Title of Invention

FUNCTIONALIZED BIS-HOMOCUBYL SYSTEMS AS NOVEL LIGANDS AND CATALYSTS IN ASYMMETRIC REACTIONS

Abstract

The present invention relates to a novel polycarbocycle derived chiral catalysts of Type 1 whose chirality and rigidity could be exploited to induce asymmetry in various organic reactions. The invention further relates to a process for preparing chiral catalyst of Type 1. The invention further relates to novel compounds prepared from catalyst of Type 1 and the process of preparing the same thereof.

Full Text

FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10; rule 13) 1. Title of the invention - FUNCTIONALIZED BIS-HOMOCUBYL SYSTEMS AS NOVEL LIGANDS AND CATALYSTS IN ASYMMETRIC REACTIONS 2. Applicant(s) (a) NAME: INDIAN INSTITUTE OF TECHNOLOGY (b) NATIONALITY: An autonomous educational institute, and established in India under the Institutes of Technology Act 1961 (c) ADDRESS : Indian Institute of Technology Bombay, Powai, Mumbai 400 076. 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention Field of the Invention The present invention relates to a novel polycarbocycle derived chiral catalysts of Type 1 whose chirality and rigidity could be exploited to induce asymmetry in various organic reactions. The invention further relates to a process for preparing chiral catalyst of Type 1. The invention further relates to novel compounds prepared from catalyst of Type 1 and the process of preparing the same thereof. Background and the prior art Asymmetric catalysis: Asymmetric reaction is a very important class of reactions in organic chemistry where a new bond is created in an enantiocontrolled manner. The elegant and economically most attractive way to introduce chirality in a chemical reaction is by using a catalytic amount of chiral controller. The search for asymmetric catalysts that provide high yields and enantioselectivity is an ongoing quest for organic chemists. Current challenges focus on the development of enantioselective catalysts with high activity and broad substrate generality directed towards efficient and environment friendly methods for the synthesis of enantiopure compounds. There have been significant advances in the field of homogeneous asymmetric catalysis, which culminated in the award in 2001 of the Nobel Prize for Chemistry to Noyori, Sharpless and Knowles for their contributions to homogeneous asymmetric hydrogenation and oxidation [Angew. Chem. Int. Ed. 2002, 41, 1998]. In the last few decades there had been tremendous progress in the development of various homo- and heterogeneous catalysts which were successful in exhibiting high level of selectivity in asymmetric reactions. Since the demands of different reactions were quite varied, the realization of the development of a universal catalyst which would find its applicability in a wide variety of reactions could never be achieved. Therefore, search for superior catalysts which could be used in different types of reactions remains a challenge for organic chemists. The "privileged class" of catalysts includes bis-oxazoline, BINOL, TADDOL, BINAP, many alkaloids, proline etc which are known to catalyze many well-known reactions. Although with all the advances in asymmetric reaction in the last few decades, there remains a challenge to develop a versatile catalyst, which can be useful for diverse reactions, under various reaction conditions. Polycyclic cage compounds: In recent years, there had been significant interest in the synthesis and chemistry of novel, highly strained polycyclic "cage" compounds for various applications. Many compounds that belong to this class possess unusual symmetry properties [Top. Stereochem. 1984, 15, 199]. With the exception of adamantane, most cage molecules contain considerable strain energy as evidenced by the following facts: (i) unusually long framework of carbon-carbon o"bonds, (ii) unusual OOC bond angle which deviates significantly from 109.5°, (iii) unusually negative heat of combustion, and (iv) unusually positive heat of formation when compared with unstrained systems. Due to their compact structure they often possess unusually high densities. These properties render them high energy density materials [Kem. Ind. 2002, 51, 51]. Some of these cage compounds are potent therapeutic agents. A recent report showed that animated polycyclic cages can be used as effective agents against Parkinson's disease [Bioorg. Med. Chem. 2004, 12, 1799] comparable in potency to 1-aminoadamantane or amantadine. Recently, a lipophilic polycyclic cage amine NGP1-01, was found to exhibit neuroprotective properties and was also used as ion channel blockers [Neurosci. Lett. 2005, 383, 49]. As for the application of these polycyclic cage compounds as a source of rigidity, Marchand et al have reported the synthesis of optically active cage functionalized crown-ether which possesses l,l'-bi'2-naphthol moiety and employed it in transport studies of chiral ammonium ions [Tetrahedron-Asymmetry. 1999, 10, 4695; Tetrahedron- Asymmetry 2003, 14, 1553]. Boyle and coworkers have attached chiral amino alcohol to pentacycloundecane (PCU) skeleton and employed it for enantioselective alkylation of benzaldehyde using diethylzinc [Tetrahedron- Asymmetry 2004, 15, 2661]. The same group has used these PCU ligands to make macrocycles which were used as chiral hosts to catalyze enantioselective Michael addition reactions [Tetrahedron- Asymmetry 2004, 15, 3775]. Vargas-Di'az et al recently demonstrated that a macrocycle, Myrtenal, derived dioxadithiadodecacycle could be used as an efficient chiral auxiliary [Org. Lett. 2007, 9, 13]. Camphor derivatives possessing a bicyclic skeleton have been used as chiral auxiliaries in many asymmetric reactions [For e.g. see: Tetrahedron-Asymmetry 2000, 11, 4127; Tetrahedron- Asymmetry 2001, 12, 1579; J. Org. Chem. 2003, 68, 915]. The asymmetric induction observed in the reported reactions was either because the chiral skeleton remained as a chiral auxiliary or a chiral moiety attached to the polycarbocyclic cage played the catalytic role. There are no examples in which the chirality of the polycarbocyclic framework was exploited to induce asymmetry. The present inventors have now found that chiral catalysts derived from bis-homocubane (BHC) would be superior to the existing class of catalysts for the following reasons : (a) The proposed BHOligands are bidendate ligands with C1 symmetry; (b) Some of them are expected to chelate well with metal complexes; (c) The cage backbone will provide enough rigidity to bring selectivity in reactions! (d) The BHC moiety enhances the lipophilicity of the ligand, which could lead to more effective recycling of the ligand; (e) The source of chirality will be chiral cage backbone with 8 fixed chiral centers which can be obtained by photocyclization of Thiele's ester followed by simple transformations; (f) since all the chiral centers are fixed/rigid, catalyst remains extremely stable, i.e. racemization doesn't take place! (g) Since both the enantiomers of the catalyst are obtained after resolution, there is scope for synthesizing both the enantiomers of the product separately and stereoselectively. Objects of the invention Accordingly, one object of the present invention is to provide a novel polycarbocycle derived chiral catalysts of Type 1 Another object of the present invention is to provide chirality and rigidity of chiral catalyst such that the same could be exploited to induce asymmetry in various organic reactions. Yet another object of the present invention is to provide novel compounds possessing functional groups as diverse as hydroxyl, amino, phosphonate/phosphate, imidazolyl, triazolyl, oxazolyl and the like prepared from catalyst of Type 1. Yet another object of the present invention is to provide a process for preparing said novel compounds. Summary of the invention According to one aspect of the present invention there is provided a novel polycarbocycle derived chiral catalysts of Type 1 Another aspect of the present invention is to provide a process for the preparation of diol substitution of the type 1 catalyst, the cage diol, said process comprising : resolving the cage diol via conversion to its disastereomeric mixture; separation of said diastereomers! and hydrolysis. Another aspect of the present invention is to provide the processes of producing the various substituted forms of Type 1 with Type 1 or cage diol as precursors. Detailed description of the invention Few representative examples include, but not limited to, compounds 2-9 possessing functional groups as diverse as hydroxyl, amino, phosphonate/phosphate, imidazolyl, triazolyl, oxazolyl etc. We envisioned that the proposed bis-homocubane (BHC) derived chiral catalysts would be superior to the existing class of catalysts for the following reasons. In the present invention, cage diol 2 [Synth. Commun. 2001, 31, 1863] was resolved via conversion to its diastereomeric mixture followed by separation of the diastereomers and hydrolysis as described below. Resolution of 2,5-bis(hydroxymethyl)pentacyclo[5.3.0.025.03'9.04,8]decane (2). To the N-carbethoxy-L-proline acid chloride (1.025 g, 5 mmol) {Tetrahedron: Asymmetry 2002, 13, 851] in CH2Cl2 (5 ml), a solution of cage diol 2 (384 mg, 2 mmol) in anh pyridine (1.5 ml, 2.5 mmol) was added dropwise at 0 C. The reaction mixture was stirred at rt for 12 h, diluted with water (5 ml) and extracted with CH2Cl2 (3x5 ml). The combined organic layer was concentrated in vacuo and the residue was passed through a silica gel column. One diastereomer was eluted out first with CH2Cl2 (100 ml) and the other with 10% methanol/CH2Cl2 (100 ml). The two fractions were separately washed with sat NaHCO3 (10 ml) followed by 5% HCl (10 ml), to remove excess proline ester and pyridine. The two organic layers were separately concentrated in vacuo to afford pure diastereomers. Isomer l: 510 mg, 48%; isomer 2- 440 mg, 42%. The diastereomer 1 was heated under reflux with IN KOH in methanol (10 mL) for 2 h. The reaction mixture was cooled and diluted with water (30 ml) and refluxed for additional 12 h. Methanol was removed in vacuo and the reaction mixture was acidified with IN HCl (10 ml). Ethyl acetate (20 ml) was added to the reaction mixture, layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The enantiopure cage diol (+)-2 was isolated by crystallization from hexane-CH2Cl2 (5:1); 175 mg, 91 yield. The above procedure was adopted for the hydrolysis of diastereomer 2 to afford cage diol (-)-2; 155 mg, 83 yield. The enantiopure cage diol (+)-2 or (-)-2, hitherto unreported, is being used as a catalyst in various asymmetric reactions. A representative example is given below. Reaction of phosphonates 11 with Boc-imines 10 catalysed by diol (+)-2. Representative procedure: To a 50 mL RB flask charged with LDA (1.5 mmol, prepared from of TrBuLi (0.9 ml, 1.5 mmol) and of N,N-diisopropyl amine (0.225 ml, 1.6 mmol)) in THF (3 ml) was added methyl phosphonate 11 (R' = H, 0.15 ml, 0.5 mmol) and the reaction mixture was stirred at -50 °C for 1 h. The cage diol (+)-2 (l mg, 0.005 mmol, 1 mol %) in THF (0.2 ml) was added followed by Boc-imine 10 (R = Ph, 205 mg, 2 mmol) and NMM (0.003 ml, 0.025 mmol). The reaction mixture was stirred for an additional 24 h at - 50 °C and then slowly warmed to 0 °C. The reaction mixture was quenched by addition of saturated aq NH4Cl (3 ml), diluted with water (10 ml) and extracted with ethyl acetate (3x4 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography by eluting with ethyl acetate: pet ether (20:80). Colourless oil, 165 mg, 92% yield, 99% ee. The B-aminophosphonates 12 synthesized in enantiopure form by our method are enzyme inhibitors and intermediates in many biochemical processes. Structure 12 includes R = alkyl, aryl, aralkyl, alkaryl etc and similarly, R' = alkyl, aryl, aralkyl, alkaryl etc. Synthesis of ligands/catalysts 3-9 which are prospective catalysts and belonging to the general structure 1 is outlined below. 2,5-Bis(diphenylhydroxymethyl)pentacyclo[5.3.0.025.039.04.8]decane (3, R = Ph). To the freshly prepared phenyl magnesium bromide ([Vogel's text book of practical organic chemistry, Addition Wesley Longman Ltd, Essex, England, 5th Ed. 1989, p 540], 20 mmol, excess), cooled to -78 °C, was added cage diester (1, X = Y = CO2Me [Tetrahedron Lett. 1968, 3485; Tetrahedron 1998, 54, 12691], 3 mmol, 744 mg) in dry THF (5 ml) dropwise over a period of 10 min. The reaction mixture was brought to rt overnight. It was poured into crushed ice (50 g), the aqueous layer was acidified with 2M H2SO4 (10 ml) and was extracted with CH2Cl2 (3x5 ml). The combined organic layer was dried over anh Na2SO4, concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/pet. ether 1:4) to afford cage diol 3 as a white solid; 595 mg, 40% yield. Structure 3 includes R = alkyl, aryl, aralkyl, alkaryl etc. 2,5-Bis(5-benzyl-4,5-dihydrooxazol-2-yl)pentacyclo[5.3.0.02.5.03,9.04,8]decane (4, R = Ph) To a suspension of cage diacid (l, X = Y = CO2H [Tetrahedron Lett. 1968, 3485; Tetrahedron 1998, 54, 12691], 300 mg, 1.36 mmol) in CH2CI2 (2 ml) at 0°C was added oxalyl chloride (1.1 ml, 1.7 g, 13.6 mmol, 10 equiv) and catalytic amount of DMF (-0.2 ml). The reaction mixture was stirred for 8 h to afford a clear solution. All volatiles were evaporated and the residue was dried in vacuo to produce the cage dicarbonyl dichloride, as a faint yellow solid, in quantitative yield (348 mg). To a solution of phenyl alaninol (1.026 g, 6.8 mmol, 5 equiv) and dry triethyl amine (0.8 ml, 549 mg, 5.44 mmol, 4 equiv) in CH2Cl2 (2 ml) was added cage dicarbonyl dichloride (348 mg, 1.36 mmol) in CH2CI2 (2 ml) drop wise at 0 "C. Stirring was continued at rt overnight and to the crude reaction mixture, Et3N (0.8 ml, 549 mg, 5.44 mmol, 4 equiv) and DMAP (33 mg, 0.2 equiv) were added. This clear solution was brought to 0 °C and MsCl (0.42 ml, 0.623 g, 5.44 mmol, 4 equiv) was added and the reaction mixture was stirred at rt for 24 h. Brine (10 ml) was added, layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 10 ml) and dried over Na2SO.-i. The cage bisoxazoline 4 was isolated as a colorless solid by recrystallization of the crude reaction mixture; 180 mg, 29% yield. Structure 4 includes R = alkyl, aryl, aralkyl, alkaryl etc. The cage diol 2 is the precursor to 5-9, most of which are potential ligands/catalysts in various asymmetric reactions. The synthesis of 5_9 is detailed below. 2,5-Bis(azidomethyl)pentacyclo[5.3.0.02'5.03,9.04,8]decane (5). To the cage diol 2 (300 mg, 1.56 mmol) in dry CH2CI2 (20 ml), cooled to 0 °C, was added pyridine (0.8 ml, 0.766 g, 9.6 mmol, 6.1 equiv) followed by mesyl chloride (0.73 ml, 9.4 mmol, 6 equiv) and DMAP (38 mg, 20 mol %). The reaction mixture was stirred for 1 h at 0 C and kept in the refrigerator overnight. It was diluted with water (15 ml), extracted with CH2CI2 (3 x 10 ml) and the combined organic layer was thoroughly washed with water (5 x 10 ml) to remove the excess mesyl chloride followed by saturated NaHCO3 (3x10 ml) and 5% dil HCI (3 x 10 ml). The organic layer was dried over anh Na2SO4 and concentrated in vacuo. The crude mesylate (500 mg) was suspended in DMF (8 ml) to which NaNs (780 mg, 12 mmol) was added followed by TBAB (68 mg, 0.3 mmol). Then the reaction mixture was heated at 90 C for 12 h and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatopraphy to afford diazide 5 as a colorless oil.' (212 mg), 62% yield. 2,5-bis(pyrrolidin-l-ylmethyl)pentacyclo[5.3.0.02'5.03'9.04,8]decane (6, NR2 = pyrrolidinyl, C4H8N). Anhydrous pyrrolidine (3.6 ml, 3.2 g, 45 mmol) was taken in a sealed tube and cooled to 0 °C. The crude dimesylate (500 mg, 1.5 mmol) in THF (2 ml) was added dropwise and the reaction mixture was heated at 100 °C for 12 h. The reaction mixture was cooled to rt, diluted with water (10 ml) and brine (10 ml) and extracted with ethyl acetate (4 x 10 ml). The organic layer was washed with brine (3 x 10 ml) dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from hexane:CH2Cl2 mixture (4:1) and pure cage diamine 5 was isolated as colourless crystalline solid; 295 mg, 70% yield. Structure 6 includes NR2 = cyclic and acyclic primary and secondary amines. 2,5-(N,N-diisopropylhexahydro-lH-[e][l,3,2]dioxaphosphepin-3-amino)-pentacyclo[5.3.0.02,5.03,9.04,8]decane (7, =Y = lone pair, X = (C3H7)2N) To a stirred solution of cage diol 2 (192 mg, 1 mmol) in THF (5 ml) at -78 °C was added -BuLi (1.3 ml, 2.2 mmol, 1.6 M solution in hexanes) dropwise. The reaction mixture was slowly brought to rt in 2 h. In another flask PCl3 (0.09 ml, 151 mg, 1.1 mmol) in THF (2.5 ml) was cooled at - 78 °C and the lithiated diol was added dropwise over a period of 15 min, keeping the internal temperature below - 70 °C. The reaction mixture was allowed to warm to rt, in 1 h. In another flask LDA (l.l mmol, prepared from of BuLi (0.168 ml, 1.1 mmol) and N,N"diisopropyl amine (0.685 ml, 1.2 mmol) in THF (2.5 ml) was generated as described before and cooled to -78 °C. It was added dropwise to the reaction mixture kept at -78 °C. The reaction mixture was stirred at '78 °C and slowly brought to rt over 2 h. The solvent was then removed in vacuo and to the semi-solid residue was added pentane (20 ml) and the resulting suspension was stirred for 1 h prior to filtration through Celite. The solvent was removed in vacuo, toluene (10 ml) was added, and the resulting suspension was stirred for 1 h prior to filtration through Celite. The solvent was evaporated in vacuo and the cage phosphoramidite 7 was isolated as a colourless oil; 45 mg, 14% yield. Structure 7 includes X = OH, Y = O; X = NR2, =Y = lone pair, where NR2 is cyclic and acyclic primary and secondary amines. 2,5-bis((lH-imidazol-l-yl)methyl)pentacyclo[5.3.0.025.039.04.8]decane (8). Imidazole (319 mg, 4.68 mmol, 3 equiv) was taken in dry THF (5 ml) to which NaH (200 mg, 5 mmol, 3.2 equiv) was added at 0 °C. After 30 min, the crude mesylate (500 mg, 1.56 mmol, 1 equiv) in THF (2 ml) was added dropwise at 0 C and the reaction mixture was stirred at rt for an additional 48 h. After the completion of the reaction, the reaction mixture was diluted with water (15 ml) and extracted with EtOAc (3x5 ml), the organic layer was washed with brine (10 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/pet ether 3-7) to afford 6 as a yellow oil; 227 mg, 50% yield. 1,2-bis((4-phenyl-lH-l,2,3-triazol-l-yl)methyl)pentacyclo[5.3.0.0.2,5.0.3,9.04,8]-decane (9, R = Ph). Cage diazide 5 (100 mg, 0.413 mmol) was suspended in t BuOH-water mixture (1^1, 2 ml). To this suspension, phenyl acetylene (0.1 ml, 84 mg, 0.82 mmol, 2 equiv), sodium ascorbate (16.3 mg, 0.08 mmol, 0.2 equiv, in two drops of water), and CUSO4.5H2O (10.3 mg, 0.04 mmol) were added and the reaction mixture was stirred at room temperature for 8 h. The reaction mixture was then extracted with CH2Cl2 (3x5 ml), the combined organic layer was washed with brine (10 ml), dried over anh Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/pet ether 1:5) to afford 9 as a white solid; 107 mg, 55% yield, mp 234 °C. Structure 9 includes R = alkyl, aryl, aralkyl, alkaryl etc.

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