Nikkomycin synthesis

However, not all nucleophiles show the same bias as shown in Scheme 4 5 on addidon to the nirroalkene The product of the addidon of potassium phthalimide has 5(R) stereochemistry fEq 4 38 This stereoselecdve addidon is applied for the synthesis of other related andbiodcs, such as nikkomycine B ... 

Enzyme preparations from liver or microbial sources were reported to show rather high substrate specificity [76] for the natural phosphorylated acceptor d-(18) but, at much reduced reaction rates, offer a rather broad substrate tolerance for polar, short-chain aldehydes [77-79]. Simple aliphatic or aromatic aldehydes are not converted. Therefore, the aldolase from Escherichia coli has been mutated for improved acceptance of nonphosphorylated and enantiomeric substrates toward facilitated enzymatic syntheses ofboth d- and t-sugars [80,81]. High stereoselectivity of the wild-type enzyme has been utilized in the preparation of compounds (23) / (24) and in a two-step enzymatic synthesis of (22), the N-terminal amino acid portion of nikkomycin antibiotics (Figure 10.12) [82]. 

Figure 10.12 Stereoselective synthesis ofthe amino acid portion of nikkomycin antibiotics and hexulosonic acids using KDPGIc aldolase.

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

Barrett and Lebold used the Brown asymmetric crotylation to prepare the homoallyhc alcohol 22 in the total synthesis of nikkomycin B 21, a natural product that exhibits fungicidal, insecticidal, and acaricidal activities14 (Scheme 3.1k). 

Several of these bioactive natural products have been successfully developed as therapeutics for clinical use. For example, Cyclosporin A is a fungal decapeptide principally used to suppress immune rejection in organ transplant patients. Mevinolin and compatin both control cholesterol synthesis in human. The search for enzyme- or receptor-targeted microbial products does not limit itself to medical use. Several commercially important antibiotics such as Nikkomycin and Avermectin have been found for agricultural applications in recent years. 

Scheme 5.38. Strategy for the synthesis of the N-terminal amino acid of Nikkomycin (top) and the general structure of Nikkomycins B, I, J, K, Z, X and Z (bottom).

Tamura, O, Mita, N, Kusaka, N, Suzuki, H, Sakamoto, M, Intramolecular cycloaddition of a-allyloxycarbonylnitrone bearing a chiral sugar auxiliary a short-step synthesis of the A-terminal amino acid component of nikkomycin Bz, Tetrahedron Lett., 38, 428-432, 1997. 

Histidine ammonia lyase (HAL, histidinase, histidine-a-deaminase, E.C. 4.3.1.3) is capable of abstracting ammonia from L-histidine (17), resulting in the formation of urocanoic acid [Scheme 12.6-4, (6)], an intermediate in the metabolism of l-histidine,n). HAL has also been identified as a key enzyme in the synthesis of secondary metabolites such as Nikkomycin in Streptomyces tendae,ul The mechanism of the enzyme has been investigated and seems to proceed via the carbanion intermediate111, 13]. Synthetic applications of HAL are difficult to achieve, particularly as the enzyme is sensitive to oxygen1131. The utility of HAL is limited to niche applications such as the synthesis of radiolabeled urocanic acids as tracers of histidine metabolism1"1. 

Schluter U, Seifert G. Chitin synthesis Inhibition by Nikkomycin in the integument of Manduca sexta An ultrastrcutural and fluroescence microscopic study. J. Invertebrate Pathol. 1989, 53, 387-391. 

Polyoxin and nikkomycin analogs Recent design and synthesis of novel peptidyl nucleosides 13HC375. 

Hayashi and co-workers used a similar strategy (Scheme 25) for the formal total synthesis of nikkomycin B (107) (96), a nucleoside peptide antibiotic isolated from the culture broth of Streptomyces tendae. In the key step, propionaldehyde (60), furfural (108), and the TBS-protected aniline 109 were reacted in the presence of... 

FIGURE 11.43 Combinatorial synthesis of nikkomycin derivatives using Ugi reaction. (From Suda, A. et al., Combinatorial synthesis of nikkomycin analogs on solid-support, Heterocycles, 55 1023, 2001.)... 

The opening of the cyclopentene moiety involved the ozonolysis of the double bond and this has been used by Hon for the synthesis of alkenyl butyrolactones. This cyclopentene cycle could also be used for the palladium-catalyzed nucleophilic substitution of the C-4 of the fused lactones. By this strategy, Aggarwal described an access to carbocyclic uracil polyoxin C and the nikkomycins analogues." " ... 

A total synthesis of nikkomycin B from a uracil nucleoside precursor has been reported. The stereoisomers (37a) of 4, 5 -... 

Nikkomycins B 61 and Bx 62 are nucleoside peptide antibiotics isolated from the culture of Streptomyces ten-They contain a (3-amino carbonyl moiety. Hayashi and co-workers developed a three-component, Mannich-type reaction mediated by L-proline and applied it to an asymmetric synthesis of the A -terminal amino acid moiety of nikkomycin B 61 and Bx 62 (formal total synthesis). As shown in Scheme 27.10, a three-component Mannich reaction using 2-furylaldehyde 55, reri-butyl-dimethylsi-loxyaniline 56, and propanal 39 gave the Mannich adduct 58 in 96% ee. In the particular case of 2-fiirylaldehyde 55, pyridine (1.5 equiv) was reported to be effective for obtaining excellent enantioselectivity. 

Hayashi Y, Urushima T, Shin M, Shoji M. The stereoselective synthesis of a-substituted p-amino secondary alcohols based on the proline-mediated, asymmetric, three-component Mannich reaction and its application to the formal total synthesis of nikkomycins B and Bx. Tetrahedron 2005 61 11393-11404. 

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