Quinolizidine-Type Alkaloids

Having developed an efficient route to the common intermediate 91, we next turned our attention to the further transformation of 91 into quinolizidine-type alkaloids (Scheme 18). The amido group in 91 was reduced with BH3 THF in THF under reflux to give amine 100. Without purification, 100 was treated with SOCI2 to yield chloride 101, which was subjected to the next reaction without purification because of instability on SiOa gel. Reductive dehalogenation of chloride 101 with LiAlH4 afforded cermizine C (87) [51]. 

Scheme 18 Completion of the total synthesis of quinolizidine-type alkaloids...

Although a number of alkaloids belonging to the simple arylquinolizidine class and the lactonic type had been synthesized, no successful synthesis of cyclophane alkaloids was accomplished until that of lythranidine (94), a unique alkaloid with a 2,6-trans disubstituted piperidine structure, was reported (28, 29). Quinolizidine metacyclophane alkaloids lythrancepines II (95) and III (96) have also been synthesized recently (30, 31). A review on the synthesis of lythranidine (94) is available in Japanese (32). 

Some quinolizidine metacyclophane alkaloids have vicinal dioxygen substitution in the quinolizidine ring. Lythrancine V (115) is an example of this type. In model studies, the vicinal diacetate 116 was prepared from 117 through four steps (36). 

Chiral syntheses of benzo[a]quinolizidine-type Alangium alkaloids 88H(27)1009. 

As regards the 21 benzo[a]quinolizidine-type Alangium alkaloids, they can be structurally classified into four types according to their substitution patterns in the aromatic ring A (i) 9,10-dimethoxy type (72), (ii) 8-hydroxy-9,10-dimethoxy type (73), (iii) 9-hydroxy-lO-methoxy type (74), and (iv) 10-hydroxy-9-methoxy type (75) 7,10,16). Thus, type 72 includes 10 alkaloids... 

The new alkaloid hystrine, C10H16N2 (liquid dihydrochloride, mp 209° [a]jj + 0°) and ammodendrine, but none of quinolizidine type (96). The former (LXV) was prepared from the latter by first reacting with hypochlorite to generate the W-chloro compound LXVI, treatment of which with alkali eliminated the elements of hydrogen chloride and hydrolyzed the acetyl group. The crude product was conveniently purified by conversion to the iV -nitroso derivative followed by reduction of the latter with cuprous chloride (97). 

Quinolizidine Alkaloids.—Previous results demonstrate that the quinolizidine skeleton in its entirety derives from lysine.Further research has indicated that lysine is a precursor of all the alkaloids of this type in five species of Leguminosae. From the levels of activity observed in the individual alkaloids it was concluded that saturated alkaloids are precursors for those with a pyridone ring. This was supported by the observation that label from radioactive sparteine (24) and lupanine (25) appeared in more highly oxidized alkaloids. (This compares with a similar situation in the biosynthesis of matrine-type alkaloids. ) A metabolic grid for the biosynthesis of quinolizidine alkaloids from lysine was proposed, based on these results,... 

In the IR spectra of lupin alkaloids, Bohlmann bands are characteristic for molecules having ra -quinolizidine rings and are useful for structural elucidation. The UV spectra of a-pyridone and multiflorine-type alkaloids show absorptions at... 

Fig. 8 Divergent strategy for the total syntheses of cemuane-type and quinolizidine-type Lycopodium alkaloids...

Nishikawa Y, Kitajima M, Kogure N, Takayama H (2009) A divergent approach for the total syntheses of cemuane-type and quinolizidine-type Lycopodium alkaloids. Tetrahedron 65 1608-1617... 

Matrine-type alkaloids [as (6)] were found to be labelled by radioactive lysine and cadaverine in Goebelia pachycarpa and to be interconvertible. Quinolizidine alkaloids of the sparteine type [as (5)] are known to arise from three molecules of lysine via a symmetrical intermediate (cadaverine). Aphylline (8) also arises from three molecules of lysine in Anabasis aphylla, but without the participation of a symmetrical intermediate. ... 

Intramolecular ene reactions. Use of Lewis acid catalysts (particularly FeCL, 15,156 16,190-101) has greatly extended the usefulness of intramolecular ene cy-clization. Thus a new diastereoselective route to corynanthe-type alkaloids involves the ene cyclization of 1 to tr s-indolo[2,3-a]-quinolizidine (2), a precursor to methyl corynantheate (3) by demethoxycarbonylation. SnCU (1 equiv.) is the only common Lewis acid that is useful for this particular ene cyclization, and even so, it also requires the presence of trifluoroacetic acid (1.5 equiv.). 

Figure 1.11. The three tribes of Fabaceae with quinolizidine alkaloids. The Sophoreae are close to the original stock of all Fabaceae. The more advanced tribes (Phaseoleae, Vicieae, and Trifolieae) are either entirely alkaloid-free or accumulate alkaloids of different origin, as in some species of Phaseoleae, Loteceae, Hedysaraceae, and Galegeae, although more primitive, are without alkaloids of the quinolizidine type. Probably an independent evolutionary line of the Fabaceae evolved which was not directly related to Sophoreae, Genisteae, and Podalyrieae tribes (Nowacki, 1960). Courtesy of the journal.

These tetracyclic and tricyclic quinolizidine alkaloids are commonly known as lupine alkaloids. The simple bicyclic alkaloids such as lupinine are produced from two lysine units via cadaverine. Tricyclic alkaloids such as cytisine are considered to be formed from tetracyclic alkaloids through anagyrine-type alkaloids (Fig. 5.2.7). 

Further investigation of the extracts of L. chinense resulted in the isolation of himeradine A (56, 0.001% yield) 42), a novel C27N3 type alkaloid consisting of a fastigiatine-type skeleton (C16N2) and a quinolizidine moiety (CnN), together with a known related alkaloid, lucidine B (66, 0.001%) 44,45,66). 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

Kinghom, A.D. and Balandrin, M.F. (1984). Quinolizidine alkaloids of the Leguminosae Structural types, analysis, chemotaxonomy and biological activities, in Pelletier, S.W., Ed., Alkaloids chemical and biological perspectives, John Wiley and Sons, New York, pp. 105-148. 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

This pathway clearly proves that the first quinolizidine alkaloid to be synthesized is (—) lupinine (two cycling alkaloids) and subsequently both (+)-lupanine and (-)-sparteine. This is a new approach to the synthesis of this type of alkaloids because in the older literature just four cycling alkaloids (lupanine and sparteine) were mentioned as the first synthesized molecules . In the cadaverine conversion, the participation of diamine oxidase is more reliable than the oxosparteine synthase mentioned by some older studies °. 

Tetracyclic quinolizidine alkaloids can be divided into two types, both according to chemical structure and, especially, biological activity. These are tetracychc alkaloids, which contain a quinohzidine nucleus, and others with a pyridone nucleus. Here, the first type of alkaloids (with a quinohzidine nucleus) will be discussed. The second type will be considered in the next sub-chapter as pyridone alkaloids. 

Sophorine was isolated from Sophora alopecuroides (26). The nature of MS decay showed that sophorine is a quinolizidine alkaloid of the lupinine type. The IR spectrum suggests the presence of a franj-quinolizidine moiety (2675-2945 cm ) and an — NH—CO— group (1605 and 1683 cm ). On the basis of chemical shift analysis and signal multiplicity of H- and C-NMR spectra as well as biosynthetic considerations, structure 59 was proposed for sophorine. 

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