Synlett 2010(1): 42-46  
DOI: 10.1055/s-0029-1218531
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereocontrolled Synthesis of Enantiopure Polyhydroxylated Azetidines via 1,2-Oxazines

Vjekoslav Dekaris, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
Further Information

Publication History

Received 24 September 2009
Publication Date:
02 December 2009 (eFirst)

Abstract

A set of new enantiopure polyhydroxylated azetidine derivatives has been prepared. The key starting materials, 3,6-dihydro-2H-1,2-oxazines, were subjected to a hydroboration-oxidation sequence to introduce the required 5-hydroxy group. Subsequent cleavage of the N-O bond with samarium diiodide, selective protection of the primary hydroxyl group, and ring closure after activation of the secondary hydroxyl group provided the protected azetidine derivatives. The efficacy of each individual step of this sequence depends on the configuration of the starting material. Three representative azetidine derivatives were converted into the deprotected polyhydroxylated azetidines which are interesting candidates as glycosidase inhibitors.

    References and Notes

  • 1a Schade W. Reissig H.-U. Synlett  1999,  632 
  • 1b Helms M. Schade W. Pulz R. Watanabe T. Al-Harrasi A. Fišera L. Hlobilová I. Zahn G. Reissig H.-U. Eur. J. Org. Chem.  2005,  1003 
  • 2a Al-Harrasi A. Reissig H.-U. Angew. Chem. Int. Ed.  2005,  44:  6227 ; Angew. Chem. 2005, 117, 6383
  • 2b Al-Harrasi A. Pfrengle F. Prisyazhnyuk V. Yekta S. Koóš P. Reissig H.-U. Chem. Eur. J.  2009,  15:  11632 
  • 3 Pfrengle F. Lentz D. Reissig H.-U. Angew. Chem. Int. Ed.  2009,  48:  3165 ; Angew. Chem. 2009, 121, 3211
  • 4 Bressel B. Egart B. Al-Harrasi A. Pulz R. Reissig H.-U. Brüdgam I. Eur. J. Org. Chem.  2008,  467 
  • 5 Bressel B. Reissig H.-U. Org. Lett.  2009,  11:  527 
  • 6a Pulz R. Watanabe T. Schade W. Reissig H.-U. Synlett  2000,  983 
  • 6b Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 
  • 7a Keck GE. McHardy SF. Wager TT. Tetrahedron Lett.  1995,  36:  7419 
  • 7b Chiara JL. Destabel C. Gallego P. Marco-Contelles J. J. Org. Chem.  1996,  61:  359 
  • 7c Revuelta J. Cicchi S. Brandi A. Tetrahedron Lett.  2004,  45:  8375 
  • 7d Young IS. Williams JL. Kerr MA. Org. Lett.  2005,  7:  953 
  • 8a Krämer B. Franz T. Picasso S. Pruschek P. Jäger V. Synlett  1997,  295 
  • For selected review articles on glyco-sidase inhibition in general, see:
  • 8b Iminosugars as Glycosidase Inhibitors   Stütz AE. Wiley-VCH; Weinheim: 1999. 
  • 8c Zechel DL. Withers SG. Acc. Chem. Res.  2000,  33:  11 
  • 8d Lillelund VH. Jensen HH. Liang X. Bols M. Chem. Rev.  2002,  102:  515 
  • 8e Winchester BG. Tetrahedron: Asymmetry  2009,  20:  645 
  • 8f Davis BG. Tetrahedron: Asymmetry  2009,  20:  652 
  • For review articles, see:
  • 9a Cromwell NH. Phillips B. Chem. Rev.  1979,  79:  331 
  • 9b Brandi A. Cicchi S. Cordero FM. Chem. Rev.  2008,  108:  3988 
  • 11a Mitsunobu O. Yamada M. Bull. Chem. Soc. Jpn.  1967,  40:  2380 
  • 11b Mitsunobu O. Synthesis  1981, 
  • 11c Yuen T. But S. Toy PH. Chem. Asian J.  2007,  2:  1340 
  • 11d For a recent review, see: Kumara Swamy KC. Bhuvan Kumar NN. Balaraman E. Pavan Kumar KVP. Chem. Rev.  2009,  109:  2551 
  • 12 Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 
10

So far we do not know at which stage of the hydroboration process the N-O bond cleavage occurs.

13

Typical Procedure for Ring Cleavage of 2d to 3b
To a suspension of samarium (1.98 g, 13.2 mmol) in THF (20 mL) under argon at r.t. 1,2-diiodoethane (2.65 g, 9.40 mmol) was added. The mixture was stirred for 2 h at r.t. and turned to a dark blue colour. Afterwards 1,2-oxazine 2d (1.50 g, 3.75 mmol) was dissolved in THF (20 mL) and added slowly to the SmI2 solution. The mixture was stirred for 4 h at r.t., then quenched with sat. NaHCO3 solution, extracted three times with Et2O, and the combined organic layers were dried with MgSO4. After filtration and removal of the solvent recrystallization with a mixture of hexane and EtOAc afforded 3b (1.27 g, 84%) as a colourless solid (mp 94-96 ˚C).
Analytical Data of (2 S ,3 R ,4 S ,4′ S )-4-Benzylamino-3-benzyloxy-4-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)butane-1,2-diol (3b)
[α]D ²0 -25.6 (c 0.40, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 1.34 (s, 6 H, Me), 2.97 (dd, J = 3.2, 8.1 Hz, 1 H, 4-H), 3.66-3.74 (m, 5 H, 1-H, 3-H, 5′-HA, NCH2), 3.88 (mc, 1 H, 2-H), 3.93 (d, J = 13.1 Hz, 1 H, NCH2), 3.98-4.03 (m, 1 H, 5′-HB), 4.35 (mc, 1 H, 4′-H), AB-system (δA = 4.49, δB = 4.55, J = 11.5 Hz, 2 H, OCH2Ph), 7.22-7.36 (m, 10 H, Ph) ppm. OH and NH could not be assigned. ¹³C NMR (126 MHz, CDCl3): δ = 25.6, 26.7 (2 q, Me), 51.9 (t, NCH2), 60.7 (d, C-4), 63.5 (t, C-1), 67.7 (t, C-5′), 72.6 (d, C-2), 72.8 (d, C-3), 73.1 (t, OCH2Ph), 75.3 (d, C-4′), 108.5 (s, C-2′), 127.5, 128.0, 128.1, 128.2, 137.5, 138.7 (4 d, 2 s, Ph) ppm. IR (KBr): 3420, 3310 (OH, NH), 3085-3030 (=CH), 2985-2855 (CH) cm. HRMS (ESI-TOF-MS): m/z calcd for C23H31NO5 [M + H]+: 402.2275; found: 402.2280.

14

This result may be improved since the reaction was only performed once and samarium(II) was consumed mostly before completion of the reaction probably by traces of air indicated by the greenish colour of the solution.

15

Typical Procedure for Ring Closure of 4a to 5a
To a solution of 4a (697 mg, 1.35 mmol) in pyridine (50 mL) under argon at r.t. MsCl (0.15 mL, 1.94 mmol) was added. The mixture was stirred 1 d at r.t. and 3 d at 50 ˚C. After quenching with 5% CuSO4 solution (50 mL) the mixture was extracted three times with Et2O, the combined organic layers were washed twice with H2O, and dried with MgSO4. After filtration and removal of the solvents, purification via silica gel column chromatography (hexane-EtOAc) afforded 5a (565 mg, 84%) as a colourless oil.
Analytical Data of (2 S ,3 S ,4 R, 4′ S )-1-Benzyl-3-benzyloxy-2-( tert -butyldimethylsiloxymethyl)-4-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)azetidine (5a)
[α]D ²0 +12.3 (c 0.9, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 0.00 (s, 6 H, SiMe2), 0.83 (s, 9 H, Sit-Bu), 1.32, 1.35 (2 s, 6 H, Me), 2.95-3.35 (m, 2 H, 4-CH2), 3.49 (mc, 1 H, 4-H), 3.85 (mc, 1 H, 2-H), 4.03 (dd, J = 4.6, 7.3 Hz, 1 H, 3-H), 3.75, 4.18 (2 d, J = 12.7 Hz, 2 H, NCH2), 4.34, 4.60 (2 d, J = 11.9 Hz, 2 H, OCH2Ph), 4.23 (mc, 2 H, 5′-H), 4.81 (mc, 1 H, 4′-H), 7.20-7.36 (m, 10 H, Ph) ppm. ¹³C NMR (126 MHz, CDCl3): δ = -5.54, -5.52 (2 q, SiMe2), 18.2, 25.9 (s, q, Sit-Bu), 25.5, 26.7 (2 q, Me), 55.7 (t, NCH2), 64.2 (t, 4-CH2), 67.9 (t, C-5′), 69.1 (d, C-2), 71.1 (t, OCH2Ph), 72.3 (d, C-4), 73.9 (d, C-4′), 74.2 (d, C-3), 108.6 (s, C-2′), 127.3, 127.5, 128.0, 128.3, 128.5, 128.7 (6 d, Ph), 138.2, 140.1 (2 s, Ph) ppm. IR (film): 3085-3030 (=CH), 2985-2855 (CH) cm. MS (EI, 80 eV, 90 ˚C): m/z (%) = 497 (2) [M+], 482 (4) [M - CH3]+, 406 (26) [M - C7H7]+, 396 (54) [M - C5H9O2]+, 91 (100) [C7H7]+. Anal. Calcd for C29H43NO4Si (497.7): C, 69.98; H, 8.71; N, 2.81. Found: C, 69.72; H, 8.61; N, 2.62.

16

The constitution and configuration of compound 7a was unequivocally proven by an X-ray analysis: Brüdgam, I.; Institut für Chemie und Biochemie, Freie Universität Berlin, unpublished results.