1. Keywords:

Alkyl hydroperoxide; Bromocyclization; Bromoperoxidase model; Marine natural product; Molecular modeling; Oxidation catalysis; Stereoselective synthesis; Strain; Terpenol; Vanadium(V) complex; X-ray crystallography.

2. Summary:

A cascade, composed of (i) oxovanadium(V)-catalyzed oxidation of bromide by tert-butyl hydroperoxide and (ii) stereoselective 6-endo-bromocyclization, affords 3-bromo-2-aryl-2,6,6-trimethyltetrahydropyrans from styrene-type tertiary alkenols in synthetically useful yields. (E)-Alkenols add the bromo- and the alkoxy substituent anti-selectively across the double bond, indicating a bromonium ion-mechanism for the ring closure. 6-endo-control of the alkenol cyclization thereby arises from the polar effect of the aryl substituent. Two methyl substituents bound to the alkene terminus are not similarly able to favor 6-endo-cyclization, because strain arising from methyl group repulsion, as the bromonium-activated p-bond and the hydroxyl oxygen approach, directs bromocyclization of tertiary prenyl-type substrates toward tetrahydrofuran formation. A hexsubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.

3. Introduction and outline:

Aplysiapyranoids are rare tetrahydropyran-derived natural products, which were isolated from the midgut gland of the sea hare Aplysia kurodai. The structure of the aplysiapyranoids shows a remarkable accumulation of carbon- and halogen-substituents (cf. Scheme 1). Nothing so far is known about the physiological role of the aplysiapyranoids and little about their medicinal chemical properties.

The challenge to prepare larger quantity for testing biological properties of the aplysiapyranoids in more detail was taken on by comparatively few groups. All reported strategies thereby relied on 6-endo-bromocyclization of appropriately substituted alkenols, for constructing the highly functionalized tetrahydropyran core. Jung and coworkers, for example, prepared accordingly aplysiapyranoid A, and derivatives named C and D, having a chlorine instead of a bromine atom attached next to the chlorovinyl group (for aplysiapyranoid A see Scheme 1). The yield of 6-endo-bromocyclized products remained in all instances remained low. We therefore developed an alternative approach, trying to improve the yield of tetrahydropyran formation by increasing dipolar attraction between the reacting entities. None of the strategies, however, satisfactorily provided a solution to the problem of the inherent low 6-endo-selectivity in synthesis of 2,2,6,6-substituted tetrahydropyrans from tert-alkenols, an objective researchers had pursued from the days of the first venustatriol-synthesis.

In a more recent project we had developed an efficient new approach for synthesis of bromotetrahydropyrans from acid labile alkenols via oxidative bromocyclization. The convincing chemoselectivity of this method prompted us to address the question of 6-endo-control in bromocyclization of tertiary d,e-unsaturated alcohols again. We wanted to understand why the strategy to bromocyclize tertiary alkenols bearing two methyl substituents at the terminal alkene carbon (prenyl-type alkenol, vide infra) fails to direct ring closures of tertiary alkenols exclusively toward the 6-endo-mode of cyclization, and what functional group would be needed to do so.

The major finding from the present study shows that an aryl and  a methyl group poses a suitable combination of substituents at the terminal alkene carbon (styrene-type alkenol, vide infra) for directing bromocyclization of tertiary alkenols to synthesis of 2,2,6,6-substituted tetrahydropyrans. Two methyl substituents are not able to similarly control regioselectivity, because strain arising from methyl group repulsion, as the bromonium-activated p-bond and the hydroxyl oxygen approach for intramolecular carbon-oxygen bond formation, guides cyclization of tertiary alkenols into the 5-exo-pathway, and thus to tetrahydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.

4. Introduction and outline:

Aplysiapyranoids are rare tetrahydropyran-derived natural products, which were isolated from the midgut gland of the sea hare Aplysia kurodai. The structure of the aplysiapyranoids shows a remarkable accumulation of carbon- and halogen-substituents (cf. Scheme 1). Nothing so far is known about the physiological role of the aplysiapyranoids and little about their medicinal chemical properties.

The challenge to prepare larger quantity for testing biological properties of the aplysiapyranoids in more detail was taken on by comparatively few groups. All reported strategies thereby relied on 6-endo-bromocyclization of appropriately substituted alkenols, for constructing the highly functionalized tetrahydropyran core. Jung and coworkers, for example, prepared accordingly aplysiapyranoid A, and derivatives named C and D, having a chlorine instead of a bromine atom attached next to the chlorovinyl group (for aplysiapyranoid A see Scheme 1). The yield of 6-endo-bromocyclized products remained in all instances remained low. We therefore developed an alternative approach, trying to improve the yield of tetrahydropyran formation by increasing dipolar attraction between the reacting entities. None of the strategies, however, satisfactorily provided a solution to the problem of the inherent low 6-endo-selectivity in synthesis of 2,2,6,6-substituted tetrahydropyrans from tert-alkenols, an objective researchers had pursued from the days of the first venustatriol-synthesis.

In a more recent project we had developed an efficient new approach for synthesis of bromotetrahydropyrans from acid labile alkenols via oxidative bromocyclization. The convincing chemoselectivity of this method prompted us to address the question of 6-endo-control in bromocyclization of tertiary d,e-unsaturated alcohols again. We wanted to understand why the strategy to bromocyclize tertiary alkenols bearing two methyl substituents at the terminal alkene carbon (prenyl-type alkenol, vide infra) fails to direct ring closures of tertiary alkenols exclusively toward the 6-endo-mode of cyclization, and what functional group would be needed to do so.

The major finding from the present study shows that an aryl and  a methyl group poses a suitable combination of substituents at the terminal alkene carbon (styrene-type alkenol, vide infra) for directing bromocyclization of tertiary alkenols to synthesis of 2,2,6,6-substituted tetrahydropyrans. Two methyl substituents are not able to similarly control regioselectivity, because strain arising from methyl group repulsion, as the bromonium-activated p-bond and the hydroxyl oxygen approach for intramolecular carbon-oxygen bond formation, guides cyclization of tertiary alkenols into the 5-exo-pathway, and thus to tetrahydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.