Additive Pummerer sequence

More recently, two distinct mechanistic pathways for the Pummerer rearrangement have been described. These are the vinylogous Pummerer pathway, and the additive Pummerer sequence. The vinylogous pathway... 

The additive Pummerer sequence proceeds via an SN2-like displacement, that is, nucleophilic attack and alkoxide departure take place in a concerted manner. This pathway has been utilized more recently for the formation of heteroatom-carbon and carbon-carbon bonds, particularly in the synthesis of polycyclic natural products and drug-like molecules. 

As was introduced earlier in this chapter tScheme 20.22 and previous section), the additive pathway in Pummerer chemistry is in competition with the vinylogous path, and its application is still in some cases unpredictable. Fortunately, Yorimitsu, Oshima, and coworkers have published a sequence of papers providing excellent applications of the additive Pummerer pathway. They used a combination of two Pummerer approaches, such that the activation of sulfoxides was done as usual by an electrophilic reagent, but they used the beginning of a so-called interrupted Pummerer reaction (vide infra) to generate the a,(3-unsaturated sulfonium salt 121. This intermediate did not follow the traditional... 

The sequence could even be prolonged by including a Pummerer reaction. Thus, treatment of 4-103 with trifluoroacetic acid (TFA) gave the furan 4-104, which underwent a cycloaddition to furnish 4-105 the erythryna skeleton 4-109 was obtained after subsequent addition of a Lewis acid such as BF3- Et20 (Scheme 4.23) [33]. It can be assumed that 4-106, 4-107 and 4-108 act as intermediates. In a more recent example, these authors also used the procedure for the synthesis of indole alkaloids of the Aspidosperma type [34]. 

Conceivably, the azo-ir system of II could be derived from the internal redox reaction implied in the elimination-addition sequence depicted in the production of III. Subsequent /3 elimination would afford the desired double bond. In the case of nitrogen as the neighboring atom the ylide intermediate of Scheme 26.1 would not be necessary since the availability of a nonbonding pair of electrons should make the use of base accessory. Thus the reaction pathway would be subsequently shortened. Moreover, the required electrophile, thionyl chloride, would be present in the reaction medium in large quantity. The prospect of a Pummerer-type rearrangement during the transformation of I into II is therefore likely. 

Lactaldehyde 689 has been used as the chiral source in an interesting synthesis of unnatural D-threonine (695) [204] (Scheme 93). The first of the two most important reactions in the sequence is the conversion of 691 to 692. The transformation proceeds by partial methano-lysis of the trichloroacetyl group followed by intramolecular conjugate addition, which forms the oxazolidinone ring in 692 stereospecifically at C-4 and C-5. The second critical reaction is a Pummerer rearrangement of 693 to 694, which introduces the requisite carboxyl function (as... 

In another example, addition of phenyl vinyl selenoxide into a mixture of an indanedione, hexamethyldisilazane, and TMSCl in dichloromethane affords the a-trimethylsiloxyselenide in 70% yield (eq 67). The reaction proceeds through a sequence of in situ formation of TMS silyl enol ether, Michael addition onto the phenyl vinyl selenoxide, and seleno Pummerer rearrangement of the resulting selenoxide. Trifluoroacetic anhydride and various other trialkylchlorosilanes give the same product for this reaction, but in much lower yields. 

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). 

Recendy, we described a useful sequence where Michael-acceptor sulfoxides 30 were obtained in two steps from homopropargylic alcohols 29 by radical addition of thiophenol and oxidation with sodium periodate. The unsaturated sulfoxides were used in a highly stereoselective intramolecular oxa-Michael reaction. The sequence provided stereoselective functionalization of the sulfoxide moiety, and the products 31 proved to be useful in the synthesis of modified furanosides 32. This represents a good exanple where sugars are prepared from acyclic precursors. The Michael addition was followed by a hydrolytic Pummerer reaction, yielding protected a-hydroxy aldehydes tScheme 20.8) that upon acidic treatment afforded 3-substituted ribofuranoses. 

The second exanple is a new synthetic approach to the synthesis of nakadomarin A 202 rscheme 20.. 38T To this end, Wnkler and coworkers developed a tandem Pummerer-Michael process.The generation of the activated thionium ion was performed by the elimination of ethanethiol from thioacetal 198. The intermediate 199 showed double reactivity, that is, a nucleophilic position on the furan to perform the Michael addition and the usual electrophilic thionium, which was in fact trapped by the enamine carbon generating tetracyclic product 200. Winkler presented the s)mthesis of a tetracyclic model system and suggested that this reaction sequence can also be applied to the synthesis of the natural product. 

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