An asymmetric dihydroxylation route to (R)-(–)-octopamine, (R)-(–)-tembamide and (R)-(–)-aegeline

A simple and efficient asymmetric synthesis of ( R )-(–)-octopamine 1 , ( R )-(–)-tembamide 2 and ( R )-(–)-aegeline 3 is described for the first time employing the Sharpless asymmetric dihydroxylation (AD) as the source of chirality. © 2006 Elsevier Science Ltd. All rights reserved.


Introduction
(R)-(-)-Octopamine 1 is a potent chiral drug possessing β-adrenergic activity. 1 (R)-(-)-Tembamide 2 and (R)-(-)-aegeline 3 are used in traditional Indian medicines and have been shown to have good hypoglycemic activity. 2Recent studies have revealed that the two enantiomers of a chiral drug usually display different biological activities 3 and in most of the aryl ethanolamine drugs, the biological activity resides mainly in the (R)-enantiomer. 4The growing need and interest in the asymmetric synthesis of these biologically useful molecules prompted us to take up their synthesis.
Various methods for the synthesis of optically active (R)-(-)-octopamine 1, 5 (R)-(-)tembamide 2 and (R)-(-)-aegeline 3 6 have been documented.These include either tedious chemical and biological methods 7 or require the costly reagents and multistep processes with overall low chemical yields. 8Recently the enzymatic reduction of α-bromo ketones 9a and α-azido ketones 9b has also been reported for their synthesis.Surprisingly there has been no report in the literature about the asymmetric synthesis of these compounds employing the Sharpless asymmetric dihydroxylation (AD) procedure.As part of our research program aimed at developing enantioselective syntheses of naturally occurring lactones, 10a-c and amino alcohols, 10d- k and the AD was envisaged as a powerful tool to chiral dihydroxy compounds offering considerable opportunities for synthetic manipulations.Herein we report a new and highly enantioselective synthesis of (R)-(-)-octopamine 1, (R)-(-)-tembamide 2 and (R)-(-)-aegeline 3 employing the AD reaction as the source of chirality.

Conclusions
In summary, a practical and highly enantioselective synthesis of (-)-octopamine, (-)-tembamide and (-)-aegeline has been achieved for the first time employing the Sharpless asymmetric dihydroxylation as the source of chirality.Thus, the results described herein constitute a short and efficient route to (-)-octopamine, (-)-tembamide and (-)-aegeline.The synthetic approach can be further extended to the asymmetric synthesis of (S)-enantiomers via α-dihydroxylation of 5 and 9 and following the reaction sequence, as shown in Schemes 1 and 2.

Experimental Section
General Procedures.Solvents were purified and dried by standard procedures before use; petroleum ether of boiling range 60-80°C was used.Melting points are uncorrected.Optical rotations were measured using sodium D line on a JASCO P-1020 microprocessor based polarimeter.Infrared spectra were recorded on ATI MATTSON RS-1 FT-IR spectrometer. 1 H NMR and 13 C NMR spectra were recorded on Bruker AC-200 spectrometer.Mass spectra were obtained with a TSQ 70, Finningen MAT mass spectrometer.Elemental analyses were carried out on a Carlo Erba CHNS-O analyzer.

4-Benzyloxystyrene 5
This was prepared following the literature procedure.10i