Selective Wittig Reaction Research Articles

An Improved and Practical Method for Synthesizing of α-Sanshools and Spilanthol

An efficient and practical route for the synthesis of α-sanshools and spilanthol is described herein. Several modifications of an existing method enabled the preparation of the (2E,6Z,8E,10E)-tetraene precursor of hydroxy-α-sanshool in good yield. A highly selective Wittig reaction employing newly synthesized phosphonium salt with low deliquescence and long-term stability yielded the desired Z-form tetraene. This improved methodology was shown to be applicable to the efficient synthesis of α-sanshool and spilanthol.

Total Synthesis of Two Possible Diastereomers of Natural 6-Chlorotetrahydrofuran Acetogenin and Its Stereostructural Elucidation.

The first total synthesis of two possible diastereomers of natural 6-chlorotetrahydrofuran acetogenin 1 has been achieved. The synthetic route features 5-exo-tet cyclization, Z selective Wittig reaction and Julia olefination for the construction of conjugated diene and enyne moieties, and stereoselective chlorination. Comparison of their 1 H and 13 C NMR data and specific rotation with those of the natural product elucidated the absolute configuration of natural (-)-6-chlorotetrahydrofuran acetogenin 1.

(E)‐Selective Wittig Reactions between a Nonstabilized Phosphonium Ylide Bearing a Phosphastibatriptycene Skeleton and Benzaldehydes

Wittig reactions between benzaldehyde derivatives and a nonstabilized phosphonium ylide bearing a phosphastibatriptycene skeleton, regarded as a tridentate aryl ligand, gave (E)‐alkenes with high selectivity in the presence of both lithium and sodium salts. As previously reported, reactions between a triphenylphosphonium ylide and benzaldehyde derivatives under the same conditions afforded mainly (Z)‐alkenes. Variable‐temperature (VT) 31P{1H} NMR spectra showed two signals, assigned to cis‐ and trans‐1,2‐oxaphosphetanes, which were observed at different temperatures (–80 °C and –40 °C, respectively) in the Wittig reaction between benzaldehyde and the nonstabilized phosphonium ylide bearing the phosphastibatriptycene skeleton, in the presence of both lithium and sodium salts, and showed the existence of equilibrium between these products at –40 °C. On the other hand, this equilibrium was not clearly observed in the reaction between the triphenylphosphonium ylide and benzaldehyde, for which only one signal was detected. The observed intermediates were confirmed to be 1,2‐oxaphosphetanes by deprotonation of the isolated β‐hydroxyalkylphosphonium salts bearing a phosphastibatriptycene skeleton and a triphenylphosphine moiety, respectively. Crossover reactions were conducted in the deprotonations of β‐hydroxyalkylphosphonium salts with TMS2NNa in the presence of p‐chlorobenzaldehyde, resulting in the observation of signals corresponding to 1,2‐oxaphosphetanes containing phenyl and p‐chlorophenyl groups at the 4‐positions, indicating the exchange process between benzaldehyde and p‐chlorobenzaldehyde at –40 °C for the phosphastibatriptycene system and at 0 °C for triphenyl derivatives. These results clearly indicated that stereochemical drift occurred at those temperatures, even in reactions using nonstabilized phosphonium ylides. The stereochemical drift in the phosphastibatriptycene system occurred at a lower temperature than in the case of the triphenyl derivative, thus explaining the (E)‐selective Wittig reactions between the benzaldehyde derivatives and the nonstabilized phosphastibatriptycene‐based phosphonium ylide in the presence of lithium and sodium salts.

Synthesis of C16–C27-fragments of bryostatins modified by 20,20-difluorination

2-Hydroxytetrahydropyrans corresponding to the C16–C27 fragment of bryostatins which have been difluorinated at C20 (bryostatin numbering) have been synthesised. The fluorine substituents were introduced by difluoroallylation. An (E)-selective Wittig reaction using a stabilised ylide provided the required methoxycarbonylmethylene substituent with excellent stereoselectivity.

ChemInform Abstract: A Short Synthesis of the Antileukemic Sesquiterpene (+)‐Caparratriene Employing Aqueous Wittig Chemistry.

AbstractThe three‐step synthesis of title compound (V) starts with the commercially available aldehyde precursor of alcohol (I) and involves a (4E) selective Wittig reaction of phosphonium bromide (III) with (R)‐citronellal as the key step.

Synthesis of γ-lactones by desymmetrization. A synthesis of (−)-muricatacin

A short synthesis of the natural potent cytotoxic agent (−)-muricatacin 1 and related unsaturated lactones from a versatile common intermediate, dienedioate 2, derived from d-mannitol or tartaric acid, is described. The strategy depends upon the desymmetrization of 7 by dihydroxylation and elaboration of the hydroxy alkyl sidechain. A route to unsaturated lactones is also described using a cis selective Wittig reaction. Since the enantiomers of 2 are available from the corresponding tartaric acids, this method provides access to both enantiomers of the described compounds and a wide range of derivatives.

Synthesis of Sphingosine‐1‐phosphonate and Homosphingosine‐1‐phosphonate

AbstractIn the first approach to homosphingosine‐1‐phosphonate, D‐glucofuranose was selectively deoxygenated at C‐5. Bond cleavage between C‐1 and C‐2 afforded a 5‐deoxy‐D‐threo‐pentose intermediate. (E)‐Selective Wittig reaction with a C14‐chain gave a C19‐intermediate, which was readily transformed into homosphingosine. Formation of a cyclic urethane containing the 3‐amino and the 4‐hydroxy group of the C19‐intermediate permitted regioselective introduction of the phosphonate group at C‐1, thus affording the target molecule after deprotection. In a second and shorter route, C18‐sphingosine was converted to a cyclic urethane containing the 2‐amino and the 3‐hydroxy group of the C18‐chain. C1‐Chain extension by a hydroxymethyl group by introduction of cyanide led to the same C19 cyclic urethane as obtained in the first route. Similarly, the C18 cyclic urethane led to the other target molecule, namely sphingosine‐1‐phosphonate. The third and shortest route to homosphingosine‐1‐phosphonate could be based on regioselective 1‐O‐tosylation of 1,2,3‐(trihydroxy)octadec‐4‐ene. Transformation into a 1,2‐epoxide, then combination of C1‐chain extension and introduction of a phosphonate group with methylphosphonate as reagent, and finally azide introduction, led after functional group liberation to the target molecule. As shown, also truncated derivatives are readily accessible by this route. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

(E)‐Selective Wittig Reactions of Garner′s Aldehyde with Nonstabilized Ylides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total syntheses of the strobilurins G, M, and N

The key reactions in the general synthesis of strobilurins are the highly ( Z)-selective Wittig reaction of an ( E)-cinnamaldehyde with the phosphorus ylide 8 derived from (1,1-dibromoethyl)triphenylphosphonium bromide, followed by bromine–iodine exchange and Pd–Cu co-catalyzed Stille cross-coupling of the resulting alkenyl iodide with methyl ( Z)-2-tributylstannyl-3-methoxyacrylate ( 7 ). The synthetic strobilurins G, M, and N were identical with the corresponding natural compounds. In addition, the (2′ S)-configuration of strobilurin G ( 1 ) was unambiguously established by oxidative degradation of the synthetic intermediate ( S)- 9 to ( R)-2,3-dihydroxyisovaleric acid.

( E)-Selective Wittig reactions of Garner's aldehyde with nonstabilized ylides

In the Wittig olefination reactions of Garner's aldehyde with certain nonstabilized ylides, the ( E)-alkenes could be produced as a major product by simply quenching the reactions with a large excess of MeOH at −78 °C. Even under the salt-free conditions, more than a 10:1 ratio of the ( E)- to ( Z)-alkene was resulted consistently from the ylides of a linear alkyl chain. Without addition of MeOH, usual selectivity for the ( Z)-alkene was obtained in a ratio of 94:6.

Structure‐odor correlation, XXV. Synthesis and Olfactory Properties of the “Inverse” Megastigmatrienone and Its Analogs

AbstractThe oxoisophorone monoacetal 2 is a convenient starting material for the synthesis of several megastigmatrienone analogs. Thus, the Wittig reaction of ketone 2, followed by deprotection, led to the dienones 7–10. The “inverse” megastigmatrienone 1 was synthesized from 2 via homologation (→11→12), Grignard reaction (→13) and hydrolysis. The mixture of the four stereoisomers of 1 is dominated by (E,E)‐1. In contrast, (Z,Z)‐1 was obtained as the main product when starting from 2 and proceeding via the reaction sequence →14 →15 →16 →17 and then (Z)‐selective Wittig reaction of aldehyde 17. Likewise, ketoaldehyde 17 is the starting material for the nor derivative 20. The odor evaluation of 1 showed that the typical strong and pleasant tobacco odor of megastigmatrienone D was by no means observed, neither in strength nor in quality. On the other hand, the four stereoisomers of 1 all exhibit a similar weak to moderate odor of floral, sweet, fresh and coumarin‐like tonalities.

Total Synthesis of (−)‐(2R)‐Dihydromyricoidine

AbstractAn asymmetric synthesis of the spermidine alkaloid (−)‐(2R)‐dihydromyricoidine (5) was performed by employing two ring‐enlargement reactions. The chiral center was introduced by a diastereoselective Michael addition of perhydropyridazine (7) to the α,β‐unsaturated ester 6. The (Z)‐CC bond was obtained by a selective Wittig reaction. The synthetic compound 5 was found to have a negative value for the specific rotation. This is in contrast to that of the natural product reported in the literature. Therefore, as an outcome of this synthesis, the absolute configuration of the natural alkaloid should be inverted to be as shown in structure V.

Studies of the synthesis of biomarkers. XI. Synthesis of 4,5-secocholestane and 4-methyl-4,5-secocholestane

4,5-Secocholestane ( 1a) and 4-methyl-4,5-secocholestane ( 1b) were synthesized from cholesterol ( 2) in five and seven steps, respectively. The key intermediate, 5-oxo-4,5-secocholestan-4-al ( 7) was reduced by the Clemmensen method to afford 1a. Meanwhile, 7 underwent selective Wittig reaction, Clemmensen reduction, and hydrogenation to give another target molecule, 1b. The structure of an unknown biomarker was shown to be different from the proposed 1a by gas chromatographic and mass spectrometric comparison.

ChemInform Abstract: Selective Wittig Reactions for the Synthesis of Variously‐Substituted 2‐Vinylindoles.

AbstractThe title compounds (IV), (VII), and (VIII) or (X) and (XI) are prepared by three variants of the Wittig reaction.

Selective Wittig Reactions for the Synthesis of Variously Substituted 2-Vinylindoles

Three selective variants of the Wittig reaction for the syntheses of 2-vinylindoles are described. The reactions are relatively easy to perform, exhibit E-selectivity, and are characterized by a good flexibility with regard to the functional groups present in the vinyl moiety.

Synthetic studies of alpha-tocopherol. 3. Synthesis of phytone.

Abstract Phytone (XI), an important intermediate in the preparation of α-tocopherol, was synthesized by a selective Wittig reaction between geranyltriphenylphosphonium halide (VII) and the aldehyde group of 2-methyl-6-oxoheptanal (VIII), followed by the hydrogenation of the product. VIII was prepared from 1,3-dimethyl-1-cyclohexene (V) by ozonolysis and reductive decomposition. V could not be obtained in a pure state by the dehydration of 2,6-dimethylcyclohexan-1-ol (II), presumably because of the isomerization of the intermediate carbonium ion. The pyrolysis of the acetate of II (III) was found to give pure V. That the hardly-pyrolizable stereoisomer of III was cis,cis-2,6-dimethylcyclohexyl-1-acetate (VI) is consistent with the cis-elimination mechanism.