Natural product synthesis Reaction

Undheim and co-workers applied their olefin metathesis strategy for the synthesis of five-membered ring spirocyclic carbocycles to synthesize six-membered ring spirocyclic carbocycles for use as templates in natural product synthesis. Reaction of 198 with 2 mol % of 3 furnished the corresponding spirocycle 199 in greater than 95% yield. 

Krafft and co-workers used olefin metathesis to prepare several inside-outside medium-size rings as scaffolds for natural products synthesis. Reaction of bicyclic lactone 267 with 10 mol % of 4 in refluxing dicholormethane gave the corresponding tricyclic lactone 269 in 88% yield after only two hours. 

Undheim and co-workers employed their olefin metathesis strategy for the synthesis of five- and six-membered ring spirocyclic carbocycles to prepare seven-membered ring spirocyclic carbocycles for use as templates in natural product synthesis. Reaction of diene 295 with 2 mol % of 3 furnished the corresponding spirocycle 296 in only 60% yield. However when diene 297 was reacted under similar conditions, the desired spirocycle 298 was obtained in 90% yield. Although no specific reason is given for the lower yield of 296, it is possible that conformational constraints and/or sterics may have played a role. 

The Boekelheide reaction has found utility in a number of synthetic applications. A notable example of its application to natural product synthesis was described by... 

In the realm of natural product synthesis, Kepler and Rehder utilized the K-R reaction to synthesize ( )-calanolide A (56), a potent non-nucleosidal human irmnunodeficiency virus (HIV-1) specific reverse transcriptase inhibitor. Propiophenone 57 was allowed to react with acetic anhydride in the presence of sodium acetate to afford benzopyranone 58 in 56% yield subsequent deacetylation of 58 gave 59. Flavone 59 was then transformed to ( ) calanolide A (56) over several steps. 

Over the years the venerable K-R reaction has been instrumental in constructing flavones for SAR programs and natural product synthesis. ... 

The condensation reaction of a CH-acidic compound—e.g. a ketone 3—with formaldehyde 1 and ammonia 2 is called the Mannich reaction, the reaction products 4 are called Mannich bases. The latter are versatile building blocks in organic synthesis, and of particular importance in natural products synthesis. 

The intramolecular Sakurai reaction allows for the synthesis of functionalized bicyclic systems. By proper choice of the reaction conditions, especially of the Lewis acid or fluoride reagent used, high stereoselectivity can be achieved, which is an important aspect for its applicability in natural products synthesis. 

The Sharpless epoxidation is one of the most important of the newer organic reactions. Although limited to allylic alcohols, it has found wide application in natural product synthesis. 

A. number of rutro compounds used m ndturdl product synthesis have been prepared by the n of alkyl halides Some recent examples are summarized m Table 2 4 fi-Nitro carbonyl compounds are important for synthesis of natural products The reaction of alkyl vinyl ketones with sodium nitrite and acetic acid in THF gives thecorrespondmgfi-nitro carbonyl compounds in42-82% ""rhis method is better for the preparation of fi-nitro carbonyl compounds than the nitration of the corresponclmg halides... 

Some more complex examples of this reaction type from the field of natural product synthesis, using a ketone, a thioenol ether, or a phenyl function as an internal nucleophile, are found in references 171-173. 

Natural products, synthesis of 829, 835, 837, 840-842, 948, 958 Nitrile oxides, reactions of 807 Nitriles - see also y-Ketonitriles reactions of 277 synthesis of 815 Nitrilimines, reactions of 277 Nitritosulphonium intermediates 206 Nitrogen compounds, as oxidizing agents 970-972... 

For overviews of applications of the Heck reaction in natural products synthesis, see (a) Link, J. T. Overman, L. E. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F., Stang, P. J., Eds. Wiley-VCH New York, 1998 Chapter 6. (b) Brase, S. de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions Diederich, F., Stang, P. J., Eds. Wiley New York, 1998 Chapter 3.6. (c) Nicolaou, K. C. Sorensen, E. J. Classics in Total Synthesis VCH New York, 1996 Chapter 31. These authors refer to the Heck reaction as "one of the true "power tools" of contemporary organic synthesis" (p. 566). 

Tietze L. F. Domino-Reactions the Tandem-Knoevenagel-Hetero-Diels-Alder Reaction and Its Application in Natural Product Synthesis J. Heterocycl. Chem. 1990 27 47-69... 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

The Suzuki reaction has proved extremely versatile and has found extensive use in natural product. synthesis. " Arylboronic acids [ArB(OH)2 are the usual substrates in this reaction together with arylhalides or triflates (Ar X, X = halogen... 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

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. 

By simple cydizations we imply reactions where only one ring is formed and for the sake of clarity these cases will be presented separately. The first example of such transformations in natural product synthesis was reported by Clive et al. in the synthesis of (i)-ceratopicanol as shown in Scheme 15 [84, 85]. 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

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... 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

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. 

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