Addition of 2-[(trimethylsilyloxy)]furan to 2-acetyl-1,4-benzoquinone using chiral non-racemic copper(II)-pybox catalysts

The Michael addition of 2-[(trimethylsilyloxy)]furan 1 to 2-acetyl-1,4-benzoquinone 2 was carried out using several Cu(II)-pybox catalysts. The furobenzofuran adduct 3 was prepared in good chemical yield but in low enantiomeric excess. The adduct 3 was converted into the menthyl carbonate derivative to allow determination of the enantiomeric excess by high field NMR spectroscopy.


Introduction
We have reported previously the uncatalyzed addition of 2-[(trimethylsilyloxy]furan to 1,4benzoquinones and 1,4-naphthoquinones that bear an electron withdrawing group at C-2, as an efficient entry into the furobenzofuran and furonaphthofuran annulation products, respectively. 1he furonaphthofuran adducts then underwent smooth oxidative rearrangement to provide the pyranonaphthoquinone skeleton present in the isochromanquinone family of antibiotics (Scheme 1). 2 As part of an on-going programme directed towards designing an asymmetric variant of this annulation sequence we have also investigated 3 the use of bis(oxazoline)-copper(II) complexes as enantiopure catalysts for the conjugate addition of 2-[(trimethylsilyloxy)]furan 1 to 2-acetyl-1,4-naphthoquinone.The aim was to prepare a chiral non-racemic furonaphthofuran intermediate, leading ultimately to enantioselective syntheses of several pyranonaphthoquinone antibiotics.This initial study proved disappointing in that only low enantioselection was observed, despite good literature precedent for high asymmetric induction using bidentate bis(oxazoline) (box) -copper(II) complexes in catalytic asymmetric Michael and Diels-Alder additions to substrates that can participate in catalyst chelation. 4Several recent papers 5,6 have reported superior results using tridentate pyridine bis(oxazoline) (pybox) catalysts rather than bidentate phenyl bis(oxazoline) (box) catalysts for enantioselective Mukaiyama aldol reactions using silyl enol ethers.Moreover, copper(II)-pybox complexes have been shown to be efficient chiral catalysts for the enantioselective Mukaiyama-Michael reaction between (E)-3-crotonyl-1,3-oxazolidin-2-one and 2-[(trimethylsilyloxy)]furan. 7Therefore, we decided to evaluate the use of these pybox-metal complexes as catalysts for the enantioselective addition of 2-[(trimethylsilyloxy)]furan 1 to 2-acetyl-1,4-benzoquinone 2 (Table 1).

Discussion
Copper(II) complexes of four pybox ligands [(S,S)-(benzyl)-pybox] 4a, [(S,S)-(iso-propyl)pybox] 4b, [(S,S)-(sec-butyl)-pybox] 4c, and [(R,R)-(phenyl)-pybox] 4d were synthesised and evaluated for their ability to catalyze the addition of 2-[(trimethylsilyloxy)]furan 1 to 2-acetyl-1,4-benzoquinone 2. The pybox ligands were readily prepared by condensation of 2,6pyridinedicarbonyl dichloride with either (S)-phenylalaninol 5a, (S)-valinol 5b, (S)-isoleucinol 5c or (R)-phenylglycinol 5d (Scheme 2).In turn, these latter amino alcohols were available from reduction of the appropriate amino acid with lithium borohydride-chlorotrimethylsilane. 8wo methods have been reported 9,10 for the synthesis of pybox ligands.In our hands, we found that a combination of these two approaches allowed a successful synthesis of the desired ligands 4a-d.The appropriate amino alcohol 5 dissolved in isopropyl acetate was added to a solution of 1.5 mol L -1 aqueous potassium hydrogencarbonate.A solution of pyridine-2,6dicarbonyl dichloride in chloroform was added and the mixture was heated at reflux for 2.5 h, affording the bisamide 6 in high yield.The open pybox bisamide 6 was then dissolved in chloroform and treated with thionyl chloride to promote ring closure to the pybox ligand 4, initially as its bis(hydrochloride) salt.This salt was surprisingly resistant towards neutralization, requiring treatment with 3 mol L -1 aqueous sodium hydroxide in methanol for 3 days to liberate the pybox ligand 4 as the free base.

Reagents and Conditions
iii.

Scheme 2
Given that higher levels of asymmetric induction were observed 11 in Diels-Alder reactions catalyzed by box-copper(II) complexes when the non-coordinating hexafluoroantimonate counterion was used, both pybox-copper(II) triflate and hexafluoroantimonate complexes were evaluated in the present study.The chiral pybox-copper(II) triflate complexes were formed by reacting pybox ligands 4a-d with copper(II) triflate in dichloromethane at room temperature for 4 h in the presence of 4 Å molecular sieves, giving characteristically blue solutions (Scheme 3).The cationic hexafluoroantimonate complexes were prepared by anion exchange from the preformed copper(II) chloride complex using silver(I) hexafluoroantimonate, followed by filtration through Celite to remove the precipitated silver(I) chloride (Scheme 3).

Scheme 3
Initial work (Table 1) focussed on the use of the catalyst prepared from the benzyl pybox ligand 4a and copper(II) triflate to induce asymmetry in the addition of 2-[(trimethylsilyloxy)]furan 1 to 2-acetyl-1,4-benzoquinone 2. Disappointingly, use of 5-37 mol% catalyst afforded only the adduct 3 as a racemate.Use of a stoichiometric quantity (1 equiv.) of the copper(II) triflate complex also afforded near-racemic adduct 3, prompting investigation of hexafluoroantimonate as an alternative counterion.Although the use of this latter complex in stoichiometric amount increased the chemical yield of adduct 3, again it was racemic.These results were mirrored in those obtained for the copper(II) complexes of the analogous phenyl pybox ligand 4d; no enantioselection was observed despite using up to a stoichiometric quantity of either the triflate or hexafluoroantimonate complex.The only evidence for stereoselection observed in the reaction of 2-[(trimethylsilyloxy)]furan 1 with 2-acetyl-1,4benzoquinone 2 arose from the use of a stoichiometric quantity of the copper(II) triflate complex of the pybox ligand 4b derived from valinol, which afforded the enantiomers of adduct 3 in a ratio of 2:1.However, use of the analogous sec-butyl pybox ligand 4c under the same conditions reverted to the formation of adduct 3 as a racemate.
The enantioselectivity of the reaction was determined by conversion of the adduct 3 into its diastereoisomeric menthyl carbonate derivatives by reaction with (+)-menthyl chloroformate.Integration of the doublets observed at δ 0.81 ppm and δ 0.83 ppm for the menthyl CHCH 3 groups at C5′ of the individual diastereoisomers allowed determination of their ratio.
It has been established that 2-[(trimethylsilyloxy)]furan 1 adds as a nucleophile in a Michael type fashion to C3 of the benzoquinone 2. 12 There is an opportunity for asymmetric catalysis if the two adjacent carbonyl oxygens of the benzoquinone preferentially form a bidentate chelate to the Lewis acid metal centre from one face.The structure of {Cu[(S,S)-(isopropyl)pybox]}(SbF 6 ) 2 containing a bound substrate (via bidentate chelation) has been determined by EPR spectroscopy, and this evidence supported the hypothesis that substrates bind to this catalyst in a five-coordinate square pyramidal geometry. 13In the Michael addition pathway, it is thought that the two electronegative triflate counterions are displaced successively by the two adjacent carbonyl oxygens on the 2-acetylbenzoquinone, resulting in square pyramidal geometry of the catalyst-substrate complex.In the enantioselective annulation in the presence of a stoichiometric amount of [Cu((S,S)valinol-pybox)](OTf) 2 ) to give furofuran 3, it appears that the adjacent carbonyl oxygens have formed a bidentate chelate to Cu(II) from one face selectively, resulting in the observed ratio of 2:1.Under all of the reaction conditions which resulted in racemic 3, the two adjacent carbonyl oxygens presumably also formed a bidentate chelate to the Lewis acid metal centre, but conjugate addition then occurred equally from both the re face and the si face.Scheme 4 shows si face attack on the chelated enone, and donation of electrons from the re face of the diene.This si, re approach would lead to (R,R)-stereochemistry in the syn furobenzofuran adduct 3. The alternative re, si approach would lead to the (S,S)-stereochemistry.
Because of the C 2 symmetry of the ligand, there is an alternative bidentate coordination which places the acetyl oxygen in the square plane (Scheme 5).Again, there are two trajectories of approach possible; Scheme 5 shows si,re interaction leading to (R,R); and re,si would again afford (S,S).It is assumed that the approach trajectory which minimises steric interaction with an isopropyl group is favoured, leading to 33% ee at best.In summary the work reported herein focuses on the use of bis(oxazoline)pyridine-copper(II) complexes as chiral catalysts for development of an asymmetric addition of 2-[(trimethylsilyloxy)]furan to 2-acetyl-1,4-benzoquinone. The results obtained indicate that even when a stoichiometric quantity of the metal complex is used only a moderate level of enantioselectivity is observed.

Experimental Section
General Procedures.Melting points were determined using a Kofler hot-stage apparatus and are uncorrected.Optical rotations were determined on a Perkin-Elmer 341 polarimeter.Infrared spectra were recorded with a Perkin-Elmer 1600 series Fourier-transform infrared spectrometer as thin films between sodium chloride plates. 1 H and 13 C NMR spectra were recorded as indicated on either a Bruker AC200 spectrometer operating at 200 MHz for 1 H nuclei and 50 MHz for 13 C nuclei, a Bruker DRX300 spectrometer operating at 300 MHz for 1 H nuclei and 75 MHz for 13 C nuclei, or a Bruker DRX400 spectrometer operating at 400 MHz for 1 H nuclei and 100 MHz for 13 C nuclei.Both 1 H and 13 C NMR spectra were interpreted with the aid of COSY, HETCOR and DEPT 135 experiments and are reported in p.p.m. downfield from tetramethylsilane as reference.High-resolution mass spectra were recorded using a VG 7070 spectrometer operating with an ionisation potential of 70 eV at a nominal resolution of 5000 or 10000 as appropriate.Fast atom bombardment (FAB+) spectra were recorded from m- nitrobenzyl alcohol as matrix.Major fragments are assigned where possible and their intensities given as percentages of the base peak.Tetrahydrofuran was dried using sodium/benzophenone and distilled prior to use.Flash chromatography was performed using either Merck Kieselgel 60 or Riedel-de-Haën Kieselgel S silica gel (both 230-400 mesh), or Merck aluminum oxide (70-230 mesh), with the indicated solvents.Compounds were visualized under ultraviolet light or by staining with iodine vapour or with vanillin in methanolic sulfuric acid.
The green mixture was transferred to a separating funnel containing aqueous NaHCO 3 (5%, 25 mL) and extracted with dichloromethane (3 x 50 mL).The combined dark reddish-brown extracts were washed with saturated aqueous NaHCO 3 (25 mL), saturated aqueous NaCl (25 mL), and dried (Na 2 SO 4 ).The organic phase was then filtered and the solvents were removed from the filtrate under reduced pressure.Purification of the residue by flash chromatography using hexanes-ethyl acetate (4:1) as eluent afforded the title adduct 3 (0.A sample of the above adduct 3 (0.048 g) in dichloromethane (16 mL) was treated with triethylamine (108 µL), 4-dimethylaminopyridine (0.011 g) and (+)menthyl chloroformate (76 µL).The resultant yellow solution was stirred for 45 min at room temperature under nitrogen, during which time it changed colour to pale orange.The mixture was diluted with dichloromethane (5 mL) and the solution was washed with water (5 mL), aqueous HCl (5 mL, 1 mol L -1 ) and aqueous NaHCO 3 (5 mL).The organic layer was dried (Na 2 SO 4 ) and concentrated under redued pressure.Purification of the residue by flash chromatography using hexanes-ethyl acetate (6: