Natural product synthesis preparation

Holland, J.M., Lewis, M and Nelson, A. (2001) First desymmetrization of a centrosymmetric molecule in natural product synthesis Preparation of a key fragment in ffie synffiesis of hemibrevetoxin B. Angew. Chem. Lnt. Ed., 40,4082—4084. 

Like many other antibodies, the activity of antibody 14D9 is sufficient for preparative application, yet it remains modest when compared to that of enzymes. The protein is relatively difficult to produce, although a recombinant format as a fusion vdth the NusA protein was found to provide the antibody in soluble form with good activity [20]. It should be mentioned that aldolase catalytic antibodies operating by an enamine mechanism, obtained by the principle of reactive immunization mentioned above [15], represent another example of enantioselective antibodies, which have proven to be preparatively useful in organic synthesis [21]. One such aldolase antibody, antibody 38C2, is commercially available and provides a useful alternative to natural aldolases to prepare a variety of enantiomerically pure aldol products, which are otherwise difficult to prepare, allovdng applications in natural product synthesis [22]. 

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

These processes have flourished, mainly due to their selectivity and versatility, to the point where cross-coupling chemistry is often the initial thinking of organic chemists in synthetic and retro-synthetic approaches [2]. In fact, nowadays it is difficult to find a contribution in fine chemical or natural product synthesis where these molecular assembly tools are not employed. This is often due to the simple preparation and handling of the reaction partners as well as their relative compatibility with several functional groups. 

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. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

A straightforward application of an Ugi reaction in natural product synthesis has been elucidated by Bauer and Armstrong [53]. These authors prepared the intermediate 9-68 in the synthesis of the complex protein phosphatase inhibitor motuporin (9-69), by using an U-4CR process starting from the acid 9-64, the aldehyde 9-65, methylamine, and the isocyanide 9-66 via 9-67. 

A number of nitro compounds used in natural product synthesis have been prepared by the nitration of alkyl halides. Some recent examples are summarized in Table 2.4. 

Nitroalkenes prepared from aromatic aldehydes are especially useful for natural product synthesis. For example, the products are directly converted into ketones via the Nef reaction (Section 6.1) or indoles (Section 10.2) via the reduction to phenylethylamines (Section 6.3.2). The application of these transformations are discussed later here, some examples are presented to emphasize their utility. Schemes 3.3 and 3.4 present a synthesis of 5,6-dihydroxyindole66 and asperidophytine indole alkaloid,67 respectively. 

The reduction of nitro ketones with baker s yeast is a good method for the preparation of chiral nitro alcohols.89 The reduction of 5-nitro-2-pentanone with baker s yeast gives the corresponding (5)-alcohol, which is an important chiral building block. Various chiral natural products are prepared from it. In Scheme 7.16, the synthesis of the pheromone of Andrena haemorrhoa is described, where the acylation of the chiral nitro alcohol followed by radical denitration is involved as key steps.89a... 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

A bromoallene 75 was prepared from 74 following the standard procedure and used in the natural product synthesis [31] of 78 (Scheme 4.19) [32]. Crimmins and Emmitte succeeded in the construction of the chiral bromoallene moiety of isolaur-allene 83 by bromination of propargyl sulfonate 81 with LiCuBr2 as a key step (Scheme 4.20) [33] (cf. Section 18.2.3). 

The relevance of the palladium-catalyzed amidocarbonylation for natural product synthesis has been demonstrated with the multi gram-scale preparation of the central amino acid of chloropeptin I ((S)-3,5-dichloro-4-hydroxyphenylglycine) as well as methionine and p-chlorophenyl alanine via the combination of amidocarbonylation and enzymatic hydrolysis (Table 4) [44]. 

As model studies and radical reactivity control have improved, the so-called cascade (or domino) reactions have emerged as a very powerful method for natural product synthesis, since they offer a unique route to prepare complex backbones from appropriately designed but quite simple precursors. A few selected reactions will be presented here. 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

Non-racemic a-substituted allylic silanes, in particular crotylsilanes, are very attractive reagents despite their rather tedious preparation. They were found to provide very high transfer of chirality in their additions to achiral aldehydes under Lewis acid catalysis (Eq. 114). These reagents have been tested several times in the context of natural product synthesis. Their diastereoselectivity (syn/anti) depends on several factors, including the natme of the aldehyde substrate, the reagent, and the natme of the Lewis acid employed. For example, the syn product can be obtained predominantly in the reaction of Eq. 114 by switching to the use of a monodentate Lewis acid such as BF3. 

Be this as it may, the CH oxidation has become an attractive and promising preparative method in natural-product synthesis. For example, dioxiranes have been used to introduce selectively a hydroxy group at the C-25 position of steroids, a challenging task not readily achieved with other oxidants. A specific case is the TFD oxidation of brassinosteroid (equation 33) . 

More complex structures, often related to natural products are prepared by organic synthesis. Among them can be mentioned (f )-3-hydroxytetradecanoic acid (the double-tail hydrophobic moiety of lipid A), sphingosine derivatives related to the ceramides or 1,2- and l,3-dialkyl(acyl)glycerols related to glyco-glycerolipids, glycerophospholipids, and GPI anchors of membrane proteins. The preparations of the above derivatives were reported several years ago but some improvements have been published more recently. 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

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