1.7- Dioxaspiro- -undecane

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. 

Polybia occidentalis W-VG Alarm (2S,6R,8S)-2,8-Dimethyl-1,7-dioxaspiro-[5.5] undecane 142 [188]... 

Enantiomers of 2,7-dimethyl-l,6-dioxaspiro[4.5]decane 28 Enantiomers of 2-Ethyl-7-methyl-l,6-dioxaspiro[4.5]decane 29 Enantiomers of 2,8-dimethyl-l,7-dioxaspiro[5.5]undecane 30 5 - Methylh eptan - 2 -ol (Z)-Non-3-en-l-ol 3,7-Dimethyloctan- l-ol Benzaldehyde 2-Phenylethanol Phenylacetonitrile Isobutyl benzoate Isopentyl benzoate Hexadecanoic acid 17-Hydroxyan drost-4-en-3-one (2)-Octadec-9-enoic acid... 

Since the advent of multipulse-NMR techniques, more detailed 1H-NMR studies on methylcyclo-hexanes547, phenylcyclohexanes548, neomenthyl halides549 and bicydo[4.4.0]decanes 550 551 have been undertaken. The two diastereomeric 4-fm-butyl-7,ll-diphenylspiro[5.5]undecane-1,9-diones (3) and (4) could be identified unambiguously552, and substituted spirodioxane cyclohexanes such as, 9- m-butyl-2-methyl-1.3-dioxaspiro[5.5]undecane (5), have also been investigated553,554. 

A solution of Et3N (1.87 g, 18.5 mmol) in CH2Cl2 (30 mL) was added portionwise over 5 min to a solution of r/A-3.4-dilluoro-l, 5-dioxaspiro[5.5]undecan-2-one in CH2C12 (60 mL) at rt. After stirring for 10 min, the mixture was washed with H20 and the organic layer dried (MgS04) and evaporated in vacuo. The residue was purified by column chromatography (short column, silica gel, hexane/F.lOAc 3 1) yield 1.55 g (47%) mp 61-62 C. 

The first precise evaluation (2A, 25) of both the anomeric and the exo-anomeric effects was obtained by studying 1,7-dioxaspiro[5.5]undecane (9) (Fig. 2). With this system, conformational analysis by low temperature nmr spectroscopy was possible because each conformational change involves a chair inversion which has a relatively high energy barrier. The steric effect could also be easily evaluated, and by adding appropriate alkyl substituents, it was theoretically possible to isolate isomeric compounds which would exist in different conformations. 

A new strategy for the synthesis of erythromycin A and closely related mac-rolide antibiotics was elaborated in our laboratory (88). This new approach to synthesis is based on the knowledge that stereoelectronic effects control the conformation of acetals. The strategy is based on the 1,7-dioxaspiro-[5.5]undecane system which was found to be conformationally rigid, existing in conformation J50 only (see Chapter 2). This is so because in this confor-mation, steric effects are at their minimum and the acetal function has... 

The masked tetrahydroxyketone 28 (Fig. 7) which can theoretically give isomers 29 and 30, was found to yield isomer 29 exclusively (26). The structure of 29 was proven by X-ray analysis. Similarly, dibromodihydroxyketone 31 can give either isomer 32 or 33. Upon cyclization, isomer 32 was the product formed (27) and its structure was also established by X-ray (28). The recently reported total synthesis of ionophore A-23187 (29), a polyether antibiotic whih possesses the 1,7-dioxaspiro[5.5]undecane skeleton having a conformation equivalent to 29 and 32 confirms these results. 

Two formal total syntheses of calcimycin have been achieved (94-96). They are similar in concept in that the retrosynthetic analyses entail disconnection of the l,7-dioxaspiro[5.5]undecane moiety of 168 to the ketodiol precursor 170 which would readily yield calcimycin on acid-catalyzed cyclization (spiro-ketalization). Further retrosynthetic fragmentation of ketodiol 170 into the pyr-... 

In an analogous manner, benzodithiepins 286 can be lithiated with n-BuLi at —40 to —20 °C and reacted with alkyl bromides458 and with epifluorohydrin459. The enantiomers of l,7-dioxaspiro[5.5]undecane and 4-hydroxy-l,7-dioxaspiro[5.5]undecane, components... 

Two important spiroketals, such as l,7-dioxaspiro[5.6]undecane (29a), the major component of the olive fruit fly (Dacus oleae) sex pheromone (Baker et ah, 1980 Fanelli et ah, 1983), and ( )-2-methyl-l,7-dioxaspiro[5.6]dodecane (29b), a component of pheromone of Andrena haemorrhoa (Bergstroem et al., 1981 Katsurada and Mori, 1984), have been prepared in a cascade process from polyfunctionalized nitroalkanes (26) (Ballini and Petrini, 1992). 

Ballini, R. and Petrini, M. 1992. Hydroxy-functionalized conjugated nitro olefins as immediate precursors of spiroketals. A new synthesis of l,7-dioxaspiro[5.5]undecane and ( )-2-methyl-l,7-dioxaspiro[5.6]dodecane. Journal of the Chemical Society, Perkin Transactions, l(23) 3159-60. 

The author also converted the product from Step 1 into 3,3-diethyl-l,5-dioxaspiro[5.5]-undecan-9-amine (I) as illustrated in Eq. 1 ... 

Finally, oxidative cyclization (HgO, I2, hiA of tqjpropriately substituted alcoholic ethers formed the basis of Kay s stereoselective syntheses of both 4-hydroxy-l,7-dioxaspiro[S.S]undecane, an olive fly pheromone component, and ( )-talaromycin B (equations 4 and 5). More recently, Danishefsky et at have further extended the scope of this spiroketal-forming reactitm in their elegant total synthesis of avermectin Ai (equation 6). ... 

Stereoselective synthesis of the substituted 1,7-dioxaspiro[5.5]undecane 2 has been performed by a simple treatment of the 3,4-dihydro-2//-pyran 1 with 4-methylbenzenesulfonic acid/water in benzene at 55 °C for 3 hours. The cydization proceeds with total stereoselectivity and only one isomer is recovered in 55% yield. The corresponding unprotected spiroketal can be obtained as a single diastereomer and the structure is determined on the basis of H-NMR data98. 

Mercuriocyclization has also been utilized in order to obtain spiroketals from hemiketals. Thus, treatment of l,10-undecadien-6-one (11) with mercury(II) acetate in water/tetrahydrofuran affords, with total regioselectivity, 2,8-bis[(chloromercurio)mcthyl]-l,7-dioxaspiro[5.5]undccanc as a diastereomeric mixture. The diastereomeric ratio was not reported but depends on the reaction time, owing to the reversibility of oxymercuration-cyclization steps. Reductive removal of mercury by sodium borohydride under phase-transfer conditions gives a good yield of 2,8-dimethyl-l,7-dioxaspiro[5.5]undecane (12) as a diastereomeric mixture101,102. 

Spiroketals are also obtained in good yield starting from hydroxy enones, although diastereo-meric mixtures are generally recovered. Only 10-hydroxy-l-tetradecen-6-one (15) cyclizes with high stereoselectivity to give 2-butyl-8-methyl-l, 7-dioxaspiro[5.5]undecane (16) in 88 % yield as a 96 4 E,E)j E,Z) diastereomeric mixture102. The major diastcrcomer is separated by preparative GLC and identified on the basis of its H-NMR spectrum. 

However, 1-hydroxy-l-phenyl-9-decene-3,5-dione (19), upon selenium-mediated cyclization, affords (L, L )-2-phenyl-8-[(phenylseleno)methyl]-l,7-dixoaspiro[5.5]undecan-4-one (20) in 50% yield with total asymmetric induction. Subsequent Raney nickel reduction gives (E.JS J-S-methyl-2-phenyl-l,7-dioxaspiro[5.5]undecan-4-one (21) in 94% yield 105-106. 

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