Synthesis of methylerythritol phosphate analogues and their evaluation as alternate substrates for IspDF and IspE from Agrobacterium tumefaciens.

The methylerythritol phosphate biosynthetic pathway, found in most Bacteria, some parasitic protists, and plant chloroplasts, converts D-glyceraldehyde phosphate and pyruvate to isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), where it intersects with the mevalonate pathway found in some Bacteria, Archaea, and Eukarya, including the cytosol of plants. D-3-Methylerythritol-4-phosphate (MEP), the first pathway-specific intermediate in the pathway, is converted to IPP and DMAPP by the consecutive action of the IspD-H proteins. We synthesized five D-MEP analogues-D-erythritol-4-phosphate (EP), D-3-methylthrietol-4-phosphate (MTP), D-3-ethylerythritol-4-phosphate (EEP), D-1-amino-3-methylerythritol-4-phosphate (NMEP), and D-3-methylerythritol-4-thiolophosphate (MESP)-and studied their ability to function as alternative substrates for the reactions catalyzed by the IspDF fusion and IspE proteins from Agrobacterium tumefaciens, which covert MEP to the corresponding eight-membered cyclic diphosphate. All of the analogues, except MTP, and their products were substrates for the three consecutive enzymes.

Syn- and anti-selective Prins cyclizations of delta,epsilon-unsaturated ketones to 1,3-halohydrins with Lewis acids.

Ten acyclic and monocyclic delta,epsilon-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 delta carbon (methallyl enones) led to increased rates (40-50-fold), while substitution at the epsilon 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.

Synthesis of enantiopure 2-C-methyl-D-erythritol 4-phosphate and 2,4-cyclodiphosphate from D-arabitol.

[reaction: see text] Two key intermediates of the newly discovered mevalonate-independent pathway for isoprenoid biosynthesis were prepared. Optically pure 2-C-methyl-D-erythritol 4-phosphate and 2,4-cyclodiphosphate were chemically synthesized from D-arabitol using a convenient benzylidene and tert-butyldimethylsilyl protection of polyhydroxylated intermediates. The new scheme offers a straightforward route to analogues and labeled forms.

Total synthesis of (+/-)-cameroonan-7alpha-ol and biomimetic rearrangements to related nopsane sesquiterpenes.

A total synthesis of the novel silphinane sesquiterpene alcohol (+/-)-cameroonanol (6-OH) from bicyclic enone 10 was accomplished by conjugate addition of crotylsilane, photochemical hydrobromination, intramolecular alkylation, and hydride reduction. The stereoisomers cameroonan-7beta-ol (18-OH) and 9-epicamerooonanols (19 and 20) were separated from isomer mixtures and the 9-desmethylcameroonanols (21-OH and 22-OH) were obtained by similar means. Solvolysis of 6-OMs and 18-OMs effected skeletal rearrangements to (+/-)-silphiperfol-6-ene (5), (+/-)-prenopsanol (7) and (+/-)-nopsanol (8), and (+/-)-silphiperfolan-7beta-ol (9) in parallel with biogenetic schemes proposed for these naturally occurring sesquiterpenes. The nor analogues 21-OMs and 22-OMs underwent solvolytic rearrangments to a similar set of nor products. The increase in solvolytic rates for the 7beta-mesylates 18-OMs and 22-OMs in comparison to the 7alpha epimers is attributed to concerted antiperiplanar Wagner-Meerwein rearrangements to the prenopsyl and norprenopsyl carbocations. Further analysis of the kinetic data and comparisons with solvolysis rates for the structurally related silphin-1beta-yl and silphin-1alpha-yl mesylates (28 and 29) are presented. The rearrangements observed afford chemical precedent for the biogenetic pathways in the literature for these silphinane sesquiterpenes.

Regio- and stereoselectivity of diethylaluminum azide opening of trisubstituted epoxides and conversion of the 3 degrees azidohydrin adducts to isoprenoid aziridines.

The regioisomer ratios (3 degrees,2 degrees /2 degrees,3 degrees ), and in some cases the stereochemistry, of vicinal azidohydrins formed in reactions of 11 trisubstituted terpene epoxides with Et(2)AlN(3) in toluene are reported. The more highly substituted azide usually predominated (3 degrees,2 degrees /2 degrees,3 degrees ratios >or= 40:1 to 2.5-1) in accord with a Markovnikov orientation and an S(N)1-like transition state. Reversed regioisomer ratios were observed with 6,7-epoxygeranyl acetate (1:2.5) and cis-1,2-epoxylimonene (1:3.3 to 1:10). The tertiary azido diols from 2,3-epoxygeraniol, 2,3-epoxyfarnesol, and 2,3-epoxynerol were formed as single isomers with inversion of configuration at C3 (>or= 35-40:1 for the C(10) azido diols). The regioselectivity was affected by the presence and proximity of oxy functional groups on the epoxide substrate (OH, OAc, and OSi-tBuMe(2)), the equivalents of Et(2)AlN(3), and additives (EtOAc or EtOH). The results and trends are rationalized by consideration of the structural and stereoelectronic characteristics of proposed diethylaluminum epoxonium ion intermediates and transition states, together with the nucleophilicity of the azide donor. Six of the 3 degrees,2 degrees azidohydrins were converted to the corresponding aziridines by primary-selective silylations of four azido diols, mesylations, and reductive cyclizations with LiAlH(4).