- 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.
- Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Stonehouse, Jeffrey P.,Thomson, James E.
-
p. 7028 - 7045
(2012/10/08)
-
- 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
- Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Stonehouse, Jeffrey P.,Thomson, James E.
-
p. 1119 - 1121
(2012/03/26)
-
- 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.
- Ensch, Corinne,Hesse, Manfred
-
p. 1659 - 1673
(2007/10/03)
-
- 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.
- Itoh,Matsuyama,Yoshida,Kamigata,Iyoda
-
p. 3121 - 3130
(2007/10/03)
-
- 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.
- Crombie, Leslie,Haigh, David,Jones, Raymond C. F.,Mat-Zin, Ab. Rasid
-
p. 2055 - 2068
(2007/10/02)
-
- 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.
- Crombie, Leslie,Haigh, David,Jones, Raymond C. F.,Mat-Zin, Ab. Rasid
-
p. 2047 - 2054
(2007/10/02)
-
- 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.
- Crombie, Leslie,Jones, Raymond C. F.,Haigh, David
-
p. 5147 - 5150
(2007/10/02)
-
- 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.
- Wasserman, Harry H.,Robinson, Ralph P.
-
p. 279 - 288
(2007/10/02)
-
- 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
- Crombie, Leslie,Jones, Raymond C. F.,Mat-Zin, Ab. Rasid,Osborne, Steven
-
p. 960 - 961
(2007/10/02)
-
- 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.
- Wasserman, Harry H.,Berger, Gregory D.
-
p. 2459 - 2464
(2007/10/02)
-
- TRANSAMIDATION REACTIONS USING β-LACTAMS. THE SYNTHESIS OF HOMALINE
-
The synthesis of the plant product, homaline, by a translactamization process involving the β-lactam, (-)-4-phenyl-2-azetidinone, is described.
- Wasserman, Harry H.,Berger, Gregory D.,Cho, Kathleen R.
-
p. 465 - 468
(2007/10/02)
-