Arbeitsgruppe Hartung

Forschung

C) Marine Bromoperoxidase

C2) Controling 6-endo-Selectivity in Oxidation/Bromocyclization Cascades for Synthesis of Aplysiapyranoids and other 2,2,6,6-substituted Tetrahydropyrans


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.

 

Scheme 1. Retrosynthetic scheme and named reactions for synthesis of the marine natural product aplysiapyranoid A

 

5. Results

Scheme 2. Catalytic cycle for vanadium(V)-catalyzed bromide oxidation by tert-butyl hydroperoxide for bromine formation (top; R = tBu, n = 1–2, cf. Scheme 3), and its use in synthesis of bromotetrahydropyrans (bottom; R’ = alkyl, Ar = e.g. Ph, p-MeOC6H4).

Scheme 3. Synthesis of oxovanadium compounds V(O)Ln(OEt) (95% for n = 1, 85% for n = 2) from auxiliaries H2L1 and H2L2 [acidic protons that are substituted by VO(OEt)2+ in the course of complex formation are printed in bold; VOL1(OEt) crystallizes as EtOH-adduct from ethanolic solution].

Figure 1. Indexing of prenyl- and styrene-type d,e-unsaturated alcohols to explore systematics of 6-endo-selectivity in bromocyclization.

Table 1. Bromocyclization of styrene-type alkenols 1df in vanadium-catalyzed oxidations

Scheme 4. Synthesis of dibromide 6 from ester 2e. a 3,5-cis:3,5-trans = 76:24. b Ratio of 3,5-cis/3,5-trans isomer [PTOH = N-hydroxypyridine-2(1H)-thione; DIC = diisopropylcarbodiimide; the atom numbering changes in going from 5 to 6 for reasons of functional group hierarchy].

Table 2. Preparation of methyl tetrahydropyranyl 2-carboxylates cis-10 and trans-10

Table 3. Preparation of aplysiapyranoid A and 5-epi-A

6. Concluding remarks:

A proper set substituents to control 6-endo selectivity for synthesis of 2,2,6,6-substituted tetrahydropyrans via alkenol bromocyclization is the combination of an aryl and a methyl substituent. The aryl group adds a polar component to the ring closure, that is not available from dimethyl substitution. Methyl substitution moreover induces strain, as the bromonium-activated p-bond and the hydroxyl oxygen of a tertiary prenyl-type alkenol approach for intramolecular carbon-oxygen bond formation, thus favoring tetrahydrofuran formation from the 5-exo-reaction.

The concept used in this study to prepare organobromines from bromide, tert-butyl hydroperoxide, and an unsaturated hydrocarbon generally is referred to as oxidative bromination. Oxidative bromination is mechanistically related to bromide oxidation by hydrogen peroxide, catalyzed by marine bromoperoxidases in nature. Vanadium complexes V(O)Ln(OEt) therefore can be regarded as functional bromoperoxidase mimics, and tert-butyl hydroperoxide the biomimetic electron acceptor. The results summarized in this work show that, functional bromoperoxidase chemistry has reached a notable degree of maturity. Modern oxidative bromination, for example, uses a buffer composed of sodium bromide and b-bromocinnamic acid to liberate protons and bromide under pH-neutral conditions, and is feasible in propylene carbonate as nontoxic solvent.

The synthetic potential of oxidative bromination for synthesis of natural products is evident from the third part of the study for synthesis of the marine natural product aplysiapyranoid A. The strategy to interconvert functional groups in a sequence of homolytic and polar reactions, adds a component to synthesis of the aplysiapyranoids that is not available from other concepts developed so far. The strength of the homolytic substitution in this approach arises from the efficiency of carbon-bromine bond formation at a sterically shielded secondary neopentyl-type carbon at tetrahydropyran. The yields associated with chlorovinyl group formation from the phenyl group, on the other hand, remained below expectation. With the wisdom of hindsight we relate the reluctance of reagents to add to substituents at C2 to strain that additionally builds up as the configuration of the attacked carbon changes from planar to tetrahedral. The increase in steric demand occurs in a severely encroached region of the 2,2,6,6-substituted tetrahydropyran and therefore is expected to require notable activation energy in order to effectively occur.

 To continue the project, we consider the aplysiapyranoids C and D as attractive targets. The latter compounds have a chlorosubstituent bound next to the vinyl group and synthesis of the products according to the outlined strategy requires development of an efficient oxidation/chlorocyclization cascade for constructing tetrahydropyran rings. A survey of the literature shows that chlorocyclization is just beginning to evolve. To develop a practical method for in situ chlorine generation from transition metal-catalyzed oxidation, therefore is a rewarding objective to pursue.

 

7. Leading References:

Controling 6-endo-Selectivity in Oxidation/Bromocyclization Cascades for Synthesis of Aplysiapyranoids and other 2,2,6,6-substituted Tetrahydropyrans. O. Brücher, U. Bergsträßer, H. Kelm, J. Hartung, M. Greb, I. Svoboda, H. Fuess, Tetrahedron 2012, 68, 6968 –6980; DOI: 10.1016/j.tet.2012.05.013.

 

Vanadium(V)-Catalyzed Oxidative Bromination of Acid Labile Alkenols and Alkenes in Alkyl Carbonates. O. Brücher, J. Hartung, ACS Catalysis 2011, 1, 1448–1454; DOI: 10.1021/cs200349c.

 

8. Funding:

Deutsche Bundesstiftung Umwelt, Deutsche Forschungsgemeinschaft.

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