Stereoselective Rearrangement of β-Hydroxy-N-acyloxazolidin-2-ones to Afford N-2-Hydroxyethyl-1,3-oxazinane-2,4-diones

Abstract

Zinc alkoxides of syn- or anti-β-hydroxy-N-acyloxazol­idin-2-ones undergo stereoselective rearrangement to afford their corresponding syn- or anti-N-2-hydroxyethyl-1,3-oxazinane-2,4-diones in good yield.

aldol reaction - diastereoselective - intramolecular rearrangement - 1,3-oxazinane-2,4-dione - zinc alkoxide

References

1a Tubulin polymerisation inhibitors, see: Mu F. Lee DJ. Pryor DE. Hamel E. Cushman M. J. Med. Chem.  2002,  45:  4774 

1b Antibacterial: Heinisch L. Wittmann S. Stoiber T. Berg A. Ankel-Fuchs D. Möllmann U. J. Med. Chem.  2002,  45:  3032 

1c Matrix metalloproteinase inhibitors: Chollet A.-M. Le Diguarher T. Kucharczyk N. Loynel A. Bertrand M. Tucker G. Guilbaud N. Burbridge M. Pastoureau P. Fradin A. Sabatini M. Fauchère J.-L. Casara P. Bioorg. Med. Chem. Lett.  2002,  10:  531 

1d Peptidoleukotriene antagonist: Brown FJ. Bernstein PR. Cronk LA. Dosset DL. Hebbel KC. Maduskuie TP. Shapiro HS. Vacek EP. Yee YK. Willard AK. Krell RD. Snyder DW. J. Med. Chem.  1989,  32:  807 

1e Cestodicidal agents: Dubey SK. Singh AK. Singh H. Sharma S. Iyer RN. Katiyar JC. Goel P. Sen AB. J. Med. Chem.  1978,  21:  1178 

2a Larksarp C. Alper H. J. Org. Chem.  1999,  64:  9194 

2b Boontheung P. Perlmutter P. Tetrahedron Lett.  1998,  39:  2629 

2c Kamal A. Rao AB. Sattur PB. Tetrahedron Lett.  1987,  28:  2425 

2d Kemp DS. Duclos JM. Bernstein Z. Welch WM. J. Org. Chem.  1971,  36:  157 

2e May EL. J. Med. Chem.  1967,  10:  505 

2f Miyano M. J. Am. Chem. Soc.  1965,  87:  3958 

2g Stenseth RE. Baker JW. Roman DP. J. Med. Chem.  1963,  6:  212 

3a Barton DHR. Liu W. Chem. Commun.  1997,  571 

3b Pintye J. Fülöp F. Bernáth G. Sohár P. Monatsh. Chem.  1985,  116:  857 

3c Sainsbury M. In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon Press; New York: 1984.  p.995-1038  ; and references contained therein.

4 For a demonstration of the synthetic potential of N-2-hydroxyethyl-1,3-oxazinane-2,4-diones see: Kamino T. Murata Y. Kawai N. Hosokawa S. Kobayashi S. Tetrahedron Lett.  2001,  42:  5249 

5 Ozaki S, and Koto K. inventors; Jpn. Tokkyo Koho, JP  19660502. For a patent on their usage as sedatives, hypnotics, anticonvulsants and depressants see: ; Chem. Abstr. 1969, 72, 43701

6 For a review on the use of oxazolidin-2-ones as chiral auxiliaries for asymmetric synthesis see: Ager DJ. Prakash I. Schaad DR. Aldrichimica Acta  1997,  30:  3 

7a Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 

7b Evans DA. Nelson JV. Taber T. Top. Stereochem.  1982,  13:  1 

7c Davies SG. Nicholson RL. Smith AD. Org. Biomol. Chem.  2004,  2:  3385 

8a Nerz-Stormes M. Thornton ER. J. Org. Chem.  1991,  56:  2489 

8b Evans DA. Rieger DL. Bilodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  113:  1047 

8c Yan TH. Tan CH. Lee HC. Lo HC. Huang TY. J. Am. Chem. Soc.  1993,  115:  2613 

8d Crimmins MT. She J. Synlett  2004,  1371 

9 Kagoshima H. Hashimoto Y. Ogura D. Saigo K. J. Org. Chem.  1998,  63:  691 

10 Walker MA. Heathcock CH. J. Org. Chem.  1991,  56:  5747 

11 Gabriel T. Wessjohann L. Tetrahedron Lett.  1997,  38:  4387 

12 Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 

For previous reports where these type of 1,3-oxazinane-2,4-diones were formed as unwanted products of other types of synthetic transformation see:

13a Mickel SJ. Sedelmeier GH. Niederer D. Schuerch F. Koch G. Kuesters E. Daeffler R. Osmani A. Seeger-Weibel M. Schmid E. Hirni A. Schaer K. Gamboni R. Bach A. Chen S. Chen W. Geng P. Jagoe CT. Kinder FR. Lee GT. McKenna J. Ramsey TM. Repiè O. Rogers L. Shieh W.-C. Wang R.-M. Waykole L. Org. Proc. Res. Dev.  2004,  8:  107 

13b Keck GE. Lundquist GD. J. Org. Chem.  1999,  64:  4482 

13c Narasaka K. Yamamoto I. Tetrahedron  1992,  48:  5743 

14 For a report where reaction of the boron enolate of a related N-propionyl-1,3-oxazinan-2-one with benzaldehyde in the presence of excess Bu₂BOTf resulted in a rearranged 1,3-oxazinane-2,4-dione product see: Abbas TR. Cadogan JIG. Doyle AA. Gosney I. Hodgson PKG. Howells GE. Hulme AN. Parsons S. Sadler IH. Tetrahedron Lett.  1997,  38:  4917 

15 Kende AS. Kawamura K. DeVita RJ. J. Am. Chem. Soc.  1990,  112:  4070 

16 Ito Y. Terashima S. Tetrahedron  1991,  47:  2821 

17

Representative Synthetic Protocol for syn -Aldol Reactions.
A 0.5 M solution of 9-BBN·OTf in hexanes (1.2 equiv) was added to a stirred solution of N-acyloxazolidin-2-one (1 equiv) in CH₂Cl₂ at 0 °C and allowed to stir for 5 min. N,N-Diisopropylethylamine (1.4 equiv) was added, the reaction stirred for 25 min at 0 °C and cooled to -78 °C. An aldehyde (1.1 equiv) was then added, the reaction was stirred for 2 h and the reaction then allowed to warm to 0 °C for 30 min. Then, pH 7.0 phosphate buffer was added, followed by a 2:1 solution of MeOH-H₂O₂. The reaction was extracted with CH₂Cl₂ (3 ×) and the combined organic extracts washed with aq NaHCO₃, brine, dried (MgSO₄) and concentrated in vacuo to afford the appropriate syn-aldol which was then purified by chromatography.

18 These conditions have been employed previously for asymmetric syn-aldol reactions using imidazolidin-2-one derived glycine enolates, see: Caddick S. Parr NJ. Pritchard MC. Tetrahedron Lett.  2000,  41:  5963 

19 We have reported previously on a single example of this rearrangement see: Feuillet FJP. Robinson DEJE. Bull SD. Chem. Commun.  2003,  2184 

20

Representative Synthetic Protocol for Rearrangement Reaction.
A 1.0 M solution of Et₂Zn in toluene (0.1 equiv) was added dropwise to a stirred solution of the syn-aldol (1 equiv) in CH₂Cl₂ at r.t. The reaction was stirred for 2 h. Then, sat. aq NH₄Cl was added and the reaction extracted with CH₂Cl₂ (3 ×). The combined organic extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo to afford the desired syn-1,3-oxazinane-2,4-dione which was then purified by chromatography.

21

All new compounds were fully characterised. Selected data for new compounds:
syn -6-Ethyl-3-(2-hydroxyethyl)-5-isopropyl-1,3-oxazinane-2,4-dione (10b): ¹H NMR (300 MHz, CDCl₃): δ = 0.97 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 1.00 (3 H, t, J = 7.5 Hz, CH₂CH ₃), 1.02 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 1.60 (1 H, dqd, J = 14.0, 7.5, 5.0 Hz, CH _AH_BCH₃), 1.80 (1 H, ddq, J = 14.0, 9.0, 7.5 Hz, CH_A H _BCH₃), 2.08-2.21 [1 H, m, J = 7.0, 5.0, CH(CH₃)₂], 2.25 (1 H, br s, OH), 2.52 (1 H, dd, J = 5.0, 4.0 Hz, CHi-Pr), 3.74 (2 H, app t, J = 5.5 Hz, CH ₂OH), 3.89 (1 H, app dt, J = 14.0, 5.5 Hz, CH _A H_BN), 4.01 (1 H, app dt, J = 14.0, 5.5 Hz, CH_A H _B N), 4.39 (1 H, ddd, J = 9.0, 5.0, 4.0 Hz, CHO). ¹³C NMR (100 MHz, CDCl₃): δ = 9.0, 18.8, 21.2, 22.3, 14.5, 43.1, 48.4, 59.8, 78.0, 151.6, 170.0. IR: 3436 (br, OH), 1749 (C=O), 1691 (C=O) cm^-1.
syn -3-(2-Hydroxyethyl)-5-isopropyl-6-[( E )-1-propenyl]-1,3-oxazinane-2,4-dione (10d): ¹H NMR (300 MHz, CDCl₃): δ = 0.97 [3 H, d, J = 7.0, CH(CH ₃)₂], 1.03 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 1.71 (3 H, d, J = 7.0 Hz, CH ₃CH=CH), 1.97 (1 H, t, J = 5.5 Hz, OH), 2.10 [1 H, m, J = 7.0 Hz, CH(CH₃)₂], 2.55 (1 H, dd, J = 7.0, 4.5 Hz, CHi-Pr), 3.74 (2 H, app dt, J = 5.5, 5.5 Hz, CH ₂OH), 3.94-3.98 (2 H, m, CH ₂N), 4.92 (1 H, app t, J = 7.0 Hz, CHO), 5.47 (1 H, ddd, J = 15.0, 7.0, 1.5 Hz, CH₃CH=CH), 5.91 (1 H, dq, J = 15.0, 7.0 Hz, CH₃CH=CH). ¹³C NMR (75 MHz, CDCl₃): δ = 17.0, 19.7, 20.3, 24.8, 43.2, 49.5, 60.1, 76.6, 122.1, 132.7, 151.3, 169.7. IR: 3430 (br, OH), 1755 (C=O), 1699 (C=O) cm^-1. (5 S ,6 R )-3-[( S )-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-methyl-1,3-oxazinane-2,4-dione (10e): [α]_D ²⁰ -6.4 (c 0.47, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.82 (3 H, t, J = 7.5 Hz, CH₂CH ₃), 0.99 (3 H, d, J = 7.5, CH ₃CH), 1.33 (2 H, m, CH ₂ CH₃), 2.50 (1 H, qd, J = 7.5, 3.5 Hz, CHCH₃), 2.99 (1 H, dd, J = 14.0, 7.0 Hz, PhCH _ACH_B), 3.16 (1 H dd, J = 14.0, 10.5 Hz, PhCH_ACH _B), 3.68 (2 H, obscured m, CHO), 3.82 (1 H, dd, J = 12.0, 4.0 Hz, CH _AH_BOH), 4.01 (1 H, dd, J = 12.0, 7.0 Hz, CH_A H _BOH), 5.04 (1 H, app dtd, J = 10.5, 7.0, 4.0 Hz, CHN), 7.10-7.15 (5 H, m, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 9.2, 9.5, 22.6, 33.7, 39.2, 56.5, 63.3, 78.4, 126.6, 128.5, 129.1, 137.4, 151.8, 173.1. IR: 3462 (br, OH), 1755 (C=O), 1700 (C=O) cm^-1.
(5 S ,6 R )-3-[( S )-1-Benzyl-2-hydroxyethyl]-6-ethyl-5-isopropyl-1,3-oxazinane-2,4-dione (10h): [α]_D ²⁰ -6.8 (c 0.59, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.84 (3 H, t, J = 7.5 Hz, CH₂CH ₃), 0.85 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 0.92 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 1.31-1.46 (1 H, dqd, J = 14.0, 7.5, 5.0 Hz, CH _AH_BCH₃), 1.45-1.61 (1 H, m, CH_A H _BCH₃), 1.94-2.05 [1 H, m, CH(CH₃)₂], 2.18 (1 H, app t, J = 4.5 Hz, CHi-Pr), 2.53 (1 H, br s, OH), 2.99 (1 H, dd, J = 14.0, 7.0 Hz, CH _AH_BPh), 3.13 (1 H, dd, J = 14.0, 10.5 Hz, CH_A H _BPh), 3.64 (1 H, obscured m, CHO), 3.82 (1 H, dd, J = 12.0, 4.0 Hz, CH _AH_BOH), 4.02 (1 H, dd, J = 12.0, 7.0 Hz, CH_A H _BOH), 5.04-5.14 (1 H, app dtd, J = 10.5, 7.0, 4.0 Hz, CHN), 7.08-7.22 (5 H, m, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 10.4, 20.2, 22.6, 23.4, 25.5, 34.3, 50.2, 56.5, 63.7, 79.4, 127.0, 128.9, 129.5, 135.0, 152.5, 171.4. IR: 3423 (br, OH), 1754 (C=O), 1691 (C=O) cm^-1.
syn -3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-2,4-dione (10i): ¹H NMR (300 MHz, CDCl₃): δ = 1.01 (3 H, d, J = 7.5 Hz, CH ₃), 2.17 (1 H, s, OH), 2.99 (1 H, qd, J = 7.5, 3.5 Hz, CHCH₃), 3.75-3.82 (2 H, m, CH ₂OH), 3.97 (1 H, app dt, J = 14.0, 5.5 Hz, CH _A H_BN), 4.05 (1 H, app dt, J = 14.0, 5.5 Hz, CH_A H _B N), 5.62 (1 H, d, J = 3.5 Hz, CHO), 7.24-7.38 (5 H, m, Ph-H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.4, 41.5, 44.6, 61.2, 78.1, 126.0, 129.2, 129.4, 134.4, 152.4, 173.2. IR: 3447 (br, OH), 1755 (C=O), 1703 (C=O) cm^-1.
syn -3-(2-Hydroxyethyl)-5-isopropyl-6-(4-methoxy-phenyl)-1,3-oxazinane-2,4-dione (10k): mp 79-81 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.87 [3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 0.98 (3 H, d, J = 7.0 Hz, CH(CH ₃)₂], 1.96 [1 H, m, J = 7.0, 4.0 Hz, CH(CH₃)₂], 2.26 (1 H, br s, OH), 2.79 (1 H, t, J = 4.0 Hz, CHi-Pr), 3.83 (3 H, s, ArOCH ₃), 3.81-3.87 (2 H, m, CH ₂OH), 4.02 (1 H, app dt, J = 14.0, 5.5 Hz, CH _A H_BN), 4.16 (1 H, app dt, J = 14.0, 5.5 Hz, CH_A H _B N), 5.71 (1 H, d, J = 4.0 Hz, CHO), 6.94 (2 H, d, J = 8.5 Hz, Ar-H), 7.29 (2 H, d, J = 8.5 Hz, Ar-H). ¹³C NMR (75 MHz, CDCl₃): δ = 19.8, 23.1, 26.0, 44.7, 52.0, 55.7, 61.3, 78.4, 114.6, 126.7, 127.1, 152.9, 160.1, 171.4. IR: 3353 (br, OH), 1740 (C=O), 1691 (C=O) cm^-1.

22

syn-1,3-Oxazinane-2,4-diones exhibit J _{( 5,6)} coupling constants of <4.5 Hz, whilst anti-1,3-oxazinane-2,4-diones exhibit J _{( 5,6)} coupling constants of >10.0 Hz; see ref. 13c, 14, 16.

23

An alternative mechanism involving zinc alkoxide-catalysed epimerisation of the α-stereocentres of syn-β-aryl-aldols 9i-l (or syn-β-aryl-1,3-oxazinane-2,4-diones 10i-l) was discounted because their acidities are similar to those of the α-stereocentres of syn-β-alkyl-aldols 9a-k that had been shown to rearrange with no loss of stereocontrol under these conditions.

24 A similar reversible retro-aldol/aldol mechanism has been proposed to explain the diastereoselectivity observed for reaction of metal enolates of N-acyl-oxazolidin-2-ones with ketones, see: Bartroli J. Turmo E. Belloc J. Forn J. J. Org. Chem.  1995,  60:  3000 

25

N-Acyl-oxazolidin-2-one-anti-aldol 15 was prepared using Evans’ magnesium halide-catalysed protocol, see ref. 12.

26

anti -3-(2-Hydroxyethyl)-5-methyl-6-phenyl-1,3-oxazinane-2,4-dione (16). ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (3 H, d, J = 7.0 Hz, CH ₃), 2.21 (1 H, br s, OH), 2.89 (1 H, dq, J = 11.5, 7.0 Hz, CHCH₃), 3.77-3.80 (2 H, app t, J = 5.5 Hz, CH ₂OH), 3.94 (1 H, dt, J = 14.0, 5.5 Hz, CH _A H_BN), 4.06 (1 H, app dt, J = 14.0, 5.5 Hz, CH_A H _B N), 5.04 (1 H, d, J = 11.5 Hz, CHPh), 7.24-7.38 (5 H, m, Ph-H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.1, 40.4, 43.5, 59.6, 80.5, 126.1, 127.9, 128.7, 134.2, 151.1, 170.5. IR: 3435 (br, OH), 1755 (C=O), 1694 (C=O) cm^-1.