text] Ring opening of steroidal spiroketals under exceptionally mild conditions is smoothly achieved via reaction with trifluoroacetyl trifluoromethanesulfonate (TFAT). The new spiroketal ring-opening protocol provides omega-trifluoroacetyl vinyl ethers in good yield and avoids difficulties that attended previously employed vigorous reaction conditions.     

The preparation of perfluoroalkenyl allenes (trienes) and pentafluorophenyl allenes

Trifluorovinyl- and (Z)-pentafluoropropenylcopper reagents readily react with propargylic halides or tosylates. With primary propargylic substrates, the major product is the alkyne. With secondary propargylic substrates, mixtures of alkyne/allene are obtained; the allene product is the major product. With tertiary propargylic substrates, the allene is regiospecifically and stereospecifically formed in good isolated yields. With pentafluorophenyl copper and primary propargylic substrates, the major product is pentafluorobenzene. With secondary and tertiary propargylic substrates, the allene is regiospecifically formed in good isolated yields.     

Generation and hetero-Diels-Alder reactions of an o-quinone methide under mild, anionic conditions: rapid synthesis of mono-benzannelated spiroketals

Deprotonation of o-hydroxybenzyl acetate with (i)PrMgCl provides a method of generating an o-quinone methide under mild, anionic conditions, such that highly sensitive exo-enol ethers can be employed as 2pi partners in hetero-Diels-Alder reactions. This process results in mono-benzannelated spiroketals such as those found in the natural products berkelic acid, the chaetoquadrins or cephalostatin 6.     

Unified, radical-based approach for the synthesis of spiroketals

[reaction: see text] Functionalization of S-(3-chloro-2-oxo-propyl)-O-ethyl xanthate 1 by two consecutive xanthate transfer reactions, followed by spirocyclization of the resulting dihydroxy ketones, provides a flexible and highly convergent access to diversely substituted spiroketals, containing five-, six-, and seven-membered rings.     

Synthesis of benzannulated steroid spiroketals by palladium-catalyzed spirocyclization of steroid alkynediols

Sonogashira coupling of 17β-acetoxy-4,5-secoandrost-3-yn-5-one with 2-iodobenzyl alcohol, followed by NABH₄ reduction afforded two epimeric steroid alkynediols that after separation underwent palladium-catalyzed spirocyclization to produce the corresponding benzannulated steroid spiroketals. The hitherto unknown spiroketals were characterized their NMR spectra and the structures were confirmed by X-ray diffraction studies.     

A gold(I)-catalyzed intramolecular reaction of propargylic/homopropargylic alcohols with oxirane

The gold(I)-catalyzed cycloisomerization of epoxy alkynes in the presence of a nucleophile is an efficient protocol to provide ketal skeletons with high stereoselectivity. An intramolecular reaction of propargylic/homopropargylic alcohols with oxirane to produce ketal/spiroketals in moderate yields under mild conditions has been reported. Moreover, the mechanism of this kind of reaction has been discussed on the basis of a series of control and (18)O tracer experiments.     

Thermodynamic favorable CO2 conversion via vicinal diols and propargylic alcohols: A metal-free catalytic method

Organocatalysis represents a promising field in chemical fixation of CO₂.Herein,a facile metal-free strategy was reported for the one-pot preparation of cyclic carbonates and a-hydroxy ketones from vicinal diols,propargylic alcohols and CO₂.Wide scope of vicinal diols and propargylic alcohols was demonstrated to be efficient under the DBU-catalyzed conditions.A plausible mechanism was proposed,which included detailed main and side reactions under the metal-free conditions.     

Iron-catalyzed three-component coupling of aldehyde, alkyne, and amine under neat conditions in air

Various iron-salts (and complexes) and especially iron(III) chloride catalyzed the three-component coupling of aldehyde, alkyne, and amine to generate propargylic amines with high efficiency under neat conditions in air. The iron-catalyzed reaction is particularly effective for reactions involving aliphatic aldehydes. The reaction is not sensitive to and occurs smoothly in water and in air. No additional co-catalyst or activator is required.     

PdII‐Catalyzed Spiroketalization of Ketoallylic Diols

A high‐yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl₂(MeCN)₂] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl‐substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted “down‐the‐chain” and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter.     

Stereocontrolled synthesis of spiroketals via a remarkable methanol-induced kinetic spirocyclization reaction

A methanol-induced kinetic spiroketalization reaction has been developed for the stereocontrolled target- and diversity-oriented synthesis of spiroketals. In contrast to existing methods for spiroketal synthesis, this reaction does not depend on thermodynamic product stability or require axial attack of an oxygen nucleophile. Stereodiverse glycals are alkylated at the C1 position with side chains bearing protected hydroxyl groups. After alcohol deprotection, the glycal is epoxidized stereoselectively, then the side chain hydroxyl is spirocyclized with inversion of configuration at the anomeric carbon by addition of excess MeOH at -63 degrees C. This spirocyclization reaction appears to proceed by MeOH hydrogen-bonding catalysis and has been used to form five- and six-membered rings with stereoisomeric substituents. In some cases, the stereocomplementary spiroketals can be also obtained by classical acid-catalyzed equilibration.     

Simple, but challenging: recent developments in the asymmetric synthesis of spiroketals

Impressive and elegant approaches to the enantioselective synthesis of spiroketals starting from achiral substrates have been described recently. These strategies based on transition-metal catalysis and organocatalysis hold great potential for further applications.