Allylic Stannanes Research Articles

Total synthesis and structure-antifouling activity relationship of scabrolide F.

An efficient synthetic strategy for scabrolide F (7), a norcembranolide diterpene that was isolated from the Taiwanese soft coral Sinularia scabra, has only recently been reported by our group. Herein, we report details of the first total synthesis of 7. The tetrahydrofuran domain of 7 was stereoselectively constructed via the 5-endo-tet cyclization of a hydroxy vinyl epoxide. The reaction of alkyl iodide 30 with dithiane 38, followed by the introduction of an alkene moiety, afforded allylation precursor 41. The coupling of alkyl iodide 42 and allylic stannane 43 was examined as a model experiment of allylation. Because the desired allylated product 44 was not obtained, an alternative synthetic route toward 7 was investigated instead. In the second synthetic approach, fragment-coupling between alkyl iodide 56 and aldehyde 58, macrolactonization, and transannular ring-closing metathesis were used as the key steps to achieve the first total synthesis of 7. We hope that this synthetic strategy provides access to the total synthesis of other macrocyclic norcembranolides. We also evaluated the antifouling activity and toxicity of 7 and its synthetic intermediates toward the cypris larvae of the barnacle Amphibalanus amphitrite. This study is the first to report the antifouling activity of norcembranolides as well as the biological activity of 7.

Direct Stannylation and Silylation of Arylmethanols by Palladium Catalysis.

A direct transformation of non-preactivated benzyl alcohols to benzyl stannanes and benzyl silanes was realized through Pd-catalyzed C(sp3)-O activation process. By using versatile tin and silicon sources, these reactions exhibit a broad substrate scope and a high efficiency under mild conditions, affording functionalized benzyl and allylic stannanes and benzylsilanes with high yields. The successful implementation of gram-scale stannylation/silylation as well as the one-pot Stille coupling reaction demonstrates the potential application of this method in organic synthesis. Both experimental and theoretical investigations reveal the mechanistic details of this reaction.

Reductive coupling of allenoates with aldehydes catalyzed by halogenotin hydride.

Hydrostannylation of allenoate 1 with halogenotin hydride (Bu2SnClH) was developed to give allylic stannane (I), which then could react with aldehyde 2. The same coupling gave allylic alcohol 3 under reductive conditions in the presence of a silane and a catalytic amount of Bu2SnClH. This catalytic protocol was applied to the synthesis of lactone 4. The resultant products 3 and 4 were subjected to oxidative conditions to provide oxacycles 5 and 6, respectively.

Photoredox-Catalyzed C-F Bond Allylation of Perfluoroalkylarenes at the Benzylic Position.

Site-selective and direct C-F bond transformation of perfluoroalkylarenes was achieved with allylic stannanes via an iridium photoredox catalyst system. The present defluoroallylation proceeds exclusively at the benzylic position through perfluoroalkyl radicals generated by a single-electron transfer from an excited photoredox catalyst to perfluoroalkylarenes. A variety of perfluoroalkyl groups are applicable: linear perfluoroalkyl-substituted arenes such as Ar-nC4F9 and Ar-nC6F13 and heptafluoroisopropylarenes (Ar-CF(CF3)2) underwent site-selective defluoroallylation. DFT calculation studies revealed that the in situ generated Bu3SnF traps F- to prevent a retroreaction from the unstable perfluoroalkyl radical intermediate, and the radical intermediate favorably reacts with allylic stannanes. The synthesis of a bis(trifluoromethyl)methylene unit containing compound, which is an analog that is useful as a pharmaceutical agent for the prophylaxis or treatment of diabetes and inflammatory diseases, demonstrated the utility of this reaction.

Dearomative Allylation of Naphthyl Cyanohydrins by Palladium Catalysis: Catalyst-Enhanced Site Selectivity.

A dearomative allylation of naphthyl cyanohydrins with allyl borates and allyl stannanes under palladium catalysis was developed. At the initial stage of this study, the dearomative reaction (C4 substitution of the aromatics) was competing with benzyl substitution. To circumvent this issue, the use of palladium and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio was found to enhance the site selectivity, furnishing the desired dearomatized products. Further derivatizations of products were also successful.

Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -stannane Nucleophiles.

We achieved regio- and stereoselective carboindation of terminal and internal alkynyl ethers using InI3 and organosilicon or -stannane nucleophiles to synthesize (Z)-β-alkoxyalkenylindiums. The carbometalation regio- and stereoselectively proceeded in anti-addition fashion, which was confirmed by X-ray diffraction analysis of (Z)-β-alkoxyalkenylindium products. Theoretical calculation on the carboindation of alkynyl ethers to elucidate the effect of an alkoxy group was conducted in parallel with calculations on a carbon analogue of the alkynyl ether. Reaction profiles and computational data of carboindation suggest that the alkoxy group enhances the interaction between InI3 and an alkyne moiety and reduces the activation energy. Many types of carbon nucleophiles such as silyl ketene acetals, silyl ketene imines, a silyl cyanide, an alkynyl stannane, and an allylic stannane were applicable to the present reaction system to give highly functionalized metalated enol ethers (β-alkoxyalkenylindiums). The prepared β-alkoxyalkenylindiums were transformed to various functionalized tetrasubstituted enol ethers by iodination followed by Suzuki coupling. The synthesis of a seven-membered ring compound containing a phenol ether moiety was accomplished using a sequential process that included the present stereoselective carboindation.

Geometrically Selective Synthesis of (E)-Enamides via Radical Allylation of Alkyl Halides with α-Aminoallylic Stannanes.

The reaction of α-(carbonylamino)allylic stannanes and alkyl halides using Et3B as a radical initiator selectively afforded (E)-enamides. A radical mechanism enables the E selectivity, which is unusual in a reaction using α-aminoallylic metals. In addition, this reaction system achieved a wide degree of functional group tolerance and an efficient chiral transfer reaction.

Regio- and Stereo-controlled Addition Reaction of Aminoallylic Stannanes to Aldehydes Mediated by Germanium Dichloride

A GeCl2-mediated addition reaction of α-(N-phthaloylamino)allylic stannane to aldehydes was achieved to give 1,2-amino alcohol derivatives in high anti-selectivity. Various types of aromatic and aliphatic aldehydes were applicable. The synthesized N-phthaloylamino alcohols were smoothly transformed to aminoalcohols by conventional methods with no loss of stereochemistry.

Improved Synthesis of the A–E Ring Segment of Ciguatoxin CTX3C by Using Intramolecular Allylations

Abstract An improved synthesis of the A–E ring segment of ciguatoxin CTX3C is described. The E ring segment was synthesized by the intramolecular reaction of allylic stannane and aldehyde with high stereoselectivity. Construction of the A–E ring framework was performed by using the intramolecular allylation of α-acetoxy ether followed by ring-closing metathesis.

Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization.

Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.

Tin powder‐promoted diastereoselective allylation of chiral acylhydrazones

An efficient method for the allylation of chiral acylhydrazones derived from aldehydes has been developed to give the corresponding allylic hydrazides in good yields and diastereoselectivities. The method uses a combination of tin powder and allylic bromide as allylation system, which avoids the use of toxic allylic stannanes while retaining their merits.

Practical Stannylation of Allyl Acetates Catalyzed by Nickel with Bu3 SnOMe.

A practical and scalable nickel-catalyzed allylic stannylation of allyl acetates with Bu3 SnOMe is described. A variety of acyclic and cyclic allyl acetates, even with base-sensitive moieties, undergoes the stannylation by using NiBr2 /4,4'-di-tert-butylbipyridine (dtbpy)/Mn catalyst system to afford highly functionalized allyl stannanes with excellent regioselectivity and yields. Furthermore, the scope of protocol is also extended by the reaction of propargyl acetates, giving rise to propargyl or allenyl stannanes. Additionally, a unique diastereoselectivity using the nickel catalyst different from the palladium was demonstrated for the stannylation of cyclic allyl acetates. In the reaction, inexpensive and stable nickel complexes, abundant reductant (Mn), and atom-economical stannyl source were used.

ChemInform Abstract: Bis‐Functionalization of 1,3‐Dienes Through 1,4‐Conjugate Addition of Amphiphilic Bis‐π‐Allyl and Related Palladium Intermediates.

AbstractBis‐allylation of functionalized 1,3‐dienes is achieved via Pd‐catalyzed coupling with allyl stannane and allyl chloride.

Stereocontrol in Asymmetric SE′ Reactions of γ-Substituted α,β-Unsaturated Aldehydes

Asymmetric SE' reactions of (E)- and (Z)-γ-substituted-α,β-unsaturated aldehydes have been studied for the stereocontrolled preparation of nonracemic alcohols. Mild exchange reactions of allylic stannanes provide access to chiral 1,3-bis(tolylsulfonyl)-4,5-diphenyl-1,3-diaza-2-borolidines. These reagents display reactivity with the γ-substituted α,β-unsaturated aldehydes, which is characterized by matched and mismatched elements of stereocontrol. Computational analysis (using density functional theory) provides valuable insights to guide reaction development.

A radical-based approach for the construction of the tetracyclic structure of resiniferatoxin

A novel radical-based strategy for accessing the unique tetracyclic skeleton of resiniferatoxin is described. The synthetic route is characterized by a stereoselective synthesis of the C-ring which has a bridgehead O,Se–acetal, a three component radical coupling of the A- and C-rings and a branched allyl stannane, and a 7-endo radical cyclization to construct the fused B-ring from the coupling adduct. The present approach attests to the power of radical reactions to realize the congested C–C bond formations required for synthesizing highly functionalized compounds.

Stereoarrays with an All‐Carbon Quaternary Center: Diastereoselective Desymmetrization of Prochiral Malonaldehydes

Tamed by chelation: The MgBr2 chelation of prochiral malonaldehydes allows diastereoselective monoaddition reactions with allyl stannane nucleophiles (see scheme; PG=protecting group, TBDMS=tert-butyldiphenylmethylsilyl, Tr=trityl). In the same pot, addition of a second nucleophile proceeds in high diastereoselectivity to generate nonsymmetric products with up to five contiguous stereogenic centers, including a chiral all-carbon quaternary center.

Palladium Pincer Complex Catalyzed Funtionalization of Electrophiles

This review describes the usefulness of palladium pincer complexes in catalytic transformations of various electrophiles. We discuss two basic approaches to the functionalization of electrophiles: (i) palladium pincer complex catalyzed additions of allylic and other substrates to electrophiles, such as sulfonyl imines, aldehydes and related reagents; and (ii) pincer complex catalyzed generation of allylmetal reagents (such as boronates and other species) followed by a direct or palladium-catalyzed functionalization of the electrophiles under one-pot conditions. The study is focused on the reactivity and selectivity aspects of pincer complex catalysis. We show, for example, that allylations of imines and aldehydes are easier to perform with pincer complexes bearing π-acceptor phosphine ligands, while generation of organometallic species can be efficiently achieved by σ-donor, selenium or nitrogen containing pincer ligands. We present several examples of chiral pincer complexes in asymmetric catalysis. The high stability and well-defined stoichiometry of pincercomplexes allow a rational design of asymmetric catalytic reactions for carbon-carbon and carbon-heteroatom bond formations. Briefly, we have also reviewed the new emerging field of pincer complexes in Pd(II)/Pd(IV)-based catalytic cycles. These processes allow redox reactions involving pincer complex catalysts without altering of the typical pincer complex topology. Keywords: Palladium, catalysis, electrophiles, organoboronates, allylation, asymmetric catalysis, chiral metal complexes, pincer complexes, cyclopropanations, Michael additions, enantioselective transformations, Palladium Pincer Complexes, Allylic Stannanes, Allylic Cyanides, Benzylic Cyanides

Enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b

An enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b has been achieved by a convergent protocol, which was featured by an enantioselective organocatalytic transfer hydrogenation of enal, a Julia–Kocienski olefination to establish the C15–C16 E-olefin moiety, a Kulinkovich reaction associated with cyclopropyl-allyl rearrangement to produce allyl stannane and ytterbium triflate and carboxylic acid promoted allylation between allyl stannane and aldehyde with tertiary alcohol at the α-position. The construction of macrolide 2 was realized by the successful implementation of RCM utilizing 5 mol % Grubbs’s second generation catalyst at room temperature with E-isomer as a single product.

PCN‐ and PCS‐Pincer Palladium Complexes as Tandem Catalysts in Homoallylation Reactions

AbstractNovel PCN‐ and PCS‐pincer palladium complexes 2‐(dimethylamino)methyl‐5‐methoxy‐6‐(diphenylphosphinoxy)phenylpalladium(II) bromide (1), 2‐(phenylimino)‐5‐methoxy‐6‐(diphenylphosphinoxy)phenylpalladium(II) bromide (2), 2‐(phenylthiomethyl)‐5‐methoxy‐6‐(diphenylphosphinoxy)phenylpalladium(II) bromide (3), 2‐(phenylthio)methyl‐5‐methoxy‐6‐(diphenylphosphinoxy)phenylpalladium(II) chloride (4) have been synthesized (55–95% yield) by using a flexible and straightforward synthetic route starting from isovanillin as the common precursor. The structures of complexes 1, 2 and, 4 in the solid state were determined using X‐ray diffraction and showed a typical pincer‐type geometry. The catalytic activities of 1–3 in the homoallylation reactions of aldehydes and allyl(tributyl)stannane as well as of their corresponding cationic complexes 1a–3a in the tandem reaction of aldehydes or sulfonimines with allyl chlorides and hexamethyldistannane were investigated. It was found that the catalytic activities are very dependent on the combination of the E‐donor moieties in the pincer ligand. Generally, PCS‐pincer complex 3 and its cationic complex 3a outperform PCN‐pincer complexes 1 and 2 as well as their cationic complexes 1a and 2a in both the homoallylation and tandem reaction. PCS‐pincer palladium complexes 3 and 3a seem to benefit in a positive sense from the combination and cooperativity of a π‐accepting phosphorus donor and a σ‐donating sulfur donor.

Stereochemical Surprises in the Lewis Acid-Mediated Allylation of Isatins

The BF(3)·OEt(2)-mediated allylation of isatin with an α-chiral allylic stannane is diastereo- and enantioselective. Conversely, allylation of any substituted isatin employing the identical protocol is not diastereoselective at all and only enantioselective for the major diastereomer having syn relative configuration. The anti isomer is, however, formed in almost racemic form. Both absolute and relative configurations are unambiguously secured by X-ray analysis of major isomers, and the stereochemical assignment of the other 3-substituted 3-hydroxy oxindoles is based on similar NMR spectroscopic characteristics. The remarkable observations are rationalized by an acyclic transition state model.