Our research interests extend over several areas of organic chemistry, including the invention of new reactions, their mechanistic studies, and synthetic applications. (Click here for Synthetic Studies of Natural Products)
A new [3 + 2] annulation strategy for the synthesis of highly functionalized five-membered carbocycles has been developed. The annulation utilizes b-phenylthio-a,b-unsaturated acylsilane 1 and methyl ketone enolate 2 as the three- and two-carbon components, respectively. Reaction of both (E)- and (Z)-1 provided exclusively diastereomeric cyclopentenols 3 and 4 in preference of 3.
This new methodology has been successfully applied to the synthesis of Untenone A (5), chromomoric acid D-II Me ester (6), the antitumor marine prostanoid clavulones (claviridenones ) (7).
Reactions of four diastereomeric 2-(2-(trimethylsilyl)ethenyl)cyclopropyl acetates 8, derived from enol silyl ether and Fischer carbene complex 9, with 2.2 equiv of MeLi at -80 ° to -30 °C afforded cyclopentenol and acyclic enol silyl ethers 12 via the corresponding cyclopropanolates in ratios depending on the vinylsilane geometry. Predominant formation of 11 over 12 from (Z)-10 irrespective of the stereochemistry at C-1 was observed. This is the first example of oxyanion-accelerated vinylcyclopropane-cyclopentene rearrangement which proceeds at unprecedentedly low temperatures.
The a-carbanion-stabilizing ability of the phenylthio and trimethylsilyl groups was compared based on the relative rate of the base-catalyzed Brook rearrangement of the b-substituted a-silylallylalcohol.
Reactions of the E and Z isomers of b-(trimethylsilyl)acryloyl(tert-butyl)dimethylsilanes 9 (X = SiMe3) with lithium enolate of a,b-unsaturated methyl ketones 10 at -80 °to -30 °C afford cis-5,6 and trans-5,6-disubstituted 3-cyclohepetenones 13, respectively. The same [3 + 4] annulation is observed in the reaction of b-(tri-n-butylstannyl)acryloyl)silanes. The annulation products are readily transformed into 4-cycloheptene-1,3-dione by treatment with NBS or mCPBA. The observed stereospecificity in the annulation is explained by the reaction pathway that involves an anionic oxy-Cope rearrangement of 1,2-divinylcyclopropanediol intermediate 12 generated via Brook rearrangement of the 1,2-adduct of and a lithium enolate. Isolation of vinylcyclopropanol derivative from the reaction of b-(tri-n-butylstannyl)acryloyl)silanes with lithium enolate of 2'-bromoacetophenone and its transformation into cycloheptenone derivative with LDA provide strong support for the proposed mechanism. Further support is obtained from the reactions of 1,2-divinylcyclopropyl acetates with 2 equiv of MeLi affording cycloheptenones stereospecifically. Also, b-alkyl-substituted acryloylsilanes 9 (X = Alkyl) and cycloalkenylcarbonylsilanes are found to participate the [3 + 4] annulation.
A tandem Brook rearrangement-intramolecular Michael reaction has been developed as a synthetic route to functionalized carbocycles. Acylsilanes, tethered by a two-, three-, or four-carbon chain to an acrylate Michael acceptor, have been prepared and used as the cyclization substrates. Treatment of these compounds with PhLi or LiP(O)(OMe)2 at temperatures below 0 °C results in the formation of four- to six-membered carbocycles in good yields.
The reaction of 4-substituted 2-(t-butyldimethylsiloxy)-1,3-butadiene with acetoxy chromium Fischer carbene complexes afforded bicyclo[4.1.0]heptene derivative, an intramolecular C-H insertion product of the initially formed Diels-Alder adduct. The role of the metal and the heteroatom ligand in the carbene complex, and of the substituent at 3-position on the C-H insertion has been examined.
Reaction of b-substituted acryloylsilanes 23 with lithium amides 24 affords a-silyl allylic alcohols 25 in high enantiomeric excess (99%) via formal hydride transfer from the chiral lithium amide.
Reaction of 3-alkyl-3-haloacryloylsilanes 17 with the lithium enolate of 1-acetyl-1-cyclopentene 18 afforded tricylco[5.3.0.01,4]decenone derivatives 20 via Brook rearrangement-mediated [3 + 4] annulation.
The reactions of acylsilanes 21 with KCN under liquid-liquid phase-transfer catalytic conditions proceeded smoothly via the Brook rearrangement to produce O-silylated cyanohydrin derivatives 22 in excellent yields. We also found that a-cyano carbanions generated by the Brook rearrangement in the reaction of (b-(trimethylsilyl)acryloyl)silane 23 can undergo alkylation at the g-position and that in the reaction of b-bromoacylsilane 25 intramolecular alkylation occurs to afford cyclopropanone cyanohydrin derivative 27.
The reaction of silyl thioketone 28 with lithium diethylphosphite 29 afforded a S-attack product 31 and products 34 and 35 arising from an S-to-O migration (30 to 32) of the phosphoryl group in the S-adduct followed by a C-to-S migration of the silyl group (thia-Brook rearrangement: 32 to 33) in different ratios depending on the reaction conditions. Also, the relative rates of occurrence of the thia-Brook (unprecedented) and Brook rearrangements were determined.
The tricyclic core of cyathins, which have been isolated from bird nest fungi and other members of this family and have been shown to have potent nerve growth factor (NGF) synthesis-stimulating activity and to be a k opioid receptor agonist, has been synthesized using a Brook rearrangement-mediated [3 + 4] annulation that we previously developed. The key [3 + 4] annulation proceeded smoothly when 43 was added to a solution of acryloylsilane 44 at -80 °C and allowed to warm to 0 °C to afford 47 as a single diastereomer in 50% yield. The observed stereoselectivity can be rationalized by a concerted pathway of the anionic oxy-Cope rearrangement of the cis-1,2-divinylcyclopropanediolate intermediate 46 which was stereoselectively derived from the 1,2-adduct 45 by the Brook rearrangement, followed by internal trapping of the generated carbanion by the ketone carbonyl. Oxidative desilylation of 47 was realized after DIBAL reduction to alcohol 48 to afford enone 49 in 79% yield.
A new route to (Z)-b-silylacryloylsilanes and the improved conditions for the [3 + 2] annulation using the acryloylsilanes and alkyl methyl ketone enolates are reported. Also, details of investigations defining a reaction course of the [3 + 2] annulation using b -phenylthio- and b -trimethylsilyl-acryloylsilanes (X = SPh, SiMe3) and alkyl methyl ketone enolates are described.
A newly developed strategy for eight-membered carbocycles via [3 + 4] annulation that involves the combination of b-substituted acryloylsilanes and enolates of cycloheptenone is described. A unique feature of this annulative approach is its capacity to generate in two steps eight-membered ring systems containing useful functionalities for further synthetic elaboration from readily available three- and four-carbon components.
Metalated O-silyl cyanohydrins of b-silyl-a,b-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.
A newly developed strategy for construction of eight-membered carbocycles via [6 + 2] annulation that involves the combination of b-alkenoyl acylsilanes and a vinyllithium derivative is described. A unique feature of this annulative approach is that it enables construction in one operation and a stereoselective manner of eight-membered ring systems containing useful functionalities for further synthetic elaboration from readily available six- and two-carbon components.
Metalated O-silyl cyanohydrins of b-silyl-a,b-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.
A newly developed strategy for eight-membered oxgen heterocycles via [3 + 4] annulation that involves the combination of b-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.
The reaction of d-silyl-g.d-epoxypentanenitrile derivatives with a base and an alkylating agent affords d-siloxy-g,d-unsaturated pentanenitrile derivatives via a tandem process that involves the formation of cyclopropane derivative by epoxy nitrile cyclization followed by Brook rearrangement and an anion-induced cleavage of the cyclopropane ring.
Reaction of d-silyl-g,d-epoxy-a,b-unsaturated acylsilanes with KCN in the presence of chloro- or cyano-formates gives highly functionalized dienol silyl ether derivatives via a two-fold Brook rearrangement-induced tandem sequence.
Reaction of γ-silyl-β,γ-epoxybutanenitrile with a base generates α-nitrile carbanion derivative of 4-siloxybut-3-enenitrile, which undergoes reaction with bis-electrophiles such as 1,ω-dihaloalkanes, ω-bromo-α,β-unsaturated esters, and bisenoates to provide highly functionalized carbocycles.
Reaction of g-p-toluenesulfonyl-a,b-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF affords a,b-unsaturated aldehydes via a Brook rearrangement-mediated tandem process under extremely mild conditions.
Reaction of trans- and cis-δ-silyl-γ,δ-epoxy-α,β-unsaturated acylsilanes with cyanide ion in the presence of an electrophile affords double Brook rearrangement products in an E/Z ratio depending on the cis/trans geometry of the epoxysilanes.
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.
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.
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.
Reactions of δ-silyl-γ,δ-epoxy-α,β-unsaturated acylsilane with alkenyl methyl ketone enolate afford highly functionalized cycloheptenone derivatives via a tandem sequence featuring the combination of Brook rearrangement-mediated [3 + 4] annulation and epoxysilane rearrangement. The reactions using an opposite combination of three and four carbon units, in which an epoxysilane moiety was incorporated in the four-carbon unit, also give satisfactory results. Also, the possibility of chirality transfer from epoxide to remote positions via the tandem sequence using an optically active epoxide has been demonstrated.
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.
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 16 through a Brook rearrangement-mediated [3 + 4] annulation using acryloylsilane 10 and 6-oxa-2-cycloheptenone 9 and its conversion into 2, which has been transformed into (+)-laurallene by Crimmins and coworkers.
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 rearrangement of chiral 3-substituted 1-propenyloxy-1-phenyl-2-propen-1-yl carbanions.
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.
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-a,a'-disubstituted oxocene structure through a Brook rearrangementmediated [3 + 4] annulation with acryloylsilane and 6-oxa-2-cycloheptenone derivative.
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.
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.
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.
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.
