Convenient Synthesis and Isolation of 1-Aminocyclopropane-1-carboxylic Acid (ACC) and N-Protected ACC Derivatives

Abstract

A convenient route to 1-aminocyclopropane-1-carboxyl­ic acid (1, ACC) and N-protected derivatives was developed. This route utilizes a bisalkylation of an O-benzyl glycine derived imine followed by global deprotection via hydrogenation. Direct isolation of ACC from a non-aqueous stream or efficient conversion to N-protected derivatives in a single flask is described.

Key words

amino acids - imine alkylation - intramolecular alkyl­ation - hydrogenation

References

• 1a Yang SF. Hoffman NE. Annu. Rev. Plant Physiol.  1984,  35:  155 
• 1b Pirrung MC. Cao J. Chen J. J. Org. Chem.  1995,  60:  5790 
• 2 Evano G. Schaus JV. Panek JS. Org. Lett.  2004,  6:  525 
• 3a Ichihara A. Shiraishi K. Sakamura S. Tetrahedron Lett.  1977,  269 
• 3b Nara S. Toshima H. Ichihara A. Tetrahedron  1997,  53:  9509 
• 3c Braslau R. Anderson MO. Tetrahedron Lett.  1998,  39:  4227 
• 4a Walsh CT. Pascal RA. Johnston M. Raines R. Dikshit D. Krantz A. Honma M. Biochemistry  1981,  20:  7509 
• 4b Chu DTW. Claiborne AK. Clement JJ. Plattner JJ. Can. J. Chem.  1992,  70:  1328 
• 5a Spadoni G. Balsamini C. Bedini A. Il Farmaco  1993,  48:  1663 
• 5b Berkowitz DB. Pedersen ML. J. Org. Chem.  1994,  59:  5476 
• 6a Rich DH. Tam JP. Synthesis  1978,  46 
• 6b Fadel A. Tetrahedron  1991,  47:  6265 
• 6c Zhu X. Gan P. Synth. Commun.  1998,  28:  3159 
• 6d Strazewski P. Tamm C. Synthesis  1987,  298 
• 6e O’Donnell MJ. Bruder WA. Eckrich TM. Shullenberger DF. Staten GS. Synthesis  1984,  127 
• 7 O’Donnell MJ. Aldrichimica Acta  2001,  34:  3 
• 8 O’Donnell MJ. Polt RL. J. Org. Chem.  1982,  47:  2663 
• 9 Jabin I. Monnier-Benoit N. Gac SL. Netchitailo P. Tetrahedron Lett.  2003,  44:  611 
• 11a

  in the heterogeneous bisalkylation, surface area and particle size of the KOH appeared to be a key variable.

• 11b

  Pulverized KOH was obtained by running KOH flakes in a food processor for 2 min in a N₂ filled glove bag to achieve a powder.

• 16a The N-acylation to give 5a,b, and 5d from the crude ACC stream followed: Paquet A. Can. J. Chem.  1982,  60:  976 
• 16b

  Isolated materials matched the literature by ¹H NMR and ¹³C NMR (see ref.^18,19).

• 18 Chu DTW. Claiborne AK. Clement JJ. Plattner JJ. Can. J. Chem.  1992,  70:  1328 
• 19 Pirrung MC. Cao J. Chen J. J. Org. Chem.  1995,  60:  5790 

10

The elimination by-product is shown in Scheme [3] .

Scheme 3

12

A representative procedure for the bisalkylation to 4 is as follows: To a 1 L round bottom flask containing NMP (300 mL) was charged(diphenylmethylene)-glycine benzyl ester (25.0 g, 76.0 mmol) and cooled to -5 °C. 1-Bromo-2-chloroethane (6.90 mL, 83.6 mmol) was added followed by portionwise addition of pulverized KOH (5 × 4.27 g, 380 mmol). The resulting orange slurry was aged for 9 h at -5 °C at which time <0.5% starting material remained. The reaction was then diluted with cold (2 °C) toluene (270 mL) and quenched with H₂O (250 mL). The organic layer was separated and washed with H₂O (2 ¥ 250 mL). Concentration and recrystallization from a heptane-toluene (9:1) solution gave 49.3 g (65%) of a white crystalline solid. Mother liquor losses accounted for 12% of 4, mp 50 °C. ¹H NMR (300 MHz, CDCl₃): d = 7.66-7.64 (m, 2 H), 7.44-7.27 (m, 11 H), 7.22-7.18 (m, 2 H), 4.97 (s, 2 H), 1.56 (dd, J = 7.5, 4.2 Hz, 2 H), 1.21 (dd, J = 7.5, 4.2 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): d = 174.7, 172.3, 140.1, 137.8, 135.9, 130.6, 129.0, 128.8, 128.6, 128.3, 128.2, 128.1, 66.5, 45.4, 20.5.

13

Detected by crude NMR.

14

Water content determined by coulometric Karl Fischer titration with Metrohm 756 titrator.

15

Attempts to bisalkylate the corresponding benzaldehyde imine failed. This route would have been advantageous in the hydrogenation step by generating a single inert by-product, toluene.

17

A representative procedure for the hydrogenation and in situ N-protection to 5c is as follows: A 500 mL Parr hydro-genation vessel was charged with [(diphenylmethyl-ene)amino]cyclopropyl benzyl ester (4, 50.0 g, 141 mmol) followed by MeOH (300 mL) and wet Pd(OH)₂/C (12.5 g, 20 wt.% Pd). The mixture was shaken under 40 psi of H₂ for 1.5 h then assayed to show quantitative formation of toluene and diphenylmethane. The crude ACC stream was charged with MeOH (36 mL), ethyl trifluoroacetate (50.4 mL, 422 mmol) and Et₃N (58.8 mL, 422 mmol) and heated to 50 °C for 3 h. The slurry was cooled to r.t., filtered through a pad of solka floc, and concentrated. The resulting residue was treated with HCl (3 M, 166 mL), stirred for 30 min and washed with heptane (3 × 140 mL). This removes the diphenylmethane by-product. The aqueous solution was saturated with NaCl and the TFA-ACC was extracted with i-PrOAc (3 × 140 mL). The combined TFA-ACC extracts were concentrated while adding heptane to 144 mg/mL. Concentration and crystallization from heptane-i-PrOAc (8:1) gave 22.2 g (80%, 113 mmol) of TFA-ACC(5c) as a white crystalline solid, mp 174 °C. ¹H NMR (300 MHz, CDCl₃): δ = 12.74 (s, 1 H), 9.91 (s, 1 H), 1.37 (dd, J = 7.8, 4.5 Hz, 2 H), 1.09 (dd, J = 7.8, 4.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.8, 157.8 (t, J = 36 Hz, 1C), 116.3 (t, J = 293 Hz, 1 C), 118.2, 114.3, 33.2, 16.5. ¹⁹F NMR: δ = -75.0.