AG Prof. Dr. J. Hartung


Oxygen-centered Radicals

A1) Natural Product Chemistry – Synthesis and Structural Characterization of the Isomuscarines

1. Keywords:

Alkoxyl radical; Bromocyclization; Muscarine alkaloid; Stereoselective synthesis; Tetrahydrofuran; Thiazolethione.


2. Summary:

Four diastereomers of 2-[(trimethylammonium)-methyl]-5-methyltetrahydrofuran-3-ol, trivially named isomuscarine, allo-isomuscarine, epi-isomuscarine, and epiallo-isomuscarine, were prepared as bromide salts from 2,4-like- and 2,4-unlike diastereomers of 3-(4-hydroxyhex-5-en-2-oxy)-4-methylthiazole-2(3H)-thione. The strategy for constructing the tetrahydrofuran nucleus of the isomuscarines is based on alkenoxyl radical 5-exo-bromocyclization, occurring 2,3-cis-selectively for the 2,4-like-4-hydroxyhex-5-en-2-oxyl radical, and 2,3-trans-selectively for the 2,4-unlike-diastereomer. A fraction of 4-hydroxyhex-5-en-2-oxyl radicals cyclizes 6-endo-selectively providing 5-bromo-2-methyltetrahydropyran-4-ols in yields between 3–15%. Substituting trimethylamine for bromide in 5-exo-bromocyclized products furnishes isomuscarine bromides, which were structurally characterized by X-ray diffraction and NMR-spectroscopy.



3. Introduction and outline:

Isomuscarines are tetrahydrofuran-derived quaternary ammonium cations structurally related to the muscarines, by changing position of the hydroxyl substituent (Figure 1). In extension to the muscarines, isomuscarine diastereomers are specified by prefices allo, epi, and epiallo for distinguishing relative configuration at the three stereocenters. The only isomuscarine prepared and structurally characterized so far is the epiallo-isomer, obtained by Joulliée and co-workers from a D-glucose-derived building block in nine synthetic steps.

Our interest in muscarine- and isomuscarine-chemistry started with the quest for selectivity control in polar and free radical bromocyclization. From an enantioselective synthesis of (+)-muscarine we learned that the hydroxyl group in position 3 of (2S,3R)-hex-5-ene-2,3-diol directs polar 5-exo-bromocyclization by the gauche effect 2,5-cis-selectively. Reversing this intrinsic stereoselectivity is feasible by changing the mechanism from polar to radical addition by converting the hydroxyl oxygen involved in C,O-formation into a radical oxygen. Oxygen radicals add to carbon-carbon double bonds via early transition states in kinetically controlled reactions with selectivity being controlled by orbital effects, torsional strain, temperature, and steric repulsion between the reaction centers.

Figure 1. Structure formulas of muscarine (top left) and isomuscarine (top right), and descriptors for specifying isomuscarine stereoisomers (bottom).

From a study on synthesis of allo-muscarine via 3-hydroxylhex-5-en-2-oxyl radical cyclization we learned that a hydroxyl group in β-position to the radical oxygen induces rapid β-fragmentation to the aliphatic chain (Scheme 1, top). Driving forces for breaking the β-carbon-carbon bond in alkenoxyl radical I are entropy, strength of the newly formed carbon-oxygen double bond, and stabilization of the liberated carbon radical by an α-hydroxyl substituent.

From the information gained by the allo-muscarine project we predicted that a hydroxyl substituent in γ-position to the radical oxygen exerts no similar rate enhancing effect for β-carbon-carbon breaking, as in regioisomer I (Scheme 1, bottom). We therefore reasoned that alkenoxyl radical II cyclizes 5-exo-selectively with stereoselectivity being guided by an interplay between polar and steric effects of the allylic hydroxyl group and the methyl substituent.

Scheme 1. Chemistry of the 3-hydroxhex-5-en-2-oxyl radical (I) (top) and proposed selectivity of the 4-hydroxhex-5-en-2-oxyl radical (II) (bottom).

The major result from the isomuscarine prodject shows that diastereomers of the 4-hydroxhex-5-en-2-oxyl radical II undergoes in solutions of bromotrichloromethane rapid, regio- and stereoselective 5-exo-bromocyclizations. The isomer described as rel-(2S,4S)-II, hereafter specified as like-II, cyclizes 2,3-cis-selectively, whereas the rel-(2S,4R)-stereoisomer of II, abbreviated as unlike-II, prefers the 2,3-trans mode of 5-exo-cyclization. Substituting trimethylamine for bromide in 5-exo-bromocyclized products affords the isomuscarines as bromide salts, which were structurally characterized by X-ray diffraction and NMR-spectroscopy.


4. Results:

 Scheme 2. Strategy for constructing the isomuscarine nucleus from 3-alkenoxythiazole-2(3H)-thione 1 and bromotrichloromethane in a radical chain reaction.

Scheme 3. Transition structure models for explaining stereoselectivity in 5-exo-cyclization of 4-hydroxyhex-5-en-2-oxyl radical unlike-II.

Scheme 4. Transition structures for modeling lowest in energy transition structures of the 2,3-cis- (upper path) and 2,3-trans-5-exo-cyclization (lower path) of 4-hydroxyhex-5-en-2-oxyl radical rel-(2S,4S)-II (like-II).

Figure 2. Ellipsoid graphics (50% probability) and structure formulas depicting conformational characteristics of isomuscarine bromide at 301 K and allo-isomuscarine bromide at 100–105 K. For presentation, (3S)-enantiomers were arbitrarily chosen from the racemate in the unit cell. Hydrogen atoms are drawn as circles of an arbitrary radius. Charges were omitted for the sake of clarity.

Figure 3. Ellipsoid graphics (50% probability) and structure formulas depicting conformational characteristics of epi-isomuscarine bromide and epiallo-isomuscarine bromide at 100–105 K (top) in the solid state. For presentation, (3S)-enantiomers were arbitrarily chosen from the racemate in the unit cell. Hydrogen atoms are drawn as circles of an arbitrary radius. Charges were omitted for the sake of clarity.


5. Concluding remarks

Bromocyclization of the 4-hydroxyhex-5-en-2-oxyl radical (II) occurs stereoselectively providing access to diastereomeric pure 2-[(trimethylammonium)-methyl]-5-methyltetrahydrofuran-3-ols, trivially named isomuscarine, allo-isomuscarine, epi-isomuscarine, and epiallo-isomuscarine. Since alkenoxyl radical reactions occur without racemization, we consider the approach also valid for preparing enantiomerically pure isomuscarines, for testing their biological properties in upcoming studies.

Isomuscarines so far have neither been described as natural products nor characterized concerning biochemical properties. The configuration of substituents required for attaining selectivity in biochemical modes of action by an isomuscarine is therefore completely unknown. From information summarized in this article and from results obtained by oxidizing structurally related alkenols it is clear that methods for preparing 2,3-trans-stereoisomers of the isomuscarines from 5-exo-cyclization in notable diastereomeric excess have to overrule an inherent driving force for the 2,3-cis ring closure of alkenoxyl radicals and unsaturated alcohols.

2,3-cis-stereocontrol in 5-exo-radical cyclizations so far is restricted to synthesis of bicyclic compounds. The polar effect exerted by an allylic heteroatom substituent therefore adds a new component to stereocontrol in oxygen radical cyclization, which is not available from alkyl- and phenyl substituents. Since alkyl groups exclusively control stereoselectivity in 4-pentenoxyl radical cyclizations by steric substituent effects, we think that the new 2,3-cis-directing effect of the allylic hydroxyl group is polar in origin. Polar substituent effects originate from a superposition of s-electron accepting and p-type non-bonding electron pair-donating effects. According to this interpretation we expect other substituents to exist, having the potential to direct 4-pentenoxyl radical cyclizations in a similar or even in a more pronounced manner 2,3-cis-selectively, which is being investigated at the moment in our laboratory.



6. Cooperation:

Prof. Dr. René Csuk, Universität Halle.

Prof. Dr. Hartmut Fuess, Technische Universität Darmstadt.


7. Leading References:

I. Kempter, B. Frensch, T. Kopf, R. Kluge, R. Csuk, I. Svoboda, H. Fuess, J. Hartung, Tetrahedron, 2014, 70, 1918–1927.  DOI: 10.1016/j.tet.2013.12.085

For a review on alkoxyl radical chemistry, see: J. Hartung, T. Gottwald, K. Špehar, Synthesis2002, 1469–1498. DOI: 10.1055/s-2002-33335