The Paternò-Büchi reaction—Mechanisms and application to organic synthesis

The [2 + 2] photocycloaddition between an electronically excited carbonyl compound and an alkene leading to oxetanes (Paternò-Büchi reaction) is one of the most investigated organic photochemical reaction. Regio-, stereo- and site selectivities are discussed as a consequence of the reaction mechanism. Spin multiplicity and electron transfer have a significant impact on the outcome of the reaction. Typical carbonyl and alkene reaction partners are presented indicating scope and limitation of the reaction. The Paternò-Büchi reaction possesses particular interest for being applied to organic synthesis, considering the difficulty for non-photochemical reactions to obtain oxetanes, with or without stereoselectivity. Mechanistic details are particularly focused. It has been applied as key step in various multi-step syntheses.     

Conformational analysis of singlet-triplet state mixing in Paternò-Büchi diradicals

Conformational dependence of spin-orbit coupling (SOC) in flexible Paternò-Büchi (PB) diradicals has been studied with high-level ab initio methods using both (i) one-electron spin-orbit Hamiltonian with parametrized (effective) nuclear charges in conjunction with a state-averaged MCSCF wave function as implemented by Robb in Gaussian 98 and (ii) complete one- and two-electron SOC with a fully optimized MCSCF triplet wave function and frozen core singlet as implemented by Furlani in the GAMESS computational package. The ab initio results revealed two distinct areas of elevated SOC values, one corresponding to the region whereby a cisoid conformation in the C-C-O-C fragment brings the two odd-electron orbitals closer to each other, and the other area corresponding to the partially eclipsed conformation lacking direct overlap between the spin centers. In this second region the 1,4-electronic communication is mediated by the oxygen's 2p-lone pair, which is suitably oriented to play the role of a "relay-antenna". The other critical factor affecting the rate of intersystem crossing (ISC)--singlet-triplet energy separation--was computed utilizing a multireference CASSCF-MP2 method to include dynamic correlation effects. The largest singlet-triplet energy gap, approximately 2 kcal/mol, was found for a gauche conformer (also a minimum SOC conformation). Rotation about the central C-O bond either toward the fully eclipsed (0 degrees ) or the partially eclipsed (120 degrees ) conformations decreases the singlet-triplet gap while increasing the value of the SOC matrix element. These computational findings support the Griesbeck model for stereochemistry of triplet PB reactions and provide a rigorous basis for predicting the probability of ISC in diradicals separated by a partially conjugated spacer.     

Studies on The Application of The Paternò-Büchi Reaction to The Synthesis of Novel Fluorinated Scaffolds

In the context of new scaffolds obtained by photochemical reactions, Paternò-Büchi reactions between heteroaromatic, trifluoromethylphenyl ketone and electron rich alkenes to give oxetanes are described. A comprehensive study has then been carried out on the reaction of aromatic ketones with fluorinated alkenes. Depending on the substitution pattern at the oxetane ring, a metathesis reaction is described as a minor side process to give mono fluorinated alkenes. Overall, this last reaction corresponds to a photo-Wittig reaction and yield amid isosteres. In order to explain the uncommon regioselectivity of the Paternò-Büchi reaction with these alkenes, electrostatic-potential derived charges (ESP) have been determined. In a second computational study, the relative stabilities of the typical 1,4-diradical intermediates of the Paternò-Büchi reaction have been determined. The results well explain the regioselectivity. Further transformations of the oxetanes or previous functionalization of the fluoroalkenes open perspectives for oxetanes as core structures for biologically active compounds.     

Charging and Charge Switching of Unsaturated Lipids and Apolar Compounds Using Paternò-Büchi Reactions

The ability to control the charge state and ionization efficiency of lipids and hydrocarbons by means of in-source Paternò-Büchi functionalization in nano-electrospray ionization mass spectrometry experiments is investigated. Ultraviolet light irradiation of acetylpyridine filled nano-electrospray emitter tips, containing unsaturated analytes, generates protonated lipid and hydrocarbon ions. Comparison of reaction yields and fragment ion abundances of functionalized unsaturated fatty acids indicate that acetylpyridine Paternò-Büchi functionalization allows to readily detect fatty acids and determine double bond positions, but fragmentation efficiency and reactivity depend on double bond position and varies between different acetylpyridine isomers. Results for methyl oleate and olefins suggest that fragment ion abundances of unsaturated compounds depend on interactions between acetylpyridine and nearby functional groups. Paternò-Büchi functionalization with acetylpyridine was used to detect and assign double bond positions of mono- and polyunsaturated fatty acid, cholesterol ester, triglyceride, and hydrocarbon standards with ion abundances that are up to 631 times higher than abundances of the same compounds prior Paternò-Büchi reaction. To demonstrate the scope and analytical robustness of the newly developed method, free fatty acids in mouse brain as well as male Schistosoma mansoni extracts and hydrocarbons in an olefin mixture are investigated. For this complex set of analytes, charging and charge switching using acetylpyridine Paternò-Büchi functionalization enable double bond position assignment and relative quantification in positive ion mode.

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The diastereoselective ortho-lithiation of Kagan’s ferrocenyl acetal. Generation and reactivity of chiral 2-substituted ferrocenecarboxaldehydes

This review focuses on the synthesis of enantiopure ferrocenyl compounds using Kagan’s acetal 3 as the starting material. The lithiation of 3 is highly diastereoselective furnishing after removal of the chiral auxiliary 2-substituted ferrocenecarboxaldehydes with high ees. Special attention is given to the chemical transformations allowed by the presence of the aldehyde functionality. Applications of the final products in asymmetric catalysis, material chemistry, and biology are also discussed.     

Paternò-Büchi(PB)反应与串联质谱结合实现不饱和脂质精确结构解析

脂质在一系列关键生命过程中发挥着重要作用。结构决定功能,因此脂质结构解析与功能研究一直受到研究者的关注。尽管质谱已成为脂质分析的最常用技术之一,但脂质的精细结构解析仍面临诸多挑战。为解决上述问题,将Paternò-Büchi(PB)光化学反应与串联质谱相结合,实现了不饱和脂质中碳碳双键■的定位以及不饱和脂质■位置异构体的定量分析。此外,该技术可与鸟枪法、液相色谱-质谱和质谱成像等技术联用,用于复杂生物样品中脂质的分析。     

Enantio- and diastereoselective synthesis of 4′-α-substituted carbocyclic nucleosides

Enantio- and diastereoselective synthesis of 4-α-alkylcarbovir derivatives 5 were achieved based on Sakai's asymmetric alkylation of β-keto esters. The key carbocyclic intermediate 14 was synthesized from 8 via an eleven-step sequence. Coupling of 14 with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis gave the target compounds 5 in moderate yields.     

A facile synthesis of α-substituted thiophenes from a functionalized 2-aminothiophene by homo- and cross-coupling reactions

A series of new α-substituted thiophenes with elongated π-conjugation are prepared by homo- and cross-coupling reactions. An efficient one-step synthesis of a key intermediate, a substituted 2-iodothiophene, via aprotic diazotization of a Gewald-like 2-aminothiophene is reported.     

Mechanism of stereo- and regioselectivity in the Paternò-Büchi reaction of furan derivatives with aromatic carbonyl compounds: importance of the conformational distribution in the intermediary triplet 1,4-diradicals

Temperature and substituent effects on the stereo- and regioselectivity have been investigated in the photochemical [2 + 2] cycloaddition reaction, the so-called Paternò-Büchi (PB) reaction, of unsymmetrically substituted furans 2a,b (2-methyl- and 3-methylfuran) with aromatic carbonyl compounds 1a,b (benzaldehyde and benzophenone). The regio-random but stereoselective (exo/endo > 97/3) formation of lower substituted oxetane 3a and higher substituted oxetane 4a is found in the reaction with benzaldehyde (1a). The exclusive stereoselectivity is not dependent on the position of methyl substituent on the furan ring and the reaction temperature. The double-bond selection (3a versus 4a) is slightly dependent on the reaction temperature (3a/4a = 55/45 to 40/60). The Eyring plots of the regioselectivity are linear. Contrastively, in the reaction with benzophenone (1b), the double-bond selection (3b versus 4b) largely depends on the reaction temperature. The Eyring plots are not linear, but the inflection points are observed. The transient absorption spectroscopic analyses (picosecond time scale) clarify the intervention of triplet 2-oxabutane-1,4-diyls in the photochemical processes. Computational studies reveal the equilibrium structures of the triplet diradicals, energy barriers between the conformers, and the equilibrium constants. A rational mechanism is herein proposed by the support of both experimental and computational investigations to account for not only the exclusive formation of the exo-configured oxetanes 3a and 4a but also the nonlinear Eyring plots observed in the reaction with 1b.     

Regio- and diastereoselective SN2′ or SN2″ reactions on chiral acetals of cyclic aldehydes promoted by PhCu,BF3

The regio- and diastereoselectivity of the addition of PhCu, BF₃ reagent on chiral acetals derived from several mono or dienic aldehydes was studied. It was found that monoethylenic acetals react regio- and diastereoselectively via an overall anti S_N2′ reaction. The regioselectivity observed with the dienic acetals seems to be strongly dependent on the nature of the acetal. In all cases the S_N2″reaction was the result of an anti process.     

Origin of a large temperature dependence of regioselectivity observed for [2 + 2] photocycloaddition (Paternò-Büchi reaction) of 1,3-dimethylthymine with benzophenone and its derivatives: conformational property of the intermediary triplet 1,4-diradicals

[reaction: see text] The [2 + 2] photochemical additions of 1,3-dimethylthymine (DMT) with benzophenone and its 4,4'-substituted derivatives (BPs), difluoro, di-tert-butyl, and dimethoxy benzophenones, have been investigated at a temperature range from -40 to 70 degrees C. The photochemical reactions, which are cycloaddition of the 5-6 double bond of DMT with the carbonyl group of BPs, the so-called the Paternò-Büchi (PB) reaction, reveal largely temperature-dependent regioselectivity. The chemical yields of one series of regioisomers, 2, decrease with the increase of the reaction temperature, but those of another regioisomer series, 3, increase, and thus the ratio of 2/3 is strongly dependent on the temperature (2/3 = ca. 70:30 to 30:70). The temperature dependence of the regioselectivity yields two linear functions in the corresponding Eyring diagrams. The Eyring plot with changed slopes is clearly indicative of the change for the selectivity-determining step in the PB reaction, in which the triplet 1,4-diradicals play a crucial role. Computational studies reveal the conformational equilibrium structures of the triplet 1,4-diradicals, energy barriers between the conformers, and the conjectural equilibrium constants from relative potential energies of the stable conformers. A proposed mechanism can reasonably explain the temperature-dependent regioselectivity and chemical yields of two regioisomers varying with the reaction temperature.     

Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes 3: Total synthesis of (+)-1-epi-castanospermine

Stereoselective allylation reactions of acyclic, chiral α-amino-β-hydroxy aldehydes containing four contiguous stereocenters were conducted. Allylation mediated by MgBr₂?OEt₂ afforded the anti-product. A plausible mechanism of the allylation reaction is also described. The resulting allylation product was used for the total synthesis of (+)-1-epi-castanospermine.     

Stereospecific synthesis of 2,3-dimethyl-1,4-thiamorpholines by cyclization of β-n-methoxycarbonylaminoalkyl vinyl sulfoxides and related compounds

Synthesis of cis- and trans-N-methoxycarbonyl-2, 3-dimethyl-l, 4-thiamorpholine and their S-oxides and S, S-dioxides by intramolecular reaction of the corresponding 2-methoxy-carbonylaBinoalkyl-2' -chloroethyl thioethers, sulfoxides and sulfones with sodium hydride in dimethylformamide at room temperature is reported. Cyclization of chlorothioethers and -sulfones is Stereospecific although, in the case of sulfones, the formed 1, 4-thiamorpholines S, S-dioxides epimerize at C(2) after long reaction times. In chlorosulfoxides, elimination of HCl is previous to cyclization which also resulted stereospecific except in the case of the acyclic starting material of R^*s,S^*1,S^*2 configuration, where epimerization at sulfur takes place.     

Enantioselective carbonyl-ene-type cyclization of α-ketoester and 2-substituted vinylsilane catalyzed by a chiral Cu-BOX complex

We developed an enantioselective carbonyl-ene-type cyclization using 2-substituted vinylsilane as a nucleophilic ene moiety catalyzed by a chiral copper-BOX complex. This reaction is the first example of enantioselective carbonyl-ene cyclization using a 1,2-disubstituted olefin. This methodology gave chiral indenols with a tetrasubstituted carbon.     

A novel and efficient synthesis of (+)- and (−)-trans-2-aminocyclohexanol by enzymatic hydrolysis

Both enantiomers of trans-2-aminocyclohexanol were obtained by enzymatic hydrolysis of (±)-2-azidocyclohexanoates using lipases and subsequent hydrogenation.     

Construction of the reaction networks for heterogeneous catalytic reactions: Fischer—Tropsch synthesis and related reactions

The key approaches to the generation of reaction networks for the synthesis of products from CO and H₂ are considered. The selection rules for the elementary steps on the surface of heterogeneous catalysts are formulated. Data on the surface compounds and steps related to reactions of CO and H₂ are analyzed and a set of transforms (models of elementary steps) for generation of the reaction network are selected. Eight variants of generation of reaction networks for the formation of C1 products with different sets of transforms (12 to 31) were tested in computer experiments, and eight reaction networks comprising 34 substances and 132 to 1647 elementary steps were obtained. The pathways to CO₂, CH₄, and CH₃OH and pairs of compounds CH₄, CO₂ and CH₄, HCOOH obtained from the reaction network (220 elementary steps) are compared with the published schemes.     

Unusual temperature dependence in the cis/trans-oxetane formation discloses competitive syn versus anti attack for the Paternò-Büchi reaction of triplet-excited ketones with cis- and trans-cylooctenes. Conformational control of diastereoselectivity in the cyclization and cleavage of preoxetane diradicals

Toluene-d(8) solutions of cis- and trans-cyclooctene (cis- and trans-1a) as well as (Z)- and (E)-1-methylcyclooctene (cis- and trans-1b) have been irradiated at temperatures between -95 and +110 degrees C in the presence of benzophenone (BP) to afford mixtures of the cis- and trans-configured oxetanes 2a,b and the regioisomeric 2b'. Correspondingly, benzoquinone (BQ) gave with cis- and trans-1a the cycloadducts cis- and trans-3a. The cis/trans diastereomeric ratios of the [2 + 2]-cycloadducts 2 and 3 display a strong temperature dependence; with cis- and trans-1a or cis-1b as starting materials, the diastereoselectivity of the oxetane formation is high at low temperature, under preservation of the initial cyclooctene configuration. With increasing temperature, the cis diastereoselectivity decreases continuously for the cis-cyclooctenes; in the case of the cis-1a, the diastereoselectivity is even switched to trans (cis/trans ca. 20:80) at very high temperatures. For the strained trans-1a, the trans-oxetanes are strongly preferred over the entire temperature range, with only minor leakage (up to 10%) to the cis-oxetanes at very high temperatures. Oxetane formation is accompanied by nonthermal trans-to-cis isomerization of the cyclooctene. The methyl-substituted trans-1b constitutes an exceptional substrate; it displays cis diastereoselectivity in the [2 + 2] photocycloaddition at low temperatures for both regioisomers 2b and 2b', and the trans selectivity increases at moderate temperature (cis/trans = 4:96), to decrease again at high temperature, especially for the minor regioisomer 2b'. This complex temperature behavior of the cis/trans diastereoselectivity may be rationalized in terms of the triplet-diradical mechanism of the Paternò-Büchi reaction. We propose that the cyclooctene may be competitively attacked by the triplet-excited ketone from the higher (syn) or the less (anti) substituted side; such syn and anti trajectories have hitherto not been considered. To account for the unusual temperature behavior in the diastereoselectivity of the present [2 + 2] photocycloaddition, we suggest that temperature-dependent conformational changes of the resulting triplet preoxetane diradicals compete with their cyclization to the cis/trans-oxetane diastereomers and retro cleavage to the cis-cyclooctene.     

[3+2] Cycloaddition reactions of 1-substituted 3,3,3-trifluoropropenes with diazo compounds and nitrilimines – synthesis of pyrazolines and pyrazoles

Chemistry of Heterocyclic Compounds - 1,3-Dipolar cycloaddition reactions of 3,3,3-trifluoropropene derivatives containing a sulfonyl, sulfamide, or sulfoximine substituent in position 1 with...     

Enantio- and diastereoselective hetero-Diels–Alder reactions between 4-methyl-substituted Rawal’s diene and aldehydes catalyzed by chiral dirhodium(II) carboxamidates: catalytic asymmetric synthesis of (−)-cis-aerangis lactone

The first catalytic asymmetric hetero-Diels–Alder (HDA) reaction between 3-tert-butyldimethylsilyloxy-1-dimethylamino-1,3-pentadiene (4-methyl-substituted Rawal’s diene) and aldehydes is described. With 3 mol % of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh₂((S)-BPTPI)₄, the cycloaddition reaction proceeded exclusively in an endo fashion and gave, after a novel sequential treatment with dimethyl acetylenedicarboxylate and acetyl chloride, the corresponding 2,3-cis-disubstituted dihydropyranones with up to 98% ee and perfect diastereoselectivity. The utility of this catalytic protocol was demonstrated by an asymmetric synthesis of the (−)-cis-aerangis lactone.