Spiro acetals

L. Hough and A. C. Richardson, From sugars to morpholines, spiro-acetals and alkaloids, in H. Ogura, A. Hasegawa, and T. Suami, (Eds.), Carbohydrates Synthetic Methods and Applications in Medicinal Chemistry, Kodansha, Tokyo, 1992, pp. 108-119. 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

Spiro acetals can also be stereoselectively hydroxylated, in high yield, with osmium tetraoxide and a catalyst. The resultant diol is formed by. vyw-hydroxylation from the least hindered side of the alkene moiety (equation 21)121. 

Acetals, ketals, and their parent carbonyl compounds participate in this reaction [51]. Both simple and functionalized acetals undergo this reaction, as shown in Eq. (55) [173]. Double allylation was noted for the spiro-acetals with 2 equiv. allylsi-lane in the presence of TiCU (Eq. 56) [174,175]. Poly-acetals with the structure shown in Eq. (57) underwent clean production of a single product [176],... 

Sapogenins Reactions of the Spiro-acetal System.—Nitrous acid, provided by sodium nitrite and boron trifluoride in acetic acid, readily nitrosates the C(23) position in a spirostan (271), giving the oxime (272), from which the 23-oxo-deriva-tive is available in high yield. Paraformaldehyde and acetic acid gave a... 

Oxidation of the spiro-acetal system occurs more easily than has generally been realized. Chromium trioxide in aqueous acetic acid for six hours gave the diketo-acid (274) in excellent yield. Alkylation of the methyl ester by Grignard... 

Other Nitrogen-containing Derivatives of Ketones Sapogenins Reactions of the Spiro-acetal System Reactions of Aldehydes, Carboxylic Acids, and their Derivatives Miscellaneous... 

Diosgenin has been converted into a-ecdysone by a multistage sequence which made use of the stereochemical features of the spiro-acetal system to attain the required configurations at C-20 and C-22 in the product. Most of the steps were already known in principle, but the reduction of the 16,22-epoxy-7,14-dien-6-one... 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

The volatile component of the mandibular secretion of Andrena haemorrhoa F. contains 2,7-dimethyl-l,6-dioxaspiro[4.6]undecane. All four thermodynamically stable stereoisomers of the Spiro acetal pheromone have been prepared using the two enantiomers of ethyl lactate (which supplies the 2-methyl substituent via butyrolactone 51) and the two enantiomers of 3-hydroxybutanoate (which supplies the 7-methyl via iodide 52). Scheme 8 shows the synthesis of the (2S, 5S, 7/ )-isomer 55. The overall yield in the sequence is 9%, and the purity of the final product is 97% [18]. 

The structures of these two compounds were obtained by extensive application of 2D NMR techniques and mass spectrometry [98]. These tetra- and penta-cyclic compounds possess long dialkyl chains and free carboxyl groups. The authors elegantly applied isotope-induced C shifts in the establishment of the nature and location of the two hydroxyl groups and the free carboxyl group in CP-225917. Two of the hydroxyl groups of CP-225917 are cyclized to form a spiro-acetal ring in compound CP-263114. The stereochemistry of these compounds was elucidated by... 

Pentanortriterpenoids.—The intriguing range of compounds isolated from the family Cneoraceae continues to be extended. The availability of tricoccin 842 the C-7 epimer of tricoccin 84 (see Vol. 10, p. 151), has led to a revision of the stereochemistry of the latter. Tricoccins 84 and 842 are now represented by structures (53) and (54) respectively. Tricoccins 816 and 82 are the bishemiacetal (55) and the corresponding peroxide (56). Both are extremely acid sensitive, readily losing water to form the spiro-acetals (57) and (58) respectively. The structures of cneorins Q (59) and NP29 (60) have been established. They differ only in the stereochemistry at C-7 and C-9. ... 

Spirophostins 9, which have been prepared as conformationally restricted analogues of adenophostins, and some spiro-acetals obtained from enol esters are covered in Chapter 2. 

Kocienski and his co-workers have described the novel intramolecular Lewis acid catalysed directed aldol reaction of the spiro-cyclic ortholactone (18 ) prepared from the fragments (185) and (186), to set up the spiro-acetal portion (I88). Milbemycin (189) was then secured from (I88) by sequential sulphone-based (Julia) olefination reactions to produce the double bonds at C10-... 

In an alternative synthesis of ( + )-milbemycin B, Baker et al. have applied their previously described spiro-acetal intermediate... 

The alkoxycarbonylation reaction is also useful for the synthesis of spiroacetals (Scheme 24) [38] Thus, certain hydroxyenones react under the standard conditions in the presence of trimethyl orthoformate (TMOF) to afford the corresponding spiroacetals via hemiketal intermediates in high yield. It is also possible to prepare spiroacetals starting from dienones (Table 3). The stereochemistry of the products was not established however, this method is of potential value for the synthesis of bioactive compounds with spiro acetal substrucmre. 

In a continuing study of the oxidation of phenols, the formation of a mixture of the spiro-acetal (49) and the phenol (52) from 2-methyl-4-t-butylphenol has been described. The spiro-acetal arises from cross-coupling of the radicals (50) and (51) followed by further oxidation of the trimeric species (52), as shown in Scheme 7. 

Formations of Cyclic and Spiro Acetals by a Tandem Intramolecular Hydrogen Abstraction-Cyclization Process (Schemes 30 through 36)... 

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