Acid-catalyzed spiroketalization

An easy, silica gel-promoted 6-endo cyclization of y-epoxy alcohol 32 to pyran 33, followed by acid-catalyzed spiroketalization of the keto diol 34, afforded the common tricyclic spiroketal fragment 35 of lituarines A, B, and C (Scheme 8.8) [20b],... 

In the final stages of the total synthesis of okadaic acid by C.J. Forsyth et al., the central 1,6-dioxaspiro[4,5]decane ring system was introduced by the enantioselective reduction of the Cl6 carbonyl group using (S)-CBS/BH3, followed by acid-catalyzed spiroketalization. ... 

A second late-stage application of the CB5-reduction was reported by Forsyth et al. in their total synthesis of okadaic acid (659) (567). This cytotoxic polyether was isolated initially from the marine spcmge Halichondria okadai in 1981 (569). In their total synthesis of this challenging target, Forsyth et al. carried out a CBS-reduction on the highly functionalized enone 660. The cmde reduction product was directly subjected to an acid-catalyzed spiroketalization to furnish the advanced intermediate 661 in 81% yield (over both steps) (Scheme 137). Final protecting group manipulations were used to accomplish the total synthesis of okadaic acid (659) (567). 

Pikho and co-workers50 found that nonanomeric [6,5]-spiroketals (having a pyranoside moiety with an equatorial CO acetal bond) can be formed under conditions of kinetic control. For instance, 62 undergoes acid catalyzed spiroacetalization giving the anomeric (most stable) acetal 63... 

Martin et al. (289) utilized the chiral bicyclic lactone 88 for a total synthesis of (+)-phyllanthocin (Scheme 6.62). Cycloaddition of 88 to acetonitrile oxide, generated in situ from hydroximoyl chloride (89), furnished cycloadduct 90 in 45% yield together with other regio- and stereoisomers. After several steps, methyl glycoside (91) could be obtained. From this, reduction-hydrolysis gave the aldol that was subjected to acid-catalyzed spiroacetalization to produce spiroketal (92), and eventually (+)-phyllanthocin (93) after two additional steps (289). The... 

We should also expect stereoelectronic control when the hydroxyl group is replaced by another nucleophile in the reaction with cyclic oxonium ions. A recent report (110) shows that hydride transfer to cyclic oxonium ion is subject to stereoelectronic control. Tricyclic spiroketal 140 (Fig. 19) undergoes an acid-catalyzed oxidation-reduction reaction to give the equatorial bicyclic aldehyde 147 stereospecifically. Similarly, spiroketals 148 and M9 gave the corresponding equatorial bicyclic ketone 150. 

The synthesis of a spiroketal fragment 450 of spongistatin 1 has been accomplished utilizing the addition of a metalated pyrone derived from 448 to propionaldehyde to give adduct 449 followed by acid-catalyzed spirocycliza-tion (Scheme 79) <20000L957>. 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

A more detailed study27 was carried out of the spiroketalization reaction. Compounds obtained by C-23 deoxygenation of intermediates in the tetrahydrocephalostatin 12 synthesis were used, with various permutations differing in their C-20 stereochemistry and also the presence or absence of benzylation at C-26. These compounds were subjected to a series of acid-catalyzed cyclizations. 

Compound 73 was reacted with methallylstannane to give a separable pair of diastereomeric alcohols (Scheme 33) in a 1 2.7 ratio favouring the desired product. The unwanted diastereomer was recycled in 79 % yield by Mitsunobu inversion. The alcohol was then benzylated to afford intermediate 74, after which reduction of the C-12 ketone yielded a 1 9 ratio of a- and (3—C-12 epimeric alcohols. The alcohols were osmylated and subjected to periodate cleavage to provide 75. This was reacted with methyl Grignard, followed by acid catalyzed cyclization with (+)-camphorsulfonic acid. Three spiroketal products 76, 77, and 78 were isolated in a 1 15 1 ratio. 

Acid-catalyzed cyclization of 12 yielded a mixture of 5/5 and 6/5 spiroketals epimeric to the natural product. In general, the ratio of spiroketal products with these intermediates is highly sensitive to the specific substitution pattern. The natural products also reflect this... 

The Brimble group reported the synthesis of acortatarin A 20 in 2012. As in the first synthesis of acortatarin A 20 by Sudhakar et al. a traditional acid-catalyzed dehydrative spiroketalization was used as one of the final steps. However, instead of performing the previously used disconnection between CIO and N9, as several other groups have reporteda Maillard-type condensation reaction between amino alcohol 50 and the sugar surrogate 51 would be used to give 49. The amine 50 would come from D-mannitol and 51 would be prepared from furfuryl alcohol on a gram scale (Scheme l )" ... 

The Tan group was the first to report a diastereoselective synthesis of acortatarin A 20 in nine steps and B 21 in ten steps, not counting the steps required to reach the pyrrole intermediate 40. Interestingly, upon completion of the synthesis of acortatarins A 20 and B 21, it was discovered that upon acid-catalyzed equilibration, the favored epimer of acortatarin B 21 was not the natural one. It is postulated that this may indicate that the biosynthesis of acortatarin B 21 is under enzymatic control and not thermodynamic control, as is often the case with spiroketals. 

SCHEME 2 Proposed acid-catalyzed interconversion of spiroketal regioisomers. 

Although spiroketal 42 contains the iodine atom in the undesired C-8 position, we reasoned that successful carbonylation, followed by acid-catalyzed equilibration of the spiroketal might allow rotation of the aromatic core, facilitating interchange between the two regioisomeric carbonylation products... 

Most examples of spiroketaHzation involve an acid-catalyzed dehydration of dihydroxy ketones. However, the required acidic conditions are not always compatible with the presence of labile functional groups. Consequently, metal-catalyzed spiroketaHzations have been developed and a wide variety of metal complexes [Au(I), Au(III), Pd(II), Hg(II), Ir(I), Rh(I), Pt(II)] can be used to access spiroketals (2012S3699). 

The spiroketal (+)-spiroxaliiie methyl ether 31 contains three secondary oxygenated ste-reogenic centers. In a showcase of current chiral technology, Barry M. Trost of Stanford University constructed (Angew. Chetn. Int. Ed. 2007, 46, 7664) the first two of the three alcohols by the enantioselective addition of an aUsyne to an aldehyde. The chiral catalyst 25 that directed the alkyne additions was derived from a commercial Hgand. The last alcohol center was derived from / -(+)-epoxypropane. Note that the spiroketal was not prepared in the usual way, by acid-catalyzed cyclization of a dihydroxy ketone, but by Pd-catalyzed cyclization of the alkyne diol 30. 

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