Diastereoselective Synthesis of 3-Phosphonomethyl-substituted Cyclohexyl- and Cyclohex-2-enylglycines

Abstract

Regio- and stereoselective 1,6-additions of lithium azaenolate derived from cyclo-[l-tert-Leu-Gly] 2 to (1E)- and (1Z)-cyclohex-2-enylidenemethyl phosphonates 3a,b and 4a,b allow a direct access to optically pure 3-phosphonomethyl-substituted cyclohexyl- and cyclohex-2-enylglycines 13A-C, 14A,B, 15A-C and 16A,B. Ten-membered ‘compact’ and ‘relaxed’ transition-state structures account for the stereochemical outcome of the conjugate additions.

Key words

cyclohexylglycines - phosphono α-amino acids - conjugate addition - stereoselectivity - 1,3-dienylphosphonates

References

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1

New address: S. Conde, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.

13

All new compounds have been isolated in a pure analytical form after chromatography (on SiO₂ or RP-18), and their spectral data (IR, FABMS and NMR) were consistent with the proposed structures.

14

The relative configurations of the vinylphosphonates can be deduced from the ⁴ JC-P observed in their ¹³C NMR spectra, due to the coupling of C-2′ with the phosphorous atom at β position. Thus, for 6a,b and 3a,b, ⁴ JC2′-P(trans) values range from 27.2-27.7 Hz, which are characteristic for the vinylphosphonates with a (E)-configuration. Conversely, for 7a,b and 4a,b, with a (Z)-configuration, ⁴ JC2′-P(cis) values range from 6.4-9.2 Hz.

15

Multigram quantities of (2S)-2-tert-butyl-3,6-dietoxy-2,5-dihydropyrazine were obtained from Novartis Kilo Laboratory. When (2S)-2,5-dihydro-3,6-dimetoxy-2-isopropylpyrazine (available from Fluka and Merck) was used for the reaction with 3a,b and 4a,b, analogous yields and selectivities were obtained. The excess of Schöllkopf’s reagent could be almost completely recovered, and showed no racemization.

18

Selected data for the cyclohexylglycines: 13A: [α]_D ²³ +10.1 (c = 2.3, H₂O); ¹H NMR (200 MHz, D₂O) δ: 1.06-1.93 (6 H, m); 2.18 (2 H, br d, J = 21.4 Hz, CH₂P); 2.55-2.75 (1 H, m, H1′); 3.44 (1 H, d, J = 3.7 Hz, H2); 4.97-5.01 (1 H, m, H2′); ³¹P NMR (81 MHz, D₂O) δ: 22.03; ¹³C NMR (60 MHz, D₂O) δ: 22.5, 26.5, 29.8, 38.2, 39.1 (d, J = 137 Hz), 59.5, 121.5 (d, J = 11.6 Hz), 139.2 (d, J = 10.3 Hz), 175.2. 13B: [α]_D ²⁷ +14.5 (c = 1.0, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.83 (3 H, d, J = 7.3 Hz, CH₃); 1.00-1.15 (1 H, m); 1.40-1.55 (1 H, m); 1.70-2.10 (3 H, m); 2.21 (2 H, d, J = 20.7 Hz, H2); 2.62-2.79 (1 H, m), 3.59 (1 H, d, J = 3.1 Hz, H2); 5.01-5.09 (1 H, m, H2′); ³¹P NMR (81 MHz, D₂O) δ: 21.15. 13C: [α]_D ²⁷ +11.7 (c = 1.1, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.83 (3 H, d, J = 7.3 Hz, CH₃); 1.00-1.61 (3 H, m); 1.70-2.39 (5 H, m); 3.70 (1 H, d, J = 2.4 Hz, H2); 4.85-4.93 (1 H, m, H2′); ³¹P NMR (81 MHz, D₂O) δ: 21.31. 14A: [α]_D ²⁴ +31.5 (c = 2.3, H₂O); ¹H NMR (200 MHz, D₂O) δ: 1.10-1.93 (6 H, m, CH₂); 2.05-2.35 (2 H, m, CH₂P); 2.61-2.79 (1 H, m, H1′); 3.57 (1 H, d, J = 3.0 Hz, H2); 5.00-5.08 (1 H, m, H2′); ³¹P NMR (81 MHz, D₂O) δ: 19.27. 14B: [α]_D ²⁶ +14.7 (c = 1.0, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.83 (3 H, d, J = 7.3 Hz, CH₃); 1.05-2.39 (8 H, m); 3.70 (1 H, d, J = 3.2 Hz, H2); 4.85-4.93 (1 H, m, H2′); ³¹P NMR (81 MHz, D₂O) δ: 21.21. HCl·15A: [α]_D ²⁶ -19.1 (c = 0.5, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.65-0.98 (3 H, m); 1.00-1.22 (1 H, m); 2.55-2.75 (1 H, m, H1Ž); 1.24-1.70 (7 H, m); 1.72-1.92 (1 H, m); 3.71 (1 H, d, J = 4.3 Hz, H2); ³¹P NMR (81 MHz, D₂O) δ: 31.14; ¹³C NMR (60 MHz, D₂O) δ: 25.9, 28.3, 33.4, 33.9 (d, J = 10.3 Hz), 34.6 (d, J = 133 Hz), 36.1 (d, J = 7.9 Hz), 39.2 (d, J = 1.6 Hz), 58.6, 172.4. HCl·15B: [α]_D ²⁴ +9.4 (c = 1.0, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.76 (3 H, d, J = 6.1 Hz, CH₃); 0.78-1.27 (3 H, m); 1.41-1.75 (9 H, m); 4.10 (1 H, d, J = 2.4 Hz, H2); ³¹P NMR (81 MHz, D₂O) δ: 30.48. HCl·15C: [α]_D ²⁴ +3.4 (c = 1.3, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.78 (3 H, d, J = 6.8 Hz, CH₃); 0.80-1.31 (3 H, m); 1.42-1.78 (9 H, m); 4.12 (1 H, d, J = 2.5 Hz, H2); ³¹P NMR (81 MHz, D₂O) δ: 30.47. HCl·16A: [α]_D ²⁴ +10.4 (c = 0.8, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.60-1.20 (5 H, m); 1.30-1.91 (10 H, m); 3.69 (1 H, d, J = 14.0 Hz, H2); ³¹P NMR (81 MHz, D₂O) δ: 30.35. HCl·16B: [α]_D ²⁸ +31.2 (c = 0.7, H₂O); ¹H NMR (200 MHz, D₂O) δ: 0.79 (3 H, d, J = 7.1 Hz, CH₃); 0.71-1.33 (3 H, m); 1.43-1.80 (9 H, m); 4.13 (1 H, d, J = 2.9 Hz, H2); ³¹P NMR (81 MHz, D₂O) δ: 30.45.

21

We have utilised the ONIOM method developed by Morokuma et al. [22] as implemented in the Gaussian 98 program package, revision A.11. Density functional theory treatment was reduced to an inner model constituted by lithiated dihydropyrazinone and butadienylphosphonic acid in the presence of two water molecules. Ethyl groups were replaced by methyl ones in the complete models.

23

Most stable disolvated TSs located at the ONIOM[B3LYP/6-31G (d):PM3] level of theory for the addition of 2 to (4R)-4b and (4S)-4b are shown in Figure [2] .