Acid Promoted Syntheses of New Enantiopure Amino Sugar Derivatives from 3,6-Dihydro-2H-1,2-oxazines

Abstract

The acid promoted rearrangement of syn-1 with HCl led to bicyclic acetal 2 from which enantiopure furan derivative 4 was obtained by hydrogenolysis. The same sequence was applied to anti-1 leading to bicyclus 3 and diastereomeric tetrahydrofuran 5. Treatment of syn-6 with pyridinium hydrogen fluoride provided either semiacetal 7 or bicyclic acetal 8, depending on the ratio of HF and pyridine. Lewis acid mediated intramolecular aldol reaction of syn-6 afforded bicyclic 1,2-oxazine 9. Protection and subsequent stereoselective reduction of 9 led to 10, which was hydrogenated to yield enantiopure amino substituted pyran derivative 11.

1,2-oxazines - reductions - furans - carbohydrates - aldol reactions

References

1 Schade W. Reissig H.-U. Synlett  1999,  632 

2 Synthesis: Dondoni A. Franco S. Junquera F. Merchan FL. Merino P. Tejero T. Synth. Commun.  1994,  24:  2537 

Reviews on the reactions of organometallic compounds with chiral nitrones:

3a Merino P. Franco S. Merchan FL. Tejero T. Synlett  2000,  442 

3b Lombardo M. Trombini C. Synthesis  2001,  759 

4 Pulz R. Watanabe T. Schade W. Reissig H.-U. Synlett  2000,  983 ; and references cited herein

5

Typical procedure, syn-1 to 2: To a stirred solution of p-TsCl (0.156 g, 0.819 mmol) in dry methanol (10 mL) at r.t. a solution of syn-1 (0.500 g, 1.64 mmol) in dry methanol (10 mL) was added. The mixture was stirred for 24 h at r.t., then sat. NaHCO₃ solution (20 mL) was added. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined extracts were dried with MgSO₄. Removal of the solvent in vacuo yielded crude 2 which was purified by column chromatography (silica gel, n-hexane-ethyl acetate, 3:2). Compound 2 was obtained as colourless crystals (0.400 g, 92%).
Analytical data of (4aS,7S,7aS)-1-benzyl-4a-methoxyhexa-hydro-1H-furo[3,2-c][1,2]oxazin-7-ol(2): ¹H NMR (CDCl₃, 500 MHz): δ = 7.41-7.25 (m, 5 H, Ph), 4.42 (dd, J = 5.6,
9.8 Hz, 1 H, 6-H_A), 4.18, 3.80 (2 d, J = 15.2 Hz, each 1 H, CH ₂Ph), 4.05 (dd_br, J ≈ 5.4, 11.7 Hz, 1 H, 7-H), 3.91 (dd, J = 1.5, 9.8 Hz, 1 H, 6-H_B), 3.88 (dd_br, J ≈ 6.3, 11.9 Hz, 1 H, 3-H_A), 3.80 (dt, J = 2.7, 11.9 Hz, 1 H, 3-H_B), 3.44 (d, J = 11.7 Hz, 1 H, OH), 3.33 (s, 3 H, OMe), 3.13 (s, 1 H, 7a-H), 2.12 (d_br, J ≈ 12.7 Hz, 1 H, 4-H_A), 1.86 (dt, J = 6.3, 12.7 Hz,
1 H, 4-H_B). ¹³C NMR (CDCl₃, 125 MHz): δ = 138.2, 128.3, 127.8, 127.1 (s, 3 d, Ph), 105.8 (s, C-4a), 76.3 (d, C-7a), 76.2 (t, C-6), 74.6 (d, C-7), 65.8 (t, C-3), 59.7 (t, CH₂Ph), 47.8
(q, OMe), 30.4 (t, C-4). Mp = 27-29 °C. [α]_D ²⁰ = +100.6
(c = 1.7, CHCl₃). IR (CCl₄): n = 3480 cm^-1 (OH), 2940-2890
(C-H). C₁₄H₁₉NO₄ (265.3) Calcd. C 63.38, H 7.22, N 5.28; found C 63.33, H 7.18, N 5.18.
2 to 4: A stirred suspension of Pd(10%)/C (0.175 g, 0.164 mmol) in dry methanol (8 mL) was saturated with hydrogen for 1 h. Then a solution of 2 (0.116 g, 0.437 mmol) in dry methanol (3 mL) was added and the mixture was stirred under hydrogen atmosphere at normal pressure for 8 h at r.t. Filtration through a pad of celite and removal of the solvent in vacuo provided 4 (0.077 g, quant.) as colourless oil.
Analytical data of (2S,3S,4R)-3-amino-4-hydroxy-2-(2′-hydroxy-1′-ethyl)-2-methoxytetrahydrofuran(4): ¹H NMR (CD₃OD, 500 MHz): δ = 4.30 (ddd, J = 0.5, 6.8, 9.5 Hz, 1 H, 5-H_A), 4.13 (ddd, J = 1.7, 4.6, 6.8 Hz, 1 H, 4-H), 3.68-3.60 (m, 2 H, 2′-H), 3.58 (dd, J = 4.6, 9.5 Hz, 1 H, 5-H_B), 3.22 (d_br, J = 1.7 Hz, 1 H, 3-H), 3.19 (s, 3 H, OMe), 2.12 (td, J = 4.4, 15.4 Hz, 1 H, 1′-H_A), 1.91 (ddd, J = 6.2, 8.7, 15.4 Hz, 1 H, 1′-H_B). ^¹³ C NMR (CD₃OD, 125 MHz): δ = 111.0 (s, C-2), 78.7 (d, C-4), 73.6 (t, C-5), 66.1 (d, C-3), 58.0 (t, C-2′), 48.0 (q, OMe), 32.3 (t, C-1′).- [α]_D ²⁰ = +52.3 (c = 0.41, CHCl₃). IR (Film): n = 3350 cm^-1 (NH, OH), 2950-2835 (C-H). MS (pos. FAB): m/z (%) = 178 (M⁺ + H, 37), 160 (M⁺ - OH, 32), 146 (M⁺ - OMe, 100), 128 (M⁺ - OH - OMe, 47), 77 (50). HRMS: calcd. for C₇H₁₄NO₃ (M⁺ - OH) 160.09737, found 160.09666.

6 Schade W. Dissertation   Technische Universität Dresden; Germany: 1999. 

7

Compound 5 was isolated as a mixture containing 14% of a so far unknown side product.

8 Hoffmann RW. Kemper B. Metternich R. Lehmeier T. Liebigs Ann. Chem.  1985,  2246 

9 Al-Harrasi A. Master thesis   Freie Universität Berlin; Germany: 2002. 

10 Greene TW. Wuts MGP. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley & Sons; New York: 1999. 

11 Watanabe Y. Kiyosawa Y. Tatsukawa A. Hayashi M. Tetrahedron Lett.  2001,  42:  4641 

12 Chan TH. In Comprehensive Organic Synthesis   Vol. 2:  Pergamon Press; Oxford, New York, Seoul, Tokyo: 1991.  p.595-625  

13 Methot J.-L. Morency L. Ramsden PD. Wong J. Léger S. Tetrahedron Lett.  2002,  43:  1147 ; and references cited herein

14a Reissig H.-U. Hormuth S. Schade W. Okala Amombo M. Watanabe T. Pulz R. Hausherr A. Zimmer R. Lectures in Heterocyclic Chemistry Vol XVI in J. Heterocycl. Chem.  2000,  37:  597 

14b Reissig H.-U. Schade W. Okala Amombo MG. Pulz R. Hausherr A. Pure Appl. Chem.  2002,  74:  175