Synthesis and configuration of the nonadecenetriol isolated from seeds of Persea americana

Article abstract of DOI:10.1039/c1ob05898c

In an effort to establish the relative as well as absolute configuration of the trypanocidally active natural nonadec-6-en-1,2,4-triol isolated from Persea americana, the (2S,4R), (2S,4S), and (2R,4R) isomers were synthesized. The stereogenic centers take

Full text of DOI:10.1039/c1ob05898c

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PAPER
Synthesis and configuration of the nonadecenetriol isolated from seeds of
Persea americana†
Xin Yan,a,b Shao-Min Zhang,a Yikang Wu*a and Po Gao*b
Received 4th June 2011, Accepted 4th July 2011
DOI: 10.1039/c1ob05898c
In an effort to establish the relative as well as absolute configuration of the trypanocidally active natural
nonadec-6-en-1,2,4-triol isolated from Persea americana, the (2S,4R), (2S,4S), and (2R,4R) isomers
were synthesized. The stereogenic centers taken from enantiopure chiral epoxy building blocks derived
from inexpensive and readily available D-glucolactone. The (2R,4R) isomer gave 1H and 13C NMR as
well as specific rotation in excellent consistence with those reported for the natural triol.
The missing piece in the structural knowledge of the natural 1,
which must be difficult to acquire for the previous investigators,
Chagas disease (American trypanosomiasis) is a potentially life-
strongly signaled a need, also an opportunity, for synthesis to
Introduction
threatening illness caused by the protozoan parasite, Trypanosoma
cruzi (T. cruzi). As one of the most serious rotozoan diseases
in Latin America, it has received broad attention from scientific
make a contribution. Having noticed this situation, we started
an enantioselective synthesis of the title triol. Through data
comparison of the synthetic and the natural samples the relative
communities.1 Recently, in their search of novel agents for the
and absolute configuration of the latter now has been established
chemotherapy of Chagas disease Abe and coworkers2 identified
with great confidence. Described below is the details of this
a previously unknown trypanocidally active compound from the
synthetic study.
MeOH extract of seeds of Persea americana (avocado), a plant
that grows in all tropical areas around the world. On the basis
of spectroscopic data, including those from HRMS, 1H as well as
13C NMR, and 2D COSY experiments, they assigned the planar
Results and discussion
The target triol (1) contains two stereogenic centers and therefore
in principle there exist four different enantiomers altogether.
However, because two of them are mirror images of the other two,
synthesis of any set of two epimers would allow3 for establishment
of the relative as well as absolute configuration of the natural 1.
For convenience we deliberately chose the (2S,4S) and (2S,4R)
isomers as our primary targets because of the readily accessible4
nature of the chiral building blocks 2 and 3. The general feature
of our initial plan is shown in Scheme 1, with the 1,3-diol and the
long linear chain units in the target structures taken from 2 or 3
and the alkene 4, respectively. The diol fragments 2 and 3 were
planned to derive from the known epoxy chiral building blocks 54
and 6,5 respectively.
structure (Fig. 1) of this compound as (E)-nonadec-6-ene-1,2,4-
triol (1). They also measured the specific rotation for this triol,
which was reported to be [a]2D4 -8.6 (c 0.25, CHCl3), but did
not disclose any further information regarding to the relative and
absolute configuration of the stereogenic centers.
It is known that cross metathesis in most cases would afford
a mixture of (E)- and (Z)- isomers of the C–C double bond.
However, because at least in some cases such isomers could be
separated and the relatively bulky substituents at both alkenic
carbons might help to enrich the thermodynamically more stable
(E)-isomer, we thought that the CM-based plans deserved a try.
Thus, using the commercially available H2C CHMgBr to open
the epoxy ring in 5 and 6, respectively, in the presence of a catalytic
amount of CuI, the corresponding alcohol 2 and 3 were obtained
in 87% and 69% yield, respectively (Scheme 2).
Fig. 1 The planar structure of the natural triol (1) isolated from Persea
americana.
aState Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032, China. E-mail: yikangwu@sioc.ac.cn
bSchool of Chemistry and Materials, Heilongjiang University, Harbin,
150080, China
1
† Electronic supplementary information (ESI) available: The H and 13C
NMR as well as IR spectra for all new compounds, tabular NMR
data comparison of the natural and synthetic (2R,4R)-1. See DOI:
10.1039/c1ob05898c
The cross coupling was then examined with 2 and the com-
mercially available tetradec-1-ene 4 as the reactants. Under the
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Scheme 1 The outline of the retrosynthetic analysis of the initial plan.
Scheme 3 The plan based on coupling of epoxides with alkyne 10.
Execution of the second plan started with reaction of 5 with
the commercially available tetradec-1-yne 10 (Scheme 4), which
led to the propargyl alcohol 8 in 84% yield. Reduction of the
triple bond in 8 was not as smooth as the preceding step. We
tried several sets of literature conditions that were well-established
for similar transformations, including LiAlH4/T◦HF at ambient
temperature8 or reflux,9 LiAlH4/diglyme/170 C10 and Red-
Al/THF/rt.11 However, in the present case essentially no reaction
occurred. Under the Na/liq. NH3/THF/t-BuOH12 conditions the
reduction did occur as anticipated, but the product turned out
to be two alkenes (in ca. 1 : 3 ratio, of similar polarity and thus
difficult to separate from each other) instead of one, even well
before the starting 8 was fully consumed.
Scheme 2 Coupling of epoxied 5 with alkyne 10 by cross metathesis.
standard conditions, the coupling product was isolated in 58%
yield. However, this sample, which was a well-shaped round spot
on TLC, turned out to be a mixture of the (E)- and (Z)-isomers (7a
and 7b) as shown by 1H NMR. Considerable efforts were made to
separate these two isomers without success. Conversion of the less
stable (Z)-isomer to the more stable (E)-isomer under some liter-
ature conditions (n-Bu3SnH/Pd(OAc)2/Et3N6 or PhSH/AIBN7)
also failed. Therefore, this approach was discontinued.
To get around the separation problem, we next switched to
an alkyne-based approach (Scheme 3), which was expected to
be able to deliver the desired alkenes in pure (E)-configuration
via a stereoselective reduction of the triple bond. This strategy
also enjoyed some other advantages, including facile generation
of the carbanion required in the coupling with the epoxides and
incorporation of the C-6 to C-19 unit into the target structures in
a single operation.
Scheme 4 Coupling of 5 with 10 and reduction with Na/liq. NH3.
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1H NMR analysis strongly suggested that the two alkenes
differed only in the position of the TBS protecting group. Judging
from the substrate structure and the reaction conditions, we
deduced that the minor product (the less polar one) was more
likely to be the one with the TBS group migrated (7a¢). Indeed, a
diagnostic oxidation of the separated minor component (7a¢) and
subsequent analysis of the oxidation product (11) by H NMR
unambiguously confirmed that the TBS group in this compound
was on the C-4 OH.
With the identity of the components in the reduction product
established, we next tried to minimize the formation of the
undesired 7a¢. To reduce the basicity of the alkoxide at the C-
4 during the reduction by changing the cation appeared to be a
potential choice. Thus, Li metal was examined in place of Na.13
To our gratification, after this modification the yield of 7a (more
polar) could be raised to 77% while that for 7a¢ (less polar) reduced
to 11% under the otherwise identical conditions (Scheme 5).
Finally, desilylation of 13 with n-Bu4NF in THF delivered the
end product (2S,4R)-1. The spectroscopic data for (2S,4R)-1 were
then measured and compared with those reported for the natural
product. The specific rotation (-5.67) and the 1H NMR data were
not very useful, from which no definite conclusions could possibly
be drawn. However, significant differences were found in the 13C
NMR at d 70.3 (nat. 72.2) and 69.2 (nat. 71.3) ppm. On the basis
of these discrepancies, it can be concluded that (2S,4R)-1 and the
natural 1 are not the same compound; the latter thus must have a
1,3-syn (either (2R,4R) or (2S,4S)) configuration.
Synthesis of (2S,4S)-1 was performed as shown in Scheme 6.
Using the same reaction sequence as that for (2S,4R)-1 but starting
with epoxide 6 instead of 5, the corresponding propargyl alcohol 9
was obtained in 88% yield. Reduction of 9 under the same Li/liq.
NH3 conditions delivered desired 14 (58%) and the TBS shifted
isomer 14¢ (17%, whose structure was also confirmed by oxidation
to 15). Compared with the reduction of 8, the TBS migration
occurred to a more significant extent. This is probably because in
the case of 8 (Fig. 2).
1
Fig. 2 The 1,3-anti relationship leads to a transition state of higher energy
(with one substituent in an axial position) than its 1,3-syn counterpart
(both R and R¢ are in equatorial positions). For clarity, the substituents
on the silicon atom are not shown.
It is noteworthy that because of the substantially larger polarity
difference between 14 (more polar) and 14¢ (less polar) than that
between 7a and 7a¢, acquisition of pure 14 by choromatography
became much easier. With access to pure 14 secured, the remaining
steps were completed in a fashion similar to that for the synthesis
of (2S,4R)-1. In the NaBH4 reduction of the intermediate aldehyde
after the NaIO4 oxidation, traces amounts of side product 17¢ (with
the TBS shifted from C-2 OH to the C-4 OH) was also observed.
Scheme 5 Reduction of 8 and subsequent elaboration into (2S,4R)-1.
Removal of the terminal acetonide in 7a was achieved under the
14
50% aq. F3CCO2H/CH2Cl2 conditions. The resultant triol 12
was treated with NaIO4 in CH2Cl2-H2O/silica gel8,15 to yield the
intermediate aldehyde, which on further reduction of the carbonyl
group with NaBH4 in MeOH afforded the corresponding alcohol
13 (63%) along with a smaller amount of 13¢ (38%).
1
Unlike its (2S,4R) counterpart, the (2S,4S)-1 showed H and
13C NMR fully consistent with those reported for the natural
1, which, along with the optical rotation of the opposite sign,
unambiguously manifested that the natural product must be an
mirror image of (2S,4S)-1.
The spectra for these two compounds were rather similar to
each other, with the most distinct differences in the OH stretching
frequency in the IR and the chemical shift difference of the geminal
To gain the triol of (2R,4R) configuration, we next started
the synthesis shown in Scheme 7. The stereogenic centers in the
end product in this case was also taken from epoxide 6, but in
a different way. The opening of the epoxy ring was achieved
through reaction with BnOH under the NaH/DMSO/THF/rt16
conditions. If using DME (MeO(CH2)2OMe) as solvent,17 no
reaction occurred even at 60 ◦C. The two hydroxyl groups were
then masked as acetates without any difficulty. However, hydrolysis
of the acetonide was rather frustrating, presumably because of the
presence of the acetates. Using 50% aq. CF3CO2H, CAS (camphor
1
protons of the CH2’s at C-1 and C-3 in the H NMR. Because
structure 13¢ does not have any primary OH and the two secondary
OH’s at C-2 and C-4 may easily form a cyclic motif through
intramolecular hydrogen bonding, it was assigned to the minor
product, which has a lower OH stretching frequency (3345 cm-1), a
smaller d splitting for the C-1 CH2 (because weaker influence from
the chiral C-2 as the substituent became smaller) and a larger d
splitting for the C-3 CH2 (being part of the 6-membered hydrogen
bonded ring).
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Further treatment of diol 20 with NaIO4/silica gel/CH2Cl2-
H2O cut off one carbon unit from the terminal as in the conversion
of 12 into 13 mentioned above, but the intermediate aldehyde was
reduced withLiAlH4 instead of NaBH4 to remove all the Ac groups
at the same time. The resulting triol 21 was then transformed
into the corresponding epoxide 22 by sequential treatment with
p-TsCl/n-Bu2SnO/Et3N/DMAP and K2CO3/MeOH to set a
stage for incorporation of the alkyne fragment. The C-6 to
C-19 unit was then introduced by reaction with alkyne 10 under
the same conditions employed previously in the conversion of 6
into 9.
Direct treatment of this diol (23) to the Li/liq. NH3 reduction
conditions led to only the corresponding debenzylation product;
essentially no reduction of the triple bond occurred. However, after
masking the diol as an acetonide in the presence of CSA (camphor-
10-sulfonic acid), the triple bond could be smoothly transformed
to the desired (E)-alkene 25 (Scheme 8) with a concurrent removal
of the benzyl protecting group at the chain terminal. On hydrolysis
of the acetonide protecting group through reaction with propane-
1,3-dithiol, the end product (2R,4R)-1 was obtained in 81%
1
isolated yield. As expected, the synthetic (2R,4R)-1 showed H
and 13C NMR as well as optical rotation in excellent consistency
with those reported for the natural 1. The configuration of natural
1 was thus established to be (2R,4R).
Scheme 6 Synthesis of (2S,4S)-1.
Scheme 8 Conversion of 23 into (2R,4R)-1.
Conclusions
In summary, in an effort to establish the relative as well as
absolute configuration of the nonadec-6-ene-1,2,4-triol isolated
from Persea american, the (2S,4R), (2R,4R), and (2S,4S) isomers
of the triol were synthesized separately through chiral pool based
routes. The (2S,4R) configuration (a priori, also the (2R,4S) one,
the other 1,3-anti isomer) can be easily excluded because of the 1H
and 13C NMR incompatible with those reported for the natural
Scheme 7 Conversion of 6 into 23.
sulphonic acid), or 1 N HCl as the catalyst to run the reaction
in CH2Cl2 at ambient temperature all led to a complex mixture.
The problem was later solved by running the reaction under the
Er(OTf)2/BnOH/CH2Cl2/rt conditions (previously reported18 for
opening epoxy ring with BnOH), which delivered the desired diol
20 in 83% yield.
1
one. Both (2R,4R) and (2S,4S) isomers show H and 13C NMR
in full consistence with those reported for the natural 1, but the
latter has a rotation of sign opposite to that for the natural one.
Thus, it can be concluded beyond all doubt that the natural 1 has
the (2R,4R) configuration.
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(1S,3R)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)octadec-5-yn-3-ol (8). n-BuLi (1.6 M, in hexanes,
1.5 mL, 2.35 mmol) was added to a solution of tetradec-1-yne
10 (0.6 mL, 2.41 mmol) in dry THF (12 mL) stirred at -78 ◦C
under N2 (balloon). The resulting white suspension was stirred at
the same temperature for 2 h. A solution of epoxide 5 (182 mg,
0.602 mmol) in dry THF (3 mL) was then introduced, followed
by BF3·Et2O (0.15 mL, 1.205 mmol). The mixture was stirred at
-78 ◦C for 3 h, when TLC showed completion of the reaction.
Aqueous saturated NH4Cl (10 mL) was added carefully. The bath
was allowed to warm to ambient temperature. The mixture was
extracted with Et2O, washed with water and brine, and dried over
anhydrous MgSO4. Filtration and rotary evaporation left an oily
residue, which was chromatographed (15 : 1 PE/EtOAc) on silica
gel to give the alcohol 8 as a colorless oil (252 mg, 0.507 mmol,
84%): [a]2D2 +1.1 (c 1.03, CHCl3). 1H NMR (400 MHz, CDCl3) d
4.10–4.00 (m, 2H), 3.99–3.90 (m, 1H), 3.87 (dd, J = 10.8, 5.3 Hz,
1H), 3.84–3.76 (m, 1H), 3.34 (d, J = 2.0 Hz, 1H), 2.41–2.26 (m,
2H), 2.20–2.10 (m, 2H), 1.90 (ddd, J = 14.7, 4.6, 2.1 Hz, 1H),
1.78–1.68 (m, 1H), 1.53–1.42 (m, 2H), 1.40 (s, 3H), 1.34 (s, 3H),
1.31–1.18 (m, 18H), 0.93–0.82 (m, 12H), 0.13 (s, 3H), 0.10 (s, 3H);
13C NMR (100 MHz, CDCl3) d 109.3, 82.8, 78.5, 76.2, 72.3, 67.6,
67.3, 41.1, 31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.0, 28.9, 28.1, 26.6,
25.8, 25.3, 22.7, 18.8, 18.0, 14.1, -4.2, -4,6; FT-IR (film) 3486,
2955, 2927, 2855, 1463, 1379, 1256, 1214, 1074, 838, 777 cm-1.
ESI-MS m/z 519.5 ([M+Na]+); EI-HRMS calcd for C29H56O4Si
(M+) 496.3948, found 496.3951.
Experimental
General
Dry THF was distilled over Na/Ph2CO under N2 prior to use. Dry
CH2Cl2, DMF and DMSO were distilled over CaH2 under N2 prior
to use. Addition of air/moisture sensitive reagents was done using
syringe techniques. PE (for chromatography) stands for petroleum
ether (b.p. 60–90 ◦C). Column chromatography was performed on
silica gel (300–400 mesh) under slightly positive pressure. NMR
spectra were recorded on a Bruker Avance 400 NMR spectrometer
operating at 400 MHz for proton. IR spectra were measured on
a Nicolet 380 Infrared Spectrometer. ESI-MS data were acquired
on a Shimadzu LCMS-2010EV mass spectrometer. HRMS data
were obtained with a Bruker APEXIII 7.0 Tesla FT-MS or an
Agilent 6538 UHD Accurate-Mass Q-TOF spectrometer. Optical
rotations were measured on a Jasco P-1030 Polarimeter.
(1S,3R)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)hex-5-en-3-ol (2). CH2 CHMgBr (1 M, in THF,
10 mL, 10 mmol) was added to a white suspension of CuI (252 mg,
1.53 mmol) in dry THF (20 mL) stirred at -40 ◦C under N2
(balloon). The resulting dark-brown mixture was stirred at the
same temperature for 20 min. A solution of epoxide 5 (572 mg,
1.89 mmol) in dry THF (4.5 mL) was then introduced. The mixture
was stirred at -40 ◦C for 3 h, when TLC showed completion
of the reaction. Aqueous saturated NH4Cl was added carefully.
The mixture was extracted with Et2O, washed with water and
brine, and dried over anhydrous MgSO4. Filtration and rotary
evaporation left an oily residue, which was chromatographed
(10 : 1 PE/EtOAc) on silica gel to give the alcohol 2 as a colorless
(1S,3R,E)-1-(tert-Butyldimethyl-silyloxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)octadec-5-en-3-ol (7a) and (1S,3R,E)-3-(tert-
butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4- yl)-
octadec-5-en-1-ol (7a¢). Li cuts (ca. 1.0 g, 144 mmol) was added
in small portions to liquid NH3 (ca. 75 mL, in a three-neck
flask) stirred in a -78 ◦C bath. To the resultant dark blue
mixture was added a solution of propargyl alcohol 8 (135 mg,
0.272 mmol) in THF (15 mL), followed by t-BuOH (10 mL). The
mixture was stirred at the same temperature for 3.5 h before an
additional portion of t-BuOH (3 mL) was introduced. The stirring
was continued at -78 ◦C for another 2 h. Aqueous saturated
NH4Cl was added carefully. The bath was allowed to warm to
ambient temperature slowly. The mixture was extracted with Et2O,
washed with water and brine, and dried over anhydrous MgSO4.
Filtration and rotary evaporation left an oily residue, which was
chromatographed (20 : 1 PE/EtOAc) on silica gel to give the
alcohol 7a¢ (the less polar component, 15 mg, 0.030 mmol, 11%)
and 7a (the more polar component, 104 mg, 0.209 mmol, 77%) as
colorless oils.
Data for 7a¢ (the less polar component): [a]2D7 -4.2 (c 0.45,
CHCl3). 1H NMR (400 MHz, CDCl3) d 5.46 (dt, J = 15.4, 7.1 Hz,
1H), 5.31 (dt, J = 15.2, 7.3 Hz, 1H), 4.07–3.98 (m, 2H), 3.98–3.87
(m, 3H), 3.40 (s, 1H), 2.32–2.22 (m, 2H), 1.97 (dd, J = 13.4, 6.5 Hz,
2H), 1.74 (dt, J = 14.6, 5.4 Hz, 1H), 1.59–1.46 (m, 1H), 1.39 (s,
3H), 1.34 (s, 3H), 1.37–1.13 (m, 20H), 0.93–0.78 (m, 12H), 0.09
(s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz, CDCl3) d 133.8, 125.4,
109.0, 78.9, 71.3, 68.83, 66.0, 39.9, 37.5, 32,6, 31.9, 29.7, 29.62,
29.61, 29.5, 29.4, 29.3, 29.2, 26.6, 25.8, 25.3, 22.7, 17.9, 14.1, -4.6,
-4.9; FT-IR (film) 3330, 2955, 2923, 2854, 1736, 1462, 1378, 1089,
1018 cm-1. ESI-MS m/z 521.5 ([M+Na]+); EI-HRMS calcd for
C28H55O4Si ([M–CH3]+) 483.3870, found 483.3869.
oil (545 mg, 1.65 mmol, 87%): [a]2D7 +6.3 (c 0.90, CHCl3). H
1
NMR (400 MHz, CDCl3) d 5.91–5.78 (m, 1H), 5.15–5.08 (m, 2H),
4.11–4.03 (m, 2H), 3.98–3.90 (m, 1H), 3.87 (dd, J = 10.8, 5.0 Hz,
1H), 3.83–3.75 (m, 1H), 2.31–2.16 (m, 2H), 1.77 (ddd, J = 14.6, 4.6,
2.2 Hz, 1H), 1.67 (ddd, J = 14.9, 9.9, 5.1 Hz, 1H), 1.41 (s, 3H), 1.35
(s, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 134.9, 117.5, 109.4, 78.3, 72.7, 67.9, 67.4, 42.5, 41.3,
26.6, 25.8, 25.4, 18.0, -4.2, -4.6; FT-IR (film) 3489, 3072, 2985,
2954, 2931, 2889, 2858, 1641, 1473, 1463, 1380, 1371, 1256,
1215, 1159, 1073, 837, 777 cm-1. ESI-MS m/z 353.4 ([M+Na]+);
ESI-HRMS calcd for C17H34NaO4Si ([M+Na]+) 353.2119, found
353.2124.
(1S,3S)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)hex-5-en-3-ol (3). The procedure was the same as
described above for the conversion of 5 into 2, except epoxide 6
(1.28 g, 4.24 mmol) was employed to replace 5, giving 3 (969 mg,
2.93 mmol, 69%, chromatographed with 10 : 1 PE/EtOAc) as a
colorless oil. [a]2D9 +22.6 (c 0.94, CHCl3). H NMR (400 MHz,
1
CDCl3) d 5.88–5.76 (m, 1H), 5.11 (dd, J = 16.8, 6.3 Hz, 2H), 4.13–
4.00 (m, 2H), 3.97–3.84 (m, 2H), 3.78 (t, J = 7.1 Hz, 1H), 2.58 (d,
J = 3.7 Hz, 1H), 2.22 (t, J = 6.7 Hz, 2H), 1.80–1.67 (m, 2H), 1.39 (s,
3H), 1.33 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 134.8, 117.6, 109.3, 78.6, 71.15, 67.22, 67.16, 42.3, 41.9,
26.5, 25.7, 25.3, 17.9, -4.2, -4.6; FT-IR (film) 3485, 3072, 2985,
2959, 2931, 2888, 2858, 1641, 1473, 1463, 1380, 1371, 1256, 1073,
1004, 914, 837, 776, 674, 513 cm-1. ESI-MS m/z 353.3 ([M+Na]+);
ESI-HRMS calcd for C17H34NaO4Si ([M+Na]+) 353.2119, found
353.2123.
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Data for 7a (the more polar component): [a]2D7 +4.6 (c 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3) d 5.51 (dt, J = 15.4, 7.0 Hz,
1H), 5.41 (dt, J = 15.3, 7.0 Hz, 1H), 4.12–4.01 (m, 2H), 3.93–
3.77 (m, 3H), 3.12 (s, 1H), 2.22–2.08 (m, 2H), 2.07–1.94 (m, 2H),
1.80–1.71 (m, 1H), 1.69–1.60 (m, 1H), 1.40 (s, 3H), 1.34 (s, 3H),
1.38–1.19 (m, 20H), 0.95–0.82 (m, 12H), 0.11 (s, 3H), 0.09 (s, 3H);
13C NMR (100 MHz, CDCl3) d 134.1, 125.8, 109.3, 78.4, 72.5,
68.2, 67.3, 41.4, 41.3, 32,7, 31.9, 29.7, 29.63, 29.62, 29.52, 29.48,
29.35, 29.2, 26.6, 25.8, 25.4, 22.7, 17.9, 14.1, -4.2, -4.6; FT-IR
(film) 3496, 2983, 2951, 2926, 2854, 1463, 1377, 1367, 1255, 1216,
1158, 1072, 967, 837, 777 cm-1. ESI-MS m/z 521.6 ([M+Na]+);
EI-HRMS calcd for C28H55O4Si ([M–CH3]+) 483.3870, found
483.3876.
(2S,4R,E)-2-(tert-Butyldimethylsilyloxy)nonadec-6-ene-1,4-diol
(13) and (2S,4R,E)-1-(tert-butyldimethylsilyloxy)-nonadec-6-ene-
2,4-diol (13¢). To a solution of NaIO4 (36 mg, 0.168 mmol) in
water (0.6 mL) was added silica gel (300–400 mesh), followed
by CH2Cl2 (3.5 mL). The mixture was stirred at ambient
temperature for 1 h. A solution of triol 12 (34 mg, 0.074 mmol) in
CH2Cl2 (3.5 mL) was added. The mixture was stirred at ambient
temperature for 1.5 h and then filtered through Celite. The
two-phase filtrate was transferred to a separatory funnel and the
phases were separated. The organic layer was washed with water
and brine before being dried over anhydrous MgSO4. Filtration
and rotary evaporation left an oily residue (the intermediate
aldehyde), which was dissolved in MeOH (2 mL). To this solution
◦
(cooled in a 0 C bath) was added NaBH4 (4 mg, 0.090 mmol).
(R,E)-3-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
The bath was allowed to warm to ambient temperature until TLC
showed completion of the reaction (ca. 1.5 h). Et2O was added,
followed by aqueous saturated NH4Cl. The phases were separated.
The organic layer was washed with water and brine before being
dried over anhydrous MgSO4. The solvent was removed by rotary
evaporation and the oily residue was chromatographed (3 : 1
PE/EtOAc) on silica gel to afford alcohol 13 (the less polar
component, 20 mg, 0.046 mmol, 62% from 12) as a colorless oil
and 13¢ (the more polar component, 12 mg, 0.028 mmol, 38%) as
a white wax.
dioxolan-4-yl)octadec-5-en-1-one (11). To
a solution of 7a
(10 mg, 0.020 mmol) in dry CH2Cl2 (1 mL) were added NaHCO3
(8 mg, 0.10 mmol) and Dess–Martin periodinane (17 mg,
0.040 mmol). The mixture was stirred at ambient temperature until
TLC showed complete of the reaction (ca. 2 h). Aqueous saturated
Na2S2O3 was added. The mixture was extracted with Et2O, washed
with water and brine, and dried over anhydrous MgSO4. Removal
of the solvent by rotary evaporation and chromatography (10 : 1
PE/EtOAc) on silica gel afforded ketone 11 (9 mg, 0.018 mmol,
90%) as a colorless oil. [a]2D7 -0.8 (c 0.6 CHCl3). 1H NMR
(400 MHz, CDCl3) d 5.45 (dt, J = 15.2, 7.0 Hz, 1H), 5.35 (dt,
J = 15.3, 7.0 Hz, 1H), 4.40 (dd, J = 6.0, 1.7 Hz, 1H), 4.30–4.21 (m,
1H), 4.17 (t, J = 8.1 Hz, 1H), 3.97 (dd, J = 5.8, 2.8 Hz, 1H), 2.74
(dd, J = 16.6, 7.5 Hz, 1H), 2.62 (dd, J = 16.7, 4.6 Hz, 1H), 2.27–2.11
(m, 2H), 2.07–1.90 (m, 2H), 1.50 (s, 3H), 1.39 (s, 3H), 1.30–1.20
(m, 20H), 0.88 (t, J = 6.5 Hz, 3H), 0.87–0.82 (m, 9H), 0.07 (s,
3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) d 208.9, 134.0,
125.3, 111.0, 80.7, 76.7, 68.1, 66.0, 45.4, 41.1, 32.7, 31.9, 31.4,
30.2, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 26.0, 25.8, 25.1, 22.7, 18.0,
14.1, -4.6, -4.8. FT-IR (film) 2959, 2926, 2855, 1716, 1464, 1374,
1254, 1080, 970, 837, 777 cm-1. ESI-MS m/z 519.5 ([M+Na]+);
ESI-HRMS calcd for C29H56O4SiNa ([M+Na]+) 519.3840, found
519.3860.
Data for 13 (the less polar component, a colorless oil): [a]D23
-3.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d 5.53 (dt, J =
14.5, 7.1 Hz, 1H), 5.39 (dt, J = 14.9, 7.4 Hz, 1H), 4.03–3.85 (m,
2H), 3.62 (dd, J = 10.2, 4.0 Hz, 1H), 3.47 (dd, J = 9.7, 7.6 Hz,
1H), 2.63 (br s, 2H), 2.27–2.11 (m, 2H), 2.00 (dd, J = 13.9, 6.8 Hz,
2H), 1.61 (ddd, J = 14.4, 8.5, 2.9 Hz, 1H), 1.51 (ddd, J = 14.3,
8.8, 3.6 Hz, 1H), 1.42–1.17 (m, 20H), 0.99–0.82 (m, 12H), 0.07
(s, 6H); 13C NMR (100 MHz, CDCl3) d 134.7, 125.6, 69.4, 68.2,
67.2, 41.0, 38.4, 32.6, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.8,
22.7, 18.3, 14.1, -5.38, -5.43; FT-IR (film) 3385, 2956, 2925, 2854,
1463, 1255, 1121, 1084, 970, 837, 778 cm-1. ESI-MS m/z 451.4
([M+Na]+); ESI-HRMS calcd for C25H52O3NaSi 451.3578; found:
451.3601.
Data for 13¢ (the more polar component, a white wax): [a]D23
1
-3.7 (c 0.6 CHCl3). H NMR (400 MHz, CDCl3) d 5.53 (dt, J =
(2R,3S,5R,E)-3-(tert-Butyldimethylsilyloxy)icos-7-ene-1,2,5-
triol (12). Aqueous CF3CO2H (50%, 0.3 mL) was added to a
solution of 7a (104 mg, 0.209 mmol) in CH2Cl2 (7 mL) stirred at
ambient temperature. The stirring was continued for 2 h, when
TLC showed completion of the reaction. The mixture was diluted
with Et2O, washed with water and brine, and dried over anhydrous
MgSO4. Filtration and rotary evaporation left an oily residue,
which was chromatographed (1 : 30 MeOH/CH2Cl2) on silica gel
to give the triol 12 (42 mg, 0.092 mmol, 73%) as a colorless oil:
[a]2D7 -0.8 (c 1.55, CHCl3). 1H NMR (400 MHz, CDCl3) d 5.37 (dt,
J = 15.2, 7.4 Hz, 1H), 5.31 (dt, J = 15.1, 7.1 Hz, 1H), 4.12–3.86 (m,
1H), 3.83–3.75 (m, 1H), 3.75–3.60 (m, 3H), 2.90 (s, 3H), 2.23–2.09
(m, 2H), 2.00 (dd, J = 13.6, 6.5 Hz, 2H), 1.75(dd, J = 5.8, 4.4 Hz,
1H), 1.57 (ddd, J = 14.5, 9.9, 4.9 Hz, 1H), 1.46–1.18 (m, 20H),
0.99–0.79 (m, 12H), 0.10 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 135.1, 125.3, 74.6, 72.3, 68.2, 63.5, 41.5, 40.6, 32.6, 31.9, 29.7,
29.61, 29.59, 29.5, 29.4, 29.3, 29.2, 25.8, 22.6, 17.9, 14.1, -4.6,
-4.7; FT-IR (film) 3365, 2954, 2925, 2854, 1463, 1253, 1082, 970,
837, 777 cm-1. ESI-MS m/z 481.9 ([M+Na]+); ESI-HRMS calcd
for C26H54O4SiNa 481.3684, found 481.3685.
14.6, 7.1 Hz, 1H), 5.39 (dt, J = 15.0, 7.4 Hz, 1H), 4.00 (dt, J = 10.3,
5.0 Hz, 1H), 3.83–3.73 (m, 1H), 3.62 (dd, J = 11.2, 4.7 Hz, 1H),
3.56 (dd, J = 11.0, 4.5 Hz, 1H), 2.25–2.07 (m, 3H), 2.01 (dd, J =
13.7, 6.8 Hz, 2H), 1.74 (ddd, J = 14.4, 6.5, 1.8 Hz, 1H), 1.56 (ddd,
J = 14.7, 10.1, 4.7 Hz, 1H), 1.42–1.18 (m, 20H), 0.96–0.82 (m,
12H), 0.113 (s, 3H), 0.102 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 135.0, 125.4, 71.1, 67.9, 66.8, 41.5, 40.8, 32.7, 31.9, 29.7, 29.6,
29.5, 29.44, 29.35, 29.2, 25.8, 22.7, 18.0, 14.1, -4.6, -4.8; FT-IR
(film) 3346, 2956, 2956, 2925, 2854, 1464, 1255, 1084, 969, 836,
777 cm-1. ESI-MS m/z 451.4 ([M+Na]+); ESI-HRMS calcd for
C25H52O3NaSi 451.3578, found 451.3594.
(2S,4R,E)-Nonadec-6-ene-1,2,4-triol ((2S,4R)-1). A solution
of n-Bu4NF (1 M, in THF, 50 mL) was added to a solution of
13 (20 mg, 0.047 mmol) in THF (2 mL). The resultant yellowish
mixture was stirred at ambient temperature for 2 h before being
concentrated on a rotary evaporator and chromatographed (1 : 15
MeOH/CH2Cl2) on silica gel to afford end triol (2S,4R)-1 as a
colorless oil (13 mg, 0.041 mmol, 88%): [a]2D2 -8.9 (c 0.25 CHCl3).
1H NMR (400 MHz, CD3OD) d 5.57–5.39 (m, 2H), 4.94 (s, 3H),
6802 | Org. Biomol. Chem., 2011, 9, 6797–6806
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3.91–3.76 (m, 2H), 3.52–3.38 (m, 2H), 2.27–2.10 (m, 2H), 2.08–
1.96 (m, 2H), 1.54–1.44 (td, J = 9.3, 3.3 Hz, 2H), 1.43–1.23 (m,
20H), 0.90 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CD3OD)
d 134.4, 127.6, 70.4, 69.4, 68.1, 42.7, 41.3, 33.9, 33.2, 31.0, 30.9,
30.8, 30.6, 30.5, 23.9, 14.6; FT-IR (film) 3302, 2954, 2916, 2849,
1469, 1379, 1061, 1023, 962, 698, 669, 647 cm-1. ESI-MS m/z
337.3 ([M+Na]+); EI-HRMS calcd for C19H38O3 314.2821, found
314.2828.
CH3+Na]+); ESI-HRMS calcd for C29H58NaO4Si 521.3997, found
521.4015.
(2R,3S,5S,E)-3-(tert-Butyldimethylsilyloxy)icos-7-ene-1,2,5-
triol (16). The procedure was the same as described above for
the cleavage of acetonide in 7a leading to 12, except that 14
(55 mg, 0.110 mmol) was employed to replace 7a, giving 16 (42 mg,
0.092 mmol, 73%, chromatographed with 1 : 30 MeOH/CH2Cl2).
1
[a]2D6 +15.9 (c 1.7, CHCl3). H NMR (400 MHz, CDCl3) d 5.53
(1S,3S)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)octadec-5-yn-3-ol (9). The procedure was the same
as described above for the reaction of 5 with 10 leading to 8, except
that epoxide 6 (200 mg, 0.662 mmol) was employed to replace 5,
giving 9 (291 mg, 0.587 mmol, 88%, chromatographed with 15 : 1
(dt, J = 14.5, 7.1 Hz, 1H), 5.36 (dt, J = 14.7, 7.4 Hz, 1H), 3.92 (dd,
J = 13.9, 7.2 Hz, 1H), 3.86 (dd, J = 9.4, 5.0 Hz, 1H), 3.78–3.68
(m, 2H), 3.59 (dd, J = 12.0, 7.6 Hz, 1H), 3.04 (s, 3H), 2.21–2.10
(m, 2H), 2.00 (dd, J = 13.7, 6.7 Hz, 2H), 1.84–1.74 (m, 1H), 1.64
(dd, J = 4.0, 3.8 Hz, 1H), 1.51–1.15 (m, 20H), 0.99–0.77 (m, 12H),
0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d 135.2,
125.3, 73.9, 71.0 66.4, 63.8, 41.6, 39.6, 32.7, 31.9, 29.64, 29.62,
29.59, 29.5, 29.4, 29.3, 29.2, 25.7, 22.7, 17.9, 14.1, -4.5, -4.9. ESI-
MS m/z 481.4 ([M+Na]+); ESI-HRMS calcd for C26H54NaO4Si
481.3684, found 481.3695.
1
PE/EtOAc) as a colorless oil. [a]2D7 +20.2 (c 0.80, CHCl3). H
NMR (400 MHz, CDCl3) d 4.09 (dd, J = 6.5 6.3 Hz, 1H), 4.06–
4.00 (m, 1H), 3.96 (s, 1H), 3.89 (dd, J = 5.9 5.4 Hz, 1H), 3.79 (d,
J = 7.3 Hz, 1H), 2.68 (s, 1H), 2.41–2.28 (m, 2H), 2.19–2.08 (m,
2H), 1.89–1.73 (m, 2H),1.52–1.42 (m, 2H), 1.40 (s, 3H), 1.33 (s,
3H),1.37–1.19 (m, 18H), 0.91–0.83 (m, 12H), 0.09 (s, 3H), 0.08
(s, 3H); 13C NMR (100 MHz, CDCl3) d 109.1, 82.8, 78.5, 76.0,
70.7, 66.9, 66.8, 41.2, 31.8, 29.6, 29.5, 29.4, 29.3, 29.1, 28.9, 28.8,
28.0, 26.4, 25.7, 25.2, 22.6, 18.7, 17.8, 14.0, -4.3, -4.7; FT-IR
(film) 3476, 2953, 2927, 2855, 1463, 1370, 1255, 1214, 1074, 837,
776 cm-1. ESI-MS m/z 519.4 ([M+Na]+); EI-HRMS calcd for
C28H53O4Si ([M-CH3]+) 481.3713, found 481.3711.
(2S,4S,E)-2-(tert-Butyldimethylsilyloxy)nonadec-6-ene-1,4-diol
(17) and (2S,4S,E)-1-(tert-butyldimethylsilyloxy)nonadec-6-ene-
2,4-diol (17¢). The procedure was the same as described above
for the conversion of 12 leading to 13 and 13¢, except that 16
(34 mg, 0.074 mmol) was employed to replace 12, giving 17 (the
less polar component, 26 mg, 0.061 mmol, 77%) and 17¢ (the
more polar component, 6 mg, 0.014 mmol, 19%) as colorless oils
(with column chromatography eluting with 3 : 1 PE/EtOAc).
Data for 17 (the less polar component): [a]2D4 +1.7 (c 0.75,
CHCl3). 1H NMR (400 MHz, CDCl3) d 5.51 (dt, J = 14.5, 7.1 Hz,
1H), 5.40 (dt, J = 14.8, 7.3 Hz, 1H), 3.92–3.80 (m, 2H), 3.57 (dd,
J = 10.2, 4.3 Hz, 1H), 3.47 (dd, J = 10.0, 6.8 Hz, 1H), 2.96 (S,
2H), 2.18 (t, J = 6.4 Hz, 2H), 2.00 (dd, J = 13.6, 6.7 Hz, 2H),
1.62 (dt, J = 14.3, 2.4 Hz, 1H), 1.51–1.40 (m, 1H), 1.39–1.19 (m,
20H), 0.96–0.82 (m, 12H), 0.12–0.04 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 134.4, 125.5, 72.6, 71.4, 67.1, 41.0, 38.4, 32.7, 31.9, 29.7,
29.6, 29.5, 29.4, 29.3, 29.2, 25.9, 22.7, 18.3, 14.1, -5.39, -5.42;
FT-IR (film) 3366, 2953, 2925, 2854, 1463, 1254, 1122, 970, 837,
777 cm-1. ESI-MS m/z 451.4 ([M+Na]+); ESI-HRMS calcd for
C25H52O3SiNa ([M+Na]+) 451.3583, found 451.3560.
Data for 17¢ (the more polar component): [a]2D6 +2.8 (c 0.30,
CHCl3); 1H NMR (400 MHz, CDCl3) d5.53 (dt, J = 15.2, 7.0 Hz,
1H), 5.39 (dt, J = 14.4, 7.0 Hz, 1H), 4.06–3.97 (m, 1H), 3.84–3.75
(m, 1H), 3.64 (dd, J = 11.3, 4.8 Hz, 1H), 3.56 (dd, J = 11.3, 4.8 Hz,
1H), 2.24–2.09 (m, 2H), 2.06–1.96 (m, 2H), 1.96–1.78 (m, 2H), 1.74
(ddd, J = 14.7, 6.3, 2.6 Hz, 1H), 1.65 (ddd, J = 14.3, 9.0, 5.2 Hz,
1H), 1.44–1.16 (m, 20H), 0.97–0.80 (m, 12H), 0.18–0.05 (m, 6H);
FT-IR (film) 3363, 2956, 2925, 2854, 1464, 1255, 1096, 1046, 970,
836, 777, 668 cm-1. ESI-MS m/z 451.4 ([M+Na]+); ESI-HRMS
calcd for C25H52O3SiNa ([M+Na]+) 451.3583, found 451.3560.
(1S,3S,E)-1-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)octadec-5-en-3-ol (14) and (1S,3S,E)-3-(tert-
butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4- yl)-
octadec-5-en-1-ol (14¢). The procedure was the same as described
above for the reduction of 8 leading to 7a and 7a¢, except that 9
(102 mg, 0.205 mmol) was employed to replace 8, giving 14¢ (the
less polar component, 33 mg, 0.066 mmol, 32%) and 14 (the more
polar component, 55 mg, 0.110 mmol, 54%) as colorless oils (with
column chromatography eluting with 30 : 1 PE/EtOAc).
Data for 14¢ (the less polar component): [a]2D5 +17.7 (c 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3) d 5.45 (dt, J = 14.4, 7.0 Hz,
1H), 5.36 (dt, J = 14.6, 7.1 Hz, 1H), 4.10–4.00 (m, 1H), 4.00–3.87
(m, 3H), 3.80–3.67 (m, 1H), 3.30 (s, 1H), 2.22 (t, J = 5.9 Hz, 2H),
1.98 (dd, J = 13.1, 6.4 Hz, 2H), 1.82 (ddd, J = 14.5 3.8 2.1 Hz,
1H), 1.55–1.44 (m, 1H), 1.40 (s, 3H), 1.34 (s, 3H), 1.38–1.19 (m,
20H), 0.93–0.82 (m, 12H), 0.112 (s, 3H), 0.107 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 134.0, 124.9, 109.1, 78.6, 73.1, 71.7, 66.2,
41.2, 38.8, 32.7, 31.9, 29.7, 29.64, 29.61, 29.5, 29.4, 29.3, 29.2, 26.6,
25.8, 25.3, 22.7, 17.9, 14.1, -4.0, -4.7; FT-IR (film) 3523, 2955,
2926, 2855, 1463, 1370, 1257, 1215, 1066, 971, 837, 775 cm-1. ESI-
MS m/z 521.5 ([M+Na]+); ESI-HRMS calcd for C29H58NaO4Si
521.3997, found 521.4016.
Data for 14 (the more polar component): [a]2D5 +13.9 (c 1.375,
CHCl3). 1H NMR (400 MHz, CDCl3) d 5.53 (dt, J = 14.4, 7.0 Hz,
1H), 5.39 (dt, J = 14.7, 7.3 Hz, 1H), 4.10 (dd, J = 12.8, 6.5 Hz, 1H),
4.06–3.99 (m, 1H), 3.93–3.83 (m, 2H), 3.78 (t, J = 7.3 Hz, 1H), 2.47
(s, 1H), 2.28–2.08 (m, 2H), 2.00 (dd, J = 13.7 6.6 Hz, 2H), 1.78–1.60
(m, 2H), 1.40 (s, 3H), 1.34 (s, 3H), 1.38–1.19 (m, 20H), 0.94–0.80
(m, 12H), 0.08 (s, 3H), 0.075 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 134.3, 125.7, 109.2, 78.6, 71.1, 67.5, 67.1, 41.8, 41.2, 32.7, 31.9,
29.7, 29.6, 29.50, 29.46, 29.3, 29.2, 26.6, 25.8, 25.3, 22.7, 17.9,
14.1, -4.2, -4.6; FT-IR (film) 3489, 2926, 2854, 1463, 1370, 1254,
1213, 1073, 970, 837, 776 cm-1. ESI-MS m/z 449.4 ([M–C4H9–
(2S,4S,E)-Nonadec-6-ene-1,2,4-triol ((2S,4S)-1). The proce-
dure was the same as described above for removal of the TBS
protecting group in 13 leading to (2S,4R)-1, except that 17 (36 mg,
0.084 mmol) was employed to replace 13, giving (2S,4S)-1 (21 mg,
0.064 mmol, 80%, chromatographed with 1 : 15 MeOH/CH2Cl2)
1
as a white wax. [a]2D2 +4.4 (c 0.35 CHCl3). H NMR (400 MHz,
CD3OD) d 5.53–5.42 (m, 2H), 4.87 (s, 3H), 3.81–3.76 (m, 2H),
3.49 (dd, J = 11.4, 4.5 Hz, 1H), 3.44 (dd, J = 11.2, 6.0 Hz, 1H),
2.26–2.17 (m, 2H), 2.07–1.99 (m, 2H), 1.68 (dt, J = 14.0, 4.5 Hz,
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1H), 1.50 (dt, J = 14.0, 8.5 Hz, 1H), 1.42–1.21 (m, 20H), 0.90 (t, J =
6.8 Hz, 3H); 13C NMR (100 MHz, CD3OD) d 134.4, 127.2, 72.1,
71.2, 67.2, 41.8, 40.5, 33.8, 33.1, 30.79 (ca. 1.5 times as intense as
other signals), 30.76 (ca. twice as intense as other signals), 30.6
(ca. 1.2 times as intense as other signals), 30.4, 30.3, 23.7, 14.4;
FT-IR (film) 3367, 2955, 2924, 2853, 1464, 1377, 1019, 968, 680,
669, 650 cm-1. ESI-MS m/z 337.2 ([M+Na]+); ESI-HRMS calcd
for C19H38O3 314.2821, found 314.2818.
and brine, and dried over anhydrous MgSO4. Filtration and rotary
evaporation left an oily residue, which was chromatographed (3 : 1
PE/EtOAc) on silica gel to give diacetate 19 (404 mg, 1.06 mmol,
93%) as a colorless oil. [a]2D6 -4.5 (c 0.85, CHCl3). 1H NMR
(400 MHz, CDCl3) d 7.36–7.27 (m, 5H), 5.11–5.04 (m, 1H), 5.04–
4.97 (m, 1H), 4.51 (dd, J = 23.1, 12.0 Hz, 2H), 4.10 (dd, J = 12.0,
6.1 Hz, 1H), 3.99 (dd, J = 8.3, 6.9 Hz, 1H), 3.73 (dd, J = 8.2,
6.3 Hz, 1H), 3.54 (ddd, J = 19.3, 10.8, 4.7 Hz, 2H), 2.12–1.99
(m, 7H), 1.89 (ddd, J = 15.0, 8.8, 6.6 Hz, 1H), 1.37 (s, 3H), 1.32
(s, 3H); 13C NMR (100 MHz, CDCl3) d 170.20, 170.18, 137.8,
128.3, 127.6, 127.5, 109.7, 76.6, 73.1, 70.6, 70.2, 69.9, 65.8, 31.6,
26.2, 25.0, 21.1, 20.9; FT-IR (film) 2987, 2936, 2881, 1740, 1454,
1372, 1235, 1062, 1027, 849, 740, 699, 605, 513 cm-1. ESI-MS m/z
403.2 ([M+Na]+); EI-HRMS calcd for C20H28O7 Na ([M+Na]+)
403.1727, found 403.1734.
(S,E)-3-(tert-Butyldimethylsilyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)octadec-5-en-1-one (15). The procedure was the
same as described above for oxidation of 7a into ketone 11, except
that 14¢ (11 mg, 0.022 mmol) was employed to replace 7a, giving 15
(11 mg, 0.022 mmol, 100%, chromatographed with 30 : 1 PE/Et2O)
as a colorless oil. [a]D25 +37.7 (c 0.55, CHCl3). 1H NMR (400 MHz,
CDCl3) d 5.44 (dt, J = 15.3, 6.3 Hz, 1H), 5.36 (dt, J = 15.3, 6.7 Hz,
1H), 4.40 (dd, J = 7.7, 5.7 Hz, 1H), 4.24 (dt, J = 11.4, 5.9 Hz,
1H), 4.16 (t, J = 8.2 Hz, 1H), 4.01 (dd, J = 8.5, 5.4 Hz, 1H), 2.79
(dd, J = 17.0, 7.0 Hz, 1H), 2.59 (dd, J = 16.7, 5.3 Hz, 1H), 2.17
(t, J = 6.2 Hz, 2H), 1.97 (dd, J = 13.3, 6.4 Hz, 2H), 1.46 (s, 3H),
1.39 (s, 3H), 1.36–1.17 (m, 20H), 0.94–0.78 (m, 12H), 0.06 (s, 3H),
0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) d 208.8, 134.0, 125.3,
110.9, 80.8, 68.2, 66.0, 45.8, 40.9, 32.7, 31.9, 29.7, 29.64, 29.62,
29.5, 29.43, 29.36, 29.2, 26.0, 25.8, 25.1, 22.7, 18.0, 14.1, -4.6,
-4.8; FT-IR (film) 2926, 2854, 1720, 1463, 1373, 1255, 1214, 1077,
970, 836, 776 cm-1. ESI-MS m/z 519.5 ([M+Na]+); ESI-HRMS
calcd for C29H56O4SiNa ([M+Na]+) 519.3840, found 519.3860.
(2S,3S,5R)-6-(Benzyloxy)-3,5-diacetoxy-hexane-1,2-diol (20).
To a solution of 19 (250 mg, 0.657 mmol) in CH2Cl2 (33 mL)
were added Er(OTf)2 (162 mg, 0.263 mmol) and BnOH (2 mL).
The mixture was stirred at ambient temperature until TLC
showed disappearance of the starting aceonide (ca. 12 h). The
mixture was concentrated on a rotary evaporator. The residue was
chromatographed (1 : 4 PE/EtOAc) on silica gel to give diol 20
(185 mg, 0.544 mmol, 83%) as a colorless sticky oil. [a]2D5 +5.3
1
(c 1.70, CHCl3). H NMR (400 MHz, CD3OD) d 7.45–7.23 (m,
5H), 5.15–5.07 (m, 1H), 5.03–4.96 (m, 1H), 4.52 (dd, J = 20.9,
12.0 Hz, 2H), 3.68 (dd, J = 11.1, 4.9 Hz, 1H), 3.55 (dd, J =
9.9, 4.8 Hz, 3H), 3.48 (dd, J = 11.6, 6.8 Hz, 1H), 2.14–1.99 (m,
7H), 1.92 (ddd, J = 15.2, 9.1, 6.6 Hz, 1H); 13C NMR (100 MHz,
CD3OD) d 172.4, 172.3, 139.4, 129.4, 128.8, 128.7, 74.2, 74.1 73.2,
72.0, 71.9, 63.8, 32.2, 21.2, 21.1; FT-IR (film) 3453, 2930, 1736,
1454, 1373, 1243, 1052, 1028, 741, 670, 607 cm-1. ESI-MS m/z
363.1 ([M+Na]+); EI-HRMS calcd for C17H24O7Na ([M+Na]+)
363.1418, found 363.1414.
(1S,3R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
butane-1,3-diol (18). A solution of BnOH (1.2 mL) in dry THF
(10 mL) was added to a solution of NaH (60% Suspension in
mineral oil, 262 mg, 6.55 mmol) in dry DMSO (10 mL) stirred
at ambient temperature. The mixture was stirred for 20 min. A
solution of 6 (1.10 g, 3.640 mmol) in dry THF (10 mL) was
introduced. The stirring was continued at the same temperature
until TLC showed complete disappearance of the starting epoxide
(ca. 24 h). Aqueous saturated NH4Cl was added. The mixture was
extracted with EtOAc twice. The combined organic layers were
washed with water and brine before being dried over anhydrous
MgSO4. Filtration and rotary evaporation left an oily residue,
which was chromatographed (2 : 1 PE/EtOAc) on silica gel to
afford 18 as a colorless oil (840 mg, 2.84 mmol, 78%). [a]2D6 +5.1
(2S,4R)-5-(Benzyloxy)pentane-1,2,4-triol (21). To a solution
of NaIO4 (433 mg, 2.02 mmol) in water (3 mL) was added silica
gel (300–400 mesh, 4.3 g), followed by CH2Cl2 (20 mL). The
mixture was stirred at ambient temperature for ca. 30 min. Diol
20 (172 mg, 0.505 mmol) was added. The stirring was continued at
ambient temperature until TLC showed complete disappearance
of the starting diol (ca. 2.5 h). Solids were filtered off. The two
phases of the filtrate were separated. The organic layer was washed
with water and brine before being dried over anhydrous MgSO4.
Removal of the drying agent by filtration and the solvent by rotary
evaporation afforded the crude aldehyde), which gave the following
1
(c 0.80, CHCl3). H NMR (400 MHz, CD3OD) d 7.50–7.20 (m,
5H), 4.55 (dd, J = 15.5, 12.2 Hz, 2H), 4.09–4.00 (m, 2H), 3.95–
3.83 (m, 2H), 3.76–3.67 (m, 1H), 3.52–3.43 (m, 2H), 1.90 (ddd,
J = 14.4, 5.8, 3.6 Hz, 1H), 1.58–1.48 (m, 1H), 1.37 (s, 3H), 1.31 (s,
3H); 13C NMR (100 MHz, CD3OD) d 139.7, 129.4, 128.9, 128.7,
110.4, 80.3, 75.2, 74.3, 71.7, 70.1, 67.4, 38.3, 26.9, 25.5; FT-IR
(film) 3442, 2987, 2870, 1454, 1371, 1256, 1212, 1128, 1066, 852,
740, 699 cm-1. ESI-MS m/z 319.0 ([M+Na]+); EI-HRMS calcd for
C16H24O5Na ([M+Na]+) 319.1516, found 319.1521.
1
data: H NMR (400 MHz, CDCl3) d 9.49 (s, 5H), 7.41–7.22 (m,
5H), 5.22–5.10 (m, 2H), 4.54 (dd, J = 28.3, 12.1 Hz, 2H), 4.12 (dd,
J = 14.4, 6.9 Hz, 1H), 3.55 (d, J = 4.4 Hz, 2H), 2.30–2.23 (m, 2H),
2.16 (s, 3H), 2.02 (s, 3H); FT-IR (film) 2960, 2924, 2854, 1738,
1454, 1372, 1259, 1234, 1093, 1021, 780, 699 cm-1.
The above obtained crude aldehyde was dissolved in dry THF
(3 mL) and chilled to -30 ◦C. LiALH4 (77 mg, 2.021 mmol)
was added in one portion. The bath was then allowed to warm
to ambient temperature while the stirring was continued until
TLC showed complete of the reaction (ca. 12 h). The mixture
was diluted with EtOAc before MeOH (1 mL) and aqueous
satrated potassium sodium tartrate (1 mL) were carefully added.
The mixture was extracted with EtOAc, washed with water and
brine, and dried over anhydrous MgSO4. Removal of the drying
(1S,3R)-4-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
butane-1,3-diyl diacetate (19). To a solution of 18 (340 mg,
1.15 mmol) in CH2Cl2 (8 mL) were added in turn DMAP (14 mg,
0.115 mmol) and pyridine (0.37 mL, 4.59 mmol) and Ac2O
(0.48 mL, 5.048 mmol). The mixture was stirred at ambient
temperature until TLC showed disappearance of the starting diol
(ca. 1.5 h). The mixture was diluted with CH2Cl2, washed with
aqueous saturated NaHCO3 and aqueous saturated CuSO4, water
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agent by filtration and the solvent by rotary evaporation left a
crude oil, which was chromatographed (1 : 15 MeOH/CH2Cl2) on
silica gel to afford triol 21 (41 mg, 0.359 mmol, 36% from diol
20) as a colorless sticky oil. [a]2D5 +1.6 (c 1.50, CHCl3). 1H NMR
(400 MHz, CD3OD) d 7.44–7.22 (m, 5H), 4.61–4.49 (m, 2H),
4.04–3.94 (m, 1H), 3.85–3.76 (m, 1H), 3.54–3.41 (m, 4H), 1.75 (dt,
J = 14.1, 4.7 Hz, 1H), 1.57 (dt, J = 16.2, 8.3 Hz, 1H); 13C NMR
(100 MHz, CD3OD) d 139.7, 129.3, 128.9, 128.6, 75.5, 74.3, 71.5,
69.8, 67.2, 37.9; FT-IR (film) 3389, 2924, 2852, 1454, 1364, 1096,
738, 698 cm-1. ESI-MS m/z 249.1 ([M+Na]+); ESI-HRMS calcd
for C12H18O4Na ([M+Na]+) 249.1097, found 249.1096.
30.3, 30.1, 30.0, 28.3, 23.7, 19.5, 14.4; FT-IR (film) 3419, 2925,
2854, 1455, 1099, 1025, 736, 698 cm-1. ESI-MS m/z 425.4 ([M+
Na]+); ESI-HRMS calcd for C26H42O3Na ([M+Na]+) 425.3026,
found 425.3017.
(4R,6R)-4-(Benzyloxymethyl)-2,2-dimethyl-6-(pentadec-2-ynyl)-
1,3-dioxane (24). A solution of diol 23 (23 mg, 0.057 mmol),
CSA (2 mg, 0.009 mmol) and Me2C(OMe)2 (0.15 ml, 1.143 mmol)
in dry CH2Cl2 (0.15 mL) was stirred at ambient temperature for
1.5 h. Et3N (0.1 mL) was added. The mixture was concentrated
on a rotary evaporator. The residue was chromatographed (15 : 1
PE/EtOAc) on silica gel to give acetonide 24 (18 mg, 0.051 mmol,
1
90%) as a colorless sticky oil. [a]2D8 -15.7 (c 0.90, CHCl3); H
(R)-1-(Benzyloxy)-3-((S)-oxiran-2-yl)propan-2-ol (22). A mix-
ture of trio 21 (55 mg, 0.243 mmol), n-Bu2SnO (7 mg,
0.0243 mmol), DMAP (3 mg, 0.0243 mmol) and Et3N (51 mL,
0.365 mmol) in MeCN (4 mL) was stirred at ambient temperature
for 20 min. p-TsCl (70 mg, 0.3648 mmol) was introduced. The
mixture was stirred at the same temperature until TLC showed
complete disappearance of the starting triol (ca. 1 h). E2O was
added and the stirring was continued. The white solids were
filtered off through Celite. The filtrate was concentrated on a
rotary evaporator to give a yellowish sticky oil, which was directly
dissolved in MeOH (2 mL). To this solution (cooled in a ice-
water bath) was added powdered K2CO3 (50 mg, 0.365 mmol).
The mixture was stirred at ambient temperature until TLC
showed complete disappearance of the tosylate (ca. 2.5 h). The
excess base was carefully neutralized before being concentrated
by rotary evaporation. The crude oil was chromatographed (2 : 1
PE/EtOAc) on silica gel to give epoxide 22 (35 mg, 0.168 mmol,
NMR (400 MHz, CD3OD) d 7.38–7.24 (m, 5H), 4.55 (s, 2H),
4.20–4.09 (m, 1H), 4.03–3.93 (m, 1H), 3.49 (dd, J = 10.1, 6.1 Hz,
1H), 3.42 (dd, J = 10.1, 4.3 Hz, 1H), 2.42–2.32 (m, 1H), 2.25–2.09
(m, 3H), 1.74 (dt, J = 12.9, 2.2 Hz, 1H), 1.45 (s, 3H), 1.35 (s, 3H),
1.50–1.24 (m, 21H), 0.90 (t, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
CD3OD) d 139.6, 129.4, 128.9, 128.7, 100.1, 83.1, 76.6, 74.8,
74.4, 69.9, 96.4, 33.8, 33.1, 30.79, 30.77, 30.75, 30.72, 30.5, 30.28,
30.26, 30.1, 29.8, 27.3, 23.7, 20.1, 19.4, 14.5; FT-IR (film) 2956,
2925, 1741, 1460, 1377, 1197, 1177, 1037, 790 cm-1. ESI-MS m/z
465.5 ([M+Na]+); ESI-HRMS calcd for C29H46O3Na 465.3348,
found 465.3340.
((4R,6R)-2,2-Dimethyl-6-((E)-pentadec-2-enyl)-1,3-dioxan-4-yl)-
methanol (25). Li cuts (ca. 0.3 g, 43 mmol) was added in
portions to liquid NH3 (ca. 20 mL, in a 50 mL round-bottom
flask) stirred in a -78 ◦C bath. To the resultant dark blue mixture
was added a solution of propargyl alcohol 24 (18 mg, 0.040 mmol)
in THF (2 mL), followed by t-BuOH (3 mL). The mixture was
stirred at the same temperature for 10 h, when the TLC showed
disappearance of the starting 24. Aqueous saturated NH4Cl
(10 mL) was added carefully. The bath was allowed to warm
to ambient temperature slowly. The mixture was extracted with
Et2O, washed with water and brine, and dried over anhydrous
MgSO4. Filtration and rotary evaporation left an oily residue,
which was chromatographed (8 : 1 PE/EtOAc) on silica gel to give
the alcohol 25 (13 mg, 0.037 mmol, 90%) as a colorless oil. [a]D27
-7.9 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) d 5.45 (dt, J =
14.6, 6.3 Hz, 1H), 5.36 (dt, J = 14.8, 6.8 Hz, 1H), 3.99–3.95 (m,
1H), 3.86–3.84 (m, 3H), 3.61–3.56 (m, 1H), 3.52–3.48 (m, 3H),
2.29–2.24 (m, 1H), 2.11–2.06 (m, 1H), 2.01–1.96 (m, 1H), 1.46 (s,
3H), 1.41 (s, 3H), 1.36–1.18 (m, 22H), 0.88 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 133.7, 124.8, 98.7, 69.7, 68.6,
66.2, 39.7, 32.6, 31.9, 31.8, 30.0, 29.7, 29.7, 29.6, 29.6, 29.5, 29.4,
29.3, 29.1, 22.7, 19.9, 14.1; FT-IR (film) 3462, 2992, 2924, 2854,
1466, 1438, 1379, 1200, 969, 870, 721 cm-1. ESI-MS m/z 377.4
([M+Na]+); ESI-MS m/z 377.4 ([M+ Na]+); ESI-HRMS calcd
for C22H42O3Na ([M+Na]+) 377.3026, found 377.3004.
1
69%) as a colorless oil. [a]2D6 -10.2 (c 1.60, CHCl3). H NMR
(400 MHz, CDCl3) d 7.44–7.27 (m, 5H), 4.56 (s, 2H), 4.10–3.98
(m, 1H), 3.49 (ddd, J = 22.0, 9.4, 3.7 Hz, 2H), 3.15–3.05 (m, 1H),
2.76 (t, J = 4.5 Hz, 1H), 2.70 (s, 1H), 2.50 (dd, J = 4.9, 2.7 Hz, 1H),
1.82 (dt, J = 14.5, 4.6 Hz, 1H), 1.66 (dt, J = 14.4, 7.1 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d 137.8, 128.4, 127.8, 127.7, 73.9, 73.3,
68.5, 49.6, 46.6, 35.9; FT-IR (film) 3348, 2924, 2856, 1496, 1454,
1364, 1096, 827, 740, 699 cm-1. ESI-MS m/z 209.1 ([M+H]+); ESI-
HRMS calcd for C12H17O3 ([M+H]+) 209.1172, found 209.1176.
(2R,4R)-1-(Benzyloxy)nonadec-6-yne-2,4-diol
(23). n-BuLi
(1.6 M, in hexanes, 0.4 mL, 0.656 mmol) was added to a solution
of tetradec-1-yne 10 (0.17 mL, 0.673 mmol) in dry THF (3.4 mL)
stirred at -78 ◦C under N2 (balloon). The resulting suspension
was stirred at the same temperature for 1 h. A solution of epoxide
22 (35 mg, 0.168 mmol) in dry THF (1 mL) was added, followed
by BF3·Et2O (0.1 mL, 0.336 mmol). The mixture was stirred at
-78 ◦C until TLC showed completion of the reaction (ca. 5.5 h).
MeOH (2 mL) was added carefully. The bath was allowed to
warm to ambient temperature. The mixture was extracted with
EtOAc, washed with water and brine, and dried over anhydrous
MgSO4. Filtration and rotor evaporation left an oil, which was
purified by column chromatography (3 : 1 PE/EtOAc) on silica
gel to deliver the diol 23 (15 mg, 0.037 mmol, 52% from 22) as
(2R,4R,E)-Nonadec-6-ene-1,2,4-triol ((2R,4R)-1, Natural 1).
A solution of 25 (11 mg, 0.031 mol), HS(CH2)3SH (12 mL,
0.11 mmol) and BF3·Et2O (16 mL, 0.11 mmol) in dry CH2Cl2
(0.5 mL) was stirred at ambient temperature for 30 min, when TLC
showed completion of the reaction. The mixture was concentrated
on a rotary evaporator. The residue was chromatographed (20 : 1
CH2Cl2/MeOH) on silica gel to give (2R,4R)-1 (8 mg, 0.025 mmol,
81%) as a white wax. [a]D27 -8.0 (c 0.45, CHCl3), (lit.2 [a]D24 -8.6 (c
0.25, CHCl3)). 1H NMR (400 MHz, CD3OD) d 5.52 (dt, J = 15.4,
1
a colorless oil. [a]2D6 -6.1 (c 0.75, CHCl3). H NMR (400 MHz,
CD3OD) d 7.44–7.22 (m, 5H), 4.60–4.50 (m, 2H), 4.10–3.92 (m,
1H), 3.88–3.80 (m, 1H), 3.50–3.41 (m, 2H), 2.41–2.24 (m, 2H),
2.19–2.08 (m, 2H), 1.92 (dt, J = 14.1, 4.7 Hz, 1H), 1.60 (dt, J =
13.7, 8.6 Hz, 1H), 1.51–1.22 (m, 20H), 0.90 (t, J = 6.5 Hz, 3H);
13C NMR (100 MHz, CD3OD) d 139.7, 129.4, 128.8, 128.6, 83.1,
77.2, 75.5, 74.3, 70.1, 69.9, 40.4, 33.1, 30.80, 30.77, 30.72, 30.5,
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6.8 Hz, 1H), 5.49 (dt, J = 15.3, 6.0 Hz, 1H), 3.86–3.81 (m, 2H),
3.55–3.45 (m, 2H), 2.22–2.19 (m, 2H), 2.07–2.02 (m, 2H), 1.71
(dt, J = 14.0, 4.4 Hz, 1H), 1.53 (dt, J = 14.3, 6.5 Hz, 1H), 1.38–
1.30 (m, 20H), 0.93 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CD3OD) d 134.4, 127.2, 72.1, 71.2, 67.3, 41.9, 40.5, 33.8, 33.1,
30.80 (ca. 1.8 times as intensive as other signals), 30.77 (ca. 2 times
as intensive as other signals), 30.6 (ca. 1.2 times as intensive as
other signals), 30.5, 30.3, 23.7, 14.4; FT-IR (KBr): 3339, 2917,
2850, 1467, 1331, 1113, 1023, 843, 717 cm-1. ESI-MS m/z 337.3
([M+Na]+); ESI-HRMS calcd for C19H38O3Na 337.2713, found
337.2707.
2 F. Abe, S. Nagafuji, M. Okawa, J. Kinjo, H. Akahane, T. Ogura, M. A.
Martinez-Alfaro and R. Reys-Chilpa, Biol. Pharm. Bull., 2005, 28,
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3 For configuration determination of a closely related natural product
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Tetrahedron, 2008, 64, 9477.
4 J.-Z. Wu, J. Gao, G.-B. Ren, Z.-B. Zhen, Y.-H. Zhang and Y.-K. Wu,
Tetrahedron, 2009, 65, 289.
5 P. Jiang, S.-M. Zhang, L. He, Y.-K. Wu and Y. Li, Tetrahedron, 2011,
67, 2651.
6 I. S. Kim, R.-D. Guang and H.-J. Yong, J. Org. Chem., 2007, 72, 5424.
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11 J. Jagel and M. E. Maier, Synthesis, 2009, 2881.
12 H. Takamura, T. Murata, T. Asai, I. Kadota and D. Uemura, J. Org.
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Acknowledgements
This work was supported by the National Basic Research Program
of China (the 973 Program, 2010CB833200), the National Natural
Science Foundation of China (21032002, 20921091, 20672129,
20621062, 20772143), and the Chinese Academy of Sciences
(KJCX2.YW.H08).
13 J. Chen, Z.-F. Shi, L. Zhou, A.-L. Xie and X.-P. Cao, Tetrahedron,
2010, 66, 3499.
14 A. B. Smith, V.-A. Doughty, C. Sfouggatakis, C. S. Bennett, J. Koyanagi
and M. Takeuchi, Org. Lett., 2002, 4, 783.
15 M. Daumas, Y. Vo-Quang, L. Vo-Quang and F.-L. Goffic, Synthesis,
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16 Y. Oikawa, T. Nikao and O. Yonemitsu, J. Chem. Soc., Perkin Trans. 1,
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Notes and references
1 For information about Chagas disease, see(a) the WHO website:
http://www.who.int/mediacentre/factsheets/fs340/en/index.html;
(b) Wikipedia, http://en.wikipedia.org/wiki/Chagas_disease.
6806 | Org. Biomol. Chem., 2011, 9, 6797–6806
This journal is
The Royal Society of Chemistry 2011
©