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

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.

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

References and Notes

1 Maslowsaka-Lipowicz I. Figlus M. Zuiderveld OP. Walkczynski K. Arch. Pharm. Chem. Life Sci.  2008,  341:  762 

2 Lu S.-F. Chen B. Davey D. Dunning L. Jaroch S. May K. Onuffer J. Phillips G. Subramanyam B. Tseng J.-L. Wei RG. Wei M. Ye B. Bioorg. Med. Chem. Lett.  2007,  1883 

3a Furegati S. Ganci W. Gorla F. Ringeisen U. Rüedi P. Helv. Chim. Acta  2004,  87:  2629 

3b Clerc C. Matarazzo I. Rüedi P. Helv. Chim. Acta  2009,  92:  14 

4 Chen Z. Davies E. Miller WS. Shan S. Valenzano KJ. Kyle DJ. Bioorg. Med. Chem. Lett.  2004,  5275 

5a Wenzel B. Sorger D. Heinitz K. Scheunemann M. Schliebs R. Steinbach J. Sabri O. Eur. J. Med. Chem.  2005,  1197 

5b Kim D.-I. Schweri MM. Deutsch HM. J. Med. Chem.  2003,  46:  1456 

5c Sakhteman A. Foroumadi A. Sharifzadeh M. Amanlou M. Rayatnai F. Shafiee A. Bioorg. Med. Chem.  2009,  17:  6908 

6a Lehmann A. Brocke C. Barker D. Brimble MA. Eur. J. Org. Chem.  2006,  3205 

6b Williams CM. Heim R. Bernhardt PV. Tetrahedron  2005,  61:  3771 

6c Barker D. Brimble MA. McLeod MD. Savage GP. Org. Biomol. Chem.  2004,  2:  1659 

6d Kraus GA. Shi J. J. Org. Chem.  1991,  56:  4147 

6e Ho GD. Anthes J. Bercovici A. Caldwell JP. Cheng K.-C. Cui X. Fawzi A. Fernandez X. Greenlee WJ. Hey J. Korfmacher W. Lu SX. McLeod RL. Ng F. Torhan AS. Tan Z. Tulshian D. Varty GB. Xu X. Zhang H. Bioorg. Med. Chem. Lett.  2009,  19:  2519 

7 House HO. Bryant WM. J. Org. Chem.  1965,  30:  3634 

8 Chan Y. Guthmann H. Brimble MA. Barker D. Synlett  2008,  2601 

9 Brimble MA. Brocke C. Eur. J. Org. Chem.  2005,  2385 

10 Barker D. Lin DH.-S. Carland JE. Chu CP.-Y. Chebib M. Brimble MA. Savage GP. McLeod MD. Bioorg. Med. Chem.  2005,  13:  4565 

11 Goodall KJ. Barker D. Brimble MA. Synlett  2005,  1809 

12

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

13a Carretero JC. Arrayás RG. de Gracia IS. Tetrahedron Lett.  1997,  38:  8537 

13b Aciro C. Claridge TDW. Davies SG. Roberts PM. Russell AJ. Thomson JE. Org. Biomol. Chem.  2008,  6:  3751 

14 Quick J. Khandelwal Y. Meltzer PC. Weinberg JS. J. Org. Chem.  1983,  48:  5199 

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,
7_A-H), 1.77-2.01 (3 H, m, 8_A-H, 6-CH ₂ ), 2.24 (1 H, ddt, J = 13.5, 6.6, 2.1 Hz, 8_B-H), 2.51 (1 H, d, J = 3.0 Hz, 4_A-H), 2.55 (1 H, d, J = 4.8 Hz, 2′_A-H), 2.87 (3 H, m, 7_B-H, 2_A-H, 4_B-H), 3.05 (1 H, d, J = 11.7 Hz, 2_B-H), 3.18 (1 H, d, J = 4.8 Hz, 2′_B-H), 3.43 (1 H, d, J = 13.5 Hz, PhCH_A), 3.53 (1 H, d, J = 13.5 Hz, PhCH_B), 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, 2_A-H, 5-H₂, 3-CH₂), 1.92-2.16 (3 H, m, 4-CH ₂, 2_B-H), 2.47 (2 H, dd, J = 11.1, 4.5 Hz, 7_A-H), 2.52 (1 H, d, J = 4.8 Hz, 2′_A-H), 2.64 (1 H, td, J = 12.0, 0.9 Hz, 7_B-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, 7_A-H), 1.35 (3 H, s, 9-CH₃) 1.42-1.58 (3 H, m, 6-CH₂, 8_A-H), 1.67-1.79 (2 H, m, 5-H, 8_B-H), 2.30-2.47 (3 H, m, 2_A-H, 4 _A-H, 7_B-H), 2.93 (1 H, dd, J = 10.8, 2.4 Hz, 4_B-H), 3.10-3.18 (3 H, m, CH _AOH, 2_B-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, 9_A-H), 2.42 (1 H, dd, J = 11.4, 1.0 Hz, 7_A-H), 2.78 (1 H, dd, J = 11.4, 6.3 Hz, 7_B-H), 3.16-3.24 (3 H, m, CH _AOH, 9_B-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, 7_A-H), 1.74-1.83 (2 H, m, 8_A-H, 6_A-H), 1.92 (1 H, m, 6_B-H), 2.09 (3 H, s, O=CCH₃), 2.18 (1 H, m, 8_B-H), 2.54 (1 H, d, J = 4.2 Hz, 2′_A-H), 2.63 (1 H, m, 4_B-H), 2.69 (1 H, d, J = 4.2 Hz, 2′_B-H), 2.83 (1 H, m 7_B-H), 2.90 (1 H, d, J = 11.4 Hz, 4_B-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, 8_A-H, CH _{2 (}CH₂)₃CH₃, CH₂CH _B(CH₂)₂CH₃, (CH₂)₂CH ₂CH₂CH₃, (CH₂)₃CH ₂CH₃], 1.81-1.90 (2 H, m, 5-H, 8_B-H), 2.34 (1 H, d, J = 10.8 Hz, CH _AOH), 2.36-2.52 (3 H, m, 4_A-H, 7_A-H, OH), 2.50 (1 H, dd, J = 11.0 Hz, 2_A-H), 2.85 (1 H, dd, J = 11.4, 2.1 Hz, 4_B-H), 3.04 (1 H, d, J = 10.8 Hz, CH _BOH), 3.12 (1 H, dd, J = 11.4, 2.1 Hz 2_B-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 [CH_{2 (}CH₂)₃CH₃], 22.7 [CH₂ CH_{2 (}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.

17a Arias-Pérez MS. Alejo A. Maroto A. Tetrahedron  1997,  53:  13099 

17b Jeyaraman R. Jawaharsingh CB. Avila S. Eliel EL. Manoharan M. Morris-Natschke S. J. Heterocycl. Chem.  1982,  19:  449 

17c Goodall KJ. Brimble MA. Barker D. Magn. Reson. Chem.  2008,  46:  75 

18 Guthmann H. Conole D. Wright E. Körber K. Barker D. Brimble MA. Eur. J. Org. Chem.  2009,  1944 

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.