Facile Synthetic Routes to 2-Oxo-1-adamantanalkanoic Acids

Abstract

A simple, fast and efficient synthesis of 2-oxo-1-adamantanacetic acid and 2-oxo-1-adamantanepropanoic acid has been developed. All of the reactions described herein proceed cleanly, with high yields, and therefore offer a new pathway to the synthesis of 1,2-disubstituted adamantanes, which constitute starting materials for many molecules with pharmacological potential.

adamantane ketoacids - protoadamantanone - stereo­selectivity - NMR

References and Notes

1a Lundahl K. Schut J. Schlatmann JLMA. Peters GB. J. Med. Chem.  1972,  15:  129 

1b Kolocouris N. Foscolos GB. Kolocouris A. Marakos P. Pouli N. Fytas G. Ikeda S. De Clercq E. J. Med. Chem.  1994,  37:  2896 

1c Kolocouris N. Kolocouris A. Foscolos GB. Fytas G. Neyts J. Padalko E. Balzarini J. Snoeck R. Andrei G. De Clercq E. J. Med. Chem.  1996,  39:  3307 

1d Zoidis G. Kolocouris N. Foscolos GB. Kolocouris A. Fytas G. Karayannis P. Padalko E. Neyts J. De Clercq E. Antiviral Chem. Chemother.  2003,  14:  155 

1e Chakrabarti J. Hotten T. Sutton S. Tupper D. J. Med. Chem.  1976,  19:  967 

1f Kolocouris A. Dimas K. Pannecouque C. Witvrow M. Foscolos GB. Stamatiou G. Fytas G. Zoidis G. Kolocouris N. Andrei G. Snoeck R. De Clercq E. Bioorg. Med. Chem. Lett.  2002,  12:  723 

1g Marazzo A. Prezzavento O. Pasquinucci L. Vittorio F. Ronsivalle G. Farmaco  2001,  56:  181 

1h Zoidis G. Fytas C. Papanastasiou I. Foscolos GB. Fytas G. Padalko E. De Clercq E. Naesens L. Neyts J. Kolocouris N. Bioorg. Med. Chem.  2006,  14:  3341 

1i Zoidis G. Papanastasiou I. Dotsikas I. Sandoval A. Dos Santos RG. Papadopoulou-Daifoti Z. Vamvakides A. Kolocouris N. Felix R. Bioorg. Med. Chem.  2005,  13:  2791 

1j Kelly JM. Quack G. Miles MM. Antimicrob. Agents Chemother.  2001,  43:  1360 

1k De Clercq E. Nat. Rev. Drug Discov.  2006,  5:  1015 

2a Chakrabarti JK. Szinai SS. Todd A. J. Chem. Soc. C  1970,  1303 

2b Chakrabarti JK. Hotten TM. Rackham DM. Tupper DE. J. Chem. Soc., Perkin Trans. 1  1976,  1893 

3

Manuscripts in preparation.

4 Lunn WHW. Podmore WD. Szinai SS. J. Chem. Soc. C  1968,  1657 

5 Bott K. Hellmann H. Angew. Chem., Int. Ed. Engl.  1966,  5:  870 

6

3-Oxatetracyclo[6.3.1.1 ^6,10 .0 ^²,6 ]tridecan-4-one ( 14)
Mp 92-93 °C. IR (mull): ν = 1789 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.50 (br d, 1 H, J = 12.0 Hz, H-13e), 1.59-1.92 (complex m, 10 H, H-7, H-9, H-10, H-11, H-12, H-13a), 1.98-2.02 (m, 1 H, H-8), 2.11 and 2.21 (2 H, AB, J _AB = 16.0 Hz, 5-H), 2.31 (d, 1 H, J = 4.0 Hz, H-1), 4.09 (d, 1 H, J = 4.0 Hz, H-2) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 26.9 (C-10), 28.5 (C-8), 29.2 (C-11), 29.7 (C-1), 36.1 (C-13), 36.4 (C-9), 36.8 (C-12), 39.2 (C-7), 42.2 (C-6), 44.4 (C-5), 87.0 (C-2), 177.2 (C=O) ppm.

7a Majersky Z. Hamesrak Z. Org. Synth.  1988,  50:  958 

7b

Optimized Procedure for the Preparation of Protoadamantanone
In an attempt to improve the yield of the literature procedure we modified the method as follows: After considerable experimentation we found that the percentage of the unreacted 1-adamantanol can be minimized by heating the reaction mixture [adamantanol, (MeCOO)₄Pb, I₂, C₆H₆] at 75-76 °C for 2 h. The resulting protoadamantanone is obtained almost pure and does not need further purification by column chromatography. [7a]

8a Abdel-Sayed A. Bauer L. Tetrahedron  1988,  44:  1873 

8b Lenoir D. Glaser R. Mison P. Schleyer P. J. Org. Chem.  1971,  36:  1821 

8c Farcasiu D. J. Am. Chem. Soc.  1973,  98:  78 

8d Lenoir D. Chem. Ber.  1973,  106:  78 

8e Tseng C. Hayda I. Abdel-Sayed A. Bauer L. Tetrahedron  1988,  44:  1893 

9a Amonoo-Neizer EH. Shaw RA. Skovlin DO. Smith BC. J. Chem. Soc.  1965,  2997 

9b Rathke M. J. Am. Chem. Soc.  1970,  92:  3222 

10

4-Hydroxytricyclo[4.3.1.0 ^³,8 ]decan-4-acetic Acid ( 12)
To a stirred solution of lithium bis(trimethylsilyl)amide (3.42 g, 19.6 mmol) in anhyd THF (55 mL) was added, over a period of 5 min, a solution of methyl acetate (1.45 g, 19.5 mmol) in anhyd THF (5 mL) at -75 °C under an argon atmosphere. After stirring the mixture for 20 min, a solution of protoadamantanone (10, 1.48 g, 9.8 mmol) in anhyd THF (10 mL) was added and the resulting suspension was stirred for 30 min at -60 °C. The mixture was treated with ice-water (15 mL), extracted with Et₂O (2 × 20 mL) and the organic phase was washed with H₂O (10 mL), HCl 5% (10 mL), H₂O (10 mL), dried (Na₂SO₄) and concentrated in vacuo. The oily residue was saponified with NaOH (0.8 g, 20 mmol) EtOH-H₂O (15 mL, 1:1) solution over 24 h at r.t. After evaporation of the solvent, the mixture was extracted twice with Et₂O (20 mL). The aqueous layer was acidified with concd HCl under cooling (0 °C). The white solid hydroxyacid formed was filtered off, washed with H₂O and dried (1.85 g, 95%); mp 185 °C (dec.; THF-n-pentane). IR (mull): ν = 3255 (OH), 1706 (C=O) cm^-1. ¹H NMR (400 MHz, DMSO): δ = 1.18-1.85 (complex m, 9 H, H-2, H-5, H-7, H-9e, H-10), 1.89 (br s, 1 H, H-6), 2.06 (br s, 1 H, H-1), 2.16-2.29 (m, 3 H, H-3, H-8, H-9a), 2.36 and 2.46 (2 H, AB, J _AB = 14.0 Hz, CH_A, CH_B) ppm. ¹³C NMR (50 MHz, DMSO): δ = 29.1 (C-6), 32.9 (C-9), 34.3 (C-8), 36.0 (C-2), 36.3 (C-1), 40.5 (C-10), 42.6 (C-7), 42.9 (C-5), 45.6 (C-3), 48.7 (CH₂COOH), 73.6 (C-4), 174.2 (C=O) ppm. Anal. Calcd for C₁₂H₁₈O₃: C, 68.54; H, 8.63. Found: C, 68.19; H, 8.28.

11

2-Hydroxy-1-tricyclo[3.3.1.1 ^³,7 ]decanacetic Acid ( 15)
A solution of 4-hydroxytricyclo[4.3.1.0^3,8]decan-4-acetic acid (12, 1.48 g, 7.0 mmol) in formic acid (20 mL) was refluxed for 30 min. After removal of formic acid under reduced pressure a viscous oil was obtained, which consisted of formic ester 13 (major product) and lactone 14 (minor product). The mixture was saponified with NaOH (1.80 g, 45.0 mmol) EtOH-H₂O (20 mL, 1:1) solution over 2.5 h in a boiling steam bath. After evaporation of EtOH, the aqueous layer was acidified with concd HCl to pH 3 under cooling (0 °C). The white solid hydroxyacid formed was filtered off, washed with H₂O and dried (1.28 g, 87%); mp 119 °C (dec.; Et₂O-n-pentane). IR (mull): ν = 3455 (OH), 1702 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.34 (br d, 1 H, J = 12.0 Hz, H-9e), 1.46 (br d, 1 H, J = 12.0 Hz, H-4e), 1.58-1.80 (complex m, 7 H, H-6, H-8, H-10, OH), 1.89 (br s, 2 H, H-5, H-7), 1.95-1.98 (m, 3 H, H-3, H-4a, H-9a), 2.16 and 2.37 (2 H, AB, J _AB = 13.0 Hz, CH_A, CH_B), 3.74 (s, 1 H, H-2) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 27.9 (C-5), 28.0 (C-7), 30.2 (C-4), 34.8 (C-3), 36.3 (C-9), 36.4 (C-6), 36.6 (C-10), 37.2 (C-1), 41.6 (C-8), 45.2 (CH₂COOH), 76.3 (C-2), 177.5 (C=O) ppm. Anal. Calcd for C₁₂H₁₈O₃: C, 68.54; H, 8.63. Found: C, 68.32; H, 8.38.

12

2-Oxo-1-tricyclo[3.3.1.1 ^³,7 ]decanacetic Acid ( 9)
To a solution of hydroxyacid 15 (1.11 g, 5.2 mmol) in acetone (40 mL) was added, during a 30 min period, Jones reagent (12 mL, 1 M) at 15 °C. After stirring for 24 h at ambient temperature, i-PrOH (3 mL) was added, and stirring was continued for an additional 1 h. The reaction mixture was filtered off and the filtrate was evaporated in vacuo. Then, H₂O (10 mL) was added and the mixture was cooled to form a precipitate which was filtered off and washed with cold H₂O to give ketoacid 9 (1.00 g, 92%) as a white solid; mp 145-146 °C (lit.: 145-146 °C). IR (mull): ν 1715 (C=O), 1700 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.84-2.09 (complex m, 12 H, H-4, H-5, H-6, H-7, H-8, H-9, H-10), 2.39 (s, 2 H, -CH ₂ COOH), 2.61 (br s, 1 H, H-3), 11.24 (br s, 1 H, -COOH) ppm. ¹³C NMR (50 MHz, CDCl₃):
δ = 27.8 (C-5, C-7), 35.4 (C-6), 39.0 (C-4, 10), 41.1
(-CH₂COOH), 43.9 (C-8, C-9), 46.5 (C-3), 48.6 (C-1), 176.5 (-COOH), 217.3 (C-2) ppm. Anal. Calcd for C₁₂H₁₆O₃: C, 69.21; H, 7.74. Found: C, 69.33; H, 7.80.

13 Chakrabarti JK. Foulis MJ. Hotten TM. Szinai SS. Todd A. J. Med. Chem.  1974,  17:  602 

14

4-Hydroxy-4-tricyclo[4.3.1.0 ^³,8 ]decane-2-propynol ( 22)
A solution of propargyl alcohol (2.06 g, 36.8 mmol) in anhyd THF (20 mL) was added dropwise to a solution of EtMgBr [prepared by the addition of a solution of ethyl bromide (8.00 g, 73.0 mmol) in anhyd THF (65 mL) to magnesium turnings (1.6 g, 66 mmol)] and the mixture was stirred for 1 h at 20 °C. Then a solution of protoadamantanone (10, 2.00 g, 13.3 mmol) in anhyd THF (20 mL) was added and the mixture was refluxed for 6 h. After stirring for 24 h at 20 °C, the mixture was hydrolyzed under ice cooling by the addition of sat. NH₄Cl solution. The aqueous phase was extracted with Et₂O (3 × 20 mL) and the combined organic extracts were washed with H₂O (3 × 20 mL) and dried (Na₂SO₄). The solvent was evaporated in vacuo and the residue formed was crystallized upon treatment with a mixture of Et₂O-PE. The solid was filtered off and washed with a cold mixture of PE-Et₂O (2.5:1) to give diol 22 (2,23 g, 82%) as a white solid; mp 106 °C (Et₂O-n-pentane). IR (mull): ν = 3278 (OH), 2361 cm^-1.¹H NMR (400 MHz, CDCl₃): δ (endo/exo, 1:1) = 1.29-1.42 (m, 2 H, H-9e, H-10a), 1.45-1.51 (m, 1 H, H-7a), 1.60-2.18 (complex m, 9 H, H-2, H-5, H-6, H-7e, H-8, H-9a, H-10e), 2.25-2.39 (complex m, 1 H, H-1), 2.44-2.49 (m, 1 H, H-3), 2.74 (br s, 2 H, 2 × OH), 4.29 (s, 2 H, -CH ₂ OH) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 28.2/29.0 (C-6), 31.5/31.6 (C-9), 32.8/34.1 (C-8), 35.4/35.6 (C-1), 36.1/36.2 (C-2), 39.4/39.9 (C-10), 42.1/42.5 (C-7), 43.2/44.5 (C-5), 46.8/47.7 (C-3), 51.0 (-CH₂OH), 68.2 (-CºC-CH₂OH), 70.6 (-CºC-CH₂OH), 80.0/80.7 (4-C) ppm. Anal. Calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.79. Found: C, 75.87; H, 8.98.

15

2-Hydroxy-1-tricyclo[3.3.1.1 ^³,7 ]decanepropanol ( 21)
A solution of diol 23 (0.88 g, 4.2 mmol) in formic acid (15 mL) was refluxed for 30 min. After removal in vacuo of formic acid an oil residue was obtained (diester 24), which was saponified with NaOH (1.90 g, 47.5 mmol) EtOH-H₂O (15 mL, 1:1) solution over 2 h in a boiling steam bath. After evaporation of EtOH, the mixture was extracted with Et₂O, the combined organic extracts were dried (Na₂SO₄) and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography using as eluents Et₂O and Et₂O-MeOH (1:1) to afford 2-hydroxy-1-tri-cyc-lo[3.3.1.1^3,7]decanepropanol (21) as a white solid (0.71 g, 81%); mp 99 °C (Et₂O). IR (mull): ν = 3322 (OH) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.10-1.15 (m, 1 H, H-9e), 1.25 (d, 1 H, CH _A CH₂CH₂OH), 1.36-1.97 (complex m, 15 H, H-3, H-4a, H-4e, H-5, H-6, H-7, H-8, H-9a, H-10, CH _B CH₂CH₂OH, CH ₂ CH₂OH), 2.31 (s, 2 H, 2 × OH), 3.65-3.69 (complex m, 3 H, H-2, -CH ₂ OH) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 25.1 (CH₂CH₂OH), 28.0 (C-5), 28.1 (C-7), 30.8 (C-4), 35.0 (C-3), 35.1 (C-9), 36.2 (C-1), 36.7 (C-6), 37.2 (CH₂CH₂CH₂OH), 37.3 (C-10), 40.4 (CH₂ CH₂CH₂OH), 63.6 (CH₂OH), 75.8 (C-2) ppm. Anal. Calcd for C₁₃H₂₂O₂: C, 74.24; H, 10.54. Found: C, 74.03; H, 10.42.

16

2-Oxo-1-tricyclo[3.3.1.1 ^³,7 ]decanopropanoic Acid ( 25)
To a solution of diol 21 (2.24 g, 10.6 mmol) in acetone (80 mL) was added, during a 1.5 h period, Jones reagent (34.8 mL, 1 M) under ice cooling. After stirring for 24 h at ambient temperature, i-PrOH (3 mL) was added and stirring was continued for an additional 1 h. The reaction mixture was filtered off and the filtrate was evaporated in vacuo. Then, H₂O (10 mL) was added to the residue and the mixture was extracted with Et₂O (3 × 20 mL). The combined organic extracts were washed with H₂O (2 × 10 mL), dried (Na₂SO₄), concentrated in vacuo and the residue formed treated with PE. The solution was cooled to -15 °C and the precipitate formed was filtered off and washed with cold PE (-15 °C) to afford ketoacid 25 (2.30 g, quantitative yield) as a white solid; mp 115-117 °C (Et₂O-n-hexane). IR (mull): ν = 1737 (C=O), 1683 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.66-1.70 (t, 2 H, J = 8.4 Hz, CH ₂ CH₂COOH), 1.79-2.01 (complex m, 10 H, H-4, H-6, H-8, H-9, H-10), 2.07 (br s, 2 H, H-5, H-7), 2.37-2.41 (t, 2 H, J = 8.1 Hz, -CH ₂ COOH), 2.52 (br s, 1 H, H-3) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 27.9 (C-5, C-7), 28.6 (-CH₂COOH), 31.0
(-CH₂CH₂COOH), 35.8 (C-8, C-10), 39.1 (C-4, C-9), 44.0 (C-6), 46.9 (C-3), 48.7 (C-1), 180.1 (-COOH), 217.7 (C=O) ppm. Anal. Calcd for C₁₃H₁₈O₃: C, 70.24; H, 8.16. Found: C, 70.03; H, 7.95.