Synthesis of the C29–C37 segment of spongistatin 1

Starting from racemic 2α-methyl-8-oxabicyclo[3.2.1]oct-6-en-3-one the spongistatin E segment has been prepared in nine steps (2.3 steps per stereogenic center) with umpolung of anomeric reactivity at C37. This 3,5-syn-diol sequence completes our methodology to all stereoisomers of 3,5,7-trihydroxy heptanoic ester building blocks functionalized for α-oxyanion chemistry.     

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).     

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).     

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.     

High stereochemical diversity and applications for the synthesis of marine natural products: a library of carbohydrate mimics and polyketide segments

We have developed a powerful concept for the rapid assembly of a series of twenty-four homochiral building blocks from simple racemic trans-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one. The series comprises eight stereochemical pentades of anomeric [3.3.1]lactone acetals, eight stereochemical tetrades of anomeric carbohydrate mimics, and eight stereotetrades of acyclic polypropionate units. The utility of these enantiopure materials (average 94% ee) in natural product synthesis is demonstrated and shown to complement the popular aldol method.     

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.     

Total synthesis of tropoloisoquinolines: imerubrine, isoimerubrine, and grandirubrine.

A unified, ready access to the tropoloisoquinoline alkaloids imerubrine (1), grandirubrine (2), and isoimerubrine (3) is delineated and features sequential application of the intramolecular Diels-Alder reaction of an acetylene-tethered oxazole and the [4 + 3] cycloaddition of an oxyallyl. A regioselective synthesis of 1 was achieved by stereo- and regioselective oxidation of an 8-oxabicyclo[3.2.1]oct-6-en-3-one cycloadduct by means of the Moriarty method. Such a post-cycloaddition functionalization complements the synthetic utility of an alpha-alkoxy-substituted oxyallyl so as to broaden the scope of the oxyallyl [4 + 3] cycloaddition reaction.     

Heterotricyclodecane XXVII. Ein weiterer Zugang zu 2,6-Dioxatricyclo [3.3.2.03,7]decan

A Further Approach to 2,6-Dioxatricyclo[3.3.2.0^3,7]decane A further synthesis of 2,6-dioxatricyclo[3.3.2.0^3,7]decane ( 10 ) is described by bridging the 9-oxabicyclo[4.2.1]non-7-en-3endo-ol ( 9 ). The latter compound was prepared by ring expansion starting from the known 8-oxabicyclo[3.2.1]oct-6-en-3-on ( 1 ).     

Oxazatricyclic noradamantanes: stereocontrolled synthesis of functionalized scopolines, related cage molecules, and drug leads

Scopolines 4 and the noradamantane scaffold are accessible from 8-oxabicyclo[3.2.1]oct-6-en-3-ones such as 6 by a concise route involving introduction of an axial amino nitrogen at C3, epoxidation, and cyclization. The resulting cage molecules are versatile drug leads.     

A bicyclo[3.2.0]hept-3-en-6-one approach to prostaglandin intermediates

[reaction:see text] The substituted cyclopentanic structures, 6-benzyloxymethyl-7-hydroxy-2-oxabicyclo [3.3.0]octan-3-one (1), a Corey lactone derivative, and 6-exo-benzyloxymethyl-2-oxabicyclo[3.3. 0]oct-7-en-3-one (2), have been obtained stereoselectively through the bicyclo[3.2.0]hept-3-en-6-one approach via 5-benzyloxymethyl-3-hydroxy-6-heptenoic acid, easily accessible from the inexpensive monoprotected cis-2-butene-1,4-diol.     

Synthesis of 2,6-dioxatricyclo[3.3.1.0]nonanes by intramolecular haloetherification and/or transannular hydroxycyclization of alkenes in [4+3]-cycloadducts

The synthesis of new difunctionalized 2,6-dioxatricyclo[3.3.1.0^3,7]nonanes is described. This type of structure is an interesting synthetic building block for potential bioactive molecules and it was prepared from 8-oxabicyclo[3.2.1]oct-6-en-3-one having a NHBoc function on C-1. This precursor was obtained by a [4+3] cycloaddition reaction of 2-tert-butoxycarbonylaminofuran and the oxyallyl cation generated in situ from 2,4-dibromo-3-pentanone. Reduction of the carbonyl group at C-3 was accomplished in high yield and stereoselective manner to afford the corresponding axial alcohol at C-3 as a major product. Further intramolecular haloetherification of this type of alcohols with NBS and I(py)2BF₄ led to the corresponding bromo and iodo-derivatives at C-8 of the 2,6-dioxatricyclo[3.3.1.0^3,7]nonane framework, in high yield. Epoxidation of 8-oxabicyclo[3.2.1]oct-6-en-3-ol followed by treatment with NaCN, NaN₃, and/or NaOH in MeOH afforded 8-hydroxy-2,6-dioxatricyclo[3.3.1.0^3,7]nonanes in high yield via a transannular hydroxycyclization mediated by a base and through an alkoxide intermediate. The new 2,6-dioxatricyclo[3.3.1.0^3,7]nonanes were tested for biological activity against HIV-1 virus and MT-4 lymphoid cell line, showing a low anti-HIV activity and a high degree of cytotoxicity.     

Oxidation of (1<Emphasis Type="Italic">S</Emphasis>,5<Emphasis Type="Italic">R</Emphasis>,7<Emphasis Type="Italic">R,S</Emphasis>)-(4,7-dimethyl-6-oxabicyclo[3.2.1]oct-3-en-7-yl) methanol with pyridinium chlorochromate

The oxidation of (1S,5R,7R,S)-(4,7-dimethyl-6-oxabicyclo[3.2.1]oct-3-en-7-yl)methanol epimeric at the C⁷ atom resulted in scalemic (5R)-5-acetyl-2-methylcyclohex-2-en-1-one.     

Photochemical rearrangement of 8-oxabicyclo[3.2.1]oct-6-en-2-ones

Irradiation of 8-oxabicyclo[3.2.1]oct-6-en-2-ones results in a 1,3-acyl rearrangement. The initial photoproduct undergoes a subsequent reaction involving hydrogen transfer followed by intramolecular cycloaddition of a ketene intermediate.     

Chiral cyclohexene block from <Emphasis Type="Italic">R</Emphasis>-(−)-carvone

The oxidation with SeO₂ of a methyl group linked to an sp²-hybridized carbon in the product of the intramolecular iodoetherification of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]-oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-yl]methanol that were oxidized to methyl (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylate. The latter by the Zn-promoted opening of the γ-oxide ring was converted into the target chiral block, methyl (4R,6R)-6-hydroxy-4-(prop-1-en-2-yl)cyclohex-1-encarboxylate.     

C1-C2 cleavage of C1-functionalized 8-oxabicyclo-[3.2.1]-oct-6-en-3-one. Stereoselective preparation of 4-substituted butenolides

Diastereoisomeric epimers at C1′ of 4-(1-methyl-2-oxo-butyl)-2-butenolide, and the corresponding saturated γ-lactones, were synthesized by hydrolysis of 1-methoxy-8-oxabicyclo[3.2.1] oct-6-en-3-one, under acidic conditions. These butenolides are interesting synthetic building blocks, precursors of biologically active natural products like insect pheromones. Their formation could be explained by a cleavage at the C1-C2 bond of the oxabicyclic precursor. On the basis of the experimental data we have proposed a mechanism of hydrolytic cleavage which is formally an intramolecular reverse Dieckmann process.     

Oxyallyls in synthesis: Preparation of tricyclic thromboxane A2 analogues

We describe the formation of 1-(dimethoxymethyl)-2-(2-phenylethenyl)-8-oxabicyclo[3.2.1]oct-6-en-3-ol (4) using oxyallyl methodology, and conversion of this into two 2,6-dioxatricyclo[3.3.1.0^3,7] nonanes (9) and (10) via iodoetherification and reduction. These compounds were then elaborated into the novel thromboxane analogues (11) and (12).     

New Synthesis of dl-sativene,dl-copacamphene,dl-cis-sativenediol and dl-helminthosporal

Photocycloadducts from dl-piperitone and 1,1-dimethoxyethylene afforded bicyclo[3.2.1]oct-6-en-8-one derivatives under glc conditions in excellent yields. The synthesis of the title sesquiterpenes was accomplished using the bridged bicyclic compounds as intermediates.     

Mn(III)-Based Oxidative Free-Radical Cyclizations of Unsaturated Ketones

Mn(III)-based oxidative free-radical cyclization of unsaturated ketones is a versatile synthetic procedure with broad applicability. For example, oxidation of cyclopentanone 1a with 2 equiv of Mn(OAc)(3).2H(2)O and 1 equiv of Cu(OAc)(2).H(2)O in AcOH at 80 degrees C for 1.5 h affords 75% of bicyclo[3.2.1]oct-3-en-8-one 8a and 15% of bicyclo[3.2.1]oct-2-en-8-one 9a. Bridged bicyclic ketones that cannot enolize further are isolated in good yield. Monocyclic beta,gamma-unsaturated ketones that can enolize are oxidized further to give gamma-acetoxy enones. The formation of bicyclo[3.3.1]non-2-en-9-one (57a) in 52% yield from 2-allylcyclohexanone (56a) suggests that kinetically controlled enolization is the rate-determining step in alpha-keto radical formation. A wide variety of examples delineating the scope, limitations, and stereoselectivity of this reaction are presented.     

A Chemical Study of Burley Tobacco Flavour (Nicotiana tabacum L.) VII. Identification and synthesis of twelve irregular terpenoids,related to solanone,including 7,8-dioxabicyclo[3.2.1]octane and 4,9-dioxabicyclo[3.3.1]nonane derivatives

Twelve novel constituents isolated from Burley tobacco condensate by semi-preparative GLC. have been identified as (E)-3,4-epoxy-5-isopropyl-nonane-2,8-dione ( A ), exo-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)methyl ketone ( B ), exo-1-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)-ethanol ( C ), (E)-5-isopropyl-8-hydroxy-8-methyl-non-6-en-2-one ( D ), (E)-5-isopropyl-6,7-epoxy-8-hydroxy-8-methyl-nonan-2-one ( E ), endo-2-(1-methyl-4-isopropyl-7,8-dioxabicyclo[3.2.1]oct-6-yl)-propan-2-ol ( F ), 3,3,5-trimethyl-8-isopropyl-4,9-dioxabicyclo[3.3.1]nonan-2-ol ( G ), (E)-5-isopropyl-non-3-ene-2,8-diol ( H ), 5-isopropyl-nonane-2,8-diol ( I ), (E)-5-isopropyl-8-hydroxy-non-6-en-2-one ( J ), 5-isopropyl-8-hydroxy-nonan-2-one ( K ), and (E)-3-isopropyl-6-methyl-hepta-4,6-dien-1-ol ( L ). Compounds A–K were synthesized from norsolanadione ( 2 ), and compound L from 2-isopropyl-5-oxo-hexanal ( 15 ). The relative configuration of the bicyclic internal acetals B, C, F, G and their δ-keto-epoxide precursors A and E is discussed. All these Burley tobacco flavour components belong to a growing family of metabolites structurally related to solanone ( 1 ). They are believed to arise from the breakdown of cembrene-type precursors.     

Rh(I)-catalyzed Pauson-Khand reaction of 1-phenylsulfonyl-1,2-octadien-7-yne derivatives

The Rh(I)-catalyzed PKR of 1-phenylsulfonyl-1,2-octadien-7-ynes and their aza derivatives exclusively produced the corresponding 9-phenylsulfonylbicyclo[4.3.0]nona-1,6-dien-8-ones and no 4-(phenylsulfonylmethylidene)bicyclo[3.3.0]oct-1-en-3-ones could be detected. Thus, the ring-closing pattern was found to be the same as those of the previously reported 3-phenylsulfonyl-1,2-octadien-7-yne derivatives. However, the formation of 4-(phenylsulfonylmethylidene)-7-oxabicyclo[3.3.0]oct-1-en-3-ones was observed as a minor product when the 5-oxa congeners were used. In addition, a larger ring-sized product, 10-phenylsulfonyl-5-azabicyclo[5.3.0]deca-1,7-dien-9-one derivative, was obtained from the 6-aza derivative of 1-phenylsulfonyl-1,2-nonadien-8-yne.