Ring Enlargement of Polyhydroxylated Pyrrolidines to Piperidines by ­Mitsunobu Reaction: A Fortuitous Synthesis of 1-Deoxy-l-allonojirimycin

Abstract

Chiral 3,4-dibenzyloxy-5-hydroxymethyl-2-thiazolyl-pyrrolidines under Mitsunobu conditions (R-OH, Ph₃P, DIAD in THF, 80 °C) afforded the corresponding R-protected pyrrolidines and 2-deoxy-piperidines in different ratios depending on the stereo­chemistry of the starting pyrrolidine and the nature of the acid R-OH. A mechanistic scheme is proposed involving the formation of an aziridinium ion as an intermediate. A piperidine derivative ­obtained in 74% yield was converted in four steps into the title ­allonojirimycin.

azasugars - 1-deoxynojirimycin - piperidines - pyrrol­idines - ring e­xpansion

References

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This article dealt with the preparation of O- and N-benzyl-protected 3,4-dihydroxy-5-hydroxymethyl-2-thiazolyl-pyrrolidines. The selective debenzylation of the primary hydroxy group to give compound 1 has been described (ref. [1] ). Under the same conditions, the 5-hydroxymethyl pyrrolidines 5 (Scheme [2] ) and 8 (Scheme [3] ) were obtained from the corresponding perbenzylated precursors.

<A NAME="RG16304ST-7">7</A>

Analytical data for compound 5. [α]_D = -4.1 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃ + D₂O): δ = 7.80 (d, 1 H, J = 3.3 Hz, Th), 7.46-7.22 (m, 16 H, 3 Ph, Th), 4.97 and 4.75 (2 d, 2 H, J = 11.6 Hz, PhCH ₂O), 4.85 (d, 1 H, J _2,3 = 1.5 Hz, H-2), 4.53 and 4.40 (2 d, 2 H, J = 11.7 Hz, PhCH ₂O), 4.31 (dd, 1 H, J _3,4 = 6.1, J _4,5 = 7.2 Hz, H-4), 4.14 and 3.98 (2 d, 2 H, J = 13.9 Hz, PhCH ₂N), 4.06 (dd, 1 H, H-3), 3.82-3.76 (m, 2 H, 2 H-6), 3.40 (ddd, 1 H, J _5,6a = J _5,6b = 2.7 Hz, H-5).

<A NAME="RG16304ST-8">8</A>

General Procedure for the Mitsunobu Reaction: To a refluxing solution of 6-OH thiazolylpyrrolidine (150 mg, 0.30 mmol), PPh₃ (120 mg, 0.45 mmol), and phenol or carboxylic acid derivative (0.60 mmol) in anhyd THF (6 mL) was added DIAD (90 µL, 0.45 mmol). The reaction mixture was stirred at 80 °C for 2 h and then concentrated. The residue was eluted from a column of silica gel (cyclohexane-EtOAc) to give the pyrrolidine 6 and the piperidine 7. Compound 6a. [α]_D = +6.8 (c 0.9, CHCl₃). Compound 7a. [α]_D = -32.0 (c 1.4, CHCl₃). Compound 6b. [α]_D = -13.7 (c 1.0, CHCl₃). Compound 7b. [α]_D = -25.5 (c 0.8, CHCl₃). Compound 6c. [α]_D = -39.2 (c 1.0, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 7.57 and 6.55 (2 d, 2 H, J = 3.3 Hz, Th), 7.34-6.90 (m, 25 H, 5 Ph), 5.04 (dd, 1 H, J _5,6a = 2.4, J _6a,6b = 12.5 Hz, H-6a), 4.78 (s, 1 H, Ph₂CH), 4.65 and 4.60 (2 d, 2 H, J = 12.2 Hz, PhCH ₂O), 4.58 (dd, 1 H, J _5,6b = 7.2 Hz, H-6b), 4.54 (d, 1 H, J _2,3 = 1.5 Hz, H-2), 4.18 and 4.08 (2 d, 2 H, J = 11.9 Hz, PhCH ₂O), 4.10 (dd, 1 H, J _3,4 = 5.2, J _4,5 = 6.6 Hz, H-4), 3.86 (dd, 1 H, H-3), 3.78 (ddd, 1 H, H-5), 3.68 (s, 2 H, PhCH ₂N). Compound 7c. [α]_D = -36.0 (c 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, 1 H, J = 3.2 Hz, Th), 7.32-7.13 and 6.93-6.89 (2 m, 26 H, 5 Ph, Th), 5.06 (ddd, 1 H, J _4,5 = 1.8, J _5,6a = 4.7, J _5,6b = 10.5 Hz, H-5), 4.97 (s, 1 H, Ph₂CH), 4.55 and 4.33 (2 d, 2 H, J = 11.8 Hz, PhCH ₂O), 4.29 and 4.07 (2 d, 2 H, J = 11.9 Hz, PhCH ₂O), 4.29 (d, 1 H, J _2,3 = 9.5 Hz, H-2), 4.10 (dd, 1 H, J _3,4 = 1.7 Hz, H-4), 3.73 and 3.17 (2 d, 2 H, J = 13.8 Hz, PhCH ₂N), 3.71 (dd, 1 H, H-3), 2.78 (dd, 1 H, J _6a,6b = 10.3 Hz, H-6a), 2.72 (dd, 1 H, H-6b).

<A NAME="RG16304ST-9">9</A>

Analytical data: compound 8: [α]_D = +16.4 (c 0.6, CHCl₃). Compound 9a: [α]_D = -4.6 (c 0.6, CHCl₃). Compound 10a: [α]_D = +10.0 (c 0.7, CHCl₃). Compound 9b: [α]_D = +10.9 (c 0.7, CHCl₃). Compound 10b: [α]_D = +20.0 (c 0.7, CHCl₃).

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<A NAME="RG16304ST-11">11</A> For a recent example of the involvement of an aziridinium ion intermediate in pyrrolidine to piperidine conversion and a collection of references on earlier examples, see: Verhelst SHL. Paez Martinez B. Timmer MSM. Lodder G. van der Marel GA. Overkleeft HS. van Boom JH. J. Org. Chem.  2003,  68:  9598 

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<A NAME="RG16304ST-15">15</A>

A mixture of 7c (40 mg, 0.06 mmol), activated 4 Å powdered molecular sieves (140 mg), and anhyd MeCN (0.7 mL) was stirred at r.t. for 10 min, then methyl triflate (13 µL, 0.12 mmol) was added. The suspension was stirred at r.t. for 15 min and then concentrated to dryness without filtering off the molecular sieves. To a cooled (0 °C), stirred suspension of the crude N-methylthiazolium salt in MeOH (0.7 mL) was added NaBH₄ (5 mg, 0.13 mmol). The mixture was stirred at r.t. for additional 10 min, diluted with acetone, filtered through a pad of Celite, and concentrated. A solution of the residue in Et₂O (30 mL) was washed with H₂O, dried (Na₂SO₄), and concentrated. To a vigorously stirred solution of the thiazolidines in MeCN (1 mL) was added H₂O (0.1 mL) and then AgNO₃ (12 mg, 0.07 mmol). The mixture was stirred at r.t. for 5 min, then diluted with 1 M phosphate buffer at pH 7 (10 mL) and partially concentrated to remove MeCN (bath temperature not exceeding 40 °C). The suspension was extracted with Et₂O (3 × 20 mL), the combined organic phases were dried (Na₂SO₄), and concentrated to give a yellow syrup. A solution of the residue in Et₂O (ca. 30 mL) was filtered through a pad of Celite and concentrated to afford 11 (30 mg, 82%) as a colorless syrup ca. 95% pure by ¹H NMR analysis. ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (d, 1 H, J = 4.7 Hz, CHO), 7.35-7.20 and 7.12-7.07 (2 m, 25 H, 5 Ph), 4.96 (s, 1 H, Ph₂CH), 4.91 (ddd, 1 H, J _4,5 = 2.4, J _5,6a = 4.9, J _5,6b = 10.7 Hz, H-5), 4.50 and 4.30 (2 d, 2 H, J = 11.9 Hz, PhCH ₂O), 4.44 and 4.32 (2 d, 2 H, J = 11.3 Hz, PhCH ₂O), 4.12 (dd, 1 H, J _3,4 = 2.0 Hz, H-4), 3.72 and 3.34 (2 d, 2 H, J = 13.8 Hz, PhCH ₂N), 3.71 (dd, 1 H, J _2,3 = 9.7 Hz, H-3), 3.34 (dd, 1 H, H-2), 2.71 (dd, 1 H, J _6a,6b = 10.6 Hz, H-6a), 2.60 (dd, 1 H, H-6b).

<A NAME="RG16304ST-16">16</A>

To a cooled (0 °C), stirred solution of 11 (30 mg, 0.05 mmol) in 5:2 Et₂O-MeOH (1 mL) was added NaBH₄ (5 mg, 0.13 mmol). The mixture was stirred at r.t. for 5 min, diluted with acetone (0.1 mL) and then 1 M phosphate buffer at pH 7 (5 mL), and partially concentrated to remove the organic solvents. The suspension was extracted with CH₂Cl₂ (3 × 20 mL), the combined organic phases were dried (Na₂SO₄), and concentrated. The residue was eluted from a column of silica gel with 3:1 cyclohexane-EtOAc to give 12 (27 mg, 90%) as a syrup; [α]_D = +2.7 (c 0.6, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 7.32-6.92 (m, 25 H, 5 Ph), 4.94 (ddd, 1 H, J _1a,2 = 10.6, J _1b,2 = 4.2, J _2,3 = 2.3 Hz, H-2), 4.92 (s, 1 H, Ph₂CH), 4.52 and 4.36 (2 d, 2 H, J = 11.6 Hz, PhCH ₂O), 4.24 and 4.19 (2 d, 2 H, J = 11.5 Hz, PhCH ₂O), 4.06 (dd, 1 H, J _3,4 = 2.4 Hz, H-3), 3.92 (ddd, 1 H, J _5,6a = 1.8, J _6a,6b = 11.0, J _6a,OH = 9.7 Hz, H-6a), 3.73 and 2.87 (2 d, 2 H, J = 14.0 Hz, PhCH ₂N), 3.73 (dd, 1 H, J _5,6b = 1.8 Hz, H-6b), 3.54 (dd, 1 H, J _4,5 = 9.6 Hz, H-4), 2.83 (dd, 1 H, J _1a,1b = 10.4 Hz, H-1a), 2.77 (dd, 1 H, H-1b), 2.76 (ddd, 1 H, H-5), 2.01 (br d, 1 H, OH).

<A NAME="RG16304ST-17">17</A>

A solution of 12 (31 mg, 0.05 mmol) in freshly prepared 0.1 M CH₃ONa in CH₃OH (2 mL) was kept at r.t. for 2 h, then neutralized with HOAc, and concentrated. A solution of the residue in CH₂Cl₂ was washed with 1 M phosphate buffer at pH 7, dried (Na₂SO₄), and concentrated. The residue was eluted from a short column of silica gel with EtOAc (containing 0.5% of Et₃N) to give the 2-OH derivative (17 mg). A vigorously stirred mixture of the alcohol, 20% Pd(OH)₂ on carbon (20 mg), and HOAc (2 mL) was degassed under vacuum and saturated with hydrogen (by a H₂-filled balloon) five times. The suspension was stirred at r.t. for 5 h under a slightly positive pressure of hydrogen (balloon), then filtered through a plug of cotton and concentrated. A solution of the crude tetrol in H₂O was eluted from a column (0.5 × 3 cm, d × h) of freshly activated Dowex 1X8-200 (HO ^- form) to give pure 13 (6 mg, 72%); [α]_D = -28.6 (c 0.2, H₂O); lit. [18] [α]_D = -35.2 (c 0.025, MeOH). ent-13: lit. [19a] [α]_D = +25.7 (c 0.65, H₂O); lit. [19b] [α]_D = +28.1 (c 0.8, H₂O). ¹H NMR (400 MHz, D₂O): δ = 3.92 (dd, 1 H, J _2,3 = J _3,4 = 2.8 Hz, H-3), 3.62 (dd, 1 H, J _5,6a = 3.0, J _6a,6b = 11.6 Hz, H-6a), 3.52 (ddd, 1 H, J _1a,2 = 5.1, J _1b,2 = 11.2 Hz, H-2), 3.46 (dd, 1 H, J _5,6b = 5.8 Hz, H-6b), 3.30 (dd, 1 H, J _4,5 = 10.3 Hz, H-4), 2.67 (dd, 1 H, J _1a,1b = 12.4 Hz, H-1a), 2.56 (ddd, 1 H, H-5), 2.50 (dd, 1 H, H-1b).

<A NAME="RG16304ST-18">18</A> Altenbach H.-J. Himmeldirk K. Tetrahedron: Asymmetry  1995,  6:  1077 

<A NAME="RG16304ST-19A">19a</A> Asano N. Oseki K. Kizu H. Matsui K. J. Med. Chem.  1994,  37:  3701 

<A NAME="RG16304ST-19B">19b</A> Ikota N. Hirano J. Gamage R. Nakagawa H. Hama-Inaba H. Heterocycles  1997,  46:  637 

<A NAME="RG16304ST-19C">19c</A> Wu W.-D. Khim S.-K. Zhang X. Cederstrom EM. Mariano PS. J. Org. Chem.  1998,  63:  841 

<A NAME="RG16304ST-19D">19d</A> Ruiz M. Ojea V. Ruanova TM. Quintela JM. Tetrahedron: Asymmetry  2002,  13:  795