The Journal of Organic Chemistry
Article
24 (434 mg, 73%, dr > 8:1) as a yellow liquid: Rf = 0.53 (20% EtOAc
1.79 (m, 5H), 1.57 (s, 3H), 1.41−1.27 (m, 4H), 1.13 (d, J = 6.0 Hz,
3H), 1.07−1.04 (m, 3H), 1.00 (s, 18H), 0.91 (d, J = 6.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 172.3, 170.3, 169.9, 136.2, 135.2, 133.5,
129.9, 128.5, 127.0, 75.7, 68.3, 59.1, 52.3, 52.0, 47.0, 44.6, 39.1, 37.5,
33.7, 32.3, 29.2, 24.9, 23.5, 20.9, 18.2, 18.2, 12.4, 11.4 ppm; IR(neat):
vmax 3398, 2974, 1637, 1629 cm−1; HRMS (ESI) m/z calculated for
C36H60N2O6SiNa [M + Na]+ 667.4118, found 667.4117.
The above compound (79 mg, 0.12 mmol) was hydrolyzed by
LiOH·H2O (15 mg, 0.36 mmol) in THF:H2O (3:1, 3 mL) in 1 h to
produce the corresponding seco acid {77 mg, quantitative, purification
SiO2, 60−120 mesh, EtOAc as eluant, thick oil, Rf = 0.36 (EtOAc)} in
quantitative yield, which was confirmed by mass spectroscopy {HRMS
(ESI) m/z calculated for C35H58N2O6SiNa [M + Na]+ 653.3962,
found 653.3965} and taken into the next reaction without any more
characterizations.
The seco acid (77 mg, 0.012 mmol) was subsequently treated with
MNBA (67 mg, 0.20 mmol) and DMAP (37 mg, 0.31 mmol) in
CH2Cl2 (100 mL) to yield macrocycle 30 (46 mg, 61%, purification
SiO2, 100−200 mesh, 15% EtOAc in hexane as eluant) as a colorless
liquid: Rf = 0.53 (25% EtOAc in hexane); [α]2D8 = −3.3 (c 0.40
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.31−7.20 (m, 5H), 6.30 (d,
J = 7.6 Hz, 1H), 5.02−4.99 (m, 1H), 4.89 (d, J = 9.6 Hz, 1H), 4.60 (m,
1H), 4.37 (dd, J = 8.0, 6.8 Hz, 1H), 3.49−3.47 (m, 2H), 3.37 (m, 1H),
3.11 (dd, J = 12.8, 4.8 Hz, 1H), 2.79 (dd, J = 12.8, 10.0 Hz, 1H), 2.61−
2.59 (m, 2H), 2.21 (m, 1H), 2.00−1.99 (m, 1H), 1.75−1.70 (m, 2H),
1.61 (s, 3H), 1.47 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H), 1.31−1.17 (m,
3H), 1.06−1.02 (m, 21H), 0.89 (d, J = 6.4 Hz, 3H), 0.83−0.80 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 170.6, 170.5, 168.0, 136.4, 135.1,
133.9, 129.6, 128.7, 127.3, 74.2, 59.1, 52.4, 45.9, 44.8, 41.1, 34.6, 34.4,
32.2, 28.9, 22.1, 21.4, 20.2, 18.2, 18.1, 12.3, 10.3 ppm; IR(neat): vmax
3331, 2926, 1737, 1632, 1447 cm−1; HRMS (ESI) m/z calculated for
C35H56N2O5SiNa [M + Na]+ 635.3856, found 635.3854.
in hexane); [α]2D8 = +153.5 (c 1.65 CHCl3); H NMR (CDCl3, 300
1
MHz) δ 7.37−7.26 (m, 5H), 5.39 (m, 1H), 5.26 (d, J = 9.6 Hz, 1H),
4.59 (dd, J = 8.9, 3.3 Hz, 1H), 3.77−3.72 (m, 1H), 3.49−3.37 (m,
3H), 3.24 (dd, J = 13.5, 4.0 Hz, 1H), 3.05 (dd, J = 12.9, 10.5 Hz, 1H),
2.90 (d, J = 11.7 Hz, 1H), 2.39−2.29 (m, 1H), 1.66 (d, J = 0.9 Hz,
1H), 1.41−1.28 (m, 4H), 1.10 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.6 Hz,
3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ
201.5, 173.1, 136.6, 134.2, 133.7, 129.6, 129.1, 127.4, 73.4, 68.6, 44.8,
37.6, 36.9, 33.5, 32.3, 32.1, 26.1, 24.0, 21.0, 18.3, 12.3, −4.2, −4.5 ppm;
IR(neat): vmax 3444, 2928, 1693 cm−1; HRMS (ESI) m/z calculated
for C28H45NO3S2SiNa [M + Na]+ 558.2508, found 558.2506.
(3R,6R,9R,E)-9-(tert-Butyldimethylsilyloxy)-4,6-dimethyl-3-
(triisopropylsilyloxy)dec-4-enoic acid (25). Same as acid 9.
Compound 24 (428 mg, 0.80 mmol) was treated with TIPS-OTf
(0.32 mL, 1.20 mmol) and 2,6-lutidine (0.28 mL, 2.40 mmol) in dry
CH2Cl2 (3 mL) to get the corresponding TIPS ether {514 mg, 93%,
yellow liquid, purification SiO2, 100−200 mesh, 2% EtOAc in hexane
as eluant}: Rf = 0.58 (10% EtOAc in hexane), HRMS (ESI) m/z
calculated for C37H65NO3S2Si2Na [M + Na]+ 714.3842, found
714.3844}, which next was treated with LiOH·H2O (94 mg, 2.23
mmol) and 30% aqueous H2O2 (0.3 mL) in THF:H2O (3:1, 4 mL) to
provide acid 25 (316 mg, 85%, purification SiO2, 100−200 mesh, 15%
EtOAc in hexane as eluant) as a colorless oil: Rf = 0.68 (15% EtOAc in
hexane); [α]2D7 = −11.6 (c 1.22 CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 5.13 (d, J = 9.6 Hz, 1H), 4.56 (t, J = 6.6 Hz, 1H), 3.76−3.70 (m,
1H), 2.66−2.51 (m, 2H), 2.33−2.23 (m, 1H), 1.61 (d, J = 1.2 Hz,
3H), 1.36−1.23 (m, 4H), 1.09 (d, J = 6.1 Hz, 3H), 1.05−1.04 (m,
21H), 0.91 (d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 174.2, 134.2, 134.1, 75.9, 69.2, 42.3, 37.3, 33.6,
32.2, 26.1, 24.1, 20.9, 18.3, 18.2, 18.1, 12.4, 11.1,-4.3, −4.5 ppm;
IR(neat): vmax 2930, 1713 cm−1; HRMS (ESI) m/z calculated for
C27H56O4Si2Na [M + Na]+ 523.3615, found 523.3614.
Calcaripeptide B (2). Following the same protocols as those
adopted for the synthesis of calcaripeptide C, macrocycle 30 (43 mg,
0.07 mmol) was treated with TBAF (1 M solution in THF, 0.10 mL,
0.10 mmol) in dry THF to produce the corresponding desilylated
compound (29 mg, 90%, purification SiO2, 100−200 mesh, 45%
EtOAc in hexane as eluant) in 2 h as a colorless oil; Rf = 0.13 (40%
(S)-Methyl 1-((S)-2-((3R,6R,9R,E)-9-(tert-Butyldimethyl-
silyloxy)-4,6-dimethyl-3-(triisopropylsilyloxy)dec-4-enamido)-
3-phenylpropanoyl)pyrrolidine-2-carboxylate (29). Same as
compound 8. Dipeptide 6c (215 mg, 0.57 mmol) in dry CH2Cl2 (3
mL) was treated with 30% TFA (0.9 mL) to afford the corresponding
Boc deprotected product, which was subsequently reacted with acid 25
(237 mg, 0.47 mmol) in the presence of DIPEA (0.16 mL, 0.94
mmol), EDCI (109 mg, 0.57 mmol), and HOBt (77 mg, 0.57 mmol)
in dry DMF(5 mL) to yield compound 29 (298 mg, 83% from 25,
purification SiO2, 100−200 mesh, 25% EtOAc in hexane as eluant) as a
thick liquid: Rf = 0.45 (15% EtOAc in hexane); [α]2D8 = −20.0 (c 3.3
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.29−7.20 (m, 5H), 6.55 (d,
J = 7.9 Hz, 1H), 5.24 (d, J = 9.5 Hz, 1H), 4.94−4.88 (m, 1H), 4.58−
4.55 (m, 1H), 4.42 (dd, J = 8.5 Hz, 4.5 Hz, 1H), 3.74 (s, 3H), 3.72−
3.68 (m, 1H), 3.52−3.48 (m, 1H), 3.06 (d, J = 8.5 Hz, 1H), 2.98 (d, J
= 5.0 Hz, 1H), 2.94−2.90 (m, 1H), 2.41−2.35 (m, 1H), 2.32−2.26 (m,
1H), 2.14−2.07 (m, 1H), 1.94−1.90 (m, 1H), 1.87−1.81 (m, 2H),
1.57 (s, 3H), 1.37−1.22 (m, 5H), 1.07 (d, J = 6.1 Hz, 3H), 1.01 (s,
21H), 0.92 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR
(CDCl3, 75 MHz, rotamer peaks are given in parentheses) δ 172.3,
170.2, 169.9, 136.3, 134.7, 133.0, 129.9(129.5), 128.4(128.6), 126.9,
75.3, 68.6, 59.0, 52.3(52.8), 52.1, 46.9, 44.6, 39.4, 37.5, 33.3(34.1),
32.0, 29.2(30.6), 26.0, 24.9, 23.9(24.1), 20.7(20.9), 18.2, 12.5, 12.4,
11.9, −4.3, −4.6 ppm; IR(neat): vmax 3314, 2928, 1751, 1634, 1448
cm−1; HRMS (ESI) m/z calculated for C42H74N2O6Si2Na [M + Na]+
781.4983, found 781.4985.
Macrocycle 30. The same procedure as described in the
preparation of compound 16. Compound 29 (272 mg, 0.36 mmol)
was first treated with CSA (8.3 mg, 0.04 mmol) in CH2Cl2:MeOH
(4:1, 4 mL) under argon to yield the corresponding TBS deprotected
compound (199 mg, 86%, purification SiO2, 100−200 mesh, 35%
EtOAc in hexane as eluant) as a thick liquid: Rf = 0.29 (40% EtOAc in
hexane); [α]2D9 = −29.4 (c 4.69 CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.28−7.19 (m, 5H), 6.48 (d, J = 8.1 Hz, 1H), 5.13 (d, J = 9.6 Hz,
1H), 4.93−4.89 (m, 1H), 4.48 (m, 1H), 4.46−4.40 (m, 2H), 3.73 (s,
3H), 3.56−3.53 (m, 1H), 3.10−3.01 (m, 1H), 2.99−2.91 (m, 1H),
2.41 (d, J = 6 Hz, 2H), 2.32−2.29 (m, 1H), 2.10−2.08 (m, 1H), 1.93−
EtOAc in hexane); [α]D28 = −56.7 (c 0.91 CHCl3); H NMR (CDCl3,
1
300 MHz) δ 7.32−7.20 (m, 5H), 6.61 (d, J = 7.8 Hz, 1H), 5.06−4.99
(m, 1H), 4.94 (d, J = 9.6 Hz, 1H), 4.62−4.56 (m, 1H), 4.35−4.31 (m,
1H), 3.50−3.42 (m, 2H), 3.39−3.35 (m, 1H), 3.15 (dd, J = 12.2, 5.1
Hz, 1H), 2.80 (dd, J = 12.2, 10.2 Hz, 1H), 2.68−2.66 (m, 2H), 2.26−
2.20 (m, 1H), 1.99−1.93 (m, 1H), 1.78 (m, 4H), 1.52−1.44 (m, 1H),
1.34−1.28 (m, 2H), 1.24 (d, J = 6.3 Hz, 3H), 1.19−1.09 (m, 2H), 0.91
(d, J = 6.6 Hz, 3H), 0.85 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
170.7, 170.5, 169.2, 136.4, 135.2, 133.8, 129.6, 128.8, 127.3, 75.5, 74.4,
59.1, 52.5, 45.9, 41.5, 41.2, 34.7, 34.6, 32.3, 28.9, 22.1, 21.6, 20.4, 11.5
ppm; IR(neat): vmax 3315, 2924, 1731, 1626, 1454 cm−1; HRMS (ESI)
m/z calculated for C26H37N2O5 [M + H]+ 457.2702, found 457.2694.
The aforementioned compound (25 mg, 0.05 mmol) was oxidized
by DMP (36 mg, 0.09 mmol) in 2 h in the presence of NaHCO3 (4.6
mg, 0.05 mmol) in dry CH2Cl2 to provide calcaripeptide B (2) (22
mg, 89%, purification SiO2, 100−200 mesh, 35% EtOAc in hexane as
eluant) as a colorless liquid: Rf = 0.35 (40% EtOAc in hexane); [α]D20
=
−117.6 (c 0.35 MeOH); 1H NMR (acetone-d6, 300 MHz) δ 7.51 (d, J
= 8.4 Hz, 1H), 7.34−7.20 (m, 5H), 6.41 (dd, J = 10.2, 1H), 5.23−5.15
(m, 1H), 4.66−4.62 (m, 1H), 4.35 (d, J = 15.0 Hz, 1H), 3.86 (d, J =
7.2 Hz, 1H), 3.43−3.35 (m, 2H), 3.18 (d, J = 15.0 Hz, 1H), 3.09 (dd, J
= 12.6, 10.2 Hz, 1H), 2.81 (dd, J = 12.6, 5.1 Hz, 1H), 2.59−2.50 (m,
1H), 2.01 (m, 1H), 1.85−1.76 (m, 2H), 1.71 (d, J = 1.2 Hz, 3H),
1.51−1.45 (m, 2H), 1.36−1.26 (m, 2H), 1.19 (d, J = 6.3 Hz, 3H),
1.17−1.13 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H); 13C NMR (Acetone-d6,
75 MHz) δ 196.4, 171.3, 170.7, 167.6, 149.4, 137.8, 136.1, 130.4,
129.4, 127.8, 74.3, 59.8, 53.5, 48.5, 46.4, 41.3, 35.7, 35.5, 34.7, 29.0,
22.6, 21.0, 20.7, 11.8 ppm; IR(neat): vmax 3313, 2926, 1734, 1680,
1620, 1452 cm−1; HRMS (ESI) m/z calculated for C26H35N2O5 [M +
H]+ 455.2546, found 455.2540.
L
dx.doi.org/10.1021/jo5019798 | J. Org. Chem. XXXX, XXX, XXX−XXX