Carbonic linkers

Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. As illustrated in the scheme below, the reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization, which proceeded irrespective of the length of the carbon linker, was employed to construct the ABC tricyclic core of manzamine A <06OL27>. 

Dup-721 (please see Fig. 2 for the structure), these tricyclic fused oxazolidinones have their aryl and oxazolidinone rings joined together by either one or two carbon linkers, resulting in the formation of the [6,5,5] and the... 

Preliminary results of DNA sequence detection using the OFRR are thoroughly described by Suter, et al.32 The experimental setup described above for tracking the resonant mode shift is used. An OFRR with RI sensitivity of about 7 nm/RIU was produced and used for these experiments. The OFRR surface was functionalized with 3APS and then DMA was used as an amine-amine crosslinker. The single-stranded oligonucleotide capture probe was synthesized with an amine functional group connected to the 5 end by a 6-carbon linker, and has a 25 base-pair sequence. ... 

Another attractive method for E ring formation featured an intramolecular [2+3]cycloaddition of an azide moiety, emanating from the indole 3-position via a two-carbon linker, to, now, an electron-rich version of the C15-C16 double bond.19 The cycloaddition precursor 10 was made via 9, in turn assembled by regioselective cocylization of protected methoxyacetylene (Scheme 5). In a puzzling turn of events, thermolysis of the azide product in toluene at moderate temperature (to minimize nitrene formation) and in low concentration (to suppress intermolecular reactions) produced the two oxidized pentacyclic products 11 and 12 in a 2 1 ratio. Performing the reaction in a more polar solvent (DMF, 80 °C, 7 d) altered the ratio to 5 1.20... 

De Groot et al. reported on the synthesis of tumor-associated protease cleavable prodmgs of paclitaxel. " The carbamate and carbonate linkers between 2 -OH of paclitaxel and tripeptides D-Ala-Phe-Lys and D-Val-Leu-Lys were used instead of ester in these prodmgs to avoid nonspecific hydrolysis of 2 -ester by widely... 

The patent describes only synthetic pathways and chemical experimental data of prepared compounds (14). No biological data were reported. Deljac et al. (1992) described compounds of symmetric bisquatemary imida-zolium type with a four-carbon linker (Figure 66.12), where R is methyl (15a, 16a), phenyl (15b, 16b), benzyl (15c, 16c), 4-methoxyphenyl (15d, 16d), and 4-fluorophenyl (15e, 16e). 

Only one compound, ( )-l,4-bis(2-hydroxyiminomethyl-3-methylimidazolinium) but-2-ene dibromide (16a), showed promising results in reactivation of AChE inhibited by the above-mentioned inhibitors, except soman (because of aging). In the same publication, two aheady known AChE reactivators, BDB-108 (17a) and BDB-109 (17b), and new compounds, BDB-107 (17c) and BDB-111 (17d), with four carbon linkers and hydroxyiminomethyl in position two or four, are discussed (Figure 66.13) (Deljac et al, 1992). 

Human erythrocyte AChE inhibited by echothiophate [(2-mercaptoethyl) trimethylammonium-0,0-diethyl-phosphorothioate iodide] was used for in vitro reactivation screening. A compound with three membered carbon linkers (28b) was the most effective from the />-seiies and a compound with seven carbon connecting chains (3 Of Ortho-7) seemed to be the most effective from the o-series. These results were explained by the authors using 3D structures. 

II trials as an anxiolytic. SAR studies showed that the 5-methoxy group, a tertiary amine, and a four carbon linker provide the optimum compromise between 5HT-1A affinity and selectivity vs. adrenergic and dopaminergic sites (447). The aminobenzopyran moiety, which is derived from the prototypical 5HT-1A ligand 8-OH-DPAT, contributes more to the 5HT-1A affinity, whereas the carbon linker has a greater impact on selectivity than on affinity. The (+) enantiomers are consistently more potent and selective than the (-) antipodes. Alnespirone binds with higher affinity (0.3 nM) and selectivity than that of either buspi-rone or ipsapirone (447,448), is a full agonist at pre- and postsynaptic 5HT-1A sites, and is active in animal models at low doses (<4 mg/ kg, ip) with no sedative effects. 

Overall, the SAR data for the linker between N-4 and the imide group show that this region does not provide any interactions with the receptor and merely acts as a spacer. Some studies point to a role for this region in the modulation of the intrinsic activity of the arylpiperazines and of their selectivity for the 5HT-1A receptor. The general observation is that potency is optimized with a four carbon linker and drops off significantly as the chain is shortened, as exemplified by the phthaloyl derivatives (99) (434). This preference is fur-... 

As an example, the 5-hydroxypentyltrimethylammonium bistriflimide [N11150H] [NTf2] can be described as an ionic moiety (trimethylammonium = N1U) linked to a reactive function (a hydroxyl group) via a five carbons linker (=50H). 

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