Asymmetric reactions natural products

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Abstract Since its discovery the chromium-mediated benzannulation reaction has been developed into a unique and useful tool in organic synthesis. In this review, topical aspects of this reaction concerning its mechanism and the chemo-, regio- and stereoselectivity are summerised and discussed in detail. Special attention is paid to the asymmetric benzannulation reaction and, finally, the importance of this reaction as a key step in the total synthesis of natural products is outlined. 

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

Helmchen G., Goeke A., Kreisz S., Krotz A Lauer H., Linz G. Cyclopentanoid Natural Products Via Asymmetric Diels-Alder Reactions Stud. Nat. Prod. Chem. 1991 8 139-158... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky s dienes) exhibit abnormal exo-selectivity. Electrostatic repulsion between the nitro and the silyloxy group of the diene induces this abnormal exo-selectivity (Eq. 8.10).17 This selective reaction has been used for the asymmetric synthesis of various natural products as shown in Scheme 8.6. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

The asymmetric allylic alkylation (AAA) reaction has been adapted for use with pyrrole nucleophiles <06JACS6054>. For example, treatment of pyrrole 55 and cyclopentene 56 with a palladium catalyst in the presence of a chiral additive gave pyrrole 57 in up to 92% ee. The latter was elaborated into piperazinone-pyrrole natural product, agelastatin A 94. 

Perhaps the most investigated reaction of organozinc compounds is their addition to the carbonyl group of aldehydes. A broad range of simple and functionalized diorganozincs and a great variety of aldehydes have been studied in this transformation. The reaction furnishes chiral secondary alcohols, which are essential building blocks in the synthesis of natural products and other important compounds. Recent studies of this transformation have been devoted to its asymmetric catalytic versions (Scheme 103). 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

William R. Roush is Warner Lambert/Parke Davis Professor of Chemistry at the University of Michigan. He received his B.S. from the University of California, Los Angeles, in 1974 and his Ph.D. from Harvard University in 1977. His research area is organic chemistry, with specialized interests in organic synthesis and natural products chemistry, stereochemistry of organic reactions, development of new methods and regents, asymmetric synthesis, and oligosaccharide synthesis. 

Yang12 has effected an intramolecular asymmetric carbonyl-ene reaction between an alkene and an a-keto ester. Reaction optimization studies were performed by changing the Lewis acid, solvent, and chiral ligand. Ligand-accelerated catalysis was observed for Sc(OTf)3, Cu(OTf)2, and Zn(OTf)2 (Equation (6)). The resulting optically active m-l-hydroxyl-2-allyl esters provide an entry into multiple natural products. 

Intermolecular cycloadditions or Diels-Alder reactions have proved to be a successful route to several valuable intermediates for natural product syntheses. In creating new chiral centers, most of these reactions apply single asymmetric induction. As mentioned in Chapter 3, in the asymmetric synthesis of the octa-hydronaphthalene fragment, the Roush reaction is used twice. Subsequent intramolecular cyclization leads to the key intermediate, the aglycones, of several natural antitumor antibiotics. On the other hand, the Diels-Alder reaction of a dienophile-bearing chiral auxiliary can also be used intramolecularly to build... 

Applications of Asymmetric Reactions in the Synthesis of Natural Products... 

The essence of asymmetric synthesis is producing a new stereogenic center in such a manner that the product consists of stereoisomers in unequal amount. In most cases, this can be achieved by the formation of a new sp3 stereocenter. There is also another type of asymmetric reaction in which the employed substrates contain either a stereogenic unit or a pro-stereogenic unit apart from the functional group, and asymmetric synthesis occurs even though the nature of the reaction is not directly related to the newly formed sp3 stereocenter. The Wittig reaction is invoked for the asymmetric synthesis of such molecules.47... 

Although the application of carboalumination to the synthesis of natural products is still in its infancy, a few preliminary results shown in Scheme 1.50 [167,168,171,172] suggest that it promises to become a major asymmetric synthetic reaction, provided that (i) the singularly important case of methylalumination can be made to proceed with S90% ee, and (ii) satisfactory and convenient methods for enantiomeric and diastereo-meric separation/purification can be developed. In this context, significant increases in ee in the synthesis of methyl-substituted alkanols from around 75 % to 90—93 % achieved through some strategic modifications are noteworthy (Scheme 1.50) [168]. Shortly before the discovery of the Zr-catalyzed enantioselective carboalumination, a fundamentally discrete Zr-catalyzed asymmetric reaction of allylically heterosubstituted alkenes proceeding via cyclic carbozirconation was reported, as discussed later in this section. 

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