The Journal of Organic Chemistry
Article
C(6‴)H); δC (125 MHz, 127 mM in neutralized CDCl3) 25.0, 26.7,
26.8, 28.8, 29.10, 29.13, 29.3, 29.38, 29.39, 29.47, 29.51, 29.54, 29.58,
29.60, 31.1 (C(4)−C(14), C(2″)−C(12″)), 33.0 (C(15), C(13″), 44.6
(C(1″)), 54.2 (C(2)), 60.8 (C(3)), 123.3 (C(5′), C(5‴)), 127.0
(p‑Ph), 128.5 (m-Ph), 128.7 (o-Ph), 135.7 (C(4′), C(4‴)), 138.0
(C(3′), C(3‴), 139.0 (i-Ph), 147.1 (C(6′), C(6‴)), 149.9 (C(2′),
C(2‴)), 176.7 (C(1)); m/z (ESI+) 671 ([M + H]+, 5%), 336 ([M +
2H]2+, 65%), 224 ([M + 3H]3+, 100%); HRMS (ESI+)
C(5‴)), 127.4 (p-Ph), 127.7 (C(14), C(12″)), 128.6, 129.6 (o,m-Ph),
131.4 (C(13), C(11″)), 135.5 (i-Ph), 135.97, 136.04 (C(4′), C(4‴)),
137.3 (C(3′), C(3‴)), 147.1, 147.2 (C(6′), C(6‴)), 149.8, 149.9
(C(2′), C(2‴)), 175.3 (C(1)); m/z (ESI+) 695 ([M + H]+, 5%), 348
([M + 2H]2+, 40%), 232 ([M + 3H]3+, 100%); HRMS (ESI+)
+
C46H68N3O2 ([M + H]+) requires 694.5306; found 694.5299.
Methyl (2R,3R,13Z,11″Z)-2-Phenyl-3-{N-[14″-(pyridin-3‴-yl)-
tetradec-11″-enyl]amino}-16-(pyridin-3′-yl)hexadec-13-enoate
30. Step 1. A solution of 245 (170 mg, 0.32 mmol, 94%
diastereoisomeric purity)18 in HCl (1.25 M in MeOH, 4 mL) was
stirred at rt for 2 h and then concentrated in vacuo. The residue was
partitioned between CH2Cl2 (10 mL) and satd aq NaHCO3 (10 mL),
and the layers were separated. The organic layer was washed with satd
aq NaHCO3 (2 × 5 mL), dried, and concentrated in vacuo to give 29
as a white solid (137 mg).
+
C44H67N3NaO2 ([M + Na]+) requires 692.5125; found 692.5121.
Methyl (2S,3R,13Z,11″Z)-2-Phenyl-3-{N-[14″-(pyridin-3‴-yl)-
tetradec-11″-enyl]amino}-16-(pyridin-3′-yl)hexadec-13-enoate
26. Step 1. A solution of 235 (297 mg, 0.55 mmol, 97:3 dr [(Z):(E)
ratio]) in HCl (1.25 M in MeOH, 4 mL) was stirred at rt for 2 h and
then concentrated in vacuo. The residue was partitioned between
CH2Cl2 (10 mL) and satd aq NaHCO3 (10 mL), and the layers were
separated. The organic layer was washed with satd aq NaHCO3 (2 × 5
mL), dried, and concentrated in vacuo to give 25 as a white solid (239
mg).
Step 2. A solution of 54,5,13 (90 mg, 0.32 mmol, 97:3 dr [(Z):(E)
ratio]) in 1,2-dichloroethane (4 mL) was added to a stirred solution of
the residue 29 from the previous step (137 mg) in 1,2-dichloroethane
(4 mL) at rt. After 5 min, AcOH (1 drop) and NaBH(OAc)3 (133 mg,
0.63 mmol) were added, and the resultant mixture was stirred at rt for
16 h, before satd aq NaHCO3 (10 mL) was added. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (eluent CHCl3/
MeOH, 99:1) gave 30 as a pale yellow oil (129 mg, 58% from 24,
∼93% diastereoisomeric purity);18 [α]D20 −17.0 (c 1.0 in CHCl3); νmax
1735 (CO); δH (500 MHz, C6D6) 1.04−1.58 (32H, m, C(4)H2−
C(11)H2, C(2″)H2−C(9″)H2), 1.85−1.96 (4H, m, C(12)H2,
C(10″)H2), 2.13−2.21 (4H, m, C(15)H2, C(13″)H2), 2.29−2.37
(4H, m, C(16)H2, C(14″)H2) 2.66−2.82 (2H, m, C(1″)H2), 3.37
(3H, s, OMe), 3.44−3.52 (1H, m, C(3)H), 3.76 (1H, d, J 10.1,
C(2)H), 5.26−5.34 (2H, m, C(14)H, C(12″)H2), 5.38−5.46 (2H, m,
C(13)H, C(11″)H2), 6.72−6.78 (2H, m, C(5′)H, C(5‴)H), 6.98−
7.09 (3H, m, C(4′)H, C(4‴)H, p-Ph), 7.13−7.19 (2H, m, m-Ph),
7.45−7.49 (2H, m, o-Ph), 8.44−8.62 (4H, m, C(2′)H, C(6′)H,
C(2‴)H, C(6‴)H); δC (125 MHz, C6D6) 25.5, 27.91, 27.93, 28.1,
29.4, 29.98, 30.03, 30.28, 30.30, 30.33, 30.36, 30.43, 30.45, 30.53, 30.7,
31.5, 31.7 (C(4)−C(12), C(15), C(2″)−C(10″), C(13″)), 33.5
(C(16), C(14″)), 47.3 (C(1″)), 51.7 (OMe), 58.2 (C(2)), 61.0
(C(3)), 123.5 (C(5′), C(5‴)), 128.0 (p-Ph), 128.8 (C(14), C(12″)),
129.2, 129.5 (o,m-Ph), 131.70, 131.72 (C(13), C(11″)), 135.7 (C(4′),
C(4‴)), 137.4, 138.4 (C(3′), C(3‴), i-Ph), 148.3 (C(6′), C(6‴)),
151.1 (C(2′), C(2‴)), 174.3 (C(1)); m/z (ESI+) 709 ([M + H]+, 5%),
355 ([M + 2H]2+, 50%), 237 ([M + 3H]3+, 100%); HRMS (ESI+)
Step 2. A solution of 54,5,13 (159 mg, 0.55 mmol, 97:3 dr [(Z):(E)
ratio]) in 1,2-dichloroethane (4 mL) was added to a stirred solution of
the residue 25 from the previous step (239 mg) in 1,2-dichloroethane
(4 mL) at rt. After 5 min, AcOH (1 drop) and NaBH(OAc)3 (235 mg,
1.11 mmol) were added, and the resultant mixture was stirred at rt for
16 h, before satd aq NaHCO3 (10 mL) was added. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (eluent CHCl3/
MeOH, 99:1) gave 26 as a pale yellow oil (233 mg, 60% from 23,
∼95% diastereoisomeric purity);18 [α]D20 −17.0 (c 1.0 in CHCl3); νmax
1734 (CO); δH (500 MHz, C6D6) 1.10−1.75 (32H, m, C(4)H2−
C(11)H2, C(2″)H2−C(9″)H2), 1.85−1.95 (4H, m, C(12)H2,
C(10″)H2), 2.14−2.21 (4H, m, C(15)H2, C(13″)H2), 2.29−2.44
(5H, m, C(16)H2, C(14″)H2, C(1″)HA), 2.47−2.56 (1H, m,
C(1″)HB), 3.30 (3H, s, OMe), 3.45−3.52 (1H, m, C(3)H), 3.85
(1H, d, J 9.1, C(2)H), 5.26−5.35 (2H, m, C(14)H, C(12″)H2), 5.38−
5.46 (2H, m, C(13)H, C(11″)H2), 6.71−6.79 (2H, m, C(5′)H,
C(5‴)H), 6.98−7.10 (3H, m, C(4′)H, C(4‴)H, p-Ph), 7.12−7.19
(2H, m, m-Ph), 7.48−7.53 (2H, m, o-Ph), 8.45−8.59 (4H, m, C(2′)H,
C(6′)H, C(2‴)H, C(6‴)H); δC (125 MHz, C6D6) 26.2, 27.9, 29.4,
30.0, 30.26, 30.32, 30.34, 30.38, 30.42, 30.5, 30.7, 31.2 (C(5)−C(12),
C(15), C(2″)−C(10″), C(13″)), 33.0 (C(4)), 33.5 (C(16), C(14″)),
46.8 (C(1″)), 51.7 (OMe), 57.1 (C(2)), 60.9 (C(3)), 123.5 (C(5′),
C(5‴)), 128.0 (p-Ph), 128.8 (C(14), C(12″)), 129.2, 129.8 (o,m-Ph),
131.71, 131.73 (C(13), C(11″)), 135.7 (C(4′), C(4‴)), 137.4, 138.1
(C(3′), C(3‴), i-Ph), 148.3 (C(6′), C(6‴)), 151.1 (C(2′), C(2‴)),
173.8 (C(1)); m/z (ESI+) 709 ([M + H]+, 5%), 355 ([M + 2H]2+,
+
C47H70N3O2 ([M + H]+) requires 708.5463; found 708.5445.
(2R,3R,13Z,11″Z)-2-Phenyl-3-{N-[14″-(pyridin-3‴-yl)tetra-
dec-11″-enyl]amino}-16-(pyridin-3′-yl)hexadec-13-enoic Acid
31 [(+)-2-epi-Nakinadine F]. A solution of 30 (60 mg, 0.085
mmol, ∼93% diastereoisomeric purity)18 in HCl (3.0 M aq, 2 mL) was
stirred at 70 °C for 80 h and then concentrated in vacuo. Purification
via ion exchange chromatography on Serdolit CG-400 I (100−200
mesh, OH− form, eluent AcOH (2.0 M aq)], followed by flash column
chromatography (eluent CHCl3/MeOH, 97:3), gave 31 as a colorless
oil (34 mg, 58%, ∼93% diastereoisomeric purity);18 [α]D20 +8.1 (c 1.0
in CHCl3); νmax 1576, 1599, 2853, 2924; δH (500 MHz, 127 mM in
neutralized CDCl3) 1.03−1.81 (32H, C(4)H2−C(11)H2, C(2″)H2−
C(9″)H2), 1.86−1.98 (4H, m, C(12)H2, C(10″)H2), 2.31−2.40 (4H,
m, C(15)H2, C(13″)H2), 2.57−2.71 (5H, m, C(16)H2, C(1″)HA,
C(14″)H2), 2.88−2.94 (1H, m, C(1″)HB), 3.30−3.41 (1H, m,
C(3)H), 3.72 (1H, d, J 8.8, C(2)H), 5.32−5.46 (4H, m, C(13)H,
C(14)H, C(11″)H2, C(12″)H2), 7.16−7.25 (3H, m, C(5′)H, C(5‴)H,
p-Ph), 7.26−7.35 (4H, m, o,m-Ph), 7.47−7.54 (2H, m, C(4′)H,
C(4‴)H), 8.36−8.50 (4H, m, C(2′)H, C(6′)H, C(2‴)H, C(6‴)H);
δC (125 MHz, 127 mM in neutralized CDCl3) 24.7, 26.8, 27.18, 27.20,
28.7, 29.1, 29.2, 29.3, 29.36, 29.40, 29.43, 29.47, 29.49, 29.50, 29.53,
29.7 (C(4)−C(12), C(15), C(2″)−C(10″), C(13″)), 33.0 (C(16),
C(14″)), 44.8 (C(1″)), 54.4 (C(2)), 60.7 (C(3)), 123.2 (C(5′),
C(5‴)), 127.1 (p-Ph), 127.7 (C(14), C(12″)), 128.5, 128.8 (o,m-Ph),
131.4 (C(13), C(11″)), 135.9 (C(4′), C(4‴)), 137.2 (C(3′), C(3‴)),
138.9 (i-Ph), 147.3 (C(6′), C(6‴)), 150.0 (C(2′), C(2‴)), 176.7
+
50%), 237 ([M + 3H]3+, 100%); HRMS (ESI+) C47H70N3O2 ([M +
H]+) requires 708.5463; found 708.5468.
(2S,3R,13Z,11″Z)-2-Phenyl-3-{N-[14″-(pyridin-3‴-yl)tetra-
dec-11″-enyl]amino}-16-(pyridin-3′-yl)hexadec-13-enoic Acid
[(−)-Nakinadine F] 27. A solution of 26 (60 mg, 0.085 mmol,
∼95% diastereoisomeric purity)18 in HCl (3.0 M aq, 2 mL) was stirred
at 70 °C for 80 h and then concentrated in vacuo. Purification via ion
exchange chromatography on Serdolit CG-400 I [100−200 mesh,
OH− form, eluent AcOH (2.0 M, aq)], followed by flash column
chromatography (eluent CHCl3/MeOH, 97:3), gave 27 as a colorless
oil (33 mg, 56%, ∼95% diastereoisomeric purity);18 [α]D20 −15.1 (c 1.0
in CHCl3); νmax 1575, 1594, 2853, 2924; δH (500 MHz, 127 mM in
neutralized CDCl3) 1.12−1.71 (32H, C(4)H2−C(11)H2, C(2″)H2−
C(9″)H2), 1.85−2.00 (4H, m, C(12)H2, C(10″)H2), 2.29−2.41 (4H,
m, C(15)H2, C(13″)H2), 2.60−2.77 (5H, m, C(16)H2, C(1″)HA,
C(14″)H2), 2.78−2.86 (1H, m, C(1″)HB), 3.05−3.16 (1H, m,
C(3)H), 3.80−3.88 (1H, m, C(2)H), 5.33−5.44 (4H, m, C(13)H,
C(14)H, C(11″)H2, C(12″)H2), 7.19−7.29 (3H, m, C(5′)H, C(5‴)H,
m,p-Ph), 7.31−7.37 (2H, m, o-Ph), 7.48−7.52 (2H, m, C(4′)H,
C(4‴)H), 8.35−8.51 (4H, m, C(2′)H, C(6′)H, C(2‴)H, C(6‴)H);
δC (125 MHz, 127 mM in neutralized CDCl3) 26.3, 26.9, 27.14, 27.17,
27.9, 28.8, 29.12, 29.20, 29.22, 29.28, 29.37, 29.38, 29.45, 29.48, 29.49,
29.7 (C(4)−C(12), C(15), C(2″)−C(10″), C(13″)), 33.0 (C(16),
C(14″)), 45.8 (C(1″)), 51.9 (C(2)), 60.0 (C(3)), 123.2 (C(5′),
L
J. Org. Chem. XXXX, XXX, XXX−XXX