Intramolecular Pummerer cyclizations

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 

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The asymmetric version of an intramolecular Pummerer-type cyclization is quite useful for the synthesis of optically active heterocyclic compounds. Only a few examples of these types of reactions have been reported, and the ee yields were low. An example of an asymmetric intramolecular Pummerer cyclization was reported... 

The mechanism of penicillin biosynthesis from the Arnstein tripeptide, 8-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV), has been extensively studied and reviewed by many chemists. Most of the biosynthetic mechanisms have been ascertained by Baldwin and Bradley using an excellent enzymatic technique.55 However, the first step in the biosynthesis of penicillin, conversion of the Arnstein tripeptide to a cis-P-lactam intermediate, is still a fascinating mechanistic problem. Although Baldwin et al. recently proposed a mechanism involving an iron-bound thioaldehyde formation route via a Pummerer-type cyclization, the intermediate for this mechanism has not been identified. The mechanism of selective formation of the cw-P-lactam ring is still also unknown (Fig. 39).56 These types of biomimetic reactions have been chemically studied. An example of an unsuccessful intramolecular Pummerer cyclization of the sulfoxide involving a cysteine moiety under standard Pummerer conditions was reported by Wolfe et al.57 Although Kaneko reported the conversion of the very simple 3-phenylsulfinyl propionamide into a P-lactam with TMSOTf/triethylamine,58 a successful biomimetic synthesis of... 

A new synthesis of ethyl 7-methoxyindole-3-acetate was accomplished by reductive cyclization of the o-nitrobenzyl cyanide 22a. The indole was then elaboarated to the tetracycle 22d by an intramolecular Pummerer reaction. <95JHC947> ch2co2c2h5... 

P-lactams from Arnstein tripeptide derivatives had not yet been carried out (Fig. 40). The intramolecular Pummerer-type cyclization of the closely related (fi)-Am-stein tripeptide analogues with SKA predominantly gave the cw-P-lactams and the (S)-Arnstein tripeptide analogues gave a mixture of cis and trans P-lactams.59a It is noteworthy that cw-P-lactams were preferentially obtained from the (/ )-substrate considering the fact that the 3-amino-P-lactam moiety of naturally occurring... 

Pyrrolo[2,l-c][l,4]benzothiazepine 297 (R=Ph) has been prepared by an intramolecular nucleophilic displacement of acetyl derivative 296 (Scheme 64 (1992H51)). The same compound and its aryl (R = Ar (1992H51)) and carboethoxy or cyano (R = C(30Et or CN (1990H1291)) analogs can also be obtained by a Pummerer rearrangement-cyclization of sulfinyl precursor 298. 

Thieno[2,3-c]furans have also been prepared in situ by the Pummerer-rearrangement cyclization reaction (96JOC6166). For transient generation of thieno[2,3-c]furans see also Kuroda et al. [91JCS(CC)1635]. These compounds proved to be reactive intermediates for inter- and intramolecular Diels-Alder reactions (see Section IV). 

Participation by aromatic rings is also possible and there are now several examples of electro M]ic aromatic substitution involving Pummerer intermediates. Equation (20), the alkylation of benzene with dimethyl sulfoxide in trifluoroacetic anhydride, illustrates the process in its inq>lest foim. As widi al-kenes, reaction with aromatics has been more widely exploit in intramolecular versions for the construction of carbocycles and heterocycles. In many cases the sulfoxide precursor is of the keto variety, thus ensuring regiospecificity in the point of cyclization. Equation (21) (formation of a six-monber carbocycle), equation (22) (formation of a six-membered sulfur heterocycle), equation (23) (formation of a six-membered nitrogen heterocycle) and equation (24) (formation of a seven-membered nitrogen, sulfur heterocycle) provide illustrations of the versatility of diis form of intramolecular aromatic alkylation. 

A combination of the Pummerer rearrangement and the Ritter reaction occurs in the reaction of acetonitrile with methyl phenyl sulfoxide (equation 25) in a mixture of irifluoroacetic acid and its anhydride, although a substantial amount of the nonnal a-acetoxylation also occurs. Participation by amido groups is also possible, the interest here being largely in the construction of lactams via the intramolecular cycli-zation mode. Whereas Wolfe and his coworkers were unable to find conditions for the cyclization of S-phenylcysteinamide sulfoxides under Pummerer conditions, Kaneko found that variously substituted... 

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). 

Pummerer rearrangement of the Michael adducts would produce reactive sul-fenium ion intermediates 49 susceptible to a second nucleophile attack intramolecular trapping by the enol oxygen would then give the cyclized products (50). This two-step transformation was achieved directly in good yield by treatment of 48 with trichloroacetic acid and acetic anhydride in refluxing toluene. MCPBA oxidation of sulfide 50 followed by spontaneous elimination afforded furan 51 in good overall yield (Table 6). 

Intramolecular additions to A-acyliminium ions (generated by Pummerer reaction) were used to prepare highly functionalized tricyclic intermediates for the synthesis of the putative alkaloid jamtine (286). Synthesis of cherylline (88) in both of its enantiopure forms was achieved using a chiral auxiliary through a sequence involving reductive amination-acid-promoted cyclization (287). 

Glycoside and nucleoside derivatives of 3-aniino-3-deoxy-4.-thio-DL-threofuranose have been synthesized starting from the thiane diol (H). Thus the 4-thioglycoside (15) was prepared from the heterocycle (16), itself obtained from (H) in seven steps, via a Pummerer rearrangement of the intermediate sulphoxide as shown in Scheme 9 Intramolecular cyclization of D-threose dithianes... 

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