Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane Using a 5-exo-trig Radical Cyclization Reaction to Assemble the C3a-Arylated Perhydroindole Substructure

Abstract

Crinane embodies the tetracyclic framework associated with some of the most common Amaryllidaceae alkaloids. It has now been prepared in 10 steps from 6,6-dibromobicyclo[3.1.0]hexane (2). The initial step involves the thermally induced electrocyclic ring opening of cyclopropane 3 and capture of the resulting π-allyl cation with benzylamine to give an allylic amine that is readily elaborated to the 3°-amine 10. This last compound was engaged in a 5- exo- trig free radical cyclization reaction to give the C3a-arylated perhydroindole 11. Compound 11 was then converted, over two steps, into (±)-crinane, the hydrochloride salt of which has been subjected to single-crystal X-ray analysis.

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

“…Elaboration of simple derivatives of these using a range of protocols, most notably palladium-catalyzed intramolecular Alder-ene reactions, then allows for their conversion into either crinine or haemanthamine-type alkaloids. Given the broad synthetic utility of the electrocyclic ring-opening/nucleophilic trapping reactions of ring-fused gem -dihalocyclopropanes in the synthesis of biologically relevant motifs, the protocols defined here should find application in a wide range of settings, including for the purposes of establishing syntheses of enantiomerically pure forms of various erythrina and aeruginosin-type 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.…”

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids

“…42 Based on this protocol, the cis-3a-arylhydroindole derivatives 18a and 18h were obtained as a single diastereoisomer with excellent efficiency and enantioselectivity (93:7 e.r.). Subsequently, 18a was readily converted to the tetracyclic compound 19 through a Pictet−Spengler cyclization in the presence of paraformaldehyde and HCO 2 H. 43 While two regioisomers were detected in the crude 1 H NMR spectra of the reaction products, the major one (r.r. 6.7:1) was determined to be the desirable product 19.…”

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 …”