Steric Course of Deprotonation/Substitution of Chelating/Dipole-Stabilizing-Group-Substituted α-Amino- and α-Oxynitriles
Carbanion-Induced [3 + 2]-Annulation of Donor-Acceptor Cyclopropanes
- The stereochemical course of electrophilic substitutions of α-nitrile metallocarbanions was investigated using deprotonation of enantioenriched α-amino- and α-oxynitriles bearing a carbamoyl or a methoxycarbonyl group in the presence of an electrophile. The results suggested that the dipole-stabilizing substituents can not only affect the configurational stability and chemical reactivity of α-nitrile metallocarbanions but also can change the steric course of the electrophilic substitution (retention vs inversion). While the reaction of α-aminonitrile bearing a dimethylaminocarbonyl group on the nitrogen atom with LiHMDS in the presence of PhCOCl resulted in the formation of a retention product (93:7), the case with that bearing a methoxycarbonyl group was reversed in favor of the inversion product (37:63). Thus, a methoxycarbonylamino group increases the degree of planarization of the anionic center with maintenance of the planar chirality more than does a ureido group, leading to preferable attack of an electrophile from the rear face.
Spontaneous Oxygenation of Siloxy-N-Silylketenimines to α-Ketoamides
- [3 + 2]-annulation of donor-acceptor cyclopropanes and ylidenemalonates in which an α-p-tosyl carbanion functions as a donor substituent is described. A notable feature of the annulation is that the auxiliary p-tosylmethyl group can be removed via a cycloreversion during the tandem annulation sequence.
Stereochemical Course of Deprotonation-Acylation of N‐Boc- and N‐Carbamoyl-2-cyano-6-methylpiperidines
- Siloxy-N-silylketenimines generated in situ from O-silyl cyanohydrins were converted to α-ketoamides by brief exposure to air or oxygen. Oxidation under extremely mild conditions can be explained by assuming the intermediacy of a 3-imino-1,2-dioxetane derivative generated via triplet-singlet intersystem crossing after the reaction of siloxy-N-silylketenimines with triplet oxygen.
Enantioselective Synthesis of Allenylenol Silyl Ethers via Chiral Lithium Amide-Mediated Reduction of Ynenoyl Silanes and Their Diels-Alder Reactions
- The stereochemical course of electrophilic substitution of α-nitrile metallocarbanions generated by deprotonation from N-Boc- and N-carbamoyl-2-cyano-6-methylpiperidines was investigated. Deprotonation in the presence of an electrophile taking advantage of the high acidity of α-nitrile protons allowed examination of the effects of a chelating group on the nitrogen atom, a countercation, and the reactivity of an electrophile on the steric course. Analyses of reactions using aroyl chlorides and methyl iodide revealed the following: : (1) the substitution reactions basically proceed with retention of configuration, (2) the extent of an inversion product increases with decreasing chelating ability of the N-substituent and with increasing leaving ability (ionic character) of a countercation (Li, Na, K) of the anionic species, and (3) the use of a more reactive electrophile results in an increase of the retention product.
Formation of 2-Cyano-2-siloxyvinylallenes via Cyanide-Induced Brook Rearrangement in γ-Bromo-α,β,γ,δ-unsaturated Acylsilanes
- An enantioselective Meerwein-Ponndorf-Verley-type reduction of ynenoylsilanes by a chiral lithium amide followed by a Brook rearrangement and anti-mode protonation across conjugated 1,3-enynes provides allene derivatives bearing a 2-siloxyvinyl moiety in high enantioselectivity. The E/Z geometry of enol silyl ethers is controlled by the geometry of the starting enyne moiety. Thus, (E)- and (Z)-enol silyl ethers are obtained from (Z)- and (E)-ynenoylsilans, respectively. The 2-siloxyvinylallene products can participate in Diels-Alder reactions with reactive dienophiles such as PTAD, which can be achieved in a one-pot operation from ynenoylsilanes.
Enantioselective Synthesis of a-Silylamines by Meerwein-Ponndorf-Verley-Type Reduction of
α-Silylimines by a Chiral Lithium Amide
- Reactions of γ-bromo-α,β,γ,δ-unsaturated acylsilanes with KCN under phase-transfer catalyst conditions using n-Bu4NCN afforded 2-cyano-2-siloxyvinylallenes via a tandem process that involves a nucleophilic attack of a cyanide ion and a Brook rearrangement-induced conjugate vinylic 1,4-elimination. Use of a chiral cyanide ion source, derived from KCN and quaternary ammonium bromide derived from cinchona alkaloids, provided nonracemic allene derivatives. Based on this result and the reaction using a chiral hydride ion source, we propose a reaction pathway in which a Brook rearrangement-mediated vinylic conjugate 1,4-elimination occurs in a syn alignment between the C-Br bond and C-Si bond in the silicate intermediate.
Enantiodivergent Deprotonation-Acylation of α-Amino Nitriles
- Meerwein-Ponndorf-Verley-type reduction of N-tosylsilylimines with chiral lithium amide affords α-silylamines in high enantioselectivity. Since the enantioselectivity observed was inconsistent with our previously proposed chair-like six-membered transition structure, we performed density functional theory (DFT) calculations on transition states using an N-phenylsulfonyl derivative as a model system. Results of the calculations showed that the structures are considerably deformed from the chair-like form with steric repulsions between the 1'-methylene group and the imine-carbon substituents playing an important role in the control of the enantioselectivity.
Chirality Transfer in Brook Rearrangement-Mediated SE2’ Solvolytic Protonation and Its Use in Estimation of the Propensity for Racemization of the α-Lithiocarbanions of the Substituents
- Deprotonation-acylation of enantioenriched α-ureidonitriles, readily derived from α-amino acids, was found to proceed in a highly enantiodivergent manner despite the required intermediacy of extremely stereolabile α-nitrile metalocarbanions. As a rationale for the enantiodivergence observed depending on the base used, in the case of less basic hexamethyldisilazides, deprotonation in which a metal cation is pre-complexed with an electrophile was proposed and the proposal was supported by DFT calculations.
Enantioselective Trapping of an α-Chiral Carbanion of Acyclic Nitrile by a Carbon Electrophile
- Chirality transfer from an α-silylalcohol to differently substituted α-carbmoyloxy- and α-siloxyallyl carbanions was investigated using a Brook rearrangement-mediated SE2’ solvolytic protonation in γ-substituted γ-carbamoyloxy- and γ-siloxy-α-silylallyl alcohols. Comparison of the extent of the chirality transfer provides a new method for semi-quantitative evaluation of the propensity for racemization of lithiocarbanions next to a conjugative electron-withdrawing group or an anion-stabilizing heteroatom substituent.
Steric Course of the Electrophilc Substitution of Lithiocarbanion Generated from (S,E)-1-Phenylbut-2-en-1-yl Diisopropylcarbamate and Influence of Solvent Effects
- An α-chiral nitrile carbanion generated by deprotonation of enantioenriched O-carbamoyl cyanohydrin was trapped in situ with ethyl cyanoformate in Et2O at -114 °C to give the corresponding ester derivative in 92% yield and 90:10 er, providing the first example of trapping of an α-chiral acyclic nitrile carbanion that has been considered to be very configurationally labile.
Enantioselective Synthesis of Siloxyallenes from Alkynoylsilanes by Reduction and
Brook Rearrangement and Their Subsequent Trapping in [4 + 2] Cycloaddition
- The effects of electrophiles and solvents on the stereochemistry of electrophilic substitution of lithiocarbanion generated from (S,E)-1-phenylbut-2-en-1-yl diisopropylcarba-mate were examined using various acids and carbon electrophiles.
Solvent Effects on the Steric Course of [2,3]-Wittig Rearrangement of (S,E)-(3-(allyloxy)prop-1-ene-1,3-diyl)dibenzene and Its Derivatives
- An enantioselective Meerwein-Ponndorf--Verley-type reduction of alkynoylsilanes by a chiral lithium amide followed by a Brook rearrangement and SE2' electrophilic substitution provides the title compounds in a one-pot process. In the case of enynoylsilanes, the generated vinylallenes undergo in situ [4 + 2] cycloaddition to afford highly functionalized polycyclic compounds with unusual facial selectivity.
Formal Total Syntheses of (+)-Prelaureatin and (+)-Laurallene by Diastereoselective Brook Rearrangement-Mediated [3 + 4] Annulation
- The effect of solvents and additives on configurational stability of chiral carbanions was examined on the basis of extent of chirality transfer in intramolecular trapping in [2,3]-Wittig rearrangement of chiral 1,3-diphenyl-1-propenyloxy-2-propen-1-yl carbanion and its derivatives. The solvent effect was also examined on the Hoffmann test.
[2,3]-Wittig Rearrangement of Enantiomerically Enriched 3-Substituted 1-Propenyloxy-1-phenyl-2-
propen-1-yl Carbanions: Effect of Heteroatoms and Conjugating Groups on Planarization of an α-Oxy-Benzylcarbanion Through a Double Bond
- The formal syntheses of (+)-prelaureatin and (+)-laurallene, halogenated eight-membered-ring ethers, are described. The key step of our strategy relies on diastereoselective construction of a trans-α,α'-disubstituted oxocene structure through a Brook rearrangementmediated [3 + 4] annulation with acryloylsilane and 6-oxa-2-cycloheptenone derivative.
Stereoselective Brook Rearrangement-Mediated SE2' Protonation of α-Hydroxy Allyl Silanes
- The effect of conjugating electron-withdrawing groups and α-anion-stabilizing heteroatom substituents on configurational stability of chiral carbanions through a double bond was examined on the basis of extent of chirality transfer in intramolecular trapping in [2,3]-Wittig rearrangment of chiral 3-substituted 1-propenyloxy-1-phenyl-2-propen-1-yl carbanions.
Diastereoselective Brook Rearrangement-Mediated [3 + 4] Annulation: Application to a Formal Synthesis of (+)-Laurallene
- Treatment of (R,Z)-3-(tert-butyldimethylsilyl)-1-cyano-3-hydroxyprop-1-enyl carbamate with a catalytic amount of a base afforded (S,E)-3-(tert-butyldimethylsilyloxy)-1-cyanoallyl diisopropylcarbamate, showing that SE2'-type reaction of allylsilicates proceeds in an anti-mode fashion. The overall process is equivalent to trapping of an enantioenriched C-chiral carbanion at a-position of nitrile group in up to 77% ee.
Chirality Transfer from Epoxide to Carbanion: Base-Induced Alkylation of O-Carbamoyl
Cyanohydrins of β-Silyl-α,β-epoxyaldehyde
- The formal synthesis of (+)-laurallene, a halogenated eight-membered ring ether, was accomplished. The synthesis involves construction of a trans α,α’-disubstituted oxocene structure 3 through a Brook rearrangement-mediated [3 + 4] annulation using acryloylsilane 1 and 6-oxa-2-cycloheptenone 2 and its conversion into 4, which has been transformed into (+)-laurallene by Crimmins and coworkers.
Tandem Epoxysilane Rearrangement/Wittig-Type Reactions Using γ-Phosphinoyl- and γ-
- Enantioselective C-C bond formation at an α-position of a nitrile group with an external electrophile can be realized, although in modest ee, with the aid of both the concerted process of the epoxysilane rearrangement and a carbamoyl group.
Epoxysilane Rearrangement Induced by a Carbanion Generated by Conjugate Addition of Enolates
of Chloroacetate and α-Chloroacetamides: Formation of Functionalized Cyclopropane Derivatives
- Reaction of γ-phosphinoyl- and γ-phosphonio-α,β-epoxysilane with a base followed by addition of a ketone or an aldehyde afforded dienol silyl ether derivatives via a tandem process that involves base-induced ring opening of the epoxide, Brook rearrangement, and Wittig-type reaction.
Asymmetric [2,3]-Wittig Rearrangement Induced by a Chiral Carbanion Whose Chirality Was Transferred from an Epoxide
- Reaction of an enoate bearing an epoxysilane moiety at the α-position with lithium enolate of 2-chloroacetamide afforded highly functionalized cyclopropane derivatives via a tandem process that involves Michael addition, ring opening of the epoxide, Brook rearrangement, and intramolecular alkylation.
γ-p-Toluenesulfonyl-α,β-epoxysilane: A New and Practical Acrolein β-Anion Equivalent
- The enantioselective [2,3]-Wittig rearrangement of 1-allyloxy-1-(naphthalen-2-yl)-4-siloxy-2,4-pentadienyl anion, derived from optically enriched 4,5-epoxy-1-(naphthalen-2-yl)-5-silyl-2-pentenyl allyl ether via a base-induced ring opening of the epoxide followed by Brook rearrangement, has been studied. The chirality of the epoxide was transferred to the alcohols in up to 97% ee, depending on the solvent used. The best result was obtained in 1,4-dioxane at a temperature above room temperature.
Stereoselective Construction of Eight-Membered Oxygen Heterocycles by Brook Rearrangement-
Mediated [3 + 4] Annulation
- Reaction of γ-p-toluenesulfonyl-α,β-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF affords α,β-unsaturated aldehydes via a Brook rearrangement-mediated tandem process under extremely mild conditions.
Tandem Base-Promoted Ring-Opening/Brook Rearrangement/Allylic Alkylation of O-Silyl
Cyanohydrins of β-Silyl-α,β-epoxyaldehyde: Scope and Mechanism
- A newly developed strategy for eight-membered oxgen heterocycles via [3 + 4] annulation that involves the combination of β-substituted acryloylsilanes and enolates of 6-oxacyclohept-2-en-1-one is described. A unique feature of this annulative approach is its capacity to generate eight-membered ring systems containing useful functionalities for further synthetic elaboration from readily available three- and four-carbon components.
- Metalated O-silyl cyanohydrins of β-Silyl-α,β-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem sequence involving base-promoted ring opening of the epoxide, Brook rearrangement, and alkylation of the resutling allylic anion. On the basis of mechanistic studies involving competitive experiments using the diastereomeric cyanohydrins, we propose a reaction pathway involving a silicate intermediates formed by a concerted process via an anti-opening of the epoxide followed by the formation of an O-Si bond.
Tandem Base-Promoted Ring-Opening/Brook Rearrangement/Allylic Alkylation of O-Silyl
Cyanohydrins of β-Silyl-α,β-epoxyaldehyde
- Metalated O-silyl cyanohydrins of β-Silyl-α,β-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem sequence involving a base-promoted ring opening of the epoxide, Brook rearrangement, and alkylation of the resulting allylic anion.