1,5-anti stereocontrol in the boron-mediated aldol reactions of beta-alkoxy methyl ketones: the role of the formyl hydrogen bond

The boron-mediated aldol reactions of certain types of beta-alkoxy methyl ketone show remarkably high levels of stereoinduction with achiral aldehydes, leading preferentially to 1,5-anti related stereocenters. Given the low levels of asymmetric induction usually observed in acetate aldol reactions, this is of great synthetic utility and has been used successfully in the total synthesis of a number of polyketide natural products. We have investigated the effects of the alkoxy protecting group (OMe, OPMB, PMP acetal, tetrahydropyran, and OTBS) present in the boron enolate on the level and sense of remote 1,5-stereoinduction, using density functional theory calculations (B3LYP/6-31G**). Our predictions of diastereoselectivity from comparison of the competing aldol transition structures are in excellent qualitative and quantitative agreement with experimentally reported values. We conclude that the boron aldol reactions of unsubstituted boron enolates proceed via boat-shaped transition structures in which a stabilizing formyl hydrogen bond exists between the alkoxy oxygen and the aldehyde proton. It is this interaction that leads to preferential formation of the 1,5-anti adduct, by minimizing steric interactions between the beta-alkyl group and one of the ligands on boron. In the case of silyl ethers, the preference for this internal hydrogen bond is not observed due to the size of the protecting group and the electron-poor oxygen atom that donates electron density into the adjacent silicon atom. We show that this stereochemical model is also applicable in rationalizing the 1,4-syn stereoselectivity of boron aldol reactions involving certain alpha-chiral methyl ketones. These detailed results may be summarized as a conformational diagram that can be used to predict the sense of stereoinduction.     

1,5-asymmetric induction in boron-mediated beta-alkoxy methyl ketone aldol addition reactions

This article presents studies that illustrate beta-alkoxy methyl ketone-derived boron enolates undergo diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this reaction is documented to be general for a variety of beta-alkoxy methyl ketone analogues and aldehyde partners. The double stereodifferentiating reactions of these enolates with chiral beta-alkoxy aldehydes have also been investigated in conjunction with the possibility of controlling the absolute stereochemistry of the aldol process. With the proper selection of reaction conditions, the proximal alkoxy substituent on either the aldehyde (1,3-induction) or the enolate fragment (1,5-induction) can be employed to control facial selectivity of the aldol addition. Selection of a boron enolate ensures dominant 1,5-anti induction from the beta-alkoxy methyl ketone-derived enolate partner while negating any influence of the beta-alkoxy aldehyde substituent. Conversely, if stereochemical control from the beta-alkoxy aldehyde is desired, a Lewis acid-catalyzed enolsilane addition ensures dominant 1,3-induction from the aldehyde beta-oxygen substituent.     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-oxygenated methyl ketones

This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of beta-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the beta-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.     

Selective 1,5-alkylidenecarbene insertion reactions on [3.2.1] oxabicyclic ethers: a new approach toward the AB ring system of ingenol

Two methods to achieve the formal aldol reaction between acetone and two oxabicyclic [3.2.1] ketones are reported. The trimethylsilyl-protected beta-hydroxy ketones are converted by a Wittig reaction into vinyl chlorides as synthetic precursors to alkylidenecarbenes. Selective 1,5 C-H over 1,5 O-Si insertion has been applied to the synthesis of a model for the ABC ring system of ingenol.     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-alkoxy methylketones

Good levels of substrate-controlled, 1,5- syn-stereoinduction are obtained in boron-mediated aldol reactions of beta-trichloromethyl-beta-alkoxy and beta-trifluoromethyl-beta-alkoxy methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group (TBS or PMB). In the case of boron aldol reactions of beta-aryl-beta-alkoxy methylketones, the 1,5- anti-adducts were obtained with high levels of diastereoselectivity only with a beta-OPMB group.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

Chiral boron enolate aldol additions to chiral aldehydes

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.     

1,5-Stereoinduction in boron-mediated aldol reactions of β,δ-bisalkoxy methylketones containing cyclic protecting groups

A study of the aldol reactions of boron enolates from methylketones that are protected with dimethylacetonide or di-tert-butylsilyl groups and that possess a trans or cis relationship between the chiral centers is presented. The main objective of this work was to evaluate the influence of the relative stereochemistry between the chiral centers and the steric and electronic influences of the cyclic protecting groups on the aldol reactions. The aldol adducts were obtained with moderate to high 1,5-anti stereoselectivity that was dependent on both the identity of the protecting group on the β,δ-oxygen stereocenters and the relative stereochemistry between the β and δ chiral centers. A theoretical analysis of the transition states involving these aldol reactions was performed utilizing DFT (density functional theory).     

Annulation of the cyclohexane ring by tandem free radical alkylation of a nonactivated delta-carbon atom-intramolecular carbanion cycloalkylation

Annulation of the cyclohexane ring by a combination of free radical and ionic reactions sequences was achieved. Free radical alkylation of the remote nonactivated delta-carbon atom involves addition of delta-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates, to radicophilic olefins, while the polar sequence involves enolate anions as intermediates which undergo a cycloalkylation reaction. Thus, the cyclohexane ring was constructed using diverse acyclic and cyclic structures as precursors of alkoxy radicals.     

Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and hydroxy-substituted allylstannanes with aldehydes

Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively with tin(iv) halides to generate allyltin trihalides which react with aldehydes to give (Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall (Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the hydroxy and methyl substituents.     

Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.     

A tandem non-aldol aldol Mukaiyama aldol reaction

[reaction: see text] A new one-pot tandem aldol process is described in which a secondary epoxy silyl ether is converted into the 1,5-bis-silyloxy-3-alkanone in good yield. Thus, treatment of the epoxy silyl ether 8 with TBSOTf and base affords the silyl enol ether 9 via non-aldol aldol rearrangement and addition of benzaldehyde and TBSOTf gives the ketone 10 with 4:1 syn selectivity. The diastereoselectivity changes to an anti preference for most aldehydes. This anti selectivity overwhelms the normal Felkin-Ahn preference; namely, the 1,5-anti isomer predominates even when it is anti-Felkin-Ahn.     

A novel synthesis of tetrahydrofuran via alkoxy radical cyclisation

Tetrahydrofurans were synthesised via 5-exo-trig cyclisation of alkoxy radical generated by unprecedented 1,5-hydrogen shift from hydroxyl group to vinyl radical.     

Synthesis of novel 2‐alkoxy(aralkoxy)‐4H‐[1,2,4]triazolo[1,5‐a]quinazolin‐5‐ones starting with dialkyl‐N‐cyanoimidocarbonates

A novel series of 2‐alkoxy(aralkoxy)‐4H‐[1,2,4]triazolo[1,5‐a]quinazolines were synthesized employing N‐cyanoimidocarbonates and 2‐hydrazinobenzoic acid as building blocks. Chemical transformation of the inherent lactam moiety in the targeted 2‐alkoxy(aralkoxy)[1,2,4]triazolo[1,5‐a]quinazolines was offered access to a variety of derivatives. J. Heterocyclic Chem., (2011).     

Influence of β-substituents in aldol reactions of boron enolates of β-alkoxy methylketones

Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of β-tert-butyl methylketones with achiral aldehydes, independent of the nature of the β-alkoxy protecting group (P = PMB or TBS). The analysis of the relative energies of the transition structures by theoretical calculations using the density functional B3LYP shows relative energies favoring the corresponding OUT-1,5-SYN transition structures, explaining the observed 1,5-syn stereoinduction.     

‘On water’ synthesis of 2,4-diaryl-2,3-dihydro-1,5-benzothiazepines catalysed by sodium dodecyl sulfate (SDS)

An efficient synthesis of 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines has been developed by the reaction of various 1,3-diaryl-2-propenones with 2-aminothiophenol in water under neutral conditions catalysed by SDS. Excellent chemoselectivity was observed for substrates possessing halogen atoms or nitro/alkoxy/thioalkyl groups which did not undergo competitive aromatic nucleophilic substitution of the halogen atoms or the nitro group, reduction of the nitro or the α,β-unsaturated carbonyl group, or dealkylation of the alkoxy/thioalkoxy groups.     

Stereo-controlled synthesis of polypropionate ester derivatives using titanium complexes

A method for the stereocontrolled synthesis of polypropionate ester derivatives by means of titanium complexes is described. The general procedure involves an allyltitanium complex which allows the formation of an enolsilane bearing two stereocentres and an alkoxy titanium complex used in a tandem aldol–Tischtschenko reaction. These two steps are very highly diastereoselective. We present here the study of the tandem aldol–Tischtschenko reaction involving enolsilanes possessing different steric hindrance. © 2000 Académie des sciences / Éditions scientifiques et médicales Elsevier SAStitanium complexes / aldol reaction / Tischtschenko reaction / asymmetric induction     

High 1,5-anti stereoinduction in boron-mediated aldol reactions of methyl ketones

[reaction: see text] We report herein a very efficient and synthetically useful 1,4-anti-1,5-anti boron-mediated aldol reaction of a chiral alpha-methyl-beta-alkoxy methyl ketone with achiral aldehydes.     

Regio- and stereochemical features of the reactions of 1,2,5-trimethylpiperidin-4-one with chalcone

The reactions of N-substituted piperidin-4-ones with benzylideneacetophenone, resulting in the synthesis of a number of heterocyclic 1,5-dicarbonyl compounds, were studied. 1,2,5-Trimethylpiperidin-4-one enters into cascade-type chalcone addition accompanied by intramolecular aldol condensation giving rise to the 3-azabicyclo[3.3.1]nonane system. The conformations of the 1,5-dicarbonyl compounds and azabicyclononanes synthesized were determined; the regio- and stereochemical features of the reactions of 1,2,5-trimethylpiperidin-4-one with chalcone were studied.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2693–2697, December, 2004.     

Reductions, Reductive Alkylations, and Intramolecular Cyclizations of Acyl Silanes with Samarium Diiodide or Tributyltin Hydride

A series of acyl silanes including aliphatic-, aromatic-, and bis-acyl silanes, as well as the acyl silanes bearing other substituents such as a bromine atom and alkenyl, succinimide, and carbonyl groups, were prepared, and their reactions with samarium diiodide or tributylstannane were studied. The reactions of acyl silanes occurred in various manners such as reductions, reductive alkylations, intramolecular radical cyclizations, pinacol couplings, aldol reactions, and Tishchenko reactions, depending on the nature of substrates and reaction conditions. Acyl silanes were generally reduced to give the corresponding alpha-silyl alcohols without transfer of silyl groups. Intramolecular radical cyclizations of 5-hexenoyl silanes and 1-silyl-1,5-pentanedione were realized to give alpha-silyl cyclopentanols and 1,2-cyclopentanediol derivatives, respectively. On treatment with samarium diiodide in tetrahydrofuran, 1-(trimethylsilyl)-1,6-hexanedione underwent a pinacol coupling reaction in the presence of t-BuOH, whereas it underwent a Tishchenko reaction in the presence of MeOH. The Tishchenko reaction of 1-silyl-1,5-pentanedione gave a delta-silyl-delta-lactone. On treating with samarium diiodide, 1-(trimethylsilyl)-1,5-hexanedione and 1,5-bis(trimethylsilyl)-1,6-hexanedione, underwent, respectively, intramolecular aldol reactions.