Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo‐ and regio‐ selective study

Abstract

The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms.Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S N 2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S N 2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S N 2 and S N 2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers.Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S N 2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S N 2 mechanism.

Toluene Dioxygenase-Catalyzed Synthesis and Reactions of cis-Diol Metabolites Derived from 2- and 3-Methoxyphenols

“…Proton H-1 showed a coupling constant of 4.3 Hz, when coupled to H-6, suggesting an axial–equatorial arrangement, and proton H-6 was coupled to H-5 with a coupling constant of 8.4 Hz, indicating that H-6 was axial and H-1 was equatorial. The tendency for electronegative allylic substituents to adopt pseudo axial positions, in six-membered rings, is well documented − and can be attributed to a combination of minimization of 1,2-allylic strain and increased hyperconjugation π–σ* C–O , even in this case with an electron-deficient alkene.…”

“…95%); m/z 302 (M + , 1%), 287 (10), 187 (14), 186(100), 147 (27), 73 (25) and the trimethylsilylated enol derivative 21 as the minor product (ca. 5%); m/z 375 (M + , 11%), 374 (33), 359 (10), 286 (87), 285 (87), 284 (26), 271 (30), 269 (18), 254 (65), 239 (10), 191 (57), 147 (340, 133 (12), 75 (20), 73 (100).…”

Double [3,3]-Sigmatropic Rearrangement in the Enzymatic Dioxygenation of Benzyl Azide: Preparation of Novel Synthetically Valuable Azido-diols

“…Allylic-azide sigmatropic shift is a well-known transformation, which has been synthetically exploited in both acyclic and cyclic substrates in the past. In our system, intermediate 5 was not detected during the transformation, which could be expected considering the loss of diene conjugation in this structure, which is recovered in the final product.…”

Reactions of enantiopure cyclic diols with sulfuryl chloride

“…We have recently reported 22 the synthesis of (1S,2R)-trans-1,2-azidohydrin 9a as the predominant product from a ring opening reaction of the corresponding epoxide, and have demonstrated that this equilibrates with the isomeric azidohydrin 10a, via an allyl azide [3,3] sigmatropic rearrangement on gentle heating, to give a 4 : 1 mixture of isomers 9a : 10a. Cyclic sulfate 3a reacted with sodium azide, at room temperature, to give, exclusively, azidohydrin 9a without evidence of azidohydrin isomer 10a.…”

“…In addition to the NMR signals for the major isomer 9a, additional signals for the compound 10a were also present. 22 (1R,2R)-1,2-Dichloro-1,2,3,4-tetrahydronaphthalene 12b. Triethylamine (0.47 mL, 3.04 mmol) and sulfuryl chloride (0.25 mL, 3.04 mmol) were added to a solution of cis-diol 8b (250 mg, 1.52 mmol) in DCM (15 mL) at 0 °C.…”