Nitrogen nucleophiles natural products synthesis

The Bernet-Vasella reductive ring opening has found many applications in carbohydrate chemistry and is a key step in several natural product synthesis [25,26]. However, the instability of the liberated aldehyde can be a problem, leading to side reactions and decomposition [27,28]. To overcome this limitation, the aldehyde has been trapped in situ by nitrogen or carbon nucleophiles. As a result, a series of domino reactions based on the Bernet-Vasella reaction has been described and applied to the total synthesis of chemically and biologically relevant products. 

Predictably, vobparicine originates from attack of the strongly nucleophilic C-22 of 66 on C-3 of 314. In fact, when a mixture of vobasinol and excess apparicine was refluxed for 2 hr in 1.5% methanolic HC1 under nitrogen, vobparicine was formed, identical in all respects with the natural product. Vobparicine was considered to be a genuine alkaloid because the conditions for its synthesis were not achieved during isolation procedure. 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

Many natural products, drugs, or plant protection agents are amino-nitrogen heterocycles. Thus, methods for their efficient synthesis are of considerable practical and technical interest. This chapter will discuss primarily the advances made in the amination of nitrogen heterocycles since the comprehensive review by Shepherd and Fedrick on Reactivity of Azine, Benzoazine, and Azinoazine Derivatives with Simple Nucleophiles was published in this series in 1%5 (65AHC145). 

The application of chiral sulfoxides to the asymmetric synthesis of biologically active compounds has recently been reviewed [3]. Conjugate addition to chiral vinyl sulfoxides has been used by several research groups to achieve the enantioselective synthesis of natural products. For example, intramolecular asymmetric conjugate addition of a nitrogen nucleophile to a chiral vinyl sulfoxide (Scheme 3) was studied by Pyne and applied to the enantioselective synthesis of (-R)-carnegine and other alkaloid systems (Scheme 3) [10]. 

Cyclic sulfites and sulfates in organic synthesis have been reviewed in a Tetrahedron report. The reactions of several carbohydrate-based sulfite and sulfate derivatives with nitrogen, carbon and sulfur nucleophiles are reported. In the area of natural products, five sulfated saikosaponins containing the trisaccharide unit 28 have been isolated as minor constituents from Bupleurum rigidum. The leaf-movement hormones, sulfated phenolic glycosides 29, have been shown to be plant specific, rather than being common to all plants. ... 

The synthesis of the natural herbicide 8-aminolevulinic acid (DALA) 54 from CMF was described in Sect. 3 of this chapter, but has also been approached directly from LA. The methods have generally relied on the halogenation of the methyl group of LA, followed by substitution with a nitrogen nucleophile which is then transformed into the primary amine. 5-Bromolevulinic 90 can be obtained by the direct bromination of LA in refluxing methanol, but the reaction suffers from poor regioselectivity, low yield, and difficult product isolation [227, 228]. 

A variation of the ANRORC reaction uses an intramolecular nucleophile to open the activated heterocycle. Vanderwal accomplished a short, formal synthesis of porothramycin A and B (not depicted) via opening of the pyridinium salt with the amide nitrogen found within 59. Product 60 contains the key functionalized pyrroline of the natural product, and the expelled Zincke aldehyde was further functionalized. 

The formation of C—N bonds is an important transformation in organic synthesis, as the amine functionality is found in numerous natural products and plays a key role in many biologically active compounds [1]. Standard catalytic methods to produce C—N bonds involve functional group manipulations, such as reductive amination of carbonyl compounds [2], addition of nucleophiles to imines [3], hydrogenation of enamides [4—8], hydroamination of olefins [9] or a C—N coupling reaction [10, 11]. Recently, the direct and selective introduction of a nitrogen atom into a C—H bond via a metal nitrene intermediate has appeared as an attractive alternative approach for the formation of C—N bonds [12-24]. 

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