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Synlett 2010(17): 2631-2635  
DOI: 10.1055/s-0030-1258778
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Synthesis of 4-Substituted 4-Hydroxypiperidines via Epoxidation-Ring Opening of 4-Methylenepiperidines

Victoria A. McKay, Sarah J. Thompson, Phuong Minh Tran, Kirsten J. Goodall, Margaret A. Brimble, David Barker*
Department of Chemistry, The University of Auckland, 23 Symonds St, Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: d.barker@auckland.ac.nz;
Further Information

Publication History

Received 2 August 2010
Publication Date:
30 September 2010 (online)

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Abstract

Reaction of 9-methylene-3-azabicyclo[3.3.1]nonanes with trifluoroperacetic acid results in stereoselective epoxidation to give the syn-epoxide. Intermolecular hydrogen bonding between the protonated tertiary amine and the peracid is responsible for the high levels of stereoselectivity.

Key words

stereoselective epoxidation - homoallylic epoxidation - bicyclic amines - 4-hydroxypiperidines

    References and Notes

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12

After a 48 h reaction >80% N-oxide 24 was returned with the remaining material being unidentified decomposition products.

15

General Procedure for the Epoxidation of 4-Methylenepiperidines
Trifluoroacetic anhydride (6 equiv) was added dropwise to a stirred solution of 30% w/w H2O2 (5 equiv) in CH2Cl2 (1 mL/mmol alkene) at 0 ˚C. The solution was stirred for 1 h prior to the dropwise addition of a solution of 4-methylene-piperidine (1 equiv) in CH2Cl2 (1 mL/mmol alkene). The mixture was allowed to warm to r.t. and stirred for a further 4 h. The reaction was then quenched by careful additon of sat. aq NaHCO3 and stirred until cessation of bubbles occurred. The volatiles were then removed in vacuo and the resultant aqueous solution extracted with EtOAc (2 × 20 mL). The combined organic phase were washed with sat. aq NaHCO3, H2O and brine, dried (MgSO4), and concentrated in vacuo to afford the crude product, which was purified by flash chromatography.
Synthesis of Alcohol 39 from Epoxide 25
n-BuLi (1.6 M in hexanes, 0.6 mL, 0.95mmol) was added dropwise to a suspension of copper cyanide (43 mg, 0.48 mmol) in THF (0.5 mL) at -78 ˚C. The suspension was allowed to warm to 0 ˚C and stirred for 30 min, cooled to -78 ˚C followed by dropwise addition of epoxide 25 in THF (0.5 mL). The solution was stirred for a further 15 min and quenched with a 9:1 mixture of sat. aq NH4Cl and aq NH4OH and concentrated in vacuo. The residue was dissolved in EtOAc, washed with sat. aq NH4Cl, H2O and brine, then dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash chromatography (5:1, hexanes-EtOAc; R f  = 0.7) to afford an alcohol (0.38 g, 89%) which was reduced with LiAlH4 (58 mg, 2.2 mmol) in THF (2 mL) at 0 ˚C. After stirring for 15 min the reaction, was quenched with sat. aq Na2SO4 and filtered through Celite and the solvent removed in vacuo. The residue was dissolved in EtOAc, washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo to yield crude product which was purified by flash chromatography (5:1, hexanes-EtOAc; R f  = 0.2) to give diol 39 (0.3g, 92%).

16

Spectroscopic Data for Selected Products
Ethyl (1 R*, 2′ S*, 5 R* )-3-Benzyl-3-azaspiro[bicyclo-[3.3.1]nonane-9,2′-oxirane]-1-carboxylate (25) ¹H NMR (300 MHz, CDCl3): δ = 1.21 (3 H, t, J = 7.2 Hz, OCH2CH 3), 1.26-1.31 (1 H, m, 5-H), 1.56-1.64 (1 H, m,
7A-H), 1.77-2.01 (3 H, m, 8A-H, 6-CH 2 ), 2.24 (1 H, ddt, J = 13.5, 6.6, 2.1 Hz, 8B-H), 2.51 (1 H, d, J = 3.0 Hz, 4A-H), 2.55 (1 H, d, J = 4.8 Hz, 2′A-H), 2.87 (3 H, m, 7B-H, 2A-H, 4B-H), 3.05 (1 H, d, J = 11.7 Hz, 2B-H), 3.18 (1 H, d, J = 4.8 Hz, 2′B-H), 3.43 (1 H, d, J = 13.5 Hz, PhCHA), 3.53 (1 H, d, J = 13.5 Hz, PhCHB), 4.06 (2 H, dq, J = 7.2, 1.5 Hz, OCH2CH 3), 7.23-7.35 (5 H, m, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 14.0 (OCH2 CH3), 21.0 (C-7), 31.1 (C-6), 34.8 (C-8), 38.5 (C-5), 46.9 (C-1), 52.91 (C-2′), 56.3 (C-4), 58.5 (C-2), 60.7 (OCH2CH3), 62.2 (C-9), 63.3 (PhCH2), 126.8 (ArCH), 128.2 (ArCH), 128.7 (ArCH), 138.4 (ArC), 172.5 (C=O). ESI-MS: m/z (%) = 316 (100) [M+], 338 (20) [MNa+]. MS: m/z calcd for C19H26NO3: 316.1907 [M]+; found: 316.1912.
Ethyl (1 R* ,2′ S* ,6 R* )-8-Benzyl-8-azaspiro[bicyclo-[4.3.1]decane-10,2′-oxirane]-1-carboxylate (28)
¹H NMR (300 MHz, CDCl3): δ = 1.22 (3 H, t, J = 7.2 Hz, OCH2CH 3), 1.41-1.51 (1 H, m, 6-H, 6-CH 2 ), 1.56-1.77 (5 H, m, 2A-H, 5-H2, 3-CH2), 1.92-2.16 (3 H, m, 4-CH 2, 2B-H), 2.47 (2 H, dd, J = 11.1, 4.5 Hz, 7A-H), 2.52 (1 H, d, J = 4.8 Hz, 2′A-H), 2.64 (1 H, td, J = 12.0, 0.9 Hz, 7B-H), 2.71 (2 H, m, 9-CH2), 3.31 (1 H, d, J = 4.8 Hz, 2′B-H), 3.53 (2 H, s, PhCH 2), 4.06 (2 H, q, J = 7.2 Hz, OCH2CH 3), 7.25-7.38 (5 H, m, Ar-H). ¹³C NMR (75 MHz, CDCl3): δ = 14.0 (OCH2 CH3), 26.4 (C-5), 26.5 (C-4), 33.0 (C-3), 35.8 (C-2), 42.2 (C-6), 50.1 (C-1), 51.6 (C-2′), 57.8 (C-7), 58.7 (C-10), 60.4 (C-9), 60.6 (OCH2CH3), 63.5 (PhCH2), 127.0 (ArCH), 128.2 (ArCH), 129.1 (ArCH), 138.9 (ArC), 173.6 (C=O). ESI-MS: m/z (%) = 330 (100) [M+], 352 (22) [MNa+]. MS: m/z calcd for C20H27NO3: 330.2064 [M+]; found 330.2074.


(1 S* ,5 R *,9 S *)-3-Benzyl-1-(hydroxymethyl)-9-methyl-3-azabicyclo[3.3.1]nonan-9-ol (29) ¹H NMR (300 MHz, CDCl3): δ = 1.23-1.32 (1 H, m, 7A-H), 1.35 (3 H, s, 9-CH3) 1.42-1.58 (3 H, m, 6-CH2, 8A-H), 1.67-1.79 (2 H, m, 5-H, 8B-H), 2.30-2.47 (3 H, m, 2A-H, 4 A-H, 7B-H), 2.93 (1 H, dd, J = 10.8, 2.4 Hz, 4B-H), 3.10-3.18 (3 H, m, CH AOH, 2B-H, OH), 3.41 (1 H, d, J = 13.2 Hz, Ph-CH A), 3.58 (1 H, d, J = 13.2 Hz, PhCH B), 3.80 (1 H, d, J = 11.1, 2.4 Hz, CH BOH). ¹³C NMR (75 MHz, CDCl3): δ = 18.2 (C-6), 22.1 (C9-CH3), 28.3 (C-8), 32.0 (C-7), 39.0 (C-1), 41.4 (C-5), 54.2 (C-4), 57.1 (C-2), 62.8 (PhCH2), 70.0 (CH2OH), 74.0 (C-9), 127.0 (ArCH), 128.3 (ArCH), 128.7 (ArCH), 138.7 (ArC). ESI-MS: m/z (%) = 276 (100) [MH+]. MS: m/z calcd for C17H26NO2: 276.1958 [MH+]; found: 276.1941.
(1 S *,6 R *,10 S *)-8-Benzyl-1-(hydroxymethyl)-10-methyl-8-azabicyclo[4.3.1]decan-10-ol (32)
¹H NMR (300 MHz, CDCl3): δ = 1.23-1.60 (7 H, m, 6-H, 5-CH2, 4-CH2, 3-CH2), 1.42 (3 H, s, 10-CH3) 2.08-2.15 (2 H, m, 2-CH2), 2.24 (1 H, dd, J = 11.1, 1.0 Hz, 9A-H), 2.42 (1 H, dd, J = 11.4, 1.0 Hz, 7A-H), 2.78 (1 H, dd, J = 11.4, 6.3 Hz, 7B-H), 3.16-3.24 (3 H, m, CH AOH, 9B-H, OH), 3.39 (1 H, d, J = 13.2 Hz, PhCH A), 3.56 (1 H, d, J = 13.2 Hz, PhCH B), 3.89 (1 H, d, J = 11.1, 2.4 Hz, CH BOH). ¹³C NMR (75 MHz, CDCl3): δ = 23.16 (C10-CH3), 25.2, 25.3, 29.6, and 35.5 (C-2, C-3, C-4, C-5), 44.1 (C-1), 46.3 (C-6), 56.5 (C-7), 59.0 (C-9) 63.3 (PhCH2), 70.3 (CH2OH), 77.9 (C-10), 127.0 (ArCH), 128.2 (ArCH), 128.9 (ArCH), 138.7 (ArC). ESI-MS: m/z (%) = 290 (100) [MH+], 272 (5) [M - OH]. MS: m/z calcd for C18H28NO2: 290.2115 [MH+]; found: 290.2105.
1-{(1 R *,2" S* ,5 R *)-3-Benzyl-3-azaspiro[bicyclo-[3.3.1]nonane-9,2"-oxirane]-1-yl}ethanone (36)
¹H NMR (400 MHz, CDCl3): δ = 1.27-1.29 (1 H, m, 5-H), 1.62 (1 H, m, 7A-H), 1.74-1.83 (2 H, m, 8A-H, 6A-H), 1.92 (1 H, m, 6B-H), 2.09 (3 H, s, O=CCH3), 2.18 (1 H, m, 8B-H), 2.54 (1 H, d, J = 4.2 Hz, 2′A-H), 2.63 (1 H, m, 4B-H), 2.69 (1 H, d, J = 4.2 Hz, 2′B-H), 2.83 (1 H, m 7B-H), 2.90 (1 H, d, J = 11.4 Hz, 4B-H), 2.94-3.00 (2 H, m, 2-CH2), 3.50 (2 H, s, PhCH 2), 7.23-7.34 (5 H, m, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 21.1 (C-7), 29.5 (O=CCH3), 31.1 (C-6), 33.1 (C-8), 38.6 (C-5), 51.1 (C-1), 52.3 (C-2′), 56.6 (C-4), 59.2 (C-2), 62.7 (C-9), 63.5 (PhCH2), 127.0 (ArCH), 128.3 (ArCH), 128.6 (ArCH), 138.7 (ArC), 209.9 (C=O). ESI-MS: m/z (%) = 285 (100) [M+]. MS: m/z calcd for C18H23NO2: 285.1728 [M+]; found: 285.1728.
(1 S *,5 R *,9 S *)-3-Benzyl-1-(hydroxymethyl)-9-pentyl-3-azabicyclo[3.3.1]nonan-9-ol (39)
¹H NMR (300 MHz, CDCl3): δ = 0.86-0.94 [4 H, m, (CH2)4CH 3, CH2CH A(CH2)2CH3), 1.15-1.60 [10 H, m, 6-CH2, 8A-H, CH 2 (CH2)3CH3, CH2CH B(CH2)2CH3, (CH2)2CH 2CH2CH3, (CH2)3CH 2CH3], 1.81-1.90 (2 H, m, 5-H, 8B-H), 2.34 (1 H, d, J = 10.8 Hz, CH AOH), 2.36-2.52 (3 H, m, 4A-H, 7A-H, OH), 2.50 (1 H, dd, J = 11.0 Hz, 2A-H), 2.85 (1 H, dd, J = 11.4, 2.1 Hz, 4B-H), 3.04 (1 H, d, J = 10.8 Hz, CH BOH), 3.12 (1 H, dd, J = 11.4, 2.1 Hz 2B-H), 3.38 (1 H, d, J = 13.2, PhCH A), 3.54 (1 H, d, J = 13.2 Hz, PhCH B), 7.19-7.28 (5 H, m, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 14.1 [(CH2)4 CH3], 18.7 (C-7), 21.5 [CH2 (CH2)3CH3], 22.7 [CH2 CH2 (CH2)2CH3], 27.8 (C-6), 31.7 [(CH2)2 CH2CH2CH3], 32.5 [(CH2)3 CH2CH3], 32.5 (C-8), 35.9 (C-5), 40.9 (C-1), 54.3 (C-4), 57.3 (C-2), 62.9 (PhCH2), 69.4 (CH2OH), 76.0 (C-9), 126.8 (ArCH), 128.2 (ArCH), 128.7 (ArCH), 139.0 (ArC). ESI-MS: m/z (%) = 332 (100) [MH+]. MS: m/z calcd for C21H34NO2: 332.2584 [MH+]; found: 332.2590.

19

The stereochemistry was again determined by analysis of the ring-opened tertiary alcohols.

20

Diols such as 29, 32, and 39 can be esterified selectively in high yields at the primary alcohol.