Synthesis of enantiopure 7-aminobicyclo[3.2.0]hept-2-en-6-ol; a potential N-O chelating ligand for enantioselective catalysis

A three step synthesis leading to the title compound in good overall yield is described. The bicyclo[3.2.0]heptane framework was formed with good stereocontrol by [ π 2s + π 2a] thermal cycloaddition of the readily available phthalimidoketene with cyclopentadiene. The racemic bicyclic β-amino alcohol 4 was conveniently obtained by mild cleavage of the phthalimide protecting group, in 60 % yield. Resolution with L-aspartic acid allowed access to the (–)- enantiomer of the required β-amino alcohol ligand 4 in 34 % yield and 98 % enantiomeric excess.


Introduction
Since Kagan's novel idea for using C2-symmetric chiral ligands for asymmetric catalysis,1 a wide variety of such ligands have been prepared.Despite the proven efficiency of such systems, several groups, including ourselves have retained an interest in, and prepared, C1-symmetric chiral ligands and shown them to be excellent inducers of asymmetry.2  For example we reported that bisphosphinite derivatives of bicyclo[3.2.0]heptane systems were excellent chiral inducers for some asymmetric hydrogenations.3Following this work, we decided to prepare a chiral "bowl-shaped" cis-β-amino alcohol based on the bicyclo[3.2.0]heptane skeleton 4, which can then be used as a new chiral ligand or auxiliary;4-6 the results of our initial studies are presented herein.

Results and Discussion
A well-documented and convenient synthetic route to bicyclo[3.2.0]heptanes involves the[π2s + π 2a] thermal cycloaddition of the appropriate ketene with cyclopentadiene.7,8 Cycloaddition of succinimidoketene and cyclopentadiene was previously reported by Page's group providing a route to racemic cis-7-aminobicyclo[3.2.0]hept-2-en-6-ol 4 in 7 % overall yield.9However, we have developed a more convenient and high yielding procedure according to the same strategy but using phthalimidoketene chemistry (Scheme 1).Commercially available N-phthaloyl glycine 1 was converted quantitatively into the corresponding acyl chloride 2 using oxalyl chloride.Treatment of 2 with triethylamine gave phthalimidoketene10 which reacted with cyclopentadiene, affording the adduct 3 in 75 % yield: NMR spectroscopy revealed that the exo isomer was present as a very minor impurity(< 5 %).
In contrast cycloaddition of phthalimidoketene with indene gave adduct 5 but only in very low yield (6 %).In the reactions of phthalimidoketene with cyclopentadiene and indene, 1 H NMR NOE experiments and X-ray crystallography confirmed the endo isomer as the major product.The preference for the formation of the less stable endo isomer is diagnostic evidence of the [π2s + π2a] mode of addition, resulting from the preferred position of the large phthalimide Page 884  ARKAT USA, Inc substituent in the corresponding transition state.8Selective hydride reduction of the ketone 3 and deprotection of the amine group were achieved using a "one-pot" sequence of reactions.TLC and NMR monitoring of the sodium borohydride reaction showed a stepwise reduction of the ketone from the less hindered exo face, followed by reduction of one of phthalimide carbonyl groups to furnish the corresponding alcohol.The intermediate was subsequently treated with acetic acid (as recommended previously for mild phthalimide cleavage11) furnishing the racemic β-amino alcohol 4 in 76 % yield.
Systematic screening of commercially available chiral acids for achieving the optical resolution of rac-4,12 led to the use of L-aspartic acid as an inexpensive and highly efficient resolving acid.Examples of tested acids that were unsuccessful in giving crystalline salts included L-tartaric, camphorsulfonic, malic and 3-chloromandelic acids.After optimisation, both enantiomers of the potential chiral ligand 4 have been obtained in 34 % yield with 98 % enantiomeric excess.Asymmetric catalysis using β-amino alcohol 4 is currently being investigated and will be reported in due course.

Experimental Section
General Pocedures.Manipulations of air and moisture sensitive materials were conducted under a nitrogen atmosphere using standard Schlenk techniques.Tetrahydrofuran (THF), diethyl ether, i-propanol and dichloromethane (DCM) were distilled prior to use.Thin layer chromatography (TLC) was carried out using aluminium sheets coated with Merck 60 F254 silica gel, Rf values are quoted and visualisation was achieved using ethanolic p-anisaldehyde followed by heating or by using a UV lamp (254 nm).Melting points are uncorrected.NMR spectra ( 1 H, 13 C) were recorded using Bruker AMX 400 spectrometer.The absolute value of the coupling constants (J) in Hz and assignments of 1 H and 13 C peaks were determined using COSY, HETCOR, 1D-nOe and DEPT135 experiments for all reported compounds.Mass spectra were recorded on Kratos profile HV3, CIPOS, Fisons TRIO1000 solid probe and VG7070E spectrometers and relative intensity is quoted.Optical rotations were measured using an Optical Activity LTD AA-1000 polarimeter operating at 589 nm.Elemental analyses were recorded on a Carlo Erba Strumentazione mod.1106 CHN analyser.Enantiomeric excess (ee) was determined by chiral gas chromatography (GC) and retention times (tR) are quoted in minutes.Chiral GC separations were accomplished using a Chiraldex ® G-TA (30 m × 0.25 mm) column from Astec.The carrier gas was helium.