Natural spiroketal

The avermectins are closely related to another group of pesticidal natural products, the milhemycins. First described by Japanese workers, milhemycins were later found to be more abundant in nature than the avermectins (7—12). Both the avermectins and milhemycins are sixteen-memhered lactones, with a spiroketal system containing two six-memhered rings. The principal difference between them is that the avermectins have an a-L-oleandrosyl-a-L-oleandrosyl disaccharide attached at the 13-position whereas the milhemycins have no 13-substituent. Milhemycin stmctures are shown in Figure 2. 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

The mbromycins constitute an unusual structural class, due to the presence of the spiroketal moiety. A more typical example of a type II PKS-derived natural product is the antitumor agent hedamycin (Scheme 10.13) [39, 40]. Hedamycin belongs to a family of closely related compounds, the pluramycins. These antibiotics have the... 

Spiroketals based upon such structures as l,7-dioxaspiro[5.5]undecane (18), occur frequently in natural products. Accordingly, an extensive amount of literature relates to the isolation and total synthesis of this type of compound. This literature was reviewed104 in 1989. The authors of Ref. 104 listed three factors that influence conformational preferences in these systems. They are (7) steric influences, (2) anomeric and related effects, and (3) intramolecular hydrogen bonding and other chelation effects. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

Conversion of furfuryl alcohol derivatives 48 to pyranones 49 (Achmatowicz oxidative ring expansion) is employed in the synthesis of spiroketal moiety of a natural product and cyclopentenones <00TL6879>. 

The recently described solid phase synthesis of 6,6 -spiroketals provides an example in which natural product analogs were completely assembled on the solid phase. The authors described solid-phase synthesis procedures to synthesize 6,6 -spiroketals, which are structural motifs found in many... 

Stereodefined spiroketals are a common structural motif in physiologically-active natural products. Richard P. Hsung of the University of Minnesota recently reported (Organic Lett. 2005, 7, 2273) that Tf,NH is a particulary effective Brpnsted acid mediator for the stereoselective coupling of vinyl lactols such as 11 with homoallylic acids such as 12. The axial ethers so produced undergo smooth ringclosing metathesis to the spiroketals. 

Substituted 7-pyrones are versatile synthetic precursors. There is strong precedent for the metalation4 and bromination5 of the 7-position, which allows 7-pyrones to be used in alkylation and aldol reactions and makes them attractive intermediates in the synthesis of polyacetate and spiroketal containing natural products.6 They can also be used as cycloaddition substrates in the construction of complex polycyclic systems as West has demonstrated.7 Furthermore, 7-pyrones have been used by Wender in an oxidopyrilium-alkene cycloaddition, a key reaction in his synthesis of phorbol.8... 

Tetr 39 2323 (1983) (Recent Advances in the Preparation and Synthetic Applications of Oxiranes) 43 3309 (1987) (Synthetic Routes to Tetrahydrofuran, Tetrahydropyran, and Spiroketal Units of Polyether Antibiodcs and a Survey of Spiroketals of Other Natural Products) SO 8885 (1994) (Chemical and Biological Synthesis of Chiral Epoxides)... 

Eight naturally occurring, structurally related avermectins are produced by Streptomyces avermitilis [7], The avermectin polyketide structure is derived from seven acetate and five propionate residues, together with a single 2-methylbutyric acid or isobutyric acid residue which forms the sec-butyl or isopropyl group attached to the C25 of the spiroketal moiety [8,9] (Fig. 1). The avermectin agly-cone is further modified by glycosylation at C13, with the attachment of two O-methylated oleandrose residues and O-methylation at C5. Thus, S. avermitilis... 

Different mechanistic interpretations of the formation of an alternating propylene/carbon monoxide copolymer of poly(spiroketal) structure were considered [107, 478, 480, 481, 489]. Any reasonable proposal, however, needs to take into account the nature of the end groups in the copolymer chains. To date this has not been possible owing to the low solubility of the copolymer in solvents other than hexafluoroisopropanol however, this solvent, probably because of its acidic nature, causes transformation of the poly(spiroketal) structure into an isomeric poly(ketone) structure [489]. The formation of a cyclic polymeric structure could be favoured by minor entropy loss due to the intramolecularity of the process [480,481] and by the peculiar conformational situation of the poly(ketone) structure [491]. 

Evans and others used this methodology to complete numerous total syntheses of natural products. For example, they built the spiroketal subunit 29 in the asymmetric synthesis of the macrolide antibiotic rutamycin B13 (Scheme 2.11). The... 

Spiroketals are not only important building blocks of polyethers but also may represent themselves highly active natural products. The suitability of oxa Diels-Alder reactions to efficiently generate this structure will be demonstrated by two impressive examples. Thus, our group prepared the mycotoxine (-)-talaromycin B 7-17 by a nine-step synthesis in 5% overall yield in enantiopure form. The... 

Recently, Kosmin has shown that bistramide A is responsible for severing actin filaments and covalently modifying actin.183 These studies indicated that, while the spiroketal and amide units of the natural product induced rapid disassembly of F-actin in vitro, the enone subunit of bistramide A was able to initiate covalent modification of actin in vitro and in live cells. These results indicate that, while PKC5 may not be the primary target of the natural product, it plays a dual role by binding to and severing F-actin and covalently sequestering... 

Spiroketal glycosides are widely distributed in nature [56] displaying a broad spectmm of biological activities. Typical examples are the papulacandines, tricyclic spiroketal glycosides... 

The preparation of the C1-C21 subunit of the protein phosphatase inhibitor tautomycin was completed by J.A. Marshall et al., and it constituted a formal total synthesis of the natural product. The spiroketal carbon of the target was introduced by the Weinreb ketone synthesis between a lithioalkyne and A/-methoxy-A/-methylurea (a carbon monoxide equivalent). The triple bond of the resulting Weinreb s amide was first reduced under catalytic hydrogenation conditions to yield the corresponding saturated amide, which was reacted with another lithium acetylide to afford an ynone. 

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