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The development of efficient catalysts and processes for synthesizing functionalized (olefinic and/or chiral) primary alcohols and fluoral hemiacetals is currently needed. These are valuable buildi...

Anti-malaria drugs chloroquine and amodiaquine and their metabolites were synthesized to incorporate 13 C and 15 N starting from U-13 C-labeled benzene to give M + 7 isotopomers. Chloroquine and its metabolites were prepared from 7-chloro-1,2,3,4-tetrahydroquinolin-4-one through an aryl substitution with the corresponding amines; and the amodiaquine and its metabolites were prepared from 4,7-dichloroquinoline in a similar fashion.

13C labeled (>M + 4) metabolites of nitrogen and sulfur-based chemical warfare agent metabolites were prepared from readily available and 13C labeled commercial starting materials. The new chemical routes are efficient in the number of chemical steps, can be scaled to afford gram quantities, and occur in good yields on the basis of the 13C label. These labeled compounds are useful as internal standards in mass spectrometry for monitoring chemical warfare agents and their metabolites. Published 2012. This article is a US Government work and is in the public domain in the USA.

Multicomponent reactions (MCRs) are not only a power- ful tool for drug discovery, they also represent an excellent method- ology for synthesis rationalization. Here we wish to illustrate the potential of MCRs in the production of generic drugs by synthesiz- ing, in racemic form, the antiplatelet agent clopidogrel and the non- steroidal antiandrogen bicalutamide, using Ugi, Petasis and Passe- rini reactions.

The synthesis of oligoethylene glycols of defined lengths possessing different end functionalities is described. The utility of these molecules towards the development of a generic membrane anchor is demonstrated.

A new route is presented to prepare analogs of nucleosides homologated at the 3′- and 5′-positions. This route, applicable to both the D- and L-enantiomeric forms, is suitable for the preparation of monomeric bis-homonucleosides needed for the synthesis of oligonucleotide analogs. It begins with the known monobenzyl ether 3 of pent-2-yne-1,5-diol, which is reduced to alkenol 4. Sharpless asymmetric epoxidation of 4, followed by opening of the epoxide 5 with allylmagnesium bromide, gives a mixture of diols 6 and 7. Protection of the primary alcohol as a silyl ether followed by treatment with OsO4, NaIO4, and mild acid in MeOH, followed by reduction, yields (2R,3R) {{[(tert-butyl)diphenylsilyl]oxy}methyl}tetrahydro-2-(2-hydroxyethyl)-5-methoxyfuran (=methyl 3-{{[(tert-butyl)diphenylsilyl]oxy}methyl}-2,3,5-trideoxy-α/β-D-erythro-hexafuranoside; 10) (Scheme 1). Protected nucleobases are added to this skeleton with the aid of trimethylsilyl triflate (Scheme 2). The o-toluoyl (2-MeC6H4CO) and p-anisoyl (4-MeOC6H4CO) groups were used to protect the exocyclic amino group of cytosine. The bis-homonucleoside analogs 11 and 14a are then converted to monothiol derivatives suitable for coupling (Schemes 3 and 4) to oligonucleotide analogs with bridging S-atoms. This synthesis replaces a much longer synthesis for analogous nucleoside analogs that begins with diacetoneglucose (=1,2 : 5,6-di-O-isopropylideneglucose), with the stereogenic centers in the final products derived from the Sharpless asymmetric epoxidation. The new route is useful for large-scale synthesis of these building blocks for the synthesis of oligonucleotide analogs.

A convergent, solution-phase synthesis was developed for the bis(methylene) sulfone-bridged oligodeoxynucleotide analogs (SNA) 5′-d(HOCH2-Tso2Tso2Tso2Cso2Tso2Tso2Tso2T-CH2SO)-3′ (35b) and 5′-d(HOCH2-Tso2Tso2Tso2Tso2Tso2Tso2Tso2T-CH2SO)-3′ (34c) (SO2 corresponds to CH2SO2CH2 instead of OP(O)(O−)(O). In these, the phosphodiester linkages are replaced by non-ionic bis(methylene) sulfone linkers. The general strategy involved convergent coupling of 3′,5′-bishomo-β-D-deoxyribonucleotide analogs functionalized at the 6′-end (CH2C(5′)) as bromides or mesylates and at the CH2C(3′) position as thiols, with the resulting thioether being oxidized to the corresponding sulfone. A single charge was introduced at the terminal CH2C(3′) position of the octamers to increase their solubility in water. During the synthesis, it became apparent that the key intermediates generated secondary structures through either folding or aggregation in a variety of solvents. This generated unusual reactivity and was unique for very similar structures. For example, although the dimeric thiol d(BzOCH2-Tso2C-CH2SH) (14b) was a well-behaved synthetic intermediate, the tetrameric thiol d(TrOCH2-Tso2Tso2Tso2toC-CH2SH) derived from the corresponding thioacetate was rapidly converted to a disulfide by very small amounts of oxidant (2829, Scheme 6), while the analogous tetrameric thiol d(BzOCH2-Tso2TsTso2T-CH2SH) (26), differing only by a single heterocycle, was oxidized much more slowly (Bz=PhCO, Tr=Ph3C, to=2-MeC6H4CO (at N4 of dc)). The sequence-dependent reactivity, well known in many classes of natural products (including polypeptides), is not prominent in natural oligonucleotides. These results are discussed in light of the proposal that the repeating negative charge in nucleic acids is key to their ability to serve as genetic molecules, in particular, their capability to support Darwinian evolution. The ability of 5′-d(HOCH2-Tso2Tso2Tso2Cso2Tso2Tso2Tso2T-CH2SO)-3′ (35b) to bind as a third strand to duplex DNA was also examined. No triple-helix-forming propensity was detected in this molecule.

We have developed a large-scale “one-pot” procedure for the conversion of commercially available [13C]- or [2H3,13C]methanol to [13C]- or [2H3,13C]methyl phenyl sulfide. [13C]methyl phenyl sulfide is a potentially versatile, chemically stable, and nonvolatile labeling precursor. In addition, we report an efficient method for the oxidation of [13C]methyl phenyl sulfide to [13C]methyl phenyl sulfone. Finally, we have used [13C]methyl phenyl sulfide to produce 13C-labeled methyl iodide, containing exactly one or two deuterons.

The hexane extract from the leaves of Dasymaschalon sootepenseCraib (Annonaceae) showed strong cytotoxic activity against the L1210 tumor cell line. Activity-directed fractionation of the extract by column chromatography on silica gel and high-pressure liquid chromatography led to the isolation of the acetogenins 1 – 4 as the main active principles. The structures of the two novel structures named sootepensin A (1) and sootepensin B (2) were elucidated by spectroscopic analysis (UV, EI- and ESI-MS, 1D- and 2D-1H- and 13C-NMR). The absolute configurations were established by 2D-NMR experiments utilizing Mosher esters. Two recently described compounds, tonkinin C (3) and tonkinesin C (4), were also isolated and are new to the genus Dasymaschalon. All four acetogenins were found to be highly cytotoxic against the L1210 tumor cell line.

A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.

A novel one-pot two-step multi component reaction of acrylic aldehydes, bromoanilines, acids and isocyanides yielding polysubstituted indoles is described. The reaction is based on the combination of an Ugi four-component reaction followed by an intramolecular Heck-reaction. The simultaneous use of formic acid and cinnamaldehydes affords in situ generation of 1H-indoles. Convertible isocyanides can also be used with success in this Ugi/Heck strategy and enable synthesis of 1H-indole-2-carboxylic acid building blocks.

The stability of the PNA (peptide nucleic acid) thymine monomer ¿N-[2-(thymin-1-ylacetyl)]-N-(2-aminoaminoethyl)glycine¿ and those of various PNA oligomers (5-8-mers) have been measured at room temperature (20 degrees C) as a function of pH. The thymine monomer undergoes N-acyl transfer rearrangement with a half-life of 34 days at pH 11 as analyzed by 1H NMR; and two reactions, the N-acyl transfer and a sequential degradation, are found by HPLC analysis to occur at measurable rates for the oligomers at pH 9 or above. Dependent on the amino-terminal sequence, half-lives of 350 h to 163 days were found at pH 9. At pH 12 the half-lives ranged from 1.5 h to 21 days. The results are discussed in terms of PNA as a gene therapeutic drug as well as a possible prebiotic genetic material.

The d -xylan-degrading enzymes of Trichoderma lignorum can be induced by several oligo- and poly-saccharides. The induction is optimal when l -arabino- d -xylan is used as carbon source. The enzymes were also produced by cells grown on glycerol in the presence of 4-thioxylobiose (4-S-β- d -xylopyranosyl-4-thio- d -xylopyranose) and methyl β- d -xylopyranoside. These inducers were not taken up by the cells. The extent of induction was, however, lower than with xylobiose. Thioxylobiose was obtained in an overall yield of 55–60% from the reaction of 1,2,3-tri-O-benzoyl-4-O-trifluoromethylsulfonyl-β- l -arabinopyranose with the sodium salt of 1-thio-β- d -xylopyranose in N′,N″,N‴-hexamethylphosphoramide, followed by O-deacylation of the resulting 4-thiodisaccharide.