Lycopodine synthesis

The third total synthesis of luciduline has been reported and is outlined in Scheme 2. The starting material is the same keto-nitrile (16) used in Heath-cock s lycopodine synthesis described above. Treatment of (16) with methanolic sodium hydroxide led directly to a mixture of the cis-lactam (31) and the corresponding tran -isomer (ratio 5 1). Condensation of (31) with ethyl tri-methylsilylacetate furnished the unsaturated ester (32), which was N-methylated to (33). Catalytic hydrogenation of (33) provided a 1 1 mixture of (34) and its C-5... 

The empimeric alcohol (107) again underwent the deprotection-retroaldol-aldol process to afford the product 108), which was used as a key intermediate in the total synthesis of 12-epi-lycopodine 109)37). 

Scheme 30. Rhodium-initiated domino cyclization for the synthesis of lycopodine 152...

Synthesis of (+)-luciduUne from 7-methyl-2,3,4,6,7,8-hexahydroquinoline The last synthesis of luciduline in its racemic form was reported in 1984 by D. Schumann [18] and is based in a synthesis of ( )-lycopodine previously described in 1982 [19]. 

Isomunchnones play a large part in the synthetic efforts Padwa and co-workers (91-94,96,98,110,111). The Lycopodium alkaloids are a large family of natural products and have inspired numerous synthetic routes to approach these compounds. Interest in this class of alkaloids stems from the myriad of biological properties they exhibit. Padwa utilized the carbonyl ylide methodology in tandem with a cationic 71-cyclization to complete a formal synthesis of ( ) lycopodine (Scheme 4.55) (96,112). 

The reactions shown in equations (49)-(51) are reminiscent of the Mannich reaction. An example of where this approach was used to great advantage for the synthesis of lycopodine (82JA1054) is illustrated in Scheme 35. In this sequence the A2-piperideine was not isolated but was prepared as a reactive intermediate. 

The isomunchnone dipole approach has been successfully applied to the synthesis of alkaloids ( )-lycopodine. As outlined in Scheme 9, 5-methylcyclohexenone 73 was converted to a-diazo imide 74 in seven steps. The diazo decomposition of 74 with Rh2(pfb)4 in CH2CI2 at 25 °C gives expected tandem ylide cycloaddition products 76 and... 

Annelation of imines.2 A key step in a recent synthesis of lycopodine (4) is the reaction of 1 with the inline 2 to yield a tricyclic ketone 3. 

Heathcock has extended his elegant approach to the synthesis of the Lycopodium alkaloids, reviewed last year (c/. Vol. 10, p. 207) in the case of lycopodine (15),7 to provide the first total synthesis of lycodine (7).8 The synthesis (Scheme 1) proceeds from the previously described cyano-enone (16) in just... 

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

A key step in the synthesis of 12-epi-lycopodine reported by Wiesner and coworkers is the intramolecular [2 + 2] photocycloaddition of a vinylogous imide and an allene. Irradiation of photosubstrate 46 produced a single cyclobutane 47, in which the allene added to the vinylogous imide anti to the methyl group (Scheme 13)31. Photoadduct 47 was converted to ketal-alcohol 48 via a three-step sequence of ketalization, epoxida-tion and reduction. Hydrolysis of the ketal unmasked the /Miydroxy ketone functionality. Retro-aldol fragmentation followed by aldol closure gave hydroxyketone 49, which was readily converted to the polycyclic alkaloid 12-epi-lycopodine. 

This reasoning, actually nothing more than a mere ramification of the classic mechanistic description of AdN reactions, turned out to be truly productive in the elaboration of an efficient and general approach to the solution of many synthetic problems. One of the first examples of the successful utilization of a sequence of independent additions of Nu and E to Michael acceptors was described by Stork,who took advantage of this stepwise plan to achieve a short-route preparation of 97 (Scheme 2.31), the advanced intermediate in the synthesis of the polycyclic alkaloid lycopodine. 

Wittig reagents have also been utilized in the synthesis of several other compounds (4R,7Z,1 lZ)-(-)-4-methylheptadeca-7,l 1-dienoic acid, a member of the sporthrix series the alkaloid ( )-lycopodine, and derivatives of l-fructose in which the carbon-backbone has been lengthened. 

Despite the fact that two syntheses of lycopodine have been reported, synthetic activity in this area has not diminished. A total synthesis of optically active annotinine (4) has been achieved. The readily available vinylogous lactam... 

An intramolecular counterpart of the photochemical step used in the formation of (6) has been successfully applied to the synthesis of 12-epi-lycopodine (14). Photolysis of (10) yielded the intermediate (11) which was converted into the diketone (12). The latter compound gave the aldol product (13) which, in four steps, produced 12-epi-lycopodine (14). An amazing simplification of the overall route resulted when it was found that the diketolactam corresponding to the ketal (15) underwent a stereospecific Michael reaction to give (13) directly in 30% yield. 

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