Controlling the regiochemistry of radical cyclizations

This review describes the results of our recent studies on the control of the regiochemistry of radical cyclizations. N-vinylic alpha-chloroacetamides generally cyclized in a 5-endo-trig manner to give five-membered lactams, whereas 4-exo-trig cyclization occurred when the cyclized radical intermediates were highly stabilized by an adjacent phenyl or phenylthio group to afford beta-lactams. The 5-exo or 6-exo cyclization of aryl radicals onto the alkenic bond of enamides could be shifted to the corresponding 6-endo or 7-endo mode of cyclization by a positional change of the carbonyl group of enamides. The 6-endo- and 7-endo-selective aryl radical cyclizations were applied to radical cascades for the synthesis of alkaloids such as phenanthroindolizidine, cephalotaxine skeleton, and lennoxamine. The 5-exo-trig cyclization of an alkyl radical onto the alkenyl bond of enamides could also be shifted to the 6-endo mode by a positional change of the carbonyl group of enamides. The 6-endo- selective cyclization was applied to the radical cascade to afford a cylindricine skeleton. Other examples of controlling the regiochemistry of radical cyclizations and their applications to the synthesis of natural products are also discussed.     

A computational study of radical haloacetal cyclizations controlled by the acetal center

The stereochemical outcome of the radical haloacetal cyclization reaction (Ueno-Stork reaction) has been examined by ab initio and other molecular orbital techniques. It was found that the stereochemistry of 5-exo- and 6-exo trig cyclizations can be accurately predicted from calculations using moderate levels of theory (UHF/6-311G** or B3LYP/6-311G**). A simplified computational procedure, easily run on a standard desktop computer, has been developed that provides excellent predictive ability for the stereochemical outcome for the reactions in question. Interestingly, a novel twist transition state has been identified for the first time in 5-exo-trig radical cyclization reactions.     

Laser flash photolysis kinetic studies of enol ether radical cations. Rate constants for heterolysis of alpha-methoxy-beta-phosphatoxyalkyl radicals and for cyclizations of enol ether radical cations

Two series of enol ether radical cations were studied by laser flash photolysis methods. The radical cations were produced by heterolyses of the phosphate groups from the corresponding alpha-methoxy-beta-diethylphosphatoxy or beta-diphenylphosphatoxy radicals that were produced by 355 nm photolysis of N-hydroxypryidine-2-thione (PTOC) ester radical precursors. Syntheses of the radical precursors are described. Cyclizations of enol ether radical cations 1 gave distonic radical cations containing the diphenylalkyl radical, whereas cyclizations of enol ether radical cations 2 gave distonic radical cation products containing a diphenylcyclopropylcarbinyl radical moiety that rapidly ring-opened to a diphenylalkyl radical product. For 5-exo cyclizations, the heterolysis reactions were rate limiting, whereas for 6-exo and 7-exo cyclizations, the heterolyses were fast and the cyclizations were rate limiting. Rate constants were measured in acetonitrile and in acetonitrile solutions containing 2,2,2-trifluoroethanol, and several Arrhenius functions were determined. The heterolysis reactions showed a strong solvent polarity effect, whereas the cyclization reactions that gave distonic radical cation products did not. Recombination reactions or deprotonations of the radical cation within the first-formed ion pair compete with diffusive escape of the ions, and the yields of distonic radical cation products were a function of solvent polarity and increased in more polar solvent mixtures. The 5-exo cyclizations were fast enough to compete efficiently with other reactions within the ion pair (k approximately 2 x 10(9) s(-1) at 20 degrees C). The 6-exo cyclization reactions of the enol ether radical cations are 100 times faster (radical cations 1) and 10 000 times faster (radical cations 2) than cyclizations of the corresponding radicals (k approximately 4 x 10(7) s(-1) at 20 degrees C). Second-order rate constants were determined for reactions of one enol ether radical cation with water and with methanol; the rate constants at ambient temperature are 1.1 x 10(6) and 1.4 x 10(6) M(-1) s(-1), respectively.     

Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.     

A study of aryl radical cyclization in enaminone esters

Aryl radical cyclization in N-phenyl, N-benzyl, and N-phenethyl enaminone esters 1a-f was studied. N-Benzyl and N-phenethyl enaminones afforded 5-exo and 6-exo cyclization products, respectively, but radical cyclization did not occur in N-phenyl enaminones. The rate constants for the 5-exo and 6-exo cyclization processes in secondary enaminones were estimated as being on the order of 10(7) s(-1) at 353 K; since DNMR experiments showed the rate constant for rotation around the enaminone C3-N bond to be on the order of 10(4) s(-1) at this temperature, the initial enaminone configuration is maintained throughout the cyclization process. PM3 calculations suggested that the nonoccurrence of endo and 4-exo cyclizations is due to the corresponding transition structures involving significant distortion of the conjugated enaminone system.     

Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization

[reaction: see text] Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.     

Round trip radical reactions from acyclic precursors to tricyclo [5.3.1.0]undecanes. A new cascade radical cyclization approach to (+/-)-isogymnomitrene and (+/-)-gymnomitrene

The synthesis and "round trip radical cyclization" of 11-iodo-2,7,11-trimethyldodec-6-en-5-one are described. The round trip cyclization is a sequence of 5-exo, 6-endo, and 5-exo cyclizations in which the last radical cyclization occurs at the same carbon atom as the initial radical generation. The key second (6-endo) cyclization produces two stereoisomers, one of which cyclizes efficiently to isogymnomitrene ketone, while the other cyclizes inefficiently to gymnomitrene ketone. Efforts to influence the kinetic or thermodynamic outcome of the second cyclization were not successful, and the results are contrasted with a related cyclization of Jung and Rayle where thermodynamic control was readily established.     

Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.     

Bioinspired total synthesis of agelastatin A

A one-two punch: two potentially biosynthetically relevant cyclizations of a keramadine analogue give agelastatin A. A diastereoselective C-ring formation, which proceeds through a 5-exo-trig cyclization or a Nazarov cyclization of a red-colored N-acyliminium intermediate, generates the three contiguous stereocenters of the cyclopentane core. A silica gel assisted cyclization of a nagelamide J analogue gives agelastatin A.     

1,4-pentadienyl-3-sulfonamides: frameworks for "disfavored" radical cascade cyclizations

[reaction: see text]. 1,4-pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction leads to a highly strained bicyclo[3.2.0] ring system.     

7-endo selective aryl radical cyclization onto enamides leading to 3-benzazepines: concise construction of a cephalotaxine skeleton

Bu3SnH-mediated radical cyclizations of 2-(2-bromophenyl)-N-ethenylacetamide gave 6-exo cyclization product 15 as the major product, whereas N-[2-(2-bromophenyl)ethyl]-N-ethenylamides gave almost exclusively 7-endo cyclization products. These results indicated that the position of the carbonyl group on enamide played an important role in deciding the course of the cyclization. The 7-endo selective cyclization was applied to concise construction of a cephalotaxine skeleton.     

8-endo versus 7-exo cyclization of alpha-carbamoyl radicals. A combination of experimental and theoretical studies

Atom transfer radical cyclization reactions of N-(4-pentenyl)iodoacetamides were investigated. The reactions were efficiently promoted by BF3.OEt2. For N-alkenyl-substituted iodoamides, excellent regioselectivity in favor of 8-endo cyclization was observed, while both 7-exo and 8-endo cyclization products were formed with the 8-endo cyclization preferred in the cases of N-(2-allylphenyl)-substituted iodoamides. Density functional theory calculations at the B3LYP/6-31G level revealed that both the s-trans and the s-cis conformational transition structures were feasible for the 8-endo cyclization of N-alkenyl-substituted alpha-carbamoyl radicals while 7-exo transition structures were much less stable. For the cyclization of N-(2-allylphenyl)-substituted alpha-carbamoyl radicals, the transition structures for 8-endo and 7-exo cyclizations were of comparable energy. These results were in excellent agreement with the experimental observations.     

Radicals masquerading as electrophiles: a computational study of the intramolecular addition reactions of acyl radicals to imines

Ab initio calculations using 6-311G**, cc-pVDZ, and aug-cc-pVDZ, with (MP2, QCISD, CCSD(T)) and without (UHF) electron correlation, and density functional methods (BHandHLYP and B3LYP) predict that cyclization of the 5-aza-5-hexenoyl and (E)-6-aza-5-hexenoyl radicals proceed to afford the 5-exo products. At the CCSD(T)/cc-pVDZ//BHandHLYP/cc-pVDZ level of theory, energy barriers (deltaE(double dagger)) of 36.1 and 47.0 kJ mol(-1) were calculated for the 5-exo and 6-endo pathways for the cyclization of the 5-aza-5-hexenoyl radical. On the other hand, at the same level of theory, deltaE(double dagger) of 38.9 and 45.4 kJ mol(-1) were obtained for the 5-exo and 6-endo cyclization modes of (E)-6-aza-5-hexenoyl radical, with exothermicities of about 27 and 110 kJ mol(-1) calculated for the exo and endo modes, respectively. Under suitable experimental conditions, the 6-endo cyclization product is likely to dominate. Analysis of the molecular orbitals involved in these ring-closure reactions indicate that both reactions at nitrogen are assisted by dual orbital interactions involving simultaneous SOMO-pi* and LP-pi* overlap in the transitions states. Interestingly, the (Z)-6-aza-5-hexenoyl radical, that cannot benefit from these dual orbital effects is predicted to ring-close exclusively in the 5-exo fashion.     

Chelation-control in the formal [3+3] cyclization of 1,3-bis-(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. One-pot synthesis of 3-aryl-3,4-dihydroisocoumarins

The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones resulted in the one-pot formation of 3-aryl-3,4-dihydroisocoumarins. The reactions proceeded by regioselective cyclization to give 6-(2-aryl-2-chloroethyl)salicylates, which underwent a silica gel-mediated lactonization. The cyclizations of protected 1-amino-5-silyloxy-hex-4-en-3-ones proved to be not regioselective.     

On the mechanism and kinetics of radical reactions of epoxyketones and epoxynitriles induced by titanocene chloride

The reactions of a series of epoxynitriles and epoxyketones induced by titanocene chloride have been studied. The kinetics of the decyanogenation of beta,gamma-epoxynitriles with Ti(III) corresponds to a radical reaction (k25 approximately 106 s-1), as demonstrated by competition experiments with H-transfer from 1,4-cyclohexadiene (1,4-CHD) or PhSH or conjugate addition to acrylonitrile. The 5-exo cyclization onto nitrile induced by Ti(III) is a radical reaction (k25 approximately 107 s-1) as seen in competition experiments with H-transfer from PhSH or the titanocene-water complex. The iminyl or alkoxyl radicals generated by 5-exo cyclization onto nitriles or ketones only undergo a reduction with Ti(III). This reaction overwhelms any alternative process, such as tandem cyclization onto alkenes or beta-scission. Iminyl radicals generated by 4-exo cyclizations onto nitriles undergo reduction with Ti(III) and beta-scission reaction in a ratio of 96:4 when the alpha-substituent is CN. Alkoxyl radicals from 4-exo cyclizations onto ketone carbonyls undergo reduction with Ti(III) and beta-scission in a ratio of 60:40 when the alpha-substituent is COOR. In nearly all the reactions studied, the role of Ti(III) is triple: a radical initiator (homolytic cleavage of oxirane), a Lewis acid (coordination to CN or C=O), and a terminator (reduction of iminyl or alkoxyl radicals).     

Free-radical-5-exo-trig cyclization of chiral 3-silylhepta-1,6-dienes: concise approach to the A-B-C ring core of hexacyclinic acid

[Chemical reaction: See text] Free-radical-mediated 5-exo-trig cyclization of hepta-1,6-dienes 6a-c incorporating an allylsilane moiety was shown to provide at low temperature exclusively the trans-cis cyclopentanes 7a-c in good yield. In contrast, the same reaction with the alkyl analogue 9a led to the formation of all four possible stereoisomers. Interestingly, extension of this sequence of radical processes to alkoxy analogues 12-14 provided the complementary cis-cis stereoisomers with modest to excellent stereoselectivity. It is noteworthy that under such conditions allylsilanes were found to be much more reactive than their alkyl and alkoxy analogues. Beckwith-Houk-type models were proposed that rationalize the stereochemical course of these 5-exo-trig cyclizations. Finally, an illustration of the value of this methodology was proposed with the synthesis of the A-B-C tricyclic unit of polyketide hexacyclinic acid 3a.     

Synthesis of the asperparaline core by a radical cascade

A concise access to the pentacyclic core structure of the asperparalines is described. The key step is a radical cascade sequence comprised of a 1,6-hydrogen atom transfer followed by 6-exo-trig and 5-exo-trig cyclizations.     

A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.     

Thermodynamic and strain effects in the competition between 5-exo-dig and 6-endo-dig cyclizations of vinyl and aryl radicals

Electronic and structural factors controlling the competition between 5-exo-dig and 6-endo-dig cyclizations of sp2-radicals were analyzed using a combination of available experimental data and computation. Although the stereoelectronically favored 5-exo pathways usually has the lower activation energy, formation of a new aromatic ring not only makes the 6-endo process favorable thermodynamically in conjugated systems but also lowers its activation barrier to the extent where the 5-exo/6-endo selectivity is controlled by subtle factors such as the different sensitivity of the two pathways to strain effects in polycyclic systems. In particular, the stronger sensitivity of the 5-exo pathway to strain leads to a crossover in selectivity. The 6-endo cyclization is kinetically favored in smaller (and strained) cycles, whereas the 5-exo cyclization has lower barriers in the larger rings.     

Intramolecular regioselective addition of radicals and carbanions to ynol ethers. A strategy for the synthesis of exocyclic enol ethers

The scope and limitations of radical and anionic cyclization reactions involving halo ynol ethers have been investigated. 5-exo and 6-exo radical cyclizations of 6-iodo and 7-iodo ynol ethers proceeded well when the oxygen of the ynol ether was bearing an ethyl group. Exocyclic iodoenol ethers resulting from these cyclizations were highly unstable and decomposed rapidly. Li-I exchange of iodo ynol ethers proceeded smoothly at −78 °C. 6-Alkoxy-5-hexynyllithiums underwent regiospecific 5-exo-dig anionic cyclization to produce five-membered rings bearing an exocyclic enol ether moiety. The cyclized vinyllithium intermediate was successfully trapped with electrophiles to afford functionalized cycloalkoxyalkylidene derivatives in modest to good yields. 7-Alkoxy-6-heptynyllithiums did not cyclize via a 6-exo anionic process.