3-Aza-cope rearrangement of quaternary N-allyl enammonium salts. Stereospecific 1,3 allyl migration from nitrogen to carbon on a tricyclic template

N-Allyl enamines can undergo a [3,3] sigmatropic rearrangement known as a 3-aza-Cope (or amino-Claisen) reaction. We explored a 3-aza-Cope reaction involving 1,3 allylic migration from nitrogen to carbon in N-allyl enammonium quaternary salts, exemplified by benzo[a]quinolizine 8 and pyrrolo[2,1-a]isoquinoline 13, with an interest in stereochemistry and mechanism. Salts 8 and 13 were accessed, respectively, through stereospecific allylation of hydroxy amines 4 and 11a/11b to give 7 and 12a/12b, which were dehydrated with trifluoroacetic acid. Allylic migration in these tricyclic tetrahydroisoquinolines occurred with high stereospecificity, with the major products 9 (from 8) and 15a (from 13) apparently deriving from a concerted suprafacial [3,3] rearrangement. The rearrangement of 8 to 9 was facile at 23 degrees C (t(1/2) = ca. 5 h) and was >98% stereospecific, whereas the rearrangement of 13 to 15a/15b required heating between 50 and 100 degrees C, with ca. 90-95% stereospecificity (t(1/2) = ca. 0.3 h at 100 degrees C). A deuterium-labeling experiment with 21 ((2)H-13) confirmed that allylic inversion accompanies the 1,3 migration en route to major isomer 22a ((2)H-15a), supporting the predominance of a concerted [3, 3] sigmatropic mechanism. However, the 5-10% loss of stereospecificity in the rearrangements of the pyrroloisoquinolines 13 and 21, reflected by formation of minor isomers 15b and 22b, respectively, indicates a minor nonconcerted reaction pathway.     

Total synthesis of (-)-callystatin A

[reaction: see text] A convergent enantioselective synthesis of the natural product (-)-callystatin A (1) is described. Key features of the synthesis include a lipase-mediated kinetic resolution to install the C5 lactone stereochemistry, a hydrozirconation-based approach to the C8-C9 trisubstituted (Z)-olefin, and a stereoselective cross-coupling of a vinyl dibromide to install the C14-C15 trisubstituted (E)-olefin.     

Synthesis of the C10-C22 bis-spiroacetal domain of spirolides B and D via iterative oxidative radical cyclization

[reaction: see text] A synthetic approach to the novel bis-spiroacetal moiety of spirolides B and D is reported. The strategy hinges upon successive formation of the spirocenters at C15 and C18 by radical oxidative cyclization, followed by base-induced rearrangement of a C19-20 alpha-epoxide to introduce the C19 hydroxyl group.     

Stereoselective synthesis of functionalized trisubstituted olefins via palladium(0)-catalyzed cross-coupling reaction

[reaction: see text]. A highly flexible and stereoselective protocol for the synthesis of branched (E)- and (Z)-trisubstituted alkenes has been developed. The key steps are hydrozirconation-iodination of (1-alkynyl)trimethylsilane followed by Negishi-type cross-coupling. The resultant (Z)-vinyl silane is iododesilylated and subjected to a second cross-coupling reaction to give the trisubstituted olefin. Model studies aimed at the construction of the C14-C15 (Z)-trisubstituted olefin of discodermolide and the C8-C9 (Z)-trisubstituted olefin of callystatin A and analogues are also described.     

Transformation of β-chalcogeno alkenylboranes into tetrasubstituted olefins

In view of generating trisubstituted vinylic chalcogen derivatives, β-chalcogeno alkenylboranes generated through the chalcogen electrophile induced rearrangements of 1-alkynyltrialkyl borates have been subjected to Suzuki-Miyaura coupling and to boron to copper transmetalation followed by alkylation. Some of the trisubstituted vinyl sulfides obtained by this latter strategy have been converted efficiently into the title olefins through the NiCl₂(dmpe) catalyzed coupling with various Grignard reagents.     

A scalable route to trisubstituted (E)-vinyl bromides

An effective, readily scalable two-step synthesis of trisubstituted (E)-vinyl bromides involving bromination of alpha,beta-unsaturated lactones followed by hydrolytic fragmentation has been developed. Several trisubstituted (E)-vinyl bromides, including multigram quantities of (+)-(E)-4-bromo-2-methyl-3-pentenol, a synthetic intermediate required for the C(8)-C(11) moieties of (+)-tedanolide (1) and (+)-13-deoxytedanolide (2), illustrate the utility of this protocol. [reaction: see text]     

Thermal sigmatropic rearrangements of isopyrazoles and pyrazolenines to pyrazoles

Thermal rearrangement of 4-allyl-, 4-dimethylallyl-, and 4-propargyl-isopyrazoles proceed by [3,3]-sigmatropic processes to pyrazoles. The migration terminus is the C(3) Me group, if present, and the rearrangement is preceded by imine-enamine tautomerism. When enamine formation is not possible the rearrangment is diverted to nitrogen. Thermal rearrangements of 4-alkyl- and 4-benzyl-isopyrazoles also occur although at higher temperatures and evidence is presented suggesting [1,5]-sigmatropic processes are involved. Some pyrazolenine to pyrazole rearrangements involving migration of ester and phenyl groups are also reported.     

Silabenzene through divalent precursors at theoretical levels

Abstract  

Based on geometries and relative energies, three different mechanisms are proposed for the rearrangements of five isomers of silacyclohexadienylidenes to silabenzene at B3LYP and MP2 levels: (1) [1,2]-hydrogen migration through a planar transition state, (2) [1,4]-hydrogen migration through a boat transition state, and (3) zip-zap mechanism, comprised of three successive [1,2]-hydrogen migrations. The above results are compared and contrasted to rearrangements of the corresponding cyclohexadienylidenes to benzene.     

Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine

Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded beta-epoxide 28 from 26 and alpha-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.     

Phorboxazole synthetic studies. 2. Construction of a C(20-28) subtarget, a further extension of the Petasis-Ferrier rearrangement

[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis-Ferrier rearrangement of an E/Z mixture of trisubstituted enol ethers (15) to assemble the C(22-26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.     

Hydration with mercuric acetate and the reduction with 9-BBN-H of 2-(1-alkenyl)-4,6-dimethyl-s-triazines

Oxymercuration-demercuration of a double bond in conjugation with the 4,6-dimethyl-s-triazin-2-yl substituent as in alkenes 1a,b gave anti-Markovnikov regioselectivity, which is explained by the electron-withdrawing nature of the triazinyl substituent. However, hydroboration of the conjugated alkenes with 9-BBN-H gave the corresponding alkanes 5a-c under normal workup conditions with or without oxidation. With time and without workup the hydroboration of 1b gave spectral evidence for the formation of intermediates 9-13 resulting from the migration of the 9-BBN moiety from the alpha-carbon to a ring nitrogen with concurrent formation of an exocyclic double bond to an alpha-carbon of the ring. Hydrolysis of the intermediates gave 5a-c. A possible mechanism involving successive allylic rearrangements is presented.     

Total synthesis of epothilone a through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C

The total synthesis of epothilone A is described by the coupling four segments 4-7 a. Three of the segments, 4, 5 and 7 a, have only one chiral center; all other chiral centers were introduced by simple asymmetric catalytic reactions. The key steps are the ring opening of epoxide 5 with acetylide 8 for the construction of the C12-C13 cis double bond and a practical hydrolytic kinetic resolution (HKR) developed by Jacobsen group for the introduction the chiral center at C3. Especially, the stereospecific epoxidation of 3-O-PMB epothilone C 3 b through long-range effect of 3-O-PMB protecting group gave high yields of the C12-C13 alpha-epoxide for the synthesis of target molecule.     

Calculation driven synthesis of an excellent dihydropyrene negative photochrome and its photochemical properties

The photochromic properties of dihydropyrenes have been substantially improved by making use of density functional theory (DFT) activation barrier calculations, which suggested that the di-isobutenylcyclophanediene 15' should have a significant barrier to thermal isomerization to the dihydropyrene (DHP) 15, which itself should resist isomerization involving migration of the internal groups to the rearranged dihydropyrene 9 (X = -CH═C(Me)(2)). As a result of these calculations, the synthesis of the colorless cyclophanediene (CPD) 15' was undertaken and achieved from the dinitrile 28 in four steps in 37% overall yield %. The cyclophanediene 15' thermally isomerized to the dihydropyrene 15 at 100 °C with t(1/2) = 4.5 h, giving an extrapolated 20 °C t(1/2) of ～16 y, consistent with the DFT calculations. No evidence for [1,5]-sigmatropic rearrangement in to 9 (X = -CH═C(Me)(2)) was observed on heating to 130 °C. The ring-opening isomerization quantum yields (?(open)) for DHP 15 in to CPD 15' were determined in cyclohexane to be 0.12 ± 0.01, which is three times greater than for the benzoDHP 1. Friedel-Crafts naphthoylation of 15 gave 70% of purple 32, which in toluene showed the largest photochemical ring-opening isomerization quantum yields (?(open)) of 0.66 ± 0.02 for any known dihydropyrene, ～nine times greater than 1 in toluene. The thermal closing of 32' to 32, although faster than for 15', gave a useful extrapolated t(1/2) of ～2 y at 20 °C.     

Photochemical and Acid-Catalyzed Rearrangements of 4-Carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one

The synthesis of 4-carbomethoxy-4-methyl-3-(trimethylsilyl)-2,5-cyclohexadien-1-one (1) in 60% overall yield from benzaldehyde is described. Irradiation (366 nm) of 1 in benzene solution gave products of type A photorearrangement; e.g., diastereomers of the 4-(trimethylsilyl)- and 5-(trimethylsilyl)bicyclo[3.1.0]hex-3-en-2-ones 8 and 9. Bicyclohexenones 9a and 9b could not be isolated, but underwent acid-catalyzed protiodesilylative rearrangements on attempted chromatography (silica gel) to give a 1:1 mixture of (E)- and (Z)-4-(carbomethoxymethylmethylene)cyclopent-2-en-1-ones 12 and 13. Irradiation (366 nm) of either 12 or 13 resulted in photoisomerization to a photostationary state that was also a 1:1 mixture. Irradiation of 8a or 8b gave equivalent mixtures of phenols 14 and 15 by way of the type B oxyallyl zwitterion 17. The available experimental evidence suggests that both 9a and 9b undergo regiospecific photorearrangement to phenol 16 with no trace of 3-methyl-4-carbomethoxyphenol (19), the product of ipso substitution of the Me(3)Si group at C(4). Phenol 15 was isolated in 65% yield from the photoreaction of 1 in benzene with 20 equiv of CF(3)CO(2)H. The acid-catalyzed rearrangement of 1 to 3-carbomethoxy-4-methylphenol (21) occurs in 91% yield by way of CO(2)Me group rearrangement to C(3) to give the Me(3)Si-stabilized carbocation 23.     

EPR studies of amine radical cations. Part 2. Thermal and photo-induced rearrangements of propargylamine and allylamine radical cations in low-temperature freon matrices

Matrix EPR studies and quantum chemical calculations have been used to characterize the consecutive H-atom shifts undergone by the nitrogen-centered parent radical cations of propargylamine (1b*+) and allylamine (5*+) on thermal or photoinduced activation. The radical cation rearrangements of these unsaturated parent amines occur initially by a 1,2 H-atom shift from C1 to C2 with pi-bond formation at the positively charged nitrogen; this is followed by a consecutive reaction involving a second H-atom shift from C2 to C3. Thus, exposure to red light (lambda > 650 nm) converts 1b*+ to the vinyl-type distonic radical cation 2*+ which in turn is transformed on further photolysis with blue-green light (lambda approximately 400-600 nm) to the allene-type heteroallylic radical cation 3*+. Calculations show that the energy ordering is 1b*+ > 2*+ > 3*+, so that the consecutive H-atom shifts are driven by the formation of more stable isomers. Similarly, the parent radical cation of allylamine 5*+ undergoes a spontaneous 1,2-hydrogen atom shift from C1 to C2 at 77 K with a t1/2 of approximately 1 h to yield the distonic alkyl-type iminopropyl radical cation 6*+; this thermal reaction is attributed largely to quantum tunneling, and the rate is enhanced on concomitant photobleaching with visible light. Subsequent exposure to UV light (lambda approximately 350-400 nm) converts 6*+ by a 2,3 H-shift to the 1-aminopropene radical cation 7*+, which is confirmed to be the lowest-energy isomer derived from the ionization of either allylamine or cyclopropylamine. Although the parent radical cations of N, N-dimethylallylamine (9*+) and N-methylallylamine (11*+) are both stabilized by the electron-donating character of the methyl group(s), the photobleaching of 9*+ leads to the remarkable formation of the cyclic 1-methylpyrrolidine radical cation 10*+. The first step of this transformation now involves the migration of a hydrogen atom to C2 of the allyl group from one of the methyl groups (rather than from C1); the reaction is then completed by the cyclization of the generated MeN + (=CH2) CH2CH2CH2* distonic radical cation, possibly in a concerted overall process. In contrast to the ubiquitous H-atom transfer from carbon to nitrogen that occurs in the parent radical cations of saturated amines, the alternate rearrangements of either 1b*+ or 5*+ to an ammonium-type radical cation by a hypothetical H-atom shift from C1 to the ionized NH2 group are not observed. This is in line with calculations showing that the thermal barrier for this transformation is much higher (approximately 120 kJ mol-1) than those for the conversion of 1b*+ --> 2*+ and 5*+--> 6*+ (approximately 40-60 kJ mol-1).     

Gas phase electronic spectra of the carbon chains C5, C6, C8, and C9

Three electronic absorption systems for C5 at 511, 445, and 232 nm and one for C6, C8, and C9 centered at 228, 259, and 288 nm have been observed in the gas phase. The C5 chain was produced in both discharge and ablation sources and detected using resonant two-color two-photon ionization spectroscopy involving 10.5 eV photons. The decay of the excited singlet electronic states indicates fast intramolecular processes on a subpicosecond time scale. The internal energy is assumed to be trapped in a triplet state for at least 15 micros. Hole-burning experiments on the 2 (3)Sigma(u)- <-- X (3)Sigma(g)- transition of C6, C8, and (1)Sigma(u)+ <-- X (1)Sigma(g)+ of C9 confirm the predissociative nature of the excited electronic states.     

Studies of silyl-accelerated 1,5-hydrogen migrations in vinylcyclopropanes.

Thermal 1,5-hydrogen (retro-ene) rearrangements of 1-silylmethylated 2-vinylcyclopropanes have been studied. cis-1-Silylmethyl-2-vinylcyclopropanes 17 and 19 undergo facile 1,5-hydrogen transposition upon mild thermolysis in benzene or toluene solution (80-110 degrees C) to give nearly quantitative yields of ring-opened 1-silyl-1,4-diene products. These reactions occur at temperatures at least 100 degrees C lower than those of the nonsilylated substrates. The silicon center and its ligands influence both the rate and stereoselectivity of diene formation, with the triphenylsilyl substrate providing the fastest reaction and highest (exclusive) stereoselectivity in forming the diene, regardless of the E/Z geometry of the vinylcyclopropane. The trimethylsilyl and triethoxysilyl compounds (19b and 19c) rearrange more slowly and with lower stereoselectivity. It is proposed that the rearrangement process takes place via a concerted suprafacial migration by one of two diastereotopic methylene hydrogens through a transition state having the silyl-carbon bond antiperiplanar to the breaking C-C bond of the cyclopropane ring. This conformational arrangement leads to weakening of the cyclopropane ring bond through orbital hyperconjugation, which facilitates the hydrogen transfer. The corresponding trans-1-silylmethyl-2-vinylcyclopropanes are thermally stable under these conditions. In contrast, cis-1-stannylmethyl-2-vinylcyclopropanes 19d,e undergo loss of the stannyl group at room temperature to afford a ring-opened 1,5-diene product 25 through a process that may take place by initial 1,5-stannyl migration.     

An evidence of contact ion pair in β-(acyloxy)alkyl radical heterolysis during copper(I)-mediated synthesis of trisubstituted alkenes

The first evidence for a unified mechanism of heterolysis in β-(acyloxy)alkyl radical involving contact ion pair (CIP) is presented for both fragmentation and rearrangement of the acyloxy group in the reaction of 1-alkoxy-2,2,2-trichloroethyl acetate with 2 mol equiv each of CuCl and bpy in refluxing DCE under a N₂ atmosphere and availed this reaction for the synthesis of Z-stereoselective trisubstituted alkenes. The stereochemistry of the trisubstituted alkenes was assigned by the uniform pattern of the chemical shift values of some relevant signals in ¹H and ¹³C NMR spectra. This assignment was further supported by the X-ray diffraction spectroscopy of Z-1-chloro-2-(4-nitrobenzyloxy)vinyl acetates.     

Coupling of Sterically Hindered Trisubstituted Olefins and Benzocyclobutenones by CC Activation: Total Synthesis and Structural Revision of Cycloinumakiol

The first total syntheses of the proposed structure of cycloinumakiol ( 1 ) and its C5 epimer ( 18 ) are achieved in a concise and efficient fashion. Starting from the known 3‐hydroxybenzocyclobutenone, 1 and 18 are obtained in nine and five steps with overall yields of 15 % and 33 %, respectively. The key for the success of this approach is the use of a catalytic C? C activation strategy for constructing the tetracyclic core of 1 through carboacylation of a sterically hindered trisubstituted olefin with benzocyclobutenone. In addition, the structure of the natural cycloinumakiol was reassigned to 19‐hydroxytotarol ( 7 ) through X‐ray diffraction analysis. This work demonstrates the potential of C? C activation for streamlining complex natural product synthesis.     

Hydrogen rearrangement and ring cleavage reactions study of progesterone by triple quadrupole mass spectrometry and density functional theory

The fragmentation mechanisms of progesterone have been studied by triple quadrupole tandem mass spectrometry (MSMS) and density functional theory (DFT). Mechanisms leading to major product ions are proposed. The data suggest that progesterone fragments preferentially via hydrogen and other rearrangements lead to neutral losses. These fragmentations are quite complex and are preceded by σ-bond cleavages in most cases. Four major pathways for progesterone fragmentation are proposed involving: (1) cleavage of ring B at C9-C10, (2) cleavage of C6-C7 bond in ring B through m/z 191, (3) two types of cleavages of ring D, and (4) ketene elimination in ring A. Pathways (1)-(3) proceed via charge-remote fragmentations while pathway (4) proceeds via charge-site initiated mechanism. The geometry of product ions in these pathways were optimized using DFT at the B3LYP/6-311G(d,p) level of theory from which the free energies of the pathways were calculated. The effect that the choice of basis sets and density functionals has on the results was tested by performing additional calculations using B3LYP/6-31G(d) and B3PW91/6-311G(d,p).