Scheme 1: Synthesis of DKP's using glycine and proline.
Experimental Data
1) Glycine methyl ester hydrochloride
The glycine (1.31g, 17.3 mmol) and methanol (20 mL) were added to a culture tube equipped
with a magnetic stirrer and cooled to 0C. Trimethylsilyl chloride (4.38 mL, 34.5 mmol) was
slowly added and stirred at room temperature and a glass tube was sealed with a Teflon lined
cap, and stirred for 48 hrs. After the completion of reaction was monitored by TLC, glycine
(1.31 g, 17.3 mmol) was used to yield 1-a (1.67 g, 13.3 mmol, 77%) as white crystals. R.
=0.48 in 17:2:1 (CHC l3: MeOH: AcOH) on silica plate, Melting point: 172~174C,
literature melting point: 175C, 'H NMR (300 MHz,DO ) 8 3.90 (s, 2H), 3.80 (s,
3H,-OC H3 ).
6) Proline methyl ester hydrochloride
2) Procedure for Z-Proline
NaOH (0.759 g, 18.9 mmol) was added to an aqueous suspension (10 mL) of one equivalent
of proline (0.728 g, 6.32 mmol). The solution was cooled to 0 C followed by the dropwise
addition of a solution of benzyl chloroformate (1.18 mL, 8.22 mmol) in 1,4-dioxane (10 mL)
The reaction mixture was stirred at room temperature overnight. Once reaction progress was
confirmed by TLC, the mixture was extracted with Et,O(3 x 10 mL) with the organic
phases being discarded. The aqueous phase was cooled to 0 C, acidified to a pH of 2 using
1M citric acid, and then extracted with DCM (3 x 20 mL). The DCM layers were combined,
washed with brine (l x 15 mL), dried with anhydrous MgSO4 , gravitation filtered, and
concentrated in vacuo to yield 2 (0.709 g, 2.84 mmol, 45%) as a viscous and colorless oil
R,=0.75 in CMA on silica; 'H NMR (300 MHz, CDCl3 ) 8 10.46 (s,1H,OH),7.40
(HZw) ZE'8-+9e(HI zH E'L=f 9) LZ't-6tt(HZZH 0'L=f p) EI'S(HSw) LZL
2.39 - 2.09 (m, 2H), 2.03 - 1.83 (m, 2H). IR (NaCl,cm-1 ) v 3035 (w, OH), 2960 (s), 2890
(w), 1750 (s, CO), 1705 (s, CO), 1420 (s), 1360 (m), 1180 (m), 1120 (s), 915 (s), 745 (s)
7) Z-Glycine
Given
EDCI coupling
3) Z-proline-glycine-methyl ester
Z-Pro-OH (0.209 g, 0.838 mmol) and glycine methyl hydrochloride (0.123 g, 9.80 mmol) and
dichloromethane (20 mL) were added in a round bottom flask. The reaction mixture was
chilled in an ice-bath followed by EDCI (0.178 g, 0.922 mmol), and triethylamine (0.15 mL,
1.01- mmol). The round flask was sealed and stirred for 48h at room temperature. The
completion of reaction mixture was confirmed by TLC. Mixture was transferred to a
separatory funnel and diluted with dichloromethane (20.5 mL) and washed with 1M citric
acid (3x15 mL). The organic phase was washed with brine, dried with 6.0 g of anhydrous
MgS O4 , filtered, and concentrated in vacuo to yield 3 (0.131 g, 0.431 mmol, 51%) as a
colorless oil. 'H NMR (300 MHz,CDCls ) 8 7.27 - 7.34 (m, 5H), 6.39 (br s, 1H, NH),
5.18 (s, 2H), 3.92 (t, J = 27 Hz, 1H), 3.73 (s