The conversion of certain microbially-derived cis - and trans -1,2-dihydrocatechols into various tetrahydro-and related-derivatives

The preparation of chirons 5 – 9 from the readily available and enantiomerically pure metabolites 1 – 4 is described.


Introduction
As part of an ongoing program concerned with the exploitation of certain types of fermentation products in synthesis, 1 we sought chemical methods for the conversion of the enantiomerically pure and C3-halogenated-cis-1,2-dihydrocatechols 1-3 into protected forms of various trans-1,2,5,6-tetrahydro-derivatives such as 5-8.The ready availability of the homochiral trans-1,2dihydrocatechol 4 through manipulation of the shikimate-chorismate pathway using geneticallyengineered E. coli 2 also prompted us to investigate related conversions of this compound.Herein we detail the utilitarian procedures that have emerged from our studies on these matters and thus provided efficient access to compounds 5-9, species which we believe will serve as useful chirons in a wide-range of synthetic applications.

Results and Discussion
Our initial studies focused on relevant chemical manipulations (Scheme 1) of the cis-1,2dihydrocatechol 1, a material readily derived by microbial dihydroxylation of o-bromoiodobenzene using a genetically engineered strain [JM109 (pDTG601)] of E. coli which over-expresses the responsible enzyme, viz.toluene dioxygenase (TDO). 3,4Thus, reaction of substrate 1 with diimide generated from potassium azodicarboxylate and acetic acid 5 resulted in removal of the less-substituted double bond and the product of this process was then reductively de-iodinated using dihydrogen in the presence of Pd on C and quinoline to afford the crystalline diol 10 (67% over two steps).(2.3 mole equiv.),methanol, 18 °C, 1h; (v) TBS-Cl (4 mole equiv.),imidazole (8.9 mole equiv.),DMF, 18 °C, 3 h.
The racemic modification of compound 10 has been reported previously. 6Selective inversion of the allylic hydroxy group within diol 10 was achieved using Mitsunobu chemistry in the same manner as described by Boyd et al. 7 and employing p-nitrobenzoic acid as nucleophile.In this way the trans-diol mono-ester 11 was obtained.The spectral data obtained on this material were fully consistent with the assigned structure, further support for which arises from a single-crystal X-ray analysis of a congener prepared in an analogous manner (see below).Saponification of compound 11 was achieved with potassium carbonate in methanol and thus producing the transdiol 12 (83% from 10), the racemic form of which has also been reported previously. 6Diol 12 was then converted into the target bis-tert-butyldimethylsilyl (TBS) ether 5 (75%) under standard conditions.
cis-1,2-Dihydrocatechol 2, obtained via TDO-mediated dihydroxylation of chlorobenzene, 4 was reduced (Scheme 2) to the tetrahydro-derivative 13 8 (75%) using dihydrogen in the presence of rhodium on alumina 8,9 and the latter compound then subjected to Mitsunobu reaction with pnitrobenzoic acid.The resulting ester 14 (78%) was hydrolysed to give the crystalline trans-diol 15 (100%), the structure (including absolute stereochemistry) of which was confirmed by singlecrystal X-ray diffraction analysis (see Figure 1 and Experimental Section).As with congener 12, compound 15 was converted into the corresponding bis-TBS ether 6 (100%) using standard methods.The enantiomerically pure cis-1,2-dihydrocatechol (3) derived from microbial dihydroxylation of iodobenzene 4 was converted (Scheme 3) into the corresponding and previously reported 7 tetrahydrocatechol 16 (99%) using diimide generated in the same manner as described above for the conversion 1 → 10.Subjection of diol 16 to the by now standard Mitsunobu reaction conditions with p-nitrobenzoic acid afforded mono-ester 17 which was converted into the trans-diol 18 (70% from 16) using potassium carbonate in methanol.This last compound was transformed into the corresponding bis-MEM ether 7 (100%) upon reaction with MEM-chloride in the presence of Hünig's base.Compound 7 participates effectively in a Ni[0]catalysed Kumada cross-coupling reaction 11 with trimethylsilylmethyl magnesium chloride to give the allylic silane 8 (93% at 59% conversion).The chemical conversion of the trans-dihydrocatechol 4 into the open-chain chiron 9 is outlined in Scheme 4. The sequence begins with the three-step conversion of substrate 4 into the hydroxymethylated system 19 according to the procedure of Mueller et al. 2 The latter compound was then subjected to reduction of the less-substituted double-bond using diimide and the resulting tetrahydrocatechol 20 (74%) underwent ozonolytic cleavage and upon reduction of the resulting ozonide with sodium borohydride a chromatographically separable mixture of the C2 epimeric forms of triol 21 (86% of a 5 : 2 mixture) was obtained.The major epimer was efficiently converted into the corresponding thiocarbonate 22 (60%) by reaction with thiophosgene in the presence of DMAP as catalyst.Unexpectedly, thiocarbonate formation was accompanied by conversion of the C7-hydroxyl group within substrate 21 into the corresponding chloride, as seen in product 22.In the final step of the reaction sequence the major epimeric form of compound 22 was treated with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine at 40 °C, thus effecting a Corey-Winter olefination reaction 12 and thereby delivering the targeted chloroalkene 9 in 63% yield.was conducted on aluminum-backed 0.2 mm thick silica gel 60 F254 plates (Merck) and the chromatograms were visualized under a 254 nm UV lamp and/or by treatment with an anisaldehyde-sulfuric acid-ethanol (3 mL : 4.5 mL : 200 mL) dip or, occasionally, with a phosphomolybdic acid-ceric sulfate-sulfuric acid-water (37.5 g : 7.5 g : 37.5 mL : 720 mL) dip, followed by heating.The quoted retardation factors (R f ) have been rounded to the first decimal place.Flash chromatography was conducted according to the method of Still and co-workers 13 using silica gel 60 (mesh size 0.040-0.063mm) as the stationary phase and the analytical reagent (AR) grade solvents indicated.Many starting materials and reagents were available from the Aldrich Chemical Company or EGA-Chemie and were used as supplied or, in the case of stable liquids, simply distilled.Drying agents and other inorganic salts were purchased from AJAX or BDH Chemicals.Reactions employing air-and/or moisture-sensitive reagents and intermediates were carried out under an atmosphere of dry, oxygen-free nitrogen in flame-dried apparatus.
Diethyl ether was dried using sodium metal and then distilled, as required, from sodium benzophenone ketyl.Methanol was distilled from magnesium methoxide.Dichloromethane was distilled from calcium hydride and toluene from sodium metal.N,N-dimethylformamide (DMF) was heated at reflux over calcium hydride for 16 h then distilled and stored over 3 Å molecular sieves.Organic solutions obtained from work-up of reaction mixtures were dried with magnesium sulfate (MgSO 4 ) then filtered and concentrated under reduced pressure on a rotary evaporator with the water bath temperature generally not exceeding 40 °C.

Synthetic Studies (1S,2R)-4-Bromo-3-cyclohexene-1,2-diol (10).
A magnetically stirred slurry of diol 1 3 (3.33 g, 10.5 mmol) and potassium azodicarboxylate (11.5 g, 59 mmol) in methanol (100 mL) maintained at 18 °C under a nitrogen atmosphere was treated dropwise with glacial acetic acid (6.9 mL, 121 mmol).Two additional portions of potassium azodicarboxylate (4.11 g, 21.1 mmol and 11.7 g, 60.2 mmol) and glacial acetic acid (2.5 mL and 10 mL) were added at the 10 h and 12 h marks and the resulting slurry stirred for a total of 34 h then quenched with NaHCO 3 (20 mL of a saturated aq solution).The separated aqueous phase was extracted with dichloromethane (3 × 30 mL).The combined organic phases were then washed with water (1 × 20 mL) and brine (1 × 20 mL) the latter causing precipitation of a flocculent white solid.This solid was removed by filtration and re-dissolved in methanol (10 mL) then the combined organic phases were dried (MgSO 4 ), filtered and concentrated under reduced pressure to give (1S,2R)-4-bromo-3-iodo- (1S,2R)-4-Bromo-3-iodo-3-cyclohexene-1,2-diol (2.35 g, 7.41 mmol) was dissolved in quinoline-methanol (150 mL of a 1 : 99 v/v mixture) and the resulting solution treated sequentially with 10% Pd on C (480 mg, 5 wt%) and NaOAc•3H 2 O (9.30 g, 2.8 mmol).The ensuing slurry was stirred vigorously at 18 °C under dihydrogen (1 atmosphere) for 36 h at which time TLC analysis indicated the complete consumption of starting material.The slurry was filtered through Celite™, Merck Type 60 silica gel (~2 g) was then added to the filtrate and the resulting mixture concentrated under reduced pressure to give a free-flowing grey powder.This powder was loaded onto the top of a flash chromatography column which was eluted with ethyl acetate-hexane (2 : 3 v/v mixture).Concentration of the relevant fractions (R f 0. The bulk of the yellow oil obtained as described immediately above was dissolved in methanol (2 mL) and the resulting magnetically stirred solution was treated, in one portion, with potassium carbonate (32 mg, 0.23 mmol).Stirring was continued for 1 h at 18 °C whereupon TLC analysis indicated the complete consumption of starting material.Silica gel (~20 mg) was therefore added and the ensuing mixture concentrated under reduced pressure to give a freeflowing white powder which was loaded onto the top of a flash chromatography column.Elution of the column with ethyl acetate-hexane (7 : 3 v/v mixture) and concentration of the relevant fractions (R f 0.2 in 1 : 1 v/v ethyl acetate-hexane) then gave the title compound 12 ( (1S,2S)-3-Chloro-3-cyclohexene-1,2-diol (13).5% Rh on alumina (1.20 g, 7 mol%) was added to a magnetically stirred solution of diol 2 (10.4 g, 71 mmol) in absolute ethanol (350 mL), a balloon of dihydrogen was attached and the reaction vessel was evacuated then flushed three times with dihydrogen.The resulting black slurry was stirred at 18 °C under an atmosphere of dihydrogen for 1.5 h whereupon TLC analysis indicated the absence of starting material.As a consequence, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give an off-white solid.This material was subject to flash chromatography (2 : 15 : 3 v/v/v methanol-diethyl ether-hexane elution) and concentration of the relevant fractions (R f 0.3, diethyl ether) gave the title compound 13 8
Concentration of fraction A (R f 0.  A magnetically stirred solution of triol 21a (296 mg, 0.72 mmol) and DMAP (530 mg, 4.34 mmol) in chloroform (7 mL), maintained under a nitrogen atmosphere, was cooled to 0 °C and treated dropwise with thiophosgene (170 µL, 2.23 mmol).The resulting mixture was stirred for 1 h at 0 °C then Merck Type 60 silica gel (~1 g) was added and the ensuing slurry concentrated under reduced pressure to give a free-flowing orange-yellow powder.This material was loaded on a short pad of Merck Type 60 silica gel and eluted with ethyl acetate-hexane (1 : 9 v/v mixture).Concentration of the filtrate under reduced pressure gave the title compound 22a (204 mg, 60%), of undetermined stereochemistry at C2, as a yellow gum, R f 0.   Images were measured on a Nonius Kappa CCD diffractometer (MoKa, graphite monochrometer) and data extracted using the DENZO package. 14Structure solution was by direct methods (SIR97) 15 and refinement was by full matrix least-squares on F using the CRYSTALS program package. 16Atomic co-ordinates, bond lengths and angles, and displacement parameters have been deposited at the Cambridge Crystallographic Data Centre (CCDC reference number 227945).

Figure 1 .
Figure 1.Anisotropic displacement ellipsoid plot 10 (with 50% probability ellipsoids) of one molecule of compound 15 derived from X-ray crystallographic data.
Measurements were carried out in a cell with a path length of 1 dm.Melting points (mp) were recorded on a Reichert hot-stage apparatus and are uncorrected.Elemental analyses were performed by the Australian National University Microanalytical Services Unit based in the Research School of Chemistry, The Australian National University, Canberra, Australia.Analytical thin layer chromatography (TLC)