Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI2/H2O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI2/H2O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the gamma-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion.     

Total synthesis of apratoxin A

[reaction: see text]. We have achieved a total synthesis of apratoxin A in which thiazoline formation was accomplished from the moCys containing amide 4 using PPh3(O)/Tf2O. Deprotection of the Troc and allyl ester in 17, coupling with tripeptide 3, and deprotection of the allyl ester and the Fmoc, followed by macrolactamization provided apratoxin A (1).     

Reversed phase high performance liquid chromatographic separation of hydroxy steroidal unsaturated esters and their hemisuccinates.

The high performance liquid chromatographic (HPLC) separation and identification of 12 isomeric and/or highly chemically related steroids with an unsaturated ester moiety at position 17 beta has been achieved. The main stereochemical features of the steroid skeleton cover 3 alpha/beta, 5 alpha/beta or delta, and 20 E/Z, bearing the alcohol or hemisuccinate group at the 3 position. The isocratic reversed phase C18 HPLC separation employed ethanol, methanol and its mixtures with water or 0.01 M phosphoric acid as the mobile phase. The best separation of the respective alcohols from their hemisuccinates has been achieved with 20% of aqueous phase content. The best separation among isomeric or related steroids has been achieved with methanol:water 8:2 and 85:15 and similar systems containing phosphoric acid.     

Enzymatic Synthesis of a CCK-8 Tripeptide Fragment

A process for the synthesis of CCK-8 tripeptide H-Gly-Trp-Met-OH catalyzed by immobilized enzyme was reported. Enzymes were used for the formation of peptide bonds and the removal of protecting group. Starting with phenylacetyl (PhAc) glycin, N-protected dipeptide PhAc-Gly-Trp-OMe was obtained by coupling PhAc-protected glycine carboxamidomethyl ester (OCam) with Trp-OMe catalyzed by immobilized papain in buffered ethyl acetate. Then the condensation between PhAc-Gly-Trp-OMe and Met-OEtoHC1 was carried out by immobilized α-chymotrypsin catalysis in solvent free system. Basic hydrolysis was followed getting PhAc-Gly-Trp-Met-OH. The PhAc-group was removed with penicillin G amidase and H-Gly-Trp-Met-OH was obtained in an overall yield of 43.9%. The reaction conversion of tripeptide in solvent free system was strongly affected by the system of basic salts added. The influence of the support materials used to deposit enzymes and structures of acyl donor and nucleophile on the reaction was also investigated.     

alpha,beta-Unsaturated and cyclopropyl acyl radicals, and their ketene alkyl radical equivalents. Ring synthesis and tandem cyclisation reactions

Treatment of the alpha,beta-unsaturated selenyl esters 12 and 14 with Bu(3)SnH-AIBN produces the corresponding 2-cyclohexenones 13 and 15 respectively via presumed alpha-ketene alkyl radical intermediates, viz. 10. By contrast, the 2,7-diene esters 34 and 39 undergo tandem radical cyclisations producing diquinanes, e.g.(76%), and the corresponding allene-substituted alpha,beta-unsaturated selenyl ester 48 gives the cyclooctadienone 56 on treatment with Bu(3)SnH-AIBN in refluxing benzene. The selenyl ester 19 derived from chrysanthemic acid produces a mixture of the gamma,delta-unsaturated aldehyde 22 and the corresponding dimer 25a on treatment with Bu(3)SnH-AIBN. Furthermore, in the presence of methanol the only product from this reaction was the bis(methyl ester) dimer 25b, thereby lending further credence to the involvement of ketene alkyl radical intermediates in these reactions, and in the aforementioned reactions involving 2,6- and 2,7-diene selenyl esters. Treatment of the cyclopropane selenyl esters and , containing keto- and oxy-group functionality in their side-chains, with Bu(3)SnH-AIBN led to excellent syntheses of the enol lactone 66 (76%) and the trans-fused bicyclo[6.1.0]nonane 67 (80-95%) respectively.     

A new reaction manifold for the Barton radical intermediates: synthesis of N-heterocyclic furanosides and pyranosides via the formation of the C(1)-C(2) bond

The first radical intermediate in the thiourethane-mediated deoxygenation of an alcohol (Barton-McCombie reaction) can participate in an exo-hex-5-enyl- or exo-hept-6-enyl-type radical cyclization when a suitable radical acceptor (e.g., alpha,beta-unsaturated ester, oxime ether, or hydrazone) is appropriately placed. Carbohydrate-derived imidazolyl and triazolyl thiourethanes with such acceptors, upon addition to excess of a good hydride donor (reverse addition), undergo efficient cyclization reactions to give N-heterocyclic furanosides, and, surprisingly even N-pyranosides. Depending on the acceptor, glycosides with either a C(2)()-amino or a C(2)()-carbon substituent are formed.     

Effect of pressure on the free radical reactions of 2-alkoxytetrahydropyrans

In free radical transformations of 2-methoxy- and 2-ethoxytetrahydropyran initiated bytert-butoxy radicals at 130°C, the relative rate of formation of -valerolactone and valeric acid ester was found to change periodically with increase in the extent of transformation, expressed astert-butyl alcohol (TBA) concentration. The ratio of lactone: ether concentration is determined not by the pressure (up to 1000 MPa) as suggested earlier, but by the amplitudes and phase displacement of the oscillations of the rates of formation of lactone and ester. These results are explained by changes in the physical structure of the solution in proportion to the buildup of reaction products as a result of which the reactivity of the 2-alkoxytetrahydropyranyl radical changes in respect of rupture of the endocyclic and exocyclic C-O bonds.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 4, pp. 822–828, April, 1992.     

Synthesis of beta-substituted alpha-amino acids via Lewis acid promoted enantioselective radical conjugate additions

[Chemical reaction: See text] Lewis acid promoted radical conjugate additions to beta-substituted alpha,beta-unsaturated alpha-nitro esters and amides were investigated. With achiral Lewis acids, there was competition between the desired radical conjugate addition and undesired alkene reduction mediated by Bu3nH. Zinc Lewis acids provided the greatest amounts of addition products with both substrate classes. Studies with Bu3nD indicated that the acidic alpha-stereocenter of the alpha-nitro ester products does not racemize under controlled workup conditions. The corresponding alpha-nitro amides racemized significantly during chromatography, but this problem could be greatly minimized by subjecting the crude adducts to subsequent transformations. Indium-mediated reduction of the nitro group followed by acylation of the resulting amine provided good yields of beta-substituted alpha-amino acid derivatives with mimimal levels of racemization. Attempts to use chiral Lewis acids in a stereoselective variant of this process revealed that Kanemasa's DBFOX/Ph ligand (14a) was uniquely effective. Moderate to good ee's and low dr's were obtained with amide substrates. Determination of the absolute configurations of the syn and anti isomers of adduct 7b showed that the hydrogen atom abstraction step was significantly more stereoselective than the radical conjugate addition step. A model for substrate binding to the chiral Lewis acid is presented.     

Asymmetric synthesis of naproxen via a pinacol-type reaction

An asymmetric pinacol-type rearrangement was used in the synthesis of (S)-naproxen. The pinacol-type reaction of a vicinal diol provided an -aryl ketone which was oxidized with sodium hypochlorite in the presence of methanol to the methyl ester of naproxen.     

Synthesis of L-α-aminoadipyl-L-serinyl-D-valine,a naturally occuring tripeptide from the fermentation of Penicillium chrysogenum

A new tripeptide, L -α-aminoadipyl-L -seryl-D-valine has been synthesized by coupling the protected L-seryl-D -valine dipeptide with an appropriately protected L -α-aminoadipic acid ester. The free tripeptide was obtained after treatment with liquid HF and purification by HPLC.     

Rapid synthesis of cyclodepsipeptides containing a sugar amino acid or a sugar amino alcohol by a sequence of a multicomponent reaction and acid-mediated macrocyclization

Cyclodepsipeptides incorporating a sugar amino acid (alcohol) have been synthesized. A three-component reaction of a sugar amino acid (SAA) derivative, an aldehyde, and a dipeptide isonitrile in refluxing methanol afforded the corresponding 5-aminooxazole which, after saponification, underwent a trifluoroacetic acid promoted macrocyclization to furnish the cyclic sugar amino acids.     

Magnetic field effects on the triplet exciplex dynamics in the duroquinone-N,N-dimethylaniline derivative systems

Magnetic field effects (MFEs) on the radical yield in the photoinduced electron transfer reaction from the p-halogen derivatives (4XDMA) of N,N-dimethylaniline to the excited triplet state of duroquinone (DQ) have been investigated in alcoholic solutions at room temperature. In 1-propanol and 1-butanol solutions, the radical yields decreased as the magnetic field increased and became nearly constant at 1-1.8 T in the DQ-4BrDMA and DQ-4IDMA systems, suggesting that the spin-orbit coupling interaction due to the heavy atoms governs the radical yield. On the other hand, in the methanol solution MFE due to a radical pair mechanism was observed. We concluded that the key intermediate to determine the radical yield is the triplet exciplex or contact radical ion pair in the 1-propanol and 1-butanol solutions, while it is the solvent-separated radical ion pair in the methanol solution.     

Photochemical studies on xanthurenic acid

The tryptophan metabolite xanthurenic acid (Xan) has been isolated from aged human cataractous lenses. The photophysical properties of Xan were examined to determine if it is a potential chromophore for age-related cataractogenesis. We found that Xan produces singlet oxygen (psi delta = 0.17 in CD3OD) with the same efficiency as the lenticular chromophore N-formyl kynurenine and quenches singlet oxygen at a rate similar (2.1 x 10(7); CD3OD) to other tryptophan metabolites found in the eye. As the mechanisms of induction of cataracts may also involve redox reactions, the interactions of hydrated electrons (e(aq)-), the azide radical (N3*) and hydroxyl radical (OH*) with Xan were studied using the technique of pulse radiolysis. The reaction rate constants of e(aq)-, N3* and OH* with Xan were found to be of the same order of magnitude as other tryptophan metabolites. The rate constant for reaction of Xan with e(aq)- solvated electrons was found to be diffusion controlled (k = 1.43 x 10(10) M(-1) s(-1); the reaction with N3* was very fast (k = 4.0 x 10(9) M(-1) s(-1)); and with OH* was also near diffusion controlled (k = 1.0 x 10(10) M(-1) s(-1)). Superoxide O2*- production by irradiated Xan in methanol was detected by electron paramagnetic resonance and substantiated by determining that the enhanced rate of oxygen consumption of Xan irradiated in the presence of furfuryl alcohol was lowered by superoxide dismutase.     

N-nitrosoamide-mediated N --> O nitroso transfer to alcohols with subsequent denitroxylation

Decomposition of certain N-benzyl-N-nitrosoamides is often accompanied by small amounts of benzaldehyde whose formation was postulated to arise from in situ formation and oxidation of benzyl alcohol. Incubation of excess benzyl alcohol with thermostable N-benzyl-N-nitrosoamides at ambient temperatures in inert solvents generates benzyl nitrite, N-benzyl amides, and benzaldehyde as the major products. Benzyl nitrite formation appears to be linked to N --> O nitroso transfer between the N-benzyl-N-nitrosoamides and benzyl alcohol, which is subject to the previously observed electronic and steric features of the acyl substituent although the former appears to play a much larger role than the latter. Benzaldehyde formation evidently arises from dehydronitrosation (denitroxylation) of the nitrite via O-N bond homolysis and H-abstraction from the resultant benzyloxy radical. Although trans-nitrosation occurs with methanol, 1 degree, 2 degree, and 3 degree alcohols, the reaction is evidently subject to steric effects at both the alpha and beta carbons of the alcohol. Additionally, carbonyl formation only occurs with 2 degrees alcohols and those that can derive resonance-stabilized carbonyls.     

Tadpole-shaped polymers based on UV-induced strain promoted azide-alkyne cycloaddition reaction

In the present study, we synthesized well-defined tadpole-shaped polystyrene (PS) via the combination of atom transfer radical polymerization (ATRP) and UV-induced strain promoted azide-alkyne cycloaddtion (SPAAC) reaction. A di-bromo ATRP initiator (Br-ini-Br) containing cyclopropenone-masked dibenzocyclooctyne group was used to prepare the linear PS with a cyclopropenone-masked dibenzocyclooctyne in the middle of the chain and bromo groups at both ends (Br-PS-Br). Then we used the single electron transfer-nitroxide radical coupling (SET-NRC) reaction to transfer the bromo end groups to azide groups (N3-PS-N3). After UV irradiation, the dibenzocyclooctyne group was quantitatively released, and intramolecularly reacted with alternative azide end group to produce the tadpole-shaped PS based on SPAAC reaction.     

Protease-catalyzed Synthesis of Bz-Arg-Gly-Asp-OMe in Full Aqueous Medium

Synthesis of N-benzoyl-argininylglycylasparagine methyl ester(Bz-Arg-Gly-Asp-OMe),a precursor tripeptide of Arg-Gly-Asp)was catalyzed by papain under kinetic control,at alkaline pH,in a full aqueous medium.The substrates were N-benzoyl-argininylglycine ethyl ester and asparagine dimethyl ester.An aqueous solution of 0.1 mol/L KCl/NaOH containing 8 mmol/L EDTA and 2 mmol/L DTT was selected as the reaction medium.The synthesized hydrophilic tripeptide was soluble in the reaction medium during the reaction process,however,the secondary hydro-lysis of the tripeptide product was not considerable.The effects of different factors,including water content,temperature,reaction time,and molar ratio of the substrates,on the yield of Bz-Arg-Gly-Asp-OMe were examined.The optimal reaction conditions were 0.05 mol/L Bz-Arg-Gly-OEt and 0.15 mol/L Asp(-OMe)2·HCl in 0.1 mol/L KCl/NaOH solution(pH 8.5),at 40 ℃,and a reaction time of 60 min,with a maximum conversion yield of 62.4%.     

Effects of electron-withdrawing substituents on DPPH radical scavenging reactions of protocatechuic acid and its analogues in alcoholic solvents

The DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity of protocatechuic acid (3,4-dihydroxybenzoic acid) and its related catechols was examined. Compounds possessing strong electron-withdrawing substituents showed high activity. NMR analysis of the reaction mixtures of catechols and DPPH radical in methanol showed the formation of methanol adducts. The results suggest that high radical scavenging activity of catechols in alcohol is due to a nucleophilic addition of an alcohol molecule on o-quinones, which leads to a regeneration of a catechol structure. Furthermore, the radical scavenging activity in alcohols would largely depend on the electron-withdrawing/donating substituents, since they affect the susceptibility toward nucleophilic attacks on o-quinone.     

Dearomative Photocatalytic Construction of Bridged 1,3‐Diazepanes

The construction of diverse sp³‐rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7‐diazabicyclo[3.2.1]octanes (bridged 1,3‐diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4‐substituted quinoline substrates, with subsequent Hantzsch ester‐promoted reduction to a dihydropyridine intermediate which undergoes in situ two‐electron ring closure to form the bridged diazepane architecture. A wide scope of N‐arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all‐carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.     

Total synthesis of rhizoxin D,a potent antimitotic agent from the fungus Rhizopus chinensis

Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the beta carbon of the (Z)-alpha,beta-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired beta-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from delta-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.     

Resolution of 1-(2-naphthyl)ethanol by a combination of an enzyme-catalyzed kinetic resolution with a fluorous triphasic separative reaction

[reaction: see text] Kinetic resolution of a fluorous ester rac-1 with Candida antarctica B lipase provided a mixture of enantioenriched alcohol (R)-2 and fluorous ester (S)-1. The mixture was subjected to a fluorous triphasic reaction to give both enantiomers of 1-(2-naphthyl)ethanol 2 in high ee without chromatographic separation or fluorous-organic liquid-liquid extractive purification.