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

1 Dondoni A. Marra A. Richichi B. Synlett  2003,  2345 

2a Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 

2b Halab L. Gosselin F. Lubell WD. Biopolymers  2000,  55:  101 

2c Dietrich E. Lubell WD. J. Org. Chem.  2003,  68:  6988 

3a Gillespie P. Cicariello J. Olson JL. Biopolymers  1997,  43:  191 

3b Takeuchi Y. Marshall GR. J. Am. Chem. Soc.  1998,  120:  5363 

3c Belvisi L. Bernardi A. Manzoni L. Potenza D. Scolastico C. Eur. J. Org. Chem.  2000,  2563 

4 Belvisi L. Bernardi A. Checchia A. Manzoni L. Potenza D. Scolastico C. Castorina M. Cupelli A. Giannini G. Carminati P. Pisano C. Org. Lett.  2001,  3:  1001 

5a Haubner R. Finsinger D. Kessler H. Angew. Chem., Int. Ed. Engl.  1997,  36:  1374 

5b Gottschalk K.-E. Kessler H. Angew. Chem. Int. Ed.  2002,  41:  3767 

5c Hynes RO. Nat. Med. (N. Y., NY, U. S.)  2002,  8:  918 

6a Dondoni A. Giovannini PP. Perrone D. J. Org. Chem.  2002,  62:  7203 

6b

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.

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).

10 Hughes DL. Org. Prep. Proc. Int.  1996,  28:  127 

11 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 

12a Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond   Stütz AE. Wiley-VCH; Weinheim: 1999. 

12b Look GC. Fotsch CH. Wong C.-H. Acc. Chem. Res.  1993,  26:  182 

12c Asano N. Curr. Top. Med. Chem.  2003,  3:  471 

12d Greimel P. Spreitz J. Stütz AE. Wrodnigg TM. Curr. Top. Med. Chem.  2003,  3:  513 

13a Tyms AS. Taylor DL. Sunkara PS. Kang MSL. In Design of Anti-AIDS Drugs   DeClerq E. Elsevier; New York: 1990.  p.257-318  

13b Winchester B. Fleet GWJ. Glycobiology  1992,  2:  199 

14 Dondoni A. Marra A. Scherrmann M.-C. Bertolasi V. Chem.-Eur. J.  2001,  7:  1371 

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).

18 Altenbach H.-J. Himmeldirk K. Tetrahedron: Asymmetry  1995,  6:  1077 

19a Asano N. Oseki K. Kizu H. Matsui K. J. Med. Chem.  1994,  37:  3701 

19b Ikota N. Hirano J. Gamage R. Nakagawa H. Hama-Inaba H. Heterocycles  1997,  46:  637 

19c Wu W.-D. Khim S.-K. Zhang X. Cederstrom EM. Mariano PS. J. Org. Chem.  1998,  63:  841 

19d Ruiz M. Ojea V. Ruanova TM. Quintela JM. Tetrahedron: Asymmetry  2002,  13:  795