Quinolizidine alkaloids synthesis

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. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

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. 

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 °. 

This group of alkaloids has a pyridone nucleus and generally takes the tetracyclic or tricyclic form. The a for pyridone alkaloids is L-lysine, while the j8, q> and X the same as for other quinolizidine alkaloids. Quinolizidine alkaloids containing the pyridone nucleus are the P from the (—/-sparteine by cleavage of the C4 unit. The first quinolizidine alkaloid with the pyridone nucleus is tricyclic cytisine, which converts to four cyclic alkaloids. In this synthesis the anagyrine, the most poisonous quinolizidine alkaloid with a pyridone nucleus, has its own synthesis pathway. 

Pummerer reaction conditions was followed by cycUzation to isomilnchnone 292 and hence to cycloadduct 293, which loses water to form a-pyridone 294. Subsequent manipulation involving deoxygenation and debenzylation completed the synthesis. In similar fashion, the azaanthraquinone alkaloid dielsiquinone was synthesized for the first time. Also, the quinolizidine alkaloids ( )-lupinine and ( )-anagyrine, and the ergot alkaloid ( )-costaclavine were synthesized using this Pummerer cyclization-cycloaddition cascade of imidosulfoxides and isomiinch-nones. 

Padwa and co-workers (232,233) adapted their thioisomiinchnone generation-cycloaddition strategy to the synthesis of several tetrahydroisoquinoline alkaloids and the indolo[2,3-a]quinolizidine alkaloid alloyohimbane 333 (Scheme 10.44). 

Panek et al. [57] used this methodology as a key step in their synthesis of the quinolizidine alkaloid (—)-217(A) which was obtained in 11 steps and 19% overall yields starting from amine 256 (Scheme 13.94). 

Interest in the detection and isolation of quinolizidine alkaloids has been maintained, and Polish chemists have continued their conformational studies, but the highlights of the year are the syntheses of quinolizidine alkaloids of Poran -thera1,2 and a novel synthesis of azaphenalene alkaloids.3... 

Although the detection and isolation of bicyclic, tricyclic, and tetracyclic quinolizidine alkaloids and stereochemical studies, increasingly aided by X-ray analysis, proceeds apace, the main emphasis this year is on synthesis of the Nuphar, azaphenalene, and phenanthroquinolizidine alkaloids. 

During 1993, Daly and co-workers reviewed the alkaloids found in amphibians [5] and Takahata et al. focused on structural assignments and the synthesis of amphibian and polyhydroxylated indolizidines [6]. Wink reviewed the characterisation, natural distribution and biological activity of lupine alkaloids [7] and systematic updates on indolizidine and quinolizidine alkaloids are annually summarized by Michael [8-14]. 

This review describes structural diversity, structural identification and biological activity of simple indolizidine and quinolizidine alkaloids, and covers the period from 1994 to 1999. A review of stereoselective methods for the synthesis of indolizidines and quinolizidines will be pubUshed in this series in the near future. 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

A novel synthesis of antofine 22, an indolizidine alkaloid, and cryptopleurine 23, a quinolizidine alkaloid, involves lithiation of trimethoxy-fihenanthrene-carbox mide. The key step in both these cases is the generation of substituted phthalides 92)... 

Intramolecular iminoacetonitrile [4-1-2] cycloaddition has been exploited in the synthesis of quinolizidine alkaloids (Scheme 54). The intermediate 187 was generated by elimination of trifluoromethanesulfinate from 188 and underwent the desired aza Diels-Alder reaction to give 189. A series of steps which included reduetive decyanation, alkylation with (Z)-3-bromo-l-chloropropene, classical resolution, and Sonogashira coupling provided the alkaloid (-)-217A 190<050L3115>. 

Synthesis of (—)-Lasubine II. A reductive desulfonylation with lithium in ammonia is employed in the total synthesis of quinolizidine alkaloid (—)-lasubine II.264 A conjugate addition of methyl (.S )-(2-pipcridyl)acetate to an acetylenic sulfone, followed by lithium diisopropylamide (LDA)-promoted intramolecular acylation is the key step in the preparation of the quinolizine structure of (—)-lasubine II (Eq. 154). 

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