Synthesis of the Right‐Side Structure of Type B Physalins

Abstract

We present a full account of our synthetic studies on the racemic DEFGH‐ring moiety of physalins, featuring domino ring transformation of a tricyclic key intermediate. We also report the results of a detailed mechanistic examination of the domino ring transformation, as well as a reoptimization of the 2,3‐Wittig rearrangement and methylation steps. Furthermore, we have newly established a method for the preparation of an optically active synthetic intermediate by enzymatic kinetic resolution. Our work provides access to both natural and nonnatural right‐side physalin structures.

Cytotoxic Physalins from Aeroponically Grown Physalis acutifolia

“…The HRESIMS and NMR data of 4 and 5 provided the molecular formula C 28 H 32 O 14 S, indicating 13 degrees of unsaturation. The 1 H NMR spectrum exhibited signals typical of a mixture of two physalin-type withanolides and contained those due to six methyl groups [δ H 1.90 (3H, s), 1.89 (3H, s), 1.56 (3H, s), 1.21 (3H, s), and 0.93 (6H, s)], H 2 -27 of the C-25(27) exocyclic methylene moiety [δ H 6.53 (1H, brs) and 5.68 (1H, brs)], and oxymethylene protons [δ H 4.40 (1H, dd, J = 13.5, 4.6 Hz) and 3.70 (1H, d, J = 13.5 Hz)], suggesting some similarities between this mixture and the known interconvertible forms of physalin F ( 8 ) . The 13 C NMR spectrum of the mixture of 4 and 5 assigned with the help of HSQC data revealed 56 carbons including typical signals for four ketone carbonyls (δ C 213.6, 212.0, 211.7, and 209.5), four lactone carbonyls (δ C 174.3, 173.8, 170.2, and 165.0), and six methyls (δ C 27.9, 25.9, 22.4, 21.6, 11.0, and 10.7).…”

Synthesis of DFGH-Ring Derivatives of Physalins via One-Pot Construction of GH-Ring and Evaluation of Their NF-κB-Inhibitory Activity

“…We tried coupling the adamantyl alkyl group with 6 , but all attempts failed. Thus, we commenced the synthesis of 5d from bicyclic enone 15 , (see Scheme A) and investigated the direct addition of the 4-(1-adamantyl)-1-butyne unit 16 to enone 15 . In the previous synthesis, the addition of lithium TMS-acetylide in the presence of CeCl 3 proceeded in high yield (for the synthesis of 6 ). , However, no reaction occurred with the corresponding acetylide generated from 16 , and the starting material was quantitatively recovered.…”

“…Thus, we commenced the synthesis of 5d from bicyclic enone 15 , (see Scheme A) and investigated the direct addition of the 4-(1-adamantyl)-1-butyne unit 16 to enone 15 . In the previous synthesis, the addition of lithium TMS-acetylide in the presence of CeCl 3 proceeded in high yield (for the synthesis of 6 ). , However, no reaction occurred with the corresponding acetylide generated from 16 , and the starting material was quantitatively recovered. We found that the desired nucleophilic 1,2-addition was accelerated in the presence of N -methylpyrrolidone (NMP) instead of CeCl 3 as an additive, and 17 was obtained in 92% yield.…”

“…Initially, we planned to introduce various functional groups into the alkyne moiety of the tricyclic compound 6, which we used as the intermediate in the previous PBright synthesis, obtaining the optically pure product in 22 steps. 7 Coppercatalyzed alkyne−azide click reaction (CuAAC) of the azide bearing a benzyl, 3-phenylpropyl, or 1-adamantylmethyl group proceeded to give the corresponding triazoles (10a, 73%; 10b, 73%; 10c, 72% yield; see Scheme 1). Removal of the TBS group of 10 with HF/pyridine in THF gave the corresponding alcohol, but this process was not found to be reproducible.…”

Natural Products from Physalis alkekengi L. var. franchetii (Mast.) Makino: A Review on Their Structural Analysis, Quality Control, Pharmacology, and Pharmacokinetics

“…In step 3, the skeletons of physalins (Types I and II) were produced from 24-methylene cholesterol [ 13 , 16 , 17 ]. Furthermore, the racemic DEFGH-ring moiety of physalins (Type I) is synthesized through enzymatic kinetic resolution [ 18 ]. The intermediate physalins were synthesized by domino ring transformation, a reoptimization of the 2,3-wittig rearrangement, and methylation steps.…”