Synthesis of the Proposed Isomers of the Deep-Sea Mussel Metabolites Bathymodiolamides A and B

Article abstract of DOI:10.1021/acs.joc.0c02726

The first total synthesis of bathymodiolamides A and B, ceramide-like metabolites of the deep-sea hydrothermal vent mussel Bathymodiolus thermophilus, was accomplished in eight linear steps starting from Garner's aldehyde and three carboxylic acids. A sequence of vinylation of Garner's aldehyde, N-acylation with lauric acid, dihydroxylation of the terminal alkene, and stepwise Steglich-Hassner esterifications of the resulting vicinal diol with the respective saturated and unsaturated carboxylic acids, which had to be prepared separately, afforded the target products in 38 and 39% yield. We found distinct discrepancies between their NMR data and antiproliferative activities and those reported for the natural isolates.

Full text of DOI:10.1021/acs.joc.0c02726

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Synthesis of the Proposed Isomers of the Deep-Sea Mussel
Metabolites Bathymodiolamides A and B
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Alexander Bar, Sofia I. Bar, Moritz Roder, and Rainer Schobert*
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ABSTRACT: The first total synthesis of bathymodiolamides A and B, ceramide-like
metabolites of the deep-sea hydrothermal vent mussel Bathymodiolus thermophilus, was
accomplished in eight linear steps starting from Garner’s aldehyde and three carboxylic
acids. A sequence of vinylation of Garner’s aldehyde, N-acylation with lauric acid,
dihydroxylation of the terminal alkene, and stepwise Steglich−Hassner esterifications of the
resulting vicinal diol with the respective saturated and unsaturated carboxylic acids, which
had to be prepared separately, afforded the target products in 38 and 39% yield. We found distinct discrepancies between their NMR
data and antiproliferative activities and those reported for the natural isolates.
comparison of their physical data and anticancer activities with
those reported for the natural isolates.
INTRODUCTION
■
The bathymodiolamides A (1) and B (2) are ceramide-related
lipid metabolites that were isolated from the deep-sea
hydrothermal vent mussel Bathymodiolus thermophilus.1 Their
absolute configurations were deduced based on NMR and
mass spectra, chemical degradation, and on a comparison of
specific optical rotations of related known compounds. These
data suggested the absolute configurations of the stereotriad of
1 and 2 to be identical to those of the known congener L-
arabino phytosphingosine (3),2 that is, 2R,3S,4R (Figure 1).
Because of their distinct apoptosis induction and cytotoxic
effect in cancer cells, they and further structurally related
metabolites from the same source organism were recently
patented for potential use in cancer chemotherapy.3 We now
report a short flexible synthetic route to the proposed
(2R,3S,4R)-isomers of bathymodiolamides A and B, and a
RESULTS AND DISCUSSION
■
Our retrosynthetic approach is outlined in Scheme 1. Both
target compounds 1 and 2 were finished by consecutive
attachment of the corresponding saturated and unsaturated
Scheme 1. Retrosynthesis of Bathymodiolamides A (1) and
B (2)
Received: November 13, 2020
Published: January 4, 2021
Figure 1. Structures of bathymodiolamides A (1) and B (2) and L-
arabino phytosphingosine (3).
https://dx.doi.org/10.1021/acs.joc.0c02726
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carboxylic acids to diol 4 followed by acetonide deprotection.
Acetonide protection of amide 5 and asymmetric dihydrox-
ylation of the alkene under substrate control should
predominantly furnish diol 4, thus installing stereogenic center
4R. Amide 5 was accessible by deprotection and N-acylation of
allylic alcohol 6 which contributes stereogenic center 3S,
established by syn-selective vinylation of R-Garner’s aldehyde
(7). The latter is readily available from D-serine4 and served as
a source of carbon atoms C1−C3 and of stereogenic center 2R.
Vinylation of 7 with vinyl zinc bromide according to
modified literature procedures5 and purification by column
chromatography afforded the syn-configured allylic alcohol 6 in
92% yield (Scheme 2). It was treated with a mixture of acetyl
Scheme 3. Synthesis of Skipped Polyunsaturated Fatty Acids
15 and 18
Scheme 2. Synthesis of Diol 4 and Its Mono Esters 9a and
9b
under Steglich−Hassner conditions, to afford the diester
amides 19a and 19b which were eventually deprotected with
pTsOH in methanol to give the target compounds 1 and 2 in
38 and 39% overall yield (Scheme 4). Their specific optical
Scheme 4. Final Steps Affording (2R,3S,4R)-
Bathymodiolamides A (1) and B (2)
chloride and methanol to cleave the boc and the aminal groups
resulting in an amine which was acylated right away with
commercially available lauryl chloride to give amide 5 in 99%
yield. Acetonide protection of its hydroxy groups left alkene 8
which was dihydroxylated under substrate control with
potassium osmate/NMO furnishing predominantly diol 4
with a syn/anti ratio of 1:5. Gratifyingly, 4 was easy to purify
via column chromatography and the absolute configuration of
the secondary alcohol was ascertained to be R by analysis of
1
the H NMR spectra of the corresponding Mosher esters (cf.
Supporting Information for details).6 The primary hydroxy
group of 4 was then esterified with palmitic acid or myristic
acid under Steglich−Hassner conditions affording the hydrox-
yesters 9a and 9b in 82 and 69% yield.
rotations of [α]D23 +14.8 (c 0.08 in MeOH) for 1 and [α]2D3
+6.7 (c 0.08 in MeOH) for 2 deviated somewhat from [α]D23
+10.8 (c 0.08 in MeOH)1 as reported for both natural isolates.
1
The required skipped trienoic and dienoic acids 15 and 18
were both prepared starting from readily available 1-bromohex-
2-yne (10)7 (Scheme 3). The copper-mediated coupling of 10
with propargylic alcohol afforded alcohol 11, which in turn was
converted into propargylic bromide 12. Coupling of 12 with 6-
heptynoic acid methyl ester8 gave triyne 13. Z-selective
reduction of 13 according to Brown’s P-2 Ni protocol9 and
saponification of resulting ester 14 led to hexadeca-6Z,9Z,12Z-
trienoic acid (15) in 57% overall yield. Undeca-4Z,7Z-dienoic
acid (18) was prepared analogously in 63% overall yield by
coupling 10 with 4-pentynoic acid methyl ester10 followed by
Z-selective reduction of diyne 16 and saponification of ester
17.
Even more conspicuous are the differences in the H and 13C
NMR spectra of our synthetic products when compared with
those reported by Andrianasolo et al.,1 for the natural isolates,
in particular, the marked differences in the chemical shifts of
the atoms of the aminotetraol moiety and in some coupling
1
constants in the H NMR spectra (cf. Table 1, Supporting
Information). This casts some doubt on the stereochemical
assignment of the aminotetraol moiety of the isolates.
The isolating group also reported the cytotoxicities of 1 and
2 as measured via a modified MTT assay. They found an IC50
= 0.4 μM for 1 and 0.5 μM for 2 against HeLa cervical cancer
cells and an IC50 = 0.1 μM for 1 and 0.2 μM for 2 against
MCF7 breast carcinoma cells.1 We tested our synthetic
products 1 and 2 for antiproliferative effects in MTT assays
against cells of HeLa, MCF7, as well as HCT-116 and its p53
To complete the synthesis, hydroxy esters 9a and 9b were
esterified with the respective oligoenoic acid 15 or 18, again
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mutant HCT-116p53−/− colon carcinoma, 518A2 human
melanoma, and U87 human glioblastoma. However, both
were virtually inactive with IC50 > 50 μM in all tested cancer
cell lines (cf. Table 2, Supporting Information). This inactivity
suggests a possibly incorrect structural assignment for both
natural compounds.
temperature and volatiles were evaporated. The residue was taken up
in THF (30 mL), and NEt3 (2.4 mL, 17.49 mmol) and lauroyl
chloride (1.5 mL, 6.41 mmol) were added. The mixture was stirred
for 18 h at room temperature, then diluted with EtOAc (50 mL), and
the organic phase was washed with 1 M HCl (75 mL), aqueous
NaHCO3 (75 mL), and brine (75 mL), dried over MgSO4, and
evaporated to dryness. The crude product was purified by flash
chromatography (CH2Cl2/MeOH 95:5) to give 5 (1.73 g, 5.78 mmol,
99%) as a white solid of mp 70−71 °C; Rf = 0.49 (CH2Cl2/MeOH
95:5); [α]2D3 +20.8 (c 1.0, CHCl3); 1H NMR (CD3OD, 500 MHz): δ
5.86 (ddd, J = 5.5, 10.5, 17.2 Hz, 1H), 5.30 (td, J = 1.6, 17.2 Hz, 1H),
5.14 (td, J = 1.6, 10.5 Hz, 1H), 4.34 (tdd, J = 1.4, 3.4, 5.5 Hz, 1H),
3.98−3.92 (m, 1H), 3.68 (dd, J = 6.4, 10.9 Hz, 1H), 3.55 (dd, J = 6.4,
10.9 Hz, 1H), 2.21 (dt, J = 1.5, 7.5 Hz, 2H), 1.65−1.55 (m, 2H),
1.35−1.25 (m, 16H), 0.90 (t, J = 7.0 Hz, 3H); 13C{1H} NMR
(CD3OD, 126 MHz): δ 176.7, 139.9, 116.0, 72.0, 62.4, 56.4, 37.3,
33.2, 30.9, 30.8, 30.7, 30.5, 27.3, 23.9, 14.6; IR νmax 3364, 2923, 2853,
2415, 1622, 1456, 1054, 991, 922 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C17H34O3N+, 300.2533; found 300.2523.
N-((4R,5R)-2,2-Dimethyl-4-vinyl-1,3-dioxan-5-yl)dodecanamide
(8). A solution of 5 (1.29 g, 4.32 mmol) in acetone (20 mL) was
treated with 2,2-dimethoxypropane (5.3 mL, 43.24 mmol) and BF3·
Et2O (55 μL, 0.43 mmol). The mixture was stirred for 3 h at ambient
temperature. NEt3 (0.5 mL) was added, and volatiles were removed
under reduced pressure. The residue was purified by flash
chromatography (n-hexane/ethyl acetate 2:1) to give 8 (1.37 g,
4.05 mmol, 94%) as colorless oil; Rf = 0.28 (n-hexan/ethyl acetate
3:1); [α]2D3 +5.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 6.11
(d, J = 9.2 Hz, 1H), 5.71 (ddd, J = 4.4, 10.7, 17.3 Hz, 1H), 5.31 (td, J
= 1.7, 17.3 Hz, 1H), 5.19 (td, J = 1.7, 10.7 Hz, 1H), 4.56 (dd, J = 1.7,
4.3 Hz, 1H), 4.12 (dd, J = 1.8, 12.0 Hz, 1H), 3.97 (dd, J = 1.8, 9.2 Hz,
1H), 3.75 (dd, J = 1.8, 12.0 Hz, 1H), 2.20 (dt, J = 3.1, 7.6 Hz, 2H),
1.65−1.57 (m, 2H), 1.50 (s, 3H), 1.46 (s, 3H), 1.33−1.21 (m, 16H),
0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 172.9,
134.7, 116.6, 99.2, 71.3, 64.6, 45.5, 36.8, 31.9, 29.7, 29.6, 29.5, 29.3,
29.2, 25.7, 22.7, 18.5, 14.1; IR νmax 3322, 2924, 2854, 1651, 1505,
1380, 1269, 1237, 1199, 1087, 985, 856 cm−1; HRMS (ESI) m/z: [M
+ H]+ calcd for C20H38O3N+, 340.2846; found 340.2838.
N-((4S,5R)-4-((R)-1,2-Dihydroxyethyl)-2,2-dimethyl-1,3-dioxan-5-
yl)dodecanamide (4). Alkene 8 (1.32 g, 3.9 mmol) was dissolved in
THF (20 mL), and K2OsO4·2H2O (75 mg, 0.19 mmol) and NMO
(50% in H2O, 2.5 mL, 11.7 mmol) were added. The mixture was
stirred for 18 h at room temperature. Water (50 mL) was added, and
the aqueous phase was extracted with EtOAc (3 × 50 mL). The
combined organic phases were washed with brine (150 mL), dried
over MgSO4, and evaporated to dryness. The crude product was
purified by flash chromatography (n-hexane/ethyl acetate 1:4) to give
diol 4 (1.12 g, 3.0 mmol, 77%) as a colorless oil; Rf = 0.30 (n-hexane/
ethyl acetate 1:2); [α]D23 +40.6 (c 1.0, CHCl3); 1H NMR (CDCl3, 500
MHz): δ 6.35 (d, J = 7.9 Hz, 1H), 5.04 (d, J = 3.7 Hz, 1H), 4.21 (dd,
J = 2.1, 12.2 Hz, 1H), 3.97 (dd, J = 1.5, 8.5 Hz, 1H), 3.88 (dd, J = 1.2,
9.2 Hz, 1H), 3.80−3.73 (m, 2H), 3.57 (td, J = 5.6, 11.3 Hz, 1H),
3.34−3.27 (m, 1H), 2.30 (dt, J = 1.4, 7.7 Hz, 2H); 2.24−2.16 (m,
1H), 1.70−1.62 (m, 2H), 1.47 (s, 3H), 1.40 (s, 3H), 1.37−1.22 (m,
16H), 0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ
175.3, 99.3, 71.7, 69.4, 64.3, 63.1, 44.0, 36.5, 31.9, 29.6, 29.5, 29.4,
29.3, 29.2, 25.7, 22.7, 18.5, 14.1; IR νmax 3316, 2923, 2853, 1640,
1528, 1460, 1382, 1271, 1199, 1087, 849, 662 cm−1; HRMS (ESI) m/
z: [M + H]+ calcd for C20H40O5N+, 374.2901; found, 374.2894. The
anti/syn ratio of 5:1 was determined by analysis of 1H NMR spectrum
of the crude product.
CONCLUSIONS
■
In summary, we developed efficient eight-step syntheses for the
(2R,3S,4R)-isomers purported for the natural bathymodiola-
mides A and B. However, discrepancies in the NMR data and
in vitro anticancer activities of our synthetic products and those
reported for the natural isolates suggest a re-evaluation of the
latter. As our synthetic route is straightforward and sufficiently
flexible to allow the synthesis of other stereoisomers of 1 and
2, it could be used to clarify the configurations of the natural
bathymodiolamides A and B and to establish reliable
structure−activity relationships.
EXPERIMENTAL SECTION
■
General Remarks. 1H NMR and 13C NMR spectra were obtained
using a Bruker DRX 500 spectrometer. Chemical shifts are given in
parts per million using the residual solvent peak as an internal
standard 7.26 ppm (proton) and 77.00 ppm (carbon) for CDCl3 and
3.31 ppm (proton) and 49.15 ppm (carbon) for MeOD. Coupling
constants (J) are quoted in Hz. Multiplicity abbreviation used: s
singlet, d doublet, t triplet, q quartet, quin quintet, sxt sextet, and m
multiplet. High-resolution mass spectra were obtained with a UPLC/
Orbitrap MS system in electrospray ionization (ESI) mode. IR spectra
were recorded with a Perkin-Elmer Spectrum 100 FT-IR spectropho-
tometer with an ATR sampling unit. Optical rotations were measured
at 589 nm (Na D line) on a PerkinElmer 241 polarimeter. Melting
points were obtained by a Buchi melting point M-565 and are
̈
uncorrected. All reagents were purchased from commercial sources
and were used without further purification. All anhydrous solvents
were used as supplied, except tetrahydrofuran and dichloromethane
which were freshly distilled according to standard procedures.
Reactions were routinely carried out under an argon atmosphere
unless stated otherwise. All glassware was flame-dried before use.
Analytical thin layer chromatography was carried out using Merck
Kieselgel 60GF254 pre-coated aluminum-backed plates. The com-
pounds were visualized with UV light (25 and/or 360 nm) and/or
potassium permanganate. Flash chromatography was performed at
medium pressure using Macherey-Nagel silica gel 60, pore size 40−63
μm with the eluent specified. (R)-Garner’s aldehyde (7),4 1-
bromohex-2-yne (10),7 6-heptynoic acid methyl ester,8 and 4-
pentynoic acid methyl ester10 were prepared according to literature
procedures.
tert-Butyl (R)-4-((R)-1-hydroxyallyl)-2,2-dimethyloxazolidine-3-
carboxylate (6) was prepared according to a modified literature
procedure.5a Tetravinyltin (2.0 mL, 10.9 mmol) in dry Et2O (50 mL)
was treated with MeLi (27.3 mL, 1.6M in Et2O, 43.6 mmol) at 0 °C.
The mixture was stirred for 15 min at 0 °C before ZnBr2 (9.8 g, 43.6
mmol) was added. After stirring for 1 h at ambient temperature, the
mixture was added to a solution of (R)-Garner’s aldehyde (7) (2.5 g,
10.9 mmol) and ZnBr2 (2.5 g, 10.9 mmol) in dry Et2O (50 mL) at
−35 °C. The mixture was allowed to warm to ambient temperature
and stirred for 3 h. Saturated aqueous NH4Cl (100 mL) was added,
and the phases were separated. The aqueous phase was extracted with
Et2O (2 × 100 mL). The combined organic phases were washed with
brine (200 mL), dried over MgSO4, and evaporated to dryness. The
crude product was purified by flash chromatography (n-hexane/ethyl
acetate 5:1) to give 6 (2.58 g, 10.0 mmol, 92%) as a white solid;
analytical data agreed with those reported.5a
Mosher Esters of Diol 4. N-((4S,5R)-4-((R)-2′-((tert-
Butyldimethylsilyl)oxy)-1′-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-
5-yl)dodecanamide. A solution of diol 4 (100 mg, 0.27 mmol) in
CH2Cl2 (20 mL) was treated with imidazole (36 mg, 0.54 mmol) and
TBSCl (44 mg, 0.29 mmol) and was stirred at ambient temperature
for 18 h. Saturated aqueous NH4Cl (10 mL) was added, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried over MgSO4 and evaporated to
dryness. The crude product was purified by flash chromatography (n-
N-((2R,3R)-1,3-Dihydroxypent-4-en-2-yl)dodecanamide (5). A
solution of 6 (1.5 g, 5.8 mmol) in MeOH (30 mL) was treated
with 2 mL AcCl at 0 °C. The mixture was stirred for 30 min at room
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hexane/ethyl acetate 5:1) to give the primary TBS-ether of diol 4 as
colorless oil (121 mg, 0.25 mmol, 93%); Rf 1= 0.50 (n-hexane/ethyl
acetate 2:1); [α]2D3 +50.2 (c 1.0, CHCl3); H NMR (CDCl3, 500
MHz): δ 6.28 (d, J = 8.9 Hz, 1H), 4.40 (s, 1H), 4.18 (dd, J = 1.8, 12.2
Hz, 1H), 4.04 (dd, J = 1.5, 8.9 Hz, 1H), 3.99 (dd, J = 1.5, 9.2 Hz,
1H), 3.78 (dd, J = 2.1, 10.7 Hz, 1H), 3.76 (dd, J = 1.8, 12.2 Hz, 1H),
3.68 (dd, J = 4.3, 10.7 Hz, 1H), 3.26 (ddd, J = 2.1, 4.3, 9.2 Hz, 1H),
2.27 (t, J = 7.6 Hz, 2H), 1.65 (quin, J = 7.6 Hz, 2H), 1.46 (s, 3H),
1.39 (s, 3H), 1.36−1.18 (m, 16H), 0.90 (s, 9H), 0.87 (t, J = 7.0 Hz,
3H), 0.07 (s, 3H), 0.06 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz):
δ 174.6, 99.2, 70.3, 70.2, 64.7, 63.2, 43.8, 36.6, 31.9, 29.6, 29.5, 29.4,
29.3, 29.2, 26.0, 25.8, 22.7, 18.6, 18.5, 14.1, −5.4, −5.3; IR νmax 3318,
2957, 2925, 2855, 1642, 1524, 1462, 1391, 1252, 1199, 1121, 1090,
834, 777 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H54O5NSi+,
488.3766; found, 488.3767.
confirming the absolute configuration of diol 4 cf. the
Supporting Information.
(R)-2-((4S,5R)-5-Dodecanamido-2,2-dimethyl-1,3-dioxan-4-yl)-2-
hydroxyethyl palmitate (9a). A solution of 4 (780 mg, 2.01 mmol)
in dry CH2Cl2 (20 mL) was treated with DMAP (26 mg, 0.20 mmol),
EDC·HCl (400 mg, 2.01 mmol), and palmitic acid (477 mg, 2.01
mmol) and stirred for 18 h at ambient temperature. The organic
phase was washed with 1M HCl (20 mL), aqueous NaHCO3 (20
mL), and brine (20 mL), dried over MgSO4 and evaporated to
dryness. The crude product was purified by flash chromatography (n-
hexane/ethyl acetate 2:1) to give 9a (806 mg, 1.32 mmol, 82%) as a
white solid; mp 52−53 °C; Rf = 0.49 (n-hexane/ethyl acetate 2:1);
[α]2D3 +38.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 6.34 (d,
J = 8.5 Hz, 1H), 4.99 (s, 1H), 4.25 (dd, J = 2.3, 11.5 Hz, 1H), 4.20
(dd, J = 1.7, 12.3 Hz, 1H), 4.12 (dd, J = 5.7, 11.5 Hz, 1H), 4.01 (dd, J
= 1.7, 8.5 Hz, 1H), 3.88 (dd, J = 1.2, 9.2 Hz, 1H), 3.77 (dd, J = 1.7,
12.3 Hz, 1H), 3.45 (ddd, J = 2.3, 5.7, 9.2 Hz, 1H), 2.33 (t, J = 7.6 Hz,
2H), 2.30 (dt, J = 3.1, 7.3 Hz, 2H), 1.69−1.56 (m, 4H), 1.43 (s, 3H),
1.38 (s, 3H), 1.35−1.19 (m, 40H), 0.87 (t, J = 7.3 Hz, 6H); 13C{1H}
NMR (CDCl3, 126 MHz): δ 175.3, 173.9, 99.4, 71.1, 67.8, 64.4, 64.3,
43.8, 36.4, 34.2, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 25.7,
24.9, 22.6, 18.4, 14.1; IR νmax 3322, 2922, 2853, 1736, 1644, 1526,
1457, 1381, 1269, 1234, 1199, 1175, 1090, 850 cm−1; HRMS (ESI)
m/z: [M + H]+ calcd for C36H70O6N+, 612.5197; found, 612.5189.
(R)-2-((4S,5R)-5-Dodecanamido-2,2-dimethyl-1,3-dioxan-4-yl)-2-
hydroxyethyl tetradecanoate (9b). Analogous to 9a, ester 9b (647
mg, 1.11 mmol, 69%) was prepared as a white solid from alcohol 4
(600 mg, 1.61 mmol), DMAP (20 mg, 0.16 mmol), EDC·HCl (308
mg, 1.61 mmol), and myristic acid (367 mg, 1.61 mmol); mp 40−41
°C; Rf = 0.37 (n-hexane/ethyl acetate 2:1); [α]2D3 +38.3 (c 1.0,
(R)-2′-((tert-Butyldimethylsilyl)oxy)-1′-((4S,5R)-5-dodecanami-
do-2,2-dimethyl-1,3-dioxan-4-yl) ethyl (S)-/(R)-3″,3″,3″-trifluoro-
2″-methoxy-2″-phenylpropanoate (S- and R-Mosher esters).
A solution of the primary TBS-ether of diol 4 (35 mg, 72
μmol) in dry CH2Cl2 (1 mL) was treated with 4-
dimethylaminopyridine (DMAP) (18 mg, 140 μmol) and
(R)- or (S)-α-methoxy-α-(trifluoromethyl)phenylacetyl chlor-
ide (MTPA-Cl; 16 μL, 86 μmol). The mixture was stirred at
ambient temperature for 18 h, and volatiles were removed in
vacuo. The crude products were purified by flash chromatog-
raphy (n-hexane/ethyl acetate 5:1) to give S-Mosher ester (40
mg, 79%) or R-Mosher ester (24 mg, 48%) as colorless oils; Rf
= 0.34 (n-hexane/ethyl acetate 5:1); IR νmax 3440, 2927, 2656,
1755, 1678, 1500, 1463, 1383, 1254, 1169, 1108, 1017, 977,
833, 776, 719 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C36H61O7NF3Si+, 704.4163; found, 704.4161; S-Mosher ester:
1
CHCl3); H NMR (CDCl3, 500 MHz): δ 6.34 (d, J = 8.5 Hz, 1H),
4.97 (s, 1H), 4.23 (dd, J = 2.1, 11.5 Hz, 1H), 4.18 (dd, J = 1.5, 12.3
Hz, 1H), 4.11 (dd, J = 5.6, 11.5 Hz, 1H), 3.99 (dd, J = 1.5, 8.5 Hz,
1H), 3.86 (dd, J = 1.2, 9.2 Hz, 1H), 3.76 (dd, J = 1.5, 12.3 Hz, 1H),
3.43 (ddd, J = 2.1, 5.6, 9.2 Hz, 1H), 2.34−2.26 (m, 4H), 1.68−1.56
(m, 4H), 1.41 (s, 3H), 1.37 (s, 3H), 1.34−1.17 (m, 36H), 0.85 (t, J =
7.0 Hz, 6H); 13C{1H} NMR (CDCl3, 126 MHz): δ 175.2, 173.9, 99.3,
71.0, 67.7, 43.8, 36.4, 34.1, 31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 25.6,
24.9, 22.6, 18.3, 14.0; IR (cm−1, neat) νmax 3344, 2922, 2853, 1737,
1645, 1526, 1461, 1381, 1200, 1090, 850 cm−1; HRMS (ESI) m/z:
[M + H]+ calcd for C34H66O6N+, 584.4884; found, 584.4879.
Nona-2,5-diyn-1-ol (11). CuI (4.60 g, 24.1 mmol), NaI (3.62 g,
24.1 mmol), Cs2CO3 (7.86 g, 24.1 mmol), and propargylic alcohol
(1.39 mL, 24.1 mmol) were added to a solution of 10 (3.0 g, 18.6
mmol) in dry DMF (25 mL). The mixture was stirred for 18 h at
ambient temperature. Saturated aqueous NH4Cl (50 mL) was added,
and the mixture was filtered over celite. The filtrate was extracted with
Et2O (3 × 50 mL), and the combined organic phases were washed
with brine (2 × 100 mL), dried over MgSO4, and evaporated to
dryness. The crude product was purified by flash chromatography (n-
hexane/ethyl acetate 5:1) to give 11 (2.25 g, 16.5 mmol, 89%) as
colorless oil; Rf = 0.12 (n-hexane/ethyl acetate 5:1); 1H NMR
(CDCl3, 500 MHz): δ 4.29−4.23 (m, 2H), 3.22−3.16 (m, 2H),
2.16−2.10 (m, 2H), 1.63 (s, 1H), 1.51 (sxt, J = 7.3 Hz, 2H), 0.96 (t, J
= 7.3 Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 81.0, 80.9, 79.3,
73.4, 51.3, 22.1, 20.6, 13.5, 9.8; IR νmax 3348, 2964, 2934, 2874, 1729,
1414, 1313, 1113, 1010 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C9H13O+, 137.0961; found, 137.0960.
1-Bromonona-2,5-diyne (12). PBr3 (0.63 mL, 6.6 mmol) and 0.1
mL pyridine were added to a solution of 11 (2.25 g, 16.5 mmol) in
Et2O (100 mL) at 0 °C. The mixture was stirred for 3 h at 0 °C and
brine (100 mL) was added. The layers were separated, and the
aqueous phase was extracted with Et2O (2 × 50 mL). The combined
organic phases were dried over MgSO4 and evaporated to dryness.
The crude product was purified by flash chromatography (n-pentane/
Et2O 20:1) to give 12 (3.22 g, 16.2 mmol, 98%) as colorless oil; Rf =
0.50 (n-pentane/Et2O 20:1); 1H NMR (CDCl3, 500 MHz): δ 3.91 (t,
J = 2.3 Hz, 2H), 3.21 (quin, J = 2.3 Hz, 2H), 2.13 (tt, J = 2.3, 7.2 Hz,
2H), 1.51 (sxt, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (CDCl3, 126 MHz): δ 82.1, 81.2, 75.2, 72.9, 22.1, 20.6, 14.9,
1
[α]2D3 −35.4 (c 1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ
7.61−7.56 (m, 2H), 7.42−7.37 (m, 3H), 6.00 (d, J = 9.2 Hz,
1H), 5.20 (td, J = 3.8, 7.9 Hz, 1H), 4.32 (dd, J = 1.8, 7.9 Hz,
1H), 3.97 (dd, J = 1.8, 12.1 Hz, 1H), 3.88 (qd, J = 1.8, 9.2 Hz,
1H), 3.82 (t, J = 3.8 Hz, 2H), 3.73 (dd, J = 1.8, 12.1 Hz, 1H),
3.62−3.58 (m, 3H), 2.07 (dt, J = 1.7, 7.5 Hz, 2H), 1.57 (quin,
J = 7.5 Hz, 2H), 1.46 (s, 3H), 1.40 (s, 3H), 1.32−1.21 (m, 16
H), 0.89 (s, 9H), 0.87 (t, J = 7.3 Hz, 3H), 0.07 (s, 3H), 0.06
(s, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 172.6, 165.5,
132.7, 129.54, 128.4, 127.4, 123.3 (1JFC = 288.8 Hz), 99.6, 84.5
(2JFC = 28.2 Hz), 74.1, 67.8, 64.8, 60.1, 55.6, 42.9, 36.6, 31.9,
29.6, 29.5, 29.4, 29.3, 25.7, 25.6, 22.7, 18.5, 18.1, 14.1, −5.6,
1
−5.7; R-Mosher ester: [α]2D3 −15.6 (c 1.0, CHCl3); H NMR
(CDCl3, 500 MHz): δ 7.59−7.53 (m, 2H), 7.43−7.37 (m,
3H), 6.13 (d, J = 8.9 Hz, 1H), 5.14 (td, J = 3.8, 7.8 Hz, 1H),
4.39 (dd, J = 1.8, 7.8 Hz, 1H), 4.01 (dd, J = 1.8, 12.0 Hz, 1H),
3.95 (qd, J = 1.8, 8.9 Hz, 1 H), 3.80 (dd, J = 1.8, 12.0 Hz, 1 H),
3.73 (ddd, J = 3.8, 11.0, 17.1 Hz, 2 H), 3.56−3.53 (m, 3 H),
2.08 (t, J = 7.9 Hz, 2 H), 1.61−1.54 (m, 2 H), 1.47 (s, 3 H),
1.43 (s, 3 H), 1.32−1.22 (m, 17 H), 0.87 (t, J = 7.0 Hz, 4 H),
0.83 (s, 9 H), −0.01 (s, 3 H), −0.03 (s, 3 H); 13C{1H} NMR
(CDCl3, 126 MHz): δ 172.9, 165.9, 132.0,129.6, 128.5, 127.7,
123.2 (1JFC = 288.8 Hz), 99.6, 84.9 (2JFC = 28.2 Hz), 74.3,
67.5, 64.7, 59.7, 55.5, 43.1, 36.6, 31.9, 29.6, 29.5, 29.4, 29.3,
25.7, 25.6, 22.7, 18.5, 18.1, 14.1, −5.6, −5.7. For an analysis6
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13.5, 10.1; IR νmax 2962, 2934, 2872, 1718, 1463, 1411, 1313, 1209,
1123 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C9H12Br+,
199.0117; found, 199.0117.
0.90 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 173.6,
130.2, 129.7, 127.6, 127.5, 51.5, 34.0, 29.3, 25.5, 22.8, 13.8; IR νmax
3011, 2957, 2872, 1740, 1436, 1360, 1196, 1160, 717 cm−1; HRMS
(ESI) m/z: [M + H]+ calcd for C12H21O2+ 197.1536, found 197.1538.
(4Z,7Z)-Undeca-4,7-dienoic acid (18). Analogous to 15, carboxylic
acid 18 (700 mg, 3.84 mmol, 98%) was prepared as colorless oil from
17 (770 mg, 3.92 mmol) and LiOH·H2O (330 mg, 7.85 mmol); Rf =
Methyl hexadeca-6,9,12-triynoate (13). Analogous to 11, ester 13
(937 mg, 3.63 mmol, 76%) was prepared as colorless oil from 12 (950
mg, 4.77 mmol), 6-heptynoic acid methyl ester (870 mg, 6.20 mmol),
CuI (1.18 g, 6.20 mmol), NaI (930 mg, 6.20 mmol), and Cs2CO3
1
1
(2.02 g, 6.20 mmol); Rf = 0.27 (n-hexane/ethyl acetate 30:1); H
0.35 (n-hexane/ethyl acetate 3:1); H NMR (CDCl3, 500 MHz): δ
NMR (CDCl3, 500 MHz): δ 3.69 (s, 3H), 3.16−3.14 (m, 4H), 2.34
(t, J = 7.5 Hz, 2H), 2.20 (tt, J = 2.2, 7.1 Hz, 2H), 2.15 (tt, J = 2.2, 7.1
Hz, 2H), 1.77−1.69 (m, 2H), 1.58−1.50 (m, 4H), 0.98 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 173.9, 80.7, 80.1, 74.9,
74.7, 74.2, 73.8, 51.5, 33.6, 28.1, 24.1, 22.1, 20.7, 18.4, 13.5, 9.8; IR
νmax 2936, 1735, 1435, 1317, 1198, 1172, 1147 cm−1; HRMS (ESI)
5.46−5.30 (m, 4H), 2.80 (t, J = 7.0 Hz, 2H), 2.43−2.36 (m, 4H),
2.03 (q, J = 7.3 Hz, 2H), 1.38 (sxt, J = 7.3 Hz, 2H), 0.90 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 179.1, 130.3, 129.9,
127.5, 127.2, 34.0, 29.3, 25.6, 22.7, 22.5, 13.8; IR νmax 3011, 2958,
2929, 2873, 1708, 1412, 1279, 1250, 1211, 931, 712 cm−1; HRMS
+
(ESI) m/z: [M + H]+ calcd for C11H19O2 , 183.1379; found,
+
m/z [M + H]+ calcd for C17H23O2 259.1693, found 259.1693.
183.1380.
Methyl (6Z,9Z,12Z)-hexadeca-6,9,12-trienoate (14). A suspension
of Ni(OAc)2·4H2O (566 mg, 2.28 mmol) in EtOH (10 mL) was
treated with NaBH4 (86 mg, 2.28 mmol) at 0 °C. The mixture was
stirred under a hydrogen atmosphere at ambient temperature for 30
min. Ethylene diamine (610 μL, 9.13 mmol) and 13 (590 mg, 2.28
mmol) were added, and stirring under a hydrogen atmosphere at
ambient temperature was continued for 3 h. The resulting suspension
was filtered over celite, and saturated aqueous NH4Cl (50 mL) was
added. The aqueous phase was extracted with Et2O (3 × 50 mL). The
combined organic phases were dried over MgSO4 and evaporated to
dryness. The crude product was purified by flash chromatography (n-
hexane/ethyl acetate 30:1) to give 14 (561 mg, 2.12 mmol, 98%) as
colorless oil; Rf = 0.27 (n-hexane/ethyl acetate 30:1); 1H NMR
(CDCl3, 500 MHz): δ 5.44−5.31 (m, 6H), 2.80 (t, J = 5.8 Hz, 2H),
2.31 (t, J = 7.6 Hz, 2H), 2.11−2.01 (m, 4H), 1.69−1.60 (m, 2H),
1.44−1.33 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (CDCl3,
126 MHz): δ 174.2, 130.2, 129.6, 128.4, 128.2, 128.1, 127.8, 51.5,
34.0, 29.3, 29.1, 26.9, 25.7, 25.6, 24.6, 22.8, 13.8; IR νmax 3011, 2929,
2858, 1741, 1436, 1198, 1171, 713 cm−1; HRMS (ESI) m/z: [M +
(R)-1-((4S,5R)-5-Dodecanamido-2,2-dimethyl-1,3-dioxan-4-yl)-2-
(palmitoyloxy)ethyl (6Z,9Z,12Z)-hexadeca-6,9,12-trienoate (19a).
A solution of 9a (244 mg, 0.40 mmol) in dry CH2Cl2 (10 mL) was
treated with DMAP (98 mg, 0.80 mmol), EDC·HCl (92 mg, 0.48
mmol), and 15 (100 mg, 0.4 mmol) and stirred for 18 h at ambient
temperature. The organic phase was washed with 1M HCl (20 mL),
aqueous NaHCO3 (20 mL), and brine (20 mL), dried over MgSO4,
and evaporated to dryness. The crude product was purified by flash
chromatography (n-hexane/ethyl acetate 5:1) to give 19a (250 mg,
0.30 mmol, 74%) as colorless oil; Rf = 0.4 (n-hexane/ethyl acetate
5:1); [α]2D3 +9.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 6.07
(d, J = 10.1 Hz, 1H), 5.43−5.30 (m, 6H), 4.93 (ddd, J = 2.4, 4.6, 9.7
Hz, 1H), 4.38 (dd, J = 2.0, 12.2 Hz, 1H), 4.19 (dd, J = 2.0, 9.7 Hz,
1H), 4.14−4.06 (m, 3H), 3.71 (dd, J = 1.5, 12.2 Hz, 1H), 2.84−2.76
(m, 4H), 2.39−2.23 (m, 4H), 2.22−2.13 (m, 2H), 2.10−1.97 (m,
4H), 1.65−1.54 (m, 6H), 1.46 (s, 3H), 1.41 (s, 3H), 1.41−1.35 (m,
4H), 1.29−1.21 (m, 40H) 0.91 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 6.9 Hz,
6H); 13C{1H} NMR (CDCl3, 126 MHz): δ 173.4, 172.6, 172.3,
130.1, 129.7, 128.4, 128.1, 128.0, 127.8, 99.5, 68.8, 68.3, 65.1, 62.1,
41.9, 36.7, 34.1, 33.9, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1,
29.0, 26.9, 25.6, 25.5, 24.9, 24.2, 22.8, 22.7, 18.3, 14.1, 13.8; IR νmax
2922, 2853, 1744, 1679, 1501, 1462, 1381, 1236, 1199, 1142, 1093,
843, 721 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C52H94O7N+,
844.7025; found, 844.7018.
+
H]+ calcd for C17H29O2 , 265.2162; found, 265.2162.
(6Z,9Z,12Z)-Hexadeca-6,9,12-trienoic acid (15). Ester 14 (550
mg, 2.08 mmol) in THF/H2O 1:1 (10 mL) was treated with LiOH·
H2O (175 mg, 4.16 mmol), and the mixture was stirred for 18 h at
ambient temperature. 1 M HCl was added (20 mL), and the aqueous
phase was extracted with EtOAc (3 × 20 mL). The combined organic
phases were dried over MgSO4 and evaporated to dryness. The crude
product was purified by flash chromatography (n-hexane/ethyl acetate
3:1) to give 15 (458 mg, 1.83 mmol, 88%) as colorless oil; Rf = 0.4 (n-
(R)-2-((4S,5R)-5-Dodecanamido-2,2-dimethyl-1,3-dioxan-4-yl)-2-
(((4Z,7Z)-undeca-4,7-dienoyl)oxy)ethyl tetradecanoate (19b). Anal-
ogous to 19a, ester 19b (658 mg, 0.88 mmol, 88%) was prepared as
colorless oil from alcohol 9b (584 mg, 1.00 mmol), DMAP (245 mg,
2.00 mmol), EDC·HCl (230 mg, 1.20 mmol), and acid 18 (182 mg,
1.00 mmol); Rf = 0.37 (n-hexane/ethyl acetate 2:1); [α]2D3 +10.7 (c
1
hexane/ethyl acetate 3:1); H NMR (CDCl3, 500 MHz): δ 11.51 (s,
1 H), 5.50−5.28 (m, 6H), 2.81 (t, J = 6.0 Hz, 4H), 2.36 (t, J = 7.5 Hz,
2H), 2.13−2.00 (m, 4H), 1.71−1.61 (m, 2H), 1.47−1.33 (m, 4H),
0.91 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 179.9,
130.2, 129.5, 128.4, 128.3, 128.0, 127.8, 33.9, 29.3, 29.0, 26.8, 25.6,
24.3, 22.8, 13.8; IR νmax 3011, 2928, 2859, 1707, 1413, 1287, 1233,
1
1.0, CHCl3); H NMR (CDCl3, 500 MHz): δ 6.09 (d, J = 9.8 Hz,
1H), 5.45−5.29 (m, 4H), 4.94 (ddd, J = 2.1, 4.3, 9.8 Hz, 1H), 4.37
(dd, J = 2.1, 12.2 Hz, 1H), 4.20 (dd, J = 2.0, 9.8 Hz, 1H), 4.14−4.07
(m, 3H), 3.71 (dd, J = 1.8, 12.2 Hz, 1H), 2.80 (t, J = 6.0 Hz, 2H),
2.45−2.32 (m, 4H), 2.30 (dt, J = 1.5, 7.5 Hz, 2H), 2.23−2.11 (m,
2H), 2.06−2.00 (m, 2H), 1.64−1.55 (m, 4H), 1.46 (s, 3H), 1.41 (s,
3H), 1.40−1.34 (m, 2H), 1.32−1.22 (m, 36H) 0.90 (t, J = 7.3 Hz,
3H), 0.87 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (CDCl3, 126 MHz): δ
173.4, 172.6, 171.9, 130.2, 129.4, 127.8, 99.5, 68.8, 68.4, 65.1, 62.1,
41.9, 36.7, 34.11, 33.9, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.6,
25.5, 24.9, 22.8, 22.7, 22.4, 18.3, 14.1, 13.8; IR νmax 2923, 2853, 1744,
1677, 1505, 1464, 1380, 1236, 1199, 1147, 1086, 843, 721 cm−1;
HRMS (ESI) m/z: [M + H]+ calcd for C45H82O7N+, 748.6086; found,
748.6088.
+
928, 711 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C16H27O2 ,
251.2006; found, 251.2009.
Methyl undeca-4,7-diynoate (16). Analogous to 13, ester 16 (1.21
mg, 6.30 mmol, 68%) was prepared as colorless oil from 10 (1.50 g,
9.3 mmol), 4-pentynoic acid methyl ester (1,35 g, 12.0 mmol), CuI
(2.29 g, 12.0 mmol), NaI (1.80 g, 12.0 mmol), and Cs2CO3 (3.92 g,
12.0 mmol); Rf = 0.3 (n-hexane/ethyl acetate 30:1); 1H NMR
(CDCl3, 500 MHz): δ 3.67 (s, 3H), 3.09 (quin, J = 2.3 Hz, 2H),
2.53−2.43 (m, 4H), 2.11 (tt, J = 2.3, 7.1 Hz, 2H), 1.49 (sxt, J = 7.4
Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (CDCl3, 126
MHz): δ 172.4, 80.5, 78.2, 75.4, 74.2, 51.7, 33.3, 22.1, 20.6, 14.6, 13.4,
9.6; IR νmax 2962, 2935, 2875, 1737, 1437, 1366, 1314, 1198, 1166,
Bathymodiolamide A (1). A solution of 19a (250 mg, 0.30 mmol)
in 5 mL MeOH was treated with pTsOH (25 mg, 0.15 mmol) and
stirred for 2.5 h at ambient temperature. Volatiles were removed
under reduced pressure, and the crude product was purified by flash
chromatography (n-hexane/ethyl acetate 1:1) to give 1 (223 mg, 0.28
mmol, 94%) as a white solid; mp 46−47 °C; Rf = 0.39 (n-hexane/
ethyl acetate 1:1); [α]D23 +14.8 (c 0.08, MeOH) {lit1: [α]2D3 +10.8 (c
+
1038 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C12H17O2 ,
193.1223; found, 193.1225.
Methyl (4Z,7Z)-undeca-4,7-dienoate (17). Analogous to 14, ester
17 (1.46 g, 7.42 mmol, 95%) was prepared as colorless oil from 16
(1.50 g, 7.81 mmol), Ni(OAc)2·4H2O (1.94 g, 7.81 mmol), NaBH4
(295 mg, 7.81 mmol), and ethylene diamine (2.1 mL, 31.22 mmol);
Rf = 0.3 (n-hexane/ethyl acetate 30:1); 1H NMR (CDCl3, 500 MHz):
δ 5.44−5.29 (m, 4H), 3.66 (s, 3H), 2.79 (t, J = 7.0 Hz, 2H), 2.42−
2.34 (m, 4H), 2.03 (q, J = 7.3 Hz, 2H), 1.37 (sxt, J = 7.3 Hz, 2H),
1
0.08, MeOH)}; H NMR (CD3OD, 500 MHz): δ 5.43−5.31 (m,
6H), 4.92−4.89 (m, 1H), 4.62 (dd, J = 2.3, 12.1 Hz, 1H), 4.12 (dd, J
= 5.8, 12.1 Hz, 1H), 4.12−4.09 (m, 1H), 4.04 (dd, J = 1.5, 9.5 Hz,
1H), 3.61 (dd, J = 8.2, 10.7 Hz, 1H), 3.53 (dd, J = 5.8, 10.7 Hz, 1H),
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2.84−2.82 (m, 4H), 2.38−2.27 (m, 4H), 2.22−2.15 (m, 2H), 2.14−
2.02 (m, 4H), 1.66−1.55 (m, 6H), 1.45−1.36 (m, 4H), 1.36−1.24
(m, 40H), 0.93 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.3 Hz, 6H); 13C{1H}
NMR (CD3OD, 126 MHz): δ 176.5, 175.3, 174.1, 131.1, 130.9,
129.5, 129.4, 129.3, 129.2, 71.8, 68.2, 64.3, 62.5, 51.9, 37.3, 35.2, 33.3,
31.0, 30.8, 30.7, 30.6, 30.5, 30.4, 28.2, 27.2, 26.8, 26.2, 25.4, 24.0,
23.9, 14.7, 14.4; IR νmax 3320, 2922, 2853, 1744, 1633, 1457, 1377,
1173, 1057, 720 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C49H90O7N+, 804.6712; found, 804.6703.
their use in the construction of a ceramide library. Bioorg. Chem. 2008,
36, 220−228.
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Ceramide derivatives as anticancer agents. U.S. Patent 10,537,545 B2,
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(4) Passiniemi, M.; Koskinen, A. M. Garner’s aldehyde as a versatile
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(5) (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Concise
and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin
and its congeners using dioxanylpiperidene, a promising chiral
building block. Org. Lett. 2003, 5, 2527−2529. (b) Coleman, R. S.;
Carpenter, A. J. Diastereoselective addition of vinyl organometallic
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configurations of marine diterpenes possessing a xenicane skeleton.
An application of an advanced mosher’s method. Tetrahedron Lett.
1989, 30, 3147−3150.
(2R,3S,4R)-Bathymodiolamide B (2). Analogous to 1, bathymo-
diolamide B (184 mg, 0.26 mmol, 97%) was prepared as a white solid
from acetonide 19b (200 mg, 0.27 mmol) and pTsOH (23 mg, 0.14
mmol); mp 43−44 °C; Rf = 0.3 (n-hexane/ethyl acetate 1:1); [α]D23
+6.7 (c 0.08, MeOH) {lit1: [α]2D3 +10.8 (c 0.08, MeOH}; H NMR
1
(CD3OD, 500 MHz): δ 5.41−5.32 (m, 4H), 4.93−4.89 (m, 1H), 4.60
(dd, J = 2.4, 12.2 Hz, 1H), 4.14 (dd, J = 5.8, 12.2 Hz, 1H), 4.12−4.09
(m, 1H), 4.05 (dd, J = 1.5, 9.5 Hz, 1H), 3.61 (dd, J = 8.5, 10.7 Hz,
1H), 3.53 (dd, J = 5.8, 10.7 Hz, 1H), 2.84−24.2 (m, 2H), 2.42−2.32
(m, 4H), 2.30 (t, J = 7.3 Hz, 2H), 2.24−2.12 (m, 2H), 2.07 (q, J = 6.7
Hz, 2H), 1.61−1.57 (m, 4H), 1.44−1.36 (m, 2H), 1.36−1.24 (m,
36H), 0.93 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.3 Hz, 9H); 13C{1H}
NMR (CD3OD, 126 MHz): δ 176.5, 175.3, 173.6, 131.1, 130.5,
129.2, 71.9, 68.2, 62.5, 51.9, 37.3, 35.3, 35.2, 33.3, 31.0, 30.8, 30.7,
30.6, 30.5, 30.4, 27.2, 26.7, 26.2, 24.1, 23.9, 23.8, 14.7, 14.4; IR νmax
3363, 2920, 2853, 1745, 1640, 1457, 1377, 1152, 1061, 722 cm−1;
HRMS (ESI) m/z: [M + H]+ calcd for C42H78O7N+, 708.5772; found,
708.5765.
(7) Zhao, L.; Lu, X.; Xu, W. Palladium(II)-catalyzed enyne coupling
reaction initiated by acetoxypalladation of alkynes and quenched by
protonolysis of the carbon−palladium bond. J. Org. Chem. 2005, 70,
4059−4063.
(8) Zhang, X.; Xie, X.; Liu, Y. Nickel-catalyzed highly regioselective
hydrocyanation of terminal alkynes with Zn(CN)2 using water as the
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02726.
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(10) Ramsay, W. J.; Bell, N. A. W.; Qing, Y.; Bayley, H. Single-
molecule observation of the intermediates in a catalytic cycle. J. Am.
Chem. Soc. 2018, 140, 17538−17546.
sı
Comparison of synthetic and isolated bathymodiola-
mides A and B; analysis of the Mosher esters of alcohol
4; NMR spectra of all compounds; and cell culture
conditions and inhibition of cell growth (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Rainer Schobert − Department of Chemistry, University
Bayreuth, Bayreuth 95440, Germany; orcid.org/0000-
0002-8413-4342; Email: Rainer.Schobert@uni-
bayreuth.de; Fax: +49 (0)921 552671
Authors
̈
Alexander Bar − Department of Chemistry, University
Bayreuth, Bayreuth 95440, Germany
̈
Sofia I. Bar − Department of Chemistry, University Bayreuth,
Bayreuth 95440, Germany
̈
Moritz Roder − Department of Chemistry, University
Bayreuth, Bayreuth 95440, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02726
Notes
The authors declare no competing financial interest.
REFERENCES
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(1) Andrianasolo, E. H.; Haramaty, L.; McPhail, K. L.; White, E.;
Vetriani, C.; Falkowski, P.; Lutz, R. Bathymodiolamides A and B,
ceramide derivatives from a deep-sea hydrothermal vent invertebrate
mussel, Bathymodiolus thermophilus. J. Nat. Prod. 2011, 74, 842−
846.
(2) Park, J.-J.; Lee, J. H.; Li, Q.; Diaz, K.; Chang, Y.-T.; Chung, S.-K.
Divergent syntheses of all stereoisomers of phytosphingosine and
1873
https://dx.doi.org/10.1021/acs.joc.0c02726
J. Org. Chem. 2021, 86, 1868−1873