Total Syntheses of the Spermine Alkaloids (−)-(R,R)-Hopromine and (±)-Homaline

Abstract

The diastereoselective synthesis of the spermine alkaloid (R,R)-hopromine (2) is described. The as yet unknown absolute configuration of naturally occurring (À)-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 (AE)-form is given.

Polyamine alkaloids

“…One of the first plants to be investigated for polyamine alkaloids, was Homalium pronyense back in 1968. 53 However, the absolute configuration of (−)-(R,R)-hopromine, one of its major alkaloids, has only been established recently by an enantioselective synthesis by Ensch et al 54 This enantiospecific synthesis of hopromine not only provided the nature-identical alkaloid, but gave, via the chiral non-racemic intermediate 11, stereoselective access to a range of other cyclic polyamine alkaloids, such as the budmunchiamines. 51 The enantiospecific preparation of (−)-(R,R)-hopromine started from enantiomerically pure L-aspartic acid (9, Scheme 2).…”

“…Using the same strategy, namely preparation of the parent eight-membered lactams and interconnection of two appropriate lactam moieties through a butylene portion, led to (±)-homaline 54 and to an enantiomerically pure hoprominol derivative. 57…”

Modular Synthesis of Functionalisable Alkoxy‐Tethered N‐Heterocyclic Carbene Ligands and an Active Catalyst for Buchwald–Hartwig Aminations

“…Other than solvents, reagents obtained from commercial sources were used without further purification. tert ‐Butyl (3‐iodopropyl)carbamate 11 ,34 Pd(acac) 2 ,35 (3‐chloropyridin‐2‐yl) 2 PdCl 2 ,36 IPr⋅HCl37 and IPr(3‐Clpy)PdCl 2 20 2d were prepared according to literature procedures. Characterisation data for B‐H reaction products and spectra for all compounds reported are presented in the Supporting Information.…”

“…tert-Butyl (3-iodopropyl)carbamate 11, [34] PdA C H T U N G T R E N N U N G (acac) 2 , [35] (3-chloropyridin-2-yl) 2 PdCl 2 , [36] IPr·HCl [37] and IPrA C H T U N G T R E N N U N G (3-Clpy)PdCl 2 20 [2d] were prepared according to literature procedures. Where stirring of the reaction mixture is indicated, magnetic stirring using a Teflon-coated stir bar was employed throughout.…”

Facile assembly of 1,5-diazocan-2-ones via cyclization of tethered sulfonamides to cyclopropenes

“…5,6 It is known that medium-sized 8-membered rings are difficult to assemble via conventional methods of cyclization, 7 largely due to the enthalpic cost incurred in the transition state as well as the decreased entropy of the cyclic products relative to their linear precursors. 8 Several alternative synthetic approaches to the eight-membered 1,5-diazocin-2-one core have been developed, including Beckman rearrangement, 9 fragmentation of 1,5-diazabicyclo[3.3.1]nonan-2-ones, 10 reductive N-N scission of tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-ones, [11][12][13][14] as well as various ring closures, exploiting intramolecular versions of reductive amination, [15][16][17][18] amine acylation, 7,[19][20][21][22] strain release-driven transamidation, [23][24][25] and S N Ar reactions. 26 Herein, we disclose a new application of metal-templated intramolecular 8-exo-trig cyclization involving nucleophilic addition of sulfonamides tethered to a cyclopropene moiety.…”