A Direct Catalytic Aldol Route to Protected β-Hydroxy-α-amino Acids

Abstract

The combination of triethylamine, magnesium(II) perchlorate and bipyridine generates a catalyst system for the efficient combination of ethyl isothiocyanatoacetate and a range of aromatic aldehydes. The products of these reactions are synthetically valuable protected β-hydroxy α-amino acids.

catalysis - amino acids - aldol reaction - Lewis acid

References

1a Vancomycin: Glycopeptide Antiobiotics   Nagarajan R. Marcel Dekker; New York: 1994. 

1b Cyclosporine A: Wenger RM. Prog. Chem. Org. Nat. Prod.  1986,  50:  123 

1c Polyoxins : Isono K. Suzuki S. Heterocycles  1979,  13:  333 

1d Cyclomarins: Renner MK. Shen Y.-C. Cheng X.-C. Jensen PR. Frankmoelle W. Kauffman CA. Fenical WE. Lobkovsky E. Clardy J. J. Am. Chem. Soc.  1999,  121:  11273 

For selected recent examples, see:

2a MacMillan JB. Molinski TF. Org. Lett.  2002,  4:  1883 

2b Loncaric C. Wulff WD. Org. Lett.  2001,  3:  3675 

2c DeMong DE. Williams RM. Tetrahedron Lett.  2001,  42:  183 

2d Kim IH. Kirk KL. Tetrahedron Lett.  2001,  42:  8401 

For example:

3a Horikawa M. Busch-Petersen J. Corey EJ. Tetrahedron Lett.  1999,  40:  3843 

3b Kobayashi S. Ishitani H. Ueno M. J. Am. Chem. Soc.  1998,  120:  431 

4 For the use of isocyanoacetates in direct catalytic aldol additions, see: Ito Y. Sawamura M. Hayashi T. J. Am. Chem. Soc.  1986,  108:  6405 

5a Evans DA. Weber AE. J. Am. Chem. Soc.  1986,  108:  6757 

5b Volkmann RA. Davis JT. Meltz CN. J. Am. Chem. Soc.  1983,  105:  5946 

5c Hoppe D. Follmann R. Chem. Ber.  1976,  109:  3047 

For examples, see:

6a Ji J. Barnes DM. Zhang J. King SA. Wittenberger SJ. Morton HE. J. Am. Chem. Soc.  1999,  121:  10215 

6b Frantz DE. Fassler R. Carreira EM. J. Am. Chem. Soc.  1999,  121:  11245 ; ref. 5a

7 For an example of alcohol additives aiding catalyst turnover, see: Evans DA. Scheidt KA. Johnston JN. Willis MC. J. Am. Chem. Soc.  2001,  123:  4480 

For impressive recent examples of TMSCl being employed as an additive in diastereoselective MgCl₂ catalysed aldol reactions, see:

8a Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 

8b Evans DA. Downey CW. Shaw JT. Tedrow JS. Org. Lett.  2002,  4:  1127 

9

A reaction using only Et₃N (no metal salt or bipyridine) provided an 8% yield of the aldol adducts after 48 h at r.t. Reactions excluding Et₃N provided no product.

10

For a recent example of Lewis acid catalysed reaction in which the addition of an external ligand was needed to achieve reaction, see ref. [6a]

11

The Preparation of 3 Serves as a Typical Procedure: Mg(ClO₄)₂ (31 mg, 0.138 mmol) and bipyridine (22 mg, 0.138 mmol) were stirred for 10 min in dry THF (5.5 mL) under nitrogen at r.t. Triethylamine (39 µL, 0.276 mmol) was then added and the mixture was cooled at 0 °C. After 10 min ethyl isothiocyanatoacetate (170 µL, 1.38 mmol) and benzaldehyde (150 µL, 1.52 mmol) were added. After 20 h at 0 °C, the reaction was quenched with a sat. aq ammonium chloride solution (5 mL). The organic layer was separated and the aq layer was extracted with dichloromethane (3 × 10 mL). The organic portions were washed with a sat. aq copper sulphate solution (5 mL) and with brine (5 mL), dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO₂, EtOAc-DCM, 2:98) to give a mixture of the syn- and anti-oxazolidinethiones, 3 (290 mg, 84%, syn:anti = 65:35), as a viscous oil. Analytical samples were prepared by recrystallisation from dichloromethane/petroleum spirit 40-60 °C.

12

Small amounts of a by-product originating from the addition of a second equivalent of ester 1 to the initially formed aldol adduct could be isolated in several experiments when conducted at r.t.

13

All new compounds were fully characterised. Selected data for novel compounds:
(4 R *,5 R *) - Ethyl 5-(4-nitrophenyl)-2-thioxo-oxazolidine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 8.28-8.24 (2 H, m), 7.71 (1 H, s), 7.57-7.54 (2 H, m), 6.19 (1 H, d, J = 9.8 Hz), 5.00 (1 H, d, J = 9.8 Hz), 3.87 (1 H, app. dq, J = 10.8 and 7.2 Hz), 3.72 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.89 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.5, 166.6, 148.8, 140.2, 128.1, 124.0, 83.9, 62.9, 62.8, 14.1.
(4 R *,5 R *) - Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.72-7.46 (4 H, m), 7.36 (1 H, s), 6.12 (1 H, d, J = 9.8 Hz), 4.94 (1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.72 (1 H, app. dq, J = 10.7 and 7.2 Hz), 0.88 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃-CD₃OD, 66:33): δ = 189.6, 167.0, 138.9, 132.2, 127.5, 118.0, 113.1, 83.7, 63.0, 62.1, 13.6.
(4 S *,5 R *)-Ethyl 5-(4-cyanophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (1 H, s), 7.75-7.54 (4 H, m), 6.03 (1 H, d, J = 6.2 Hz), 4.44 (1 H, d, J = 6.2 Hz), 4.41-4.29 (2 H, m), 1.37 (3 H, app. t,
J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 188.2, 167.2, 141.6, 132.8, 126.1, 117.9, 113.4, 84.0, 64.4, 63.4, 14.2.
(4 R *,5 R *) - Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (1 H, s), 7.53-7.50 (2 H, m), 7.23-7.18 (2 H, m), 6.04 (1 H, d, J = 9.8 Hz), 4.90 (1 H, d, J = 9.8 Hz), 3.85 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.74 (1 H, app. dq, J = 10.7 and 7.2 Hz), 0.89 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.8, 166.9, 132.4, 132.0, 128.6, 124.2, 84.7, 62.9, 62.7, 14.0.
(4 S *,5 R *)-Ethyl 5-(4-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (1 H, s), 7.58-7.55 (2 H, m), 7.31-7.26 (2 H, m), 5.93 (1 H, d, J = 6.2 Hz), 4.43 (1 H, d, J = 6.2 Hz), 4.39-4.27 (2 H, m), 1.35 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 188.4, 167.5, 135.6, 132.2, 127.2, 123.6, 84.8, 64.5, 63.2, 14.2.
(4 R *,5 R *) - Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.54-7.47 (3 H, m), 7.29-7.27 (2 H, m), 6.04 (1 H, d, J = 9.8 Hz), 4.91 (1 H, d, J = 9.8 Hz), 3.86 (1 H, app. dq, J = 10.8 and 7.2 Hz), 3.76 (1 H, app. dq, J = 10.8 and 7.2 Hz), 0.90 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.8, 166.8, 135.5, 133.0, 130.5, 130.0, 125.5, 122.8, 84.4, 62.9, 62.8, 14.0.
(4 S *,5 R *)-Ethyl 5-(3-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (1 H, s), 7.57-7.53 (2 H, m), 7.37-7.29 (2 H, m), 5.94 (1 H, d, J = 6.2 Hz), 4.45 (1 H, d, J = 6.2 Hz), 4.41-4.28 (2 H, m), 1.36 (3 H, app. t, J = 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 188.7, 167.7, 139.1, 132.9, 131.0, 128.8, 124.4, 123.4, 84.8, 64.8, 63.6, 14.6.
(4 R *,5 R *) - Ethyl 5-(2-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.58-7.23 (5 H, m), 6.41 (1 H, d, J = 9.0 Hz), 5.00 (1 H, d,
J = 9.0 Hz), 3.80 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.66
(1 H, app. dq, J = 10.7and 7.2 Hz), 0.82 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.8, 166.9, 132.6, 132.3, 130.7, 127.8, 127.7, 122.1, 84.5, 62.2, 61.2, 13.6.
(4 S *,5 R *)-Ethyl 5-(2-bromophenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (1 H, s), 7.62-7.25 (4 H, m), 6.34 (1 H, d, J = 4.7 Hz), 4.46 (1 H, d, J = 4.7 Hz), 4.37-4.27 (2 H, m), 1.35 (3 H, app. t,
J = 7.3 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 188.8, 167.4, 135.5, 133.3, 130.8, 128.1, 127.6, 120.9, 84.6, 64.0, 63.0, 14.2.
(4 R *,5 R *) - Ethyl 5-(4-methoxyphenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.51 (1 H, s), 7.25-7.21 (2 H, m), 6.90-6.86 (2 H, m), 6.04 (1 H, d, J = 9.8 Hz), 4.86 (1 H, d, J = 9.8 Hz), 3.84 (1 H, app. dq, J = 10.7 and 7.2 Hz), 3.80 (3 H, s), 3.73 (1 H, app. dq, J = 10.7 and 7.2 Hz), 0.88 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.9, 167.1, 160.7, 128.3, 125.4, 114.1, 85.5, 63.0, 62.5, 55.7, 14.0.
(4 S *,5 R *)-Ethyl 5-(4-methoxyphenyl)-2-thioxo-oxazoli-dine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (1 H, s), 7.34-7.32 (2 H, m), 6.96-6.92 (2 H, m), 5.90 (1 H, d, J = 6.2 Hz), 4.47 (1 H, d, J = 6.2 Hz), 4.37-4.25 (2 H, m), 3.82 (1 H, s), 1.34 (3 H, app. t, J = 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 188.6, 167.7, 160.4, 128.5, 127.3, 114.4, 85.8, 64.4, 62.9, 55.4, 14.2.
(4 R *,5 R *) - Ethyl 5-(2-naphthyl)-2-thioxo-oxazolidine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.86-7.83
(4 H, m), 7.55-7.50 (3 H, m), 7.39-7.36 (1 H, m), 6.26 (1 H, d, J = 9.8 Hz), 4.97 (1 H, d, J = 9.8 Hz), 3.64 (1 H, app. dq, J = 10.4 and 7.2 Hz), 3.48 (1 H, app. dq, J = 10.4 and 7.2 Hz), 0.55 (3 H, app. t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl₃): δ = 189.7, 166.7, 133.5, 132.5, 130.3, 128.4, 128.1, 127.6, 126.9, 126.7, 126.4, 123.3, 85.4, 62.8, 62.2, 13.4. (4 S *,5 R *)-Ethyl 5-(2-naphthyl)-2-thioxo-oxazolidine-4-carboxylate. ¹H NMR (400 MHz, CDCl₃): δ = 7.92-7.85
(5 H, m), 7.55-7.53 (2 H, m), 7.48-7.46 (1 H, m), 6.14 (1 H, d, J = 6.2 Hz), 4.56 (1 H, d, J = 6.2 Hz), 4.42-4.29 (2 H, m), 1.38 (3 H, app. t, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 189.1, 168.1, 134.1, 133.8, 133.1, 129.7, 128.5, 128.0, 127.3, 127.1, 125.6, 122.6, 86.1, 64.9, 63.4, 14.6.