D) Aerobic Oxidation

Stereoselective Synthesis of Sidechain-Functionalized Tetrahydropyrans from 5-Hexenols

1. Keywords: Addition; Aerobic oxidation; Alkenol; Alkene; Bromocyclization; Catalysis; Dioxygen; Cobalt(II) complexes; Michael acceptor; Radical; Stereoselective synthesis, Tetrahydropyran.


2. Summary: Molecular oxygen stereoselectively converts 5-hexenols into 2,6-trans-, 2,5-trans-, and 2,4-cis-derivatives of 2-methyltetrahydropyran via oxidative cyclization/radical functionalization cascades, when activated by fluoro-substituted cobalt(II) bis-(b-diketonate) complexes in solutions of cyclohexa-1,4-diene (CHD). Aerobic 5-hexenols oxidations in solutions of bromotrichloromethane and CHD, furnish products of 6-exo-bromocyclization, as exemplified by synthesis of diastereomerically pure 2,4,6-substituted tetrahydropyrans. The cobalt-method extends to intermolecular alkane/alkanol-cross coupling and to multicomponent reactions between dimethyl fumarate, CHD, a 5-hexenol, and dioxygen, providing a-tetrahydropyranyl-2-methyl succinates in synthetically useful yields.


3. Introduction and outline: Constitutionally dissymmetric tetrahydropyrans are secondary metabolites, biosynthetically formed from terpenols, acetogenins, polyketides, and oxidative enzymes.Terminal oxidants to bring about the alkenol ring closure in biosynthesis are dioxygen and hydrogen peroxide, being activated by metalloproteins. The protein coordinating a metal co-factor controls electronic properties of the oxidant and folding of the alkenol chain at the active site for attaining stereospecific oxidative tetrahydropyran ring closure.

In organic synthesis, as in biosynthesis, the important method for constructing constitutionally dissymmetric tetrahydropyrans (cf. Figure 1) is the 5-hexenol ring closure. Since the alkenol oxygen and the carbon-carbon double bond of non-Michael-type substrates are nucleophiles, one of the functional groups has to be converted into an electrophile for accomplishing the alkenol cyclization.

Changing polarity at the alkenol oxygen is feasible by abstracting the hydroxyl hydrogen, providing an alkenoxyl radical. 5-Hexenoxyl radicals add 6-exo-selectively to non-activated carbon-carbon double bonds with rate constants of 107 s–1 and above, to furnish 2,4-cis, 2,5-trans-, and 2,6-cis-isomers of sidechain functionalized tetrahydropyrans as major products, when trapped by a suitable heteroatom donor.

Changing polarity at the alkenol p-bond is feasible by activating the alkene subunit using soft Lewis acids, such as gold(III)- or mercury (II) compounds, or alternatively by oxidants such as bromine, high-valent transition metal oxo compounds, or transition metal peroxido complexes. Electrophile-induced 5-hexenol cyclizations furnish in most instances ~70/30-mixtures of stereoisomers, containing the 2,3-trans-, 2,4-cis-, 2,5-trans-, and 2,6-cis-stereoisomer in excess. This stereochemical sequence and the degree of diastereoselection reflects conformational preferences associated with transition structures of C,O-cyclization, hereafter referred to as substrate control.

Successful concepts for improving stereoselectivity in substrate-controlled alkenol cyclizations use specially designed auxiliaries for sterically blocking the unwanted mode of cyclization, for example, in transition metal-catalyzed oxidations. Approaches for reversing stereoselectivity in substrate-controlled 5-hexenol ring closures commonly change the mechanism for intramolecular carbon oxygen-bond formation, as successfully put into practice by dichloroacetylperrhenate/dichloroacetic anhydride-mediated cyclizations, and oxidations of 1,6-dienes or hept-6-ene-1,2-diols by high-valent transition metal oxo compounds. 1,6-Dienes and hept-6-ene-1,2-diols under such conditions furnish derivatives of trans-2,6-bis(hydroxymethyl)-tetrahydropyran in notable diastereomeric excess. Both methods are for structural reasons not the method of choice for finalizing synthesis of constitutionally dissymmetric 2,6-substituted tetrahydropyrans, such as Diospongin B or Centrolobin (Figure 1).

Figure 1. General structure formulas for constitutionally dissymmetric and symmetric 2,6-substituted tetrahydropyran nuclei (X = e.g. OH), and examples for tetrahydropyran natural products showing (2S,6S)- (i.e. 2,6-like)-configuration (cf. Diospongin B) and (2R,6S)- (i.e. 2,6-unlike)-configuration (cf. Centrolobin).


For stereoselectively preparing constitutionally dissymmetric tetrahydropyrans by a new approach (Scheme 1), we chose to oxidize 5-hexenols by molecular oxygen in cobalt(II)-catalyzed reactions. The method extends the Mukaiyama-oxidation of 4-pentenols, which uses dioxygen and tert-butyl hydroperoxide as terminal oxidants. Shi and Pagenkopf and their collaborators applied the the Mukaiyama-method for landmark contributions on stereoselective synthesis of tetrahydrofuran natural products. Changing the original Mukaiyama-auxiliary to fluorinated diketones allowed us to use air as exclusive terminal oxidant without the need to add tert-butyl hydroperoxide. The true potential of the cobalt-method for synthesis of cyclic ethers became apparent from mechanistic studies, uncovering that the aerobic 4-pentenol oxidation furnishes (tetrahydrofuran-2-yl)methyl radicals in the oxidative step, allowing to prepare a variety of side chain-functionalized tetrahydrofurans by heteroatom-trapping or addition to Michael-type alkenes (for a related mechanism devised as concept for the present study on tetrahydropyran synthesis, see Scheme 1).

Scheme 1. Concept for tetrahydropyran formation from aerobic 5-hexenol oxidation (step i) and radical trapping (step ii); [H] = hydrogen atom from, e.g. cyclohexa-1,4-diene (CHD); R = aryl or alkyl; L = 1-arylbutane-1,3-dione monoanion (Table 1); X–Y = e.g. CHD or BrCCl3; the dashed line indicates triplet-dioxygen (3O2)-binding to cobalt(II) bis-(b-diketonate) complex CoL2 (for structure formula of CoL2, refer to section 2.1).


In a project on alkenol methylsulfanyl-cyclization, we discovered that a 1,2-disubstituted 5-hexenol furnishes a diastereomerically pure 2,3,6-substituted tetrahydropyran, when oxidized by air in the presence of a cobalt(II)-diketonate complex. In the present study we systematically investigated stereodirecting effects exerted by one substituent in position 1 or 2, and by two substituents in 5-hexenol positions 1,2 or 1,3. We furthermore explored (tetrahydropyran-2-yl)-methyl radical-trapping by heteroatom donors and alkenes, for diversifying carbon radical trapping.

The major results from the study show that 5-hexenols yield 2,6-trans-, 2,5-trans-, and 2,4-cis-substituted tetrahydropyrans as major products, when exposed at elevated temperatures to air and cyclohexa-1,4-diene in solutions of toluene, containing a fluorinated cobalt bis-(b-diketonate) complex. Oxidizing 5-hexenols in solutions of bromotrichloromethane chemoselectively gives 6-exo-bromocyclized products in up to 89% yield, as exemplified by synthesis of diastereomerically pure 2,4,6-substituted tetrahydropyrans. Multi-component reactions between 5-hexenols, dioxygen, dimethyl fumarate, and cyclohexa-1,4-diene (CHD), catalyzed by cobalt complexes furnish a-tetrahydropyranyl-2-methyl succinates in synthetically useful yields.



4. Results:

Scheme 2. Preparation of fluorinated bis-[butane-1,3-dionato(–1)]-cobalt(II) complexes (X = H, R = CF3 for 5).

Scheme 3. Stereoselective tetrahydropyran formation from rel-(1R,2R)-1,2-diphenylhexenol  and rel-(1S,2S,3R,5R)-2-(buten-4-yl)-6,6-dimethylbicyclo[3.1.1]heptan-3-ol.


Scheme 4. Products of aerobic oxidation/alkene-trapping cascades.

Scheme 4. Products of intermolecular carbon-oxygen bond formation from aerobic cobalt-catalyzed oxidation.


5. Concluding remarks: Molecular oxygen, when activated by 4,4,4-trifluoro-1-phenylbutane-1,3-dione-derived cobalt complex 5, is a chemoselective reagent for stereoselectively converting 5-hexenols into derivatives of 2-methyltetrahydropyran. The reaction is a two-step cascade, proceeding via intermediate (tetrahydropyran-2-yl)-methyl radicals, which are trapped by the reductant cyclohexa-1,4-diene, or alternatively by bromotrichloromethane, or by dimethyl fumarate in combination with cyclohexa-1,4-diene.

The cross-over from oxidative reactivity for generating carbon radicals to reductive for chemoselectively trapping carbon radicals without providing alkyl hydroperoxides and typical successor products, such as carbonyl compounds or alcohols, probably is the most important benefit from the cobalt method for synthesis of cyclic ethers. Carbon radical trapping offers more perspectives for diversifying syntheses than polar reactions. Selectivity in radical substitutions and additions is marginally affected by solvents or additives such as Lewis-acids or other polar components. In radical chemistry, selectivity arises to significant extend from kinetic parameters, being influenced predominantly by orbital effects, temperature and reactant concentration. Changing the chemical nature of the trapping reagent by replacing a heteroatom donor by an alkene often leaves the underlying chemistry largely unaffected. Polar transformations often experience considerable selectivity changes upon such modifications.

The second noteworthy characteristic of aerobic cobalt-catalyzed 5-hexenol cyclization is the unusual 2,6-trans-selectivity. The procedure therefore is a valuable supplement to existing 2,6-cis-selective electrophile-induced 5-hexenol cyclizations. For synthesis of ethers, cobalt chemistry has even more attractive features to offer as shown by intramolecular cross coupling reactions. This chemistry has the potential to provide new answers to standing questions in syntheses of other heterocycles than tetrahydrofurans or tetrahydropyrans. Also we think that cobalt-chemistry may contribute to develop useful new approaches to intermolecular cross coupling of nucleophiles, once the central question about the chemical nature of the intermediate that guides selectivity in oxidative carbon-oxygen bond formation is settled


6. Cooperation:

Dr. Karin Kink, Karlsruhe Institute of Technology.

Dr. Sigfried Schindler, Universität Giessen.


7. Leading References:

Stereoselective Synthesis of Sidechain-Functionalized Tetrahydropyrans from 5-Hexenols. P. Fries, M.K. Müller, J. Hartung, Tetrahedron, 2014, 70, 1336–1347.

Aerobic Oxidation/Homolytic Substitution-Cascade for Stereoselective Methylsulfanylcyclization of 4-Pentenols. P. Fries, M.K. Müller, J. Hartung, Org. Biomol. Chem. 2013, 11, 2630–2637; DOI: 10.1039/j.C3OB26590K.

How Molecular Oxygen Binds to Bis-(trifluoroacetylacetonato)-cobalt(II): ab intio and Denstity Functional Theory Studies. A. Kubas, J. Hartung, K. Fink, Dalton Trans. 2011, 11298–11295; DOI: 10.1039/c1dt10724k.

Functionalized Tetrahydrofurans from Alkenols and Olefins/Alkynes via Aerobic Oxidation-Reductive Radical Addition Cascades. P. Fries, J. Hartung, J. Am. Chem. Soc. 2011, 133, 3906–3912.

Reductive and Brominative Termination of Alkenol Cyclization in Aerobic Cobalt-Catalyzed Reactions. D. Schuch, P. Fries, M. Dönges, J. Hartung, J. Am. Chem. Soc. 2009, 131, 12918–12920.

8. Funding:

Schering Stiftung, Fonds der Chemischen Industrie, NanoKat.

9. Cooperation:

Prof. Dr. Hartmut Fuess, TU Darmstadt.

10. Leading Reference:

Aspects of Structural Thiohydroxamate Chemistry – On a Systematic in the 5-(p-Methoxyphenyl)-4-methylthiazole-2(3H)-thione Series. J. Hartung, U. Bergsträsser, K. Daniel, N. Schneiders, I. Svoboda, H. Fuess, Tetrahedron2009, 65, 2567–2573.