Spiroketal construction

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. 

In another interesting application of this procedure, the acid-mediated cascade cyclization of (3-diketone diepoxide 73 involves the participation not only of the two oxirane rings and of the secondary alcoholic group, but also of one of the two carbonyl groups. In this way, besides the two adjacent C and D THF rings, the simultaneous construction of the spiroketal function between the B and C rings of etheromycin is obtained (compound 74, in a 70 30 mixture with 12 -epi compound Scheme 8.19) [37]. 

Scheme 8.32 Second-generation construction of the AB spiroketal system of spongistatin.

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... 

Wipf and co-workers developed a general route for the construction of the spiroketal naphthodecalines (155) using PIDA in CF3CH2OH and the first total syntheses of palmarumycin CPX (42) and ( )-deoxypreussomerin A (43), which are fungal metabolites showing antitumor and antibiotic activities [117, 118] (Scheme 27). 

Being able to use HMPA to promote [1,4]-Brook rearrangements is at the heart of the versatility of 67 as an equivalent for the synthon 68.53 55 The first alkylation is followed by addition of the second electrophile in the presence of HMPA, allowing the construction of molecules such as 69, a spiroketal component of the spongistatin antitumour agents.54... 

Photosensitized oxidation of a bis(2-trimethylsilylfuran) followed by spirocyclization of the intermediate bis(7-hydroxybutenolide) was employed to construct the tricyclic bis(spiroketal) cote of prunolides. As shown in... 

A more recent example of a functionalized alkyne addition can be seen in Crimmin s synthesis of tala-romycin A (equation 42). ° This particular alkynide is an equivalent of the formyl acetone dianion and its use has been generalized as an entry into the spiroketal portion of the milbemycins (Scheme 20). This approach differs from the Hanessian strategy in that formation of the C(17> (21) pyran ring is constructed last, through use of the alkynic unit. 

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. ... 

The total synthesis of milbemycin-p developed by Williams et al. [124] involves construction of three units the spiroketal moiety (A), carbon chain with a remote chiral centre at C-12 (B) and the substituted benzoic acid (C). Unit (A) is prepared starting from citronellol (154), while unit (B) was prepared starting from (-)-(3S)-citronellal (162) (Scheme 20). A and B were joined after transmetalation of the tetrahydropyranyl ether 166 to give 167 (Scheme 21), which is allowed to react with the aldehyde A to give 168. Further steps are shown in scheme 22. 

Photooxygenation of furanosyl furans can lead to either O- or C-furanosides, depending on the transformation of the intermediate endoperoxides <05JOC6503>. Photosensitized oxidation of 2-trimethylsilylfuran was used to construct the fcw-spiroketal core of prunolides. As shown below, both the (Z)- and ( -isomers provided the same 2 1 mixture of the trans and cis products <05OL2357>. 

On the synthetic front, the discovery of these alkaloids has sparked interest in the construction of unsymmetrical pyrazines, and the methods developed will be useful in other settings as well. The Fuchs group has successfully accomplished landmark syntheses of tetrahydrocephalostatin 12, cephalostatin 7, cephalostatin 12, and ritterazine K and is clearly close to a synthesis of dihydrocephalostatin 1. These efforts have added significantly to the areas of steroid and spiroketal chemistry. 

The 6,6-spiroketal system of the northern segment was constructed via their developed LACDAC reaction and oxidative cyclization at C21 (Scheme 63). 

The ABCD segment 538 was then constructed (Scheme 76). The Julia coupling of 528 and 535 followed by methylenation afforded adduct 536. The AB spiroketal system was constructed by functional group manipulation to give 537, which was converted into ketoaldehyde 538 via protective group manipulation and oxidation. The spiroketal 539, which is a key intermediate for Kishi s total synthesis of altohyrtin A (4a), was also synthesized from 537. 

Malic acid-derived ( S)-pantolactone (257) has been used as a starting point for the stereoselective construction of the C-14 to C-25 spiroketal subunit of calyculin (Scheme 35) [87]. 

This observation provided a large degree of S3mthetic freedom with respect to the order in which the spiroketal and phthalide moieties were constructed. The initial focus of the project was therefore the construction of the carbon framework required for spiroketalizatirHi. 

THPs, six-membered ring lactones, or 6,6-spiroketals are common units encountered in natural product structures. As RCM is a versatile and che-moselective reaction, aU these heterocycles can be constmcted by using this reaction. In general, the formation of the C3—C4 bond is preferred to construction of the C2—C3 bond, which is more problematic (2006H705). Even if the RCM can be realized under mild conditions, and has also an excellent functional group tolerance, the main drawback of this reaction is that the stereochemistry of the substituents has to be controlled prior to the RCM (Scheme 25). 

All three alkynes can be incorporated into a single molecule, making the reaction entirely intramolecular. This has been used in a synthesis of Cryptoacetalide 11.60 (Scheme 11.21). The triyne 11.58 was constructed by coupling a diyne 11.56 containing a carboxylic acid with an alkynol 11.57. A ruthenium catalyst was found to be most effective for the cyclotrimerization, combined with microwave heating. The synthesis was completed by deprotection and free-radical spiroketal formation. 

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