A Concise Stereoselective Total Synthesis of (2R,2′R)-threo-(+)-Methyl­phenidate via a Ring-Closing Metathesis Protocol

Palakodety Radha Krishna; Krishnarao Lopinti

doi:10.1055/s-2007-982577

LETTER

A Concise Stereoselective Total Synthesis of (2R,2′R)-threo-(+)-Methylphenidate via a Ring-Closing Metathesis Protocol [1]

Palakodety Radha Krishna*, Krishnarao Lopinti
D-206/B, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
e-Mail: prkgenius@iict.res.in;

Abstract

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Abstract

In the synthesis of (2R,2′R)-threo-(+)-methylphenidate, a ring-closing metathesis approach was adopted to construct the piperidine ring, while Sharpless asymmetric epoxidation was used for the efficient generation of two contiguous stereocenters.

Key words

(2R,2′R)-threo-(+)-methylphenidate - ritalin - attention deficit hyperactivity disorder (ADHD) - cis-allylic alcohol - Sharpless asymmetric epoxidation - bisolefin - ring-closing metathesis (RCM)

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References

References and Notes

IICT communication number 070106.

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Spectral Data of Selected Compounds: Compound 7a: white solid; mp 49-52 °C; [α]_D -10.30 (c = 0.55, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 7.23-7.35 (m, 5 H, ArH), 5.69-5.89 (m, 1 H, olefin), 5.03-5.12 (m, 2 H, olefin), 3.88-4.12 (m, 3 H, OCH, OCH₂), 2.88 (td, J = 4.50, 6.73 Hz, 1 H, CHPh), 2.15-2.27 (m, 1 H, allylic), 1.95-2.09 (m, 1 H, allylic). ¹³C NMR (75 MHz, CDCl₃): δ = 138.44, 134.72, 129.37, 128.57, 127.19, 118.13, 71.52, 64.53, 52.55, 39.49. IR (KBr): 3386, 3077, 3028, 2929, 1453, 1037, 915, 703 cm^-1. LC-MS: m/z (%) = 215 (17) [M + 23]. Anal. Calcd for C₁₂H₁₆O₂: C, 74.97; H, 8.39. Found: C, 74.95; H, 8.40. Compound 10: [α]_D -26.70 (c = 0.75, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 7.60-7.70 (m, 5 H, ArH), 7.37-7.34 (m, 6 H, ArH), 7.14-7.25 (m, 4 H, ArH), 5.71-5.91 (m, 1 H, olefin), 5.04-5.15 (m, 2 H, olefin), 3.97-4.15 (m, 2 H, CHN₃, CH), 3.74 (dd, J = 4.92, 9.85 Hz, 1 H, CH), 2.80-2.89 (m, 1 H, CH), 2.18 (t, J = 6.44 Hz, 2 H, allylic), 1.05 (br s, 9 H, t-Bu). IR (KBr): 3069, 2931, 2858, 2102, 1427, 1109, 701, 503 cm^-1. LC-MS: m/z (%) = 456 (30) [M + 1]. Anal. Calcd for C₂₈H₃₃N₃OSi: C, 73.80; H, 7.30. Found: C, 73.74; H, 7.28. Compound 11: [α]_D +25.80 (c = 0.55, CH ₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 7.53-7.62 (m, 4 H, ArH), 7.30-7.41 (m, 6 H, ArH), 7.19-7.25 (m, 3 H, ArH), 7.12 (br s, 1 H, NH), 6.97-7.00 (m, 2 H, ArH), 6.41 (td, J = 4.53, 8.69 Hz, 1 H, olefin), 5.86 (d, J = 9.82 Hz, 1 H, olefin), 3.96-4.07 (m, 2 H, OCH, NCH), 3.85 (dd, J = 3.78, 10.58 Hz, 1 H, OCH), 2.84-2.91 (m, 1 H, CH), 1.93-2.00 (m, 2 H, allylic), 1.09 (br s, 9 H, t-Bu). ¹³C NMR (75 MHz, CDCl₃): δ = 166.03, 140.24, 135.64, 135.56, 132.62, 129.97, 129.86, 128.79, 128.05, 127.88, 127.8, 127.34, 124.65, 67.67, 54.78, 51.88, 28.89, 26.9, 19.07. IR (KBr): 3370, 2924, 2854, 1675, 1611, 1109, 702 cm^-1. LC-MS: m/z (%) = 456 (34) [M + 1]. Anal. Calcd for C₂₉H₃₃NO₂Si: C, 76.44; H, 7.30. Found: C, 76.41; H, 7.28. Compound 13: [α]_D +21.32 (c = 0.75, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.51-7.57 (m, 3 H, ArH), 7.29-7.38 (m, 6 H, ArH), 7.11-7.25 (m, 6 H, ArH), 3.98 (dd, J = 6.04, 10.20 Hz, 1 H, OCH₂), 3.89 (dd, J = 5.67, 10.58 Hz, 1 H, OCH₂), 2.89-3.06 (m, 2 H, CH₂NH), 2.74-2.81 (m, 1 H, CHNH), 2.60 (td, J = 2.64, 11.71 Hz, 1 H, CHPh), 2.19-2.24 (m, 1 H, NH), 1.61 (dd, J = 12.84, 43.81 Hz, 2 H, CH₂), 1.17-1.44 (m, 4 H, 2 × CH₂), 1.01 (br s, 9 H, t-Bu). ¹³C NMR (75 MHz, CDCl₃): δ = 139.30, 135.60, 135.30, 134.80, 129.60, 128.80, 128.20, 127.60, 127.13, 67.40, 62.30, 59.20, 50.90, 45.80, 30.16, 29.60, 26.80, 26.50, 25.60, 24.70, 24.50, 23.40, 22.70, 18.90. IR (KBr): 3356, 2930, 2855, 1427, 1109, 702 cm^-1. LC-MS: m/z (%) = 444 (35) [M + 1]. Anal. Calcd for C₂₉H₃₇NOSi: C, 78.50; H, 8.41. Found: C, 78.49; H, 8.44. Compound 15: white solid; mp 78-80 °C; [α]_D +12.70 (c = 0.50, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 7.19-7.37 (m, 5 H, ArH), 4.60 (d, J = 12.08 Hz, 1 H), 4.00 (d, J = 12.84 Hz, 1 H), 3.66-3.70 (m, 1 H), 3.47-3.55 (m, 2 H), 3.01 (d, J = 12.08 Hz, 1 H), 2.84 (d, J = 10.8 Hz, 1 H), 1.62-1.66 (m, 2 H), 1.50 (br s, 9 H, t-Bu), 1.32-1.43 (m, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 156.40, 141.20, 128.80, 128.50, 126.70, 80.40, 63.50, 50.20, 45.80, 39.80, 28.40, 26.03, 25.36, 18.80. IR (KBr): 3448, 2928, 2840, 1681, 1598, 1258, 1158 cm^-1. LC-MS: m/z (%): 328 (26) [M + Na]. Anal. Calcd for C₁₈H₂₇NO₃: C, 70.79; H, 8.91. Found: C, 70.77; H, 8.93. Compound 16: white solid; mp 115-120 °C; [α]_D = -40.66 (c = 0.80, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 7.25-7.46 (m, 5 H, ArH), 4.73-5.03 (m, 1 H, NCH), 4.10 (d, J = 11.7 Hz, 1 H, CHPh), 3.88-4.00 (m, 1 H, NCH), 2.85-3.14 (m, 1 H, NCH), 1.72-1.88 (m, 6 H, 3 × CH₂), 1.42 (br s, 9 H, t-Bu). ¹³C NMR (75 MHz, CDCl₃): δ = 176.90, 154.8, 135.88, 128.80, 128.70, 127.80, 79.88, 54.02, 53.04, 51.17, 39.80, 38.30, 29.67, 28.23, 25.20, 18.80. IR (KBr): 3447, 2924, 2854, 1631, 1260, 760 cm^-1. LC-MS: m/z (%) = 342 (22) [M + 23]. Anal. Calcd for C₁₈H₂₅NO₄: C, 67.69; H, 7.89. Found: C, 67.66; H, 7.85.

A Concise Stereoselective Total Synthesis of (2R,2′R)-threo-(+)-Methyl­phenidate via a Ring-Closing Metathesis Protocol [1]

A Concise Stereoselective Total Synthesis of (2R,2′R)-threo-(+)-Methylphenidate via a Ring-Closing Metathesis Protocol [1]