Syntheses of asymmetric 2-benzopyrans. The influence of aromatic halogen substituents on the intramolecular cyclisation of enantiopure tethered phenolic lactaldehydes

The syntheses of enantiopure brominated and chlorinated phenolic lactaldehydes are described as well as an investigation into their cyclisation to form the corresponding 2-benzopyran-4,5-diols. It is found that the choice of halogen is important in these processes.


Introduction
In model studies 1 involving the assembly of monochiral 2-benzopyrans as intermediates in natural product synthesis, we established a convenient route from the benzyl alcohol 1 and ethyl (S)-lactate 2 to the enantiopure aS,2S phenolic lactaldehyde 3 in a sequence of reactions that maintained the stereochemical integrity at the asymmetric centre.This lactaldehyde was converted into the 2-benzopyran-4,5-diol 4 in high yield in a completely diastereoselective reaction using titanium tetraisopropoxide (Scheme 1).For the assembly of the natural products themselves 2 the regioselectively halogenated tethered phenolic lactaldehyde 5 or 6 was required in the enantiomeric aR,2R form, derived from the more expensive methyl (R)-lactate.The purpose of this halogen was to control the regiochemistry of a subsequent reaction. 3We now report the syntheses of each of these aldehydes 5 and 6 and an investigation into their cyclisations to form the desired 2-benzopyrans 7 and 8.

Results and Discussion
Syntheses of the halogenated benzyl alcohols 16 and 17 The starting material chosen for the assembly of the chlorinated alcohol 16 was commercially available ortho-chlorophenol.This was converted into the known 2-bromo-6-chloro-1,4benzoquinone 9 through dibromination 4 followed by oxidation. 5Reduction with sodium dithionite afforded the corresponding hydroquinone, which was selectively monobenzylated at the less hindered hydroxyl group to yield the 4-benzyloxy derivative 10 as the major product (42%), together with the dibenzylated product 11 in 20% yield.Methylation of the remaining phenolic group of the monobenzyl ether 10 afforded the differentially protected hydroquinone dialkyl ether 12 in 85% yield.Lithium-halogen exchange using butyl lithium followed by reaction with acetaldehyde replaced the bromine atom selectively with the required hydroxyethyl substituent to provide the target chlorinated benzyl alcohol 16 in a yield of 63%, together with the debrominated starting material 5-benzyloxy-2-methoxychlorobenzene (34%).
whereas only the αR configuration was required.It was anticipated that the nucleophilic substitution process involving the replacement of the activating trichloroacetimidate group by the nucleophilic lactate alcohol oxygen would be more S N 1-than S N 2-like in character, particularly since the benzylic carbocation produced from the trichloroacetimidate would enjoy further stabilization from the ortho-methoxy substituent.The ratio of the diastereoisomeric benzylprotected lactates would therefore not be expected to alter if the starting imidate were monochiral if the reaction proceeded via an S N 1 mechanism, but would if an S N 2 mechanism were involved, in which the nucleophilic alcohol displaced the departing imidate.Any improvement in the proportion of the αR stereoisomer would nevertheless be an advantage and the trichloroacetimidate was therefore prepared as almost exclusively a single enantiomer.It was recognized that, for an S N 2 process, the (αS) enantiomer of the alcohol 17 would be required to yield the αR,2R lactate through inversion, but only the less expensive (S)-enantiomer of the required reducing agent was immediately available in our laboratory and this would produce the αR enantiomer, so this was used as a model.The acetophenone 15 was therefore subjected to enantioselective reduction using freshly prepared (S)-oxazaborolidine (CBS-catalyst ) and borane-dimethyl sulphide complex, 6 to give the (αR) enantiomer 24 of the benzyl alcohol 17. 7 A 98% yield was obtained when the reaction was undertaken at -23 o C, and the enantiomeric excess was determined as 94%.A lower enantiomeric excess, 82%, was obtained when the reaction was performed at the higher temperature of 0 o C.This was then converted as before into the enantiopure (αR) trichloroacetimidate 25.When this was reacted with isobutyl (R)-lactate an approximately 1:1 mixture of the benzyl-protected lactates 22 was obtained (Scheme 2).This supported an S N 1-like carbocation for this process.

Scheme 2
The individual lactaldehydes 27 and 30 were the next targets, and these were best obtained directly as a mixture (66% yield) through reduction of the mixture of esters 22 with diisobutyl aluminium hydride, together with the individual alcohols 26 (9%) and 29 (10%).The mixture of aldehydes was, however, inseparable, and so the ester mixture 22 was reduced with lithium borohydride to afford the mixture of alcohols, which was separated chromatographically to give the individual diastereoisomers 26 (36%) and 29 (33%).Lithium aluminium hydride was not used in this reaction in view of its removal of the aromatic bromine atom in the reduction of the ketone 15 as described above.Each of these alcohols 26 and 29 was oxidized separately to the corresponding aldehyde using Swern's method, 8 the aldehyde 27 being obtained in a yield of 72% and the diastereoisomer 30 in 86%.
For the corresponding chloro compounds, the same sequence of reactions was followed as used above for their brominated analogues.Thus the alcohol 16 was converted into its trichloroacetimidate 20, and thence into the inseparable mixture of benzyl-protected lactate esters 23.Reduction of this mixture with lithium aluminium hydride afforded the mixture of alcohols 34.Unlike the corresponding brominated alcohols 26 and 29 above and those used in the model study, 1 the individual chlorinated alcohols of the diastereoisomeric mixture 34 could not be separated chromatographically.They were therefore oxidized as a mixture, using the Swern method, to the related mixture of aldehydes 35.

Generation of the phenolic lactaldehydes and an investigation into their cyclisations
The mixture of chlorinated phenolic lactaldehydes 36 was generated through benzylic hydrogenolysis of the corresponding benzyl ethers 35.These phenolic materials were unstable on standing and so were subjected immediately as a mixture of diastereoisomers to treatment with titanium tetraisopropoxide under ultrasonic radiation, conditions which had led in the model studies 1 to high yields of 2-benzopyran-4,5-diols, for each of the starting materials 3 and its benzyl epimer.In the present study, however, where the sole difference in the substrates (other than that the model compounds were the enantiomers of the aldehydes 36) was their regioselective chlorination, no cyclisation product 7 was observed under identical reaction conditions, only starting materials being recovered.Hydrogenolysis of the brominated benzyl ether 27 afforded the unstable brominated phenolic lactaldehyde 6, which was immediately cyclised with titanium tetraisopropoxide under ultrasonic radiation, whereupon the product 7-bromo-2-benzopyran-4,5-diol 8 was immediately converted into the diacetate 28 in an overall yield for the two steps of 74%, thus averaging 86% for each step.The cyclisation step was completely diastereoselective and the stereochemistry of the 2benzopyran-4,5-diol 8 and its diacetate 28 were readily identified from their 1 H NMR spectra; in particular, for the diacetate from the coupling constant between 3-H and 4-H, which was found to be 5.0 Hz, and the chemical shift of 3-H was δ 4.10.These values agree closely with those (4.8Hz and δ 4.11) found for the model diacetate of the diol 4, 1  Hydrogenolysis of the benzyl epimeric lactaldehyde 30 gave the phenol 31, which was immediately cyclised to the mixture of C-4 epimeric 4,5-diols 1 32 and 33 in a ratio of 1:1.

Conclusions
The successful diastereoselective cyclisation of tethered phenolic lactaldehydes to form enantiopure 2-benzopyran-4,5-diols using titanium tetraisopropoxide under ultrasonic radiation is influenced by electron availability on the aromatic ring.Chlorine substitution of this ring para to the desired reaction site prevents cyclisation, whereas the less electronegative bromine facilitates ready ring-closure.Bromine is therefore the halogen of choice in completing the syntheses of the desired natural products.

Experimental Section
General Procedures.Nuclear magnetic resonance spectra were recorded using either a Hitachi R24B spectrometer ( 1 H 60 MHz), a Bruker AM-300 spectrometer ( 1 H 300 MHz, 13 C 75.5 MHz) or a Bruker Avance DPX-300 spectrometer ( 1 H 300 MHz, 13 C 75.5 MHz).All spectra were run on the Bruker AM-300 spectrometer or the Bruker Avance DPX-300 spectrometer unless otherwise stated.All 1 H spectra were recorded at ambient temperature in deuterochloroform (CDCl 3 ) using tetramethylsilane (TMS) as an internal standard.In the 13 C NMR spectra, assignments of signals with the same superscript are interchangeable.Mass spectra were recorded on either a Hewlett Packard 5986 spectrometer at 35 eV, or on a Perkin Elmer ITD Ion Trap Detector spectrometer at 55 µA with automatic gain control.High resolution mass spectra were recorded on a VG Autospec High Resolution Mass Spectrometer at the University of Western Australia.Infrared spectra were recorded as thin films between KBr plates for oils and as KBr discs for solids using a Perkin Elmer 1720-X Fourier Transform Spectrometer.Melting points are uncorrected and were recorded on a Reichert hot stage apparatus.Optical rotations were recorded for chloroform solutions of c 1.0 at 20 o C using an Optical Activity PolAAr 2001 polarimeter.The sonication bath used was a Branson B3200-E4 operating at a frequency of 44-50 kHz.Kugelrohr refers to a Kugelrohr distillation apparatus.Elemental analysis were carried out by either the Australian National University Analytical Service Unit or by the Canadian Microanalytical Service Ltd. Column chromatography was performed on columns prepared as slurries of Merck silica gel 60 (70-230 mesh) in the eluent.Preadsorption was carried out on Merck silica gel 60 (35-70 mesh).Radial chromatography was performed using Merck silica gel 60 PF 254 .Preparative layer chromatography was performed on glass plates coated with Carmag silica gel as a 0.3 mm thick layer, while thin layer chromatography was carried out on aluminium plates coated with Merck Kieselgel 60 F 254 .Petroleum ether refers to the fraction of boiling point 65 o C to 70 o C. All solvents were purified by distillation and, if necessary, were dried according to standard methods.The amount of residual water present in solvents was determined using a Metrohm Karl Fischer Coulometer 684.