Bicyclic acetals acid hydrolysis

The diacetylated ethane-1-hydrox-1,1-diphosphonic acid is prepared by dissolving the diphosphonic acid in acetic acid and adding acetic anhydride [114]. The sodium salt can be directly converted to the free acid form by passing it through an hydrogen cation exchanger. The bicyclic dimer is prepared by basic hydrolysis of diacetylated cyclic dimer, as shown in Eq. (70) ... 

The intermediate alkylation products from enamines are hydrolyzed, even by water.266 The adducts with a,/3-unsaturated ketones are more stable, and in this case hydrolysis by aqueous acetic acid— sodium acetate is required.32 Further condensation to give bicyclic unsaturated ketones frequently occurs.267, 268... 

In general, bicyclic acetals are highly reactive toward acid-catalyzed hydrolysis. For example, the hydrolysis of 2,7-dioxabicyclo[2.2.1]heptane (2) in aqueous acetone containing dichloroacetic acid was 2.5 x 104 times faster than that of an acyclic reference compound, dimethyl acetal. [77] 2,6-Dioxabicyclo[Z2.1]heptane (79) is more reactive, and hydrolyzed 6.9 x 10s times faster than dimethyl acetal. [78] These rate accelerations for bicyclic acetals arise from a partial liberation of the ring strain on hydrolysis, and have been correlated to the reactivities of bicyclic acetals in the cationic ring-opening polymerization. [5]... 

In a synthesis of the immunosuppressant Sanglifehrin A, two hydroxyl groups and a ketone were mutually protected as an acetal [Scheme 1.33].60 The ketone was generated by a Wacker oxidation of the terminal alkene 33.1 whereupon it was immediately converted to the bicyclic acetal 33.2 on treatment with acid. The acetal 33.2 survived the many steps required to elaborate the complex intermediate 33.3 but its stability was to exact a price the synthesis languished on the cusp of completion until conditions were found to hydrolyse the acetal without insult to the remaining delicate functionality. Hie three functional groups were eventually reclaimed in a modest 33% yield by interrupting the hydrolysis at 50% completion. 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

A convenient synthesis of (— )- xo-brevicomin (87) utilizes a radical chain reaction of methyl vinyl ketone with (45, 5R)-4-benzyloxymethyl-5-iodomethyl-2,2-dimethyl-l,3-dioxo-lane (209), prepared by treating the (R,R)-tartaric acid derivative 141 with triphenylpho-sphonium iodide in the presence of imidazole. Adduct 215, after acidic hydrolysis of the isopropylidene protecting group, furnishes the bicyclic acetal 216. Subsequent debenzylation and tosylation followed by methylation with lithium dimethylcuprate provides 87 in an overall yield of 17% from (R,R)-tartaric acid. The optical purity of 87 corresponds to greater than 99% ee (Scheme 50). Carrying out a similar series of transformations with ( S,5)-tartaric acid leads to ( + )-exo-brevicomin (90) [78]. 

One should keep in mind that further functionalization can also be built-in function on the substrate itself. Thus, for instance, acetals upon acidic hydrolysis allow an intramolecular aldolization-crotonization. This transformation produces chiral bicyclic a,p-unsaturated compoimds. These compounds are important intermediates for the synthesis of sesquiterpene derivatives. For instance, this procedure has been recently used in the alternative synthesis of axane derivatives [87] isolated from the marine sponge Axinella cannabia (Scheme 22) [33]. 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

The route using the amino acid acetal for preparation of the bicyclic intermediate for Vanlev is snmmarized in Scheme 17.6. The amino acid acetal is converted to the dimethyl acetal methyl ester, then conpled with N-protected homocystine to give a dipeptide dimer. The dimer is converted to the monomer with dithiothreitol or tributylphosphine. Acidification of the monomer gives the aldehyde that cyclizes to the bicyclic intermediate with concomitant hydrolysis of the ester. 

On diene condensation with butadiene, the 4-methoxy-2,5-toluquinone (307) obtained from toluquinone in three stages with a yield of 26% formed the cis adduct (308), which on alkaline isomerization and reduction gave the trans-C/D glycol (309). Treatment of this with an aqueous dioxane solution of sulfuric acid led to hydrolysis and dehydration to a hydroxyketone forming an acetate (310). The treatment of compound (310) with metallic zinc in acetic anhydride enabled a CD fragment to be obtained, the so-called "Woodward s ketone" (311) this completed the formation of the bicyclic precursor. 

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