Synthesis of Non-Natural Products

Intramolecular Coupling Reactions of Aldehydes and Ketones 6.2.2.1 Synthesis of Non-Natural Products 

Cycloalkenes and cyclopolyenes Cycloalkenes can be prepared in all ring sizes 

Product TiCI, Reducing Agent Solvent Yield (%) Ref. 

Transannular coupling reactions have allowed access to the higher orthocyclo-phane derivative 87 [120, 121], the triply-bridged cyclophane 88 [122], as well as the highly distorted cone calix[4]arenes 89 (R = CH2CH20Et) [123] and 90 (R = nPr) [124]. 

Thiophenes and selenophenes While the intramolecular reductive coupling of di-keto sulfides or selenides has been known since 1985, with the synthesis of a series of symmetrically and unsymmetrically substituted 2,5-dihydrothiophenes and se- 

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The Boekelheide reaction has been applied to the synthesis of non-natural products with the preparation of quaterpyridines serving as an example. The sequence began with the 2,4-linked bipyridyl-N-oxide 25. Execution under the typical reaction conditions produced the expected bis-pyridone 26. Treatment with POCI3 afforded the corresponding dichloride that was submitted to a palladium-catalyzed coupling with 2-stannyl pyridine to produce the desired quaterpyridine 27. 

As an example of the use of alkynes in the synthesis of non-natural products, Hubert and Hubert have synthesized the novel bicyclic macrocycle (29) by high dilution treatment of the tris alkynide (27) with the tribromide (28). 

P.Eaton, Synthesis of Non-natural Products Challenge and Reward, Tetrahedron (Symposium in Print), 1986, 42, 1549. Reagents for Organic Synthesis, Vo1 12, M.Fieser, John Wiley and Sons New York. 1986. 

Many new sugar based products present the advantage of being non-toxic and biodegradable. The products resulting from the telomerization of 1 with appropriate nucleophiles such as alcohols, amines, water, or carbon dioxide serve generally as useful intermediates in the synthesis of various natural products and fine chemicals [60-63], as precursors for plasticizer alcohols [56, 64], components of diesel fuels [65], surfactants [11, 66], corrosions inhibitors, and non-volatile herbicides [67]. 

Inter- and intramolecular cycloaddition reactions of furans followed by transformation of adducts were employed in the synthesis of complex natural products <02T9903>. As shown below, an intramolecular Diels-AIder reaction served as a key step to set up the D-homo- 10-epi-adrenosterone with non-natural configuration at C-10 <02CEJ1051>. 

The first example of the synthesis of a natural product by non-enzymic cyclization of a squalene derivative has been provided by Sharpless. Picric acid-induced cyclization of eryt/iro-18,19-dihydroxysqualene-2,3-oxide (18) resulted in the formation of a mixture of products from which ( )-malabaricanediol (19) could be isolated in 7% yield. The crythro-dihydroxysqualene oxide (18) was synthesized from squalene via the internal trans-oxide (20) and erythro-dio (21). The formation of the bromo-ether (22) permitted selective epoxidation of the other terminal double bond. Zinc dust reduction of (22) followed by mild alkaline... 

The use of these auxiliaries in anti aldol reactions has been described, though not by generation of the anticipated ( )-enolate. Instead, the typical (Z)-enolate is formed, and then precomplexation of a Lewis acid with the reacting aldehyde diverts the reaction away from a cyclic transition state [23]. The contrasting stereochemical trends of the catalyzed and non-catalyzed reactions are evident in an early approach to muamvatin (Scheme 9-13) [24]. Alternatively, Oppolzer has reported the Lewis acid catalyzed anti aldol reaction of a silyl enol ether derived from sultam 38 [25]. In general, however, this methodology has seen limited use in the synthesis of complex natural products. 

This three-component coupling reaction, with its greater than 150 year history, continues to enjoy great utility. It is the most efficient synthesis of non-natural amino acids due to its generality, simplicity, and low cost. These attributes are particularly attractive to process chemists where the cost of goods is a key driver for the scale up and development of chemical matter. Initial studies around this reaction gave rise to racemic versions of the product. However, more recent examples of the Strecker reaction have focused on asymmetric variations to provide optically active a-aminonitriles or a-amino acids. 

Tlie sequential reactions in elongating acyl transfers in the synthesis of polyketide natural products and non-ribosomal peptide antibiotics such as erythromycin, rapamycin, epotliilone, lovastatin, penicillins, cyclosporin and vancomycin resemble molecular solid-state assembly lines. Such multimodular enzymes may be utilized in combinatorial biosynthesis by way of reprogramming for the manufacture of unnaUiral analogs of natural products. 

The synthesis of the natural product (-)-sibirine (72), a compound containing an unusual 2-azaspiro[5,5]undecane skeleton, was described by Iwata [53], The method involved initial attack of allylmagnesium bromide on the non-racemic vinylic sulfoxide (73) (Scheme 4.38), followed by a Pummerer-type reaction (or isomerization) of the double bond as illustrated in Scheme 4.39 [54]. 

Because of this integration, control of carbohydrate reactivity is increasingly required, not only in the traditional areas of monosaccharide and oligosaccharide synthesis, but also for the preparation of carbohydrate mimics such as C-glycosides and imino sugars, and in the synthesis of glycosylated natural products and intermediates for non-carbohydrate compounds. 

When acetaldehyde is used as the only substrate, the initial aldol product can serve again as a suitable acceptor for sequential addition of a second donor molecule to give (3R,5R)-2,4,6-trideoxyhexose 133 (Figure 5.60) [282, 283]. Cyclization to stable hemiacetals masks the free aldehyde and thus effectively precludes formation of higher-order adducts. When the first acceptor is an a-substituted acetaldehyde, related aldol products from tv ofold donor additions can be prepared that are structurally related to mevino-lactone. Combination of a RibA-catalyzed initial addition to other aldolases such as FruA or NeuA in a consecutive addition reaction has also been studied for synthesis of non-natural sugars [277, 282]. 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

In the area of allenic non-natural product chemistry, the synthesis of the [34]alle-nophane 14 (Scheme 2.4) is particularly noteworthy, with all four of its allenic bridges being formed through subsequent SN2 substitution reactions of propargylic acetates with a methyl magnesium cuprate [14] (see Section 2.5 for an alternative synthesis of macrocyclic allenes). 

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