Asymmetric Carbonyl Migration of α-Amino Acid Derivatives via Memory of Chirality

Abstract

N-tert-Butoxycarbonylcarbamates of α-amino acid derivatives underwent asymmetric carbonyl migration by treatment with KHMDS in DMF to give α-amino acid derivatives with an additional ester group at the newly formed tetrasubstituted carbon center in up to 99% ee.

Key words

amino acids - chirality - stereoselectivity - tetrasubstituted carbon - carbonyl migration

References and Notes

• For asymmetric intermolecular alkylation via memory of chirality, see:
• 1a Kawabata T. Yahiro K. Fuji K. J. Am. Chem. Soc.  1991,  113:  9694 
• 1b Kawabata T. Wirth T. Yahiro K. Suzuki H. Fuji K. J. Am. Chem. Soc.  1994,  116:  10809 
• 1c Kawabata T. Suzuki H. Nagae Y. Fuji K. Angew. Chem. Int. Ed.  2000,  39:  2155 
• For asymmetric intramolecular alkylation via memory of chirality, see:
• 2a Kawabata T. Kawakami S. Majumdar S. J. Am. Chem. Soc.  2003,  125:  13012 
• 2b Kawabata T. Matsuda S. Kawakami S. Monguchi D. Moriyama K.
  J. Am. Chem. Soc.  2006,  128:  15394 
• 2c Kawabata T. Moriyama K. Kawakami S. Tsubaki K. J. Am. Chem. Soc.  2008,  130:  4153 
• 3 For asymmetric intramolecular conjugate addition via memory of chirality, see: Kawabata T. Majuumdar S. Tsubaki K. Monguchi D. Org. Biomol. Chem.  2005,  3:  1609 
• 4 For Dieckmann condensation via memory of chirality, see: Watanabe T. Kawabata T. Heterocycles  2008,  76:  1593 
• For recent reviews on asymmetric synthesis via memory of chirality see:
• 5a Kawabata T. Fuji K. Top. Stereochem.  2003,  53:  175 
• 5b Zhao H. Hsu D. Carlier PR. Synthesis  2005,  1 
• 5c Kawabata T. Asymmetric Synthesis and Application of α-Amino Acids   ACS Symposium Series 1009:  American Chemical Society; Washington DC: 2009.  p.31-56  
• 6 Basel Y. Hassner A. J. Org. Chem.  2000,  65:  6368 
• 7 Brunner M. Saarenketo P. Straub T. Rissanen K. Koskinen AMP. Eur. J. Org. Chem.  2004,  3879 
• 10a Mermerian AH. Fu GC. J. Am. Chem. Soc.  2003,  125:  4050 
• 10b Shaw SA. Aleman P. Vedejs E. J. Am. Chem. Soc.  2003,  125:  13368 
• 10c Shaw SA. Aleman P. Christy J. Kampf JW. Va P. Vedejs E. J. Am. Chem. Soc.  2006,  128:  925 
• 11a Takayama E. Nanbara S. Nakai T. Chem. Lett.  2006,  35:  478 
• 11b Takayama E. Kimura H. Angew. Chem. Int. Ed.  2007,  46:  8869 

8

The most stable conformer B was generated by a molecular modeling search (MCMM 50,000 steps) with OPLS 2005 force field and GB/SA solvation model for chloroform using MacroModel (V. 9.0); see Supporting Information.

9

The possibility that the present asymmetric migration proceeds without the intervention of an axially chiral enolate cannot be excluded. Alternative route may involve a concerted S_Ei process. This route was excluded by the experimental results in the case of asymmetric cyclization shown in Scheme  [5] (refs. 2a and 2c). By analogy, we assume that the present asymmetric carbonyl migration would proceed through an axially chiral enolate intermediate.

12

One-Pot Procedure for 2a (Table 2): A solution of Boc₂O (105 mg, 0.48 mmol) in DMF (1.0 mL) was added to a solution of 3 (R = Bn; 120 mg, 0.40 mmol) and DMAP (5.0 mg, 0.04 mmol) in DMF (4.1 mL) at r.t. After being stirred for 30 min, the mixture was cooled to -60 ˚C, KHMDS (0.47 M in THF solution, 1.3 mL, 0.60 mmol) was added dropwise to the mixture. The reaction mixture was stirred at -60 ˚C for 3 h and then poured into sat. aq NH₄Cl and extracted with EtOAc. The combined organic layers were washed with sat. aq NaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated in vacuo. The residue was purified by preparative TLC (SiO₂, hexane-EtOAc = 9:1) to give (R)-2a (82 mg, 53%, 98% ee) as a colorless oil.
HPLC conditions: Daicel Chiralpak OJ-H; hexane-i-PrOH, 9:1; flow 0.5 mL/min; t _R = 8.4 (R), t _R = 9.9 (S); [α]_D ^²5 +2.6 (c = 2.1, CDCl₃). ^¹H NMR (600 MHz, CDCl₃): δ = 7.33-7.38 (m, 5 H), 7.17-7.24 (m, 5 H), 5.91 (ddt, J = 15.1, 9.6, 5.5 Hz, 1 H), 5.20 (d, J = 15.1 Hz, 1 H), 5.16 (ABq, J _AB = 12.3 Hz, Δν = 10.6 Hz, 2 H), 5.08 (d, J = 9.6 Hz, 1 H), 3.22-3.29 (m, 1 H), 3.26 (ABq, J _AB = 14.4 Hz, Δν = 18.4 Hz, 2 H), 3.19 (dd, J = 13.1, 5.5 Hz, 1 H), 1.29 (s, 9 H). ^¹³C NMR (150 MHz, CDCl₃): δ = 170.1, 168.5, 135.9, 135.7, 135.2, 130.3, 128.9, 128.53, 128.49, 127.9, 126.8, 116.1, 82.6, 70.8, 67.1, 45.9, 36.8, 27.7. IR (CDCl₃): 1728, 1456, 1369, 1190, 1151 cm^-¹. ESI-MS (+): m/z = 418 [M + Na], 340, 278, 204. HRMS: m/z calcd for C₂₄H₂₉NO₄Na: 418.1994; found: 418.1953.