Amphimedosides A-C: Synthesis, chemoselective glycosylation, and biological evaluation

Article abstract of DOI:10.1021/jo302640y

The amphimedosides, discovered in 2006, are the first examples of naturally occurring glycosylated alkoxyamines. We report syntheses of amphimedosides A-C that feature a stereoselective oxyamine neoglycosylation and found that these alkaloids display mode

Full text of DOI:10.1021/jo302640y

Note
pubs.acs.org/joc
Amphimedosides A−C: Synthesis, Chemoselective Glycosylation,
And Biological Evaluation
Joseph M. Langenhan,* Edouard Mullarky, Derek K. Rogalsky, James R. Rohlfing, Anja E. Tjaden,
Halina M. Werner, Leonardo M. Rozal, and Steven A. Loskot
Department of Chemistry, Seattle University, Seattle, Washington 98122, United States
S
* Supporting Information
ABSTRACT: The amphimedosides, discovered in 2006, are the first examples of naturally occurring glycosylated alkoxyamines.
We report syntheses of amphimedosides A−C that feature a stereoselective oxyamine neoglycosylation and found that these
alkaloids display modest cytotoxicity toward seven diverse human cancer cell lines, exhibiting IC50 values ranging from 3.0 μM to
greater than 100 μM.
We planned to generate amphimedosides A−C (1a−c)
through chemoselective glycosylation of the corresponding
aglycons (12a−c; Figure 4). These in turn would be generated
from protected iodoalcohols and pyridylalkynes using method-
ologies similar to those developed by Baldwin and Lee for the
generation of the hachijodines.12
To begin, pyridylalkyne 4a was synthesized from commercial
3-(pyridine-3-yl)propanol (2) using Swern oxidation13 followed
by Seyferth−Gilbert homologation11 with Bestmann’s reagent
(Figure 2).14 Since 5-(pyridin-3-yl)pentanol is not commer-
cially available for conversion to pyridylalkyne 4b, we generated
4b from lithiated 3-picoline as was reported previously.11
To assemble the requisite pyridylalcohols 7a−c, we coupled
deprotonated pyridylalkynes 4 with protected iodo alcohols 5a
and 5b using the conditions developed by Baldwin and Lee
(Figure 3).12 Isolated yields for 6a and 6b were good, but the
highest yield we obtained for 6c was 28% (with 21% recovery
of 4a). Despite this low yield, deprotection using ammonium
fluoride in methanol15 afforded pyridyl alcohols 7a−c in
adequate enough amounts for us to proceed.
We were uncertain how to convert alcohols 7a−c to the
corresponding methoxyamines most efficiently. We considered
two options, nucleophilic displacement using deprotonated N-
(tert-butoxycarbonyl)-protected methoxyamine9c,16 and oxida-
tion followed by reductive amination.9e,17 To explore the
viability of the first option, we conducted a model study that
explored different leaving groups and reaction conditions
(Table 1). Unfortunately, isolated yields were low for all the
conditions we investigated; the highest yield obtained was 54%.
Concerned that the conversion of alcohols 7a−c to the
arine sponges have long been a source of biologically
Mactive natural products, including cytotoxic alkaloids.
Many such alkaloids are 3-alkylpyridine derivatives1 containing
an aliphatic chain terminated by functional groups including
amines,2 N-methoxyamines,3 N-methyl-N-methoxyamines,4 N-
methyl-N-hydroxylamines,3a oximes,3c or aldehydes.3c In 2006,
Matsunaga, Fusetani, and co-workers reported the first
examples of glycosylated 3-alkylpyridines, which they named
the amphimedosides.5 These secondary metabolites contain
unique O-methyl-N-(β-D-glucopyranosyl)hydroxylamine termi-
ni and are modest cytotoxins toward murine leukemia cells. We
and others have previously shown that glycosylated hydroxyl-
amines can be generated using oxyamine neoglycosylation, a
chemoselective glycosylation methodology that employs
reducing sugars to form closed ring neoglycosides, thus
revealing a synthetic route to these interesting alkaloids.6−11
Motivated by their unique glycosidic linkages, we pursued a
synthesis of amphimedosides A−C (Figure 1) by using
oxyamine neoglycosylation. The promising biological activities
of amphimedosides A−C led us to examine the cytotoxicity of
these alkaloids toward several human cancer cell lines.
Figure 1. Amphimedosides A−C are 3-alkylpyridines that contain
unique O-methyl-N-(β-D-glucopyranosyl)hydroxylamine termini.
Received: December 4, 2012
Published: January 31, 2013
© 2013 American Chemical Society
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Figure 2. Generation of pyridylalkyne intermediates.
Figure 3. Synthesis of pyridyl alcohols 7a−c.
Since the late 1990s, it has been known that secondary
alkoxyamines react with unprotected and unactivated reducing
sugars under mild conditions to provide cyclic neoglyco-
sides.6−11 This methodology, known as oxyamine neo-
glycosylation, has been shown to favor formation of β-
pyranosides when D-glucose is used. Based on the desired β-
anomeric stereochemistry of amphimedosides A−C and the
fact that this strategy can be employed without the use of
activating or protecting groups, we used this glycosylation
method. As shown in Figure 5, we treated aglycons 12a−c with
D-glucose under mildly acidic conditions for 2 days, providing
amphimedosides A−C (1a−c) in excellent stereoselectivities
Table 1. Effect of Reaction Conditions on Isolated Yield of
N-Boc-Protected-O-methoxyamine
a
b
entry
X
conditions
THF, 40 °C
THF, 40 °C
isolated yield (%)
1
OTs (8a)
OMs (8b)
OMs (8b)
OMs (8b)
OMs (8b)
OMs (8b)
Br (8c)
39
17
17
33
38
34
25
37
32
39
54
2
3
THF, rt
4
NaI, THF, rt
5
THF/DMPU (3:1), rt
NaI, THF/DMPU (3:1), rt
THF, 40 °C
1
(100% β-anomer). The H and 13C NMR spectroscopic data
6
for 1a−c are identical to published data for the natural
products.5 Unfortunately, the yields of the neoglycosylation
reactions were low, and our attempts to improve them were not
fruitful.18
Fusetani and co-workers found that amphimedosides A−C
(1a−c) displayed significant cytotoxicity against P388 murine
leukemia cells (IC50 = 21.7, 23.0, and 10.4 μM, respectively).5
Related, but nonglycosylated, 3-alkylpyridines display similar
potency. For example, methoxyamines niphatesine H (the
aglycon of amphimedoside C, 12c) and niphatyne A (13) are
moderately cytotoxic (IC50 = 6.0 μM, 1.5 μM)3b,c as are O-
methyl oximes niphatesine E (14) and niphatesine F (15)
(Figure 6).3b
Based on these preliminary findings, we decided to assess the
cytotoxicity of oximes 11a−c, methoxyamines 12a−c, and
amphimedosides A−C (1a−c) toward human cancer cell lines
representing a range of tumor types including lung, prostate,
liver, colon, breast, and skin (Figure 7). Amphimedosides A−C
(1a−c) displayed modest cytotoxicity (IC50 = 10 to greater
than 100 μM) toward the seven cell lines tested. Interestingly,
1a−c were at least three times more potent against Hep3B cells
than any other cell line examined. Oxime ethers displayed
cytotoxicity profiles similar to 1a−c but with slightly
7
8
Br (8c)
THF, rt
9
Br (8c)
NaI, THF, rt
10
11
Br (8c)
THF/DMPU (3:1), rt
NaI, THF/DMPU (3:1), rt
Br (8c)
a
Reactions were run with N-(tert-butoxycarbonyl)-O-methoxyamine
(1.5 equiv), sodium hydride (2.7 equiv), and substrate 8 (1.0 equiv) in
the indicated solvent (1 mL/mmol substrate) at the indicated
b
temperature for 3−6 d. Following SiO2 column chromatography.
corresponding bromides would lower further the overall yield
of the methoxyamine installation sequence, we turned our
attention to reductive amination.
Alcohols 7a−c were oxidized using Swern conditions, and
the resulting aldehydes (10a−c) were converted to the
corresponding O-methyl oxime ethers (11a−c) using methoxy-
amine hydrochloride in the presence of pyridine (Figure 4).7
Oximes 11a−c were subsequently reduced using sodium
cyanoborohydride in acetic acid to provide the aglycons of
amphimedosides A−C (12a−c) in excellent yields. The overall
yields of 12a−c from 7a−c (three steps) ranged from 40 to
65%.
Figure 4. Amphimedoside aglycons 12a−c were produced from 7a−c via oxidation followed by reductive amination.
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Figure 5. Oxyamine neoglycosylation of 12a−c produced amphimedosides 1a−c in excellent stereoselectivities but in low yields.
absence of activating and protecting groups, it is interesting to
consider the biosynthesis of this glycosidic linkage. Typically,
the glycosylation of secondary metabolites is mediated by
glycosyltransferases using activated nucleotide diphosphosugar
(NDP-sugar) donors. However, because of the unique
reactivity of secondary alkoxyamines, it is also theoretically
possible that glucose itself serves as the sugar donor in
amphimedoside biosynthesis. Such a transformation seems less
likely than the canonical enzymatic process since oxyamine
neoglycosylations require high sugar concentrations, acid, and
heat, and since secondary alkoxyamine glycosylation can be
accomplished in vitro using glycosyltransferases and NDP-sugar
donors.19
Figure 6. Structures of nonglycosylated 3-alkylpyridines that are
related to amphimedosides A−C.
EXPERIMENTAL SECTION
■
General Procedure for Model Study To Produce O-Methyl-
N-octyl-N-(tert-butoxycarbonyl)hydroxylamine (9). NaH (2.7
equiv) was added to a solution of THF or 3:1 THF/DMPU (1 mL/
mmol of 8), and the resulting mixture was cooled to 0 °C. N-(tert-
Butoxycarbonyl)-O-methoxyamine (1.5 equiv) was added dropwise,
and the mixture was warmed to rt. A substrate (8) was added, and the
solution was stirred at the temperature shown in Table 1 for 3−6 d.
The reaction mixtures were diluted with water and extracted with
EtOAc (4×). The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated. The crude product
mixtures were purified by SiO2 column chromatography eluting with
49:1 toluene/EtOAc to provide 9 (TLC Rf = 0.36 in 49:1 toluene/
EtOAc) as an oil: IR νmax (thin film) 2930, 2857, 1705, 1458, 1367,
1252, 1168, 1081 cm−1; 1H NMR (CDCl3, 400 MHz) δ 3.67 (s, 3H),
3.41 (dd, 2H, J = 7.3 Hz), 1.58 (m, 2H), 1.49 (s, 9H), 1.28 (m, 10H),
0.87 (t, 3H, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 156.5, 81.1,
diminished potency. In contrast, amphimedoside aglycons
12a−c were nonselective but more potent than 1a−c (IC50
=
2−36 μM). Thus, it appears glucosylation may slightly enhance
cell line selectivity but may diminish overall potency. It is
possible that efforts to glycorandomize10 the amphimedosides
or to generate linkage-diversified derivatives7a,c might provide
cytotoxins with improved activities.
In summary, amphimedosides A−C were synthesized in
overall yields ranging from 3 to 20% (7−9 steps). The
amphimedosides, as well as the corresponding oximes and
methoxyamines, displayed modest cytotoxicity against a panel
of human cancer cell lines. Given our demonstration that 12a−
c can be glycosylated to form the amphimedosides in the
Figure 7. Summary of IC50 data from cytotoxicity assays. Reciprocal IC50 values are shown for clarity, and error bars indicate the calculated standard
error. Where bars are not visible, the IC50 values were >100 μM. A table containing IC50 values can be found in the Supporting Information.
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62.3, 49.2, 31.9, 29.42, 29.36, 28.5, 27.3, 26.9, 22.8, 14.2; HRMS (ESI,
TOF) m/z (M + Na) calcd for C14H29NO3Na 282.2045, obsd
282.2042.
petroleum ether (3×). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated. The crude
product mixture was purified by SiO2 column chromatography eluting
with 3:7 EtOAc/hexane to provide 6c (TLC Rf = 0.47 in 3:7 EtOAc/
hexane) as an oil (1.26 g, 28% yield): IR νmax (thin film) 3070, 2934,
3-(Pyridin-3-yl)propanal (3a). Oxalyl chloride (0.52 mL, 6.20
mmol) was added to CH2Cl2 (4.4 mL) and cooled to −78 °C. DMSO
(0.55 mL, 7.75 mmol) was added dropwise followed by a solution of
3-pyridinepropanol (0.4 mL, 3.10 mmol) in CH2Cl2 (0.72 mL). The
resulting mixture was stirred at −78 °C for 45 min, and then
triethylamine (1.73 mL, 12.4 mmol) was added dropwise. The solution
was warmed to rt and was stirred for 30 min, diluted with diethyl ether
(100 mL), filtered, and concentrated. The crude product mixture was
purified by SiO2 column chromatography eluting with 1:1 EtOAc/
hexane to provide 7a (TLC Rf = 0.33 in EtOAc) as an oil (290.0 mg,
69% yield). Spectral data for 3a matched those previously reported.20
3-(Pyridin-3-yl)but-1-yne (4a). A solution of dimethyl-1-diazo-2-
oxopropylphosphonate14 (2.36 g, 12.26 mmol) in anhydrous MeOH
(7.8 mL) was added to aldehyde 3a (1.38 g, 10.22 mmol) under
nitrogen. Anhydrous K2CO3 (2.70 g, 20.44 mmol) was added, and the
resulting mixture was stirred overnight. The reaction was quenched
with water and then extracted with diethyl ether (4×). The combined
organic layers were washed with satd aq NaHCO3 and brine, dried
over Na2SO4, filtered, and concentrated. The crude product mixture
was purified by SiO2 column chromatography eluting with 1:1 EtOAc/
hexane to provide 4a (TLC Rf = 0.40 in 1:1 EtOAc/hexane) as an oil
(1.15 g, 85% yield). Spectral data for 4a matched those previously
reported.21
1
2856, 1574, 1472, 1427, 1111 cm−1; H NMR (CDCl3, 400 MHz) δ
8.49 (d, 1H, J = 2.1 Hz), 8.46 (dd, 1H, J = 4.8, 1.6 Hz), 7.67 (m, 4H),
7.55, (ddd, 1H, J = 7.8, 2.3, 1.8 Hz), 7.39 (m, 6H), 7.21 (ddd, 1H, J =
7.8, 4.8, 0.7 Hz), 3.65 (t, 2H, J = 6.6 Hz), 2.79 (t, 2H, J = 7.3 Hz), 2.46
(tt, 2H, J = 7.2, 2.3 Hz), 2.11 (tt, 2H, J = 7.0, 2.3 Hz), 1.64−1.21 (m,
16H), 1.04 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 150.4, 148.0,
136.4, 136.2, 135.8, 134.5, 129.7, 127.8, 123.4, 82.2, 78.8, 64.3, 32.9,
29.9, 29.86, 29.77, 29.7, 29.4, 29.3, 29.1, 27.1, 26.0, 21.0, 19.5, 18.9;
HRMS (ESI, TOF) m/z (M + H) calcd for C35H48NOSi 526.3505,
obsd 526.3502.
16-(Pyridin-3-yl)-hexadec-11-yn-1-ol (7a). Protected alkyne 6a
(1.02 g, 1.85 mmol) was dissolved in MeOH (10.3 mL), NH4F (1.08
g, 34.8 mmol) was added, and the resulting mixture was stirred at
reflux overnight. Additional NH4F (1.00 g, 32.2 mmol) was added at 3
and 4 h to promote reaction completion. The reaction was diluted
with satd aq NaHCO3 and water (1:1) and extracted with ethyl acetate
(3×). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude product mixture was
purified by SiO2 column chromatography eluting with 1:1 EtOAc/
hexane followed by 95:5 EtOAc/MeOH to provide 7a (TLC Rf = 0.17
in 3:7 EtOAc/hexane) as an oil (0.484 g, 83% yield): IR νmax (thin
1
film) 3339, 2928, 2855, 1578, 1463, 1425 cm−1; H NMR (CDCl3,
16-(Pyridin-3-yl)-1-(tert-butyldiphenylsilyloxy)hexadec-11-
yne (6a). Alkyne 4b12 (0.515 g, 3.23 mmol) was dissolved in THF
(6.6 mL) and DMPU (2.02 mL, 16.8 mmol), and the resulting mixture
was cooled to −78 °C. After 10 min, n-BuLi in hexanes (2.88 mL, 3.88
mmol, 1.348 M) was added dropwise. After 30 min at −78 °C, a
solution of 5b12 (4.39 g, 8.41 mmol) in THF (13.2 mL) was added
dropwise via cannula, and the reaction was stirred overnight at rt. The
reaction mixture was quenched with water and extracted with
petroleum ether (3×). The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated. The crude
product mixture was purified by SiO2 column chromatography eluting
with 3:7 EtOAc/hexane to provide 6a (TLC Rf = 0.41 in 3:7 EtOAc/
hexane) as an oil (1.02 g, 57% yield): IR νmax (thin film) 3071, 2925,
400 MHz) δ 8.44 (m, 2H), 7.50 (ddd, 1H, J = 7.7, 2.1, 1.7 Hz), 7.21
(ddd, 1H, J = 7.8, 4.8, 0.7 Hz), 4.06 (t, 1H, J = 6.7 Hz), 3.64 (t, 2H, J =
6.6 Hz), 2.63 (dd, 2H, J = 7.6, 7.6 Hz), 2.20 (m, 2H), 2.14 (m, 2H),
1.76−1.23 (m, 20H); 13C NMR (CDCl3, 100 MHz) δ 149.6, 146.9,
137.7, 136.0, 123.3, 80.7, 79.5, 62.5, 32.8, 32.4, 30.1, 29.5, 29.41, 29.40,
29.1, 29.0, 28.8, 28.4, 25.8, 18.7, 18.5; HRMS (ESI, TOF) m/z (M +
H) calcd for C21H34NO 316.2640, obsd 316.2650.
14-(Pyridin-3-yl)tetradec-9-yne-1-ol (7b). Protected alkyne 6b
(3.20 g, 6.10 mmol) was dissolved in MeOH (33.9 mL), NH4F (3.56
g, 114.7 mmol) was added, and the resulting mixture was stirred at
reflux overnight. Additional NH4F was added at 4 and 6 h to promote
reaction completion (1.2 g, 38.7 mmol and 1.0 g, 32.2 mmol,
respectively). The reaction was diluted with satd aq NaHCO3 and
water (1:1) and extracted with ethyl acetate (3×). The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude product mixture was purified by SiO2 column
chromatography eluting with 1:1 EtOAc/hexane followed by 95:5
EtOAc/MeOH to provide 7b (TLC Rf = 0.13 in 3:7 EtOAc/hexane)
as an oil (1.53 g, 87% yield). Spectral data for 7b matched those
previously reported.12b
14-(Pyridin-3-yl)tetradec-11-yn-1-ol (7c). Protected alkyne 6c
(1.26 g, 2.39 mmol) was dissolved in MeOH (3.3 mL), NH4F (1.40 g,
45.0 mmol) was added, and the resulting mixture was stirred at reflux
overnight. Additional NH4F (0.50 g, 16.1 mmol) was added at 3 and 4
h to promote reaction completion. The reaction was diluted with satd
aq NaHCO3 and water (1:1) and extracted with ethyl acetate (3×).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude product mixture was
purified by SiO2 column chromatography eluting with 1:1 EtOAc/
hexane followed by 95:5 EtOAc/MeOH to provide 7c (TLC Rf = 0.45
in 7:3 EtOAc/hexane) as an oil (0.666 g, 97% yield): IR νmax (thin
film) 3326, 3050, 2932, 2855, 1742, 1578, 1425, 1266 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 8.49 (d, 1H, J = 1.9 Hz), 8.46 (dd, 1H, J = 4.8,
1.6 Hz), 7.56 (ddd, 1H, J = 7.8, 2.2, 1.7 Hz), 7.22 (ddd, 1H, J = 7.8,
4.8, 0.7 Hz), 3.64 (t, 2H, J = 6.6 Hz), 2.79 (t, 2H, J = 7.2 Hz), 2.47 (tt,
2H, J = 7.1, 2.3 Hz), 2.11 (tt, 2H, J = 7.0, 2.3 Hz), 1.66−1.21 (m,
16H); 13C NMR (CDCl3, 100 MHz): δ 150.1, 147.7, 136.1, 123.2,
82.0, 78.5, 63.1, 32.8, 32.5, 29.5, 29.39, 29.36, 29.1, 28.9, 28.8, 25.7,
20.6, 18.6; HRMS (ESI, TOF) m/z (M + H) calcd for C19H30NO
288.2327, obsd 288.2319.
1
2854, 1575, 1472, 1462, 1427, 1111 cm−1; H NMR (CDCl3, 400
MHz) δ 8.44 (m, 2H), 7.67 (m, 4H), 7.49 (ddd, 1H, J = 7.8, 2.2, 1.8
Hz), 7.39 (m, 6H), 7.20 (ddd, 1H, J = 7.7, 4.8, 0.6 Hz), 3.65 (t, 2H, J =
6.4 Hz), 2.62 (t, 2H, J = 7.6 Hz), 2.19 (m, 2H), 2.13 (m, 2H), 1.73 (m,
2H), 1.57−1.24 (m, 18H), 1.04 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 150.0, 147.3, 137.6, 135.8, 135.6, 134.2, 129.5, 127.6, 123.3,
80.8, 79.5, 64.0, 32.6, 32.5, 30.2, 29.6, 29.5, 29.4, 29.2, 29.1, 28.9, 28.5,
26.9, 25.8, 19.2, 18.7, 18.6; HRMS (ESI, TOF) m/z (M + H) calcd for
C37H52NOSi 554.3818, obsd 554.3818.
14-(Pyridine-3-yl)-1-(tert-butyldiphenylsilyloxy)tetradec-9-
yne (6b). Alkyne 4b12 (1.37 g, 8.63 mmol) was dissolved in THF
(17.6 mL) and DMPU (5.39 mL, 44.7 mmol), and the resulting
mixture was cooled to −78 °C. After 10 min, n-BuLi in hexanes (8.0
mL, 10.35 mmol, 1.30 M) was added dropwise. After 30 min at −78
°C, a solution of 5a12 (11.36 g, 23.0 mmol) in THF (35.2 mL) was
added dropwise via cannula, and the reaction was stirred overnight at
rt. The reaction mixture was quenched with water and extracted with
petroleum ether (3×). The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated. The crude
product mixture was purified by SiO2 column chromatography eluting
with 3:7 EtOAc/hexane to provide 6b (TLC Rf = 0.25 in 3:7 EtOAc/
hexane) as an oil (3.16 g, 70% yield). Spectral data for 6b matched
those previously reported.12b
14-(Pyridine-3-yl)-1-(tert-butyldiphenylsilyloxy)tetradec-11-
yne (6c). Alkyne 4a (1.14 g, 8.70 mmol) was dissolved in THF (17.7
mL) and DMPU (5.44 mL, 45.2 mmol), and the resulting mixture was
cooled to −78 °C. After 10 min, n-BuLi in hexanes (8.0 mL, 10.4
mmol, 1.30 M) was added dropwise. After 30 min at −78 °C, a
solution of 5a12 (11.82 g, 22.6 mmol) in THF (35.5 mL) was added
dropwise via cannula, and the reaction was stirred overnight at rt. The
reaction mixture was quenched with water and extracted with
16-(Pyridin-3-yl)hexadec-11-yn-1-al (10a). Oxalyl chloride
(17.0 μL, 0.103 mmol) was added to CH2Cl2 (0.15 mL) and cooled
to −78 °C. DMSO (18.0 μL, 0.257 mmol) was added dropwise
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followed by a solution of 7a (32.4 mg, 0.103 mmol) in CH2Cl2 (0.1
mL). The resulting mixture was stirred at −78 °C for 45 min, and then
triethylamine (57.0 μL, 0.411 mmol) was added dropwise. The
solution was allowed to warm to rt and was stirred for 30 min, diluted
with diethyl ether (4 mL), filtered, and concentrated. The crude
product mixture was purified by SiO2 column chromatography eluting
with 2:3 EtOAc/hexane to provide 8a (TLC Rf = 0.27 in 3:2 hexane/
EtOAc) as an oil (20.1 mg, 62% yield): IR νmax (thin film) 3425, 2932,
2855, 2719, 1723, 1423 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.77 (t,
1H, J = 1.8 Hz), 8.44 (m, 2H), 7.50 (ddd, 1H, J = 7.8, 2.2, 1.8 Hz),
7.21 (ddd, J = 7.8, 4.8, 0.7 Hz), 2.63 (dd, 2H, J = 7.7, 7.7 Hz), 2.42 (td,
2H, J = 7.1, 1.9 Hz), 2.19 (m, 2H), 2.13 (m, 2H), 1.77−1.24 (m,
18H); 13C NMR (CDCl3, 100 MHz): δ 203.0, 149.7, 147.0, 137.9,
136.1, 123.4, 80.7, 79.5, 62.6, 43.9, 32.5, 30.1, 29.3, 29.13, 29.09, 29.07,
28.8, 28.4, 22.1, 18.7, 18.5; HRMS (ESI, TOF) m/z (M + H) calcd for
C21H32NO 314.2483, obsd 314.2487.
14-(Pyridin-3-yl)tetradec-9-yn-1-al (10b). Oxalyl chloride (0.81
mL, 1.62 mmol) was added to CH2Cl2 (0.5 mL) and cooled to −78
°C. DMSO (0.14 mL, 2.03 mmol) was added dropwise followed by a
solution of 7b (233.1 mg, 0.811 mmol) in CH2Cl2 (0.2 mL). The
resulting mixture was stirred at −78 °C for 45 min, and then
triethylamine (0.45 mL, 3.24 mmol) was added dropwise. The solution
was allowed to warm to rt and was stirred for 30 min, diluted with
diethyl ether (30 mL), filtered, and concentrated. The crude product
mixture was purified by SiO2 column chromatography eluting with 2:3
EtOAc/hexane to provide 8b (TLC Rf = 0.15 in 3:2 hexane/EtOAc) as
an oil (175.7 mg, 76% yield): IR νmax (thin film) 3423, 2930, 2858,
1723, 1423 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.76 (t, 1H, J = 1.9
Hz), 8.45 (m, 2H), 7.50 (ddd, 1H, J = 7.7, 2.1, 1.6 Hz), 7.21 (ddd, J =
7.7, 4.8, 0.6 Hz), 2.63 (dd, 2H, J = 7.6, 7.6 Hz), 2.42 (td, 2H, J = 7.3,
1.8 Hz), 2.19 (m, 2H), 2.14 (m, 2H), 1.77−1.20 (m, 14H); 13C NMR
(CDCl3, 100 MHz) δ 203.0, 150.1, 147.4, 137.7, 135.9, 123.4, 80.7,
79.8, 44.0, 32.6, 30.3, 29.14, 29.08, 29.0, 28.7, 28.5, 22.1, 18.8, 18.6;
HRMS (ESI, TOF) m/z (M + H) calcd for C19H28NO 286.2170, obsd
286.2175.
(CDCl3, 100 MHz) δ 152.0, 151.1, 149.8, 147.1, 137.7, 135.9, 124.2,
123.3, 80.7, 79.5, 61.5, 61.2, 32.5, 30.2, 29.4, 29.32, 29.27, 29.2, 29.1,
28.9, 28.5, 26.7, 26.2, 25.5, 18.7, 18.5; HRMS (ESI, TOF) m/z (M +
H) calcd for C22H35N2O 343.2749, obsd 343.2765.
14-(Pyridin-3-yl)tetradec-9-yn-1-al O-Methyl Oxime (11b).
Aldehyde 10b (50.8 mg, 0.178 mmol) was dissolved in MeOH (0.4
mL) and pyridine (320 μL, 0.392 mmol). MeONH3Cl (22.3 mg, 0.267
mmol) was added, and the solution was stirred for 3 h then
concentrated. The resulting residue was dissolved in CH2Cl2, washed
with satd aq NaHCO3 (3×) and brine, dried over Na2SO4, filtered, and
concentrated. The crude product mixture was purified by SiO2 column
chromatography eluting with 1:1 EtOAc/hexane to provide a
1
diastereomeric mixture (1.5:1 E/Z by H NMR) of 11b (TLC Rf =
0.58 and 0.39 in 1:1 hexane/EtOAc) as an oil (38.8 mg, 70% yield): IR
1
νmax (thin film) 2936, 2857, 1726, 1575, 1463, 1422, 1057 cm−1; H
NMR (CDCl3, 400 MHz) δ 8.45 (m, 2H), 7.50 (m, 1H), 7.36 (t,
0.6H, J = 6.2 Hz), 7.21 (dd, 1H, J = 7.7, 4.1 Hz), 6.62 (t, 0.4H, J = 5.4
Hz), 3.86 (s, 1.2H), 3.81 (s, 1.7H), 2.63 (dd, 2H, J = 7.6, 7.6 Hz), 2.30
(td, 0.86H, J = 7.5, 5.5 Hz), 2.16 (m, 5.2H), 1.77−1.25 (m, 14H); 13C
NMR (CDCl3, 100 MHz) δ 152.1, 151.2, 150.1, 147.5, 137.7, 135.9,
32.7, 30.3, 29.2, 29.1, 29.0, 28.8, 28.6, 26.8, 25.5, 18.9, 18.7; HRMS
(ESI, TOF) m/z (M + H) calcd for C20H31N2O 315.2436, obsd
315.2426.
14-(Pyridin-3-yl)tetradec-11-yn-1-al O-Methyl Oxime (11c).
Aldehyde 10c (115.1 mg, 0.403 mmol) was dissolved in MeOH (0.9
mL) and pyridine (130.4 μL, 1.612 mmol). MeONH3Cl (50.5 mg,
0.605 mmol) was added, and the solution was stirred for 3 h and then
concentrated. The resulting residue was dissolved in CH2Cl2, washed
with satd aq NaHCO3 (3×) and brine, dried over Na2SO4, filtered, and
concentrated. The crude product mixture was purified by SiO2 column
chromatography eluting with 1:1 EtOAc/hexane to provide a
1
diastereomeric mixture (1.5:1 E/Z by H NMR) of 11c (TLC Rf =
0.54 and 0.35 in 1:1 hexane/EtOAc) as an oil (105.2 mg, 83% yield):
IR νmax (thin film) 3413, 2930, 2855, 1634, 1465, 1424, 1047 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 8.49 (d, 1H, J = 2.0 Hz), 8.47 (dd, 1H, J =
4.7, 1.5 Hz), 7.56 (dt, 1H, J = 7.6, 1.9 Hz), 7.36 (t, 0.6H, J = 6.3 Hz),
7.22 (ddd, 1H, J = 7.6, 4.7, 0.5 Hz), 6.63 (t, 0.4H, J = 5.4 Hz), 3.86 (s,
1.2H), 3.82 (s, 1.7H), 2.79 (t, 2H, J = 7.3 Hz), 2.46 (tt, 2H, J = 7.1, 2.4
Hz), 2.30 (m, 0.8H), 2.20−2.09 (m, 3.2H), 1.51−1.23 (m, 14H); 13C
NMR (CDCl3, 100 MHz) δ 152.2, 151.2, 150.2, 147.8, 136.3, 136.1,
123.3, 82.0, 78.6, 62.8, 61.7, 61.3, 32.7, 29.6, 29.50, 29.46, 29.42, 29.38,
29.2, 29.1, 28.9, 26.9, 26.4, 25.7, 20.8, 18.8; HRMS (ESI, TOF) m/z
(M + H) calcd for C20H31N2O 315.2436, obsd 315.2440.
O-Methyl-N-(16-(pyridin-3-yl)hexadec-11-ynyl)hydroxyl-
amine (12a). Oxime 11a (37.4 mg, 0.109 mmol) was dissolved in
AcOH (0.7 mL), and NaCNBH3 (117.0 mg, 0.186 mmol) was added.
After 1 h, the reaction mixture was diluted with CH2Cl2 and washed
with satd aq NaHCO3 (2×). The aqueous layers were extracted with
CH2Cl2, and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The crude product
mixture was purified by SiO2 column chromatography eluting with 1:1
EtOAc/hexane to provide 12a (TLC Rf = 0.25 in 1:1 hexane/EtOAc)
as an oil (38.0 mg, 100% yield): IR νmax (thin film) 2930, 2855, 1757,
1427, 1111 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.44 (m, 2H), 7.50
(dt, 1H, J = 7.7, 1.8 Hz), 7.20 (dd, 1H, J = 7.7, 4.6 Hz), 5.57 (br s,
1H), 3.54 (s, 3H), 2.91 (dd, 1H, J = 7.2, 7.2 Hz), 2.63 (dd, 1H, J = 7.7,
7.7 Hz), 2.19 (m, 2H), 2.13 (m, 2H), 1.73 (m, 2H), 1.58−1.17 (18H);
13C NMR (CDCl3, 100 MHz) δ 149.9, 147.3, 137.5, 135.7, 123.2, 80.7,
14-(Pyridin-3-yl)tetradec-11-yn-1-al (10c). Oxalyl chloride in
CH2Cl2 (0.72 mL, 1.43 mmol, 2 M) was added to CH2Cl2 (0.45 mL)
and cooled to −78 °C. DMSO (0.13 mL, 1.79 mmol) was added
dropwise followed by a solution of 7c (206.0 mg, 0.717 mmol) in
CH2Cl2 (0.2 mL). The resulting mixture was stirred at −78 °C for 45
min, and then triethylamine (0.40 mL, 2.87 mmol) was added
dropwise. The solution was allowed to warm to rt and was stirred for
30 min, diluted with diethyl ether (30 mL), filtered, and concentrated.
The crude product mixture was purified by SiO2 column
chromatography eluting with 2:3 EtOAc/hexane to provide 8c
(TLC Rf = 0.35 in 3:2 hexane/EtOAc) as an oil (115.1 mg, 56%
1
yield): IR νmax (thin film) 2918, 2850, 1463, 1265 cm−1; H NMR
(CDCl3, 400 MHz) δ 9.77 (t, 1H, J = 1.8 Hz), 8.49 (d, 1H, J = 1.8
Hz), 8.47 (dd, 1H, J = 4.8, 1.5 Hz), 7.56 (ddd, 1H, J = 7.8, 2.1, 1.8
Hz), 7.22 (ddd, 7.7, 4.8, 0.6 Hz), 2.63 (t, 2H, J = 7.3 Hz), 2.46 (tt, 2H,
J = 7.2, 2.3 Hz), 2.43 (td, 2H, J = 7.4, 1.9 Hz), 2.11 (td, 2H, J = 7.0, 2.3
Hz), 1.67−1.23 (m, 14H); 13C NMR (CDCl3, 100 MHz) δ 203.2,
150.2, 147.9, 137.5, 136.2, 123.3, 78.7, 44.1, 32.7, 29.5, 29.4, 29.3, 29.2,
29.1, 28.9, 25.6, 22.2, 20.8, 18.8; HRMS (ESI, TOF) m/z (M + H)
calcd for C19H28NO 286.2170, obsd 286.2198.
16-(Pyridin-3-yl)hexadec-11-yn-1-al O-Methyl Oxime (11a).
Aldehyde 10a (70.7 mg, 0.226 mmol) was dissolved in MeOH (0.5
mL) and pyridine (400 μL, 0.496 mmol). MeONH3Cl (28.2 mg, 0.338
mmol) was added, and the solution was stirred for 3 h and then
concentrated. The resulting residue was dissolved in CH2Cl2, washed
with satd aq NaHCO3 (3×) and brine, dried over Na2SO4, filtered, and
concentrated. The crude product mixture was purified by SiO2 column
chromatography eluting with 1:1 EtOAc/hexane to provide a
79.5, 61.8, 51.9, 32.5, 30.1, 29.7, 29.50, 29.46, 29.12, 29.11, 28.9, 28.4,
27.3, 27.2, 18.7, 18.5; HRMS (ESI, TOF) m/z (M + H) calcd for
C22H37N2O 345.2905, obsd 345.2892.
O-Methyl-N-(14-(pyridin-3-yl)tetradec-9-ynyl)hydroxyl-
amine (12b). Oxime 11b (185.9 mg, 0.616 mmol) was dissolved in
AcOH (3.8 mL), and NaCNBH3 (65.8 mg, 1.046 mmol) was added.
After 1 h, the reaction mixture was diluted with CH2Cl2 and washed
with satd aq NaHCO3 (2×). The aqueous layers were extracted with
CH2Cl2, and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The crude product
mixture was purified by SiO2 column chromatography eluting with 1:1
EtOAc/hexane to provide 12b (TLC Rf = 0.28 in 1:1 hexane/EtOAc)
1
diastereomeric mixture (1:2.1 E/Z by H NMR) of 11a (TLC Rf =
0.51 and 0.25 in 1:1 hexane/EtOAc) as an oil (63.3 mg, 82% yield): IR
1
νmax (thin film) 2934, 2855, 1744, 1575, 1464, 1423, 1049 cm−1; H
NMR (CDCl3, 400 MHz) δ 8.39 (m, 2H), 7.44 (m, 1H), 7.29 (t,
0.3H, J 6.7), 7.15 (dd, 1H, J = 7.8, 4.8 Hz), 6.55 (t, 0.7H, J = 5.6 Hz),
3.79 (s, 2.3H), 3.74 (0.5H); 2.56 (t, 2H, J = 7.7 Hz), 2.26 (td, 1.4H, J
= 7.3, 5.4 Hz), 2.15−2.04 (m, 4.7H), 1.70−1.18 (m, 18H); 13C NMR
1674
dx.doi.org/10.1021/jo302640y | J. Org. Chem. 2013, 78, 1670−1676

The Journal of Organic Chemistry
Note
as an oil (123.9 mg, 67% yield): IR νmax (thin film) 2932, 2856, 1575,
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectral data of all new compounds and IC50
values for 1a−c, 11a−c, and 12a−c. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
1
1463, 1423, 1026 cm−1; H NMR (CDCl3, 400 MHz) δ δ 8.45 (m,
S
2H), 7.50 (m, 1H), 7.21 (dd, 1H, J = 7.7, 4.7 Hz), 4.57 (br s, 1H), 3.54
(s, 3H), 2.91 (dd, 1H, J = 7.3, 7.3 Hz), 2.63 (dd, 1H, J = 7.6, 7.6 Hz),
2.19 (m, 2H), 2.13 (m, 2H), 1.73 (m, 2H), 1.56−1.26 (m, 16H); 13C
NMR (CDCl3, 100 MHz) δ 149.9, 147.2, 137.6, 135.8, 123.3, 80.7,
79.5, 61.8, 51.9, 32.5, 30.1, 29.4, 29.1, 29.0, 28.8, 28.4, 27.2, 27.1, 18.7,
18.5; HRMS (ESI, TOF) m/z (M + H) calcd for C20H33N2O
317.2592, obsd 317.2578.
AUTHOR INFORMATION
Corresponding Author
*Tel: 206-296-2368. Fax: 206-296-5786. E-mail: langenha@
seattleu.edu.
■
O-Methyl-N-(14-(pyridin-3-yl)tetradec-11-ynyl)hydroxyl-
amine (12c). Oxime 11c (80.3 mg, 0.256 mmol) was dissolved in
AcOH (1.6 mL), and NaCNBH3 (27.3 mg, 0.435 mmol) was added.
After 1 h, the reaction mixture was diluted with CH2Cl2 and washed
with satd aq NaHCO3 (2×). The aqueous layers were extracted with
CH2Cl2, and the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The crude product
mixture was purified by SiO2 column chromatography eluting with 1:1
EtOAc/hexane to provide 12c (TLC Rf = 0.26 in 1:1 hexane/EtOAc)
as an oil (80.9 mg, 86% yield): IR νmax (thin film) 3054, 2987, 1421,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Noel Peters for performing cytotoxicity assays and
̈
Douglas Latch, Martin Sadilek, and Loren Kruse for MS
assistance. The authors were supported by the Camille and
Henry Dreyfus Foundation, the Research Corporation, the MJ
Murdock Charitable Trust, and Seattle University.
1
1354 cm−1; H NMR (CDCl3, 400 MHz) δ 8.48 (m, 2H), 7.56 (ddd,
1H, J = 7.7, 2.1, 1.7 Hz), 7.22 (ddd, 1H, J = 7.7, 4.8, 0.6 Hz), 5.54 (br
s, 1H), 3.54 (s, 3H), 2.91 (dd, 2H, J = 7.3, 7.3 Hz), 2.79 (dd, 2H, J =
7.7, 7.7 Hz), 2.46 (tt, 2H, J = 7.1, 2.3 Hz), 2.11 (tt, 2H, J = 7.0, 2.5
Hz), 1.67−1.22 (m, 16H); 13C NMR (CDCl3, 100 MHz): δ 150.1,
147.7, 136.1, 136.0, 123.2, 81.9, 78.5, 62.6, 61.8, 52.0, 32.6, 29.52,
29.46, 29.2, 29.0, 28.8, 27.3, 27.2, 20.7, 18.7; HRMS (ESI, TOF) m/z
(M + H) calcd for C20H33N2O 317.2592, obsd 317.2580.
REFERENCES
■
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9:1 MeOH/CHCl3 (1.3 mL), AcOH (7.6 μL, 132.3 μmol) was added,
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̀
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1
white powder (32.2 mg, 51% yield). H and 13C NMR data for 1b
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2857, 1426, 1082, 1027 cm−1; HRMS (ESI, TOF) m/z (M + H) calcd
for C26H43N2O6 479.3121, obsd 479.3121.
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1
white powder (24.5 mg, 33% yield). H and 13C NMR data for 1c
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2855, 1427, 1083, 1027 cm−1; HRMS (ESI, TOF) m/z (M + H) calcd
for C26H42N2O6Na 501.2940, obsd 501.2935.
Cytotoxicity assays. Compounds 1a-c, 11a-c, and 12a-c were
dissolved in DMSO (30 mM). Assays were conducted as previously
reported (see Supporting Information for IC50 values).7c
1675
dx.doi.org/10.1021/jo302640y | J. Org. Chem. 2013, 78, 1670−1676

The Journal of Organic Chemistry
Note
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5),7 DMF/AcOH cosolvent mixtures, or acidic aqueous buffers.
Unfortunately, reacting 12b with D-glucose in DMF/AcOH (3:1)6
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