Stevens Rearrangement of a Cyclic Hemiacetal System: Diastereoselective Approach to Chiral α-Amino Ketone

Abstract

The base-promoted reaction of ammonium ylide 1a, which forms a cyclic hemiacetal structure, is shown to afford the anti-hemiacetal 3a in high diastereopurity, via the Stevens re­arrangement followed by efficient thermodynamic epimerization.

Key words

acetal - amino alcohols - stereoselective synthesis - ­ketones - rearrangements

References

• Reviews:
• 1a Pine SH. Org. React.  1970,  18:  404 
• 1b Markó I. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.913-974  
• 2 Ollis WD. Ray M. Sutherland IO. J. Chem. Soc., Perkin Trans. 1  1983,  1009 
• Only a few successful examples are reported so far. For these the stereocontrol is based on the chirality transfer from chiral nitrogen atom of the ammonium salt to carbon:
• 3a Hill RK. Chan T.-H. J. Am. Chem. Soc.  1966,  88:  866 
• 3b Naidu BN. West FG. Tetrahedron  1997,  53:  16565 
• 3c Glaeske KW. West FG. Org. Lett.  1999,  1:  31 
• Selected examples:
• 4a Tomooka K. Okinaga T. Suzuki K. Tsuchihashi G. Tetrahedron Lett.  1989,  30:  1563 
• 4b Tomooka K. Yamamoto H. Nakai T. J. Am. Chem. Soc.  1996,  118:  3317 
• 4c Tomooka K. Nakazaki A. Nakai T. J. Am. Chem. Soc.  2000,  122:  408 
• 4d Tomooka K. Yamamoto H. Nakai T. Angew. Chem. Int. Ed.  2000,  39:  4500 

5

All new compounds were fully characterized by IR, ¹H and ¹³C NMR analyses. Data for selected compounds are as follows. Compound 1a: mp 202-204 °C (dec.). ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.96 (s, 3 H), 3.25 (s, 3 H), 3.55 (dd, J = 12.9, 2.4 Hz, 1 H), 3.93 (d, J = 12.9 Hz, 1 H), 4.05 (dd, J = 13.4, 2.6 Hz, 1 H), 4.99 (dd, J = 13.4, 11.6 Hz, 1 H), 5.13 (dd, J = 11.6, 2.6 Hz, 1 H), 7.40-7.70 (m, 11 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 45.9, 54.1, 58.2, 67.2, 71.1, 95.0, 126.1, 128.2, 128.3, 129.2, 130.9, 131.4, 141.3. Anal. Calcd for C₁₈H₂₂BrNO₂: C, 59.35; H, 6.09; N, 3.85. Found: C, 58.77; H, 5.96; N, 3.88. Compound anti-2a: mp 136-139 °C. ¹H NMR (300 MHz, CDCl3): δ = 2.42 (s, 6 H), 3.61 (ddd, J = 3.9, 9.0, 11.1 Hz, 1 H), 3.88 (dd, J = 3.9, 11.4 Hz, 1 H), 4.13 (dd, J = 9.0, 11.4 Hz, 1 H), 4.86 (d, J = 11.1 Hz, 1 H), 7.04-7.22 (m, 4 H), 7.34-7.51 (m, 4 H), 7.71 (d, J = 7.5 Hz, 1 H). ¹³C NMR (75 MHz, CDCl3): δ = 42.4, 45.0, 68.8, 70.4, 126.1, 127.1, 128.0, 128.4, 128.6, 133.1, 139.0, 139.5, 196.6. Anal. Calcd for C₁₈H₂₁NO₂: C, 76.29; H, 7.47; N, 4.94. Found: C, 75.77; H, 7.37; N, 4.95. Compound anti,syn-3a: ¹H NMR (300 MHz, CDCl3): δ = 2.12 (s, 6 H), 3.30 (d, J = 8.7 Hz, 1 H), 3.70 (ddd, J = 7.2, 8.7, 9.0 Hz, 1 H), 3.98 (dd, J = 7.2, 9.0 Hz, 1 H), 4.52 (dd, J = 9.0, 9.0 Hz, 1 H), 7.24-7.42 (m, 8 H), 7.71-7.74 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 45.0, 48.7, 74.4, 81.1, 104.2, 126.0, 126.9, 127.7, 128.1, 128.2, 129.0, 142.7, 143.8.

6

The relative stereochemistry of 1a was determined by NOE experiment as shown below (Figure [1] ).

7

It is considered that potassium ethoxide formed in the reaction mixture acts as a base.

8

Typical procedure: To a solution of the ammonium salt 1a (50 mg, 0.137 mmol) in EtOH (5 mL) at 0 °C was added potassium tert-butoxide (30.8 mg, 0.274 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 12 h. The mixture was quenched by the addition of phosphate buffer (pH 7) and the organic layer was dried and concentrated in vacuo. Purification of the residue by PTLC (SiO₂, hexane/EtOAc = 2/1) gave (2R*,3R*)-2-dimethyl-amino-4-hydroxy-3-phenylbutyrophenone (anti-2a, 13.4 mg, 35% yield) and (2S*,3R*,4R*)-3-dimethylamino-tetrahydro-2-hydroxy-2,4-diphenylfuran (anti,syn-3a, 15.6 mg, 40% yield).

9

The relative stereochemistry of anti,syn-3a was determined by NOE experiment as shown below (Figure [2] ).

10

Anti-5 and anti,syn-6 were obtained as a chromatographically inseparable mixture.

11

Conformational analysis of the rearrangement products was carried out with the MacroModel 8.0 package and PC Spartan Pro 1.0.5. Conformational search was performed with Mixed MCMM/LowMode method (1000 structures) using MM2* force field. Further geometry optimization and the potential energy calculation of the most stable conformers were performed by PM3 calculation using Spartan.

12

The hemiacetal (2R,5R)-1a was prepared from (R)-2-phenylglycinol (99% ee) purchased from Aldrich.

13

This result is consistent with the reported steric course of Stevens rearrangement: see ref. 1.

14

Similar solvent effect in terms of the asymmetric transmission was reported by Ollis and colleagues, see ref. 2.