Conjugation and hyperconjugation in conformational analysis of cyclohexene derivatives containing an exocyclic double bond

The equilibrium geometry, ring-inversion pathway barriers for analogues of cyclohexene with an exocyclic double bond have been studied using the MP2/6-311 G(d,p) level of theory. The equilibrium conformation of the ring depends on conjugation between the endocyclic and exocyclic double bonds. Interactions between conjugated double bonds include the pi-pi conjugation and interactions between the lone pair of the heteroatom of the exocyclic double bond and the sigma-antibonding orbital of the endocyclic single bond. In the case of the tetrahydrocycles with double bonds separated by a methylene group the balance between the pi --> sigma* hyperconjugation interactions between the exocyclic double bond and the neighboring methylene group and the n --> sigma* interaction between the lone pair of the heteroatom and the sigma-antibonding orbitals of the C(sp(2))-C(sp(3)) bond determine the geometrical parameters of the ring. The character of the potential-energy surface around the saddle point depends on the position of the exocyclic double bond and the orientation of the hydrogen atom attached to the heteroatom of the V group of the periodic table in the tetrahydrocycles with double bonds separated by a methylene group.     

Endocyclic vs exocyclic olefin formation from 4-piperidones via the wittig reaction

The reaction of 1-methyl-4-piperidone and 1-benzoyl-4-piperidone with triethyl phosphono-acetate in the presence of excess base yields both the endocyclic and exocyclic olefins. However, treatment of 1-methyl-4-piperidone with diethyl cyanomethylphosphonate, even in the presence of excess base, yielded only the exocyclic olefin. Factors affecting isomer distribution during the course of the reaction are presented. The isolation of an exocyclic tetrahydropyridine from the sodium borohydride reduction of the methiodide of 4-pyridylacetonitrile is reported.     

17O-NMR Spectra of Mesoionic Compounds: The polarized carbonyl group

The ¹⁷O-NMR spectra of 5 mesoionic compounds have been measured; in two cases, the peak attribution between endo- and exocyclic O-atoms has been made unambiguous by synthesizing specifically O-labelled samples. The signal of the exocyclic O-atom appears at particularly high field, closer to the values of enolate than of carbonyl O-atoms. The cyclic O-atom resonates close to values of furans (or isoxazol, if bound to N). The exocyclic O-atom is much more susceptible to structure and substituent variations than the endocyclic, an observation which is in favour of a chain-conjugated (non-aromatic) structure 1E .     

Temporary phosphate tethers: a metathesis strategy to differentiated polyol subunits

[reaction: see text] Studies probing reactivity and selectivity of cross metathesis (CM) with an exocyclic olefin in a P-chiral bicyclo[4.3.1]phosphate triester are described. Studies have revealed a Type III CM reactivity pattern for the exocyclic olefin within this phosphate triester. This versatile method allows for simple, selective manipulation of a P-chiral building block en route to advanced polyol subunits.     

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.     

Rotation about the exocyclic carbon-carbon double bond of amino dienes of the indolo[2,3-a]-and benzo[a]quinolizidine series

Quinolizidines containing an exocyclic double bond at C-2 (1,2) give on mild oxidation the amino dienes (3,4), as mixtures of geometric isomers with respect to the exocyclic double bond. The free enthalpy of activation for the rotation about the double bond has been estimated by NMR.     

Kinetics and mechanism of hydrolysis of N-acyloxymethyl derivatives of azetidin-2-one

The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C-O fission and formation of an exocyclic beta-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the beta-lactam carbonyl carbon atom, to form the corresponding N-hydroxymethylazetidin-2-ones. Calculations carried out at the B3LYP/6-31+G(d) level of theory also support that nucleophilic attack by water takes place at the exocyclic carbon rather than at the beta-lactam carbonyl carbon of the iminium ion. The mechanism for the acid-catalyzed pathway involves a preequilibrium protonation, probably at the beta-lactam nitrogen, followed by rate-limiting alkyl C-O fission with formation of an exocyclic iminum ion. The base-catalyzed hydrolysis involves rate-limiting hydroxide attack at the ester carbonyl carbon. These results imply formation of a beta-lactam system containing a positively charged amide nitrogen atom that hydrolyzes via a pathway that preserves the beta-lactam structure in the product and provide further evidence that cleavage of the beta-lactam C-N bond is not as facile as is commonly imagined.     

Stereoselective synthesis of dibenzoxapine containing tetrasubstituted exocyclic alkenes via cascade methylboronic acid coupling reactions

A stereoselective method for the preparation of dibenzoxapine containing tetrasubstituted exocyclic E-alkenes has been developed. The key reaction involves an intramolecular cyclocarbopalladation of alkynes to form a vinylpalladium species and subsequently coupling the vinylpalladium with methylboronic acid. The approach provides a straightforward method for the synthesis of tetrasubstituted exocyclic E-alkenes.     

Access to macrocyclic endocyclic and exocyclic allylic alcohols by nickel-catalyzed reductive cyclization of ynals

Ni-catalyzed reductive macrocyclizations of ynals are reported. Disubstituted alkynes afford either endocyclic or exocyclic allylic alcohols depending on the ligand. Phosphine ligands favor the formation of endocyclic olefins, whereas N-heterocyclic carbene ligands favor the formation of exocyclic olefins. Terminal alkynes provide 1,2-disubstituted olefins with N-heterocyclic carbene ligands.     

ω,ω′-Diphospholylalkanes

Abstract

The reaction of compounds (1) with lithium or sodium can lead to different results depending on the length of the exocyclic chain : when n=1,2 or 4, we observe cleavage of both exocyclic P-C bonds, giving pure phospholyllithium or sodium.     

Core-modified, meso-alkylidenyl porphyrins and their expanded analogues: a new family of nonplanar porphyrinoids

New core-modified, meso-alkylidenyl porphyrinoids bearing multiple exocyclic double bonds were synthesized and characterized. The synthesis was accomplished using a typical "3 + 1"-type condensation approach. Stable exocyclic tautomers bearing double bonds at the meso positions, as well the corresponding endocyclic tautomers, were isolated in the case of both thiabenziporphyrin and thiapyriporphyrin products prepared in the course of this study. On the other hand, only the exocyclic tautomer was isolated in the case of the congeneric oxapyriporphyrin and oxabenziporphyrin. Expanded analogues of the exocyclic forms of oxabenziporphyrin and thiabenziporphyrin were also isolated as minor products. A single-crystal X-ray diffraction analysis of the expanded thiabenziporphyrin (20) revealed that all four pyrrole rings displayed an inverted geometry, presumably reflecting the strong hydrogen-bonding extant between the pyrrole N-H proton and the carbonyl group of the malonate moiety in the solid state. On the other hand, the expanded oxabenziporphyrin (14) was found to possess a severely distorted geometry with only one pyrrole ring being inverted. Careful analysis of the structure revealed that the solid-state geometry of the expanded macrocycles correlates well with the internal angle defined by the 2- and 5 substituents and the centers of the furan (14) or thiophene (20) subunits.     

Rearrangement of the (6S,8R,11S) and (6R,8S,11R) exocyclic 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal to N2-deoxyguanosine cyclic hemiacetal adducts when placed complementary to cytosine in duplex DNA

trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. The Michael addition of deoxyguanosine to HNE yields four diastereomeric exocyclic 1,N(2)-dG adducts. The corresponding acrolein- and crotonaldehyde-derived exocyclic 1,N(2)-dG adducts undergo ring-opening to N(2)-dG aldehydes, placing the aldehyde functionalities into the minor groove of DNA. The acrolein- and the 6R-crotonaldehyde-derived exocyclic 1,N(2)-dG adducts form interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Only the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence context. Moreover, as compared to the exocyclic 1,N(2)-dG adducts of acrolein and crotonaldehyde, the cross-linking reaction is slow (Wang, H.; Kozekov, I. D.; Harris, T. M.; Rizzo, C. J. J. Am. Chem. Soc. 2003, 125, 5687-5700). Accordingly, the chemistry of the HNE-derived exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry has been compared with that of the (6R,8S,11R) adduct, when incorporated into 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). When placed complementary to dC in this duplex, both adducts open to the corresponding N(2)-dG aldehydic rearrangement products, suggesting that the formation of the interstrand cross-link by the exocyclic 1,N(2)-dG adduct of (6S,8R,11S) stereochemistry, and the lack of cross-link formation by the exocyclic 1,N(2)-dG adduct of (6R,8S,11R) stereochemistry, is not attributable to inability to undergo ring-opening to the aldehydes in duplex DNA. Instead, these aldehydic rearrangement products exist in equilibrium with stereoisomeric cyclic hemiacetals. The latter are the predominant species present at equilibrium. The trans configuration of the HNE H6 and H8 protons is preferred. The presence of these cyclic hemiacetals in duplex DNA is significant as they mask the aldehyde species necessary for interstrand cross-link formation.     

The influence of exocyclic phosphorous substituents on the intrinsic stability of four-membered heterophosphetes: a theoretical study

Four-membered heterophosphetes such as oxaphosphetes, thiaphosphetes, and azaphosphetes have long been considered desirable target molecules for organic chemists because of their interesting structural features. In spite of extensive investigation, only one azaphosphete and one thiaphosphete have been synthesized to date. In this paper, two possible conformers of these four-membered rings, as well as their open-ring phosphorane forms with a set of exocyclic substituents and a few ring heteroatoms were studied by molecular computations. The results suggested that the relative stability of these compounds is strongly dependent on the electronic effect of the exocyclic P-substituents. Three different types of exocyclic substituents X were recognized. However, only the strong electron-withdrawing substituents (X=F, CN, OCN, SCN) were able to stabilize the ring forms, providing the possibility to design stable heterophosphetes on the basis of the present computational results.     

Dimroth-type rearrangement of 1-benzyl- and 1-glycosyl-5-aminoimidazoles to 4-(N-substituted amino)imidazoles

An efficient route is described to an unusual exocyclic 4-β-d-ribofuranosyl-aminoimidazole nucleoside, related 4-N-benzylaminoimidazoles and imidazole analogues of precursors in the de novo biosynthesis of purines, via a regiospecific and stereoselective base-catalysed Dimroth-type rearrangement of 1-ribofuranosyl and 1-benzyl-5-aminoimidazoles. Use of a ¹⁵N labelled precursor showed the unequivocal endo- to exocyclic translocation of the nitrogen atom during the rearrangement.     

Alkylation of nucleic acids by the antitumor agent COMC

[reaction: see text]. Mass spectral data are presented indicating that the antitumor agent 2-crotonyloxymethyl-2-cyclohexenone (COMC) is capable of alkylating oligonucleotides via a mechanism involving an electrophilic exocyclic enone intermediate. Under physiological conditions, the exocyclic enone is likely the glutathionylated 2-exomethylenecyclohexenone. This supports a recent hypothesis that the antitumor activity of COMC arises from alkylation of nucleic acids and/or proteins critical to cell function and not from competitive inhibition of glyoxalase I by an adduct of COMC and glutathione.     

Mechanism of the glutathione transferase-catalyzed conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones to GSH adducts

Human glutathione (GSH) transferase (hGSTP1-1) processes with similar kinetic efficiencies the antitumor agents 2-crotonyloxymethyl-2-cyclohexenone (COMC-6), 2-crotonyloxymethyl-2-cycloheptenone (COMC-7), and 2-crotonyloxymethyl-2-cyclopentenone (COMC-5) to 2-glutathionylmethyl-2-cyclohexenone, 2-glutathionylmethyl-3-glutathionyl-2-cycloheptenone, and 2-glutathionylmethyl-2-cyclopentenone, respectively. This process likely involves initial enzyme-catalyzed Michael addition of GSH to the COMC derivative to give a glutathionylated enol(ate), which undergoes nonstereospecific ketonization, either while bound to the active site or free in solution, to a glutathionylated exocyclic enone. Free in solution, GSH reacts at the exomethylene carbon of the exocyclic enone, displacing the first GSH to give the final product. This mechanism is supported by the observation of multiphasic kinetics in the presence of high concentrations of hGSTP1-1 and the ability to trap kinetically competent exocyclic enones in aqueous acid using COMC-6 and COMC-7 as substrates. That the exocyclic enone is formed by nonstereospecific ketonization of an enol(ate) species is indicated by the observation that COMC-6 (chirally labeled with deuterium at the exomethylene carbon) gives stereorandomly labeled exocyclic enone. The isozymes hGSTP1-1, hGSTA1-1, hGSTA4-4, and hGSTM2-2 catalyze the conversion of COMC-6 to final product with similar efficiencies (K(m) = 0.08-0.34 mM, k(cat) = 1.5-6.1 s(-)(1)); no activity was detected with the rat rGSTT2-2 isozyme. Molecular docking studies indicate that in hGSTP1-1, the hydroxyl group of Tyr108 might serve as a general acid catalyst during substrate turnover. The possible significance of these observations with respect to the metabolism of COMC derivatives in multidrug resistant tumors is discussed.     

Photocycloaddition Reactions of 2‐(Alk‐3‐en‐1‐ynyl)cyclohex‐2‐enones

The newly synthesized 2‐(alk‐3‐en‐1‐ynyl)cyclohex‐2‐enones 4 undergo photodimerization (chemo‐ and regio‐)selectively at the exocyclic C?C bond to give diastereoisomeric mixtures of 1,2‐dialkynyl‐1,2‐dimethylcyclobutanes. On irradiation of 4 in the presence of 2‐chloroacrylonitrile, cyclobutane formation occurs again (chemo‐ and regio‐)selectively at the exocyclic C?C bond to afford diastereoisomeric mixtures of 2‐alkynyl‐1‐chloro‐2‐methylcyclobutanecarbonitriles. Similarly, compounds 4 undergo photoaddition to 2,3‐dimethylbuta‐1,3‐diene exclusively at the exocyclic C?C bond to afford mixtures of [2+2] and [4+2] cycloadducts.     

Stereoselectivity in the Diels‐Alder Cycloadditions of a Facially Dissymmetric Bicyclo[2.2.2]octadiene‐Grafted Maleic Anhydride with Exocyclic Butadienes. Unexpected Facial Selectivity in the Cycloaddition with 2,3,5,6‐tetramethylidenebicyclo[2.2.2]octene

The Diels‐Alder cycloadditions of facially dissymmetric maleic anhydride 1 with facially nonequivalent exocyclic 1,3‐butadienes(dimethylidenebicyclo[2.2.2]octene 3 and 2,3,5,6‐tetramethylidenebicyclo[2.2.2]‐octene ( 4 )) were investigated. In each cycloaddition, the reaction occurred via the course in which 1 added exclusively by its syn‐face (same face as the etheno‐bridge) onto either π‐face of the exocyclic 1,3‐butadiene systems to produce only two of the four possible stereoisomeric monocycloadducts ( 8a / 8b and 9a / 9b ). In the Diels‐Alder cycloaddition of 1 with bis‐exocyclic butadiene 4 , however, both monocycloadducts 9a and 9b underwent subsequent cycloaddition with distinctive facial selectivity to produce the C_s‐symmetric bis‐cyclohexanobarrelene 10a as only bis‐cycloadduct.     

Rapid generation of macrocycles with natural-product-like side chains by multiple multicomponent macrocyclizations (MiBs)

A small parallel library of peptoid macrocycles with natural-product-derived side chains of biological importance was produced by Ugi-type multiple multicomponent macrocyclizations including bifunctional building blocks (Ugi-MiBs). Diverse exocyclic elements of high relevance in natural recognition processes, i.e., all functional amino acid residues (e.g., Cys, Arg, His, Trp) and even sugar moieties, can be introduced in a one-pot process into different types of peptoid-containing macrocyclic skeletons. This is exemplified by the use of a diamine/diisocyanide combination of Ugi-MiBs and N-protected alpha-amino acids or carboxy-functionalized carbohydrates as source for the natural-product-like exocyclic elements. Employed as the acid components of the multiple Ugi reactions, they appear as N-amide substituents on the macrocyclic cores. The use of different diamines and diisocyanides allows an easy variation of the N- to C-directionality and therefore of the position of the exocyclic elements.     

Hybridization in methylenecyclopropane and related molecules having exocyclic double bonds

The hybridization in methylenecyolopropane, dimethylenecyclopropane, bisethanoallene, and related molecules containing double bonds externally attached to a cyclopropane ring is considered by applying the method of maximum overlap. The results show that the bond overlap of an exocyclic double bond is larger than the bond overlap of a normal C=C bond, and double bonds in allenes have even larger overlap than an exocyclic C=C bond. The results of the calculations are correlated with some available experimental data.