Cyclization alkaloid synthesis

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. - ... 

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). 

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. 

The reduction of heterocyclic compounds is a versatile process of great use in the synthesis of alkaloids185. The choice of catalyst is crucial however, as illustrated by the indolizidine alkaloid synthesis shown in Scheme 34185a. The reduction of 37 to 38 proceeds with a very high degree of stereocontrol which sets up the correct framework for intramolecular cyclization to complete a short synthesis of y-lycorane 39186. 

Scheme 2. Nickel powder promoted 5-endo-trig radical cyclization in erythrina alkaloid synthesis...

Marks et al. [77, 294]. The formation of heterocyclic nitrogen compounds is of relevance in natural products, particularly in alkaloid synthesis, when the formation of the C-N bond occurs with asymmetric induction. The cyclization is not restricted to primary amines and produces 2-methylheterocycles (5-, 6-, 7-membered) with >99% regioselectivity and a new asymmetric center adjacent to the heterocyclic nitrogen atom (Scheme 17). 

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 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. 

Enamide cyclizations, application in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in vitro, 18, 323 (1981) Ephedra bases, 3, 339 (1933)... 

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... 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

Chapter 4. Application of Enamide Cyclizations in Alkaloid Synthesis Ichiya Ninomiya and Takeaki Naito... 

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.- - ... 

Fig. 170, Tandem ay.a-Cope rcarrangement-Mannich cyclization (bold lines) in alkaloid synthesis.

Catalytic palladium-ene cyclizations may also open new perspectives in alkaloid synthesis, considering the smooth formation of pyrrolidines and piperidines. Scheme 46 and Table 14 illustrate the cyclizations of palladium-ene precursors (I) (221 entries 1-4) and (J) (223 entries 5, 6) containing a nitrogen atom as part of the bridge. The leaving group in (223) can even be a simple hydroxy group (entry 6). ... 

Scheme 6-11 Heck cyclizations in Strychnos alkaloid synthesis.

Scheme 35. Applications of 6-exo Heck cyclization in indole alkaloid synthesis...

Vinylsilane- and alkynylsilane-terminated cyclization in synthesis of alkaloids 86CRV857. 

In their route to (- )-3, Hua and his coworkers demonstrated Ae usefiilness of chiral a-sulfinyl ketimine anions as intermediates in alkaloid synthesis (Scheme 4) (43). Treatment of the anion of 28 with (S)-( - )-menthyl p-toluenesulfinate afforded a 1 1 mixture of the separable diastereomers 29 and 30, while use of (/ )-( + )-menthyl p-toluenesulfinate afforded the enantiomers ent-29 and ent-30. Conjugate addition of the anion of 30 to methyl 2-(rerr-butoxycarbonylamino)acrylate was followed by spontaneous cyclization to give the unsaturated indolizidines 31 and 32 in a ratio of 2 3. Similar treatment of the anion of ent-29 yielded 33 and 34 in the ratio 1 2. Both sets of indolizidine diastereomers were readily separated by chromatography. The synthetic routes converged when reduction of either 32 or 33 with Raney nickel gave the same 5-oxoindolizidine 35, fiom which ( - )-slaihimine... 

We view acetylenic sulfoxide 1 as a two-carbon synthon in alkaloid synthesis. Our general approach, as depicted in Scheme 4, called for a Michael addition of Nu1 to the terminal acetylenic position followed by a cyclization by Nu2 (an intramolecular second Michael addition). This Michael addition cyclization step will build up the basic skeleton of the alkaloid system and at the same time control the absolute stereochemistry of the newly created chiral center through asymmetric induction of the chiral sulfoxide moiety. Finally, the sulfoxide can be transformed to another functional group (X) or used to promote the formation of another bond with Nu3 via trapping of the sulfenium ion intermediate under Pummerer rearrangement conditions (Scheme 4). 

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