Wittig Ylide Research Articles

Diversity-Oriented Synthesis (DOS) of On-DNA Peptidomimetics from Acid-Derived Phosphonium Ylides.

The DNA-encoded library (DEL) technology represents a revolutionary drug-discovery tool with unprecedented screening power originating from the association of combinatorial chemistry and DNA barcoding. The chemical diversity of DELs and its chemical space will be further expanded as new DNA-compatible reactions are introduced. This work introduces the use of DOS in the context of on-DNA peptidomimetics. Wittig olefination of aspartic acid-derived on-DNA Wittig ylide, combined with a broad substrate scope of aldehydes, led to formation of on-DNA , -unsaturated ketones. The synthesis of on-DNA multi-peptidyl-ylides was performed by incorporating sequential amino acids onto a monomeric ylide. Di-, tri- and tetrameric peptidyl-ylides were validated for Wittig olefination and led to on-DNA , -unsaturated-based peptidomimetics, an important class of intermediates. One on-DNA aryl Wittig ylide was also developed and applied to Wittig olefination for synthesis of on-DNA chalcone-based molecules. Furthermore, DOS was used successfully with electron-deficient peptidomimetics and led to the development of different heterocyclic cores containing on-DNA peptidomimetics.

A Systems Approach to a One-Pot Electrochemical Wittig Olefination Avoiding the Use of Chemical Reductant or Sacrificial Electrode.

An unprecedented one‐pot fully electrochemically driven Wittig olefination reaction system without employing a chemical reductant or sacrificial electrode material to regenerate triphenylphosphine (TPP) from triphenylphosphine oxide (TPPO) and base‐free in situ formation of Wittig ylides, is reported. Starting from TPPO, the initial step of the phosphoryl P=O bond activation proceeds through alkylation with RX (R=Me, Et; X=OSO2CF3 (OTf)), affording the corresponding [Ph3POR]+X− salts which undergo efficient electroreduction to TPP in the presence of a substoichiometric amount of the Sc(OTf)3 Lewis acid on a Ag‐electrode. Subsequent alkylation of TPP affords Ph3PR+ which enables a facile and efficient electrochemical in situ formation of the corresponding Wittig ylide under base‐free condition and their direct use for the olefination of various carbonyl compounds. The mechanism and, in particular, the intriguing role of Sc3+ as mediator in the TPPO electroreduction been uncovered by density functional theory calculations.

Normal, Abnormal, and Cascade Wittig Olefinations of α-Oxoketenes.

α-Oxoketenes generated in situ by a thermal Wolff rearrangement have been found to participate as 1,2- and 1,4-ambident C-electrophilic/O-nucleophilic reagents towards donor/acceptor carbonyl-stabilized Wittig ylides. This resulted in the very direct and practical syntheses of functionalized allenes by a normal Wittig olefination, 4H-pyran-4-ones by an abnormal Wittig olefination, or 4H-pyranylidenes following a Wittig/abnormal Wittig cascade sequence as a function of the substrates combination employed. Mechanistic experimental and computational studies provided a full rational for these reactivity switches. Some unusual mechanistic features for Lewis acid-free Wittig olefinations were identified in this series such as the involvement of betaine intermediates and some degree of reversibility in the normal Wittig olefination. The abnormal Wittig olefination was fully uncovered.

Wittig Ylide Mediated Decomposition of N-Sulfonylhydrazones to Sulfinates.

N-Sulfonylhydrazones generate sulfinates selectively when treated with a stabilized Wittig ylide in a polar aprotic solvent at elevated temperature. The transition metal and base free decomposition method is applicable to N-sulfonylhydrazones generated from a number of aromatic and heteroaromatic aldehydes and ketones. In the case of N-tosylhydrazones derived from O-allyl and O-propargyl salicylaldehydes, selective formation of sulfinate occurs over intramolecular [3 + 2]-cycloaddition reaction.

Direct Wittig Olefination of Alcohols.

A base-promoted transition metal-free approach to substituted alkenes using alcohols under aerobic conditions using air as the inexpensive and clean oxidant is described. Aldehydes are relatively difficult to handle compared to corresponding alcohols due to their volatility and penchant to polymerize and autoxidize. Wittig ylides are easily oxidized to aldehydes and consequently form homo-olefination products. By the strategy of simultaneously in situ generation of ylides and aldehydes, for the first time, alcohols are directly transferred to olefins with no need of prepreparation of either aldehydes or ylides. Thus, the di/monocontrollable olefination of diols is accomplished. This synthetically practical method has been applied in the gram-scale synthesis of pharmaceuticals, such as DMU-212 and resveratrol from alcohols.

Exocyclic Olefinic Maleimides: Synthesis and Application for Stable and Thiol-Selective Bioconjugation.

Michael addition reactions between biological thiols and endocyclic olefinic maleimides are extensively used for site-specific bioconjugation. The resulting thio-succinimidyl linkages, however, lack stability because of their susceptibility to thiol exchange. Reported herein is that in contrast to their endocyclic counterparts, exocyclic olefinic maleimides form highly stable thio-Michael adducts which resist thiol exchange at physiological conditions. A high-yielding approach for synthesizing a variety of exocyclic olefinic maleimides, by 4-nitrophenol-catalyzed solvent-free Wittig reactions, is reported. Mechanistic studies reveal that the catalyst facilitates the formation of the Wittig ylide intermediate through sequential proton donation and abstraction. Overall, this report details an improved thiol bioconjugation approach, a facile method for synthesizing exocyclic olefinic maleimides, and demonstrates that phenolic compounds can catalyze ylide formation.

Exocyclic Olefinic Maleimides: Synthesis and Application for Stable and Thiol‐Selective Bioconjugation

AbstractMichael addition reactions between biological thiols and endocyclic olefinic maleimides are extensively used for site‐specific bioconjugation. The resulting thio‐succinimidyl linkages, however, lack stability because of their susceptibility to thiol exchange. Reported herein is that in contrast to their endocyclic counterparts, exocyclic olefinic maleimides form highly stable thio‐Michael adducts which resist thiol exchange at physiological conditions. A high‐yielding approach for synthesizing a variety of exocyclic olefinic maleimides, by 4‐nitrophenol‐catalyzed solvent‐free Wittig reactions, is reported. Mechanistic studies reveal that the catalyst facilitates the formation of the Wittig ylide intermediate through sequential proton donation and abstraction. Overall, this report details an improved thiol bioconjugation approach, a facile method for synthesizing exocyclic olefinic maleimides, and demonstrates that phenolic compounds can catalyze ylide formation.

ChemInform Abstract: Sequential One‐Pot Isomerization—Wittig Olefination—Hydrogenation.

AbstractThe Pd‐catalyzed isomerization of allylic alcohols to aldehydes and subsequent addition of Wittig ylides gives α,β‐unsaturated carbonyl compounds in one pot.

Stereoselective Synthesis of β‐Proline Derivatives from Allylamines via Domino Hydroformylation/Wittig Olefination and Aza‐Michael Addition

AbstractUnder appropriate reaction conditions, a domino hydroformylation/Wittig olefination can be accomplished with derivatives of allylamines and stabilized Wittig ylides. A further highly diastereoselective aza‐Michael reaction yields β‐proline derivatives. These are, for example, useful as building blocks for alkaloid syntheses.

A Concise Approach for the Synthesis of Core Fragment C7-C15 of (+)-Migrastatin Using Desymmetrization Strategy

The core fragment C7-C15 the (+)-migrastatin was constructed in a stereoconvergent manner utilizing desymmetrization approach. The strategy involved the generation of Z-configuration of trisubstituted double bond at C11-C12, epimerization at C10, ring opening of the pyran lactol with C2 Wittig ylide, and regioselective Sharpless dihydroxylation.

Competing ring cleavage of transient O-protonated oxaphosphirane complexes: 1,3-oxaphospholane and η2-Wittig ylide complex formation

O-Protonation and ring cleavage of oxaphosphirane complexes 1a,b enabled the synthesis of novel compounds such as the bicyclic 1,3-oxaphospholane complex 5 and the η(2)-Wittig ylide complex 7, which demonstrate the emerging chemistry of this new reactive intermediate. Whereas P-O bond cleavage occurred, in the first case, thus revealing the superior ability of the P-bonded Cp* group to stabilize cationic charge, in the second case competing C-O and P-O bond cleavages occurred, thus leading to a mixture of complexes 3, 4 and 7.

A Reverse Wittig Coupling with Trifluoroacetaldehyde: A Convenient One-Step Synthesis of Trifluoromethyl Alkenes

A novel, mild synthesis of aryl-3,3,3-trifluoropropenes by Wittig olefination of benzylphosphonium ylides with in-situ generated trifluoroacetaldehyde is described. The in-situ formed trifluoroacetaldehyde efficiently traps the Wittig ylides and yields trifluoromethyl alkenes without the troublesome handling. The scope of the reaction was tested in reaction of trifluoroacetaldehyde with a wide variety of benzylphosphonium ylides. The α-trifluoromethyl alkenes were isolated in good to excellent yields in a convenient one step process. Keywords: Trifluoroacetaldehyde ethyl hemiacetal, fluoral, witting coupling, aryl-α-trifluoromethyl-alkenes

Nucleophilicity Parameters for Phosphoryl-Stabilized Carbanions and Phosphorus Ylides: Implications for Wittig and Related Olefination Reactions

The kinetics of the reactions of four phosphoryl-stabilized carbanions 1a-d and four phosphorus ylides 1e-h with benzhydrylium ions 2a-h and structurally related quinone methides 2i-m have been determined by UV-vis spectroscopy. The second-order rate constants (k) correlated linearly with the electrophilicity parameters E of 2a-m, as required by the correlation log k = s(N + E) (J. Am. Chem. Soc. 2001, 123, 9500-9521), allowing us to calculate the nucleophile-specific parameters N and s for phosphoryl-substituted carbanions and phosphorus ylides. In this way, a direct comparison of the nucleophilic reactivities of Horner-Wadsworth-Emmons carbanions and Wittig ylides became possible. Ph(2)PO- and (EtO)(2)PO-substituted carbanions are found to show similar reactivities toward Michael acceptors, which are 10(4)-10(5) times higher than those of analogously substituted phosphorus ylides. The relative reactivities of these nucleophiles toward benzaldehydes differ significantly from those toward carbocations and Michael acceptors, in accordance with a concerted [2 + 2] cycloaddition being the initial step of these olefinations reactions. Effects of the counterion (K(+), Na(+), or Li(+)) on the nucleophilicities of the phosphoryl-stabilized carbanions in DMSO have been studied. Whereas the effects of K(+) and Na(+) are almost negligible for all types of carbanions investigated, Li(+) coordination reduces the reactivities of phosphonate-substituted acetic ester anions (1a) by a factor of 10(2) while the reactivities of phosphonate-substituted acetonitrile anions (1b) remain almost unaffected.

Intramolecular [3+2] cycloaddition of a nitrilium phosphane ylide complex to the P-phenyl group of a Wittig ylide.

Intramolecular [3+2] cycloaddition of a nitrilium phosphane ylide complex to the P-phenyl group of a Wittig ylide.

Synthesis, spectroscopic, and structural properties of spirocyclopropanated bicyclobutylidenes and their radical cations.

The spirocyclopropanated bicyclobutylidenes 3-7 have been prepared by McMurry coupling of the corresponding spirocyclopropanated cyclobutanone (3 and 5), Staudinger-Pfenniger reaction (4), oxidative coupling of a Wittig ylide (4) or Wittig olefination of perspirocyclopropanated cyclobutanone (6 and 7). The structure of the parent 2a and the perspirocyclopropanated bicyclobutylidene 5 was determined by X-ray crystallography which disclosed considerable steric congestion around the double bond. As a result 5 did undergo addition of dichlorocarbene, epoxidation with meta-chloroperbenzoic acid, and cyclopropanation with CH2I2/ZnEt2, but did not add the more bulky dibromocarbene. The reaction of 5 with tetracyanoethene proceeded smoothly, but led to a formal [3+2] cycloadduct across the proximal single bond of one of the inner cyclopropane rings. The consecutive spirocyclopropanation of bicyclobutylidene led to a bathochromic shift in the UV spectra of 12 and 17nm, respectively, for each pair of beta- and alpha-spirocyclopropane groups. In the He(I)-photoelectron spectra of these bicyclobutylidenes, the effect of spirocyclopropanation upon their pi-ionization energies (pi-IE,) was found to be almost additive, leading to a lowering of 0.05 eV per any additional beta-spirocyclopropane, and 0.28-0.22 eV per additional alpha-spirocyclopropane group; this indicates an increasing nucleophilicity of the double bonds in the order 1 < 4 < 3 < 5. Following the radical cations of the three symmetrical bicyclobutylidenes without (2a, b) and with six (5) spiroannelated cyclopropane rings, the radical cations of two symmetrical bicyclobutylidenes with two (4) and four (3) such rings were studied by ESR spectroscopy. Whereas 2b.+, 3.+, and 5.+ could be generated by electrolytic oxidation of the corresponding hydrocarbons in solution, the spectra of 2a.+ and 4.+, with unsubstituted 2,2',4,4'-positions, were observed upon radiolysis of their neutral precursors in a Freon matrix. On going from 2a.+ to 4.+, the coupling constant [aH] of the eight beta protons in the 2,2',4,4'-positions of bicyclobutylidene increases from 2.62 to 3.08 mT, and that of the four gamma protons in the 3,3'-positions changes from 0.27 to 0.049 to 0.401 mT on passing from 2a.+ via 2b.+ to 3.+. Computations by means of the density functional theory (DFT) at the B3LYP/6-311+G*//B3LYP/6-31G* level reproduce well the experimental hyperfine data.

Heteroorganic betaines. 6. Structure and reactivity of silicon-containing organophosphorus betaines with the –S—Si—C—P+ fragment: a DFT study

The structures of silicon-containing organophosphorus betaines –S—SiR1 2—CR2 2—P+R3 3 and their ylide isomers were calculated using the density functional approach with the gradient-corrected PBE functional and extended TZ2P basis set. Three possible pathways of thermal decomposition of these betaines were analyzed. These are (i) cleavage of the central C—Si bond with the formation of a Wittig ylide and silanethione, (ii) intramolecular nucleophilic S N-substitution with elimination of phosphine PR3 3 and the formation of silathiirane (the Corey—Chaikovscky transformation), and (iii) a Wittig-type decomposition followed by the formation of substituted silaethylene. The structures of products and transition states of these reactions were calculated. The cis-gauche conformation of the –S—Si—C—P+ fragment of betaines was found to be the most stable. This is in agreement with the results of X-ray diffraction study and can be rationalized by strong Coulomb attraction between the cationic and anionic centers. The betaines are stable toward retro-Wittig thermal decomposition. The Corey—Chaikovscky formation of thiirane is preferable under conditions of thermal decomposition. Retro-Wittig-type decomposition of betaines followed by the formation of silanethione is favored by intra- and intermolecular coordination of donor ligands.

ONE-POT OXIDATION AND WITTIG OLEFINATION OF ALCOHOLS USING O-IODOXYBENZOIC ACID AND STABLE WITTIG YLIDE1*

Benylic, allylic, and propargylic alcohols, as well as diols, can be oxidized with o-iodoxybenzoic acid (IBX) in the presence of stabilized Wittig ylide[1] to generate α,β-unsaturated ester in one pot. This is useful when the intermediate aldehydes are unstable and difficult to isolate. *IICT communication no. 4369.

Azetidin‐3‐ones from (S)‐α‐Amino Acids and Their Reactions with Nucleophiles: Preparation of some azetidine‐containing amino‐alcohol and amino‐acid derivatives

AbstractThe reactions of azetidin‐3‐ones 6–10, readily available from the amino acids L‐alanine, L‐phenylalanine, L‐valine, L‐lysine, and L‐aspartic acid, via the corresponding diazo ketones, with nucleophilic reagents such as complex hydrides, Grignard compounds, an ester enolate, and a Wittig ylide give the expected products 11–19 in good yields and mostly in high diastereoselectivities. New amino‐alcohol, γ‐amino‐ and γ‐amino‐β‐hydroxy‐carboxylic‐acid derivatives of known configurations are thus available.

Cycloadditionen, XXII [1]. Synthese und thermische Reaktion von S-(Alkyl/Aryl)- 2.3-butadienthiosäure-estern / Cycloadditions, XXII [1]. Synthesis and Thermal Reaction of S-(Alkyl/Aryl)-2,3-butadienethioates

While the S-alkyl- or S-phenyl-2,3-butadienethioates 4 a-c are synthesized via the usual “Wittig ylide way”, the corresponding 2-methyl-2,3-butadienethioates 9 a-d and the 2-methyl-4.4-diphenyl-2,3-butadienethioates 9 e,f are obtained by condensation of the allenic acids 7 a,b with the thiols and thiophenols 8 in the presence of dicyclohexylcarbodiimide (DCC) and a catalytic am ount of 4-dimethylaminopyridine (DMAP). In contrast to N- or O-phenyl 2,3- butadienamides or -esters, resp., the phenyl derivatives of 4 and 9 do not undergo the intram olecular Diels-Alder reaction, but by heating, all representatives of 4 only decompose, while 9 a-d and 9 e,f rearrange to 3-alkyl(aryl)thio-2-cyclobuten-1-ones 12a-d and to 3-arylthio- 1-naphthols 14a, b, resp. Heating of the cyclobutenone 12d in the presence of N-methylaniline furnishes the 2-butenanilide 16. On reacting 1-phenylthio-1-propyne 17 with diphenylketene 18, the diphenylacetate 19 is isolated, where the naphthol derivative 14a represents the ester moiety.

Stereoselective Syntheses of Ethyl (Z)- and (E)-Octa-2,6-dienopyranosiduronates from Ethyl 2,3-Dideoxy-α-D-erythro-hex-2-enopyranoside

(Z)- and (E)- isomers of oct-2,6-dienopyranosiduronates have been synthesized in a completely stereoselective manner from ethyl 2,3-dideoxy-α-D-erythro-hex-2-enopyranoside. The selectivity of the processes is dictated by an unexpected opposite stereochemical behavior towards stabilized Wittig ylides of protected and unprotected 4-hydroxy derivatives in hex-2-enopyranoside-6-aldehydes.