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S-Substituted N-(thioalkyl)phthalimides 2 underwent photocyclization to give azathiacyclols, up to 16-membered ring compounds, in good yields. The cyclization occurred between an imide carbonyl group and a terminal sulfide group located in a remote position from the carbonyl group. The quantum yield of cyclization was determined as 0.042 (acetonitrile) for N-(5-methylthiopentyl)phthalimide (2a) and the efficiency of remote cyclization was not significantly affected by the chain length examined. Quenching studies of 2a using isoprene or 1,3-cyclohexadiene showed linear Stern-Volmer plots with the slopes of kqτ = 340 M−1 or 630 M−1, respectively. The effective concentration (Ceff) of photocyclization was estimated within the limits of 0.01 M < Ceff < 0.1 M for 2a from a competition experiment with the intermolecular photoaddition of dimethyl sulfide. The efficient cyclophilic nature of remote photocyclization can be rationalized by an enhanced proton transfer from the sulfide group which is possibly located close to the carbonyl group to form a radical ion pair complex by an electron transfer process.

Treatment of 16 α-amino acid esters with isoamyl nitrite in the presence of a small amount of organic acid in chloroform or benzene, followed by chromatographic purification on alumina was found to afford the corresponding α-substituted-α-diazo esters ( 1 ) in fairly good yields.

A new stereoselective synthesis of methyl α-L-amicetoside (11), methyl α-L-mycaminoside (14) and methyl α-L-oleandroside (17) starting from L-alanine is described. It is shown that methyl 2, 3, 6-trideoxy-α-L-hex-2-enopyranosid-4-ulose (8) is readily accessible from L-alanine in optically pure state and is a potential intermediate for the synthesis of various kinds of 6-deoxy-L-hexoses.

The synthesis and adrenergic activity of the stereoisomeric aryl-substituted 1-aminotetralins (3, 4, and 7) and 1-aminoindans (5 and 6), rigid structures related to the benzylamine derivatives (2), are presented. Among this series of compounds tested, trans-5, 6-dihydroxy-1-methylamino-2-(3, 4, 5-trimethoxyphenyl)-1, 2, 3, 4-tetrahydronaphthalene (3b) was the most active tracheal relaxing compound, which was approximately ten times as active as the corresponding cis isomer (4b) and about two times as active as 2b. The structure-activity relationship in this series is discussed.

For a total synthesis of the optically active carene congeners from optically active α-amino acids, several attempts were made on intramolecular cyclization of 2-cyclohexenyl esters of α-substituted α-diazoacetic acid (III) which were derived from the corresponding amino acid esters. One of the optically active diastereoisomers (X) which was obtained by separation of 2-cyclohexenyl L-alaninate was diazotized with isoamylnitrite and then cyclized using Cu powder as a catalyst to afford the optically active lactone (XIX). XIX was then converted into the key intermediate (XXI) having the bicyclo[4, 1, 0]heptane ring system, from which (+)-2-carene was synthesized.

α-Diazo-β-phenyl-propionic acid esters (II) prepared from the phenylalanine derivatives (I) were readily decomposed by the alkoxide in tetrahydrofuran to give trans-cinnamic acid esters (III) stereoselectively, while the decomposition of II in the presence of boron trifluoride etherate and dicyclohexylcarbodiimide in methylene chloride afforded ciscinnamic acid esters (IV) as sole reaction products.

4-Phenyl-3-butenyl-and 5-phenyl-4-pentenyl-amine were acylated with chloride of methyl hydrogen succinate, glutarate and adipate yielding six kinds of ester amide (VIIa, b, c, d, e, f), all of which except (VIId) were cyclized with ease on being treated with POCl3 in boiling benzene, giving three pyrrolines (VIIIa, b, c) and two hydropyridines (VIIIe, f). These were reduced and each were converted into the corresponding lactams (Xa, b, c, e, f), from which benzylidene group was removed by ozonization furnishing 5 kinds of title compounds (XIa, b, c, e, f). Their structures were supported by converting one (XIe) of them to the known 1-quinolizidinone, which was identified with the authentic specimen.

A new synthesis of rac-nicotine was described. For this end the removal of the benzylidene group of 2-substituted 3-benzylidene-1-pyrroline prepared by Sugasawa and Ushioda was first examined. For the best effect, the starting materials ((I) : 2-methyl ; (IXa) : 2-phenyl) were reduced by sodium borohydride and the reduction products were acylated to yield ((IIIa) : 1-acetyl-2-methyl ; (IIIb) : 1-benzoyl-2-methyl ; (XIIa) : 1-benzoyl-2-phenyl). These were cleaved via the corresponding ozonides to yield 3-pyrrolidinones, which were characterized appropriately. This method was successfully extended to 2-(3-pyridyl)-3-benzylidene-1-pyrroline to afford 1-benzoyl-2-(3-pyridyl)-3-pyrrolidinone, whose tosylhydrazone was converted into 1-benzoyl-2-(3-pyridyl)-3-pyrroline according to the method of Bamford and Stevens. The latter was reduced catalytically to rac-nornicotine, from which rac-nicotine was obtained smoothly by Eschweiler-Clark's method.

N, S-Bis-tert-butoxycarbonyl-L-cysteine (I), a novel protected cysteine derivative, is proposed for glutathione synthesis. I was obtained in one step reaction from L-cysteine and tert-butoxycarbonyl chloride. The reaction of tert-butoxycarbonyl azide with L-cysteine also gave I but in low yield. The protecting groups on the nitrogen and sulfur atoms of I are stable under the usual conditions used in peptide synthesis and can be removed selectively by mild acidic or alkaline conditions. These groups are also removed simultaniously by a strong acidic reagent such as hydrogen chloride of high concentration in acetic acid. Synthesis of glutathione was performed employing I as a new type of intermediate.

A new stereoselective synthesis of methyl α-L-amicetoside (11), methyl α-L-mycaminoside (14) and methyl α-L-oleandroside (17) starting from L-alanine is described. It is shown that methyl 2, 3, 6-trideoxy-α-L-hex-2-enopyranosid-4-ulose (8) is readily accessible from L-alanine in optically pure state and is a potential intermediate for the synthesis of various kinds of 6-deoxy-L-hexoses.

Pyroglutamylhistidyltryptophyl-(O-Bzl) seryl-(O-Bzl) tyrosylglycylleucyl-(NG-nitro)-arginylprolylglycinamide was synthesized by successive fragment condensations of three peptide derivatives, pGlu-His-NHNH2, Boc-Trp-(O-Bzl) Ser-(O-Bzl) Tyr-Gly-NHNH2 and Boc-Leu-(NG-nitro) Arg-Pro-Gly-NH2 ; the latter two were prepared by the modified solid phase method using bromoacetylpolystyrene resin as carrier. Removal of all the protecting groups from the decapeptide derivative was easily effected by hydrogenolysis over a new type of catalyst, colloidal palladium on PVP. Thus the present reduction method made the large scale production of the peptide quite easy.

Pyroglutamylhistidyltryptophyl-(O-Bzl) seryl-(O-Bzl) tyrosylglycylleucyl-(NG-nitro)-arginylprolylglycinamide was synthesized by successive fragment condensations of three peptide derivatives, pGlu-His-NHNH2, Boc-Trp-(O-Bzl) Ser-(O-Bzl) Tyr-Gly-NHNH2 and Boc-Leu-(NG-nitro) Arg-Pro-Gly-NH2 ; the latter two were prepared by the modified solid phase method using bromoacetylpolystyrene resin as carrier. Removal of all the protecting groups from the decapeptide derivative was easily effected by hydrogenolysis over a new type of catalyst, colloidal palladium on PVP. Thus the present reduction method made the large scale production of the peptide quite easy.

RENIN is said to split a leucyl–leucine bond in alpha 2 globulin substrate—angiotensinogen—to yield a decapeptide, angiotensin I. Angiotensin I is subsequently converted into an octapeptide, angiotensin II, by a converting enzyme contained in plasma. Angiotensin II has a pressor activity. We have studied the effects of synthetic peptides with a leucyl–leucine bond and their derivatives on the activity of renin in the formation of angiotensin. The peptides were di-, tri-, tetra- and pentapeptides with leucyl–leucine bonds at the C-terminal end, in the middle position, at the N-terminal end or with one of the other structures as shown in Table 1.