Synthesis of 13a-methylphenanthroindolizidines using radical cascade cyclization: synthetic studies toward (±)-hypoestestatin 1

A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is demonstrated.     

Ab initio studies of the allylic hydroxylation: DFT calculation on the reaction of 2-methyl-2-butene with selenium dioxide

The mechanism of the allylic oxidation of 2-methyl-2-butene with selenium dioxide has been investigated by ab initio quantum mechanics. Transition states for two major steps (an ene reaction and a [2,3]-sigmatropic rearrangement) of this reaction have been optimized by the B3LYP/6-311+G(d,p) method. A comparison of the energies of the transition states shows that the anti-endo and syn-endo approaches are the efficient routes in the ene reaction and the methyl (C4) group is sited in a pseudo-equatorial environment in cyclic transition states during the [2,3]-rearrangement. Calculations also show the kind of the terminal alkyl (C4) substituents may control (E)-selectivity in the formation of the allylic alcohols.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Camphor and Isocamphanone in the Synthesis of Disubstituted Acetylene Alcohols,Ethers, and Esters

By treating 1-octyne and phenylacetylene with butyllithium the corresponding lithium acetylides were obtained that with camphor and isocamphanone provided along streospecific process 2-exo-(1-octynyl or 2-phenyl-1-ethynyl)-2-endo-lithiumoxy-5,5,6-trimethylbicyclo[2.2.1]heptane and 2-endo-(1-octynyl or 2-phenyl-1-ethynyl)-2-exo-lithiumoxy-1,7,7-trimethylbicyclo[2.2.1]heptane. The hydrolysis of these lithium alcoholates occurred selectively and resulted in individual tertiary terpene alcohols containing exo-acetylene substituent in the case of camphor, endo-acetylene fragment in the case of isocamphanone. The alcohols reacted with methyl, ethyl, or butyl iodides in the presence of hexamethylphosphoramide to afford ethers, and with benzoyl chloride to furnish disubstituted esters of benzoic acid.     

Reaction modes of oxidative dimerization of epoxycyclohexenols

Of the 16 possible modes of the oxidation-6π-electrocylization-Diels-Alder reaction cascade for an epoxyquinone, and eight for a 2-alkenyl-3-hydroxymethyl-2-cyclohexen-1-one, only the endo-anti(epoxide)-anti(Me)-hetero and endo-anti(Me)-hetero are respectively observed, while both the endo-anti(epoxide)-anti(Me)-hetero and exo-anti(epoxide)-anti(Me)-homo reaction modes occur with epoxy-4-hydroxycyclohexenones owing to a hydrogen-bonding interaction.     

5-Nitroisocoumarins from tandem Castro-Stephens coupling—6-endo-dig cyclisation of 2-iodo-3-nitrobenzoic acid and arylethynes and ring-closure of methyl 2-alkynyl-3-nitrobenzoates with electrophiles

Reaction of 2-iodo-3-nitrobenzoic acid with arylalkynyl copper(I) reagent gave 3-aryl-5-nitroisocoumarins. Castro-Stephens coupling was followed by in situ Cu-catalysed ring-closure. ¹H NMR and X-ray crystallography showed the cyclisations to be 6-endo, contrasting with reports of 5-exo cyclisation of analogous 2-iodobenzoate esters with alkynes. Sonogashira couplings of methyl 2-iodo-3-nitrobenzoate with phenylacetylene and with trimethylsilylacetylene gave the corresponding 2-alkynyl-3-nitrobenzoate esters. With HgSO₄, the phenylalkyne underwent 6-endo cyclisation to give 5-nitro-3-phenylisocoumarin. The disubstituted alkyne esters gave 4-phenylselenylisocoumarins with PhSeCl. 5-Nitro-3-phenyl-4-phenylselenylisocoumarin shows significant sterically-driven distortion of the isocoumarin ring. Reaction of methyl 3-nitro-2-phenylethynylbenzoate with ICl gave the 4-iodoisocoumarin. Thus the nitro group tends to direct these electrophile-driven cyclisations towards the 6-endo mode.     

A cascade radical-mediated macrocyclisation–transannulation approach to oestrogen steroids

A new approach to ring A aromatic steroids, based on cascade 13-endo-trig/dig macrocyclisations followed by sequential 5-exo-trig and 6-exo-trig transannulations, exemplified in the syntheses of the cis,anti,trans tetracycle 9 and the trans,syn tetracycle 13 from the ortho-substituted aryl polyen(yne) precursors, 8 and 12 respectively, is described.     

Enhanced reactivity in radical cyclizations of hydrazones using the silicon-tethered 1-bromovinyl group

A silicon-tethered 1-bromovinyl group was shown to function as a radical precursor for tin-mediated vinyl additions to chiral α- or β-hydroxyhydrazone. In contrast to related thiyl-mediated methods, these vinyl bromides were not limited to the 5-exo cyclization mode. A series of Si-tethered 5-exo and 6-exo cyclizations formed the corresponding five- and six-membered exo-methylene-substituted oxasilacycles. Treatment with fluoride cleaved the Si-C and Si-O bonds to afford the corresponding allylic hydrazines. Diastereoselectivities ranged from 2:1 to 25:1 (anti:syn) for the 5-exo cyclizations, depending on the size of the exocyclic substituent, but 6-exo cyclization was not diastereoselective. A variant involving Tamao oxidation of the exo-methylene oxasilacyclopentane intermediate afforded a methyl ketone, a net process corresponding to addition of a radical acyl anion equivalent.     

Convenient switching of 7-endo/6-exo radical cyclization

7-endo/6-exo Selectivity of radical cyclization to α,β-unsaturated amides was readily controlled by the presence or absence of a temporary substituent, a phenylthio or chlorine group, at the α-position of the acceptor.     

Substituted 2-norbornyl carbenes

A series of endo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have been generated by pyrolysis of the sodium salt of the tosylhydrazone precursors. The endo-6-trimethylsilyl and endo-6-thiomethoxy substituted carbenes give 1,3-migration of these substituents to the carbene center. However groups such as methyl, CH₂SiMe₃, phenyl, and methoxy are ineffective 1,3-migrating groups. The facile 1,3-migration of trimethylsilyl and thiomethoxy has been rationalized in terms of stabilized transition states where the migrating group interacts effectively with the carbene vacant orbital. In the cases of endo-6-thiomethoxy and methoxy derivatives, the carbene also inserts effectively into the methyl group of the substituent. Heteroatom stabilization of the transition state for C-H insertion facilitates these processes. Certain exo-6-substituted bicyclo[2.2.1]hept-2-yl carbenes have also been generated. While the exo-6-thiomethoxy and carbomethoxy systems give exclusive 1,3-hydrogen migration, the exo-6-sulfonyl derivative gives, in addition to 1,3-hydrogen migration, an alkene product derived from 1,2-hydrogen migration. The lowered propensity for 1,3-hydrogen migration is attributed to the strong electron-withdrawing sulfonyl group, which decreases the hydridic 1,3-interaction with the carbene vacant orbital.     

Synthesis of spiroindolenine derivatives by a tandem radical-oxidation process

In the present work, a novel stereoselective radical cyclization/oxidation/spirocyclization cascade process using a mixture of n-Bu₃SnH/ dilauroyl peroxide is described. The proposed mechanism for this later process combines a 6-endo cyclization of an aryl radical onto an enamide double bond, and a consecutive oxidative-ionic spirocyclization at C-3 of an indole nucleus. All processes led to the construction of new spiroindolenine derivatives in a one-step synthesis starting from relatively simple starting materials. The organic peroxide appears to act as the initiator and the oxidant.     

An Endo-Selective Epoxide-Opening Cascade for the Fast Assembly of the Polycyclic Core Structure of Marine Ladder Polyethers

The rapid synthesis of marine ladder polyethers from polyepoxide precursors (in analogy with the biosynthetic pathway hypothesized by Nakanishi) is hampered by the fact that the exo-selective epoxide-opening cyclization cascade that gives THF-type polyethers is preferred over the endo-selective cascade that gives the desired products. We found that perfluoro-tert-butanol (PFTB) cooperating with 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]BF₄) can promote endo-selective epoxide-opening cyclization reactions of trisubstituted epoxy alcohols. Starting from readily accessible homochiral polyepoxy alcohols with a methyl group at all the endo-cyclization sites, we were able to construct polyethers up to five consecutive fused 6-, 7-, and/or 8-membered rings in one step. Notably, molecules with the 7/7/6/6 and 7/7/6/7/6 polyether frameworks of hemibrevetoxin B and brevenal, respectively, could be synthesized in 40 % and 17 % chemical yields.     

A new synthesis of the 2,2,3,5,6,6-substituted tetrahydropyran aplysiapyranoid A and its 5-epimer

The vanadium(V)-catalyzed oxidation of bromide in the presence of methyl (E)-2-(1-hydroxy-1-methylethyl)-5-phenyl-4-hexenoate furnished 5,6-trans-5-bromo-6-phenyl-2,2,6-trimethyl-3-methyloxycarbonyltetrahydropyran, which was converted into the marine natural product aplysiapyranoid A and its 5-epimer, via a short sequence of decarboxylative bromination and transition metal-based procedures for transforming a phenyl into a chlorovinyl substituent.     

A copper-catalyzed domino radical cyclization route to benzospiro-indolizidinepyrrolidinones

In this Letter the synthesis of benzospiro-indolizidinepyrrolidinones is described by a domino atom transfer radical cyclization reaction using a copper catalyst. The structure of one of the products was established by single crystal X-ray diffraction. The investigated precursors, bearing a homo allyl substituent on the N-indole, result in a 5-exo-trig, followed by a 6-endo-trig cyclization. When the N-indole is substituted with an allyl group, only the spiro-cyclization occurs.     

Total synthesis of (±)-heliannuol C and E via aromatic Claisen rearrangement

The total synthesis of heliannuol C and E from a common intermediate are described. Key steps in the synthesis include a regioselective aromatic Claisen rearrangement to install the (1-vinyl)-4-methyl-3-pentenyl substituent and regioselective biomimetic 7-endo and 6-exo phenol epoxide cyclizations to form the cyclic ether moieties.     

Carbon Participation in the Solvolysis of Tertiary Norbornyl Derivatives Norbornanes. Part 15. 6-substituted 2-methylnorbornyl 2-exo- and 2-endo-2,4-dinitrophenyl ethers

The solvolysis rates and products of the tertiary 2-methyl-2-exo- and -2-endo-norbornyl 2,4-dinitrophenyl ethers 1 and 2 , (X = 2,4-(NO₂)₂₂C₆H₃O) have been determined. The different sensitivities of the rates of these ethers to the inductive effect of substituents at C(6) indicate that graded bridging of C(2) by C(6) occurs in the ionization of the exo-ethers 1 , not, however, in the ionization of the endo-ethers 2. In both cases hydrolysis leads to 2-methyl-2-exo-norbornanols only. Consequently, substitution takes place with retention at C(2) in the exo-series 1 and with inversion at C(2) in the endo-series 2. It is concluded that stereoelectronic and polar effects, rather than steric bulk effects, determine the high exo/endo rate ratios of the parent norbornyl derivatives 1a and 2a .     

Development of aspartic acid ligation for peptide cyclization derived from serine/threonine ligation

Based on a mechanism analogous to the serine/threonine ligation, the aspartic acid ligation, which is facilitated by the γ-amino alcohol based ligation and oxidation, is developed and applied to the synthesis of cyclic peptides. The γ-hydroxyl group triggers the ring-chain tautomerization via a 6-endo-trig process,while the δ-hydroxyl group facilitates the oxidative cleavage of the vicinal diol to give carboxylic acid.     

Polar versus steric effects in the solvolysis of 6endo-substituted 2endo-norbornyl p-toluenesulfonates. Norbornanes,Part 8

The solvolysis rates and products of the 6endo-R-substituted 2endo-norbornyl toluenesulfonates 6a – 6i have been determined. The rates of 6a – 6g correlate with the inductive constants σ the 6endo-substituents and are not related to the size of the latter. It is therefore concluded that polar rather than steric effects control the exo/endo-rate ratios of norbornyl sulfonates. Products are derived mainly from rearranged 6exo-R-norbornyl cations when the substituent is an electron donor and from unrearranged 6endo-R-substituted cations when the substituent is an electron acceptor.     

Synthesis of trans-fused polycyclic ethers with angular methyl groups using sulfonyl-stabilized oxiranyl anions

An efficient method has been developed for the synthesis of trans-fused tetrahydropyrans with angular methyl groups adjacent to the ring oxygen. The procedure involves the coupling reaction of a sulfonyl-stabilized oxiranyl anion with an appropriate triflate followed by 6-endo cyclization, and is effective for the construction of 6/6- and 6/7/6-cyclic ether ring systems with sterically congested 1,3-diaxial methyl groups.     

An efficient approach to isoquinoline via AgNO3-promoted 6-endo-dig cyclization followed by oxidative elimination of o-alkynylarylaldimines and its application in fluoride recognition

A novel 6-endo-dig cyclization followed by oxidation/elimination of o-alkynylarylaldimines with 4-hydroxybenzylamine was developed for preparation of isoquinolines. The intermediates of this tandem reaction were monitored by mass spectroscopy (MS) to confirm the reaction pathway. This methodology was further applied to the design and synthesis of a novel ratiometric chemosensor for determination of fluoride.