Ansa, chain

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

A good example for such a situation is a recent report on the synthesis of the macrotricyclic core 63 of roseophilin [40,41]- RCM was able to form the rather strained ansa chain of this target molecule only after the cyclization had been biased by a conformational control element X which helps to bring the unsaturated chains closer together and lowers the enthalpic barrier during ring formation (Scheme 18). 

The same strategy can be applied to complete the conversion from 58 to 61, as described in Scheme 7-13. Nearly the same sequence is performed for the conversion from 58 to 59, from 59 to 60, and from 60 to 61. Diethylzinc addition and subsequent methylation of the hydroxyl group provides 62 in a ratio of 4.6 1. In this manner, the synthesis of this key intermediate containing all eight chiral centers present in the ansa chain has been completed. 

Further transformation of 62 to the ansa chain (+ )-66 is briefly summarized in Scheme 7-14 without a detailed discussion. Compound ( )-66 has now been properly functionalized for coupling with the aromatic unit of rifamycin. 

The aldol reaction that establishes two chiral centers in one step has been applied to the synthesis of the ansa chain 66 by Kishi s group as discussed above. Seven chiral centers out of the eight present in the corresponding 66a can be constructed in a different way through a convergent series of four... 

At this juncture, it is useful to look at Table 7-1, in which the syntheses of erythronolide and the ansa chain are used as examples to show that reagent-controlled syntheses are clearly more advantageous than substrate-controlled reactions in terms of three criteria the overall yield, overall stereoselectivity, and number of steps involved in each of the syntheses. A careful examination of Table 7-1 clearly shows the advantages of this strategy. 

Target Molecule 6-Deoxyerythronolide B Erythronolide A Derivative Ansa Chain of Rifamycin B 66 66... 

The synthesis of aldehyde 48 proceeds in 16 steps from (S)-39 in 15% yield and 75% stereoselectivity. The brevity, efficiency, and selectivity of this synthesis rivals alternative acyclic diastereoselective approaches to the rifamycin ansa chain, (see footnote 4 in reference 3i), thereby providing a clear testimony to the potential of the tartrate allylboronates as reagents for complex synthetic problems. 

In 5,7-polymethylene derivatives of cyclohepta[c]furan-6-ones, the C=0 band is shifted from 1682 down to 1628 cm1 on lengthening the ansa chain from 7 up to 10 members (85MI3). 

A further method to induce chirality in the pyridoxamine-mediated transamination reactions was developed by Kuzuhara et al. [13]. They synthesized optically resolved pyridinophanes (21, 22) having a nonbranched ansa chain" between the 2 - and 5 -positions of pyridoxamine. With the five-carbon chain in 21 and 22, the two isomers do not interconvert readily. In the presence of zinc(n) in organic solvents such as methanol, tert-butanol, acetonitrile, and nitromethane, they observed stereoselective transamination between pyridinophanes and keto acids. The highest ee%s are 95 % for d-and L-leucine by reaction of the corresponding a-keto acid with (S)- and (R)- 22, respectively. On the basis of kinetic analysis of the transamination reactions, Kuzuhara et al. originally proposed a mechanism for the asymmetric induction through kinetically controlled stereoselective protonation to the carboanion attached to an octahedral Zn(n) chelate intermediate. However, they subsequently raised some questions about this proposal [14]. 

Kuzuhara et al. synthesized an optically resolved pyridoxal analog having an ansa chain" between the 2 - and 5 -positions (45) [46]. The aldolase-type reaction of 45 and glycine with either acetaldehyde or propionaldehyde afforded the corresponding P-hy-droxy-a-amino acid with 27-77% ee. The erythro isomers were 1.2-1.8 times dominant over threo ones. The (S) -enantiomer of the pyridoxal derivative furnished the (S)-amino acid in excess. Accordingly, the reaction occurred on the same face as was occupied by the ansa chain. We have confirmed these results [47]. 

Naphthomycin has been isolated from a Streptomyces species28. Its structure has been elucidated and shown to belong to the class of naphthalenic ansamycins (Fig. 3)29 In contrast to these compounds, however, the skeleton of the ansa chain contains six additional C-atoms. Very recent structural studies of the chromo-phore have shown that naphthomycin possesses a hydroxyl group in position 6 and is unsubstituted in position 8 (W. Keller Schierlein, personal communication). It thus resembles the streptovaricin precursor protostreptovaricin I (Fig. 8). A further characteristic of naphthomycin is that it contains a halogen in the chromophore. 

Investigations of the biosynthesis of the rifamycins, streptovaricins and geldanamycin proved that the ansa chain of the ansamycins is synthesized as proposed by Woodward. The isolation of the precursors rifamycin W, damavaricin C and D and the protostreptovaricins, together with the fact that rifamycin B and tolypomycin Y are cosynthesized by Streptomyces tolypophorus26 make it probable that the rifamycins, streptovaricins and tolypomycin Y have a common progenitor. 

Studies using 14C-labelled precursors and C-l3 carbon magnetic resonance have suggested that the biosynthesis of the benzenic ansamycin geldanamycin follows essentially the same pathway as that of the rifamycins and streptovaricins50. Geldanamycin is composed of 3 acetate and four propionate units which are attached to a C7N unit in the same direction of growth as is found in rifamycins and streptovaricins. The incorporation of three acetate units into the ansa chain, as opposed to two in the naphthalenic ansamycins, excludes the existance of a common precursor. 

Karlsson, A., Sartori, G., White, R.J. Rifamycin Biosynthesis further studies on origin of the ansa chain and chromophore, Europ. I. Biochem. 47, 251 (1974)... 

Both ( )- and (Z)-crotylboronates have been used in several applications in natural product synthesis. " One application of both the allylboronate and ( )-crotylboronate reagents is found in the synthesis of the C(19)-C(29) segment of rifamycin S. The desired stereochemistry at C(25)-C(26) of the rifamycin ansa chain is set with excellent stereocontrol (>95 5) and high yield (87%) (eq 8). " ... 

Analogous sequences have been used in the synthesis of the ansa chain of rifamycin [100,101] and in the synthesis of the avermectin Bia spiroketal unit 52 [102]. The retrosynthetic plan used is described in Scheme 11.30 and leads to the same intermediate, 118. 

Schreiber, S.L., Wang, Z., and Schulte, G., Group selective reduction of acetals related to the ansa chain of the streptovaricins. Conformational and stereochemical analysis. Tetrahedron Lett., 29, 4085, 1988. 

Halichlorine (789) ([a]o +240.7°, c 0.54, MeOH), isolated from the Japanese sponge Halichondria okadai, is a complex alkaloid possessing a novel spiro-quinolizidine macrolide structure (537). Elucidation of the structure was based on detailed analysis of coupling constants and NOE effects in the NMR spectrum The absolute configuration of the ansa chain was inferred by degradation to the... 

The high syn stereoselectivity attained in zirconium enolate aldol reactions has proved useful in complex natural product synthesis. The zirconium-mediated aldol reaction of the chiral ethyl ketone (9) with a chiral aldehyde has been used by Masamune et al. to give selectively adduct (10), which was further elaborated into the ansa chain of rifamycin S (equation 1). Good enolate diastereofacial selectivity is also obtained here and leads to a predominance of one of the two possible syn adducts. A zirconium enolate aldol reaction also features in the Deslongchamps formal total synthesis of erythromycin A, where the di(cyclopentadienyl)chiorozirconium enolate from methyl propionate adds with high levels of Cram selectivity to the chiral aldehyde (11) to give the syn adduct (12 equation 2). A further example is... 

Rifamycin W (104) was isolated from a mutant strain of Norcardia mediterranei [187] and its structure was determined [188] on the basis of spectroscopic studies in comparison with rifamycin S (102). Rifamycin W (104) is transformed by the parent Norcadia strain into rifamycin S and therefore is thought to be the biosynthetic intermediate of all the rifamycins [187]. The total synthesis carried out by Tatsuta et al. has allowed the elucidation of the complete stereochemistry of compound (104) [189]. The synthesis has been accomplished by coupling the segments of the aliphatic ansa-chain (E) and the aromatic nucleus (F). 

The unique structures and important biological activities of the streptovaricins have attracted considerable attention of synthetic chemists. There are several synthetic approaches to the streptovaricin ansa chains and also to the naphthoquinone nucleus. Several building blocks for the synthesis of the ansa chain of streptovaricin A (105) have been prepared by aldol condensations, [194] by ring-opening of epoxides [195] and by the strategy termed pyranosic homologation [196]. 

The stereoselective synthesis of compound (113) by means of the ring opening of epoxides is described in Scheme 49. The starting diolefin [197] was regio and stereoselectively diepoxidized to the corresponding diepoxy alcohol, which was then transformed into a dicarbonate and finally into the pentaacetate (113), which contains all nine stereocenters of streptovaricin A ansa chain. 

The pyranosidic homologation strategy has been also applied to the synthesis of compound (114) [196a,b], which also contains the nine stereocenters of streptovaricin A ansa chain (Scheme 50). Compound (114) was prepared starting from a D-glucose derivative, after conversion into a dipyranoside [196a] and thence tripyranoside [196d]. 

The synthesis of the Cl-Cl5 segment (116) [198] of streptovaricin D (109) has been carried out from the aldehyde (115) [199], an enantiomer of an intermediate used by the same authors in the synthesis of the rifamycin ansa chain. Compound (105) was submitted to the Evans aldol procedure to give an aldol, which was transformed into the corresponding acetonide. Ozonolysis to the expected aldehyde and crotylmetallation with chromium(II) chloride provided a 5 1 mixture of diastereoisomers. The major component was acylated, giving only one diastereoisomer after ozonolysis and crotylboration. Final introduction of the corresponding (2 ,4Z)-dienoate unit by two subsequent Horner-Wadsworth-Emmons olefinations afforded compound (116) (Scheme 51). 

These ansamycins are characterized by a 19-membered ring lactam, in which the ansa tether bridges the meta positions on a substituted benzoquinone moiety. The ansa chain contains seven stereocenters, one isolated double bond and a (Z, )-dienamide. 

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