Sequence doubling strategy

An impressive achievement of this strategy has been the construction of three-dimensional structures. Utilizing branched phenylacetylene sequences, double cyclization yielded macrobicyclic arrays 54 and 55 [43]. The zenith of Moore s approach is macrotricycle 56, a freely hinged system with a sizable 36xl2xl2A molecular cavity [44]. 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

Jacobsen demonstrated that the (salen)Cr system used to effect intermolecular, cooperative asymmetric azidolysis of meso-epoxides (Schemes 7.3 and 7.5) could be applied to sulfur-centered nucleophiles (Scheme 7.13). In order to overcome moderate enantioselectivity (<60% ee), a dithiol nucleophile was employed as part of a double resolution strategy in which the minor enantiomer of the monoaddition product reacts preferentially to form the meso- bis-addition product, thereby increasing the ee of the C2-symmetric bis-addition product. Enantiopure 1,2-mer-capto alcohols (>99% ee) were obtained from the meso-epoxide in ca. 50% overall yield by a burdensome (though effective) multistep sequence, [23]. 

Fig. 2 RNAi inducers used in antiviral strategies. In general, RNAi is induced either by transfection of synthetic siRNAs into cells, or by stable or transient intracellular expression of double-stranded siRNA precursors (shRNA, e-shRNA, IhRNA, or pri-miRNAs). After transcription in the nucleus shRNAs, IhRNAs and e-shRNAs are exported to the cytoplasm and subsequently diced into mature siRNAs. Pri-miRNAs modified to encode antiviral siRNAs first undergo cleavage by Drosha before they are exported to the cytoplasm. Here the antiviral pre-miRNAs (also called shRNA-miRs) are processed by Dicer into the mature miRNAs. After loading of the antisense strand of the siRNAs/miRNAs into RISC, the complex will target and cleave viral transcripts bearing the complementary sequences...

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

In 2003, Williams and Mander reported a method designed to access the hetisine alkaloids (Scheme 1.3) [27]. This approach, based upon a previously disclosed strategy by Shimizu et al. [28], relied on arylation of a bridgehead carbon via a carbocation intermediate in the key step. Beginning with (1-keto ester 46, double Mannich reaction provided piperidine 47. Following a straightforward sequence, piperidine 47 was transformed to the pivotal bromide intermediate 48. In the key step, bromide 48 was treated with silver (I) 2,4,6-trinitrobenzenesulfonate in nitro-methane (optimized conditions) to provide 49 as the most advanced intermediate of the study, in 54 % yield. 

Allyl alcohols readily react with trichloroacetonitrile to give the corresponding trichloroacetimidates 145. Activation of the double bond with electrophilic reagents results in ring closure to yield oxazolines 146. The most commonly employed electrophiles include iodine, iodine monochloride, phenylselenyl chloride, and mercuric trifluoroacetate. Other nitriles including cyanogen bromide and N,N-dimethylcyanamide can also be used. Since oxazolines readily hydrolyze to amides, the net effect of this reaction sequence is to produce p-amino alcohols 147 from an allyl alcohol. This strategy has been employed in numerous total syntheses of natural products. Examples are listed in Table 8.18 (Fig. 8.7 Scheme 8.43). ° ... 

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