- Intramolecular OH...Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif
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Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH...F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time - and in contrast to earlier reports - the occurrence of OH...F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH...F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH...F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the "rule of shielding" applies to OH...F IMHB energies. Surprisingly, the predicted OH...F IMHB energies are only moderately weaker than these of the corresponding OH...OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.
- Linclau, Bruno,Peron, Florent,Bogdan, Elena,Wells, Neil,Wang, Zhong,Compain, Guillaume,Fontenelle, Clement Q.,Galland, Nicolas,Le Questel, Jean-Yves,Graton, Jér?me
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supporting information
p. 17808 - 17816
(2015/12/08)
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- Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: Kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols
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Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinonemediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a. On the other hand, enantioselective reaction of trisubstituted acetal rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)-C(27) ansachain of rifamycin S.
- Harada, Toshiro,Egusa, Takayuki,Igarashi, Yasuto,Kinugasa, Motoharu,Oku, Akira
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p. 7080 - 7090
(2007/10/03)
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- Syntheses of β-resorcylic acid derivatives, novel potato micro-tuber inducing substances isolated from Lasiodiplodia theobromae
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The syntheses of β-resorcylic acid derivatives 1 and 2, isolated from fungus Lasiodiplodia theobromae, and their dimethyl ethers were accomplished. (R)-(-)-1,3-Butanediol was used as a chiral source of the side chain C6-synthon. The dianion of the benzoic acid moiety was alkylated with C6-bromide to give the desired skeleton. Several β-resorcylic acid derivatives including 1 and 2 were synthesized via hydrogenation, lactonization, demethylation and esterification. The (R)-configuration of the stereogenic center in the side chain was proved by this synthesis. It is confirmed that two phenolic hydroxy groups are required for 1 and 2 to exhibit potato micro-tuber inducing activity.
- Yang,Toshima,Yoshihara
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p. 5377 - 5384
(2007/10/03)
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- Asymmetric Synthesis of Functionalized Secondary Alcohols by Catalytic Ring-Cleavage Reactions of Cyclic Acetals Derived from (R)-1,3-Butanediol
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In the presence of a catalytic amount (0.1-0.2 molar amount) of a 2-phenyl-1,3,2-oxazaborolidin-5-one, prepared by the reaction of dichlorophenylborane and N-(trifluoromethylsulfonyl)-L- phenylalanine, and enol silyl ethers ((R2)2C=C-(R3)OTMS; R3 = t-BuS, EtS, EtO, Ph) (1.1-1.5 molar amount), chiral cyclic acetals 6 derived from (R)-1,3-butanediol and aldehydes undergo an efficient ring-cleavage reaction with the inversion of the stereochemistry at the acetal carbon to give the anti isomer of the corresponding products with high stereoselectivity. The reaction is applicable to acetals derived from aromatic, aliphatic, and α,β-unsaturated aldehydes. Not only enol silyl ethers, but also methallyltrimethylsilane and allyltributyltin, can be employed as nucleophiles, leading to the selective formation of the anti isomer of the corresponding allylated ring-cleavage products. Removal of the chiral auxiliary from these ring-cleavage products by a two-step sequence ((i) PCC (ii) Bn2NH2(CF3CO2)) furnishes enantiomerically enriched β-hydroxy carbonyl compounds and homoallyl alcohols. A modest level of kinetic resolution is observed in the ring cleavage of a racemic acetal catalyzed by a phenylboron compound derived from N-mesyl-L-phenylalanine.
- Kinugasa, Motoharu,Hanada, Toshiro,Egusa, Takayuki,Fujita, Katsuhiro,Oku, Akira
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p. 3639 - 3650
(2007/10/03)
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- Stereochemistry of carbanions derived from 1,3-dioxanes
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Proton abstraction from 4-methyl-1,3-dioxane (1), 2-phenyl-1,3-dioxane (4), 4-phenyl-1,3-dioxane (5), trans-4-methyl-2-phenyl-1,3-dioxane (7), and cis- (12) and trans-2-methyl-4-phenyl-1,3-dioxane (6) by means of BuLi/KO-t-Bu ("Lochmann-Schlosser base") gave the corresponding carbanions as shown by subsequent deuteronation with EtOD. In contrast, attempted proton abstraction from cis-2-phenyl-4-methyl-1,3-dioxane (3) under the same conditions was unsuccessful, as was abstraction from phenylcyclohexane. Competitive experiments showed that abstraction of the equatorial hydrogen from 7 was about 4 times faster than corresponding abstraction from 6 and that abstraction of the equatorial hydrogen in 6 was well over 25 times faster than abstraction of the axial hydrogen in 12. Deuteronation of the 2-phenyl carbanion from 7 gave the trans isomer 8 in a 70:1 or greater ratio. Deuteronation of the carbanion derived from 6 or 12, in contrast, produced the axial and equatorial 4-phenyl compounds 10 and 11 in a ratio of only about 2:1. The preliminary conclusion that the carbanion derived from 2-phenyl-1,3-dioxane is largely pyramidal, similar to that from 2-phenyl-1,3-dithiane,8 whereas the 4-phenyl-1,3-dioxanyl carbanion is planar, similar to the phenylcyclohexyl (benzylic) carbanion,13 was confirmed by 13C NMR study of these carbanions. The ion derived from 4-phenyl-1,3-dioxane is red and shows the large upfield shifts of the ortho and para ring carbons also seen in the phenylcyclohexyl carbanion13 and characteristic of planar benzylic carbanions.12 In contrast, the orange carbanion derived from 2-phenyl-1,3-dioxane (which was very unstable and easily oxidized), to the extent that measurement was possible, showed the smaller upfield para carbon shift characteristic of pyramidal benzylic carbanions.8b,12 It is concluded that, while two adjacent oxygen atoms mildly stabilize equatorial carbanions (presumably inductively), the destabilizing effect of antiperiplanar lone pairs prevents the 2-phenyl carbanion from becoming planar and inhibits abstraction of the axial hydrogen in compound 3. Reprotonation of the pyramidal ion is stereoselective from the equatorial side. In contrast, in the 4-phenyl carbanion, benzylic resonance stabilization overrides the antiperiplanar effect of one neighboring oxygen atom: Both axial and equatorial hydrogen atoms at C(4) can be abstracted and the carbanion is planar; accordingly reprotonation is essentially nonstereoselective.
- Jernigan, Mary T.,Eliel, Ernest L.
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p. 9638 - 9644
(2007/10/02)
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- Enantiomerically Pure Synthetic Building Blocks with Four C-Atoms and Two or Three Functional Groups from β-Hydroxy-butanoic, Malic, and Tartaric Acid
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The pool of chiral, non-racemic electrophilic building blocks, which are available from simple natural products in both enantiomeric forms is enlarged by the epoxides 3, 5, and 10, by the tosylate 12a, and by the aldehydes 18 (cf. symbols A-D, 14, and Scheme 1).Key steps of the conversions leading from hydroxyacids to the building blocks are: epoxide-opening by triethylborohydride (1 --> 2a) and tosylate reduction (12a --> 12b); the Mitsunobu inversion (2a --> 4a); the reduction of (R,R)-tartaric ester to (R)-malic ester by NBS (N-bromosuccinimide) opening of the benzaldehyde acetal 8 and tin hydride reduction (6c -->7c); the enantiomer enrichment of optically active ethyl β-hydroxy-butanoate through the crystalline dinitrobenzoate 21b.Detailed procedures are given for large scale preparations of the key intermediates.The enantiomeric purities of the building blocks are secured by correlations.
- Hungerbuehler, Ernst von,Seebach, Dieter,Wasmuth, Daniel
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p. 1467 - 1487
(2007/10/02)
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