Total synthesis of (±)-bruguierol A via an intramolecular [3+2] cycloaddition of cyclopropane 1,1-diester

Total synthesis of natural product (±)-bruguierol A was accomplished in 10-steps and with an overall 16.8% yield. The embedded unique 8-oxabicyclo[3.2.1]octane core skeleton in this natural product was constructed via a novel Sc(OTf)₃-catalyzed intramolecular [3+2] cycloaddition of cyclopropane, which was developed recently in this laboratory. This general synthetic strategy can be potentially applied to the synthesis of a broad range of structurally related natural products.     

TiCl4-promoted tandem carbonyl or imine addition and Friedel-Crafts cyclization: synthesis of benzo-fused oxabicyclooctanes and nonanes

A new and convenient synthesis of benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives are described. The reaction involved a TiCl(4)-mediated tandem carbonyl or imine addition followed by a Friedel-Crafts cyclization to provide these functionalized derivatives in good to excellent yields and high diastereoselectivity.     

Stereocontrolled Routes to Bridged Ethers by Tandem Cyclizations

Ring contraction of a 3,4-epoxyalcohol, then lactolization and electrophilic attack are the steps in the domino cyclization protocol for the formation of 8-oxabicyclo[3.2.1]octane systems [Eq. (a)].     

Asymmetric synthesis of the northern half C1-C16 of the bryostatins

Starting from 8-oxabicyclo[3.2.1]oct-6-en-3-one and racemic 2,2-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one, the C1-C16 segment of the bryostatins has been synthesized in 30 steps and 9% overall yield (17 steps longest linear sequence). Fragment coupling by dithiane strategy and protecting group manipulations provided an advanced chemodifferentiated northern half segment.     

Synthesis of bruguierol A employing ring closing metathesis

An expedient synthesis of bruguierol A encompassing a novel 2,3-benzo-8-oxabicyclo[3.2.1]octane ring system is described employing ring closing metathesis to generate the oxa-bridged tricyclic core.     

Reaction of neorl with thallium(III) perchlorate

Reaction of nerol ($\text{1}$) with thallium(III) perchlorate gave 6-oxabicyclo[3.2.1]octane derivatives ($\text{2}$) and ($\text{3}$), and 6,9-dioxabicyclo[3.3.1]nonane derivatives ($\text{4a–d}$) as the cyclization products.     

Concise entry to both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one based on novel oxidative etherification: formal synthesis of (+)-sundiversifolide

Both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6) have been synthesized from 4-hydroxycyclohept-2-enone (3) on the basis of a novel oxidative cyclo-etherification using PhI(OH)OTs (Koser's reagent). (-)-(1S,5R)-8-Oxabicyclo[3.2.1]oct-3-en-2-one [(-)-6, 95% ee] was expeditiously transformed to (+)-sundiversifolide (1).     

Sulfide extrusion from the methylsulfonium salts of 8-thiabicyclo [3.2.1]oct-2-enes and the related sulfonium salts by methyllithium

The methysulfonium salts of 2-methylene-8-thiabicyclo[3.2.1]octane and 8-thiabicyclo[3.2.1]oct-2-enes underwent sulfide extrusion by methyllithium to give dimethyl sulfide and the hydrogen shift products (cycloheptadienes) and/or the closure products (bicycloheptenes).     

Synthesis of 2-substituted (+/-)-(2r,3r,5r)-tetrahydrofuran-3,5-dicarboxylic acid derivatives

An efficient synthesis of 2-substituted (+/-)-(2R,3R,5R)-tetrahydrofuran-3,5-dicarboxylic acid derivatives has been developed. Starting from 5-norborne-2-ol, the key intermediate (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) was synthesized in an efficient six-step sequence. The key transformation is the base-catalyzed methanolysis-rearrangement of (+/-)-6,7-exo,exo-(isopropylidenedioxy)-4-exo-iodo-2-oxabicyclo[3.2.1]octan-3-one (14). Further manipulation of the 3-substituent of (+/-)-methyl 5,6-exo,exo-(isopropylidenedioxy)-2-oxabicyclo[2.2.1]heptane-3-exo-carboxylate (15) followed by deprotection of the diol moiety and ring opening catalyzed by RuCl(3)/NaIO(4) gave the title compounds in good yield.     

Corner Bromination of 2-Methyl-endo-tricyclo[3.2.1.0(2,4)]octane and -oct-6-ene

Reaction of 2-methyl-endo-tricyclo[3.2.1.0(2,4)]octane (1) with bromine in CCl(4) gave 2-exo,3-endo-dibromo-2-endo-methylbicyclo[3.2.1]octane (3) which rearranges on silica to 2-exo,6-endo-dibromo-1-methylbicyclo[2.2.2]octane (4). Reaction in methanol gave 4-endo-bromo-2-exo-methoxy-2-endo-methylbicyclo[3.2.1]octane (10) and 4-endo-bromo-2-endo-methoxy-2-exo-methylbicyclo[3.2.1]octane (11) formed by corner attack of the bromine electrophile with C2-C4 bond rupture and inversion of configuration at the site of electrophilic attack. Reaction of 2-methyl-endo-tricyclo[3.2.1.0(2,4)]oct-6-ene (2) with bromine in CCl(4) and methanol gave products of reaction at the alkene site.     

Skeletal rearrangements of <Emphasis Type="Italic">cis</Emphasis>-(-)-7,8-epoxycarveol derivatives promoted by triethylsilyl trifluoromethanesulfonate

Diastereoisomeric couples of (1R,5R,6RS)-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-en-6-ylmethanols and their epoxide precursors, (5R,2′RS)-2-methyl-5-(2-methyloxiran-2-yl)cyclohex-2-en-1-ols, in the presence of triethylsilyl trifluoromethanesulfonate underwent [3.2.1]→[3.3.1] skeletal rearrangement with formation of scalemic mixtures of (1R,5R,6R)- and (1R,5R,6S)-2,6-dimethyl-6-triethylsiloxy-8-oxabicyclo[3.3.1]non-2-enes; the (6R)-stereoisomer was isolated as individual substance.     

Asymmetric Syntheses of 8-Oxabicyclo[3,2,1]octanes: A Cationic Cascade Cyclization

High octane: A novel and practical syntheses of 8-oxabicyclo[3.2.1]octanes using a cationic cascade cyclization reaction has been developed (see scheme; TIPS=triisopropylsilyl). The diastereomer of the cyclization product isolated depends upon whether the acetal or aldehyde substrate is used.     

Cyclocondensations of (+)-camphor derived enaminones with hydrazine derivatives

Reactions of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor with hydrazines afforded the corresponding fused pyrazoles. Similarly, fused pyrazoles were obtained upon reaction of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with ortho-unsubstituted phenylhydrazines, while reactions with ortho-substituted phenylhydrazines and with hydrazine hydrochloride resulted in ‘ring switching’ type of transformation to furnish 2-aryl-4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones.     

A Tandem Horner-Emmons Olefination-Conjugate Addition Approach to the Synthesis of 1,5-Disubstituted-6-azabicyclo[3.2.1]octanes Based on the AE Ring Structure of the Norditerpenoid Alkaloid Methyllycaconitine

A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues based on the AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-6-acetamido-6-azabicyclo[3.2.1]octane (28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo[3.2.1]octane (3) are also described.     

Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Stereoselective carbonyl reductions of chloro-substituted 8-oxabicyclo[3.2.1]oct-6-en-3-ones

The lithium aluminium hydride reduction of 2,2,4,4-tetrachloro-8-oxabicyclo[3.2.1]oct-6-en-3-one (8) was reinvestigated. In contrast to most halogeno-substituted oxabicyclic ketones, which give predominantly the corresponding endo alcohols, the expected (3endo)-2,2,4,4-tetrachloro-8-oxabicyclo[3.2.1]oct-6-en-3-ol (9n) is formed in a minute proportion. An X-ray structure analysis of the dominating product gave proof of the exo-alcohol, i.e., (3exo)-2,2,4,4-tetrachloro-8-oxabicyclo[3.2.1]oct-6-en-3-ol (9x). On the other hand, reduction of trichloroketone 11, 2,2,endo-4-trichloro-8-oxabicyclo[3.2.1]oct-6-en-3-one, and the methoxy-substituted chloroketones 13 and 14 provided the corresponding endo alcohols (12 and 15).     

Synthesis of (1s,5r)-karahana ether and (1s,5r)-karahana lactone,the optically active forms of unique monoterpenes wit

(1$\text{S}$,5$\text{R}$)-(-)-Karahana ether (8,8-dimethyl-2-methylene-6-oxabi-cyclo[ 3.2.1]octane) and (1$\text{S}$,5$\text{R}$)-(-)-karahana lactone (8,8-dimethyl-2-methylene-6-oxabicyclo [3.2.1]octan-7-one) were synthesized from ($\text{S}$)-3-hydroxy-2,2-dimethylcyclo-hexanone. The natural karahana lactone was shown to be almost racemic ($\text{ca}$. 1.3 % e.e.).     

Scope and limitations of the double [4+3]-cycloadditions of 2-oxyallyl cations to 2,2'-methylenedifuran and derivatives

The reactivity of various 2-oxyallyl cations toward 2,2'-methylenedifuran (1b), 2,2'-(hydroxymethyl)difuran (1c), 2,2'-(trimethylsilylmethylene)difuran (1d), and di(2-furyl)methanone (1e) has been explored. Difuryl derivatives 1c, 1d, and 1e refused to undergo formal double [4+3]-cycloadditions. Conditions have been found to convert 1b into meso-1,1'-methylenedi[(1R,1'S,5S,5'R)- (3) and (+/-)-1,1'-methylenedi[(1RS,1'SR,5SR,5'RS)-8-oxabicyclo[3.2.1]oct-6-en-3-one] (4) that do not require CF(3)CH(OH)CF(3) as solvent. High yields of meso-1,1'-methylenedi[(1R,1'S,2S,2'R,4R,4'S,5S,5'R)- (5) and (+/-)-1,1'-methylenedi[(1RS,1'RS,2SR,2'SR,4RS,4'RS,5SR,5'SR)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one] (6) have been obtained when 1b was reacted with 2,4-dibromopentan-3-one (7h) and NaI/Cu.     

Synthesis and reactions of 2-aryl-8-oxabicycloc[3.2.1]oct-6-en-3-ones

A number of 1-aryl-1-bromopropanones have been prepared and converted into the corresponding oxyallyl carbocations. These were reacted with furan to produce the expected 2-aryl-8-oxabioyclo[3.2.1]oct-6-en-3-ones, as well as a number of interesting side-products. These included 3-aryl-propanoic acid esters produced via Favorskii rearrangements. Attempts to cleave the ether linkage in the cycloadducts using bromotrimethylsilane produced instead 1-aryl-3-furylpropanones in excellent yield.     

Study on the Reaction of CIS-1-Acetyl-2-Aryl-6,6-Dimethyl-5,7-Dioxospiro-[2,5]-4,8-Octadiones with Methanol

Cis-l-acetyl-2-aryl-6,6-dimethyl-5,7-dioxo-spiro-[2,5]-4,8-octadiones 3a-d (X=p-CH₃, p-Cl, H, p-NO₂) reacted with anhydrous methanol in a sealed tube at 80°C to form trans, cis-α-carbomethoxy-β-(α′-methoxy-α′-aryl)-γ-methoxy-γ-methyl-γ-butyrolactones 4a-d and cis, cis-α-carbomethoxy-β-(α′-methoxy-α′-aryl)-γ-methoxy-γ-methyl-γ-butyrolactones 5a-d in good yield.