Alkaloid syntheses cyclization reactions

Intramolecular imino Diels-Alder cyclization is a useful method in alkaloid synthesis. The reaction is highly stereoselective but gives results opposite to those usually found in closely analogous all-carbon systems. Thus, the diene (284) on pyrolysis gives the single trans cycloadduct (286). The reaction is rationalized by assuming initial formation of the... 

Aliphatic amine derivatives such as amides, carbamates and sulfonamides also participate in Pd - catalyzed intramolecular C-N bond formation. The relative reactivity of these amino nucleophiles toward cyclization has been evaluated in the PdCL-catalyzed cyclization of iV-protected 4-pentenylamines and 5-hexenylamines, and it was found to be urea > carbamate > tosylamide > benzamide. The PdCl2(CH3CN)2-catalyzed dehydrative cyclization of alkenyl urethanes bearing an allylic hydroxyl group has been elegantly applied to the synthesis of chiral piperidine alkaloids. The cyclization reaction occurs with complete stereocontrol in good yields in the presence of 15-20 mol % of catalyst without any reoxidant (eq 16). 

Intramolecular amination with allylic acetates is used for the synthesis of cyclic alkaloids 175]. Cyclization of 293 affords the six-membered ring compound 294 rather than a four-membered ring. The reaction is particularly... 

Partial hydrogenation of the quaternary pyridinium salts in the presence of triethylamine on palladium in methanol has been used for the synthesis of a large number of alkaloids. The tetrahydropyridine derivatives thus formed undergo various cyclization reactions in acidic media (89). 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

Padwa s group has not only developed highly efficient domino reactions using transition metal catalysis, but they are also well known for their unique combinations of a cycloaddition and a N-acyliminium ion cyclization. An example of this strategy, which is very suitable for the synthesis of heterocycles and alkaloids, is the reaction of 4-98 to give 4-101 via the intermediates 4-99 and 4-100 (Scheme 4.22). Furthermore, 4-101 was transformed into the alkaloid (+)-y-lycorane 4-102 [32]. 

The thermal reaction of the compound (318) may be chosen as an example to show the usefulness of the benzocyclobutene — o-xylylene rearrangement in alkaloid synthesis U1). On heating (318) at 120 °C, an intermediate product (319) was formed, which cyclized to give the compound (320). This method formulated the key step in the total synthesis of the alkaloid chelidonine (321) ni). 

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

Such lanthanide catalysts were also used in hydroamination/cyclization strategies for the synthesis of the alkaloid (+)-xenovenine. This reaction of enantiomerically pure 147 leading to 148 via two C-N bond formations was used in a late step of the synthesis after a hydrogenation, the natural product was isolated (Scheme 15.46) [100]. 

The molybdenum-mediated arylamine cyclization was also applied to the total synthesis of pyrano[3,2-a]carbazole alkaloids (Scheme 26). Reaction of the 5-aminochromene 71 with the complex salt 62 affords the complex 72, which on oxidative cyclization provides girinimbine 73, a key compound for the transformation into further pyrano[3,2-a] carbazole alkaloids. Oxidation of 73 with DDQ leads to murrayacine 74, while epoxidation of 73 using meta-chloro-perbenzoic acid (MCPBA) followed by hydrolysis provides dihydroxygirinim-bine75 [113]. 

Chapter 4 by J.J. Li reviews radical cyclization reactions in the total synthesis of indole alkaloids. The use of free radical chemistry in the synthesis of alkaloids has grown markedly because of the mild reaction conditions, tolerance of a wide variety of functional groups, and the good stereoselectivities. 

The above described total synthesis shows the application of the (7-carbonyl radical-initiated tandem cyclization reaction for the first generation of (+)-paniculatine. With this method starting from 2-substituted-5-(R)-cyclohexenone 5 Sha and co-workers obtained 15 (=1) in 21 steps. Furthermore the HBr-salt of this alkaloid was prepared and subjected to a single X-ray analysis, which unambiguously confirmed the structure and stereochemistry of this synthetic (+)-paniculatine. 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

The photochemical electrocyclic reaction of acrylamides represents a versatile strategy for alkaloid synthesis. Thus, (S)-pipecoline has been synthesized using the photochemical cyclization of enantiomerically pure acrylamide derivatives in the presence of NaBH4, which causes reduction of the imonium intermediate. The lactam may then easily be transformed into the desired heterocyclic compound (Scheme 9.26) [38]. 

The SRN1 mechanism represents an excellent alternative to accomplishing the following intramolecular cyclization reaction (Scheme 10.42), which constitutes one of the steps in the synthesis of rugulovasines A and B (20, a-H and P-H), novel structures within the family of ergot alkaloids [58]. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

This chapter reviews the synthesis of alkaloids and related compounds by the use of photochemical or thermal cyclization reactions of conjugated systems, unconjugated systems structurally related to or derived from what... 

Studies of alkaloid synthesis provide another example of aminomethylation with concurrent molecular rearrangement (Fig. 69). In this case the methyleneimmonium ion is inserted into a tetrahydroisoquinolinc ring, and the cyclization occurs by reaction with a brominated aromatic ring activated by alkoxy groups.- - ... 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

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