Structures of Daphniphyllum Alkaloids

The carbon skeletons of the Daphniphyllum alkaloids consist of thirty or twenty-two carbon atoms. Probably the C22 alkaloids are formed by oxidative cleavage of eight carbon atoms from the C30 compounds. Methyl homodaphniphyllate [23, m/e 359(M+), 286, and 272], one of the representative C22 alkaloids, was isolated from the fruits of D. macropodum (19) but not from the bark and leaves of the same plant. The structure of this alkaloid (23) was deduced by chemical transformation from daphniphylline (1) which had already been carried out in several steps. Oxidation of deacetyldaphniphylline (2) with NaI04 followed by reduction with NBH afforded daphnialcohol [24, mp 239-241.5° (as hydrochloride) C21H350N], which was further converted via the corresponding tosylate (25, mp 107.5°) and nitrile (26, mp 156°) to homodaphniphyllic acid (27), which was directly treated with 20% methanolic HC1 to afford methyl homodaphniphyllate (23). This alkaloid was also obtained in 20% yield by Beckmann... 

So far, more than 250 alkaloids have been reported from 15 species oi Daphniphyllum genus. It is highly likely that further phytochemical investigations on the other species will result in much more isolations of Daphniphyllum alkaloids with structural variation s. 

Total syntheses of Daphniphyllum alkaloids are still ongoing, and the biosynthesis of Daphniphyllum alkaloids requires thorough studies to elucidate the intermediates and the relevant enzymes. The biological activities of Daphniphyllum alkaloids should be extensively investigated. In addition, plants of the genus Daphniphyllum produce the structurally diverse and complex alkaloids, which should play an important role for the plant itself from the evolutionary perspective. Biological/ecological role of these alkaloids in the life cycle of the plant should be paid much more attentions. 

A list of the Daphniphyllum alkaloids is given in Table I. In addition to two alkaloids of undetermined structure, neodaphniphylline (28) and neoyuzurimine, both of which have been isolated in very small quantities (Vol. X, p. 556, and Vol. XII, p. 472), three more structurally unknown alkaloids (alkaloids Ax and A2, and yuzurimine-D) have been obtained from the bark and leaves of D. macropodum (14, 21). In particular, the carbon skeletons of the alkaloids Aj and A2 seem to be considerably different from those of the other alkaloids cited in parts A-E, on the basis of their spectral data. 

Daphniphyllum macropodum contains a great variety of related alkaloids whose structures are quite complex and novel (Section II). It is structurally evident that these alkaloids with an isopropyl or a potential isopropyl group are regarded as a terpene alkaloid. Bio-genetieally, these Daphniphyllum alkaloids, particularly C22 alkaloids, have been proposed to be derived from four molecules of mevalonic acid (MVA) and one acetate unit (15, 39). However, the recent tracer experiments showed that these alkaloids could be biosynthesized from six MVA molecules through a squalene-like intermediate. Accordingly, they should be included in a group of triterpene alkaloid. 

Quite recently, three new alkaloids were isolated as minor components from the fruits of the plant Daphniphyllum teijsmanni Zollinger and their structures also determined on the basis of their physical and chemical data (43). In addition, the structure of yuzurine,9 one of the alkaloids of undetermined structure (see Section II, F), was also elucidated by means of an X-ray crystallographic analysis of its methiodide (44). 

In addition to several newly reported diterpenoid alkaloids, the structures of some forty alkaloids have been revised on the basis of recent work. The structures presented in this Report have been revised from those reported in the literature to reflect these recent corrections. The level of efforts directed toward the synthesis of diterpenoid alkaloids was substantially reduced this year, with only a description of the synthesis of napelline by Professor Wiesner s group appearing. No reports of new work on the Daphniphyllum diterpenoid alkaloids were available to our laboratories. 

Yuzurimine C, a minor squalene-derived alkaloid from Daphniphyllum mac-ropodum,n has been assigned the structure (5). A search for further compounds to support the postulated biogenetic pathway from squalene to the Daphniphyllum alkaloids has resulted in the isolation of daphniteijsmanine (6) from D. teijsmanii.12 It is structurally very similar to secodaphniphylline. Treatment of the mesylate (8) of the sodium borohydride reduction product of N-acetylsecodaphniphylline (7) with acetic acid afforded N-acetyldaphniteijsmanine acetate (see Chapter 6, p. 214). Further chemical interrelations in this series have been described.13... 

Since Hirata et al. began research into daphniphyllum alkaloids in 1966, a number of new alkaloids have been discovered. As a result, the number of known daphniphyllum alkaloids has grown markedly in recent years to a present count of 118 (compounds 1-118). These alkaloids, isolated chiefly by Yamamura and Hirata et al. are classified into six different types of backbone skeletons [1-3]. These unusual ring systems have attracted great interest as challenging targets for total synthesis or biosynthetic studies. This chapter covers the reports on daphniphyllum alkaloids that have been published between 1966 and 2006. Since the structures and stereochemistry of these alkaloids are quite complex and the representation of the structure formula has not been unified, all the natural daphniphyllum alkaloids (1-118) are listed. Classification of the alkaloids basically follows that of the previous reviews [1,2], but sections on the newly found skeletons have been added. 

During the course of our studies for biogenetic intermediates of the daphniphyllum alkaloids, a project was initiated on the alkaloids of D. humile. A series of new daphniphyllum alkaloids, daphnezomines A-S (37-55), which were isolated from the leaves, stems, and fruits of D. humile, are of considerable interest from a biogenetic point of view. All these structures are listed in Figure 18.6. 

An asymmetric total synthesis of (—)-secodaphniphylline was carried out using a mixed Claisen condensation between (—)-methyl homosecodaphniphyllate (11) and a carboxylic acid derivative 154 with the characteristic 2,8-dioxabicyclo[3.2.1]octane structure commonly found in the daphniphyllum alkaloids (Scheme 18.23) [68,69]. The necessary chirality was secured by an asymmetric Michael addition reaction of... 

A. Structure.— The plant Daphniphyllum macropodwn Miq. contains a great variety of related alkaloids (see Table). Three main N-heterocyclic skeletons occur, represented by daphniphylline (152), secodaphniphylline (156), and yuzuri-mine (157). Within the daphniphylline group, notable variations in the oxygen heterocycle occur in daphmacrine (154) and daphnimacropine (155). Macrodaph-nine (161) is the A-oxide of yuzurimine. The structures of representative members... 

The chemistry of the Daphniphyllum alkaloids has focused on the biogenetic aspects of their occurrence. The search for proposed biosynthetic intermediates among the minor alkaloids of these plants has resulted in the isolation and structure elucidation of five new bases. Accomplishments have included interconversions of the Daphniphyllum alkaloids by bond formation or fission. The compounds isolated thus far have been divided into five structural types and are reviewed as diterpenoids... 

The structure of yuzurine was determined to be (88) by an X-ray crystallographic study of the methiodide derivative, employing a heavy-atom method. This structure accounts for the observed chemical and physical data. The proposed biosynthetic pathway from yuzurimine-B (89) is indicated in Scheme 2. Yuzurine, which may be included in the yuzurimine class, differs from the previously isolated Daphniphyllum alkaloids in that it has no 2-azabicyclo-[3,3,l]nonane system. 

Structural and synthetic studies of the diterpene alkaloids of the Aconitum, Delphinium, and Garrya species continue to provide more insight into the chemistry of these complex bases. In recent years Japanese workers have isolated a series of isoprenoid alkaloids from plants of Daphniphyllum macropodum Miquel. Structural work on four new alkaloids representing three new structural types has been reported during this year. 

A heavy-atom X-ray crystal-structure analysis of methyl IV-bromoacetyl-homosecodaphniphyllate (53) established the structures of secodaphniphylline and methyl homosecodaphniphyllate as (54) and (55), respectively. " The absolute configuration of this derivative was determined by anomalous dispersion procedures. These alkaloids are members of another new group of alkaloids isolated from Daphniphyllum macropodum. 

This alkaloid contains the 2-azabicyclo[3,3,l]nonane ring system characteristic of all the Daphniphyllum alkaloids. It represents a new structural type, having four rings with the C-8 atom common in a spiro-system. Its skeleton may be related to methyl homodaphniphyllate (59) by insertion of a single carbon unit (C-26) and lactonization. 

Daphnilactone-B. The fruits of Daphniphyllum macropodum Miquel yield as a major alkaloidal component daphnilactone-B, C22H31NO2, m.p. 92—94°C. Spectral data indicated the presence of a secondary methyl group, a vinyl proton, and a lactone ring. The structure of this compound was established as (60) by an... 

---