Ionophore antibiotics synthesis

Recently, Nicolaou et al.167) reported an elegant asymmetric synthesis of the ionophore antibiotic X-14547 A (153) isolated at Hoffmann-La Roche from Strepto-myces antibioticus NRRL 8167. The key step in this synthesis was an enantioselective a-alkylation of n-butanal via its SAMP-hydrazone (151) to produce the intermediate (152). The asymmetric induction as determined by NMR-spectra of the product SAMP-hydrazone, was 95 % e.e. 

The a-pyrone (635) undergoes an exothermic Diels-Alder reaction with 1-diethylamino-1-propyne to afford the cycloadduct (636) (77JOC2930). Only a single regioisomer is produced, which is in line with the expected polarization of these reagents (Scheme 144). A Diels-Alder reaction of the same a-pyrone with 1-dibenzylamino-l-propyne affords an aniline derivative which has been employed in a chiral synthesis of the aromatic portion of the ionophore antibiotic lasalocid (80JA6178). 

Claisen rearrangements of silyl ketene acetals have been used in numerous syntheses, including the synthesis of the ionophore antibiotic Calcimycin outlined in Figure Si3.12. 

The Descostes group [14] has used this strategy of cyclization for the synthesis of the analogues of the ionophore antibiotic with anomeric spiro-structure 46 by irradiating the 4-hydroxyl-2-butanone glucoside 45 in benzene (Scheme 8.13). 

Total synthesis of macrolide and ionophore antibiotics containing fragments of tetronic acid 92YZ358. 

Phenylsulfonyl)tetrahydropyran 369 has been lithiated with w-BuLi at — 78 °C to give the anion 370, which has been allowed to react with alkyl halides and carbonyl compounds (Scheme 97)548. The corresponding 2-substituted derivatives suffered after aqueous work-up spontaneous /3-elimination of benzenesulfmic acid to give products 371. When the alkyl halide has an additional protected hydroxy group at the y- or 5-position (such as in compound 372), spiroketals (e.g. compound 373, Scheme 97) were obtained, this methodology having been applied to the synthesis of ionophore antibiotic CP 61,405 (routiennocin)550. 

As with the TMS ethers discussed in the previous section, TES ethers are subject to widely variable rates of cleavage depending on the steric and electronic environment, For example, in a synthesis of the polyether ionophore antibiotic Salinomycin, a primary TES ether was cleaved in preference to a tertiary TES ether by using HF pyridine complex at room temperature [Scheme 4.18].21... 

Synthetic Applications. (5 )-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) was first described in 1971 as an intermediate in the synthesis of o-ribose from r-glutamic acid. Since then, this lactone and its (f )-enantiomer have found widespread use as chirons for constructing a rich variety of natural products ranging from simple pheromones to complex macrocycles and ionophore antibiotics. The chemical manipulation of these chirons often involves lactone cleavage at an early stage, - - as illustrated by the preparation of suitable intermediates for the synthesis of the Vespa orientalis pheromone (R)-S-n-hexadecanolactone (14) (eq 4), the antiviral fungal metabolite brefeldin A (15) (eq 5), and (7aa)-cp/-hemibrevetoxin B (16) (eq 6). ... 

Various examples of use of alkenyltin/vinyl iodide couplings in natural-product synthesis have been provided Evans and Black [33] have obtained the macrolide insecticide (+)-A83 453A [(+)-lepicidin A] (Scheme 4-7), Burke et al. the ionophore antibiotic X-14547A [34] (Scheme 4-8), Kende et al. [35] lankacidin C (Scheme 4-9), while Han and Wiemer [36] have used the combination alkenyltin/vinyl triflate in the total synthesis of (+)-jatrophone. 

In the synthesis of an ionophore antibiotic, a bicyclic sulfone made by oxidation of the corresponding sulfide with PhSeSePh/H202 to avoid double bond oxidation was coupled with an allylic bromide in 97% yield and high stereoselectivity. The sulfonyl group was finally eliminated in basic medium to create a trans-dxene (Scheme 66). 

Strategy and methodology for the total synthesis of polyether ionophore antibiotics 00CRV2407. 

Alder reaction, catalysed by dimethylaluminium chloride, has been employed in a new total synthesis of pseudomonic acids A and C from hexa-1,5-diene. In a further study of the ionophore antibiotic lasalocid (3), it has been subjected to Mannich and Baeyer-Villiger reactions. The former took an unusual course in that the carboxyl was replaced by an aminomethyl group. The natural ionophore X-14547A (4) has been synthesized from two separately prepared segments (5) and (6) of the molecule. ... 

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