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Synlett 2004(10): 1711-1714  
DOI: 10.1055/s-2004-829566
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Alessandro Dondoni*a,b, Barbara Richichib, Alberto Marra*a,b, Daniela Perronea
a Laboratorio di Chimica Organica, Dipartimento di Chimica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
b Interdisciplinary Center for the Study of Inflammation, Università di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
Fax: +39(0532)291167; e-Mail: adn@dns.unife.it;
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Publication History

Received 30 April 2004
Publication Date:
15 July 2004 (online)

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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.

Key words

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

    References

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7

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).

8

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).

9

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).

15

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).

16

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).

17

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).