Asymmetric Synthesis Of Naturally Occuring Spiroketals

Molecules 2008, 13, 1942-2038; DOI: 10.3390/molecules13081942
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molecules
ISSN 1420-3049 www.mdpi.org/molecules Review

Asymmetric Synthesis of Naturally Occuring Spiroketals
B. Rama Raju and Anil K. Saikia * Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India E-mail: rajchem44@gmail.com * Author to whom correspondence should be addressed;E-mail: asaikia@iitg.ernet.in. Received: 21 July 2008; in revised form: 22 August 2008 / Accepted: 22 August 2008 / Published: 28 August 2008

Abstract: Spiroketals are widely found as substructures of many naturally occurring compounds from diverse sources including plants, animals as well as microbes. Naturally occurring spiroketals are biologically active and most of them are chiral molecules.This article aims at reviewing the asymmetric synthesis of biologically active spiroketals for last 10 years (1998-2007). Keywords: Synthesis; Asymmetric; Natural product; Spiroketal

1. Introduction Spiroketals occur in Nature as subunits of miscellaneous natural products and are found in microbes, fungi, plants, insects and marine organisms. Spiroketals are cyclic ketals in which two rings arejoined by a single atom, the spiro atom, and the two ketal oxygens flanking the spiro atom, each belonging to one of the rings. The spiroketal ring system exists in a wide variety of natural products of varying complexity. Most of the naturally occurring spiroketals are biologically active compounds [13], such as, for example, the reveromycins [4, 5], which contains spiroketal skeletons, and areinhibitors of the mitogenic activity of epidermal growth factor. Similarly, the cephalostatins are highly potent cell growth inhibitors [6, 7]. Moreover, the telomerase-inhibiting activity of griseorhodin and rubromycin is attributed to the presence of a spiroketal moiety in these natural products [8, 9]. Various spiroketals from insects are volatile, simple molecules and act as pheromones [10].Over years, these natural products have become important synthetic targets not only for the challenges they present but also because of their pharmacological importance.

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The major challenge frequently encountered in the asymmetric synthesis of spiroketals is the stereoselective assembly of the spirocyclic structure with a linking carbon atom, which usually is asterogenic centre but can easily isomerize under mild acidic conditions. On the other hand the advantage is that most of the natural products possess the thermodynamically favored configuration and conformation of the spirocentre thus favoring ring closure under equilibrium conditions [11]. 2. Asymmetric Total Synthesis of Natural Spiroketals 2.1 Enantioselective Total Synthesis of OkaspirodiolOkaspirodiol (1) was isolated as a secondary metabolite from Streptomyces species Gö TS 19 [12]. Okaspirodiol readily isomerizes under mild acidic conditions to three additional isomers: 1a, 1b, and 1c (Figure 1). The six membered rings of all isomers possess a chair-like conformation with a sterically favored equatorial methyl group. Structures 1 and 1a, both having (S)-configuration at C-5, benefitfrom two anomeric effects because of the axial-quasi-axial arrangement of the spiro C-O bonds, and therefore are more stable than the other two (R)-configured isomers 1b and 1c. On the other hand, natural product 1 is thermodynamically less stable than 1a, most probably due to the cis relationship between C-3 and C-4 substituents in 1. The hydrogen bond between C-4 hydroxyl group and O-6 also makes1 and 1a more stable. Figure 1. Structures of compounds 1, 1a-1c.
OH
12 7

O
6 1

5

OH
11

OH O O 1a

OH

O HO 1b

O

O HO

O

4

O

3 2

1

HO

1c

HO

From the above discussions it is deduced that total synthesis of 1 from a spirocyclisation of an acyclic or monocyclic precursor under equilibrium conditions might be possible. Bender et al. have reported...