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

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.

Key words

1,2-oxazine - hydroboration - samarium diiodide - azetidine - intramolecular substitution

References and Notes

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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′-H_A, NCH₂), 3.88 (m_c, 1 H, 2-H), 3.93 (d, J = 13.1 Hz, 1 H, NCH₂), 3.98-4.03 (m, 1 H, 5′-H_B), 4.35 (m_c, 1 H, 4′-H), AB-system (δ_A = 4.49, δ_B = 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^-¹. 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 (m_c, 1 H, 4-H), 3.85 (m_c, 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 (m_c, 2 H, 5′-H), 4.81 (m_c, 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^-¹. 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.