Total Synthesis of Grandisine D

Abstract

Total synthesis of grandisine D (5) was achieved by a Brønsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for the construction of the aza-fused bicyclic systems of pyrrolizidine and stemona alkaloids.

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

“…5, 170.3, 135.0, 116.9, 93.0, 70.5, 63.6, 39.7, 35.6, 32.2, 20.9, 15.2 9, 170.7, 134.9, 117.2, 88.2, 67.7, 65.4, 39.9, 34.5, 32.1, 20.7, 15.5 193.6, 172.7, 170.3, 154.0, 134.6, 93.4, 70.2, 63.7, 39.1, 35.5, 31.4, 20.9, 15.2 (3.26 mL) was stirred at room temperature for 2 h. After concentration, the crude product was purified by column chromatography on silica gel (hexane/ AcOEt 1:2) to afford aldehyde 11 as a brown oil (245 mg, 73 %). N N U N G (1S,8aR) 2,3,5,6, and (1S,8aS)-8-formyl-3-oxo- 1,2,3,5,6,8a-hexahydroindolizin-1yl acetate (cis-14): Me 2 S (1.64 mL, 22.3 mmol) and TfOH (3.29 mL, 37.1 mmol) were added to a solution of aldehyde 11 (4.00 g, 14.9 mmol) in CH 3 CN (75 mL) at À35 8C. The resulting mixture was allowed to warm to room temperature and stirring was continued for 2 h. The reaction was quenched with saturated aqueous NaHCO 3 (70 mL).…”

“…When BF 3 ·OEt 2 instead of TMSOTf was used, the stereo-A C H T U N G T R E N N U N G selectivity was slightly lowered (entry 5). After experimentation, the use of a Brønsted acid, such as Tf 2 NH or TfOH, was found to give a good yield with high stereoselectivity (entries [6][7][8]. In place of Me 2 S, the use of Ph 3 P or nBu 3 P as a nucleophile was not successful (entries 9-10).…”

“…It features three contiguous stereocenters, of which C-7 and C-8 are trans with respect to C-9, in the indolizidine moiety, as do grandisines C (3) and E (6). [3b] Inspired by the proposed biogenetic pathway, [3a] we envisaged synthesis of grandisines B (2) and F (4) via grandisine D (5), and describe herein the first total synthesis of 2, 4, and 5 [6] from the common key intermediate 9, which is closely related to 5 (Scheme 1). The synthesis of 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).…”

Biomimetic Synthesis of Ornithine/Arginine and Lysine‐Derived Alkaloids: Selected Examples

“…These complex structures also stimulated state of the art total syntheses[54]. Pictet-Spengler reaction under catalytic hydrogenation conditions.…”