Spiroketals synthesis

Ley, S.V., Lygo, B., Organ, H.M., and Wonnacott, A., Wittig and Homer-Wittig coupling reactions of 2-substituted cyclic ethers and their application to spiroketal synthesis, Tetrahedron, 41, 3825, 1985. 

An alternative construction which incorporates much of the alkyl functionality on to the alkyne portion and which carries the required methoxycarbonylalkyl substituent in the correct configuration at C-17 was reported by Langlois (equation 43). This process and recently modified versions of the Hanessian spiroketal synthesis seem to correlate well. ... 

Stereoselective synthesis with carbon dioxide, including preparation of cyclic carbonates, polycarbonates, and oxazolidinone 13ASC2115. Strategies for spiroketal synthesis based on transition metal catalysis ... 

Scheme 7.2. Double diastereodifferentiation in solid-phase aldol reactions toward spiroketal synthesis.

Li, Y., Zhou, R, Forsyth, C. J. (2007). Gold(I)-catalyzed bis-spiroketalization synthesis of the trioxadispiroketal-containing A-D rings of azaspiracid. Angewandte Chemie International Edition, 46, 279-282. 

Ley SV, Lygo B, Sternfeld F, Wonnacott A. Alkylation reactions of anions derived from 2-benzenesulphonyl tetrahydropyran and their application to spiroketal synthesis. Tetrahedron 1986 42 4333- 342. 

II. Spiroketal synthesis and stereochemical assignment by NMR spectroscopy. Tetrahedron Lett., 36, 8351-8354. 

Regioselecdve reducdon of 2-nitrocycloalkanones withsndiiun borohydnde affords Oj-nitro alcohols. This reacdon is applied to the synthesis of spiroketals as shovm in Eq. 5.17, in which spiro[4,5 - and spiro[4,6 ketal systems are obtained in good yields. "... 

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. 

From intermediate 43, the path to monensin would seemingly be straightforward. A significant task which would remain would be the construction of the l,6-dioxaspiro[4.5]decane substructure of monensin. You will note that the oxygen atoms affixed to carbons 5 and 12 in 43 reside in proximity to the ketone carbonyl at C-9. In such a favorable setting, it is conceivable that the action of acid on 43 could induce cleavage of both triethylsilyl ethers to give a keto triol which could then participate in a spontaneous, thermodynamically controlled spiroketalization reaction. Saponification of the C-l methyl ester would then complete the synthesis of monensin. 

You will note that the oxygen atoms attached to carbons 5 and 12 in 43 reside in proximity to the C-9 ketone carbonyl. Under sufficiently acidic conditions, it is conceivable that removal of the triethylsilyl protecting groups would be attended by a thermodynamically controlled spiroketalization reaction.30 Indeed, after hydro-genolysis of the C-26 benzyl ether in 43, subjection of the organic residue to the action of para-toluenesulfonic acid in a mixture of methylene chloride, ether, and water accomplishes the desired processes outlined above and provides monensin methyl ester. Finally, saponification of the methyl ester with aqueous sodium hydroxide in methanol furnishes the sodium salt of (+)-monensin [(+)-1], Still s elegant synthesis of monensin is now complete.13... 

Having retraced the remarkably efficient sequences of reactions which led to syntheses of key intermediates 14 and 15, we are now in a position to address their union and the completion of the synthesis of the spiroketal subunit (Scheme 6b). Regiocontrolled deprotonation of hydrazone 14 with lithium diisopropylamide (LDA), prepared from diisopropylamine and halide-free methyl-lithium in ether, furnishes a metalloenamine which undergoes smooth acylation when treated with A-methoxy-A-methylcarboxa-mide 15 to give the desired vinylogous amide 13 in 90% yield. It is instructive to take note of the spatial relationship between the... 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

Scheme 8.8 Synthesis of the tricyclic spiroketal fragment of lituarines.

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. 

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

The oxidation of 2,5-disubstuted furans by singlet oxygen was exploited for the synthesis of [5,5,5] and [6,5,6] bis-spiroketals <06OL1945>. An unusual regioselective photooxidation of 3-bromofuran to 2- and 3-bromo- hydroxybutenolides, as depicted below, was reported. The mechanism for the observed base-dependent regioselective deprotonation of the endoperoxide intermediate was not determined <06OL4831>. 

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>. 

Alder (hDA) reaction <00CEJ3755> and the electrochemical oxidation of m-hydroxyalkyl tetrahydropyrans offers a different approach to spiroketals <00TL4383>. The synthesis and stereochemistry of insect derived spiroacetals has been reviewed <00S1956>. 

Oxidation of the aminonaphthols 91 gives the quinone spiroketals 92, analogues of palmarumycin <00TL9105>. The first total synthesis of (+)-diepoxin a 93 has been achieved from a naphthoquinone . 

Scheme 27 Compounds isolated from shield bugs, and synthesis of a spiroketal produced by the shield bug Cantao parentum [152]...

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