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29.9 Product Class 9: Spiroketals

DOI: 10.1055/sos-SD-029-00536

Ley, S. V.; Milroy, L.-G.; Myers, R. M.Science of Synthesis, (200729613.

General Introduction

The spiroacetal, which is more commonly referred to as a spiroketal, is a distinguished architectural feature of many simple and complex natural products with important and varying biological properties. They exist in a number of differing ring arrangements and some of the most abundant include [6,6]-, [6,5]-, and [5,5]-spiroketals. There is also an array of dispiroketal combinations found in many natural products (Scheme 1).

Scheme 1 Spiroketal and Dispiroketal Arrangements

The spiroketal system has been subject to considerable inquiry by the scientific commu­nity for many years and has provided an impetus for chemists to gain better and more efficient access to this heterocyclic substructure. While the collective pool of knowledge and synthetic expertise in this area has grown substantially, this is still a maturing field of organic chemistry that continues to intrigue and inspire. There have been a number of reviews in the literature that cover spiroketal synthesis,[‌1‌‌5‌] as well as their isolation from insect[‌6‌] and marine[‌7‌,‌8‌] sources (Scheme 2). Their applications in protecting group chemistry[‌9‌] and other aspects of organic synthesis[‌10‌] have also been reviewed.

Scheme 2 Spiroketal-Containing Natural Products

Traditionally, strategies for spiroketal synthesis have tended to focus on common routes to a pre-spiroketal (the intermediate immediately preceding the target spiroketal) via a key bond-forming step, with the subsequent pre-spiroketal to spiroketal step rarely more than a triviality. However, greater variation and novelty in the formation of spiroketal compounds is now being seen, and this has led to more flexible approaches for preparing highly functionalized arrangements.

Accompanying the challenges of spiroketal synthesis comes the need for careful consideration of the stereoelectronics associated with its pivotal OCO ketal bonding system. More often than not, it is this that governs the spiroketals' configurational arrangement, ahead of other influences such as steric interactions and intramolecular hydrogen bonding.

The most thermodynamically favored spiroketal form, and therefore the most prevalent in natural products, is often the one where the individual CO bonds of the OCO bonding system are positioned axially (relative to the ring unit they are connected to), with steric effects minimized (Scheme 3). Theories have been formulated to rationalize this axial preference over the more sterically favored equatorial orientation; the most significant of these is a through-bond stereoelectronic-based argument popularly termed the anomeric effect.[‌11‌‌13‌] This stereoelectronic effect has been used more widely to explain the configurational arrangement of other molecular systems, in addition to spiroketals and other sugar-based ring systems. Spiroketals that differ in their configurational arrangement at the acetal carbon possess a specific E and Z stereochemical nomenclature (Scheme 3).[‌14‌]

Scheme 3 Configuration and Stereochemistry in Spiroketals[‌11‌‌14‌]

The anomeric effect can be described in terms of a net stabilizing overlap between the high-energy, nonbonding electrons of the individual CO oxygens and the antibonding σ*-orbital of their adjacent geminally bonded CO bonds constituting the OCO bonding system. The net stabilizing anomeric contribution is maximized when the nonbonding electrons and the antibonding σ*-orbital are positioned antiperiplanar to one another, allowing for optimal overlap [Scheme 4, situation (a)].[‌11‌‌13‌]

Scheme 4 The Anomeric Effect in Spiroketals[‌11‌‌13‌]

In the case of the diaxial spiroketal, two such anomeric effects are in operation and this is therefore the most stabilizing configuration (Scheme 3). For axialequatorial [Scheme 4, situation (b)] and equatorialequatorial arrangements, this stabilization effect reduces in line with the number of operating anomeric effects. Spiroketals whose anomeric stabilization is nonmaximal are often referred to as non-anomeric and are also present in structurally diverse, biologically active natural products.[‌15‌] They represent a significant synthetic challenge in light of the added lability of the least anomerically stabilized ketal CO bond, and have been reviewed as their own separate subclass.[‌15‌] In general, this synthetic overview will cover the synthesis of spiroketals with maximal anomeric stabilization.

In terms of structural analysis, the characterization of spiroketals requires care and attention, especially since configurational differences at the ketal carbon can be difficult to distinguish. While there are few guiding markers to assist with characterization in spiroketal synthesis, the authors' experience is that the 13C NMR spectroscopy signal of the quaternary ketal carbon center (typically found in the range δ 90110 in CDCl3) is helpful.[‌16‌] Monosubstituted [6,6]-spiroketals at the 2- and/or 8-positions have downfield tertiary signals in both 1H NMR (δ 3.54.5 in CDCl3) and 13C NMR (δ 6580 in CDCl3), which may assist in assigning other ring substituents through long-range correlation spectroscopic studies. Differentiating between stereochemical or configurational isomers is possible using NOE spectroscopic analysis when X-ray crystallography is not available. This becomes easier in the case of more substituted spiroketal ring systems. In general, these methods can be applied to other-sized spiroketal ring systems.

Returning to the scope of this review, it should be noted that the most successful syntheses of spiro-containing natural products have depended very much on an efficient and reliable route to the spiroketal component, around which the retrosynthetic strategy is often centered. This review aims to highlight the best of these methods and cover the rich variation of approaches employed by the chemist to this special molecular feature.

References