Spiroketals, asymmetric synthesis

Evans and others used this methodology to complete numerous total syntheses of natural products. For example, they built the spiroketal subunit 29 in the asymmetric synthesis of the macrolide antibiotic rutamycin B13 (Scheme 2.11). The... 

The spiroketal (5) results from a HDA reaction and is a source of a-cyclocitral derivatives, the formal products of the conjugate addition of acetate (Scheme 2). An important aspect of this asymmetric synthesis is that the auxiliary chiral diol can be reeycled <97TL4309>. 

A versatile chiral substrate 278 for asymmetric synthesis has been prepared through the hypervalent iodine induced spiroketalization of phenols 277 with a chiral substituted ethanol unit O-tethered to the ortho position (Scheme 3.116) [347], This reaction has been successfully utilized in the asymmetric total synthesis of the natural product (-l-)-biscarvacrol. 

Mechanisms and energetics for Br0nsted-acid-catalysed glucose condensations, dehydration, and isomerization reactions have been reviewed. Recent developments in the asymmetric synthesis of spiroketals have been reviewed and the potential for further application of transition metal catalysis and organocatalysis has been highlighted. ... 

The stereochemical problems associated with the asymmetric synthesis of spiroketals are considerably more complicated in the context of synthesis of stereochemically rich, densely substituted structures. The field remained largely uncharted until a study by Evans directed towards the total synthesis of the antibiotic calcimycin (A-23187, 146, Figure 6.6) [74]. Analysis of the various possible diastereomeric products from a spirocyclization event suggested that the naturally occurring spiroketal unit could be directly as-... 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

Scheme 3. Asymmetric solid-phase synthesis of compounds with the 6,6 -spiroketal skeleton.

Barun, O., Sommer, S., Waldmann, H. Asymmetric sohd-phase synthesis of 6,6-spiroketals. Angew. Chem. Int. Ed. 2004, 43, 3195-3199. 

The synthesis of the C1-C15 AB spiroketal 457 is described in Scheme 65. The synthesis of the C8-C15 fragment 453 started with allyl TMS 450, prepared by Evans asymmetric alkylation. Addition of 450 to aldehyde 451 with SnCl4 stereo-selectively afforded a-alcohol 452, which was converted into methyl ketone 453 through a sequence of four steps involving Mitsunobu inversion. The synthesis of... 

Scheme 7.1. Asymmetric aldol reactions on solid phase for synthesis of spiroketal library.

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