Masazumi Ikeda

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

Abstract Bu 3 SnH 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.

Asymmetric radical cyclization leading to β-lactams: Stereoselective synthesis of chiral key intermediates for carbapenem antibiotics PS-5 and thienamycin

Abstract A stereoselective synthesis of β-lactams by 4-exo-trig radical cyclizations of N-[2,2-bis(phenylthio)ethenyl]-α-bromo amides bearing a chiral inductor on the nitrogen atom has been examined. Bromide 8, upon treatment with Bu3SnH in the presence of AIBN in boiling benzene, gave a mixture of (4S)-2-azetidinone 12a and its (4R)-isomer 12b in a ratio of 71:29 and 69% combined yield. Similar treatment of α-bromobutanamide 11 with Bu3SnH afforded trans-(4S)-2-azetidinone 17a as the major product along with its (4R)-isomer 17b (70:30, 77% combined yield). Compound 17a was converted into 24, a chiral key intermediate in the synthesis of (+)-PS-5 (25). The cyclization of bromide 28 bearing an additional stereogenic center [(S)-oxygen functionality] at the side chain proceeded with much higher (4S)-stereoselectivity to give azetidinone 29a as the major product together with its (4R)-isomer 29b in a ratio of 78:22 and 40% combined yield. Compound 29a was converted, via an inversion of the oxygen functionality, into 37, a chiral key intermediate in the synthesis of (+)-thienamycin (38). A possible explanation for the observed diastereoselectivity in radical cyclizations is presented.

Effect of Temperature of 5-Endo- and 4-Exo-Trig Radical Cyclizations of N-Vinylic α-Halo Amides

Abstract The radical 3a generated from N -vinylic trichloroacetamide 1a provided the 5- endo-trig cyclization product 2a in boiling toluene, whereas, at room temperature, gave the 4- exo-trig cyclization product 9 . The results may be explained in terms of the reversibility of 4- exo cyclization.

Synthesis of podophyllotoxin derivatives by means of tributyltin hydride- or palladium-mediated cyclization of α-benzylidene-β-(o-bromobenzyl)-γ-lactones

Abstract Synthesis of podophyllotoxin derivatives based on an aryl radical cyclization of α-benzylidene-β-( o -bromobenzyl)-γ-lactones 20 and 21 has been examined. Treatment of a mixture of the alcohols 18a and 18b ( ca. 1:1), prepared from 6-bromopiperonal ( 10 ) in 7 steps, with methanesulfonyl chloride gave a ca. 3:1 mixture of the chlorides 19a and 19b , which was treated with DBU to give the ( Z )- and ( E )-α-benzylidene-γ-lactones 20 and 21 in 64 and 22% yields, respectively. Thermolysis of the mixture of the sulfoxides 23a and 23b , prepared from 18a,b , afforded the E -isomer 21 as a major product. The Z -benzylidenelactone 20 when treated with Bu 3 SnH in the presence of AlBN gave the 6- endo-trig radical cyclization product, (±)-deoxyisopicropodophyllin ( 24 ), and the 5- exo-trig cyclization product 25 in 29 and 49% yields, respectively. The E -isomer 21 , however, gave only the 5- exo cyclization product 25 . On the other hand, treatment of 20 with PdCl 2 (PPh 3 ) 3 gave (±)-γ-apopicropodophyllin ( 29 ) in 75% yield. Similar treatment of 21 afforded no cyclization product, but, in the presence of sodium formate (H − source), gave the 5- exo cyclization product 25 in 84% yield.

Total synthesis of (±)-cephalotaxine

A total synthesis of (±)-cephalotaxine has been achieved in a stereoselective manner by a synthetic sequence involving an acid-catalysed cyclisation of the α-sulphinylacetamide 12 as a key step.

A new, general entry to 4-substituted indoles. Synthesis of (S)-(−)-pindolol and (±)-chuangxinmycin

Abstract A new method for synthesis of 4-substituted indoles has been developed by using the 7-arylthio-6-7-dihydroindol-4(5H) one5 as a common intermediate. The method was applied to the synthesis of (S)-(−)-pindolol (11) and (±)-chuangxinmycin (16).

SULFUR-DIRECTED 5-EXO SELECTIVE ARYL RADICAL CYCLIZATION ONTO ENAMIDE : A SIMPLE ROUTE TO CHILENINE

Abstract Bu 3 SnH-mediated aryl radical cyclization of the N -( o -bromoaroyl)enamine 5 took place in a 5- exo - trig manner exclusively to give isoindolone 7, which was transformed into the key intermediate 11 for the synthesis of isoindolobenzazepine alkaloid chilenine (2).

Chemo- and stereoselective dirhodium(II)-catalyzed C-H insertion reaction of 5,6-dioxygenated 2-diazo-3-oxohexanoates: Synthesis of an optically active highly functionalized cyclopentane

Abstract Methyl (S)-α-diazo-2,2-dimethyl-β-oxo-1,3-dioxolane-2-butanoate (4), upon treatment with dirhodium(II) tetraacetate in refluxing dichloromethane, gave methyl (1S,5S)-2,2-dimethyl-7-oxo-3,8-dioxabicyclo[3.2.1]octane-1-carboxylate (5) via oxonium ylide formation/1,2-shift. On the other hand, a similar treatment of methyl (S)-5,6-bis[tert-butyldimethylsilyl(TBDMS)oxy]-2-diazo-3-oxohexanoate (9a) afforded the C-H insertion product 10 which was directly reduced with lithium aluminum hydride to give stereoselectively (1R,2R,3S,5R)-2,3-bis(TBDMSoxy)-5-hydroxycyclopentanemethanol (13) in 52% yield from 9a.

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.

Remarkable rate acceleration of the solvent-free Baeyer–Villiger reaction on the surface of NaHCO3 crystals for sterically congested cyclic and acyclic ketones

Abstract Baeyer–Villiger reactions of sterically crowded cyclic and acyclic ketones are remarkably accelerated by carrying out the reactions under solvent-free conditions in the presence of powdered NaHCO 3 . The corresponding lactones and esters have been obtained in excellent yields.