Synlett 2009(6): 991-993  
DOI: 10.1055/s-0028-1087964
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Scalable Synthesis of β-Amino Esters via Reformatsky Reaction with N-tert-Butanesulfinyl Imines

Kristin Brinner*, Brandon Doughan, Daniel J. Poon*
Novartis Institutes for Biomedical Research, 4560 Horton St., MS 4.5, Emeryville, CA 94608-2916, USA
Fax: +1(510)9233360; e-Mail: daniel.poon@novartis.com;
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Publikationsverlauf

Received 16 December 2008
Publikationsdatum:
16. März 2009 (online)

Abstract

The Reformatsky reagents derived from ethyl bromoacetate and tert-butyl bromoacetate add cleanly, in high yield, and with good diastereoselectivity to N-tert-butanesulfinyl aldimines and ketimines. Importantly, this reaction scales well (>50 mmol), and affords products upwards of 70% yield over three steps, starting from commercially available N-tert-butanesulfinamide, aldehydes, and ketones.

    References and Notes

  • 1 Davies SG. Smith AD. Price PD. Tetrahedron: Asymmetry  2005,  16:  2833 
  • 2a Brinner K. Ellman JA. Enantioselective Synthesis of β-Amino Acids   Juaristi E. Soloshonok VA. Wiley and Sons; Hoboken: 2005. 
  • 2b Cole DC. Tetrahedron  1994,  50:  9517 
  • 2c Juaristi E. Lopez-Ruiz H. Curr. Med. Chem.  1999,  6:  983 
  • 2d Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1:  1 
  • 2e Hart DJ. Ha DC. Chem. Rev.  1989,  89:  1447 
  • 3 Ishitani H. Ueno M. Kobayashi S. J. Am. Chem. Soc.  2000,  122:  8180 
  • 4 Davis FA. Szewczyk JM. Reddy RE. J. Org. Chem.  1996,  61:  2222 ; and references cited therein
  • 5 Tang TP. Ellman JA. J. Org. Chem.  2002,  67:  7819 ; and references cited therein
  • 6 Clark JD. Weisenburger GA. Anderson DK. Colson P.-J. Edney AD. Gallagher DJ. Kleine HP. Knable CM. Lantz MK. Moore CMV. Murphy JB. Rogers TE. Ruminsky PG. Shah AS. Storer N. Wise BE. Org. Process Res. Dev.  2004,  8:  51 
  • 7 Staas DD. Savage KL. Homnick CF. Tsou NN. Ball RG. J. Org. Chem.  2002,  67:  8276 
  • 8 Koizumi T. Hirai H. Yoshii E. J. Org. Chem.  1982,  47:  4004 
  • 9 Graf E. Boeddeker H. Justus Liebigs Ann. Chem.  1958,  613:  111 
  • 15 Perrin DD. Armarego WLF. Perrin DR. Purification of Laboratory Chemicals   2nd ed.:  Pergamon; Oxford: 1980.  p.547 
  • 16 Fürstner A. In Organozinc Reagents: A Practical Approach   Knochel P. Jones P. The Practical Approaches in Chemistry Series, Oxford University Press; Oxford: 1999.  p.287 
  • 17 Liu G. Cogan DA. Owens TD. Tang TP. Ellman JA. J. Org. Chem.  1999,  64:  1278 
10

Acros: (S)-3-amino-3-phenylpropionic acid ethyl ester hydrochloride; CAS 167834-24-4.

11

Preparation of Zn/Cu
Large-scale reactions require the preparation of Zn as previously described. [¹5] [¹6] The zinc was then thoroughly dried in a vacuum oven at 70 ˚C for at least 24 h. The dried Zn dust and CuCl were then combined in appropriate amounts in a dry mortar, ground to a fine powder, then transferred to the reaction vessel.

12

Compound 2
A three-necked 1 L round-bottom flask, reflux condenser, and addition funnel were oven-dried overnight, assembled with a mechanical stirrer under positive argon pressure and allowed cool to r.t. The flask was charged with Zn dust (31.3 g, 478 mmol, 10 equiv) and CuCl (4.7 g, 47.8 mmol, 1.0 equiv). The two solids were mixed under a slow stream of nitrogen while the flask was dried with a flame. The flask was allowed to cool to r.t. and dry THF (100 mL) was added to produce a dark slurry. The resulting reaction mixture was heated to reflux temperature and stirred vigorously for 30 min. The heating bath was then removed while maintaining vigorous stirring, and the addition funnel was then charged with ethyl bromoacetate (17.7 mL, 119.5 mmol, 2.5 equiv) and dry THF (44 mL). CAUTION: EXOTHERMIC REACTION. The ethyl bromoacetate solution was slowly and carefully added dropwise until reflux was re-initiated. The addition was continued at a rate that maintained a controllable reflux. Once addition was complete, the reaction mixture was stirred for an additional 30 min at ambient temperature, then at 50 ˚C for 30 min. The reaction mixture was then cooled to 0 ˚C, and the addition funnel charged with N-tert-butanesulfinyl benzaldimine (1, prepared as previously described, [¹7] 10.0 g, 47.8 mmol. 1.0 equiv) and dry THF (50 mL). This solution was then added dropwise to the reaction mixture, which was stirred for an additional 4 h at 0 ˚C. The reaction mixture was filtered through a pad of Celite, washing the Zn and the filter pad with Et2O (2 × 100 mL). The filtrate was washed with 0.25 M aq citric acid (200 mL), sat. aq NaHCO3 (2 × 200 mL), sat. aq NaCl (1 × 100 mL), dried (Na2SO4), and concentrated in vacuo to afford the N-tert-butanesulfinyl-protected β-amino ester (13.8 g, 46.5 mmol, 97%) as a clear oil that solidified upon standing. ¹H NMR (300 MHz,CDCl3): δ = 7.34-7.26 (m, 5 H), 4.78 (m, 1 H), 4.69 (m, 1 H), 4.09 (q, J = 6.9 Hz, 2 H), 2.86 (d, J = 6.3 Hz, 2 H), 1.25 (m, 12 H). ¹³C NMR (75.5 MHz, CDCl3): δ = 171.5, 140.9, 128.8, 128.2, 127.5, 61.1, 55.9, 42.5, 22.8, 14.3. ESI-LR: m/z calcd for C15H23NO3S [M + H]+: 298.1; found: 298.0.

13

Compound 3
A 500 mL round-bottom flask was charged with compound 2 (13.0 g, 43 mmol), EtOH (48 mL, 1.1 equiv), and 1 M HCl in Et2O (87 mL, 87 mmol, 2.0 equiv). The reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo, the resultant residue dissolved in 100 mL 0.1 M aq HCl. The solution was washed with Et2O (100 mL) and hexanes (100 mL), and aqueous layer was basified to pH = 9 by the addition of solid Na2CO3. The solution was extracted with EtOAc (2 × 100 mL), washed with brine (1 × 100 mL), the organics dried (Na2SO4), and concentrated to afford (S)-3-amino-3-phenylpropionic acid ethyl ester (3) as a colorless oil (6.05 g, 31.4 mmol, 73%). ¹H NMR (300 MHz, CDCl3): δ = 7.33-7.23 (m, 5 H), 4.41 (dd, J = 7.0 Hz, 6.7, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 2.64 (d, J = 6.7 Hz, 2 H), 1.92 (br s, 2 H), 1.23 (3 H, J = 7.0 Hz, 3 H). ¹³C NMR (300 MHz, CDCl3): δ = 172.2, 144.8, 128.8, 127.6, 126.4, 66.7, 52.8, 44.4, 14.4. [α]D ²² -3.8 (c 1.0, EtOH); lit. [α]D ²² -2.4
(c 0.13, EtOH) [8] ; [α]D ²² -3.6 (c 1.0, EtOH). [9]

14

Synthesis of Authentic Diastereomeric Mixtures
The crude reaction material of N-sulfinyl β-amino ester products (5 mg) was dissolved in EtOH (0.5 mL) and 1.0 M HCl in Et2O (0.5 mL). After stirring at r.t. for 1 h, the reaction was concentrated, the residue dissolved in EtOH (2 mL), and concentrated again. The crude β-amino ester was then dissolved in CH2Cl2 (1.0 mL) and DIPEA (0.3 mL), and racemic tert-butanesulfinyl chloride (0.15 mL) was added. The reaction was stirred overnight, then concentrated, and filtered through a short SiO2 column (EtOAc-hexanes, 3:1). The products were resolved by LC-MS and HPLC (20-70% MeCN, 10 min).