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Notes: Structure Determination of Unusual Rearrangement Products of S-(1-Alkenyl)sulfoximides by Collisionally Activated Dissoication Mass Spectrometry (CAD-MS)The Molecular ions of s-(l-alkenyl)--N-(p-tolyl)sulfoximides 1 are transformed into the N(phenylsufenyl)sulfonamides 3+ by a 1,2-migration of the alkenyle group to the O-atom of the sulfoximide function followed by a 2,3-sigmatropic rearrangement. The structure of the production e has been unambiguouslydetermined by the CAD method, showing the identity of the ion e (m/z368) obtained from 1a and from 4a.

Notes: The asymmetric synthesis of (+)-3-oxacarbacyclin (1) from cis-bicyclo[3.3.0]octane-2,5-dione has been achieved. A notable feature in this synthesis is an asymmetric Horner-Wadsworth-Emmons (HWE) reaction. A further key step is the stereoselective deprotonation of a chiral bicyclic ketone, having a high local symmetry about the carbonyl group, with lithium (R,R)-bis(phenylethyl)amide in the presence of lithium chloride. The route described also allows the synthesis of the anti-thrombotic and anti-metastatic prostacyclin analogs cicaprost and eptaloprost. The flexibility of this route should also provide access to further side-chain modified analogs of 1.

Notes: The structures of the norbornenyl and norbornyl sulfones exo-5, endo-5 and endo-6 have been determined experimentally, by X-ray analysis, and theoretically by ab initio calculations (HF/6-31+G*). X-ray crystal structure analyses of the lithiated allylic norbornenyl and norbornyl sulfones endo-3/ent-endo-3·2diglyme and endo-4/ent-endo-4·2diglyme revealed dimeric O-Li contact ion pairs devoid of C-Li bonds. The anions of endo-3/ent-endo-3·2diglyme and endo-4/ent-endo-4·2diglyme adopt both the endo conformation (C2-S) and are characterized by in the exo direction pyramidalized anionic C atoms. The degree of pyramidalization of the C2 atom of 3 is higher than that of 4. Ab initio optimizations (HF/6-31+G*) of the structures of the anions of methylenenorbornene I and methylenenorbornane II resulted in local minima featuring non-planar C2 atoms which are pyramidalized in the exo direction in both cases, but to different degrees. In both cases cryoscopy of 3 and 4 in THF at -108.5 °C revealed approximately 1:1 mixtures of monomers and dimers. The sulfones exo-5, endo-5, exo-6 and endo-6 as well as the lithiosulfones 3 and 4 were studied by NMR spectroscopy. 1H-NMR (400 MHz), 13C-NMR (100 MHz) and 6Li-NMR (44 MHz) spectroscopy of 3 and 4 at -100 °C in [D]8THF revealed in each case only one set of signals, independent of the configuration of the starting sulfones. This indicates in both cases that attainment of both the monomer-dimer and the endo/exo equilibria of 3 and 4 is fast on the NMR time scale. According to 6Li{1H}- and 1H{1H}-NOE experiments of 3 and 4 the monomeric and dimeric species endo-3 and endo-4, having endo anions, seem to be preferred in THF solution. Ab initio calculations of the anions of 3 and 4 resulted in structures endo-3(-Li+), exo-3(-Li+), endo-4(-Li+) and exo-4(-Li+) (HF/6-31+G*), whose atomic point charges were calculated by the method of Kollman et al. The C2 atoms of endo-3(-Li+) and endo-4(-Li+) are pyramidalized in the exo direction whereas the C2 atoms of exo-3(-Li+) and exo-4(-Li+) are pyramidalized in the endo direction. According to the calculations, the endo anions are more stable than the exo anions. There is good agreement between the optimized structures of the free anions and the experimentally determined structures of the anions of the contact ion pairs in the crystal. Reactions of 3 and 4 with DX, MeI, EtI, nPrI and nHeI occurred at the C2 atom under the selective formation of the corresponding endosulfones endo-8a-e and endo-9a-e, respectively, in all cases. Thus, an earlier report on the selective formation of the exosulfone exo-9b in the reaction of 4 with MeI has to be revised. Product ratios were independent of the configuration of the starting sulfones and varied with the nature of the electrophile. Selectivities were highest in the case of the norbornyl species 4. Reaction of 3 with PhCHO occurred at the α position (C2) to afford the alcohols endo-8f and exo-8f (88:12) as single diastereomers and at higher temperatures at the γ position (C8), whereas reaction of 4 with PhCHO took place at the γ position even at low temperatures. Methylation of endo-5 and exo-5 at -105 °C by both the stepwise method and by the in situ method gave different ratios of exo- and endo-methylation products. The selectivities of reaction of 3 and 4 with electrophiles have been rationalized by the Curtin-Hammett/Winstein-Holness concepts. It is proposed that endo-3 (endo-4) and exo-3 (exo-4) are conformationally labile on the time scale defined by the rate of their reactions with electrophiles, and are attacked by electrophiles with high selectivities from the exo and the endo face, respectively, because of the shielding by the phenyl group and the direction of the pyramidalization of the anionic C atom. Preferential formation of the endosulfones is thus ascribed to exo attack of electrophiles on endo-3 (endo-4) being faster than endo attack on exo-3 (exo-4) because of Houk's staggering effect. Methylation of 3 and 4 by the in situ method showed 3, whose C2 atom is stronger pyramidalized, to be more reactive than 4. The base-catalyzed H/D exchange of sulfones endo-5, exo-5, endo-6 and exo-6 with NaOCD3 in CD3OD proceeded in all cases with a high degree of retention of configuration.

Notes: The asymmetric Horner-Wadsworth-Emmons (HWE) reaction of the prochiral ketones 8a/b with the phosphonoacetates 10a, ent-10a, 10b and rac-16, which contain 8-phenylmenthol, 8-phenylnormenthol and trans-2-(triphenylsilyl)-cyclohexanol, respectively, as chiral auxiliaries, were studied. The HWE reaction of 8a with the phosphonoenolates Li-10a/b at low temperatures gave the esters 7a/b and 11a/b in high yields with diastereoselectivities up to 97:3. The (E)-configured esters 7a/b serve as starting material for the total synthesis of (+)-3-oxacarbacyclin. Similarly, the reaction of 8b with ent-Li-10a gave the esters ent-7b and ent-11b in a ratio of 95:5 in 82% yield. The olefination of 8b with rac-16 afforded a mixture of the esters rac-17 and rac-18, of yet unassigned configuration, in a ratio of 70:30. The HWE reactions of 8a/b with Li-10a, ent-Li-10a and rac-Li-10b show linear temperature-diastereoselectivity relationships. The stereochemical course of the HWE reactions can be understood in terms of a selective addition of the chiral (E)-configured phosphonoenolate from its least hindered side to the ketone 8 at the convex side. The asymmetric Peterson reaction of 8b with the silyl enolate Li-20 gave the esters ent-7b and ent-11b in a ratio of 89:11. The diastereomerically pure β-hydroxy esters 22, rac-25 and 27, which contain 8-phenyl-menthol, trans-2-(triphenylsilyl)cyclohexanol and 3-{[(3,5-dimethylphenyl)phenylsulfonyl]amino}isoborneol, respectively, as chiral auxiliaries, were prepared by a highly selective addition of the enolates Li-21, rac-Li-24 and Li-26 to the ketone 8b. The asymmetric Martin dehydration of 22, rac-25 and 27 with the sulfurane 23 proceeds with stereoselectivities ranging from 82:18 to 99:1. Interestingly, the HWE, Peterson and Martin reactions involving 8-phenylmenthol as the chiral auxiliary all proceed with the same sense of asymmetric induction.

Notes: Eine ausgefeilte Synthese der homochiralen Bausteine 2a und ent-2a mittels der „Enantiotopos-Enzym-Konzeption“ für die enantioselektive Totalsynthese von Cyclopentanoiden wird beschrieben. Deren Schlüsselschritte sind die nahezu quantitative, PLE-katalysierte asymmetrische Verseifung des meso-Diesters 8 zum homochiralen Halbester 9, dessen Absolutkonfiguration durch Röntgenstruktur-Analyse des (-)-Ephedrinsalzes 12 bestimmt wurde; die Gewinnung von optisch reinem 9 und ent-9 durch Racematspaltung von rac-9 mit (+)- und (-)-Ephedrin; die enantiodivergente Synthese der Lactone 18 und ent-18 aus 9 sowie die enantiokonvergente Synthese von 18 oder ent-18 aus 9 sowie die enantiokonvergente Synthese von 18 oder ent-18 aus 9 und ent-9 durch wahlweise chemoselektive Reduktion der Ester- und Carboxygruppe und schließlich die regioselektive Dieckmann-Cyclisierung der isomeren Diester 23b/24b bzw. ent-23b/ent-24b zu den cyclopentanoiden Zielverbindungen 2a und ent-2a. Die Strukturen von 23b, 24b, rac-2b und rac-29 wurden durch INADEQUATE-13C-NMR-Experimente bestimmt. Dieckmann-Cyclisierung des trans-Diesters rac-31 führt ebenfalls zu rac-2a und rac-26a.

Notes: Ausgehend von dem enantiomerenreinen 1H-Cyclopenta[c]furanon-Derivat 7a gelingt über die Stufen der 1H-Cyclopenta[c]furanon-Derivate 8a, 11a und 20 sowie der Cyclopentan-Derivate 23 und 24 die Synthese eines neuen Prostaglandin-Bausteins, des homochiralen α-Methylencyclopentanons 1, das in einer 1,4-Additions-Carbonylolefinierungs-Sequenz die enantioselektive Synthese von Prostaglandinen 5 und Prostacyclinen 6 ermöglichen sollte. Konfiguration und Konformationen der Hydroxyester-Derivate 8 und 9, die die Stereochemie von 1 festlegen, wurden durch Röntgenstruktur-Analyse, 1H-NMR-Spektroskopie und Kraftfeldrechnungen ermittelt. Zentraler Schritt der zu 1 führenden Synthesefolge ist die Hydroxylierung des Brückenkopf-Enolates 19 zum Hydroxylacton 20. Untersuchungen an 19 und den analogen Enolaten 13a - c in Verbindung mit Literaturdaten ergeben, daß Brückenkopf-Enolate von Bicyclo[3.3.0]octan-Typ mit Elektrophilen mit über 95% diastereofacialer Selektivität zu den cis-verknüpften substituierten Bicyclen reagieren. Nach Kraftfeldrechnungen der Enolate 17a und 18 sind für die hohe π-faciale Selektion von 13a - c, 19 und analoger Verbindungen vermutlich nicht nur sterische sondern auch stereoelektronische Gründe maßgebend, da für 17a im Gegensatz zu 18 ein nichtplanares Enolat-Fragment resultiert. - 1 reagiert mit dem Cuprat 25 zum homochiralen Cyclopentanon-Derivat 26 mit 2α-Konfiguration. Mit der Synthese von 29c aus 11a wurde ein Weg zur stereoselektiven Anbindung von ω-Seitenketten an 3 erfolgreich erprobt.