Studies on the Lithiation of Hydroxypyrrolidines: Synthesis of Polyhydroxy­lated Pyrrolidines via Chiral Enecarbamates

Abstract

The chiral endocyclic enecarbamate 14 has been obtained by deprotonation-elimination from the N-Boc pyrrolidine 5 (or its racemic counterpart from 15). Efficiently stereocontrolled epoxidation-methanolysis of 14 afforded α-alkoxy carbamates, which undergo completely stereoselective nucleophilic substitutions to give trisubstituted dihydroxypyrrolidines.

Key words

lithiation - LIDAKOR - enecarbamates - oxidations - ­nucleophilic substitutions - iminosugars

References and Notes

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18

Enecarbamate 13
A Schlenk tube was charged with a solution of pyrrolidine 5 (1.07 g, 2.5 mmol) in dry THF (6 mL) under a nitrogen atmosphere. The solution was cooled at -78 ˚C and TMEDA (0.75 mL, 5.0 mmol) and a cyclohexane solution of s-BuLi (1.4 M, 3.6 mL, 5.0 mmol) were added. The mixture was stirred at -78 ˚C for 1 h, then added with dry MeOH (1 mL) and left to warm to r.t. The reaction was quenched with H₂O (6 mL) and the mixture extracted with Et₂O (3 × 10 mL). The collected organic phases were dried over Na₂SO₄, then filtered and concentrated to afford crude 13 (1.10 g, 100%, 1.5:1 mixture of two rotamers in CDCl₃), which was used without further purification due to the easy elimination of the silyloxy group under acidic conditions. ^¹H NMR (200 MHz, CDCl₃): δ = 6.81 and 6.67 (d, J = 3.6 Hz, 1 H), 5.03 (m, 2 H), 3.80-3.46 (m, 2 H), 1.48 (s, 9 H), 0.91 and 0.89 (s, 9 H), 0.09 and 0.08 (s, 6 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 151.5 (s), 150.9 (s), 132.4 (d), 109.8 (d), 80.4 (s), 73.6 (d), 72.5 (d), 54.6 (t), 54.1 (t), 28.2 (q), 25.7 (q), 25.6 (q), 18.0 (s), 17.9 (s), -4.6 (q), -4.7 (q).
Enecarbamate 14
A Schlenk tube was charged with a solution of pyrrolidine 13 (1.0 g, 3.3 mmol) in dry THF (6 mL) under a nitrogen atmosphere. The solution was added with TBAF in dry THF (1.1 M, 6.2 mL, 7.26 mmol). The resulting solution was left under stirring at r.t. for 1 h. The mixture was quenched with H₂O (6 mL), extracted with Et₂O (3 ¥ 10 mL), and the collected organic phases were dried over Na₂SO₄. After filtration, the solution was concentrated and purified by column chromatography (PE-EtOAc-concd NH₃, 4:0.9:1) to afford compound 14 (0.372 g, 62%, 1:1 mixture of two rotamers in CDCl₃). [α]_D ^²5 -167.7 (c 1.9, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 6.78 and 6.66 (s, 1 H), 5.14 (br s, 1 H), 4.84 (ddd, J = 7.8, 3.0, 2.8 Hz, 1 H), 3.75-3.53 (m, 2 H), 2.75 (br s, 1 H), 1.43 (s, 9 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 151.6 (s), 151.0 (s), 133.0 (d), 109.7 (d), 80.7 (s), 72.7 (d), 71.7 (d), 54.5 (t), 54.0 (t), 28.2 (q).

31

For cyanation of a related substrate, see ref. 25e.

32

Synthesis of Pyrrolidines 22-24 - General Procedure
A Schlenk tube was charged with a solution of pyrrolidine 21 (80 mg, 0.17 mmol) in dry CH₂Cl₂ (6 mL) under a nitrogen atmosphere. The solution was cooled at -78 ˚C and the appropriate silylated reagent (trimethylsilylcyanide (0.045 mL, 0.34 mmol), trimethylsilylazide (0.043 mL, 0.34 mmol), or allyltrimethylsilane (0.054 mL, 0.34 mmol) and BF₃˙OEt₂ (0.030 mL, 0.24 mmol) were added. The mixture was left at -78 ˚C under stirring for 1.5-2 h. The solution was quenched with sat. Na₂CO₃ (1 mL) and left to warm to r.t., then was extracted with CH₂Cl₂ (3 × 3 mL), and the collected organic phases were dried over Na₂SO₄. After filtration and concentration, the crude material was purified by column chromatography (PE-Et₂O, 15:1).
Compound 22: 52% yield, R _f  = 0.11, white solid, mp 97-99 ˚C. ^¹H NMR (400 MHz, CDCl₃, 2:1 mixture of two rotamers): δ = 4.55 and 4.38 (d, J = 6.8 Hz, 1 H), 4.16-4.11 (m, 2 H), 3.44 (d, J = 12.0 Hz, 1 H), 3.36 (dd, J = 11.6, 3.6 Hz, 1 H), 1.51 and 1.47 (s, 9 H), 0.95-0.92 (m, 18 H), 0.16-0.09 (m, 12 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 153.6 (s), 153.3 (s), 116.0 (s), 81.8 (s), 81.1 (s), 73.5 (d), 73.0 (d), 72.4 (d), 71.4 (d), 52.6 (d), 51.7 (d), 50.2 (t), 49.7 (t), 28.3 (q), 25.7 (q), 25.6 (q), 18.1 (s), -4.4 (q), -4.6 (q), -4.8 (q).
Compound 23: 56% yield, R _f  = 0.47, colorless oil. ^¹H NMR (400 MHz, CDCl₃, 2:1 mixture of two rotamers): δ = 5.18 and 5.05 (d, J = 2.0 Hz, 1 H), 4.20-4.16 (m, 1 H), 3.81 (dd, J = 3.4, 2.0 Hz, 1 H), 3.50 and 3.44 (dd, J = 9.9, 6.3 Hz, 1 H), 3.36 and 3.28 (dd, J = 9.9, 7.5 Hz, 1 H), 1.52 and 1.50 (s, 9 H), 0.90 and 0.89 (s, 18 H), 0.09 (s, 12 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 154.2 (s), 81.3 (s), 80.6 (s), 78.9 (d), 78.7 (d), 77.4 (d), 76.6 (d), 70.7 (d), 70.2 (d), 49.9 (t), 49.4 (t), 28.2 (q), 25.8 (q), 25.6 (q), 18.1 (s), 18.0 (s), -4.5 (q), -4.7 (q), -4.9 (q), -5.1 (q).
Compound 24: 77% yield, R _f  = 0.26, colorless oil. ^¹H NMR (400 MHz, CDCl₃, 2:1 mixture of two rotamers): δ = 6.10-5.79 (m, 1 H), 4.98 (d, J = 16.2 Hz, 1 H), 4.92 (d, J = 9.2 Hz, 1 H), 4.08-4.04 (m, 1 H), 4.02-3.98 (m. 1 H), 3.83 and 3.68 (q, J = 5.8 Hz, 1 H), 3.52 (dd, J = 12.0, 4.8 Hz, 1 H), 3.27 and 3.20 (d, J = 12.0 Hz, 1 H), 2.74-2.35 (m, 2 H), 1.45 (s, 9 H), 0.91-0.89 (s, 18 H), 0.08-0.05 (s, 12 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 155.0 (s), 138.0 (d), 137.7 (d), 115.1 (t), 79.6 (s), 73.8 (d), 73.5 (d), 71.8 (d), 59.5 (d), 59.2 (d), 52.5 (t), 35.0 (t), 28.4 (q), 26.0 (q), 25.8 (q), 18.3 (s), 18.0 (s), -4.6 (q), -4.8 (q).