Spiroacetals stereochemistry

Alder (hDA) reaction <00CEJ3755> and the electrochemical oxidation of m-hydroxyalkyl tetrahydropyrans offers a different approach to spiroketals <00TL4383>. The synthesis and stereochemistry of insect derived spiroacetals has been reviewed <00S1956>. 

M. A. Brimble, D. P. Furkert, Chemistry of Bis-Spiroacetal Systems Natural Products, Synthesis and Stereochemistry, Curr. Org. Chem. 2003, 7, 1461-1484. 

The product is still a hydrazone, and it needs hydrolysing to the ketone with 1 M HC1. These conditions cause immediate hydrolysis of the THP protecting groups and then cyclization to the spiroacetal, which forms with complete control over stereochemistry— a single diastereoisomer is formed in which both alkyl groups go equatorial and both oxygens axial. 

An anti aldol reaction with Felkin control was now needed to couple the two spiroacetal fragments and generate the correct stereochemistry at C15 and C f, of the spongistatins. A study of the individual fragments indicated that while the enolate showed little facial selectivity, the aldehyde component had a considerable bias for the desired Felkin product. Best results were obtained with the lithium-mediated aldol coupling, which gave adduct 104 in good yield and acceptable selectivity [56 c]. 

Shortly after this Tachibana s group published an improved procedure which employs Corey s asymmetric dihydroxylation protocol [21] to install the correct stereochemistry in ring M. Under these conditions there is apparently no hemi-acetal ring opening and the intermediate triol closes virtually quantitatively to the spiroacetal. The successful execution of this ring synthesis is given in Fig. 21 [22],... 

Preparation of another fragment began with 182 [75]. The asymmetry of the secondary hydroxyl groups of 183 and that of the tertiary one of 184 was derived from Sharpless epoxidation and Sharpless dihydroxylation. Acidic treatment to remove the acetonide group afforded tricychc spiroacetal 185. The stereochemistry was confirmed by NOE observed in the dithiane 169. 

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. 

Looking back at the Nakahara synthesis, it relies heavily on the use of cyclic compounds to set relative stereochemistry. The absolute stereochemistry at Cio and Cig came from D-glucose. The stereochemistry at Cn, C16 and C19 was controlled by constraints imposed by cyclic compounds. And the stereochemistry at Ci4 and Cig was controlled by thermodynamics. We will now look at a synthesis that uses a different strategy for construction of the spiroacetal substructure of calcimycin. 

The stereochemistry of spiroacetals (both synthetic and naturally occurring) can largely be divided into two categories—the so-called anomeric or axial/axial conformers, and non-anomeric or axial/equatorial conformers. In 6,6-spiroacetals, four possible conformations exist (Fig. la-2d) with varying relative stabilities, which are interchangeable via ring flipping [2]. 

Recently, Aponick et al. [106] reported a study wherein alkyne triols 160,162,164, and 166 underwent spirocyclization with a Au(l) catalyst to give the unsaturated spiroacetals 161,163, and 165 (Scheme 40). The effect of the stereochemistry of the propargyUc alcohol was also investigated it was found that 3-anti relative... 

Attention then turned to synthesis of the C28-C38 spiroacetal from alkyne triol 173. Alkyne triol 173 was obtained as a 1 1.5 mixture of l,3-antUl,3-syn epimers. As seen in Aponick et al. s earlier work [106], the regioselectivity of the Au(I)-catalyzed spirocycUzation was profoundly influenced by the relative stereochemistry of the 1,3-diol. Thus, the, 3-syn triol gave a mixture of the 6,6- and 5,7-spiroacetals 174—175, while the, 3-anti triol gave the desired 6,6-spiroacetal 174 selectively. 

Jacobs, M.F., Glenn, M.P., McGrath, M.J., Zhang, H., Brereton, L, and Kitching, W. (2001) Stereoselective synthesis and stereochemistry of seven isomeric spiroacetal structures based on the C17-C28 fragment (CD rings) of spongistatin 1. ARKIVOC, 114-137. 

---