Ring closure reactions of bicyclic prolinol and prolin ester enantiomers

Starting from the of bicyclic proline ester, ethyl exo -2-azabicyclo[2.2.1]heptane-3-carboxylate (+) -5 several hydantoines and thiohydantoines were prepared by acidic ring closure of the corresponding urea or thiourea derivatives. Enantiomer (-) -5 was reduced to 2-azanorbornylmethanol 12 , which was transformed to 5,8-methanooxazolo-and thiazolo[3,4-a ]pyridine derivatives. The structures, stereochemistry and relative configurations of the synthesized compounds were proved by NMR.


Introduction
α-Amino acids, both natural and unnatural, play a central part in biology and chemistry. 1They are fundamental constituents of proteins and other biologically important compounds and one of the most frequently used sources of chiral starting materials for organic synthesis.The synthesis and application of bicyclic α-amino acids have received much attention of recent years.Many of these amino acids are carriers of pharmaceutical activities, 2,3 and they have been used as building blocks for the synthesis of conformationally constrained peptides. 4Among them exo-2azabicyclo[2.2.1]heptane-3-carboxylic acid has received attention as a conformationally more rigid substitute for prolin in biologically active peptides 5-7 and in the design of chiral ligands used in asymmetric catalysis. 8,9 Ester derivatives of prolin exhibit interesting pharmacological effects: the L-proline ester of 2,6-diisopropylphenol (Propofol) derivative was synthetized by Trapini et al.This prolinate highly soluble and stable in water at physiological pH and rapidly hydrolyzed in plazma, could have potential as a water-soluble propofol prodrug for parenteral administration. 10Analogues of (N-glyoxyl)propyl proline esters and chiral bicyclic proline esters have good binding affinity toward FKBP12, suggesting their potential therapeutic utility in treating degenerative disorders of the nervous system. 11Prolin esters and prolinol are widely used for the preparation of bicyclic oxazolidine, 9, 12-18 but its 2-azanorbornane derivatives 19,20 have not been extensively investigated.
Amino ester 5 can be used as a starting substance for the preparation of other bifunctional compounds, e.g.amino acids, 1,2-aminoalcohols 21,22 and 1,2-diamines 23 and it has a few applications in the syntheses of other heterocycles. 24,25 The synthesis and stereochemistry of bicyclic saturated heterocycles with condensed skeleton containing two heteroatoms have been the subject of our study for a long time. 26Previously several methods have been published for the preparation of cisor trans-cycloalkane-fused 1,3heterocycles. 26As a continuation of this work our aim was to prepare enantiomeric bicyclic prolin esters (−)-5 and (+)-5 and prolinol derivatives and to synthesize some 2-azanorbornanefused heterocycles.

Results and Discussion
Amino ester (−)-5 and (+)-5 were prepared according to reported methods with small modifications.The syntheses of the key intermediate 4, is based on the finding that chiral imines with cyclopentadiene gives the [4+2]-cycloadduct.In spite of the reaction is highly exoselectivity, the separation of the major exo-isomer in the reaction from its diastereomers was accomplished by flash chromatography 27, 28 .Multigram scale synthesis of the aza-Diels Alder adducts ethyl and methyl (1R,3R,4S)-2-[(1S)-1-phenylethyl]-azabicyclo[2.2.1]hept-5-ene-3carboxylate has been performed by Andersson et al. 9 In this new protocol no purification of the intermediates, ethyl and methyl glyoxylate and the imine used for the Diels-Alder reaction, was necessary.The authors found that the methyl ester analogue of 4 could be easily recrystallized from pentane to afford diastereomerically pure adduct in 56 % yield.The ethyl ester 4 have been separated from its diastereomers by column chromatography.
Our synthetic route to amino ester 5 is shown in Scheme 1.The synthesis started with oxidative cleavage of diethyl L-tartarate with sodium periodate, yielding the product, ethyl glyoxylate 1 in 1 h. 24The aza-Diels-Alder reaction between 3 (derived from ethyl glyoxylate 1 and (S)-(-)-1-phenylethylamine 2) and cyclopentadiene, in the presence of trifluoroacetic acid and boron trifluoride diethyl etherate, have been performed in a one-step procedure. 9The crude hetero Diels-Alder adduct 4 could not crystallized from pentane, it was purified by column chromatography.Hydrogenation of the double bond of 4 and concomitant removal of the phenylethyl groups by hydrogenolysis in the presence of Pd(OH) 2 /C afforded amino ester (−)-5.
The α-amino acid ester (+)-5 was prepared from (R)-(+)-1-phenylethylamine by the same method.The enantiomeric purity of amino esters 5 were checked (ee > 99%) by chiral gas chromatography.When benzylisocyanate was reacted ester base (+)-5 the corresponding urea 8 was formed which was cyclised with ethanolic hydrogen chloride to hydantoin 9. Some related bicyclic hydantoins and thiohydantoins has been designed and synthesized in an enantiomeric manner by Salvati et al. 29 Some of the compounds are potent antagonist to the androgen receptor. 30-32 When amino ester base (+)-5 was reacted with 2-chloroethyl isothiocyanate, N-thiazoline derivative 10 was formed.This intermediate was attempted to cyclise with ethanolic hydrogen chloride but the formation of the tetracyclic 11 was not observed.The amino alcohol 12 was prepared from amino ester (−)-5 by LiAlH 4 reduction. 2812 can be used as a chiral ligand for asymmetric transfer hydrogenation of ketones, 28 and as a starting material for ring-closure reactions. 19,20The synthesis of heterocycle 14 started from the pchlorophenyl isothiocyanate adduct of 12. Treatment of thiourea 13 with ethanolic hydrogen chloride under reflux provided thiazolidine 14 (Scheme 4).The possible Z-E isomerism of 14 was not investigated.
When amino alcohol 12 was condensed with p-nitrobenzaldehyde in methanol, the reaction reached completion within a few hours.After evaporation of the solvent the formation of two epimeric oxazolo[1,5-a]pyridine derivatives 15 was observed, of which the two epimers could be separated by crystallization.As the NMR spectra indicated, in the major epimer 15 H-3 locates on the same side as the bridge carbon C-9 of the norbornene skeleton.The 1 H and 13 C NMR signals of 6a-d, 7a-d, 8−10, and 12−15 were assigned with the help of dqf-COSY, multiplicity-edited HSQC and HMBC experiments.The relative stereochemistry of the products was deduced mainly from NOESY experiments and proton-proton coupling constants.Many of the proton and carbon NMR signals were quite broad at 298 K in DMSO-d 6 (and even more so in CDCl 3 ) due to some fast-intermediate chemical exchange processes such as hindered rotation of the substituents and because of the presence of small, unresolved protonproton couplings within the 1 H spin system of the 2-azanorbornane moiety.The reaction intermediates, e.g.compounds 6, generally displayed broader NMR lines than the ring-closed products.In the NMR spectra of each product, only one set of signals was observed indicating that any thermodynamically favoured dynamic processes were either relatively fast on the NMR time scale at the applied experimental conditions (in DMSO at 298 K at the field of a 500 MHz instrument), or slow enough so that additional form(s) do not become clearly detectable in the sample within a few hours after dissolution in DMSO.However, many of the 1 H NMR signals were quite broad possibly due to some fast-intermediate chemical exchange process such as hindered rotation of the substituents, and due to the presence of small, unresolved proton-proton couplings within the 1 H spin system of the 2-azanorbornane moiety.In every case, the NMR spectra were consistent with the expected structures.
The ethoxycarbonyl substituent is in an exo position in the starting 2-azanorbornanes (−)-5 and (+)-5 yielding products that are exo substituted at C-8a if the configuration is retained during the synthesis.Compounds 6a-d, 7a,b (major products), 7c,d, 8, 9 and 15 (minor product) were indeed found to be exo substituted/fused, as deduced from the NOE cross peak between H-8a (or H-3 for the intermediates) and the endo-proton at C-7 (C-5 for the intermediates), and from the lack of such a cross peak between H-8a (H-3) and the syn-proton at the methylene bridge carbon C-9 (C-7).Remarkably, the minor products of 7a and 7b did have the inverted configuration at C-8a resulting in and endo-fused imidazolidine ring, as proven by the NOE correlation between H-8a and H-9syn in the NOESY spectra of these compounds.
Product 15 exhibited two epimers with respect to the asymmetric carbon C-3, of which the major and the minor form could be separated pure by crystallisation.The major and minor epimers of 15 were again identified by their NOE correlations.For the major form a strong NOE is observed between protons H-9syn and H-3, as well as between H-5 and H-3.Therefore the major epimer is the one in which H-3 locates on the same side as the bridge carbon C-9 of the norbornene skeleton.In case of the minor epimer of 15 the ortho protons of the p-nitrophenyl group (7.70 ppm) displayed and NOE correlation with H-9syn (1.47 ppm) whereas H-3 (5.34 ppm) was NOE correlated with H-8a (3.28 ppm).This establishes that in the minor epimer the aryl group is on the same face of the tricyclic skeleton as the methylene bridge.

Experimental Section
General Procedures.Melting points were determined with a Koffler apparatus and are not corrected.Merck Kieselgel 60F254 plates were used for TLC: the eluent was toluene-MeOH 4:1.Column chromatography was performed on silica gel (Merck 60, 70-230 mesh).NMR-spectra were acquired using Bruker Avance 400 and 500 spectrometers (equipped with BBI-5mm-Zgrad-ATM and BBO-5mm-Zgrad probes) operating at 399.75 and 500.13MHz for 1 H and 100.53 and 125.77MHz for 13 C, respectively.No sample spinning was used.DMSO-d 6 was used as solvent with tetramethylsilane (TMS) as an internal standard (δ TMS = 0.00 ppm for both 1 H and 13 C), and the probe temperature was set at 298 K. Spectra were processed by a PC with Windows XP operating system and XWin-NMR software. 1H NMR spectra were acquired with single-pulse excitation using a 30° flip angle, 2.3 µs (BBI) or 3.0 µs (BBO) pulse width, 10.3 kHz spectral width and 3.17 s acquisition time, and processed with 0.3 Hz exponential weighing prior to Fourier transform. 13C NMR spectra were acquired with single-pulse excitation and broadband proton decoupling (waltz-16) using a 30° flip angle, 4.2 µs (BBI) or 2.3 µs (BBO) pulse width, 30.0 kHz spectral width and 1.09 s acquisition time, and processed with 1.0 Hz exponential weighing prior to Fourier transform.The gradient-selected dqf-COSY, NOESY, multiplicity-edited HSQC and HMBC 2D NMR experiments were acquired using vendorprovided pulse programs (cosygpmfqf, noesygpph, hsqcedetgpsisp2 and hmbcgplpndqf, respectively).The NOESY mixing time was set at 0.3 s, and the HSQC and HMBC experiments were optimized for a one-bond C,H coupling constant of 145 Hz and long-range coupling constants of 10 Hz.The electron ionization (EI) mass spectra were recorded on a VG ZABSpec mass spectrometer (VG Analytical, Division of Fisons, Manchester, UK), that was equipped with Opus V3.3X program package (Fisons Instruments, Manchester, UK).The ionization energy was 70 eV and source temperature 160 °C.Small samples dissolved in methanol were placed into a quartz capillary tube and methanol was evaporated with hot air.Thereafter the sample was taken into the ionization chamber via the solid insertion probe.Perfluorokerosine (PFK) was used for calibration of the mass scale.The elemental compositions of the molecular ions were determined by peak matching (10% valley definition) using 10000 resolution.Cyclopentadiene was obtained from its dimer by heating at 200 °C.The ee values of the esters (+)-5 and (−)-5 were determined by gas chromatography on a Chrompack CP Chiracel-Dex CB column (25 m).Amino esters (−)-5 and (+)-5 were derivatised with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) and pyridine (P) before the gas chromatographic analysis.To a solution of ester 5 (