Diversity-Oriented Approach Toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon

Abstract

Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-)-maritidine, (-)-oxomaritidine, and (+)-mesembrane is reported. Scaffold 1 is found as a prime structural motif in a wide variety of the AAs and is a novel synthon toward designing a divergent route for the synthesis of these natural products. This is established in a few steps, starting from a chiral aza-bicyclo-heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective ring opening with allylmagnesium bromide, a key step that generates a crucial quaternary stereocenter, fixing the stereochemistry of the rest of the molecule at an early stage. One carbon truncation followed by intramolecular reductive amination led to the desired core 1 in a multigram scale.

Iron porphyrin-catalysed C(sp3)–H amination with alkyl azides for the synthesis of complex nitrogen-containing compounds

“…[52][53][54] As shown in Scheme 3, azide 6 underwent intramolecular unactivated C(sp 3 )-H amination to afford 7 in 95% yield, from which (±)-mesembrane could be obtained according to the reported procedure. 55…”

Chemoselective Strategy for the Direct Formation of Tetrahydro-2,5-methanobenzo[c]azepines or Azetotetrahydroisoquinolines via Regio- and Stereoselective Reactions

“…The construction of the 2,5-methanotetrahydro-2 H -2-benzazepine skeleton ( 2 ) has been achieved through only three main strategies: Pictet–Spengler reaction ,− or a ring closure of the pyrrolidine derivative, , an intramolecular [3 + 2]-cycloaddition, , and via intramolecular N -alkylation . Other special examples have also been reported like lactamization …”

Application of Electrocyclic Ring-Opening and Desymmetrizing Nucleophilic Trappings of meso-6,6-Dibromobicyclo[3.1.0]hexanes to Total Syntheses of Crinine and Haemanthamine Alkaloids

“…Such diverse properties have prompted extensive efforts to develop total syntheses of the crinane and haemanthamine alkaloids. A range of approaches has been devised over the past four to five decades. ,, A particularly effective strategy involves the formation of C3a-arylated perhydroindoles that embody the A-, C- and D-rings of the target framework 1 or ent - 1 . Subjecting these perhydroindoles to a Pictet–Spengler reaction then establishes the required B-ring and so completing the assembly of these alkaloids. , Two key challenges associated with implementing such protocols more broadly are (i) the limited capacities currently available for introducing functionality (oxygenation) at C11 within the ethano-bridge of alkaloids such as (+)- 4 , (+)- 5 , (+)- 6 , (−)- 7 , (+)- 8 and (+)- 9 and, (ii), the restrictions on generating such systems in enantiomerically pure form.…”