Synthesis of DKPs and Screening against GPCR Targets
THF (10 mL) was added into the vial followed by addition of
methanol (10 mL) and water (10 mL). The vial was tightly sealed
and placed on a mechanical shaker. After 15 h, the resin was filtered
and washed with methanol and dichloromethane alternatively
(10 mL × 3) in a filtration tube equipped with frit and a stopcock.
A solution of acetic acid and water (1/1, v/v, 20 mL) was added to
mix with the resin in the filtration tube, and the cleavage solution
was collected into a vial. The AcOH/H2O cleavage step was
repeated three more times. All four cleavage solutions were
concentrated, dried on Genevac, and combined to give the final
product 29 as a yellow solid (260 mg, 93% yield).
Hz, 3H), 1.03 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.5, 170.9, 151.3, 146.5, 145.0, 130.1, 130.0, 129.6, 129.3,
125.1, 122.7, 117.6, 114.1, 67.1, 62.6, 62.4, 56.1, 56.0, 49.5, 36.4,
36.1, 27.2, 27.0, 24.1, 23.7, 21.8, 21.1; HRMS (CI/NH3) m/z calcd
for C30H36BrN3O3 565.1940, found 565.1954.
20
Homodimer 54: yield, 16%; oil, [R]D -94.0° (c 2.54, ethyl
acetate); IR (thin film) νmax 2959, 2926, 2855, 1680, 1453, 1380,
1321, 1240, 686 cm-1; H NMR (400 MHz, CDCl3) δ 7.35 (s,
1
(2S,5R,6R)-6-(4-(Furan-2-yl)phenyl)-5-methylpiperidine-2-
carboxylic acid 29: this compound was synthesized from cis-9a
using general procedures 3 and 4; yield 93% (two steps); yellow
2H), 7.33 (d, J ) 8.4 Hz, 2H), 7.20 (t, J ) 7.2 Hz, 2H), 7.08 (d,
J ) 7.2 Hz, 2H), 4.49 (d, J ) 6.4 Hz, 2H), 3.95 (dd, J ) 5.2, 13.2
Hz, 2H), 2.26-2.20 (m, 2H), 1.95-1.85 (m, 4H), 1.76-1.66 (m,
2H), 1.27-1.21 (m, 2H), 1.00 (d, J ) 6.4 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 171.3, 146.4, 130.4, 130.1, 129.4, 124.9, 122.7,
62.6, 56.2, 36.5, 27.3, 24.2, 21.0.
20
solid, mp 152-155 °C; [R]D -3.9° (c ) 0.45, MeOH); IR (thin
film) νmax 3416, 2928, 2818, 2555, 2361, 1615, 1396, 1277, 1010,
1
738 cm-1; H NMR (400 MHz, CD3OD) δ 7.76 (d, J ) 8.4 Hz,
2H), 7.58 (d, J ) 1.6 Hz, 1H), 7.53 (d, J ) 8.4 Hz, 2H), 6.84 (d,
J ) 3.6 Hz, 1H), 6.53 (dd, J ) 1.6, 3.6 Hz, 1H), 3.82 (d, J ) 10.8
Hz, 1H), 3.63 (dd, J ) 3.2, 12.8 Hz, 1H), 2.39-2.35 (m, 1H),
2.17-2.06 (m, 2H), 1.93-1.82 (m, 1H), 1.56-1.46 (m, 1H), 0.75
(d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 173.8, 154.5,
144.1, 136.0, 133.2, 130.2, 125.3, 113.1, 107.3, 67.6, 62.2, 35.0,
33.6, 27.9, 18.6; HRMS (CI/NH3) m/z calcd for C17H20NO3
286.1365, found 286.1401.
General Procedure 5. Hetero-cyclodimerization of Pipecolic
Acids 39 and 40: To remove the trace amounts of water/methanol,
pipecolic acids 39 and 40 were individually mixed with toluene
and concentrated on Genevac EZ-2 evaporator. Dry 39 (29.7 mg,
0.1 mmol) and 40 (30.4 mg, 0.1 mmol) were added to a 1-dram
vial. A 0.25 M solution of HATU in DMF (0.8 mL, 0.2 mmol)
and a 3 M solution of collidine in DMF (0.2 mL, 0.6 mmol) were
added. After stirring at room temperature for 19 h, the reaction
mixture was concentrated on a Genevac EZ-2 evaporator. The
residue obtained was treated with saturated aqueous ammonium
chloride solution (8 mL) and extracted with ethyl acetate (10 mL
× 3). The combined organic solution was washed with aqueous
saturated sodium bicarbonate (15 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated. The crude products were
separated by preparative HPLC (t ) 0 min, 80:20 water:acetonitrile
to t ) 10 min, 20:80 water:acetonitrile to t ) 20 min, 20:80 water:
acetonitrile; flow rate ) 10 mL/min) with MS/ELSD triggered
fraction collection. The desired fractions were concentrated in a
Genevac EZ-2 evaporator to afford heterodimer 53 (16 mg, 28%),
homodimers 54 (9 mg, 16%), and 55 (8 mg, 14%).
Homodimer 55: yield, 14%; oil; [R]D20 -25.8° (c 0.55, acetone);
IR (thin film) νmax 3476, 2959, 2850, 1673, 1600, 1453, 1377, 1239,
1
1119, 995, 777 cm-1; H NMR (400 MHz, CDCl3) δ 7.16 (t, J )
8.0 Hz, 2H), 6.75-6.73 (m, 4H), 6.64 (d, J ) 7.2 Hz, 2H), 4.76
(d, J ) 5.6 Hz, 2H), 4.04 (dd, J ) 4.8, 12.4 Hz, 2H), 3.79-3.76
(m, 8H), 3.10-3.07 (m, 8H), 2.23-2.16 (m, 2H), 2.14-2.07 (m,
2H), 1.99-1.81 (m, 4H), 1.29-1.20 (m, 2H), 1.08 (d, J ) 6.8 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 170.9, 151.4, 145.0, 129.4,
117.7, 113.9, 113.8, 67.1, 62.0, 55.8, 49.3, 35.9, 26.6, 23.1, 22.2;
HRMS (CI/NH3) m/z calcd for C34H45N4O4 573.3363, found
573.3497.
Acknowledgment. This work was generously supported by
NIGMS CMLD Initiative (P50 GM067041 J.A.P., Jr.), NIH
grants (B.L.R.), and the NIMH Psychoactive Drug Screening
Program (B.L.R.). We thank Dr. Emil Lobkovsky (Cornell
University) for X-ray crystal structure analysis, Mr. Chris
Singleton (Boston University) for assistance with NMR and LC-
MS, Ms. Lindsay Koblitz (Boston University) for providing anti-
1, and Professors John Snyder, Scott Schaus, and Dr. Sarathy
Kesavan (Boston University) for helpful discussions. We also
thank Waters Corporation, CEM Corporation, and Zinsser North
America for assistance with instrumentation.
Heterodimer 53: yield, 28%; oil, [R]D20 -71.2° (c 1.0, acetone);
IR (thin film) νmax 2958, 2854, 1652, 1600, 1492, 1383, 1263, 1172,
1
838 cm-1; H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.34 (d, J
Supporting Information Available: Experimental procedures,
compound characterization data, including X-ray crystal data for
33 (CIF), chromatographic separation of products of cyclodimer-
ization, and biological data for Figures 6 and 7. This material is
) 8.0 Hz, 1H), 7.24 (t, J ) 7.6 Hz, 1H), 7.14 (t, J ) 8.0 Hz, 1H),
7.08 (d, J ) 8.0 Hz, 1H), 6.79 (s, 1H), 6.76 (d, J ) 8.0 Hz, 1 H),
6.63 (d, J ) 7.2 Hz, 1H), 4.64 (d, J ) 6.8 Hz, 1H), 4.54 (d, J )
6.8 Hz, 1H), 4.01 (dd, J ) 3.2, 5.2 Hz, 1H), 3.98 (dd, J ) 3.2, 4.8
Hz, 1H), 3.83 (t, J ) 4.8 Hz, 4H), 3.14-3.12 (m, 4H), 2.27-2.17
(m, 3H), 2.00-1.89 (m, 4H), 1.85-1.71 (m, 3H), 1.06 (d, J ) 6.4
JO061758P
J. Org. Chem, Vol. 71, No. 23, 2006 8945