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The first total syntheses of fuzinoside (1b) were achieved from d -galactose through two strategies (BCA and ABC) in 11 (total yield: 5.0%) and 15 (total yield: 3.7%) steps, respectively. Comparison of NMR data of synthetic compound 1b and those of the fuzinoside isolated from the lateral roots of Aconitum carmicaelii suggests that the structure reported in the literature 1 , 2 might not be accurate. The synthetic fuzinoside (1b) exhibited moderate cardiac activity in the isolated bullfrog heart assay.

We have corrected (Tetrahedron 2013, 69, 5859–5866) the structures of diterpenoid alkaloids reported in the Journal of Natural Products 2012, 75, 1145–1159. Our follow-up experiments compel us to present further revisions and clarifications on the diterpenoid alkaloids: (1) The naturally occurring forms of carmichaelines B, C, and D in Shi's paper (Journal of Natural Products 2012, 75, 1145–1159) are neither quaternary ammonium hydroxides 2–4 nor the initially revised trifluoroacetates. They are indeed the vakognavine-type C20-diterpenoid alkaloids 11–13. (2) The samples' concentration is the critical factor to the signals' intensity for F3CCOO− in the alkaloid trifluoroacetates. Incorporation of TFA into the corresponding salts resulted in signals' enhancement due to the closeness of δ values (∼116 ppm, ∼159 ppm) of free TFA and those of F3CCOO−. After removal of free TFA, the carbon signals of CF3COO− could become weaker, but their chemical shifts remained almost unchanged. The possible reason might be the ionization of TFA in acetone. (3) The NMR data cannot distinguish TFA from trifluoroacetates (e.g., F3CCOONa and C19-diterpenoid alkaloid trifluoroacetates), indicating that the signal at around δ −76 cannot be used to exclude the existence of trifluoroacetates. In addition to the NMR and CSI-MS data, 1H–15N HMBC technique was also used to distinguish the free alkaloids from their trifluoroacetates. (4) The X-ray crystallographic analysis of compound 20 confirmed that the ‘new alkaloid’ (-b) in the Shi's paper is indeed the known compound aconifine trifluoroacetate. (5) Collectively, Shi's paper mixed-up the free alkaloids with their salts and the concepts of structure and conformation. Naming different structures with A-b and A-c is also confusing.

Eleven C19-diterpenoid alkaloids reported in Shi's paper were isolated or synthesized. Their 13C NMR and DEPT spectra were recorded using (CD3)2CO+TFA as solvents. Comparison of the acquired NMR data with those reported in Shi's paper, in combination with the fact that all alkaloids, expect for 8, 27, and 28, reported in Shi's paper were isolated using TFA as part of solvent system, led to the following revisions of Shi's paper: (1) compounds 1–4, 6, 7a, 9–26 should be their respective trifluoroacetates. Their structures were revised as 1a–4a, 6a, 7a′, 9a–26a; (2) compounds 7, 27a, and 28a are trifluoroacetates of free bases 8, 27, and 28, respectively; compound 7 should be corrected as 7b; (3) ring A of free bases (such as 8, 27, and 28) exists as chair conformation; while ring A of the protonated versions (such as 7, 27a, 28a, 6a, 9a–26a) exists as boat conformation. Consequently, compounds 7 and 8 are apparently not a pair of conformational isomers, instead, they are indeed a free base and its protonated version existing as a trifluoroacetate, respectively; (4) ‘new’ compounds 6, 13, and 15 are the protonated versions 6a, 13a, and 15a, respectively, of the corresponding known alkaloids, aconifine, deoxyaconitine, 14-benzoylaconine. In addition, all 1H (13C) NMR data for the free bases of new compounds 8, 9, 10, 17, and 24 (Tables 3 and 4) were also assigned based on their 2D NMR spectra.

Treatment of imines 5 and 7 , both prepared from the C 19 -diterpenoid alkaloid deltaline ( 1 ), with NaNO 2 –HCl resulted in the formation of diterpene 6 with an eight-membered ring through a sequence of denitrogenation and enlargement of ring B. In addition, two unusual skeletal rearrangements of diterpene 6 were also observed, leading to two structurally novel products 8 and 10 . The structures of compounds 8 and 10 were confirmed by their X-ray crystallographic analyses and 2D NMR data.

O-Demethylation at C-1 in the C19-diterpenoid alkaloids is very challenging. In this paper, it was firstly observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction. After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be readily removed by treatment with HBr–HOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxidation, deformylation, and SN2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.

Lactam 2, prepared from deltaline (1), is an analog of C19-diterpenoid alkaloid with a hydroxyl group at C-6 and a ketone carbonyl group at C-7. Treatment of this lactam with thionyl chloride or methanesulfonyl chloride, or reaction of this lactam under Chugaev condition led to an unusual rearrangement of its E/F ring system to yield a lactone 10 in a yield range of 43–74%. The structure of 10 was confirmed by its 2D NMR data and X-ray crystallographic analysis.

An tricyclic AEF fragment of C19-diterpenoid alkaloid bearing an angular methyl group and the oxygen function groups at C-1 and C-6 was successfully synthesized. The synthesis features a stereoselective intramolecular Diels–Alder reaction and a highly efficient intramolecular Mannich reaction as well as efficient functional groups transformations.

A concise strategy for construction of B/C/D ring system of C19-diterpenoid alkaloids was described, which features a highly diastereoselective intramolecular Diels–Alder reaction of masked o-benzoquinone and an efficient Wagner–Meerwein 1,2-shift rearrangement. The functional group transformations of rearrangement product 19 demonstrate a potential for stereoselective installation of oxygen functions on D-ring of many type of C19-diterpenoid alkaloids.

An AE azabicyclic fragment, with a β-hydroxyl group at C-5 and a substituent at C-1, of the C 19 -diterpenoid alkaloids, was synthesized. The key reactions include an intramolecular Claisen-type condensation, double Mannich reaction, and stereoselective nucleophilic addition of carbonyl group with the assistance of steric effect of 1β-substituent.

Pyrolysis of carboxylic acid group at C-4 of 2, an oxidation product from the C19-diterpenoid alkaloid lycoctonine 1, generated an unexpected but novel rearranged product 13 (37%). The structure of 13 was confirmed by its 2D NMR data and its single crystal X-ray crystallographic analysis. In addition, hydrogenolysis of 13 in the presence of acetic acid yielded the N–C6 bond fission products 16 and 17, which represents the first hydrogenolysis involving the breakage of the N–C6 bond of the diterpenoid alkaloids. Some new observations on the oxidation of lycoctonine 1 were described as well.

A novel approach to the highly functionalized taxane ABC ring system through chemical conversion of the C19-diterpenoid alkaloid deltaline (1) was achieved in six steps (1→17) in 18% overall yield mainly by Grob fragmentation, fission of the Δ9(14) double bond, followed by aldol condensation, and Pelletier's cleavage process.

Two methods for the synthesis of N,19-seco norditerpenoid alkaloids were developed. One method prepared new N,19-seco norditerpenoid alkaloids possessing an oxaziridine group from yunaconitine in five steps involving acetylation, imination, quaternization, formation of N,O-mixed ketal, and oxidation in 50% overall yield. Another method provided a series of novel N,19-seco norditerpenoid alkaloids bearing the oximino or nitro groups through oxidation of the imine N-oxides with HIO4 in moderate yields. Two novel aconane- type diterpenes were synthesized from an N,19-seco nitro compound and an imine N-oxide through Nef reaction and HIO4 oxidation, respectively, in moderate yields. q 2002 Elsevier Science Ltd. All rights reserved.

Treatment of 3-acetylyunaconitine 2 from yunaconitine 1 with NBS at 40°C for 12 h afforded the 3-acetylyunaconitine azomethine 3 (48%). Reaction of 3 with CH 3 I in MeOH at room temperature overnight gave the iminium salt 4 (100%). Unexpectedly, treatment of 4 with 5% NaOH in methanol at room temperature for 20 min produced the rearrangement alkaloid 5 (38%) besides other unidentified compounds. Acetylation of 5 with Ac 2 O/pyridine containing a small amount of TsOH gave its two derivatives 6 (28%) and 7 (56%). The structure of 5 was confirmed using 2D NMR spectra and single crystal X-ray analysis of its acetyl derivative 7 .

Treatment of 14-methylsulfonyl pseudaconine 3 with DMF-NaOH at 150 degreesC for 10 h afforded the desired C-nor and 12,13-seco norditerpenoid alkaloids 16 alpha -methoxyl ketone 7 (70%) and 16 beta -methoxyl ketone 8 (15%) as a pair of epimers. Reaction of 7 with Br-2-HOAc at room temperature for 1.5-2 h produced the phenols 9 (40%), 10 (10%) and 13 (29%). Whereas, treatment of 8 with Br-2-HOAc under same conditions as the case for 7 gave phenolic compound 9 (38%) besides the by-product alpha -bromoketone 14 (25%). (C) 2001 Elsevier Science Ltd. All rights reserved.