Synthesis of 2-Fluoro Analogues of Frontalin (original) (raw)
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Synthesis of (−)-(1S,5R)- and (+)-(1R,5S)-trifluoroanalogues of frontalin
Tetrahedron Letters, 1999
The synthesis of enantiomerically pure (-)-(1S,5R)-1-trifluoromethyl frontalin 7 starting from (-)-(1R)-menthyl (S)-toluene-4-sulfinate, 5-pentenylmagnesium bromide and methyl trifluoroacetate is described. The synthetic procedures to obtain the enantiomer (+)-(1R,5S)-7 are also mentioned. Absolute stereochemistry was unambiguously assigned by X-ray analysis of intermediates 3 and 5.
Nature Chemistry
Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl-and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereoand enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl-and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown. The ease, economy, efficiency and selectivity with which organofluorine compounds are accessed is in the exclusive purview of chemical synthesis 1,2. Efficient transformations that deliver valuable fluoro-organic products with high diastereo-and/or enantioselectivity open fresh vistas in drug discovery 3-5 , and facilitate the development of improved agrochemicals 6 and/or superior polymeric materials 7. Among the areas to be impacted are oligonucleotide therapeutics and glycomimetic drug design 8-11 , where 2-fluoro-substituted monosaccharides are key (Fig. 1a). An example is sofosbuvir, sold under the name Sovaldi, which is used for the treatment of chronic hepatitis C virus infection 12-15. A more potent derivative of Sovaldi has a fluoro,bromo-substituted stereogenic C2 (ref. 16). Bioactive pyranosides with a fluoro-substituted C2 are similarly sought-after, a prominent member being sialyltransferase inhibitor 3F ax-Neu 5 Ac 17,18. These latter compounds are components of cancer vaccine candidates 19,20 that can be used discretely, or in combination with other drugs, to counter viral infections 21 , including COVID-19 (refs. 22-24). In light of evidence vis-à-vis the beneficial impact of a trifluoromethyl group on bioavailability and/or metabolic stability of a therapeutic candidate 2,3 , the development of efficient and stereoselective pathways for the synthesis of unexplored furanosides and pyranosides with a trifluoromethyl-and fluoro-substituted C2 (refs. 2,25) is particularly desirable (Fig. 1a). Oxonium ion generation and the ensuing saccharide ring cleavage, a preamble to depurination 26,27 , might then be thwarted by the strong electronic pull caused by the trifluoromethyl-and fluoro-substituted stereogenic carbon (compared
The Journal of Organic Chemistry, 2001
The stereoselective synthesis of both enantiomers of trifluoro frontalin (-)-(1S,5R)- and (+)-(1R,5S)-8, as well as of diastereomeric monofluoro frontalines (-)-(1R,2R,5R)-18 and (-)-(1R,2S,5R)-20, analogues of the bioactive component of the aggregation pheromone of the Scolytidae insect family, has been accomplished starting from (-)-(1R)- and (+)-(1S)-menthyl (S)-toluene-4-sulfinate as a source of chirality and methyl trifluoroacetate or fluoroacetate, respectively, as sources of fluorine. The C-1 stereocenters were installed via stereoselective epoxidation of beta-sulfinyl ketones 2 and 13 with diazomethane. The bicyclic core was obtained by totally stereocontrolled and chemoselective tandem Wacker oxidation/intramolecular ketalization of the intermediate unsatured sulfinyl diols 5, 15, and 19. Axially fluorinated (-)-20 elicited a strong electroantennographic response in laboratory tests on females of Dendroctonus micans, whereas equatorially fluorinated (-)-18 and the trifluoroanalogue (-)-8 showed modest responses. Field trials using (-)-20 were not indicative owing to the locally scarce population of D. micans, but it showed some attractiveness for other Coleoptera families.
Formal Synthesis of (-)-Frontalin through Diastereoselective Hydrocyanation of a β-Keto Sulfoxide
Synthesis, 2008
The diastereoselective synthesis of (S)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)butan-1-ol (9), an intermediate in the asymmetric synthesis of the pine beetle pheromone (-)-frontalin [(1S,5R)-1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane] (1), has been accomplished starting from the b-keto sulfoxide 2, derived from glutaric anhydride. The key step of the synthetic sequence is the diastereoselective hydrocyanation of 2 by diethylaluminum cyanide.
Chiral Monofluorobenzyl Carbanions: Synthesis of Enantiopure β-Fluorinated β-Phenylethylamines
Chemistry - A European Journal, 2011
The ability of fluorine atoms to modulate molecular properties, such as metabolic stabilities or binding affinities, has converted fluorine substitution in a powerful tool in medicinal chemistry and chemical biology. [1] Since fluorinated compounds occur extremely rarely in nature, [2] the strategic incorporation of fluorine into biologically active small molecules has attracted considerable attention in drug-discovery research. [3] To this end several methodologies have been devised in recent years. [4] While the chemistry of trifluoro-and difluoroalkyl derivatives has been studied in some detail, [5] the synthesis and reactivity of the corresponding mono-A C H T U N G T R E N N U N G fluoroalkyl derivatives is only recently emerging and still remains as a challenging task nowadays. The most often applied approach for preparing optically pure monofluorinated compounds is the reaction of nucleophiles with electrophilic fluorinated reagents. [6] However, the synthetic usefulness of these reactions is rather limited due to their moderated scope and the disadvantages associated with the use of complex, tedious, and even sometimes toxic reagents. Thus, alternative routes using nucleophilic monofluorinated carbanions as reagents have gained interest in the last years, with the most important contributions coming from the groups of Prakash and Olah, [7] Hu, [8] and Shibata and Toru. [9] The main limitation of these reagents arises from the usually low thermal stability of fluorinated carbanions, [7a] which undergo side reactions, for example, a-fluoride elimination. The strategies used so far to avoid this problem involved increasing the stability of the anions by incorporating electronwithdrawing groups (usually sulfonyl functionality) to the carbanionic center, [7-9] the elimination of which, which is not stereoselective, is frequently required at the final steps of the process. In consequence, monofluoromethylations [10] are the processes usually performed with these strategies, which never allow for the synthesis of compounds containing chiral fluorinated carbons. [11] To overcome these limitations, we reasoned that the use of chiral groups able to stabilize carbanionic centers without being directly connected to them (long-distance stabilization) could offer new opportunities for stereoselective alkylfluorination. As we have recently demonstrated, the ortho-sulfinyl group provides stability to lithiated benzyl carbanions, which is traduced in highly stereoselective reactions with different electrophiles. [12] Hence, we decided to evaluate the potential of (S)-2-p-tolylsulfinylbenzyl fluoride (S)-1 as a precursor of stabilized monofluorinated benzyl carbanion (Scheme 1). We focused our attention on reactions with N-sulfinylimines (the best electrophiles in reactions with other sulfinyl benzyl carbA C H T U N G T R E N N U N G anions) [13] due to the significant biological and pharmaceutical activities [3a, 14] of the resulting b-fluoroamines and the low number of methods reported for their preparation in optically pure form. [15] 2-Fluoro-2-phenethylamines are important chiral derivatizing agents and efficient inhibitors of monoamine oxidases. [16] Additionally, these reactions would open a new route for the synthesis of the enantiomer
Synthesis, 2003
Chlorodifluoromethyl groups were introduced into the 2-position of the glycals 1, 5, 8, and 11 by dithionite-mediated addition of CF2ClBr. The reaction proceeded stereoselectively, i.e. the CF2Cl-group is always found trans to the neighbouring substituent at C-3 in the products. Because the primarily formed glycosyl bromides hydrolyse easily, the corresponding 2-chlorodifluoromethyl-2-deoxypyranoses 3, 6, 9, and 12 were isolated. Only 3,4,6-tri-Oacetyl-2-chlorodifluoromethyl-2-deoxy-D-glucopyranosy1 bromide (2) was stable enough for chromatographic separation. The unprotected anomeric pyranoses 3, 6, 9, and 12 were acetylated by acetic anhydride/pyridine yielding the 1-O-acetyl derivatives 4, 7, 10, and 13. These compounds are suitable glycosyl donors, just as the anomeric phenyl thioglycosides 16 and 17 generated from 1,3,4-tri-O-acetyl-2-chlorodifluoromethyl-2-deoxy-D-arabinopyranside (7) and thiophenol (BF3-catalysis). Furthermore, the reactivity of glucosyl bromide 2, 6-deoxy-L-glucose derivative 13 and thioglycosides 16, 17 was investigated. On treatment of glucosyl bromide 2 with pyridine, the 2-chlorodifluoromethyl substituted glycal 14 is formed as the result of HBr elimination. Furthermore, the chlorodifluoromethyl group of compounds 14 and 16 was converted into a methoxycarbonyl group by refluxing in methanolic sodium methoxide (products 15 and 19, respectively). Finally, the thioglycosides 16 and 17 were subsequently deacetylated by CsF on alumina (yielding the dihydroxy derivatives 18 and 20) and acetalized with chloral/DCC (18 forming acetal 21 and carbonate 22) and acetone (20 forming acetal 23), respectively. X-ray analyses are given for the 1-O-acetate 4 and the thioglycosides 21 and 24.