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

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<A NAME="RD13702ST-1B">1b</A> Cyclosporine A: Wenger RM. Prog. Chem. Org. Nat. Prod.  1986,  50:  123 

<A NAME="RD13702ST-1C">1c</A> Polyoxins : Isono K. Suzuki S. Heterocycles  1979,  13:  333 

<A NAME="RD13702ST-1D">1d</A> 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 

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<A NAME="RD13702ST-2B">2b</A> Loncaric C. Wulff WD. Org. Lett.  2001,  3:  3675 

<A NAME="RD13702ST-2C">2c</A> DeMong DE. Williams RM. Tetrahedron Lett.  2001,  42:  183 

<A NAME="RD13702ST-2D">2d</A> Kim IH. Kirk KL. Tetrahedron Lett.  2001,  42:  8401 

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<A NAME="RD13702ST-3A">3a</A> Horikawa M. Busch-Petersen J. Corey EJ. Tetrahedron Lett.  1999,  40:  3843 

<A NAME="RD13702ST-3B">3b</A> Kobayashi S. Ishitani H. Ueno M. J. Am. Chem. Soc.  1998,  120:  431 

<A NAME="RD13702ST-4">4</A> For the use of isocyanoacetates in direct catalytic aldol additions, see: Ito Y. Sawamura M. Hayashi T. J. Am. Chem. Soc.  1986,  108:  6405 

<A NAME="RD13702ST-5A">5a</A> Evans DA. Weber AE. J. Am. Chem. Soc.  1986,  108:  6757 

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<A NAME="RD13702ST-6A">6a</A> Ji J. Barnes DM. Zhang J. King SA. Wittenberger SJ. Morton HE. J. Am. Chem. Soc.  1999,  121:  10215 

<A NAME="RD13702ST-6B">6b</A> Frantz DE. Fassler R. Carreira EM. J. Am. Chem. Soc.  1999,  121:  11245 ; ref. 5a

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<A NAME="RD13702ST-8A">8a</A> Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 

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<A NAME="RD13702ST-9">9</A>

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.

<A NAME="RD13702ST-10">10</A>

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]

<A NAME="RD13702ST-11">11</A>

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.

<A NAME="RD13702ST-12">12</A>

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.

<A NAME="RD13702ST-13">13</A>

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.