Solvolysis of Caryophyllen-8β-yl Derivatives: Biomimetic Rearrangement−Cyclization to 12-Nor-8α-presilphiperfolan-9β-ol

The solvolyses of caryophyllen-8β-yl p-nitrobenzoate (14-OpNB) and 15-norcaryophyllen-8β-yl tosylate (15-OTs) were investigated as potential model reactions for the biogenesis of the tricyclic presilphiperfolanol sesquiterpenes. Buffered solvolysis of 14-OpNB in 60% aqueous acetone at 125 °C afforded caryophyllene (3) as major product, accompanied by small amounts of caryophyllen-8β-ol (14-OH) and 5,8-cyclocaryophyllen-4α-ol (16). In contrast, 15-OTs underwent a stereospecific rearrangement−cyclization to 12-nor-8α-presilphiperfolan-9β-ol (17) upon solvolysis in 60% aqueous acetone at 75 °C. The structure and stereochemistry of this trans,cis,trans-tricyclo[6.2.1.05,11]undecane derivative were established by NMR correlation spectroscopy and X-ray crystallography. Two different mechanisms (paths A and B) for the conversion of 15-OTs to 17 by initial 1,2-migration of either the external or internal cyclobutane ring bonds (C10 and C1) followed by π−σ cyclization onto the trans double bond are discussed

Synthesis of 2,7-Cyclofarnesol and 2,7-Cyclogeranylgeraniol: Prenylogs of β-Cyclogeraniol

Synthesis of 2,7-Cyclofarnesol and 2,7-Cyclogeranylgeraniol: Prenylogs of β-Cyclogeranio

Solvolysis of Caryophyllen-8β-yl Derivatives: Biomimetic Rearrangement−Cyclization to 12-Nor-8α-presilphiperfolan-9β-ol

The solvolyses of caryophyllen-8β-yl p-nitrobenzoate (14-OpNB) and 15-norcaryophyllen-8β-yl tosylate (15-OTs) were investigated as potential model reactions for the biogenesis of the tricyclic presilphiperfolanol sesquiterpenes. Buffered solvolysis of 14-OpNB in 60% aqueous acetone at 125 °C afforded caryophyllene (3) as major product, accompanied by small amounts of caryophyllen-8β-ol (14-OH) and 5,8-cyclocaryophyllen-4α-ol (16). In contrast, 15-OTs underwent a stereospecific rearrangement−cyclization to 12-nor-8α-presilphiperfolan-9β-ol (17) upon solvolysis in 60% aqueous acetone at 75 °C. The structure and stereochemistry of this trans,cis,trans-tricyclo[6.2.1.05,11]undecane derivative were established by NMR correlation spectroscopy and X-ray crystallography. Two different mechanisms (paths A and B) for the conversion of 15-OTs to 17 by initial 1,2-migration of either the external or internal cyclobutane ring bonds (C10 and C1) followed by π−σ cyclization onto the trans double bond are discussed

The Dioxanone Approach to (2<i>S</i>,3<i>R</i>)-2-<i>C</i>-Methylerythritol 4-Phosphate and 2,4-Cyclodiphosphate, and Various MEP Analogues

Efficient syntheses of the non-mevalonate pathway intermediates 2-C-methylerythritol 4-phosphate (MEP) and 2-C-methylerythritol 2,4-cyclodiphosphate (ME-2,4-cycloPP), as well as the parent tetrol 2-C-methylerythritol, in enantiopure form from (2S,4R)-cis-2-phenyl-4-tert-butyldimethylsilyloxy-1,3-dioxan-5-one are reported. The 2S configuration of the C-methyl group was installed by highly axial-face selective addition of CH3MgBr (20:1) to the chiral dioxanone carbonyl group. Primary selective mono-phosphorylation and 2,4-bis-phosphorylation, followed by desilation and hydrogenolysis to the free mono- and diphosphates, and, in the latter case, cyclization to form the eight-membered phosphoryl anhydride, afforded MEP and ME-2,4-cycloPP in good yields. The C2 epimeric analogues, 2-C-methylthreitol and its 4-phosphate, were accessed by LiAlH4 reduction of the cis,cis epoxide of (2S,4R)-4-tert-butyldimethylsilyloxymethyl-5-methylene-2-phenyl-1,3-dioxane, primary-selective phosphorylation, and cleavage of the silyl, benzylidene, and benzyl protecting groups. Regioselective cleavage of the acetal ring of 1,3-benzylidene 2-C-methylerythritol silyl ether by ozonolysis afforded a 1,2,3-triol 3-monobenzoate intermediate that was converted to the novel amino sugar, 1-amino-1-deoxy-2-C-methylerythritol

A Novel Cyclopropane Ring Fragmentation of Bicyclo[3.1.0]hexene Epoxides to 2,5-Dienals

A Novel Cyclopropane Ring Fragmentation of Bicyclo[3.1.0]hexene Epoxides to 2,5-Dienal

Scope and Mechanism of Intramolecular Aziridination of Cyclopent-3-enyl-methylamines to 1-Azatricyclo[2.2.1.0^2,6]heptanes with Lead Tetraacetate

A series of seven cyclopent-3-en-1-ylmethylamines bearing one, two, or three methyl substituents at the C2, C3, C4, or Cα positions, including the unsubstituted parent, was accessed by ring-closing metatheses of α,α-diallylacetonitrile (or methallyl variants) and α,α-diallylacetone followed by hydride reductions or reductive amination, or by Curtius degradations of α,α-dimethyl- and 2,2,3-trimethylcyclopent-3-enylacetic acids. Oxidation of the primary amines with Pb(OAc)4 in CH2Cl2, CHCl3 or benzene in the presence of K2CO3 effected efficient intramolecular aziridinations, in all cases except the α-methyl analogue (16), to form the corresponding 1-azatricyclo[2.2.1.02,6]heptanes, including the novel monoterpene analogues, 1-azatricyclene and the 2-azatricyclene enantiomers. The cumulative rate increases of aziridination reactions observed by 1H NMR spectroscopy in CDCl3 resulting from the presence of one or two methyl groups on the cyclopentene double bond, in comparison to the rate of the unsubstituted parent amine (1:17.5:>280), indicate a highly electrophilic intermediate as the nitrene donor and a symmetrical aziridine-like transition state. A mechanism is outlined in which the amine displaces an acetate ligand from Pb(OAc)4 to form a lead(IV) amide intermediate RNHPb(OAc)3 proposed as the actual aziridinating species

2-Azapinanes: Aza Analogues of the Enantiomeric Pinyl Carbocation Intermediates in Pinene Biosynthesis

The enantiomeric 2-azapinanes, aza analogues of the pinyl carbocation intermediates in pinene biosynthesis, were synthesized from (−)- and (+)-cis-pinonic acids. The individual reactions in the 5-step sequence were Beckmann rearrangement of the pinonic acid oximes, cyclization to the N-acetyl lactams, hydrolysis to the NH-lactams, N-methylations, and LiAlH4 reductions. The anti stereochemistry of the N-methyl groups in the salts with respect to the gem-dimethyl bridge was established by NOE measurements and by X-ray diffraction analysis

Syn- and Anti-Selective Prins Cyclizations of δ,ε-Unsaturated Ketones to 1,3-Halohydrins with Lewis Acids

Ten acyclic and monocyclic δ,ε-unsaturated ketones, with and without methyl substituents on the double bond, underwent halide-terminated Prins (halo-Prins) cyclizations under anhydrous conditions in the presence of Lewis acids. TiCl4, TiBr4, BCl3, and BBr3 promoted syn-selective cyclizations to sterically congested chloro- and bromohydrins, while SnCl4, SnBr4, InCl3, ZrCl4, and several other Lewis acids effected highly anti-selective reactions to furnish the corresponding trans halohydrins. The stronger Lewis acids (TiX4 and BX3) favor the syn process that involves axial delivery of a halide ligand. Competition experiments showed that substitution at the δ carbon (methallyl enones) led to increased rates (40−50-fold), while substitution at the ε position (cis and trans crotyl enones) retarded the rate and eroded the selectivity of the cyclizations. The trends in syn vs anti selectivity, reactivity, and effects of different Lewis acidic metal halides are rationalized by competitive reaction pathways proceeding through syn carbocation−halide ion pairs and a higher order transition state that leads to inversion of configuration and formation of trans halohydrins, along with cyclic olefins arising from proton elimination

Syn- and Anti-Selective Prins Cyclizations of δ,ε-Unsaturated Ketones to 1,3-Halohydrins with Lewis Acids

Ten acyclic and monocyclic δ,ε-unsaturated ketones, with and without methyl substituents on the double bond, underwent halide-terminated Prins (halo-Prins) cyclizations under anhydrous conditions in the presence of Lewis acids. TiCl4, TiBr4, BCl3, and BBr3 promoted syn-selective cyclizations to sterically congested chloro- and bromohydrins, while SnCl4, SnBr4, InCl3, ZrCl4, and several other Lewis acids effected highly anti-selective reactions to furnish the corresponding trans halohydrins. The stronger Lewis acids (TiX4 and BX3) favor the syn process that involves axial delivery of a halide ligand. Competition experiments showed that substitution at the δ carbon (methallyl enones) led to increased rates (40−50-fold), while substitution at the ε position (cis and trans crotyl enones) retarded the rate and eroded the selectivity of the cyclizations. The trends in syn vs anti selectivity, reactivity, and effects of different Lewis acidic metal halides are rationalized by competitive reaction pathways proceeding through syn carbocation−halide ion pairs and a higher order transition state that leads to inversion of configuration and formation of trans halohydrins, along with cyclic olefins arising from proton elimination

2-Azapinanes: Aza Analogues of the Enantiomeric Pinyl Carbocation Intermediates in Pinene Biosynthesis

The enantiomeric 2-azapinanes, aza analogues of the pinyl carbocation intermediates in pinene biosynthesis, were synthesized from (−)- and (+)-cis-pinonic acids. The individual reactions in the 5-step sequence were Beckmann rearrangement of the pinonic acid oximes, cyclization to the N-acetyl lactams, hydrolysis to the NH-lactams, N-methylations, and LiAlH4 reductions. The anti stereochemistry of the N-methyl groups in the salts with respect to the gem-dimethyl bridge was established by NOE measurements and by X-ray diffraction analysis