Monensin stereoselectivity

The confomiational preferences and stereoselective reactions of a number of macrocyclic systems have been studied. The stereochemical results have been explained on the basis of the model of local conformer control. The epoxidation of a macrocyclic alkene containing the substitution pattern (21) provides a single epoxide having the stereochemistry (22). A macrocycle containing a l,S-diene system adepts the local confoimation (23) that is iree of torsional strain epoxidation of (23) from the less hindered side fiimishes the syn-diepoxide (24). The MCPBA epoxidations of the unsaturated macrocyclic lactones (25) and (2Q are stereoselective (equations 9 and 10). In the epoxidation of (26) six new chiral centres are introduced the reaction product is a 20 1 1 mixture of triepoxides. The tiiepoxide (27) is closely related to the C(9)-C(23) segment of monensin B. 

Control of acyclic stereochemistry. The five contiguous stereocenters of aldehyde 5, an intermediate in Kishi s total synthesis of monensin (6), were established by the hydroboration reactions of 1 and 3, which afforded 2 and 4, respectively, with high stereoselectivity (8 1 diastereomer ratio for 1 12 1 for 3). Kishi argues that the... 

Systematic studies on the chelation-controlled additions were carried out, varying the type of alkoxy group, the carbon nucleophile, the solvent and the temperature. It was found that a-alkoxy ketones react highly stereoselectively with Grignard reagents in THF (equation 24). Alkyllithiums were not effec-tive. -6 The generalization was made use of in the synthesis of the polyether antibiotic monensin. ... 

An instructive example of a 7i-facial, homoallylic OH-directed stereoselective epoxidation in an acyclic system, used for the construction of the natural product monensin, is depicted belowC As expected, the more electron-rich trisubstituted double bond in A would be more susceptible to epoxidation than the terminal double bond. To minimize allylic 1,3-strain between the ethyl group and the CH2CH=CH2 appendage, A should preferentially adopt the conformation B, in which the smallest substituent H (hydrogen) is now in the same plane as the ethyl group. This places the hydroxymethyl moiety (CH2OH) in proximity to the P-face of the double bond, leading, after treatment with mCPBA, to the formation of epoxide diastereomer C. 

Similarly, a 1,1 4,6] rearrangement unification technique of furanoid and pyranoid precursors is applied in the stereoselective construction of the monensin building blocks 11a and b549. 

Because of the high selectivities observed in chelation-controlled additions, it is often used in stereoselective total syntheses. For example, highly selective additions of Grignards were used in the synthesis of the ionophores monensin [43,44] and lasalocid [45,46], shown in Figure 4.13. 

Scheme I. The Cane-Celmer-Westley hypothesis for the biosynthesis of monensin A (3) (a) stereoselective epoxidation (b) polyepoxide cascade it is assumed that the OH group at C(26) is also introduced during the epoxidation step.

Polyether antibiotics contain tetrahydrofuran rings. In monensin 11, three tetrahydrofuran rings are linearly connected. The molecule contains 17 asymmetric centres. Stereoselective syntheses for monensin have been elaborated [18]. In nonactin 12, the rings are interconnected in an a,a -orientation via ester groupings. Nonactin is therefore classed as a macrolide antibiotic. Polyethers of the type 11/12 are capable of facilitating ion transport across biological membranes they are, therefore, also known as ionophores. 

In 1S>93 Ireland et al. reported the total synthesis of monensin A using a modified approach (Scheme4.115) [110]. Rearrangement of the pyranyl propionate as in the tirandamycic add synthesis established the C4—C5 bond with 7 1 diastereoselectivity (Eq. 1). The challenging Cl 6 4° center was installed in high yield, albeit with no stereoselectivity (Eq. 2). Finally, the C12 4° stereocenter was installed in 51% overall yield, but with the desired isomer as the minor product (Eq. 3). 

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