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Notizen: 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.

Notizen: Asymmetric total syntheses of 3-oxacarbacyclin (4) and 3-oxaisocarbacyclin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium (R,R)-bis(phenylethyl)amide (12) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14-19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω-side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd-catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49. The key step in the construction of the α-side chain in 4 is a Horner-Wadsworth-Emmons reaction of ketone 7c with the 8-phenylnormenthol-containing phosphonoacetate 56 which gave ester 60 of 90% de. Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β-unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ-unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β-unsaturated ester 61 was converted to the ß,γ-unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.

Notizen: 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.

Notizen: 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.

Notizen: A formal asymmetric synthesis of pentalenolactone E (1b) and pentalenolactone F (1a) has been accomplished. Ozonolysis of the diphenyl-substituted triquinane 3 and Kauffmann methylenation of ketone 5 with WOCl3-2 MeLi yielded the unsubstituted triquinane 9. The crucial rearrangement of the linear triquinanoid lactone 11 to the angular triquinanoid lactone 14a was accomplished using orthoformate and acid in methanol. Subjecting triquinanes 14a/b to the selenoxide method gave triquinene 15. Homologation of γ-lactone 15 to the angular diquinanoid δ-lactone 2 via a Horner-Wadsworth-Emmons or Peterson reaction of hemiacetals 16a/b was, however, not successful. Chemoselective reduction of 14a afforded hemiacetals 21a/b, reaction of which with the phosphonate salt 17a ultimately led to the ketene dithioacetal 22. The angular intermediates 25a/b were obtained from 22 by reduction to give the linear hemiacetals 24a/b, which rearranged to the dithio ortholactones 25a/b in the presence of acid. Introduction of the double bond and deprotection were accomplished via selenation of 25a/b with N,N-diethylbenzeneselenylamide and treatment of selenides 30a/b with silver nitrate. The unsaturated aldehydes 28 and 29 thus obtained were converted to 2 and 31, respectively, by oxidation with manganese dioxide in the presence of sodium cyanide, methanol and acetic acid. Alkene 2 was isolated by crystallization.