CHIRALITY 18:383–394 (2006)
Bicyclic Glutamic Acid Derivatives UDO MEYER,1 PHILIPPE BISEL,1 EDGAR WECKERT,2 AND AUGUST WILHELM FRAHM1* 1 Department of Pharmaceutical Chemistry, Albert-Ludwigs-Universita¨t, Freiburg, Germany 2 Hasylab, Hamburg, Germany
ABSTRACT For the second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids via Strecker reaction of chiral ketimines, the cyanide addition as the key stereodifferentiating step produces mixtures of diastereomeric a-amino nitrile esters the composition of which is independent of the reaction temperature and the type of the solvent, respectively. The subsequent hydrolysis is exclusively achieved with concentrated H2SO4 yielding diastereomeric mixtures of three secondary a-amino a-carbamoyl-gesters and two diastereomeric cis-fused angular a-carbamoyl g-lactams as bicyclic glutamic acid derivatives, gained from in situ stereomer differentiating cyclisation of the secondary cis-a-amino a-carbamoyl-g-esters. Separation was achieved by CC. The pure secondary trans-a-amino a-carbamoyl-g-esters cyclise on heating and treatment with concentrated H2SO4, respectively, to diastereomeric cis-fused angular secondary a-amino imides. Their hydrogenolysis led to the enantiomeric cis-fused angular primary a-amino imides. The configuration of all compounds was completely established by NMR methods, CD-spectra, and by X-ray analyses of the (aR,1R,5R)-1-carbamoyl-2-(1-phenylethyl)2-azabicyclo[3.3.0]octan-3-one and of the trans-aS,1S,2R-2-ethoxycarbonylmethyl-1-(1-pheC 2006 Wiley-Liss, Inc. nylethylamino)cyclopentanecarboxamide. Chirality 18:383–394, 2006. V KEY WORDS: a-amino nitrile esters; asymmetric Strecker synthesis; stereomer differentiating cyclisation; 3-azabicyclo[4.3.0]nona-2,4-diones; 2-azabicyclo[3.3.0]octan-3-ones; X-ray crystallography
INTRODUCTION
The two families of the ionotropic (iGluR) and the metabotropic glutamate receptors (mGluR) are still exciting targets for drug development. Consequently structural features of conformationally restricted analogues of L-glutamic acid have received increasing attention in recent years in the field of medicinal chemistry.1,2 Stereodifferentiating reactions like the asymmetric variation of the classical Bucherer–Bergs reaction3–6 or the asymmetric Strecker synthesis,7–12 give access to such cycloaliphatic amino acids. Structures including cyclic isoleucines, bis- and tris-homo-threonines, and homolysines as homochiral cycloaliphatic b-substituted a-quaternary aamino acids with two adjacent chiral centres, have been successfully created by means of the latter protocol.13–16 More recently, we have shown that this route is also capable for the synthesis of cyclic trans-tris(homoglutamic) acids.17 In the course of this investigation we realised that the secondary a-amino a-carbamoyl-g-esters, as their precursors, are also key intermediates for the synthesis of bicyclic glutamate derivatives.18 Herein we wish to report on the access to and on the elucidation of the relative and absolute configuration of those 3-azabicyclo[4.3.0]nona-2,4-diones and 2-azabicyclo[3.3.0]octan-3ones. C 2006 Wiley-Liss, Inc. V
MATERIALS AND METHODS Chemistry
Melting points were determined using a Mel-Temp II apparatus (Devices Laboratory, USA) and are uncorrected. 1H and 13C NMR spectra were recorded at 300 and 75.4 MHz, respectively, on a Varian Unity 300 spectrometer with chloroform-d and methanol-d4, respectively, as internal standards. The chemical shifts are reported as d-values using the solvent peaks as reference. For the bicyclic compounds, numbering of atoms for NMR signal assignment is not according to IUPAC rules (see Scheme 3 footnote y ). Optical rotations were measured on a Perkin-Elmer 241 polarimeter. Hydrostatic column chromatography (CC) was carried out on silica gel Si60 (70-230mesh), Fa. Merck (Art.Nr.9385) (hexane (CH)/ethyl acetate (EA) 60:40 as mobile phase) with a ratio of 160 g stationary phase for 1-g diastereomeric mixture to be separated, with a flow rate of ca 30 drops/min *Correspondence to: August Wilhelm Frahm, Department of Pharmaceutical Chemistry, Albert-Ludwigs-Universita¨t, Albertstrasse 25, D79104, Freiburg, Germany. E-mail:
[email protected] Received for publication 30 September 2005; Accepted 23 December 2005 DOI: 10.1002/chir.20260 Published online 4 April 2006 in Wiley InterScience (www.interscience.wiley.com).
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and fractions of 10 mL (7 min). Detection was achieved on TLC-alufolia silica gel F254, Fa. Merck, (Art.Nr.5554) (CH/EA 70:30 as mobile phase) with Ninhydrin-reagent. Semipreparative HPLC was performed on LiChrosorb1 Si 60 (5 lm) 250-10 (Hibar1 ready-made columns) with a gradient HPLC-pump Waters 600, EA/methanol (MeOH) 95:5 as mobile phase, a flow rate of 3.0 mL/min and UV detection at 254 nm. Drying of organic extracts during the workup of reactions was performed over anhydrous Na2SO4 with subsequent filtration. Evaporation of solvents was accomplished under reduced pressure with a rotatory evaporator. HRMS (EI, 70 eV) was performed on a Finnigan MAT 8200 spectrometer at the Department of Biochemistry and Organic Chemistry, University of Freiburg. Hydrolysis of the a-Amino Nitriles 3a–d and ent-3a–d
A solution of mixtures 3a–d and ent-3a–d, respectively,17 (9.0 g, 30 mmol) in CH (30 mL) was added dropwise to concentrated H2SO4 (60 mL) at 108C. Stirring was maintained at 108C for 3 h and at r.t. for a period of 96 h. The mixture was poured onto ice (300 g), and the solids were filtered off. The filtrate was adjusted to pH 8 with concentrated ammonia and extracted with diethyl ether (Et2O) (33 200 mL). The combined organic extracts were washed with water, brine, dried, concentrated, and finally dried in high vacuum. (aS,1S,2R)-2-Ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide (4a). Crystallization of the crude mixture from hydrolysis of 3a–d from EA/CH 7:3 afforded 4a (2.3 g, 24%) as colourless 25 þ2 (c 0.64, MeOH), NMR crystals. mp 1388C, [a]D 17 data. Further crystallisation with EA/CH 6:4 ¼ >8:2 gave a 1:1 mixture of 5c and 5d (for separation see under 5d). The residue of this mother liquor was subjected to column chromatography (CC) on SiO2. (aS,1R,2S)-2-Ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide (4b). Rf 0.26, (CH/EA 7:3) as a colourless oil (700 mg, 7%). The hydrochloride was obtained upon treatment with HCI/Et2O. mp 205– 2078C, [a]D25 73 (c 0.7, MeOH), NMR data.17 (aS,1S,2S)-2-Ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide (4c). Rf 0.22 (CH/EA 7:3) as colourless oil (12 mg, 8:2 gave a 1:1 mixture of ent-5c and ent-5d (see under ent5d). The residue of this mother liquor was subjected to CC on SiO2. (aR,1S,2R)-2-Ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide (ent-4b). Rf 0.26 (CH/ EA 7:3), as a colourless oil (700 mg, 7%). The hydrochloride was obtained upon treatment with HCl/Et2O. mp 17 206–2098C, [a]25 D þ68 (c 0.23, MeOH), NMR data. (aR,1R,2R)-2-Ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide (ent-4c). Rf 0.22 as colourless oil (12 mg, 8/2; iv: CC of the residue of the above crystallisation on Si 60 eluted with EA/CH 4/6; v: Semipreparative HPLC on LiChrosorb1 Si 60 (5 lm) 250-10 (Hibar1 ready-made column) eluted with EA/MeOH 95:5; vi: ammonium formate, Pd/C (10%), ethanol, reflux, 1 h.
a
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Scheme 2. Pathway to the 1-amino-2-carboxymethylcyclopentane carboxylic acids 8a-b with (R)-(þ)-phenylethylamine (R-PEA) as chiral auxiliary (for I–VI see Scheme 1 footnote; * for structure formula see Scheme 1).
(1.59 g, 5.0 mmol) and Pd/C (10%) (1.40 g) in EtOH (250 mL). The reaction mixture was refluxed for 1 h, cooled, filtered through a pad of Celite1, washed with EtOH, concentrated and dried in high vacuum yielding 7a (969 mg, 91%), [a]D25 8 (c 0.465, MeOH) (3% imide 6a, cyclisation in solution), and 7b (980 mg, 92%), [a]D25 þ5 (c 0.465, MeOH) (6% imide 6b, cyclisation in solution), respectively, as a colourless oil, NMR data.17 X-Ray Analysis of the Bicyclic g-Lactam ent-5c
Two independent molecules are present in the elemental cell with the two differing conformations I and II (see Fig. 3 below). The structure and the configuration could be assigned with certainty. The complete X-ray data are deposited at the Cambridge Crystallographic Data Centre.
Crystal data (CCDC No 251425): C16H20N2O2, Mr ¼ 272.35, MoKa-radiation, a ¼ 9.044 (5) A˚, b ¼ 10.949 (5) ˚ , c ¼ 29.514 (5) A ˚ , a ¼ 908, b ¼ 908, g ¼ 908, V ¼ A ˚ 3, Z ¼ 4, T ¼ 1208K. 2923.0 A RESULTS AND DISCUSSION Chemistry
We have extensively studied the asymmetric variation of the Strecker synthesis starting from racemic 2-substituted cycloalkanones with one prochirality and one chirality centre. In the first step of the basic reaction scheme, the ketone is condensed with an enantiomerically pure 1phenylethylamine (1-PEA) to the corresponding ketimine mixture, which is reacted with a cyanide equivalent to the corresponding stereomeric a-amino nitriles in the Chirality DOI 10.1002/chir
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Scheme 3. Hydrolysis of the 2-ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentane carbonitriles 3a–d to the 2-ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamides 4a–c, the bicyclic a-amino imides 5a–b, and the bicyclic a-carbamoyl g-lactams 5c–d. y Numbering of atoms in bicyclic compounds is deviating from IUPAC rules for consistency in NMR signal assignment.
actual stereo determining addition step and can in general be controlled either thermodynamically or kinetically upon variation of the solvent and the temperature. The aamino nitriles with already fixed configuration at the new chiral centre are then partially hydrolysed to the corresponding configurationally stable secondary a-amino carboxamides. At this stage, the different stereoisomers can then be separated by chromatographic methods and the individual compounds are hydrogenolysed to the primary a-amino carboxamides which are finally hydrolysed to the cyclic primary a-amino acids.16,19 The synthetic strategy applied to the targeted cyclic tris(homoglutamic) acids (i.e., trans-2,3-propanoglutamic acids), starts from racemic 2-carbethoxymethylcyclopentanone 1 prepared from cyclopentanone by a classical Stork enamine procedure.20 The following imine condensation is run with a slight excess of (S)-1-PEA and (R)-1PEA, respectively, under azeotropic removal of water in refluxing benzene and leads to a mixture of only the two diastereomeric (E)-imines E-2 and ent-E-2, respectively, in a ratio of 57:43 (Schemes 1 and 2).21 If the reaction is performed in higher boiling solvents, some aminolysis of the ester function is observed. The subsequent Lewis acid-catalysed cyanide addition with trimethylsilylcyanide (TMSCN) is run under thermodynamic conditions at r.t.
in methanol and leads to a mixture of the four theoretically feasible diastereomeric a-amino nitrile esters (cis/ trans-2R/S) 3a–d and (cis/trans-2R/S) ent-3a–d, respectively, with an additional stereo centre at C-1 in a ratio of 56:22:17:5, and an overall yield of 85%. This actual diastereoselective step was studied in detail with consecutive variation of cyanide source, solvent, temperature, and catalysts, such as Lewis acids, phase-transfer catalyst, and cyclodextrin additives. It is noteworthy that in contrast to previous work13–16 the overall cis/trans diastereoselectivity could not be reversed upon solvent and temperature changes, with the consequence that the above ratio of the four diastereomeric a-amino nitrile esters gained under thermodynamic conditions could not be altered. Thus, even at low temperature in aprotic solvents, the reaction is driven by the thermodynamic stability of the four feasible a-amino nitrile esters. The subsequent chemoselective hydrolysis of the diastereomeric mixtures of the a-amino nitrile esters 3a–d and ent-3a–d, respectively, proved troublesome. Indeed, this step is achieved only with concentrated H2SO4 at 108C in n-hexane for 96 h under preservation of the stereomeric ratio. Under these quite harsh reaction conditions, the obtained configurationally stable secondary aamino carbamoyl-g-esters 4a–c and ent-4a–c, respec-
Scheme 4. (a) Cyclisation of the trans-configured secondary a-amino a-carbamoyl-g-ester 4b to the 1-(1-phenylethylamino)-3-azabicyclo[4.3.0]nona2,4-dione (5b). (b). Cyclisation of the cis-configured secondary a-amino a-carbamoyl-g-ester 4c to the 1-carbamoyl-2-(1-phenylethyl)-2-azabicyclo[3.3.0]octan-3-one) (5c). Chirality DOI 10.1002/chir
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Fig. 1. Structure formula of the 1-(1-phenylethylamino)-3-azabicyclo[4.3.0]nona-2,4-dione (5a) and the 1-carbamoyl-2-(1-phenylethyl)2-azabicyclo[3.3.0]octan-3-one (5c) with their respective 2-H- and 6b-H-protons. [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com]
tively, are prone to undergo more or less in situ cyclisation to the follow up a-amino imides 5a–b and ent-5a–b, respectively, and a-carbamoyl g-lactams 5c–d and ent5c–d, respectively. The second expected secondary cis-aamino carbamoyl-g-esters 4d and ent-4d, respectively, could therefore not be identified (Scheme 3). Accordingly, the crude reaction mixture obtained in an overall yield of 67% consisted of five different compounds: the three a-amino carbamoyl-g-esters 4a, 4b, and 4c and the two g-lactams 5c–d in a ratio of 57:23:12:4:4 together with traces of the two bicyclic imides 5a–b. The same applies for the ent-series. The fractional crystallisation of the respective crude reaction mixture of the secondary a-amino carbamoyl-gesters from oversaturated CH/EA solutions (6:4 ¼ > 7:3 ¼ > 8:2) yields within 20 min the pure secondary trans-2ethoxycarbonylmethyl-1-(1-phenylethylamino)-cyclopentanecarboxamides 4a and ent-4a, respectively, in reasonable yields followed by a 1:1 mixture of the bicyclic a-carbamoyl tertiary g-lactams 5c and 5d and ent-5c and ent-5d, respectively, after two hours. Upon heating of the solutions during the crystallisation process, both the trans-esters 4a and 4b obviously cyclise partially to the bicyclic secondary a-amino imides 5a and 5b, whereas the cis-ester 4c predominantly cyclises to the tertiary g-lactam 5c. The final mother liquor is therewith composed of only the two trans-esters 4a and 4b, the imides 5a and 5b and the g-lactam 5c in the ratio 32:36:10:5:17 with traces of cis-ester 4c
