88931-13-9

Upstream product

• 88909-11-9 (R,S)-1-(4-chlorobutyl)-5-methyl-4-phenyl-1,5-diazacyclooctan-2-one 
• 88931-12-8 (R,S)-5-methyl-4-phenyl-1,5-diazacyclooctan-2-one 
• 110-52-1 1,4-dibromo-butane 
• 32975-62-5 (S)-(+)-5-methyl-4-phenyl-1,5-diazacyclooctan-2-one 
• 173398-08-8 (R)-(-)-5-methyl-4-phenyl-1,5-diazacyclooctan-2-one 
• 31925-54-9 (R,S)-N-(2-cyanoethyl)-N-methyl-β-phenyl-β-alanine 
• 88931-10-6 (R,S)-N-(2-aminopropyl)-N-methyl-β-phenyl-β-alanine 
• 50-00-0 formaldehyd 
• 88931-11-7 (S)-(-)-4-phenyl-1,5-diazacyclooctan-2-one 
• 1356849-82-5 methyl (S)-3-[N-(3'-chloropropyl)-N-methylamino]-3-phenylpropanoate 
• 1356849-83-6 methyl (S)-3-[N-(3'-azidopropyl)-N-methylamino]-3-phenylpropanoate 
• 1356849-84-7 C₁₄H₂₂N₂O₂ 
• 1356849-80-3 methyl (3S,αR)-3-[N-( 3'-chloropropyl)-N-(α-methyl-4''-methoxybenzyl)amino]-3-phenylpropanoate 
• 1356849-81-4 methyl (S)-3-(3'-chloropropylamino)-3-phenylpropanoate 

Relevant academic research and scientific papers

Asymmetric syntheses of the homalium alkaloids (-)-(S, S)-homaline and (-)-(R, R)-hopromine

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R)-hopromine. The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (-)-(R,R)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4′R,4′′S)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (-)-(R,R)-hopromine.

Asymmetric synthesis of (-)-(S,S)-homaline

The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybe

Total syntheses of the spermine alkaloids (-)-(R,R)-hopromine and (±)-homaline

The diastereoselective synthesis of the spermine alkaloid (R,R)-hopromine (2) is described. The as yet unknown absolute configuration of naturally occurring (-)-hopromine (2) is (R,R) and was established by comparison of the reported specific rotation of the natural product with that of the synthetic one. Preparation of the characteristic bis-8-membered lactam scaffold was carried out by convergent build-up of basic chiral azalactam units 21a and 21b and subsequent iterative linking (Schemes 5 and 6). Key steps in the analogous syntheses of 4-alkyl-hexahydro-1,5-diazocin-2(1H)-ones 21a and 21b were the introduction of the unbranched alkyl side chains into their common precursor 14 via cuprate reaction and the Sb(OEt)3-assisted cyclization of the open-chain intermediates 20a and 20b, respectively (Schemes 3 and 4). The chiral iodoester 14 was prepared from commercially available (+)-L-aspartic acid (12). Based on the synthetic strategy developed for (R,R)-hopromine (2), a rapid access to the parent alkaloid homaline (1) in its (±)-form is given.

Asymmetric synthesis of 4-phenyl-1,5-diazacyclooctan-2-one using optically active vinyl sulfoxides

Both enantiomers of (S)- and (R)-4-phenyl-1,5-diazacyclooctan-2-ones (7) were synthesized stereoselectively with good optical purity by the asymmetric conjugate addition of pyrazolidine to optically active vinyl sulfoxides, t-butyl (E)-2-[(R)- and (S)-p-tolylsulfinyl]cinnamates, respectively. Starting from 7, a synthesis of optically active homaline was achieved.

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.

NEW APPROACHES TO THE SYNTHESIS OF SPERMINE AND SPERMIDINE ALKALOIDS

New approaches to the formation of macrocyclic lactams are described involving successive ring expansion of 8-lactams and other heterocyclic systems.These methods have been used in the synthesis of a number of spermine and spermidine alkaloids including homaline, celacinnine, dihydroperiphylline, chaenorhine and verbascenine.

THE USE OF β-LACTAMS IN THE SYNTHESIS OF SPERMINE AND SPERMIDINE ALKALOIDS. TOTAL SYNTHESIS OF HOMALINE

The optically active plant product homaline (6) has been synthesized in a convergent sequence starting with β-phenyl-β-alanine and putrescine (14).The key transformation in this sequence is the ring expansion by transamidation of a functionalized chiral β-lactam precursor.

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