Methods unnatural products

Conjugate addition [2] to Midiael acceptors is die most important and usefid reaction in orgatiocopper diemistiy, and die reaction is ofien used as die key step in die syndiesis of numerous natural and unnatural products. Perhaps one of die most efficient methods for die syndiesis of quaternary carbon centers is organo-copper-mediated conjugate addidon to /, / -disubstituted enones. 

This route provides a convenient method for synthesizing deltacyclenes 89 which have been proven to be useful in the synthesis of highly strained unnatural products of theoretical interest [88]. Diels-Alder reactions of norbornadiene (88) have been successfully activated by a nickel catalyst [89] (Scheme 3.17). Amarked influence of the catalyst on the endo-exo diastereoselectivity has been observed. 

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... 

Microbiological Methods. The low substrate specificity of many of the enzymes involved in GA biosynthesis in Gibberella fujikuroi has been utilized for the preparation of higher plant GAs. Suitable analogs of the natural GA-precursors are converted by the fungus to the corresponding GA analogs. It is usual to prevent the synthesis of the natural GAs in order to facilitate purification of the unnatural products. A mutant strain, Bl- la, in which GA biosynthesis is blocked early in the pathway (67) (between ent-kaurenal and ent-kaurenoic acid) has been used. 

We have developed two methods for the synthesis of natural and unnatural products from D-glucose. Enantio-and diastereo-switching method established a new strategy for the synthesis of four possible stereomers for natural products synthesis, and this powerful method was successfully applied to the synthesis of unnatural protein phosphatase inhibitors. The second synthetic method involved the preparation of the urea-glycosidic linkages for the synthesis of glycopeptide mimics. 

Enantio-switching Method for the Synthesis of Natural and Unnatural Products from Sugar Synthons... 

The importance of a branched chiral amines in nature and as substructures in biologically active unnatural products led to the rapid development of an impressive number of methods to synthesize this class of compounds in enantiomerically enriched forms. It is quite spectacular to see how many very efficient methods have appeared since the early twenty first century. Furthermore, catalytic asymmetric methods now exist to transfer sp , sp, or sp nonstabilized carbanion nucleophiles to a wide range of activated imines. Even if the past 10 years have witnessed phenomenal advances in this area, Ellman s chiral auxiliary method is still very attractive. Indeed, it is the only one that allows the addition of the three kinds of nucleophiles using the same dass of reagents and it also possesses numerous other... 

Live DH, Armitage IM, Dalgarno DC, Cowburn D (1985) Two-dimensional H- Cd chemical-shift correlation maps by H-detected multiple-quantum NMR in metal complexes and metalloproteins. J Am Chem Soc 107 1775-1777 Martin GE, Crouch RC (1991) Inverse-detected two-dimensional NMR methods applications in natural products chemistry. J Nat Prod 54 1-70 Martin GE, Crouch RC (1994) Two-dimensional NMR experiments in natural and unnatural products chemistry. In Croasmun WR, Carlson RMK (eds) Two-dimensional NMR spectroscopy - applications for chemists and biochemists, chap 11, 2nd edn. VCH, New York, pp 873-914... 

The pivotal role of natural a-amino acids among a myriad of biologically active molecules is widely appreciated, and is of particular importance in the pharmaceutical industry. Unnatural a-amino acids also have a prominent position in the development of new pharmaceutical products. It has been shown that substitution of natural a-amino acids for unnatural amino acids can often impart significant improvements in physical, chemical and biological properties such as resistance to proteolytic breakdown, stability, bioavailability, and efficacy. One of the many synthetic methods available for the production of enantiomerically enriched a-amino acids is the metal-catalyzed enantioselective reduction of a-de-hydroamino acid derivatives [90]. 

These defects have spurred attempts to prepare analogs. The techniques used have been (1) natural fermentation (in which the penicillin-producing fungus is allowed to grow on a variety of complex natural nutrients from which it selects acids for incorporation into the side chain), (2) biosynthetic production (in which the fermentation medium is deliberately supplemented with unnatural precursors from which the fungus selects components for the synthesis of "unnatural" penicillins), (3) semisynthetic production (in which 6-aminopenicillanic acid (2) is obtained by a process involving fermentation, and suitably activated acids are subsequently reacted chemically with 6-APA to form penicillins with new side chains) and (4) total synthesis (potentially the most powerful method for making deep-seated structural modifications but which is at present unable to compete economically with the other methods). 

D-Proline (16) is an unnatural amino acid and an important chiral synthon for the synthesis of a variety of biologically active compounds. There are few chemical methods for asymmetric synthesis of this compound. Almost all processes for the production of D-proline at scale are based on resolution of d/-prolinc, and most of them involve the racemization of L-proline (17). 

The photolysis of Barton esters (N-hydroxy-2-thiopyridone esters, 43) proved to be an efficient method for generating carbon-centered radicals that are exploited for the regioselective alkylation of electron-deficient olefins a thiopyridyl unit is likewise incorporated into the end products. In a recent application, Barton esters were found useful in the synthesis of natural and unnatural disubstituted maleimides or maleic anhydrides by way of two consecutive radical addition steps, as described in Scheme 3.27 [72]. 

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