Natural product synthesis single stereogenic center

Domino Michael/aldol addition processes unquestionably represent the largest group of domino transformations. Numerous synthetic applications - for example, in natural product synthesis as well as for the preparation of other bioactive compounds - have been reported. Thus, the procedure is rather flexible and allows the use of many different substrates [12]. In this process it is possible, in theory, to establish up to two new C-C-bonds and three new stereogenic centers in a single step. For example, Collin s group developed a three-component approach. 

While pyruvate aldolases form only a single stereogenic center, the aldolases specific for dihydroxyacetone phosphate (DHAP, 22) as a nucleophile create two new asymmetric centers at the termini of the new C—C bond. Particularly useful for synthetic applications is the fact that nature has evolved a full set of four stereochemically unique aldolases [27] for the retroaldol cleavage of ketose 1-phosphates 23-26 (Fig. 12). In the direction of synthesis this formally allows the deliberate preparation of any one of the possible four diastereomeric aldol adducts in a building block fashion [15,22,27] by simply choosing the complementary enzyme and starting materials for full control over constitution and absolute configuration of the desired product. 

The deMayo-type photochemistry of 1,3-dioxin-4-ones has been beautifully applied by Winkler et al. to the synthesis of complex natural products. Substrate 133 gave under sensitized irradiation (with acetone as cosolvent) product 134 as single diastereoisomer (Scheme 6.47). The diastereoselectivity results from cyclic stereocontrol exerted by the two stereogenic centers in the spiro-bis-lactone part of the starting material. After installation of the furan, saponification and bond scission in a retro-aldol fashion generated a keto carboxylic add, which produced the natural product ( )-saudin (135) by simultaneous formation of two acetal groups [128]. 

Dipolar cycloaddition of nitrones to alkenes has been widely utilized for the synthesis of many nitrogen-containing natural products. Indeed, in this process, up to three stereogenic centers are built up in a single step, often in a highly stereoselective manner. Louis and Hootele recently reported the first highly selective 1,3-dipolar cycloaddition between an a,P-unsaturated sulfoxide and a cyclic ni-... 

The purpose of this book is to highlight the problems associated with the production of chiral compounds on a commercial scale. With the movement by pharmaceutical companies to develop single enantiomers as drug candidates, the focus has turned to problems associated with this subclass of organic synthesis. The major classes of natural products are also discussed since the stereogenic center can be derived from nature through the use of chiral pool starting materials. 

In the remainder of this chapter, we will present another total synthesis in which transannular Diels—Alder reactions would appear to play an essential role in Nature s construction of a natural product. That work is the 2001 total synthesis of (—)-FR182877 (1) in which the Sorensen group at The Scripps Research Institute executed not one, but two transannular Diels—Alder reactions in a single cascade to establish five rings and seven stereogenic centers from a 19-membered macrocyclic pentaene precursor. 

In the course of a total synthesis of the diterpenoic tetraol (+)-aphidicolin, Des-longchamps and coworkers developed a domino transannular Diels-Alder/aldol reaction of macrocyclic trienyl oxo aldehyde 88, which closed four rings and assembled the entire skeleton of the natural product in one transformation. Heating 88 in a sealed tube in toluene at 230 °C for 24 h in the presence of triethylamine as proton scavenger first initiated the transannular Diels-Alder reaction, which was followed by the intramolecular aldol reaction to deliver tetracycle 90 in excellent yield and as a single diastereomer (Scheme 8.26) [47]. Three new carbon-carbon a-bonds and four new stereogenic centers were established with complete stereocontrol. 

Since intramolecular transannular aldol reactions create two new rings and at least two new stereogenic centers in a single process, the corresponding cyclic p-hydroxy ketones are useful for the synthesis of polycyclic natural products. The trons-4-fluoro proline 48 is superior to (S)-proline in catalysis of this type of reaction, affording excellent diastereoselectivity and enantioselectivity (Scheme 28.4). The utility of this reaction has been demonstrated in a total synthesis of (-l-)-hirustene (50), is a fungal metabolite first isolated from the basidiomycete Coriolus consors [27]. 

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