Formation of Cyclic Amino Acid Derivatives
J . Org. Chem., Vol. 66, No. 21, 2001 6903
(m, allyl, CH2TMS), 1.75-1.3 (m, Leu), 1.1-0.9 (m, Leu), 0.16/
0.07 (s, TMS). 13C NMR (CDCl3): δ 172.5/171.4 (s), 170.1/170.0
(s), 155.8/155.7 (s), 143.9/143.8 (s), 143.6 (s), 141.1 (s), 134.2/
132.7 (d), 127.5 (d), 126.9 (d), 125.0 (d), 119.8 (d), 119.3/118.2
(t), 66.9/66.6 (t), 62.4/60.0 (d), 52.3/51.9 (q), 49.5/48.7 (d), 47.0
(d), 43.4/42.8 (t), 41.8 (t), 35.6 (t), 33.9/33.2 (t), 24.3 (d), 23.5/
23.4 (d), 21.7/21.3 (q), -0.8/-2.3 (q, TMS). HRMS: calcd for
C31H42N2O5Si (M+) 550.2863, found 550.2864. [R]D -69° (c 1.4,
CHCl3).
trimethylsilanylmethyl-2-allyl)-Gly-OH (250 mg. 0.47 mmol),
H-Leu-Leu-Leu-Leu-NH2*CF3CO2H (247 mg, 0.42 mmol), HABT
(64 mg), DIC (0.073 mL), DIEA (0.100 mL), and MeCN (10
mL) were used in the coupling reaction. Purification by
crystallization (MeOH, Et2O) afforded 20 (512 mg, 81%, 1:2
mixture of rotamers) as a colorless powder. 1H NMR (400 MHz,
D3COD): δ 7.8 (mc, FMOC), 7.6 (mc, 6 H, FMOC), 7.4 (mc, 6
H, FMOC), 7.3 (mc, 6 H, FMOC), 5.9 (mc, 1 H, 2-H), 5.7 (mc, 2
H), 5.2-5.0 (m, 6 H), 4.7-4.55 (m, 3 H), 4.4-4.0 (m, 12 H),
3.00 (d, J ) 16 Hz, 1 H), 2.6-2.45 (m, 11 H), 1.8-1.45 (m, 45
H), 1.0-0.8 (m, 90 H), 0.16 (s, 9 H, TMS), 0.07 (s, 18 H, TMS).
IR (ATR, cm-1): ν 3355 (m), 1526 (s), 1350 (s), 803 (m), 731
F MOC-Gly-Gly-(N-tr im eth ylsila n ylm eth yl-2-a llyl)-Gly-
OMe (r a c-17b). Following the procedure F, rac-2 (350 mg,
1.6 mmol), FMOC-Gly-Gly-OH (691 mg, 1.9 mmol), HABT (265
mg), DIC (0.302 mL), DIEA (0.332 mL), and MeCN (10 mL)
were used in the coupling reaction. Purification by FC with
CH2Cl2/MeOH (50:1, Rf ) 0.14) afforded rac-17b (880 mg, 98%,
1:1 mixture of rotamers) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 7.77, 7.61 (2d, J ) 8 Hz, FMOC), 7.40, 7.31 (2t, J )
8 Hz, FMOC), 6.96 (d br, J ) 16 Hz, NH), 5.81 (ddt, J ) 18,
10, 7 Hz, allyl)/5.70 (ddt, J ) 17, 10, 7 Hz, allyl), 5.47 (mc,
NH), 5.25-5.1 (m, allyl), 4.41 (mc, FMOC), 4.29/3.83 (dd, J )
10, 6 Hz, 2-H), 4.24 (t br, J ) 7 Hz, FMOC), 4.2-3.9 (m, 2 ×
Gly), 3.74/3.72 (s, CO2Me), 2.96 (d, J ) 16 Hz, CH2TMS), 2.85-
2.55 (m, allyl, CH2TMS), 0.16/0.05 (s, TMS). 13C NMR
(CDCl3): δ 170.1/169.7 (s, CO2Me), 62.1/59.2 (d, C-2), 52.4/52.1
(q, CO2Me); FMOC: 156.4, 143.7, 141.1 (3 s), 127.5, 126.9,
125.0, 119.8 (4d), 67.1 (t), 46.9 (d); 2-allyl: 133.9/132.0 (d),
119.6/118.2 (t), 33.3/33.1 (t); Gly: 168.8 (s), 167.5/167.0 (s), 44.1
(t), 41.4/41.2 (t); CH2TMS: 40.5/35.5 (t), -0.8/-1.9 (q).
HRMS: calcd for C29H37N3O6Si (M+) 551.2452, found 551.2439.
F MOC-Gly-Gly-(N-tr im eth ylsila n ylm eth yl-2-a llyl)-Gly-
Gly-Gly-NH2 (r a c-19). Sa p on ifica tion of th e Meth yl Ester
r a c-17b. A solution of LiOH (0.3 N, 16 mL) was added to a
solution of rac-17b (880 mg, 1.6 mmol) in THF (20 mL) at 0
°C. After 30 min at 0 °C the reaction mixture was added to
HCl (0.3 N, 50 mL) and EtOAc (50 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(3 × 20 mL). The colorless solid (704 mg) obtained after
evaporation of the solvent was used without purification for
the next step. Peptide coupling: 150 mg (0.28 mmol) of the
solid, HABT (41 mg, 0.28 mmol), DIC (0.048 mL, 0.28 mmol),
and DIEA (0.047 mL, 0.28 mmol) were dissolved in DMF (5
mL). After 30 min a suspension of H-Gly-Gly-NH2*HCl (94 mg,
0.56 mmol) and DIEA (0.031 mL, 0.18 mmol,) in DMF (2 mL)
was added. After 2 h the reaction mixture was added to Et2O
(10 mL), and the crude product was obtained by filtration.
Purification by FC with CH2Cl2/MeOH (50:1 f 1:1) afforded
rac-19 (105 mg, 57%, 5:1 mixture of rotamers) as a colorless
(m). MS (FAB, m-nitrobenzyl alcohol): m/z (%) 1011 (M+
+
Na, 12), 989 (M+ + H, 30), 973 (M+ - Me, 100). CD (c ) 0.76
mM in TFE) λmax [nm] (mol. ellip.): 186 (210681), 200
(-47663), 213 (39469), 237 (-42408).
Ben zoyl-Gly-Mp r -OMe (r a c-21a ). Following the proce-
dure P, rac-17a (82 mg, 0.22 mmol), BP (10 mg), and ADC (10
mg) yielded after purification by FC with CHCl3/EtOAc (2:1,
Rf ) 0.29) a 1:3 mixture of rac,cis- and trans-21a (14 mg, 24%)
as a colorless oil. HRMS: calcd for C16H20N2O4 (M+) 304.1423,
found 304.1424. rac,trans-21a : 1H NMR (500 MHz, CDCl3):
δ 7.83 (d, J ) 8 Hz, Ph), 7.54, 7.47 (2 t, J ) 8 Hz, Ph), 7.24 (s
br, NH), 4.66 (dd, J ) 10, 2 Hz, 2-H), 4.4-4.2 (m, Gly), 3.85
(mc, 5-H), 3.77 (s, CO2Me), 3.13 (dd, J ) 9, 9 Hz, 5-H′), 2.6
(mc, 4-H), 2.20 (ddd, J ) 13, 6, 2 Hz, 3-H), 1.91 (dt, J ) 13, 10
Hz, 3-H′), 1.16 (d, J ) 7 Hz, 4-Me). 13C NMR (CDCl3): δ 172.2
(s, CO2Me), 167.2 (s, Gly), 133.8 (s, Ph), 133.6, 128.5, 127.1
(3d, Ph), 59.1 (d, C-2), 52.8 (t, C-5), 52.3 (q, CO2Me), 42.4 (t,
Gly), 36.7 (t, C-3), 32.5 (d, C-4), 17.2 (q, 4-Me). Differing values
of rac,cis-21a : 1H NMR: δ 4.49 (dd, J ) 10, 10 Hz, 2-H), 3.78
(s, CO2Me), 3.22 (dd, J ) 10, 10 Hz, 5-H′), 2.5 (mc, 3-H), 2.45
(mc, 4-H), 1.65 (dt, J ) 12, 10 Hz, 3-H′), 1.19 (d, J ) 7 Hz,
4-Me). 13C NMR: δ 172.4 (s, CO2Me), 59.6 (d, C-2), 53.1 (t,
C-5), 52.4 (q, CO2Me), 37.1 (t, C-3), 33.8 (d, C-4), 16.8 (q, 4-Me).
F MOC-Gly-Mp r -OMe (22a ). Following the procedure P,
18a (88 mg, 0.18 mmol), BP (10 mg), and ADC (10 mg) yielded
after purification by FC with MTBE/hexane (3:1, Rf ) 0.33) a
1:2 mixture of cis- and trans-22a (25 mg, 33%) as a colorless
oil. HRMS: calcd for C24H26N2O5 (M+) 422.1842, found 422.1845.
trans-22a : 1H NMR (500 MHz, CDCl3): δ 7.81, 7.65 (2d, J )
8 Hz, FMOC), 7.44, 7.35 (2t, J ) 8 Hz, FMOC), 5.80 (mc, NH),
4.64 (dd, J ) 10, 2 Hz, 2-H), 4.41 (d, J ) 8 Hz, FMOC), 4.27
(t br, J ) 8 Hz, FMOC), 4.1 (mc, Gly), 3.9-3.7 (m, 5-H), 3.75
(s, CO2Me,), 3.07 (dd, J ) 9, 9 Hz, 5-H′), 2.45 (mc, 4-H), 2.18
(ddd, J ) 13, 6, 2 Hz, 3-H), 1.88 (dt, J ) 13, 10 Hz, 3-H′), 1.14
(d, J ) 7 Hz, 4-Me). 13C NMR (CDCl3): δ 172.2 (s, CO2Me),
58.9 (d, C-2), 52.6 (t, C-5), 52.2 (q, CO2Me), 36.6 (t, C-3), 32.3
(d, C-4), 17.0 (q, 4-Me); FMOC: 156.1, 143.7, 141.1 (3 s), 127.5,
127.0, 125.0, 119.8 (4d), 67.0 (t), 46.9 (d); Gly: 166.9 (s), 43.2
(t br). Differing values of cis-22a : 1H NMR: δ 4.46 (dd, J ) 9,
9 Hz, 2-H), 3.9-3.7 (m, 5-H), 3.76 (s, CO2Me,), 3.15 (mc, 5-H′),
2.6-2.3 (m, 3-H, 4-H), 1.62 (dt, J ) 12, 10 Hz, 3-H′), 1.17 (d,
J ) 7 Hz, 4-Me). 13C NMR: δ 172.2 (s, CO2Me), 59.4 (d, C-2),
52.8 (t, C-5), 52.7 (q, CO2Me), 36.8 (t, C-3), 33.7 (d, C-4), 16.7
(q, 4-Me).
F MOC-Ala -Mp r -OMe (22b). Following the procedure P,
18b (60 mg, 0.12 mmol), BP (5 mg), and ADC (5 mg) yielded
after purification by FC with MTBE/hexane (3:2, Rf ) 0.13) a
1:2 mixture of cis- and trans-22b (30 mg, 57%) as a colorless
oil. HRMS: calcd for C25H28N2O5 (M+) 436.1998, found 436.2001.
trans-22b: 1H NMR (500 MHz, CDCl3): δ 7.81, 7.64 (2d, J )
8 Hz, FMOC), 7.44, 7.31 (2t, J ) 8 Hz, FMOC), 5.75 (d br, J
) 8 Hz, NH), 4.66 (dd, J ) 9, 3 Hz, 2-H), 4.6 (mc, Ala), 4.38 (d
br, J ) 7 Hz, FMOC), 4.26 (t br, J ) 7 Hz, FMOC), 3.82 (dd,
J ) 9, 8 Hz, 5-H), 3.78 (s, CO2Me), 3.27 (dd, J ) 9, 9 Hz, 5-H′),
2.55 (mc, 4-H), 2.16 (ddd, J ) 12, 6, 3 Hz, 3-H), 1.89 (dt, J )
12, 9 Hz, 3-H′), 1.45 (mc, Ala), 1.13 (d, J ) 7 Hz, 4-Me). 13C
NMR (CDCl3): δ 172.3 (s, CO2Me), 58.7 (d, C-2), 53.5 (t, C-5),
52.2 (q, CO2Me), 36.4 (t, C-3), 32.6 (d, C-4), 17.2 (q, 4-Me);
FMOC: 155.6, 143.8, 141.3 (3 s), 127.7, 127.0, 125.1, 119.9 (4
d), 67.0 (t), 47.1 (d); Ala: 171.3 (s), 48.2 (d), 18.4 (q). Differing
values for cis-22b: 1H NMR: δ 5.81 (d br, J ) 8 Hz, NH),
4.49 (dd, J ) 8, 8 Hz, 2-H), 3.94 (dd, J ) 10, 8 Hz, 5-H), 3.79
(s, CO2Me), 3.18 (dd, J ) 10, 10 Hz, 5-H′), 2.5 (mc, 3-H), 2.4
1
powder. H NMR (500 MHz, CDCl3): δ 7.84 (s br, NH), 7.75
(d, J ) 8 Hz, FMOC), 7.6 (mc, FMOC), 7.38, 7.29 (2t br, J ) 8
Hz, FMOC), 6.98, 6.56 (2s br, NH), 5.8-5.6 (m, allyl), 5.15 (mc,
allyl), 4.54 (dd, J ) 10, 6 Hz, 2-H), 4.4 (mc, FMOC), 4.25-3.6
(m, FMOC, 4 × Gly, CH2TMS, 2-H), 3.01, 2.80 (2 d, J ) 16
Hz, CH2TMS), 2.9-2.45 (m, CH2TMS, allyl), 0.18/0.01 (s,
TMS). 13C NMR (CDCl3): δ 173.0/172.5 (s, CO2Me), 63.5/60.2
(d, C-2); FMOC: 156.9, 143.7, 141.2 (3 s), 127.7, 127.0, 125.1,
119.9 (4 d), 67.1 (t), 47.0 (d); 2-allyl: 133.8/133.1 (d), 119.4/
118.2 (t), 33.0/32.7 (t); CH2TMS: 41.2/35.7 (t), -0.6/-1.6 (q,
TMS); Gly: 170.7, 170.2, 169.3, 168.0 (4s), 44.1, 43.5, 42.6,
41.7 (4t). MS (FAB, m-nitrobenzyl alcohol): m/z (%) 673 (M+
+ Na, 10), 651 (M+ + H, 20), 520 (M+ - [NH-Gly-Gly-NH2],
30).
FMOC-Leu -(N-tr im eth ylsilan ylm eth yl-2-allyl)-Gly-Leu -
Leu -Leu -Leu -NH2 (20). Sa p on ifica t ion of t h e Met h yl
Ester (-)-18d . A solution of LiOH (4 N, 5 mL) was added to
a solution of (-)-18d (590 mg, 1.1 mmol) in THF (10 mL) and
water (5 mL). After 5 h HCl (6 N, 3 mL) was added, followed
by a saturated Na2CO3 solution (5 mL) and a solution of
FMOC-Cl (312 mg) in THF (5 mL). After 3 h the reaction
mixture was acidified (pH ) 2) and extracted with EtOAc (10
× 20 mL). Purification by FC with CH2Cl2/MeOH (gradient,
50:1 f 1:1) afforded FMOC-Leu-(N-trimethylsilanylmethyl-
2-allyl)-Gly-OH (424 mg, 72%) as a colorless solid. IR (ATR,
cm-1): ν 3307 (w), 1718 (s), 1640 (m), 1599 (m), 759 (m), 740
(s). HRMS: calcd for C30H40N2O5Si 536.2707, found 536.2707.
Peptide coupling: Following the procedure F, FMOC-Leu-(N-