Synthesis of natural and unnatural

Copper-Mediated Synthesis of Natural and Unnatural Products... 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

The Barton-Zard pyrrole synthesis has now been extensively applied to synthesis of natural and unnatural products containing pyrrole units. Methyl 4-methylpyrrole-2-carboxylate is the trail-maker pheromone of the Texas leaf-cutting ant Atta texana.24 It is readily prepared by the Barton Zard method in 60% yield (Eq. 10.22).22... 

Enzymes are useful catalysts for a broad diversity of chemical reactions that enable the synthesis of natural and unnatural highly pure pharmaceutically active compounds. However, proteins themselves can also be the pharmaceutical ingredients. 

The utility of small ring conjunctive reagents in total syntheses appears to be very great. The convulated structural correlations between the target and a starting material hamper its ready adaptation. The facility and stereochemical implications make the rethinking of retrosynthetie analysis well worth the effort. To illustrate some of this potential, several applications in the total synthesis of natural and unnatural products are analyzed. 

Intramolecular nitrile oxide cycloadditions were first studied by Garanti and coworkers (24) in 1975, employing 0-allyl derivatives of salicylic aldehyde. The first example of a carbocycle-forming process was reported in 1977 (25). This process (sometimes referred to as INOC) has seen many extensions and applications for the synthesis of natural and unnatural products alike, notably by the groups of Kozikowski, Curran, Fukumoto, and Shishido (see Section 6.4). 

Despite numerous efforts to develop the asymmetric phase-transfer-catalyzed alkylation of 2 into a powerful method for the synthesis of natural and unnatural a-amino adds, the stereochemistry of the alkylation of 2 with chiral electrophiles has scarcely been addressed. 

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