Mass spectrometry of onium compounds—II. Carnitine and O-acyl derivatives

Carnitine and its O-acyl derivatives undergo two major pyrolytic reactions in the mass spectrometer. Firstly elimination of water from carnitine or acid from acylcarnitine takes place followed by intramolecular displacement and formation of crotonyl lactone and trimethylamine. Secondly intramolecular displacement occurs with formation of a substituted γ-lactone and trimethylamine. For the lower acid derivatives only the elimination pathway is important. For carnitine and higher derivatives both processes are important. The electron induced fragmentations of the major pyrolysis products are relatively simple. The most important pathways for the major components are discussed. The pyrolytic composition and mode of fragmentation are characteristic and can be used for identification purposes.     

Regio- and stereoselective selenium dioxide allylic oxidation of (E)-dialkyl alkylidenesuccinates to (Z)-allylic alcohols: synthesis of natural and unnatural butenolides

The first SeO(2) induced (Z)-selective allylic alcohol formation of dialkyl alkylidenesuccinates has been demonstrated to accomplish one-step syntheses of several essential butenolides and fused butenolides via an unusual E- to Z- carbon-carbon double bond isomerisation followed by the lactonization pathway. The observed regio- and stereoselective SeO(2) allylic oxidation protocol has also been extended to the diastereoselective total synthesis of bioactive natural product isomintlactone, its direct conversion to mintlactone and an example of the base-catalyzed intramolecular rearrangement of γ-lactone to δ-lactone.     

Physico-chemical aspects of polyethylene processing in an open mixer. Part 29: Experimental kinetics and mechanisms of γ-lactone formation

The experimental kinetics for γ-lactone formation shows more complexity than that for acids. Nonetheless, it can be concluded to the existence of a constant rate of formation from the beginning of the experiments with polyethylene melts. There is an additional term contributing to γ-lactone formation in the initial stages that is cubic in processing time. In the advanced stages of processing, in the high temperature range (170-200 °C), the concentration of γ-lactones increases linearly with the processing time.There are many mechanisms susceptible to give γ-lactones on polyethylene melt processing. Some of them are based on decomposition of intermediates formed directly on chain propagation. This is so for the α,γ-keto-hydroperoxides in 4-position to hydroxyl groups. Since decomposition of these intermediates is very fast, the reaction might account for a constant rate of γ-lactone formation from the beginning of polyethylene processing. Decomposition of the α,δ-keto-hydroperoxides formed on intramolecular reactions on chain propagation is not so fast as that of the α,γ-keto-hydroperoxides. Nonetheless, it might account for part of the delayed formation of γ-lactones. The same is valid for the mechanisms based on peroxidation of aldehydes and γ-hydroxy trans-vinylene groups that involve intermediates that are formed on polyethylene peroxidation. They might be important for explaining the cubic term as well as γ-lactone formation in the advanced stages of polyethylene processing.     

A synthetic route to the hexahydrobenzofuran nucleus of avermectins via diazoketone cyclization

A hexahydrobenzo[AB]furan characteristic of the avermectins and certain milbemycins was synthesized via acid-catalyzed intramolecular addition of a diazoketone to a γ-lactone; subsequent transformations led to structures containing much of the functionality and stereochemistry present in the corresponding segments of these macrolides.     

Enantioselective synthesis of rumphellaone A via epoxy nitrile cyclization

The first enantioselective synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane derivative incorporating a γ-lactone ring as its structural feature, has been achieved by using base-induced intramolecular cyclization of an epoxy nitrile intermediate to install its cyclobutane skeleton as well as three contiguous stereocenters as the key transformation.     

Formal synthesis of salinosporamide A via NHC-catalyzed intramolecular lactonization

An N-heterocyclic carbene (NHC) catalyzed intramolecular lactonization to prepare densely functionalized bicyclic γ-lactam-γ-lactone adducts from enals is reported. This method has been applied to the formal synthesis of salinosporamide A, a potent 20S proteasome inhibitor and anti-cancer therapeutic.     

Samarium(II) iodide-induced cascade reaction for tricyclic γ-lactone synthesis from acyclic keto diesters

Cascade reaction involving reductive cyclization, Dieckmann condensation, and lactonization of E- and Z-dimethyl 2-methyl-8-oxoundec-2-enedioates and Z-dimethyl 2-methyl-7-oxodec-2-enedioate with samarium(II) iodide was found to stereospecifically produce cis and trans bicyclo[4.4.0]decane (decalin) ring systems and trans bicyclo[4.3.0]nonan (perhydroindane) ring system each consisting of γ-lactone, respectively.     

A novel D-ring modified taxoid: synthesis and biological evaluation of a γ-lactone analogue of docetaxel

The synthesis of a novel D-ring modified docetaxel analogue, in which the oxetane ring is replaced with a γ-lactone, was achieved from 10-deacetylbaccatin III. The key steps of the synthesis include the direct acetylation of the secondary hydroxyl group at C-5 and D-ring opening and intramolecular aldol reaction to form the γ-lactone. In MTT assays, this analogue proved to have equipotent cytotoxicity relative to paclitaxel towards HCT8, HePG2 and BGC23 cancer cell lines, and be more potent than paclitaxel against A549 and A375. It represents the first example of D-ring modified taxoids with significant cytotoxicity.     

An efficient synthesis of the CD rings model for merrilactone A

A synthetic route to the CD rings of merrilactone A was explored by using the model system 9a, which was easily converted from 7,7-dibromohepta-2,6-dienoic acid ethyl ester (8) by the successive Stille-Mizoroki-Heck reaction. The D ring 14 was constructed by applying the intramolecular Tsuji-Trost reaction to the formation of a γ-lactone, whereas the formation of the C ring 18 was effectively accomplished in one step by methylation and conjugate addition toward 1,1-dibromo-1-alkene 17 using Miyashita’s protocol.     

Direct synthesis of pyran-lactones related to naphthoquinoneantibiotics

Simple benzopyrans with a fused γ-lactone unit are prepared from an o-disubstituted arene by direct intramolecular alkoxycarbonylation/lactonization promoted by palladium diacetate; the process gives high yields and moderate stereoselectivity, favoring the $\text{cis}$ lactone over $\text{trans}$ by a factor of 5:1.     

Enantioselective cyclization of 4-alkenoic acids via an oxidative allylic C-H esterification

An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a π-allyl Pd intermediate generated by an allylic C-H activation to give γ-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand, SPRIX, was indispensable for this asymmetric transformation.     

Synthesis of allyl phosphine oxides/boranes via Horner reaction of bis(diphenylphosphine)ethane monoxide reagent with an aldehyde

The Horner-Wittig addition-elimination reaction using bis(diphenylphosphine)ethane monoxide [DIPHOS(O)] with an aldehyde affords Z-allyl phosphine oxides/boranes. Alternatively, the stereoselective Lewis acid mediated intermolecular reduction of its γ-ketobisphosphoranes and stereoselective intramolecular reduction of γ-ketophosphine·borane derivatives followed by elimination of diphenylphosphinate affords E-allyl phosphine oxides/boranes with good to high selectivity. Allyl phosphine oxides are common intermediates in the synthesis of polyenes.     

Physico-chemical aspects of polyethylene processing in an open mixer. Part 32: Formal kinetics of γ-lactone formation from secondary products. Heterogeneous kinetics

Oxidation of aldehydes and γ-hydroxy-trans-vinylene groups can yield γ-lactones. These intermediates account for γ-lactone formation in the advanced stages of polyethylene processing in air. The acyl-peroxy radical formed on free radical induced oxidation of aldehydes can abstract intramolecularly a δ-hydrogen atom to yield a peracid. Reaction of the alkyl radical formed in this reaction with the hydroperoxide group of the peracid gives a γ-lactone with simultaneous release of a hydroxyl radical. The calculated rate of γ-lactone formation according to the mechanism envisaged decreases slightly with increasing temperature (activation energy of about −5 kcal/mol). It is in agreement with the experiments that do not show significant activation energy in the high temperature range for the advanced stages of polyethylene processing. The calculated rate of γ-lactone formation is found to increase by a factor of about 2.7 if the processing experiments are performed in pure oxygen instead of in air. This is close to the experimental factor of about 2.Peroxidation of γ-hydroxy-trans-vinylene groups can also yield γ-lactones. The first possibility involves addition of a peroxy radical to the double bond followed by oxygen addition to the alkyl radical. This reaction possibly yields an α-peroxy-hydroperoxide. Intramolecular decomposition involving the two reactive groups of the α-peroxy-hydroperoxide can give an ozonide that on thermal decomposition yields among others an acid group in 4-position to the alcohol. The activation energy calculated is strongly negative so that the rate should decrease strongly with increasing temperature. Hence, the mechanism cannot contribute significantly to γ-lactone formation in the whole temperature range of the experiments. This is so in spite of the fact that the rate is estimated to increase by a factor of about 1.7 on passing from air to pure oxygen, which is close to the experimental value of approximately 2. The second possibility of transformation of γ-hydroxy-trans-vinylene groups is based on stress-induced oxygen addition to the double bond. Acid catalyzed decomposition of the allylic hydroperoxide that is formed in the reaction yields a pair of aldehydes with one of the aldehyde groups in 4-position to the alcohol group. Peroxidation of the aldehyde pair can give an acid group in 4-position to the hydroxyl group so that a γ-lactone can be formed. The activation energy calculated for the process is very small and the effect of the oxygen concentration corresponds to an increase by a factor of approximately 4.5 on passing from air to pure oxygen. It is postulated that simultaneous contribution by different mechanisms might well account for the experimental value of about 2.The heterogeneous kinetics discussed in detail allows for complementary data interpretation. It is especially suited for the understanding of the advanced stages of polyethylene processing, after some induction time.     

Total synthesis of myceliothermophins A-E

Total synthesis of an antitumor compound myceliothermophin A and related compounds based on a convergent synthetic strategy was investigated. A common decalin skeleton of myceliothermophins was stereoselectively constructed by an IMDA reaction. The fully elaborated precursor of myceliothermophins was obtained via aldol reaction of N-protected γ-methoxylactam with decalin aldehyde. By using Teoc group for the protection of nitrogen atom of lactam ring, selective deprotection prior to the hydrolysis of methoxyaminal moiety was successfully achieved to obtain γ-methoxylactams (myceliothermophins C and D). Subsequent hydrolysis of these compounds afforded the corresponding γ-hydroxylactam, and myceliothermophins A and B in high yield. Myceliothermophin E was also synthesized by dehydration of the obtained γ-hydroxylactams. The absolute configurations of myceliothermophins A-E were also successfully determined.     

Investigating the mechanism of 1,3,5-cycloheptatriene formation: Condensation of 1-methylethyl 3-oxo-4-(triphenylarsoranylidene)butanoate with 7-methoxy-3,7-dimethyloctanal

Condensation of [3-(1-methylethoxycarbonyl)-2-oxopropyl]triphenylarsonium bromide 8 with 7-methoxy-3,7-dimethyloctanal 10 in the presence of a base gave bis(1-methylethyl) 4,7-dihydroxy-2-(6-methoxy-2,6-dimethylheptyl)-3,5,7-cycloheptatriene-1,3-dicarboxylate 7b. The formation of 7b can be explained by a number of consecutive steps. The mechanism, strongly supported by liquid secondary ion mass spectrometry, suggests that an aldol condensation of the γ-arsonium ylide 2b and the aldehyde 10 takes place as the initiating step and is followed by a Michael addition of the aldol product and the γ-arsonium ylide 2b. Then an intramolecular nucleophilic substitution and elimination of triphenylarsine, followed by base-catalyzed elimination of a second molecule triphenylarsine takes place to produce 7b. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:411–418, 1998     

Analysis of the nonvolatile oxidation products of polypropylene I. Thermal oxidation

The nonvolatile products in thermal-oxidized polypropylene sheet have been quantitatively identified by infrared analysis and chemical reaction. The molecular weight changes with oxidation have been studied by gel-permeation chromatography. It was determined that there is a functional group at each end of a chain. A general oxidation mechanism scheme for polypropylene is presented. The discovery of γ-lactone is an indication of the importance of an intramolecular backbiting process. The overall functional group distribution is found to differ from that found in a polyethylene sheet.     

A New Route to Cycloheptane-Fused Butyrolactones Based on Cyclopropylcarbinol Solvolysis

A sizeable number of naturally occurring hydroazulenes feature a γ-lactone-fused cycloheptane ring.¹ These substances have attracted widespread interest in recent years both as potential chemotherapeutic agents² and as challenging synthetic targets. In connection with a program directed toward the synthesis of sesquiterpene lactones we have examined a number of synthetic routes to prototypes of the cycloheptane class. The scheme reported in this communication is based on the expected participation of an appropriately substituted carboxylic ester function in the solvolysis of a cyclopropylcarbinyl system.³ As shown below, the hypothetical reaction could a priori follow two pathways to give either a γ-lactone (Path A) or a δ-lactone (Path B). From the standpoint of natural products synthesis, both pathways would be of great interest.⁴     

Total synthesis of (±)-sacidumlignan D

The first total synthesis of (±)-sacidumlignan D featuring a Zn-mediated Barbier reaction and reverse Wacker oxidation to form the key γ-lactone, its diastereoselective α-methylation followed by reduction cyclization, was documented.     

An iterative acetylene-epoxide coupling strategy for the total synthesis of longimicin C

Longimicin C, a naturally occurring annonaceous acetogenin possessing a C₂-symmetrical bis-THF moiety and a short hydrocarbon chain between its THF-containing region and a terminal γ-lactone, was synthesized for the first time. The total synthesis was successfully achieved by an iterative acetylene-epoxide coupling strategy. d-Mannitol was used to establish the bis-THF-containing segment, in which the additional stereochemistries were introduced by Sharpless dihydroxylations and intramolecular Williamson etherifications. Regioselective epoxide-openings by the appropriate terminal acetylenes allowed coupling and elaboration of all four fragments including the introduction of three essential hydroxyls into the proper sites of the target skeleton.     

Palladium-catalyzed reaction of butadiene and carbon dioxide

The selective syntheses of the δ-lactone 2-ethylidene-6-hepten-5-olide and of the γ-lactone 2-ethyl-2,4-heptadien-4-olide by the palladium-catalyzed reaction of carbon dioxide and butadiene are described. Mechanistic studies showed that the formation of the γ-lactone proceeds by a consecutive reaction via the δ-lactone. The products are accounted for in terms of a reaction path involving an allylic palladium carboxylate complex as a key intermediate.