A Flexible Approach to Grandisine Alkaloids: Total Synthesis of Grandisines B, D, and F

Abstract

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human delta-opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4-addition of ammonia to 9. Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita-Baylis-Hillman (MBH) reaction via the N-acyl iminium ion.

Intramolecular Baylis-Hillman reaction: synthesis of heterocyclic molecules

“…Intramolecular BH reactions of molecule 80 having an α,β-unsaturated aldehyde-iminium ion system has been employed by Tamura and co-workers for synthesis of the natural products/biologically active molecules grandisines B, D and F (81, 82 and 83) according to the sequence shown in Scheme 24. 52,53 The required α,β-unsaturated aldehyde-iminium ion system 80 was prepared from easily accessible pyrrolidin-2-one derivative 79 (Scheme 24). Webber and Krische 54 have elegantly used intramolecular BH-reaction as the key step in formal synthesis of (±)-quinine (Scheme 25 -Path A).…”

A Versatile Enantioselective Synthesis of Azabicyclic Ring Systems: A Concise Total Synthesis of (+)‐Grandisine D and Unnatural Analogues

“…Grandisine D (41) was previously synthesized by Tamura and co-workers in 18 steps (12.5 % overall yield) employing a Brønsted acid-mediated Morita-Baylis-Hillman ring-closure reaction as the key step; however, two steps suffered from poor stereocontrol. [26] Tamura was also able to convert 41 into grandisine B (38) through a tandem imination/amination reaction sequence. [26] Two years later, Taylor and co-workers improved on the synthesis of 41, requiring only 13 steps (10 % overall yield) from commercial starting materials, and featuring a new alkyne-acetal cyclization reaction.…”

“…[26] Tamura was also able to convert 41 into grandisine B (38) through a tandem imination/amination reaction sequence. [26] Two years later, Taylor and co-workers improved on the synthesis of 41, requiring only 13 steps (10 % overall yield) from commercial starting materials, and featuring a new alkyne-acetal cyclization reaction. [27] Our retrosynthesis led to the same key aldol chemistry as that employed by Tamura and Taylor, [26,27] but a fundamentally new approach to the indolizidine core (Scheme 7).…”

“…[26] Two years later, Taylor and co-workers improved on the synthesis of 41, requiring only 13 steps (10 % overall yield) from commercial starting materials, and featuring a new alkyne-acetal cyclization reaction. [27] Our retrosynthesis led to the same key aldol chemistry as that employed by Tamura and Taylor, [26,27] but a fundamentally new approach to the indolizidine core (Scheme 7). [28] Thus, 41 would be accessed by an aldol reaction between 8formylindolizidine 45 and known (S)-5-methylcyclohexanone 44.…”

“…Our synthetic 41 was in complete agreement with the reported spectral and rotation data for the natural product [24] as well as the previous synthetic efforts. [26,27] Thus, the total synthesis of grandisine D (41), employing our azabicyclic methodology, required only 11 steps from commercial starting materials in 16.4 % overall yield and with excellent stereocontrol throughout. Notably, based on the work of both Tamura [26] and Taylor, [27] the total synthesis of (+)-grandisine (41) also constitutes a formal total synthesis of (À)-grandisine B (38).…”