A s y m m e t r i c S y n t h e s i s o f 4 ¢ -e p i -T r a c h y c l a d i n e s A a n d BAbstract: The first asymmetric synthesis of 4¢-epi-trachycladines A and B is reported. Starting from 2,2-dimethyl-1,3-dioxan-5-one the title nucleosides were synthesised in 14 steps employing the SAMP-/RAMP-hydrazone methodology. The dioxanone-SAMPhydrazone was first transformed into a trisubstituted derivative by a triple a-/a¢-alkylation. Removal of the chiral auxiliary and subsequent reduction gave the corresponding alcohol, which could be transformed over four steps into TBS-protected 2¢-C-methyl-5¢-deoxy-L-lyxose. The trachycladines were then obtained via the corresponding triacetate using standard Vorbrüggen and silyl-HilbertJohnson conditions in an overall yield of 18-21%. Such 2¢-Cbranched ribonucleosides are potential agonists for adenosine receptors and play an important role in drug discovery.
The direct kinetic formation of spiroketals from mixed ketal-alcohol precursors under acid catalysis was studied using four differently substituted systems. In all cases, the exclusive formation of the anomeric isomer was observed under equilibrating conditions. However, the formation of the nonanomeric spiroketal isomer was observed if the reaction was performed under kinetic conditions using an appropriately tuned acid. Water had a dramatic accelerating effect on the spiroketalization reactions that were performed in THF, and the highest yields of the nonanomeric products were obtained in aqueous THF. The nonanomeric/anomeric product ratio was also strongly affected by the substituents and the stereochemistry of the starting alcohol.
The asymmetric synthesis of (1S,3R,5R,7S)‐(+)‐sordidin and 7‐epi‐(1S,3R,5R,7R)‐(–)‐sordidin, both components of the natural male‐produced aggregation pheromone of the banana weevil Cosmopolites sordidus (Germar), starting from 2,2‐dimethyl‐1,3‐dioxan‐5‐one is described. Two of the stereogenic centers were generated by three α‐alkylations of the corresponding RAMP‐hydrazone. Diastereoselective epoxide opening as another key step of the synthesis employing the aza‐enolate of 3‐pentanone SAEP‐hydrazone as nucleophile and subsequent acidic intramolecular acetalisation furnished the sordidin C‐7 epimers in good overall yield (39 %) as a 1.5:1 diastereomeric mixture. The epimers could be separated by preparative GC and thus, each of them could be obtained in high diastereomeric and enantiomeric purity (de ≥ 97 %, ee ≥ 98 %). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
A s y m m e t r i c S y n t h e s i s o f 2 -K e t o -1 , 3 -d i o l s a n d P r o t e c t e d 1 , 2 , 3 -T r i o l s Abstract: The asymmetric synthesis of 1,3-dihydroxy-2-ketones bearing two quaternary stereocenters in a-and a¢-position starting from 2,2-dimethyl-1,3-dioxan-5-one-SAMP-hydrazone is described. The protocol involves four consecutive a/a¢-alkylations, the last one being carried out in the presence of DMPU as additive. After acidic cleavage of both the chiral auxiliary and the acetal function in a two-phase system, the title compounds are obtained with high stereoselectivity (de ≥ 91-97%, ee ≥ 96%) and in moderate to very good overall yields (14-61%). In addition, 1,2-quaternary 1,3-protected 1,2,3-triols were obtained by nucleophilic 1,2-addition to the carbonyl group as single stereoisomeres (de, ee ≥ 96%) in excellent yields.The tertiary alcohol moiety bearing a methyl group as one of its substituents can be found in a large number of polyoxygenated biologically active natural products. For instance, it is a characteristic structural feature in sugars such as L-mycarose 1 as part of the antibiotic erythromycin 2 or L-olivomycose 3 present in apoptolidin. 4 Furthermore it can be found in trachycladine A and B, which were isolated from the marine sponge Trachycladus laevispirulifer (Carter) and belong to the class of nucleosides with remarkable biological activity. 5 Also pheromones, for example sordidin, 6 the aggregation pheromone of the banana weevil Cosmopolites sordidus (Germar) or frontalin, 7 one of the aggregation pheromones of the southern pine beetle Dendroctonus frontalis, contain this tertiary alcohol subunit. In addition, it is a structural element in biologically active compounds such as staminol A, 8 neoilludin A and B 9 or anisatin 10 and citreoviral, 11 which proved to be potent neurotoxins. Convenient methods for the formation of quaternary stereocenters have been reviewed by Martin, 12 Fuji, 13 Corey, 14 Christoffers, 15 Overman, 16 and Yus et al. 17 The major routes to highly enantiomerically enriched tertiary alcohols are the 1,2-addition to prochiral ketones, 18 the Jacobsen epoxidation 19 of alkenes with subsequent cleavage or the Sharpless dihydroxylation 20 of trisubstituted alkenes.Recently we reported on the asymmetric synthesis of protected 2-keto-1,3-diols and 1,2,3-triol building blocks bearing one quaternary stereogenic center starting from easily available 2,2-dimethyl-1,3-dioxan-5-one 21 employing the SAMP/RAMP-hydrazone methodology. 22,23 We have now extended this highly stereoselective alkylation technique towards an efficient diastereo-and enantioselective synthesis of 1,3-diol derivatives bearing two quaternary centers in 1,3-or in 1,2-position, respectively.As depicted in Scheme 1 the asymmetric synthesis of the title a,a¢-quaternary 2-keto-1,3-diols 4 was achieved following our protocol of sequential a-alkylations of dioxanone-SAMP-hydrazone 1 24 and subsequent cleavage of both the chiral auxiliary and the acetal moiety.The dioxanone-SAMP-hydrazone (S)-1 was...
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