Calcimycin synthesis

One of the low points of the first calcimycin synthesis is introduction of the pyrrole unit via an aldol condensation. The yields are bw and the stereocontrol at Ci9 Is probably marginal. The Grieco synthesis disconnects calcimycin between C213 and the 2-position of the pyrrole. Therefore a significant difference between this approach and the Evans approach Is an attempt to achbve better control of stereochemistry at C g. A secondary difference is that C was to be Introduced with complete control of stereochemistry rather than relying on thermodynamics for stereocontrol. It will be seen that a consequence of this plan is... 

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. 

In total synthesis of the structurally unique natural product calcimycin (15), Grieco and others used Ireland-Claisen rearrangement of the ester 17 to synthesize the key intermediate (18)7 (Scheme 1.3g). Monosilylation of the diol 16 followed by treatment with propionyl chloride in pyridine gave rise to the ester 17 in 90% yield. Treatment of 17 with LDA in THF at —78 C, subsequent addition of ferf-butyldimethylsilyl chloride in HMPA, and brief heating of the resulting silylketene acetal provided the corresponding silyl ester. Subsequent hydrolysis of the silyl ester and esterification with diazomethane gave 18 in 90% yield from 17. 

Another useful system is o-nitrophenyl selenocyanate and tributylphos-phine (Bu3P), developed by Grieco and co-workers,104-106 which has been employed in the synthesis of intermediates leading to the ionophone antibiotic calcimycin.103... 

As illustrated in Scheme 11.10, enone 32, prepared from D-glucal in a multistep sequence, was reacted with lithium dimethylcuprate. Clean axial attack of the reagent at C4 gave the substituted ketone 33. Subsequent Wittig methylation and reduction was used to introduce the second methyl group of 34, a key intermediate in the synthesis of a-multistriatin. The same sequence was used in the preparation of calcimycin (A23187), the 4-C-methyl synthon 33 being used to construct the two required chirons [50]. 

The antibiotic calcimycin (or A23187) is a widely used probe for calcium ion transport in biological systems. A synthesis of the core of this antibiotic has been developed [15]. Although little stereoselectivity is associated with this method it is rather remarkable in that two ring closures are involved, the first involving hemi-acetal formation and the second an electrophilic closure (Fig. 12). 

A synthesis of the ionophore antibiotic A 23187 (calcimycin) has been completed, using D-glucose as a source of the enone (34), and... 

L-lsoleucine. A full account has been given of the synthesis of the spiroketal antibiotic A23187 (calcimycin) from glucose (see Vol. 18, p.250-1). Full details have also been reported for the synthesis of a glucose-derived fragment, mentioned last year (Vol. 19, p.256), corresponding to C(9)- C(14) of okadaic acid, and the total synthesis of the complete structure of this marine toxin has... 

In 1982 Grieco et al. reported the total synthesis of calcimycin (Scheme 4.117) [113]. They took advantage of the stereospecific feature of the Ireland-Claisen rearrangement by converting two epimeric alcohols to the same rearrangement product. For the yS-propionate, they employed the Ireland conditions for generating the F-silyl ketene acetal and for the a-propionate, the Z-silyl ketene acetal. Both transformations proceeded in high yield. 

Just as with lasonollde A, these targets are amenable to convergent syntheses. It is not surprising that there are features common to all of the calcimycin syntheses. There are some strategic differences, however, and these will emerge as we oohsider each approach. We wil begin with the first synthesis of... 

This synthesis of calcimycin was one of the first total syntheses of an ionophore. It was preceeded by syntheses of nonactin (Gerlach and Schmidt), followed shortly by syntheses of lasalocid A (X537A) (Ireland), and then by the landmark syntheses of monensin (2) developed by Kishi and Still. The Evans synthesis illustrates the importance of symmetry in synthesis design, and documented observations that were clearly useful to those that followed. The synthesis suffered somewhat from stereocontrol, particularly... 

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