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A new and effective approach toward epoxide opening of a 7,17-seco-7,8-epoxy-C19-diterpenoid alkaloid is herein described. The starting epoxide was prepared from naturally occurring yunnaconitine via a nine-step transformation. Treatment of this epoxide with trifluoroacetic anhydride in dioxane at 110 degrees C followed by reduction with sodium boron hydride generated two epoxide opening compounds 7 and 8. Each of their structures is characteristic of a Δ8,15 bridgehead double bond and a 7β-oxygen-substituted group.

The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.

The first biomimetic conversion from the aconitine-type C(19)-diterpenoid alkaloids to the corresponding alkaloids of lactone-type C(19)-diterpenoid alkaloid has been achieved. Chasmanine was used as starting material with Baeyer-Villiger oxidation as a key reaction. It was also observed that the oxygenated group at C-16 did not change the relative migration tendencies of C-13 and C-9 during the oxidation. Meantime, a novel D-ring fragmented compound was obtained during the course of the present investigation. The plausible mechanism of the formation of this compound was also proposed.

Four novel taxoid analogs were conversionally synthesized from the C(19)-diterpenoid alkaloid deltaline, and their cytotoxic activities were evaluated against a small panel of cancer cell lines.

From the whole herbs of Delphinium majus, three new C(19)-diterpenoid alkaloids, majusines A-C (1-3), and six new C(20)-diterpenoid alkaloids, majusimines A-D (4-7) and majusidine A and B (8 and 9), have been isolated, together with 15 known compounds. The structures of compounds 1-9 were elucidated by spectroscopic data interpretation.

Four new norditerpenoid alkaloids, leueantines A (1), B (2), C (3), and D (4), were isolated from the roots of Aconitum hemsleyanum var. leueanthus. The structures of 1-4 were established by spectroscopic evidence.

Treatment of a 7,17-seco-type C19-diterpenoid alkaloid (3), prepared from deltaline (8), with triethylamine in either DMF or TEG (triethylene glycol) at 120 degrees C provided two interesting compounds 6 and 7. The structures of compounds 3, 6, and 7 were established based on extensive interpretations of their 1D and 2D NMR data. Compound 6, a lycoctonine-type C19-diterpenoid alkaloid, can be transformed from alkaloid 3 via Grob fragmentation, Prins reaction, and intramolecular disproportionation. The mechanism of the formation of compound 6 was confirmed by deuteration experiments. Product 7 was formed through a pinacol-like rearrangement of alkaloid 3.

A series of new bisbenzylisoquinoline alkaloids was partially synthesized from tetrandrine and fangchinoline and evaluated for their ability to reverse P-glycoprotein-mediated multidrug resistance (MDR) in cancer cells. All the test compounds increased the intracellular accumulation rate of rhodamine 123 in MDR cells (Bel7402 and HCT8), and most exhibited more potent MDR-reversing activity relative to the reference compound verapamil. Compounds 8, 10, 13, and 14 enhanced intracellular accumulation of doxorubicin in Bel7402 and HCT8 cells.

The O-acyl group at C-1 of two C₁₉-diterpenoid alkaloids 2 and 5 was transferred to the secondary amine nitrogen to form amides 3 and 6 in the basic condition. This kind of O-to-N intramolecular acyl migration could be caused by the near distance between the nucleophilic nitrogen atom and the carbonyl group of the ester at C-1 in the C₁₉-diterpenoid alkaloids, which is consistent with the conformation of rings A and E in the C₁₉-diterpenoid alkaloids.

The conversional synthesis of taxoids by the BAC sequence from the C(19)-diterpenoid alkaloids, 14-acetyltalatisamine (1), yunaconitine (12), and 14-acetylchasmanine (19), was designed and explored. Two aconane-type diterpenes 17 and 28, the advanced intermediates for our conversional synthesis, were synthesized. The key steps include the rupture of the C(7)-C(17) bond, the formation of imine, and the denitrogenation.

Further phytochemical investigation of the whole herb of Delphinium anthriscifolium var. savatieri resulted in the isolation of two new C20-diterpenoid alkaloids, anthriscifolmines I (1) and J (2). The structures of the two new alkaloids were elucidated on the basis of spectral data, including 2D NMR and HRESIMS.

The diterpenoid alkaloids, with an intriguing chemistry and numerous varied bioactivities, constitute the largest and most complicated group of terpenoid alkaloids. Among them, the C19-diterpenoid alkaloids have attracted extensive and lasting attention from researchers. This chapter with 1075 references systematically summarizes the past 30 years of studies on the C19-diterpenoid alkaloids, covering the classification and distribution, biogenesis and biosynthesis, applications in the phytochemotaxonomy of Chinese Aconitum L., spectral properties (1H and 13C NMR, MS), X-ray crystallographic analysis, chemical reactions and chemical conversions (as a continuation of Volume 42 of this treatise), and pharmacological activity of this important group of alkaloids. This review on the C19-diterpenoid alkaloids, in combination with two previous reviews in this treatise (C20-diterpenoid alkaloids, Volume 59, and C18-diterpenoid alkaloids, Volume 67), will present readers with a complete and updated profile of the diterpenoid alkaloids. The only exception is the description of the total syntheses of the diterpenoid alkaloids, which will be summarized in a subsequent individual chapter.

Six new bisbenzylisoquinoline alkaloids, racemosidines A-C (1-3) and racemosinines A-C (4-6), and four known compounds were isolated from the roots of Cyclea racemosa. Compound 1 is the first bisbenzylisoquinoline alkaloid reported that has diphenyl ether bridges at C-11/C-7' and C-8/C-12' and a benzyl-phenyl ether bridge at C-7/C-11'. Structures and absolute configurations of 1-6 were established by interpretation of spectroscopic data and confirmed by X-ray crystallographic analysis of representative compounds. Compounds 1-3 exhibited significant cytotoxicity against HCT-8 and BEL-7402 tumor cells, and compound 1 was also cytotoxic against A2780 tumor cells.

Three new C(19)-diterpenoid alkaloids, umbrosumines A-C (1-3), and 11 known compounds (4-14) were isolated from the roots of Delphinium umbrosum. Their structures were elucidated on the basis of the spectroscopic data interpretation.

In the title study, the synthesis of the vital intermediate C-nor-aconanone (3) from 4 was completed through 11 steps, mainly including semipinacol rearrangement, formation of the imines by the treatment of 10 or 20 with NBS, the cleavage of N–C(19) bonds in 11 or 21 by treatment with m-CPBA and subsequently with LTA, as well as the rupture of the N–C(17) bonds in 22 by a modified Nef reaction (NaH/t-BuOH → KMnO4/H2O). One-pot procedure was successfully developed starting from 11 or 21 to afford the N,19-seco-C-nor product 15 or 22, respectively, in reasonably good yields.

Seven new C19-diterpenoid alkaloids, circinasines A-G (1-7), together with six known compounds, talatisamine, yunaconitine, senbusine A, sachaconitine, hemsleyanisine, and isohemsleyanisine, were isolated from the roots of Aconitum hemsleyanum var. circinatum. The structures of 1-7 were determined by the interpretation of spectroscopic data and by the single-crystal X-ray crystallographic analysis of 6 and the acetonide derivative of 1. In addition, the structures of hemsleyanisine and isohemsleyanisine were revised from 8 and 9 to 10 and 11, respectively.

Three new C20-diterpenoid alkaloids, trifoliolasines D−F (1−3), were isolated from the aerial parts of Delphinium trifoliolatum, and their structures were determined by the interpretation of spectroscopic data and by the single-crystal X-ray crystallographic analysis of 1.

A new conversional synthesis of the ABC ring system of taxoids from the C19-diterpenoid alkaloid lycoctonine was developed in 6 steps with 2% overall yield. The distinctive features of the conversion include pinacol rearrangement, enlargement of ring B, and opening of a four-membered ring.

The lasting attention that researchers have devoted to diterpenoid alkaloids is due to their various bioactivities and toxicities, structural complexity, and intriguing chemistry. From 1998 to the end of 2008, more than 300 new diterpenoid alkaloids were isolated from Nature. This review focuses on their structural relationships, and investigations into their chemical reactions, synthesis, and biological activities. A table that lists the names, plant sources, and structural types is given along with 363 references.