Synthesis of Chiral, Chelating Ligands
301
temperature, and then filtered and washed with dilute acid fol-
lowed by distilled water. The product was purified by silica gel
chromatography (CH2Cl2/MeOH, 96/4). Yield: 40–60% after
chromatography.
2.86 (s, 3H, NMe), 1.49 (m, 6H, CHMe2 and CHCH2CH),
3
3
0.77 (d, 6H, J 10, CHCH3), 0.74 (d, 6H, J 10, CHCH3). δC
(75 MHz, 298 K, D2O) 177.7 (COOH), 164.8 (CONH), 56.8
(MeNCH2), 52.9 (NHCH), 42.8 (NMe), 39.7 (CHCH2CH),
24.5 (CHMe2), 22.2 (CHCH3), 20.6 (CHCH3). m/z (ESI+) 769
[2M + Na], 747 [2M + H], 396 [M + Na], 374 [M + H]. Calc.
for C17H31N3O6Na: 396.2111 [M + Na]. Found: 396.2116.
MIDA-[Phe(OH)]2: νmax/cm−1 (CsF) 1667. δH (400 MHz,
298 K, (D6)DMSO) 8.25 (br, 2H, NH), 7.20 (m, 10H, C6H5),
4.50 (ddd, 3J 9.0, 3J 9.0, 3J 4.8, 2H, NHCH), 3.11 (dd, 2H, 2J
NTA-[Gly(OMe)]3: δH (500 MHz, 298 K, CDCl3) 7.77 (br
3
3
t, 3H, J 3.4, NH), 4.04 (d, 6H, J 3.6, NHCH2), 3.71 (s, 9H,
OMe), 3.39 (s, 6H, NCH2). δH (500 MHz, 298 K, D2O) 3.98
(s, 6H, NHCH2), 3.67 (s, 9H, OMe), 3.44 (s, 6H, NCH2). δC
(125 MHz, 298 K, CDCl3) 171.2 (COOMe), 170.9 (NHCO),
58.7 (NCH2), 52.4 (COOCH3), 40.8 (NHCH2). δC (125 MHz,
298 K, D2O) 173.1 (COOMe), 171.4 (NHCO), 57.1 (NCH2),
52.3 (COOCH3), 40.5 (NHCH2). m/z 427 [M + Na].
3
2
13.8, J 4.8, CH2Ph), 3.01 (br, 4H, NCH2), 2.91 (dd, 2H, J
13.8, 3J 9.7, CH2Ph), 2.03 (br s, NMe) (COOH not observed).
δC (100 MHz, 298 K, (D6)DMSO) 172.9 (CONH), 169.2 (br,
COOH), 137.7 (ipso-C of C6H5), 129.2, 128.3, 126.5 (ortho,
meta, para-C of C6H5), 59.9 (br, NCH2), 53.2 (NHCH), 42.2
(NMe), 36.6 (CH2Ph). m/z (ESI+) 442.2 [M + H]. Calc. for
C23H28N3O6: 442.1973 [M + H]. Found: 442.1965.
NTA-[Phe(OMe)]3 (Mixture of Diastereomers):[15] νmax
/
cm−1 (CH2Cl2 solution): νCO 1738, 1680. δH (300 MHz, 298 K,
CDCl3) 7.36–7.08 (m, 18H, NH and C6H5), 4.79 (m, 3H,
NHCH), 3.72 (s, 9H, OMe), 3.25–2.90 (m, 12H, CH2Ph and
NCH2). m/z (ESI+) 697 [M + Na], 675 [M + H]. Calc. for
C36H42N4O9Na [M + Na]: 697.2849. Found: 697.2839.
NTA-[Gly(OH)]3: νmax/cm−1 (THF) 1752, 1684. δH
(300 MHz, 298 K, D2O) 3.92 (s, 6H, NHCH2), 3.50 (s, 6H,
NCH2) (COOH not observed). m/z (ESI+) 385 [M + Na].
NTA-[Leu(OH)]3: δH (500 MHz, 298 K, D2O) 7.32 (m, 3H,
NH), 4.31 (m, 3H, NHCH), 3.39 (s, 6H, NCH2), 1.62–1.52 (m,
9H, CHMe2 and CHCH2CH), 0.83 (d, 9H, 3J 3.6, CHCH3), 0.79
NTA-[Leu(OMe)]3: νmax/cm−1 (MeOH solution): νCO 1749,
1664. δH (300 MHz, 298 K, CDCl3) 7.71 (br d, 3H, 3J 8.5, NH),
2
4.60 (m, 3H, NHCH), 3.71 (s, 9H, OMe), 3.41 (d, 3H, J 15,
NCH2), 3.20 (d, 3H, 2J 15, NCH2), 1.74–1.56 (m, 9H, CHMe2
and CHCH2CH), 0.92 (d, 9H, 3J 2.4, CHCH3), 0.90 (d, 9H, 3J
2.3, CHCH3). δC (75 MHz, 298 K, CDCl3) 174.9 (COOMe),
170.5 (CONH), 58.2 (NCH2), 52.4 (OMe), 50.6 (NHCH), 40.3
(CHCH2CH), 24.8 (CHMe2), 23.0 (CHCH3), 21.3 (CHCH3).
m/z (ESI+) 1167 [2M + Na], 1145 [2M + H], 595 [M + Na], 573
[M + H]. Calc. for C27H48N4O9Na [M + Na]: 595.3319. Found:
595.3306.
3
(d, 9H, J 3.5, CHCH3) (COOH not observed). δC (125 MHz,
298 K, D2O) 176.3 (COOH), 172.7 (CONH), 57.7 (NCH2),
51.4 (NHCH), 39.3 (CHCH3H2CH), 24.4 (CH3HMe2), 22.2
(CHCH3), 20.4 (CHCH3). m/z (TOF+) 531 [M + H].
NTA-[Phe(OH)]3: νmax/cm−1 (CsF) 1659. δH (400 MHz,
298 K, (D6)acetone) 8.1 (br, not integrated, NH), 7.23–7.08 (m,
15H, C6H5), 4.67 (dd, 3H, 3J 9.6, 3J 4.5, NHCH), 3.19 (dd, 3H,
2J13.9, 3J4.5, CH2Ph), 2.91(m, 9H, CH2PhandNCH2)(COOH
not observed). δH (400 MHz, 298 K, (D6)DMSO) 8.32 (br, 3H,
NH), 7.22–7.12 (m, 15H, C6H5), 4.54 (br dd, 3H, NHCH), 3.12
(dd, 3H, 2J13.7, 3J4.3, CH2Ph), 2.87(br, 9H, NCH2 andCH2Ph)
(COOH not observed). δH (400 MHz, 298 K, D2O) 7.22 (m,
NTA-[Asp(OMe)(OMe)]3: νmax/cm−1 (CH2Cl2 solution):
3
νCO 1737, 1681. δH (500 MHz, 298 K, CDCl3) 7.72 (d, 3H, J
8.6, NH), 4.92 (m, 3H, NHCH), 3.71 (s, 9H, OMe), 3.66 (s,
2
2
9H, OMe), 3.46 (d, 3H, J 15, NCH2), 3.24 (d, 3H, J 15 Hz,
NCH2), 2.99 (dd, 3H, 2J 17, 3J 6.0, CHCH2CO), 2.88 (dd, 3H,
2J 17, 3J 4.7, CHCH2CO). δC (125 MHz, 298 K, CDCl3) 171.5
(COOMe), 171.2 (COOMe), 169.8 (NHCO), 58.4 (NCH2), 52.8
(OMe), 52.1 (OMe), 48.4 (NHCH), 35.8 (CHCH2CO). m/z
(ESI+) 643 [M + Na], 621 [M + H]. Calc. for C24H36N4O15Na
[M + Na]: 643.2075. Found: 643.2082.
2
15H, C6H5), 4.65 (br dd, 3H, NHCH), 3.30 (dd, 3H, J 14.2,
2
3
3J 4.1, CH2Ph), 2.91 (dd, 3H, J 13.7, J 10.3, CH2Ph), 2.57
(d, 3H, 2J 16.8, NCH2), 2.51 (d, 3H, 2J 16.1, NCH2) (NH
and COOH not observed). δC (100 MHz, 298 K, (D6)acetone)
174.1 (COOH), 171.1 (CONH), 138.3 (ipso-C of C6H5), 130.0,
129.1, 127.4 (ortho, meta, para-C of C6H5), 58.3 (NCH2), 54.3
(NHCH), 37.8 (CH2Ph). m/z (ESI+) 655.4 [M + Na]. Calc. for
C33H36N4O9Na: 655.2376 [M + Na]. Found: 655.2367.
Typical Deprotection Conditions for Benzyl Esters
A small amount of Pd/C (∼2 mg) was added to an ethanol
(50 mL)solutionorsuspensionofthecompound(∼400 mg).The
mixture was subjected to a hydrogen atmosphere from a balloon
with stirring (NTA-[Gly(OBz)]3, NTA-[Leu(OBz)]3, MIDA-
[Leu(OBz)]2), or using a Parr hydrogenator, 30 psi were applied
(NTA-[Phe(OBz)]3, MIDA-[Gly(OBz)]2, MIDA-[Phe(OBz)]2).
After stirring for 1 h, the solution was filtered through Celite and
the solvent was removed under vacuum. The free acids of the
glycine derivatives MIDA-[Gly(OH)]2 and NTA-[Gly(OH)]3 are
extremely hygroscopic so no yield was recorded. For the other
free acids, yields were above 80%.
MIDA-[Gly(OH)]2: δH (300 MHz, 298 K, D2O) 4.01 (s,
4H, CH2COOH), 3.80 (s, 4H, MeNCH2), 2.88 (s, 3H, NMe).
δC (100 MHz, 298 K, D2O) 175.0 (COOH), 166.1 (CONH),
57.6 (MeNCH2), 43.5 (NMe), 42.7 (NHCH2). m/z (ESI+)
561 [2M + K], 545 [2M + Na], 284 [M + Na], 262 [M + H].
Calc. for C9H15N3O6Na: 284.0859 [M + Na]. Found: 284.0868.
Because of the hygroscopic nature of this compound, no IR
spectrum could be obtained.
Deprotection Conditions for NTA-[Asp(OMe)(OMe)]3
The methyl ester (0.50 g, 0.81 mmol) was weighed into a round
bottomed flask and distilled water (10 mL) was added. The ester
was not completely soluble. Six equivalents of the metal hydro-
xide (NaOH or LiOH) per NTA were weighed into a separate
flask and dissolved in water. The base was added to the ester
and the mixture was stirred overnight at room temperature. The
water was removed under vacuum leaving a hygroscopic white
solid that was insoluble in alcohols or THF.
NTA-[Asp(ONa)(ONa)]3: δH (500 MHz, 298 K, D2O) 4.30
(dd, 3H, 3J 9.9, 3J 3.9, NHCH), 3.30 (s, 6H, NCH2), 2.54 (dd,
3H, 2J 16, 3J 4.0, CHCH2), 2.35 (dd, 3H, 2J 16, 3J 10, CHCH2).
δC (125 MHz, 298 K, D2O) 178.8 (COONa), 178.5 (COONa),
172.3 (CONH), 56.6 (NCH2), 53.0 (NHCH), 39.5 (CHCH2).
Acknowledgements
MIDA-[Leu(OH)]2: δH (300 MHz, 298 K, D2O) 8.49 (br d,
J.K. acknowledges UniChe for a summer scholarship. We thank Dr Joanne
Blanchfield for helpful discussions.
2H, 3J 12, NH), 4.17 (m, 2H, NHCH), 3.96 (s, 4H, MeNCH2),