Five-membered Lactams Research Articles

Stereochemically controlled syntheses of indole-substituted dihydrofuran-2-ones and a pyrrolidin-2-one

In order to obtain constrained analogues of tryptophane, five-membered lactams and lactones bearing 4-indolyl and 3-carboxylic groups were prepared in a completely diastereoselective manner, resulting in a trans relationship. Furthermore, the use of chiral precursors in the synthesis yielded enantiomerically pure compounds with three contiguous chiral centres.

Photochemical Reactions of N-(2-Halogenoalkanoyl) Derivatives of Anilines

The photochemical reactions of 2-substituted N-(2-halogenoalkanoyl) derivatives 1 of anilines and 5 of cyclic amines are described. Under irradiation, 2-bromo-2-methylpropananilides 1a – e undergo exclusively dehydrobromination to give N-aryl-2-methylprop-2-enamides (=methacrylanilides) 3a – e (Scheme 1 and Table 1). On irradiation of N-alkyl- and N-phenyl-substituted 2-bromo-2-methylpropananilides 1f – m, cyclization products, i.e. 1,3-dihydro-2H-indol-2-ones (=oxindoles) 2f – m and 3,4-dihydroquinolin-2(1H)-ones (=dihydrocarbostyrils) 4f – m, are obtained, besides 3f – m. On the other hand, irradiation of N-methyl-substituted 2-chloro-2-phenylacetanilides 1o – q and 2-chloroacetanilide 1r gives oxindoles 2o – r as the sole product, but in low yields (Scheme 3 and Table 2). The photocyclization of the corresponding N-phenyl derivatives 1s – v to oxindoles 2s – v proceeds smoothly. A plausible mechanism for the formation of the photoproducts is proposed (Scheme 4). Irradiation of N-(2-halogenoalkanoyl) derivatives of cyclic amines 5a – c yields the cyclization products, i.e. five-membered lactams 6a, b, and/or dehydrohalogenation products 7a, c and their cyclization products 8a, c, depending on the ring size of the amines (Scheme 5 and Table 3).

Methods for Preparing Cyclic β-Cyclopentadienyl(dicarbonyl)iron-substituted α,β-Unsaturated Carbonyl Compounds: Precursors to Annulated α,β-Butenolides and γ-Lactams

Methods for the synthesis of cyclic [η5-C5H5(CO)2Fe]-substituted (Z)-enals from cyclic ketones are described. With a single transformation five-membered lactams as well as lactones are accessible from these organometallic reagents.

A Novel Approach to Chiral, Nonracemic Pyrrolidines by 5-exo-trig Diastereoselective Radical Cyclization on Acrylamides Derived from (−)-8-Aminomenthol

α,β−Unsaturated amides supported on perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol as chiral auxiliaries undergo regio- and stereoselective 5-exo-trig radical cyclization leading to diastereomeric five-membered lactams. These cyclization products are transformed into enantiopure 3,4-disubstituted pyrrolidines by reduction with aluminum hydride followed by removal of the menthol appendage.

β- and γ-lactams by nickel powder mediated 4-exo or 5-endo radical cyclisations. A concise construction of the mesembrine skeleton

N-Alkenyl trichloroacetamides, upon treatment with nickel powder and acetic acid in refluxing 2-propanol undergo reversible 4-exo radical cyclisation. The cyclised radical can be trapped in different ways leading to β-lactams. When the trap is omitted or not efficient enough, unusual irreversible 5-endo cyclisation occurs affording functionalised five-membered lactams. Synthesis of bicyclic γ-lactams has also been examined providing in few steps an access to the Sceletium alkaloids skeleton.

The Preparation and Biological Activity of Lactam-Based, Non-Steroidal, Inhibitors of Human Type-1 Steroid 5α-Reductase.

A Beckmann rearrangement of cis- and trans-fused 3,4,4a,9,10,10a-hexahydrophenanthren-1(2H)-one oximes has yielded three azepines. An in vitro assay of the azepines and (3aSR,9bSR)-6-methoxy-3-methyl-1,3,3a,4,5,9b-hexahydro-2H-benz[e]indol-2-one, prepared in four steps from naphthalene-1,6-diol, against human type-1 steroid 5α-reductase, revealed the tricyclic five-membered lactam to be a potent inhibitor (IC50 733 nM).

Diastereoselective 5- exo- trig radical cyclisation on N-Acryloyl-tetrahydro-1,3-oxazines. A novel approach to enantiopure 3-substituted pyrrolidines

N-Acryloyl-2-(phenylselenomethyl)-tetrahydro-1,3-oxazine 1 generates a carbon-centred radical in the presence of tri- n-butyltin hydride and A1BN. This radical underwent diastereoselective 5- exo-trig cyclisation leading to a mixture of five-membered lactams 2a and 2b (d.e. 68%). Chromatographic separation of the diastereomers and elimination of the chiral auxiliary provided enantiopure ( R)-3-methylpyrrolidine in good chemical yield.

Photocyclization of Enamides. 38. Reductive Photocyclization of a-(Methylthio)- and a-(Arylthio)enamides

Reductive photocyclization of α-(methylthio)enamide (2) gave exclusively six-membered lactams (3) and (4) while the same reaction of α-(arylthio)enamides (6) and (12) was found to afford five-membered lactams (7) and (13) as major products. A novel total synthesis of (±)-polyzonimine (18b) was accomplished by applying the newly found reductive photocyclization of α-(naphthylthio)enamide leading to the formation of five-membered lactams

Cycloadditionen, XX Thermisch induzierte intramolekulare Reaktionen bei 2-Methyl-2,3-butadienamiden / Cycloadditions, XX Thermally Induced Intramolecular Reactions of 2-Methyl-2,3-butadienamides

The 2-methyl-2,3-butadienamides 4a—m are directly synthesized by the reaction of the corresponding allenic acid chloride 2 with the secondary amines 3. At heating, 4a—j undergo the intramolecular Diels-Alder reaction, by using their ω-standing double bond and the π-system of the directly bonded phenyl groups or of the “methylenic” bonded arenes or furans. Thereby the tricycles 6a—g (bearing five-membered lactam moreties) and/or the tricycles 7-9 (bearing six-membered lactam moreties) are formed. The influence of the geminai methyl group on the chemoselectivity and on the velocity of the IMDA reactions is investigated. The N-allyl derivatives of 4 (s. 41 and m) form the bicycles 10 by intramolecular [2+2]-Cycloaddition.

Formation of five-membered lactams by 5-endo-trigonal radical cyclisations of 2-chloro-N-(cycloalk-1-enyl)acetamides: new synthesis of erythrinane skeleton

Free-radical cyclisations of a range of 2-chloro-N-(cycloalk-1-enyl)acetamides have been examined. The enamide 5, upon treatment with Bu3SnH in the presence of azoisobutyronitrile, underwent cyclisation via the carbamoylmethyl radical 6 in a ‘disfavoured’ 5-endo-trig manner to give octahydro-1-methylindol-2-one 8. Similarly, the enamides 10 and 11 gave the corresponding octahydroindol-2-ones 12–15. The N-(3,4-dihydro-2-naphthyl) derivative 16, however, afforded the β-lactam 17 instead of a γ-lactam. The phenyl-substituted congener 24 and the benzocycloheptenyl derivative 29 gave again the five-membered lactams 25 and 30, respectively. The difference in the mode of cyclisations among substrates 5, 16, 24 and 29 has been discussed in terms of the electronic stability and/or the steric congestion of the radical intermediates formed by ring closure of the carbamoylmethyl radical. The carbonyl group incorporated into the five-membered lactams proved to be essential for the 5-endo-trig radical cyclisation, by examination of the reactions of the enamides 33 and 38, in which only the former gave five-membered lactams, viz. compounds 34 and 35. The tandem cyclisation initiated by the carbamoylmethyl radical has also been examined. The method was applied to the synthesis of perhydroerythrinane 58.

Radical cyclizations of N-vinylic α-chloroacetamides. 5- endo-trig and 4- exo-trig cyclizations

Bu 3SnH mediated radical cyclizations of N-vinylic α-chloroacetamides proceeded in a “disfavored” 5- endo-trig manner to give five-membered lactams. Some exceptions where the 4- exo cyclization predominates are also described.

Reductive Photocyclization of a-Methylthio- and a-Arylthioenamides

Reductive photocyclization of α-methylthio- and α-arylthioenamides (2a-c) gave six-membered lactams (3a-d) and five-membered lactams (4a,b)

Synthesis of five-membered lactams by α-carbamoyl radical cyclisations

Free-radical cyclisation of N-allyl-α-carbamoyl radicals generated by tributyltin radical-mediated cleavage of carbon–chlorine or carbon–sulphur bonds has been studied in some detail. The radicals substituted at the α position by methylthio (phenylthio), chloro, methyl, phenyl, methoxy, or acetoxy groups underwent smooth cyclisation in a 5-exo-trig manner to give five-membered lactams in which the trans-isomer predominated. In contrast, the N- or α-unsubstituted, or α-sulphonyl-substituted, radicals gave predominantly or exclusively the reduction products. Cyclisation of the N-β-methylallyl system proceeded again regioselectively to give the five-membered lactam.

The Photocyclization of N,N-Dialkyl β-Oxo Amides on Silica Gel

Abstract β-Oxo amides 1 adsorbed on silica gel underwent photocyclization via δ-hydrogen abstraction to give the five-membered lactams 2. No severe restrictions on the molecular motion could be observed in the photoreaction on the silica-gel surface. However, the relative photoreactivity of N,N-dibenzyl-2-benzoylacetamide (1a) to N,N-dibenzyl-2-benzoylpropionamide (1b) increased greatly on the silica-gel surface compared to that in solution, probably because of the greater keto content on the surface.

Alkene cyclisations of N-alkenyl-α-(methylsuiphinyl)acetamides and N-alkenyl-α-chloro-α-(methylthio)acetamides: novel synthesis of five-, six-, and seven-membered lactams

On being treated with trifluoroacetic anhydride, N-isopropenyl-N-methyl-α-(methylsulphinyl)acetamide (4a) underwent cationic alkene cyclisation to give the six-membered lactams (6) and (7), whereas the N-but-2-enyl (4b) and N-(3-methylbut-2-enyl) derivatives (4c) afforded the five-membered lactams (8) and (9), and (10), respectively. A similar treatment of the N-prop-2-enyl derivative (4d) gave only the Pummerer rearrangement product (12), which, on further treatment with trifluoroacetic acid, afforded the five-membered lactams (13) and (14). On the other hand, N-but-2-enyl-α-chloro-N-methyl-α-(methylthio)acetamide (5b), when treated with stannic chloride or silica gel, or when heated without solvent, gave the lactam (8). Treatment of N-prop-2-enyl derivative (5d) with stannic chloride yielded the lactams (14) and (15). The cyclisations of N-alk-3-enyl derivatives (4e), (4f), and (5e) giving seven-membered lactams are also described.

Peptide models of protein metastable binding sites: competitive kinetics of isomerization and hydrolysis.

alpha 2-Macroglobulin and the complement components C3 and C4 each contain a metastable binding site that is essential for covalent attachment. Two cyclic peptides are useful models of these unusual protein sites. Five-membered lactam 1 (CH3CO-Gly-Cys-Gly-Glu-Glp-Asn-NH2) contains an internal residue of pyroglutamic acid (Glp). Fifteen-membered thiolactone 2 (CH3CO-Gly-Cys-Gly-Glu-Glu-Asn-NH2 15-thiolactone) contains a thiol ester bond between Cys-2 and Glu-5. These isomeric hexapeptides are spontaneously interconverted in water. Competing with the two isomerization reactions are three reactions involving hydrolysis of 1 and 2. These five processes were found to occur simultaneously under physiologic conditions (phosphate-buffered saline, pH 7.3, 37 degrees C). Best estimates of the five rate constants for these apparent first-order reactions were obtained by comparing the observed molar percentages of peptides 1-4 with those calculated from a set of exponential equations. Both isomerization reactions (ring expansion of 1 to 2, k1 = 6.4 X 10(-5) s-1; ring contraction of 2 to 1, k-1 = 69 X 10(-5) s-1) proceeded faster than any of the hydrolysis reactions: alpha-cleavage of 1 with fragmentation to form dipeptide 3 (k2 = 3.3 X 10(-5) s-1), gamma-cleavage of 1 with ring opening to yield mercapto acid 4 (k3 = 0.35 X 10(-5) s-1), and hydrolysis of 2 with ring opening to give 4 (k4 = 1.9 X 10(-5) s-1). The isomerization rate ratio (k1/k-1 = 10.9) agreed with the isomer ratio at equilibrium (1:2 = 11 starting from 1 and 10 starting from 2). The alpha/gamma regioselectivity ratio (k2/k3 = 9.7) for hydrolysis of the internal Glp residue of 1 was consistent with results for model tripeptides. Part of the chemistry of the protein metastable binding sites can be explained by similar isomerization and hydrolysis reactions.

Bannucine ? a new dihydroindole alkaloid from Catharanthus roseus(L) G.Don

A new dihydroindole alkaloid, ‘bannucine,’ has been isolated from the leaves of Catharanthus roseus(L) G.Don, and has been found to have a five-membered lactam ring attached to the vindoline moiety.

Photochemistry of chloroacetanilide derivatives: rearrangement, cyclization, and solvolysis

N-Chloroacetylamines on photolysis in methanol, rearrange to give N-substituted glycine esters and methyl esters. Conditions have been established for the formation of a five-membered lactam system by cyclization. A dual mechanism is shown to be operative in the photolysis of the chloroacetamide function in polar and non-polar solvents, giving solvolytic and hydrogen-abstracted products respectively.

Pummerer reaction intermediate as an initiating function for cationic olefin cyclization

Treatment of N-(2-methyl-2-propenyl)-N-methyl-α-(methylsulfinyl)acetamide ( 6a ) with trifluoroacetic anhydride caused the cationic olefin cyclization through a Pummerer reaction intermediate to give the six-membered lactams 7 and 8 . Similar reaction converted N-2-butenyl-N-methyl-a-(methylsulfinyl)acetamide ( 6b ) to the five-membered lactam 9 , and N-2-propenyl-N-methyl-α-(methylsulfinyl)- acetamide ( 6c ) to the five-membered lactams 11 and 12 .

Photochemical synthesis of 1,2,3,4-tetrahydroisoquinolin-3-ones and oxindoles from N-chloroacetyl derivatives of benzylamines and anilines. Role of intramolecular exciplex formation and cis conformation of amide bonds.

Although N-chloroacetyl derivatives of benzylamines (2, 8) and anilines (21, 25, 29) disappeared quite rapidly when irradiated with a high pressure mercury lamp, no photocyclization to six- and five-membered lactams occurred. Measurements of fluorescence quenching and disappearance quantum yields of N-chloroacetyl-(3, 4-dimethoxylphenyl)-alkylamines having various lengths of alkyl chain revealed that the shorter the alkyl chain is, the more efficient the exciplex formation is. Therefore, the failure of photocyclization seemed to be due to trans conformation of amide bonds in the benzylamine and aniline derivatives. Introduction of an alkyl group on the amide nitrogen changed the stable conformation of amides from trans to cis, and hence N-alkyl-N-chloroacetylbenzylamines (11, 13, 15, 17, 19) readily gave the corresponding 1, 2, 3, 4-tetrahydroisoquinolin-3-ones (12, 14, 16, 18, 20) on irradiation. Oxindoles (36, 38, 40, 41, 43, 46) were similarly synthesized by photocyclization of N-alkyl-N-chloroacetylanilines (35, 37, 39, 42, 45).