88931-12-8

Upstream product

• 88931-10-6 (R,S)-N-(2-aminopropyl)-N-methyl-β-phenyl-β-alanine 
• 50-00-0 formaldehyd 
• 88909-10-8 (R,S)-4-phenyl-1,5-diazacyclooctan-2-one 
• 100-42-5 styrene 
• 76497-43-3 (R,S)-N-methyl-β-phenyl-β-alanine 
• 31925-54-9 (R,S)-N-(2-cyanoethyl)-N-methyl-β-phenyl-β-alanine 
• 88909-09-5 N-(3-chloropropyl)-4-phenylazetidin-2-one 
• 5661-55-2 4-phenylazetidin-2-one 

Downstream Products

• 88931-14-0 epi-Homaline 
• 109742-24-7 1-<(Z)-4-chlorobut-2-enyl>-5-methyl-4-phenyl-1,5-diazacyclooctan-2-one 
• 20410-93-9 1,1'-(butane-1,4-diyl)bis[hexahydro-5-methyl-4-phenyl-1,5-diazocin-2(1H)-one] 
• 109742-27-0 (Z)-1,4-bis-(5-methyl-2-oxo-4-phenyl-1,5-diazacyclooctanyl)but-2-ene 
• 49620-05-5 hopromalinol 

Relevant academic research and scientific papers

Synthesis of the Alkaloid Homaline in (+/-) and Natural (S,S)-(-) Forms, using Amination and Transamidative Ring Expansion in Liquid Ammonia

Synthesis of the alkaloid homaline in (+/-) and natural (S,S)-(-) forms is reported.Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examined. (+/-)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclisation, and then by amination and transamidative ring expansion from N-(3-chloropropyl)-4-phenylazetidin-2-one in liquid ammonia, followed by N-methylation.Coupling through a 1,4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (+/-) and meso forms. (R)-(-)-Phenylglycine was converted via (S)-β-phenyl-β-alanine into an (S)-β-lactam which was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liquid ammonia.Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S)-(-)-homaline identical with the natural material.

Synthesis of the Alkaloids Hopromine, Hoprominol and Hopromalinol, using Transamidation Methods

Synthesis of the unsymmetrical Homalium alkaloids hopromine, hoprominol and hopromalinol, in diastereoisomeric mixture form, is reported.The component eight-membered azalactams are first prepared.N-(3-Halogenopropyl)-4-pentyl- and -4-heptyl-azetidin-2-ones are aminated and ring expanded in liquid ammonia to give, after reductive methylation, the corresponding 4-alkyl-5-methyl-1,5-diazacyclooctan-2-ones.Synthesis of the 4-(2-hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl β-lactam ring expansion to the eight-membered 4-allylazalactam, followed by methylation, epoxidation and epoxide opening with lithium dibutylcuprate.A similar epoxidation-cuprate sequence was carried out on the epoxypropyl β-lactam, as its N-tert-butyldimethylsilyl derivative, and led to a convenient copper-catalysed N- to O-migration of the protection; this migration is examined.Alkylation gave O-TBDMS-protected N-(3-chloropropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and transamidated in excellent yield, to give, after methylation, a superior sequence to the required eight-membered hydroxy azalactam.Although satisfactory for attachment of the first azalactam unit, a dibromobutane coupling system proved unreactive for the second.Couplings with unmethylated, methylated, and benzyloxycarbonyl-protected azalactams were examined using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as the bridging unit.Employing the latter, coupling the first N-methylated azalactam with potassium bis(trimethylsilyl)amide as the base, and then the second with bis(trimethylsilyl)amide-sodium hydride as the base system, provided a satisfactory synthetic outcome.Hydrogenation under acidic conditions gave the unsymmetrical structures hopromine, hoprominol and hopromalinol, as well as the more simple and symmetrical alkaloid, homaline.

SYNTHESIS OF UNSYMMETRICAL SPERMINE ALKALOIDS OF THE HOMALIUM GROUP

Spermine alkaloids homaline, hopromalinol, hopromine, and hoprominol are prepared by sequential coupling of 4-substituted 5-methyl-1,5-diazacyclooctan-2-ones, available by transamidation from 4-substituted azetidin-2-ones, to 1,4-dichlorobut-2-ene.

Synthesis of Homaline and epi-Homaline

5-Methyl-4-phenyl-1,5-diazacyclo-octan-2-one has been prepared by cyclisation of an acyclic precursor or by transamidation from 4-phenylazetidin-2-one, and converted into natural (-)-homaline and epi-homaline: the approach is applicable to the synthesis o