Strategies towards the synthesis of calyciphylline A-type Daphniphyllum alkaloids

Abstract

The Daphniphyllum alkaloids are a diverse family of natural products rich in number and structural diversity that have been known for many decades. However, the structurally unique subclass of calyciphylline A-type alkaloids has only recently been discovered and is relatively unexplored. Several noteworthy core syntheses and the development of a wide range of novel synthetic strategies have been achieved. This includes strategies based on intramolecular Michael addition, Pd-catalysis, cycloaddition, and Mannich-type reactions. This review will provide an overview of these synthetic studies.

Synthesis of Azabicyclic Building Blocks for Daphniphyllum Alkaloid Intermediates Featuring N‐Trichloroacetyl Enamide 5‐endo‐trig Radical Cyclizations

“…The organic extract was dried, concentrated, and purified by chromatography (hexane/AcOEt, 99 : 1!75 : 25) to give β-keto ester 1d (1.3 g, 5.3 mmol, 84 %) as a yellow oil. 1 3 ). 13 C-NMR (100 MHz, CDCl 3 ): 207.9 (C(1)); 172.5 (CO 2 Et); 109.4 (C(5)); 64.5 and 64.3 (OCH 2 ); 61.4 (OCH 2 ); 58.7 (C(2)); 37.0 (C(7)); 36.5 (C(4)); 34.1 (C(3)); 29.3 (C(6)); 14.0 (CH 3 C(1)); 172.9 (CO 2 Et); 109.4 (C(5)); 64.5 and 64.3 (OCH 2 ); 61.2 (OCH 2 ); 58.8 (C(2)); 36.4 (C(7)); 34.3 (C(4)); 33.9 (C(3)); 30.2 (C (6) Benzyl-2,2,2-trichloro-N-(9-methyl-1,4-dioxa…”

“…After cooling to room temperature, the mixture was filtered by passage through a plug of Na 2 SO 4 with benzene and concentrated to give the corresponding enamido ester 1d' (683 mg, quantitative yield) as a yellow solid. 1 To a solution of 1d' (682 mg, 2.9 mmol) in CH 2 Cl 2 (8 mL) containing Et 3 N (800 μl, 5.8 mmol), was added dropwise Cl 3 CCOCl (640 μl, 5.8 mmol) in CH 2 Cl 2 (1.8 ml) at 0°C. After heating at reflux temperature for 24 h, the mixture was concentrated, redissolved in CH 2 Cl 2 , and washed with aqueous 1 N HCl, and brine.…”

“…The organic extract was dried, concentrated, and purified by chromatography (hexane/AcOEt, 97.5 : 2.5!50 : 50) to give 2d (741 mg, 55 %) as a yellow oil. 1 1,2,3,4,5,7-hexahydro-3aH-spiro[cyclohepta[b]pyrrole-6,2'-[1,3]dioxolane]-3a-carboxylate (5d). To a solution of 3d (31 mg, 0.08 mmol) in THF (0.3 ml) was added a solution of LDA (1 M in THF, 150 μl, 0.13 mmol) dropwise at À 78°C.…”

“…The organic extracts were dried, filtered through a silica gel pad, concentrated, and purified by chromatography (hexane to hexane/AcOEt 1 : 1) to give 5d (16 mg, 47 %, brsm = 73 %) as a mixture of diastereomers (5 : 3) and as an oil. For the major epimer: 1 (7). To a solution of 5a (125 mg, 0.36 mmol) in Et 2 O/H 2 O (3 : 4, 2.5 ml) at room temperature was added NaIO 4 (235 mg, 3.0 equiv.)…”

Total Synthesis of (−)‐Daphenylline

“…[1] These Daphniphyllum alkaloids show structural diversity and are classified into 14 structural types based on their characteristic ring systems.Daphenylline (1), isolated from the fruit of D. longeracemosum by Hao and co-workers in 2009, is the first member of the Daphniphyllum alkaloids that contains ab enzene ring in the core structure ( Figure 1). [2] Daphenylline includes ar earranged 22-norcalyciphylline At ype skeleton, [3] the highly fused hexacyclic system of which has attracted significant attention in the chemical community.W hile several synthetic studies have been reported to date, [4,5] Li and co-workers recently accomplished the first total synthesis of (À)-daphenylline.…”