Synthesis of linear aza and thio analogues of acetogenins and evaluation of their cytotoxicity

Article abstract of DOI:10.1002/ejoc.201300767

We report the stereoselective synthesis of thio and aza analogues of Annonaceous acetogenins. The synthetic route allows easy variation of the stereochemistry and of the thio- and aza-fragments. Kinetic resolution of terminal bis-epoxides was used to set two remote stereocentres with high enantio- and diastereoselectivities in one step. The cytotoxicity of the analogues was assessed using the HeLa cell line. Four aza and two thio analogues of Annonaceous acetogenins were synthesized according to a general synthetic route. Two remote stereocentres in the analogues were set with high enantio- and diastereoselectivity in one step by hydrolytic kinetic resolution of a terminal bis-epoxide. Copyright

Full text of DOI:10.1002/ejoc.201300767

FULL PAPER
DOI: 10.1002/ejoc.201300767
Synthesis of Linear Aza and Thio Analogues of Acetogenins and Evaluation of
Their Cytotoxicity
Piret Villo,*[a] Lauri Toom,[a] Elo Eriste,[a] and Lauri Vares*[a]
Keywords: Natural products / Asymmetric synthesis / Kinetic resolution / Enantioselectivity / Cytotoxicity
We report the stereoselective synthesis of thio and aza ana-
logues of Annonaceous acetogenins. The synthetic route al-
lows easy variation of the stereochemistry and of the thio-
and aza-fragments. Kinetic resolution of terminal bis-epox-
ides was used to set two remote stereocentres with high en-
antio- and diastereoselectivities in one step. The cytotoxicity
of the analogues was assessed using the HeLa cell line.
some structural features have been shown to be necessary
for their biological activity. The central region with flanking
Introduction
The Annonaceous acetogenins are a very interesting class OH-groups is thought to play an important role, and it has
of biologically active natural products that show cytotoxic also been shown that the hydrocarbon chain that connects
and immunosuppressive effects.[1] They include one of the the central region with the butenolide moiety has an opti-
most potent inhibitors of NADH-ubiquinone oxido- mal length of 13 carbon atoms for a strong inhibition ef-
reductase (complex I) from the mitochondrial electron- fect.[8] Whether or not the butenolide is necessary, or
transport system, as well as inhibitors of NADH oxidase of whether it can be replaced by a structurally similar moiety
plasma membranes of cancer cells that interrupt the intra- is under debate.[9] Continued studies of the acetogenins and
cellular synthesis of ATP.[2] Natural acetogenins are found their analogues will hopefully further clarify their mode of
in species belonging to the tree family Annonaceae in the action. Based on the results of many promising in vitro as-
Magnoliales order, native to tropical and sub-tropical re- sessments, and also of in vivo studies in mice[10] and in-
gions.[3,4] Since the first acetogenin, Uvaricin (Figure 1), sects,[11] the acetogenins are considered to be a promising
was isolated,[5] acetogenins have been under increasing sci- group of compounds in the search for new drug leads.
entific attention, and to date, more than 400 members of
It has been reported that when the acetogenin structure
this class of compounds have been isolated. The acetogenins is simplified by replacing the THF unit with a linear moiety
are characterized by an unbranched fatty acid chain that is containing heteroatoms, the biological activities of the sim-
normally terminated by a butenolide moiety, and one to plified structures are comparable with those of the natural
three THF (or THP) rings with adjacent hydroxy groups in compounds. Various linear acetogenin analogues have been
the central region of the hydrocarbon chain.[6] Due to their synthesized in which the THF units have been substituted
potent biological activities, especially the selective cytotoxi- for polyether units,[12] hydroxy groups,[13] or amine-contain-
city against tumour ells, the synthesis of acetogenins and ing moieties.[14] For example, Zhu-Jun Yao and co-workers
their derivatives are the subject of increasing interest.[7] Al- have reported the synthesis of analogues containing a poly-
though structure–activity relationships need to be refined, ether unit[15] (I; Figure 2), and a bis-amide unit[16] (II). Both
Figure 1. Uvaricin.
of these compounds have cytotoxicities comparable to
known anti-cancer agents. Also, in the case of analogue I,
the presence of the hydroxy group at C-4 clearly enhanced
the biological activity compared to when it was absent.
This inspired us to explore the enantioselective synthesis
of linear aza analogues 1–4 (Figure 3) with a hydroxy group
[a] Institute of Technology, University of Tartu,
Nooruse 1, Tartu 50411, Estonia
E-mail: piret.villo@ut.ee
lauri.vares@ut.ee
http://www.tuit.ut.ee/140999
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300767.
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Aza- and Thio-Analogues of Acetogenins
Figure 2. Examples of non-THF acetogenin analogues.
Figure 3. Synthesized aza and thio analogues 1–6.
at C-4, and to assess their cytotoxicities. Thio analogues
5 and 6 were also prepared, and their cytotoxicities were
compared to those of the aza analogues. Many biologically
Results and Discussion
We envisioned two variations of the synthetic route, one
active natural compounds contain sulfur atoms,[17] but sul- based on Jacobsen’s HKR, and the other on the Sharpless
fur has not been reported as a component of natural ace- AD method. The retrosynthetic analysis for analogues 1, 2,
togenin structures. Moreover, divalent sulfur can act as a 5, and 6 is outlined in Figure 4a, and is based on the HKR
hydrogen-bond donor comparable with the oxygen of an method. According to this convergent synthetic route, there
ether moiety, albeit weaker in strength.[18] And bearing in are two main fragments that must be coupled by an epox-
mind the importance of hydrogen bonding during binding ide-opening reaction in the latter stages. These are termed
to enzyme active sites, this could make the thio analogues the left-hand fragment, which contains the amine or thiol
of acetogenins an interesting subject along with the aza an- moieties, and the right-hand fragment 7 or 8, an epoxide
alogues.
containing a terminal γ-lactone or a butenolide unit,
Jacobsen’s hydrolytic kinetic resolution (HKR)[19] and respectively. We envisioned that the left-hand fragment
Sharpless asymmetric dihydroxylation (AD)[20] were both could be derived from a chiral epoxide (S)-9, after epoxide
used to install the stereochemistry in the synthetic ana- opening by an amino or a thiol. The synthesis of (S)-9
logues. Jacobsen’s kinetic resolution is a well-established could be achieved by subjecting racemic epoxide 9 to HKR
method that has also been successfully used on terminal conditions. The racemic epoxide can be obtained from com-
mono-epoxides with different nucleophiles.[21] Bis-epoxides, mercial sources or by oxidation of alkene 10 using mCPBA
on the other hand, are more rarely used as substrates in (m-chloroperbenzoic acid). The right-hand fragment 7 or 8
HKR.[19a,22] Recently, we reported an efficient and highly could be obtained by alkylation of lactone 12 with iodide
stereoselective hydrolytic and aminolytic kinetic resolution 11, which is a functionalized derivative of 13. Epoxy-diol
of terminal bis-epoxides,[23] and this method has been used 13 could, in turn, be synthesized by subjecting bis-epoxide
for the synthesis of the aza and thio analogues reported in 14 to HKR conditions to install two remote stereocentres.
this paper.
The bis-epoxide can be obtained by oxidation of commer-
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Figure 4. Retrosynthetic analysis of analogues 1–6 using a) Jacobsen’s HKR of mono- and bis-epoxides; b) Sharpless AD of olefins.
cially available diene 15 using mCPBA. Lactone 12 can be
synthesized from (S)-propylene oxide and (phenylthio)-
acetic acid. Due to the possibility of epimerization of the
unsaturated lactone ring under basic conditions,[24] mild re-
action conditions were chosen where possible, and the inser-
tion of the double bond into the lactone ring was planned
to be one of the last steps.
For analogues 3 and 4, a synthetic route based on the
Sharpless AD method was planned (Figure 4b). This gives
diastereomers that are not accessible by the HKR method,
as the stereocentres are installed one at a time. The left- and
right-hand fragments are to be coupled during the latter
steps of the synthesis, similarly to the route in Figure 4a.
But here, chiral epoxide (R)-9 was to be derived from chiral
diol 17, after asymmetric dihydroxylation of alkene 10. We
planned that right-hand fragment 16 would be synthesized
by subjecting alkylation product 18 to AD conditions and
converting the resulting diol into the epoxide. Iodide 19 is
a derivative of diol 20, which we planned to obtain by
asymmetric dihydroxylation of diene 15.
For the synthesis of the left-hand fragments, HKR and
AD can both be used to give epoxides (S)-9 and (R)-9
(Scheme 1), but HKR gives higher enantioselectivity.
When olefin 10 was subjected to osmium-catalysed asym- Scheme 1. Synthesis of (S)-9 and (R)-9 by HKR and AD.
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metric dihydroxylation conditions with chiral ligand DMPU (N,NЈ-dimethylpropyleneurea)[32] and Et3B-pro-
(DHQD)2PHAL, diol 17 was formed in excellent yield and moted processes[33] were investigated, but without success.
with an enantiomeric ratio of 92:8.[25,26] On the other hand, The optimal result was achieved by using LDA (lithium di-
when racemic epoxide 9 was subjected to HKR conditions, isopropylamide) and HPMA (10 equiv.), and under these
(S)-9 was isolated with an excellent enantiomeric ratio of conditions, 7 was formed in 78% yield. Oxidation of the
99.9:0.1[27] and in high yield (49% from a theoretical maxi- sulfide moiety in 7 followed by elimination gave the buten-
mum of 50%).
olide unit in 8. It was noted that the elimination of the
The importance of choosing HKR over AD becomes phenylsulfenic acid occurred either during the oxidation of
more relevant in the synthesis of the right-hand fragments, the sulfide moiety or during the work-up without subse-
where two stereocentres are set. The two approaches to the quent heating of the material.
right-hand fragments by AD and by HKR are shown in
Scheme 2. The asymmetric dihydroxylation of diene 15 was
terminated after ca. 50% conversion (monitored by TLC
analysis) to give diol 20 with an er of 92:8.[25] To use HKR,
diene 15 was first oxidized by mCPBA into bis-epoxide 14,
which consisted of (R,R)-14 (25%), (S,S)-14 (25%), and
meso isomer (R,S)-14 (50%). Then under HKR conditions,
the meso derivative was converted into 13 in high yield, with
an excellent er of 99.3:0.7 and a good dr of 97:3.[28] During
the reaction, the aforementioned (R,R)-14 stereoisomer was
transformed into a tetrol, and the (S,S)-14 enantiomer re-
mained unaffected in the reaction mixture. Thus, in contrast
to the AD approach, both of the olefin moieties in 15 can
be functionalized simultaneously when using HKR, and
also a higher enantioselectivity can be achieved.
Scheme 3. Synthesis of right-hand fragments 7 and 8 by HKR.
Diol 20 was converted into compound 18 following a
route similar to that used for the conversion of 13 into 7
(Scheme 4). Asymmetric dihydroxylation of 18 gave diol 23,
which was converted into epoxide 16.
Initial efforts were directed towards the preparation of
aza analogue 1. Epoxide (S)-9 was converted into amino
alcohol 24 by treatment with ethylene-1,2-diamine at 50 °C
(Scheme 5). When epoxide 8 was treated with amino
alcohol 24 under similar conditions, no product was
formed, so the second epoxide-opening reaction had to be
explored more closely. Since the presence of the butenolide
unit in 8 excludes the use of basic conditions and elevated
temperatures, the reaction was investigated with some ad-
ditional Lewis acid catalysts. Several transition metal chlor-
Scheme 2. Synthesis of 20 by AD, and of 13 by HKR.
ides and triflates were tested,[34,35] and it was found that at
room temperature they all gave ca. 30% of the coupled
The primary hydroxy group in epoxy-diol 13 was regiose- product after reaction times of 2–3 d, and the unreacted
lectively tosylated[29] using pTsCl and Bu2SnO (cat.) to give starting materials were recoverable. When the reaction was
21 (Scheme 3). After protecting the secondary hydroxy heated to 40 °C, the yield doubled, but raising the tempera-
group as a silyl ether, tosylate 22 was converted into iodide ture further resulted in the formation of unidentified by-
11. Next, alkylation of the lithium enolate derived from products. Finally, epoxide 8 was opened by 24 in the pres-
lactone 12[30] with 16 was investigated. In an attempt to ence of La(OTf)3 at 40 °C to give the coupled product in
replace HMPA (hexamethylphosphoramide) as an additive, 65% yield after 2 d. After removing the silyl ether, analogue
which has previously been used in similar alkylations,[31] 1 was formed.
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Scheme 4. Synthesis of right-hand fragment 16 by AD. TBDMS = tert-butyldimethylsilyl.
Scheme 5. Synthesis of aza analogue 1.
The synthesis of analogue 2 is summarized in Scheme 6.
Compounds 3 and 4, the N-methylated derivatives of 1
Since we have previously shown that N-nosyl protected and 2, were prepared by a synthetic route based on the
amino alcohols perform well as nucleophiles in epoxide- Sharpless AD method (Scheme 7). Treatment of epoxide
opening reactions,[26] epoxide (S)-9 was treated with 2- (R)-9 with N,NЈ-dimethylethylene-1,2-diamine gave 28,
nitrobenzenesulfonamide (NH2Ns) at elevated temperatures which was then coupled with right-hand fragment 16 to give
for 4 d to give amino alcohol 25 in high yield. Somewhat 29. Treating this material with MeSO3H, followed by oxi-
surprisingly, the coupling reaction between this material dation and elimination, gave the derivative containing the
and epoxide 7 proceeded slowly, and 12 d were required to butenolide unit along with some amount of final product 3.
reach an acceptable conversion to 26. As it is difficult to After hydrolysis of the silyl ether in the remaining material,
remove the N-nosyl group in the presence of the butenolide analogue 3 was isolated in a combined yield of 87% over
moiety, the protecting group had to be removed before the two steps. Analogue 4 was prepared following a route iden-
sulfide was oxidized. Thus, compound 26 was treated with tical to that used for compound 3, except that methylamine
1-decanethiol and DBU (1,8-diazabicycloundec-7-ene)[36] to was used as the nucleophile in the first epoxide-opening re-
give secondary amine 27. This was followed by quaternary action.
ammonium salt formation with MeSO3H, oxidation, and
Thio analogues 5 and 6 were prepared from (S)-9 follow-
subsequent thermal elimination of the sulfoxide moiety to ing a route based on HKR (Scheme 8). Different conditions
give analogue 2. Gratifyingly, the silyl protecting group was were investigated for the epoxide-opening reaction with
also removed during the salt formation/oxidation/elimi- sulfides. The best results were obtained using InCl3 as a
nation sequence. Analogue 2 was isolated in 63% yield over catalyst.[37] The reaction between (S)-9 and 1,2-ethanedi-
three steps.
thiol in the presence of InCl3 in iPrOH gave 32 in 61%
Scheme 6. Synthesis of aza analogue 2. TEBA = benzyltriethylammonium chloride.
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Aza- and Thio-Analogues of Acetogenins
Scheme 7. Synthesis of aza analogues 3 and 4.
Scheme 8. Synthesis of thio analogues 5 and 6.
yield. Next, sulfide 32 was coupled with epoxide 8 to give Biological Evaluation
33, which was deprotected to give thio analogue 5. The final
analogue, compound 6, was prepared following an identical
route but using 2,2Ј-thiodiethanethiol as the nucleophile.
The antiproliferative activity of analogues 1–6 against
the HeLa cell line are given in Table 1 as the concentration
The 1H and 13C NMR spectra of aza analogues 2, 3, and of compound necessary to give one-half the maximum re-
4 show the presence of some minor contamination, which sponse (ED50). Rotenone, a known complex I inhibitor,[39]
is believed to be diastereomers resulting from epimerization was used as a reference. After 24 h of treatment, all of the
in the butenolide unit after the elimination of phenylsulf- aza analogues (i.e., 1–4) showed cytotoxicity ED50 Ͻ 10 μm,
enic acid at elevated temperatures. No such epimerization and performed more effectively than rotenone (ED50
=
was observed in aza analogue 1, nor in thio analogues 5 77.5 μm). The thio analogues (i.e., 5 and 6) had less effect
and 6, where the unsaturated lactone ring was formed at on cell growth than the aza analogues, and they needed
room temperature. Despite all of the investigations concern- concentrations of around 100 μm or higher to reach the ef-
ing the lactone ring unit of the acetogenins, there does not fective dose.
seem to be a consensus about the exact structural require-
The best result was obtained with N,NЈ-dimethylated di-
amine analogue 3, which, at a concentration of 3 μm, had a
ment for biological activity.[38]
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tion Cell Proliferation Assay, Promega, Madison, WI, USA). The
MTS assay measures the activity of mitochondrial dehydrogenases
by measuring their conversion of tetrazolium salts into formazan.
Briefly, the cells were seeded in 96-well plates at a density 1 ϫ 104
cells per well in DMEM-high glucose medium (100 μL) 1 d before
treatment. The test compounds were diluted with DMSO
(0.01 mm–10 mm). The cells were treated with the serial dilutions
of the test compounds (not exceeding 1% v/v in final concentra-
tion), and the treated cells were incubated for 24 h at 37 °C in a
humidified chamber in an atmosphere containing 5% CO2. Rote-
none, a classical complex I inhibitor, was used as a positive control.
MTS was added to cells according to the manufacturer’s general
protocol. The quantity of formazan produced was measured col-
ourimetrically by absorbance at 490 nm on a Tecan Sunrise micro-
plate absorbance reader, and is directly proportional to the number
of living cells in culture. All experiments were performed in tripli-
cate, and the relative cell viability (%) was expressed as the percent
absorbance of the control (cells treated with 1% DMSO).
Table 1. Antiproliferative activity of compounds 1–6 against the
HeLa cell line.[a]
Entry
Compound
ED50 [μm][b]
1
2
3
4
5
6
7
1
5.7
8.2
3.1
2
3
4
7.7
5
91.0
Ͼ100
77.5
6
rotenone[c]
[a] HeLa cell line, human epitheloid cervix carcinoma. [b] ED50,
effective dose. [c] Rotenone was used as reference as a complex I
inhibitor.
cytotoxicity of 34.7Ϯ4.4%, and at 5 μm had a cytotoxicity
of 91.9Ϯ3.3% (ED50 = 3.1 μm). Based on our findings, the
epimerization of the α,β-unsaturated lactone ring in 3 did
not seem to have a great effect on its biological activity, as
the antiproliferative activity of 3 falls in the same range as
its non-methylated counterpart 1 (ED50 = 5.7 μm), for
which no epimerization was detected. N-Methylated ana-
logue 4 and non-methylated analogue 2 had similar effective
doses of 7.7 μm and 8.2 μm, respectively. It seems that aza
analogues with diamine moieties, whether methylated or
not, are more cytotoxic than monoamine analogues.
General Remarks: 1H and 13C NMR spectra were recorded at 400.1
and 100.6 MHz, respectively. For compound 1, the 13C NMR spec-
trum was recorded at 201.2 MHz. The chemical shifts for the 1H
and 13C NMR spectra are given in ppm, and are calibrated using
residual solvent signals (for 1H, CDCl3: δ = 7.26 ppm, and for 13C,
CDCl3: δ = 77.0 ppm). The following abbreviations are used for
multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; br. s, broad singlet; vt, virtual triplet. Reactions were moni-
tored by thin-layer chromatography (TLC), and TLC plates were
visualized either by UV detection or by staining with KMnO4 or
phosphomolybdic acid solution. Purification of reaction products
was done by flash chromatography using silica gel 60 (0.040–
0.063 mm, 230–400 mesh). In HPLC analysis, signals were detected
by a diode-array detector. For HRMS analysis, an LTQ Orbitrap
analyser was used. An FTIR spectrophotometer (ATR) was used
for IR analysis. All reagents and solvents were obtained from com-
mercial sources and were used without further purification.
Conclusions
Four aza analogues 1–4 and two thio analogues 5 and 6
were synthesized according to a general synthetic scheme
that allows facile variability of the central heteroatom-con-
taining portion of the molecule. Hydrolytic kinetic resolu-
tion of bis-epoxides was successfully used to establish two
remote stereocentres with high enantio- and diastereoselec-
tivity in a single step. All the analogues synthesized under-
went preliminary in vitro studies against the HeLa cell line.
While the aza analogues showed a 50% cell-viability re-
duction at concentrations under 10 μm, the thio analogues
had less effect, needing concentrations of around 100 μm
or above to reach an effective dose. Although we observed
epimerization in the α,β-unsaturated lactone ring for aza
analogues 2–4, the bioassay studies did not show significant
differences in activity between analogues 2–4 and the non-
epimerized analogue 1.
1,2-Epoxydodecane (9): A solution of 1-dodecene 10 (1500 mg,
8.91 mmol) in CH2Cl2 (10 mL) was cooled to 0 °C, and mCPBA
(17.82 mmol, 3994 mg, Ͼ77% purity) was added. The reaction
mixture was stirred for 16 h at room temp., then it was quenched
with Na2S2O3 (satd. aq.). The phases were separated, and the aque-
ous phase was extracted three times with CH2Cl2. The combined
organic extracts were dried with MgSO4, filtered, and concentrated
to dryness. The residue was redissolved in petroleum ether, and the
solution was filtered and then concentrated in vacuo to dryness.
The residue was purified by flash chromatography on silica (5%
EtOAc in petroleum ether) to give 9 (1626 mg, 99%) as a clear oil.
1H NMR (400.1 MHz, CDCl3): δ = 2.87 (m, 1 H), 2.71 (dd, J =
5.0, 4.0 Hz, 1 H), 2.43 (dd, J = 5.0, 2.7 Hz 1 H), 1.54–1.17 (m, 18
H), 0.85 (vt, 3 H). The 1H NMR spectroscopic data is in agreement
with the data for commercially available 1,2-epoxydodecane.
Experimental Section
(S)-1,2-Epoxydodecane [(S)-9]: (S,S)-(salen)cobalt(II) (28 mg,
0.047 mmol) was dissolved in toluene (0.5 mL), and AcOH (10 μL,
0.18 mmol) was added. The solution was stirred at room temp.
open to air for 1 h, and then it was concentrated in vacuo to dry-
ness. The residue was dissolved in THF (0.5 mL), and 1,2-epoxydo-
decane 9 (862 mg, 4.67 mmol) was added. The mixture was cooled
to 0 °C and stirred for 5 min. Then H2O (46 μL, 2.57 mmol) was
added at 0 °C. The reaction mixture was stirred at room temp. for
16 h, then it was concentrated in vacuo to dryness. The residue
was purified by column chromatography on silica (10% EtOAc in
petroleum ether) to give product (S)-9 (423 mg, 49%) as a beige
oil. [α]2D3 = –6.6 (c = 0.3, CH2Cl2) {ref.[41] for (R)-1,2-epoxydo-
Cell Culture: Human cervical cancer cell line HeLa (American Type
Culture Collection via LGC, Sweden) was cultured in Dulbecco’s
Modified Eagle Medium (DMEM) with high glucose and with l-
glutamine. The medium was supplemented with 10% fetal bovine
serum (FBS), sodium pyruvate (1 mm), penicillin (100 U/mL),
streptomycin (100 μg/mL) and 1% nonessential amino acids (fur-
ther denoted as complete medium; PAA Laboratories GmbH, Aus-
tria). Cell cultures were cultivated at 37 °C in a humidified 5% CO2
incubator.
In vitro Proliferation Assay: Long-term toxicity was evaluated using
an MTS[40] proliferation assay (CellTiter 96® Aqueous One Solu-
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Aza- and Thio-Analogues of Acetogenins
decane: [α]2D3 = +6.0 (c = 0.3, CH2Cl2)}. 1H NMR (400.1 MHz,
CDCl3): δ = 2.84 (m, 1 H), 2.67 (dd, J = 5.0, 4.0 Hz, 1 H), 2.39
0.72 mmol), and pTsCl (145 mg, 0.76 mmol) were added. The reac-
tion mixture was stirred for 17 h at room temp. Then the mixture
(dd, J = 5.0, 2.7 Hz, 1 H), 1.51–1.16 (m, 18 H), 0.83 (vt, 3 H) ppm. was diluted with CH2Cl2, and NaHCO3 (satd. aq.) was added. The
13C NMR (100.6 MHz, CDCl3): δ = 52.3, 47.0, 32.4, 31.8, 29.56,
phases were separated, and the aqueous phase was extracted three
times with CH2Cl2. The combined organic extracts were dried with
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
29.52 (two overlapping signals), 29.42, 29.2, 25.9, 22.6, 14.0 ppm.
IR: ν = 2924, 2854, 1465, 914, 833, 721 cm–1. The er of 99.9:0.1
˜
was measured from a tosyl derivative of (S)-9 by HPLC analysis fied by column chromatography on silica (1–2% MeOH in CH2Cl2)
[CHIRALPAK IA column, 2% iPrOH in hexane, 1.0 mL/min; R
isomer 38.8 min (minor), S isomer 49.1 (major)]. See Supporting
Information for further details.
to give product 21 (253 mg, 87%) as a white solid, m.p. 58–60 °C.
[α]2D0 = –8.2 (c = 1.15, CHCl3). H NMR (400.1 MHz, CDCl3): δ
1
= 7.79–7.75 (m, 2 H), 7.35–7.31 (m, 2 H), 4.00 (dd, J = 9.9, 2.8 Hz,
1 H), 3.85 (dd, J = 9.9, 7.0 Hz, 1 H), 3.79 (m, 1 H), 2.88 (m, 1 H),
2.72 (m, 1 H), 2.44 (m, 1 H), 2.42 (br. s, 3 H), 2.30 (br. s, 1 H),
1.53–1.17 (m, 20 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
144.9, 132.6, 129.8, 127.8, 73.9, 69.3, 52.3, 47.0, 32.5, 32.3, 29.4,
1,2:13,14-Diepoxytetradecane (14): mCPBA (3.30 g, 14.74 mmol,
Ͼ77% purity) was added in one portion to a cooled (0 °C) solution
of 1,13-tetradecadiene 15 (1.14 g, 5.89 mmol) in CH2Cl2 (20 mL).
The mixture was stirred at 0 °C for 30 min, then it was allowed to
warm to room temp. and stirred for a further 2 h. After TLC indi-
cated that the starting material had been consumed, Na2S2O3 (20%
aq.; 50 mL) was added, and the mixture was stirred for 5 min. Fur-
ther Na2S2O3 (20% aq.; 30 mL) and CH2Cl2 (30 mL) were added.
The phases were separated, and the aqueous phase was extracted
with CH2Cl2 (3 ϫ 40 mL). The combined organic extracts were
dried with MgSO4, filtered, and concentrated in vacuo. The residue
was dissolved in hexanes, and the solution was filtered. Purification
by flash column chromatography on silica (10% EtOAc in hexanes)
gave product 14 (1.23 g, 92%) as a beige oil. 1H NMR (400.1 MHz,
CDCl3): δ = 2.86 (m, 2 H), 2.70 (dd, J = 5.0, 4.0 Hz, 2 H), 2.42
(dd, J = 5.0, 2.7 Hz, 2 H), 1.53–1.17 (m, 20 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 52.2, 46.9, 32.3, 29.4–29.3, 25.8 ppm. IR:
29.3, 25.8, 25.1, 21.5 ppm. IR: ν = 3374, 2923, 2854, 1596, 1357,
˜
1176, 960, 836, 813, 736, 667 cm–1. HRMS: calcd. for C21H34O5S
[M + H]+ 399.2199; found 399.2192.
(R)-2-(tert-Butyldimethylsilyloxy)-12-[(S)-oxiran-2-yl]dodecyl-4-
methylbenzenesulfonate (22): Tosylate 21 (677 mg, 1.70 mmol) was
dissolved in dry DMF (10 mL), and imidazole (289 mg, 4.25 mmol)
and TBDMSCl (512 mg, 3.40 mmol) were added at 0 °C. The reac-
tion mixture was stirred at room temp. overnight. Then the mixture
was diluted with EtOAc, and brine was added. The phases were
separated, and the aqueous phase was extracted three times with
EtOAc. The combined organic extracts were dried with NaSO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica (10% EtOAc in hexanes) to give
product 22 (643 mg, 73%) as a clear oil. [α]2D0 = –0.5 (c = 1.2,
CHCl3). 1H NMR (400.1 MHz, CDCl3): δ = 7.79–7.75 (m, 2 H),
7.34–7.30 (m, 2 H), 3.90–3.76 (m, 3 H), 2.88 (m, 1 H), 2.72 (dd, J
= 5.0, 4.0 Hz, 1 H), 2.44 (dd, J = 5.0, 2.7 Hz, 1 H), 2.43 (br. s, 3
H), 1.55–1.12 (m, 20 H), 0.82 (br. s, 9 H), 0.01 (br. s, 3 H), –0.004
(br. s, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 144.6, 132.9,
129.7, 127.8, 73.1, 69.8, 52.2, 46.9, 33.9, 32.3, 29.45, 29.40, 29.37,
ν = 2933, 2854, 1461, 1407, 1257, 836 cm–1. HRMS: calcd. for
˜
C14H26O2 [M + H]+ 227.2005; found 227.1999.
(2R,13S)-13,14-Epoxytetradecane-1,2-diol (13): (S,S)-(salen)co-
balt(II) (14 mg, 22 μmol) was dissolved in CH2Cl2 (1 mL), and
AcOH (5 μL, 90 μmol) was added. The mixture was stirred at room
temp. open to air for 1 h, during which time the colour turned from
dark red to brown. Then the solution was concentrated to dryness
in vacuo. The residue was redissolved in THF (2 mL), and this
solution was added to bis-epoxide 14 (510 mg, 2.25 mmol). The
solution was cooled to 0 °C, and H2O (38 μL, 2.14 mmol) was
added. The reaction mixture was stirred at room temp. for 16 h.
Then the mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica (2–6% MeOH in
CH2Cl2) to give 13 (250 mg, 44% from theoretical 50% yield) as a
white solid. Rf (13) = 0.8 in 50% EtOAc/petroleum ether [Rf (14) =
0.3 in 50% EtOAc/petroleum ether; Rf (tetrol) = 0.9 in 10% MeOH/
CH2Cl2], m.p. 60–61.3 °C. [α]2D0 = –6.0 (c = 1.15, CHCl3). 1H NMR
(400.1 MHz, CDCl3): δ = 3.75–3.62 (m, 2 H), 3.43 (m, 1 H), 2.90
(m, 1 H), 2.74 (dd, J = 5.0, 4.0 Hz, 1 H), 2.46 (dd, J = 5.0, 2.7 Hz,
1 H), 2.05 (br. s, 1 H), 1.93 (br. s, 1 H), 1.56–1.22 (m, 20 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 72.2, 66.6, 52.3, 47.0, 33.0,
29.32, 25.8, 25.6, 24.6, 21.5, 17.9, –4.6, –4.9 ppm. IR: ν = 2927,
˜
2858, 1365, 1180, 836, 779 cm–1. HRMS: calcd. for C27H48O5SSi
[M + H]+ 513.3064; found 513.3050.
(R)-13-tert-Butyldimethylsilyloxy-14-iodo-(S)-1,2-epoxytetra-
decane (11): A concentrated reaction mixture of tosylate 22
(570 mg, 1.11 mmol) and NaI (250 mg, 1.66 mmol) in DMF (1 mL)
was stirred overnight at 60 °C. Then the mixture was concentrated
to dryness on a rotary evaporator, and the residue was purified by
column chromatography on silica (5% EtOAc in hexanes) to give
product 11 (429 mg, 82%) as a clear oil. 1H NMR (400.1 MHz,
CDCl3): δ = 3.53 (m, 1 H), 3.19 (m, 2 H), 2.90 (m, 1 H), 2.74 (dd,
J = 5.0, 4.0 Hz, 1 H), 2.46 (dd, J = 5.0, 2.7 Hz, 1 H), 1.64–1.21
(m, 20 H), 0.90 (br. s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 71.4, 52.3, 47.1, 36.9, 32.4, 29.5
(overlapping signals), 29.4, 25.9, 25.8, 24.9, 18.0, 14.0, –4.3,
32.3, 29.5, 29.4–29.3, 29.2, 25.8, 25.4 ppm. IR: ν = 3475, 3313,
˜
2916, 2850, 1469, 1072, 848 cm–1. HRMS: calcd. for C14H28O3 [M
+ H]+ 245.2111; found 245.2106.
–4.5 ppm. IR: ν = 2928, 2854, 1465, 1253, 1083, 836, 775 cm–1.
˜
HRMS: calcd. for C20H41IO2Si [M + H]+ 469.1993; found
469.1978.
The stereomeric ratios for 13 were determined by chiral HPLC
analysis after derivatization. The dr of 97:3 was measured after
tosylation of 13 to give 21 (Phenomenex LUX Cellulose-1 column,
10% iPrOH in hexane, 1.5 mL/min, major isomer 8.83 min, minor
isomer 9.94 min). The er of 99.3:0.7 was measured after prepara-
tion of a thiol derivative (Phenomenex LUX Cellulose-1 column,
20% iPrOH in hexane, 1.5 mL/min, minor isomer 14.5 min, major
isomer 17.3 min). For further details, see Supporting Information.
(5S)-3-{(R)-2-[(tert-Butyldimethylsilyl)oxy]-12-[(S)-oxiran-2-yl]-
dodecyl}-5-methyl-3-(phenylthio)dihydrofuran-2(3H)-one (7):
n-Butyllithium (2.5 m; 308 μL, 0.77 mmol) was added to a cooled
solution of N,N-diisopropylamine (108 μL, 0.77 mmol) in THF
(0.5 mL) under an argon atmosphere, and the mixture was stirred
for 30 min at 0 °C. The LDA solution was then transferred to lact-
one 12 (147 mg, 0.70 mmol) by cannula, and the resulting solution
was stirred for a further 30 min at 0 °C. Then iodide 11 (301 mg,
0.64 mmol) was dissolved in HMPA (1.1 mL) and THF (0.5 mL),
and this solution was added to the reaction mixture by cannula.
(R)-2-Hydroxy-12-[(S)-oxiran-2-yl]dodecyl-4-methylbenzenesulf-
onate (21): Epoxy-diol 13 (178 mg, 0.72 mmol) was dissolved in
CH2Cl2 (5 mL), and Bu2SnO (3 mg, 14 μmol), Et3N (101 μL,
Eur. J. Org. Chem. 2013, 6886–6899
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6893

P. Villo, L. Toom, E. Eriste, L. Vares
FULL PAPER
The reaction mixture was warmed to room temp. and stirred over-
night. Then the solution was diluted with EtOAc, NH4Cl (satd.
aq.) was added, and the phases were separated. The organic phase
was extracted three times with EtOAc, washed with brine, dried
with MgSO4 and filtered. After concentration in vacuo, the residue
was purified by flash chromatography (6% EtOAc in petroleum
ether) to give 7 (261 mg, 78 %) as a colourless oil. 1H NMR
(400.1 MHz, CDCl3): δ = 7.57–7.51 (m, 2 H), 7.40–7.29 (m, 3 H),
4.58 (m, 0.3 H, minor isomer), 4.50 (m, 0.7 H, major isomer), 4.24
(m, 0.7 H, major), 3.84 (m, 0.3 H, minor), 3.03 (dd, J = 14.0,
7.6 Hz, 0.7 H), 2.89 (m, 1 H), 2.72 (m, 1 H), 2.44 (dd, J = 5.0,
2.7 Hz, 1 H), 2.09–1.79 (m, 3 H), 1.55–1.15 (m, 25 H), 0.88 (br. s,
9 H, major), 0.85 (br. s, 3 H, minor), 0.15 (br. s, 3 H), 0.11 (br. s,
3 H), 0.03 (br. s, 1 H, minor), 0.01 (br. s, 1 H, minor) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 177.4 (major), 175.0 (minor),
136.9, 136.6, 130.4 (minor), 129.8 (minor), 129.6 (minor), 129.5
(major), 128.9 (major), 128.8 (major), 73.5 (minor), 73.2 (major),
70.2 (minor), 69.4 (major), 55.4 (major), 55.0 (minor), 52.2, 47.0,
42.0 (minor), 41.6 (minor), 41.2 (major), 39.5 (major), 38.4 (major),
37.9 (minor), 32.4, 29.6 (major), 29.5 (minor), 29.4–29.3 (overlap-
ping signals), 25.9–25.8 (overlapping signals), 24.3; 21.2 (major),
20.3 (minor), 17.9, –3.79 (minor), –3.87 (major), –4.16 (minor)
was purified by flash chromatography (5% EtOAc in petroleum
ether) to give the silylated product (644 mg, 82%).
The silylated compound (580 mg, 1.16 mmol) and NaI (874 mg,
5.83 mmol) were added to acetone (3 mL), and the mixture was
heated at 65 °C overnight. Then the reaction mixture was cooled
to room temp., and EtOAc and brine were added. The phases were
separated, and the aqueous phase was extracted three times with
EtOAc. The combined organic extracts were dried with Na2SO4,
filtered, and concentrated in vacuo to dryness. The residue was
purified by flash chromatography (3% EtOAc in petroleum ether)
to give the iodated product (458 mg, 86%).
LDA (1.5 m; 323 μL, 0.58 mmol) was added to a cooled solution
of lactone 12 (121 mg, 0.58 mmol) in THF (2 mL) under an argon
atmosphere, and the mixture was stirred at 0 °C. Then the iodated
compound (240 mg, 0.53 mmol) in HMPA (510 μL) was added to
the reaction mixture at 0 °C. The reaction mixture was stirred over-
night at room temp. Then EtOAc and NH4Cl (satd. aq.) were
added. The phases were separated, and the aqueous phase was ex-
tracted three times with EtOAc. The combined organic extracts
were dried with Na2SO4, filtered, and concentrated in vacuo to
dryness. The residue was purified by flash chromatography on silica
(3 % EtOAc in petroleum ether) to give alkylated product 18
(210 mg, 74 %) as an inseparable mixture of diastereomers. 1H
NMR (400.1 MHz, CDCl3): δ = 7.58–7.52 (m, 2 H), 7.40–7.30 (m,
3 H), 5.81 (m, 1 H), 4.96 (m, 2 H), 4.60 (m, 0.3 H), 4.51 (m, 0.7
H), 4.25 (m, 0.7 H), 3.85 (m, 0.7 H), 3.04 (dd, J = 14.0, 7.6 Hz, 0.7
H), 2.08–1.80 (m, 5 H), 1.49–1.18 (m, 21 H), 0.90 (br. s, 5 H), 0.87
(br. s, 4 H), 0.15 (br. s, 2 H), 0.12 (br. s, 2 H), 0.03 (br. s, 1 H),
0.01 (br. s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 177.5,
175.0, 139.1, 137.0, 136.6, 129.5, 128.9, 128.8, 114.0, 73.6, 73.2,
70.2, 69.4, 55.4, 42.0, 41.1, 39.4, 38.5, 33.7, 29.7, 29.5–29.4, 29.1,
ppm. IR: ν = 2927, 2854, 1762, 1253, 1184, 1002, 833, 775,
˜
694 cm–1. HRMS: calcd. for C31H52O4SSi [M + H]+ 549.3428;
found 549.3417.
(S)-3-{(R)-2-[(tert-Butyldimethylsilyl)oxy]-12-[(S)-oxiran-2-yl]-
dodecyl}-5-methylfuran-2(5H)-one (8): A solution of 7 (91 mg,
0.16 mmol) in CH2Cl2 (1 mL) was cooled to –20 °C and mCPBA
(41 mg, 0.18 mmol, Ͼ77% purity) was added. The reaction mixture
was stirred at –20 °C for 1.5 h. Then the reaction was quenched
with Na2S2O3 (satd. aq.), and the mixture was allowed to warm to
room temp. The phases were separated, and the aqueous phase was
extracted three times with CH2Cl2. The combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (8% EtOAc in petro-
leum ether) to give 8 (64 mg, 88 %) as a clear oil. 1H NMR
(400.1 MHz, CDCl3): δ = 7.11 (m, 1 H), 4.99 (m, 1 H), 3.93 (m, 1
H), 2.89 (m, 1 H), 2.72 (dd, J = 5.0, 4.0 Hz, 1 H), 2.45 (dd, J =
5.0, 2.7 Hz, 1 H), 2.41 (m, 2 H), 1.55–1.19 (m, 23 H), 0.86 (br. s, 9
H), 0.04 (br. s, 3 H), 0.01 (br. s, 3 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 173.9, 151.4, 130.8, 77.4, 70.1, 52.3, 47.0, 36.9, 32.7,
32.4, 29.6, 29.5, 29.49, 29.48, 29.46, 29.3, 25.9, 25.8, 25.1, 18.9,
28.8, 25.9, 25.9, 24.4, 21.3, 17.9, –3.8, –3.9 ppm. IR: ν = 2927,
˜
2854, 1762, 1462, 1438, 1253, 1180, 837, 775, 748, 690 cm–1. The
analytical data is in agreement with that reported in the litera-
ture.[42]
(5S)-3-{(2R)-2-[(tert-Butyldimethylsilyl)oxy]-13,14-dihydroxytetra-
decyl}-5-methyl-3-(phenylthio)dihydrofuran-2(3H)-one (23): Com-
pound 18 (531 mg, 0.99 mmol) was added to a cooled (0 °C) mix-
ture of K2OsO2(OH)4 (1.5 mg, 0.004 mmol), (DHQD)2PHAL
(15 mg, 0.02 mmol), K3[Fe(CN)6] (984 mg, 2.99 mmol), and K2CO3
(441 mg, 3.19 mmol) in tBuOH/H2O (1:1, 20 mL). The reaction
mixture was stirred at 4 °C overnight. Solid Na2S2O3·5H2O was
added, and then the mixture was stirred for a further 1 h. Then the
phases were separated, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were washed with brine,
dried with Na2SO4, filtered, and concentrated in vacuo to dryness.
Diol 23 (560 mg, 99% crude yield) was used in the next step with-
out further purification. Compound 23 is a 1:3 mixture of dia-
stereomers, the signals of the major diastereomer are given: 1H
NMR (400.1 MHz, CDCl3): δ = 7.46–7.40 (m, 2 H), 7.25–9.19 (m,
3 H), 4.41 (m, 1 H), 4.14 (m, 1 H), 3.59–3.50 (m, 2 H), 3.48 (dd, J
= 11.2, 2.6 Hz, 1 H), 3.27 (dd, J = 11.2, 7.7 Hz, 1 H), 2.93 (dd, J
= 14.0, 7.7 Hz, 1 H), 1.98–1.68 (m, 3 H), 1.39–1.05 (m, 23 H), 0.79
(br. s, 6 H), 0.75 (br. s, 3 H), 0.04 (br. s, 3 H), 0.01 (br. s, 3 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 177.5, 136.4, 130.1, 129.4,
128.8, 73.2, 72.0, 69.2, 66.5, 55.2, 41.0, 39.2, 38.3, 32.9, 30.9, 29.5–
18.0, –4.4 ppm. IR: ν = 2927, 2854, 1755, 1462, 1319, 1253, 1072,
˜
833, 775 cm–1. HRMS: calcd. for C25H46O4Si [M + H]+ 439.3238;
found 439.3228.
(5S)-3-{(R)-2-[(tert-Butyldimethylsilyl)oxy]tetradec-13-en-1-yl}-5-
methyl-3-(phenylthio)dihydrofuran-2(3H)-one (18):[42] A mixture of
diol 20 (400 mg, 1.75 mmol), Bu2SnO (17 mg, 0.07 mmol), Et3N
(244 μL, 1.75 mmol), and pTsCl (334 mg, 1.75 mmol) was stirred
at room temp. overnight. Then the mixture was diluted with EtOAc
and filtered, and brine was added. The phases were separated, and
the aqueous phase was extracted three times with EtOAc. Then the
combined organic extracts were dried with Na2SO4, filtered, and
concentrated in vacuo to dryness. The crude tosylate (637 mg,
95%) was used in the next step without further purification.
The tosylate (604 mg, 1.57 mmol) was dissolved in dry DMF
(2.5 mL), and imidazole (268 mg, 3.94 mmol) and TBDMSCl
(261 mg, 1.73 mmol) were added. The reaction mixture was stirred
at room temp. for 5.5 h. Then EtOAc and brine were added, the
phases were separated, and the aqueous phase was extracted three
times with EtOAc. The combined organic extracts were dried with
Na2SO4, filtered, and concentrated in vacuo to dryness. The residue
29.2, 25.8–25.7, 25.4, 24.2, 21.1, 17.8, –3.9 ppm. IR: ν = 3367, 2924,
˜
2854, 1766, 1462, 1253, 1184, 1064, 1006, 833, 775, 748, 690 cm–1.
HRMS: calcd. for C31H54O5SSi [M + H]+ 567.3534; found
567.3536.
(5S)-3-{(R)-2-[(tert-Butyldimethylsilyl)oxy]-12-[(R)-oxiran-2-yl]-
dodecyl}-5-methyl-3-(phenylthio)dihydrofuran-2(3H)-one (16):
6894
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6886–6899

Aza- and Thio-Analogues of Acetogenins
Bu2SnO (10 mg, 0.04 mmol), Et3N (146 μL, 1.05 mmol), and pTsCl
(28 mg, 0.2 mmol) in 1,4-dioxane (1.0 mL) was heated at 90 °C for
(200 mg, 1.05 mmol) were added to a solution of 23 (560 mg, 20 h. The mixture was then cooled to room temperature, diluted
0.99 mmol) in CH2Cl2 (9 mL), and the mixture was stirred over-
night at room temp. Then the mixture was filtered, and CH2Cl2
and brine were added. The phases were separated and the aqueous
phase was extracted three times with CH2Cl2. The combined or-
ganic extracts were dried with MgSO4, filtered, and concentrated
in vacuo to dryness. The residue was purified by flash chromatog-
raphy (10–15% EtOAc in petroleum ether) to give the tosylated
product (681 mg, 94%) as a beige oil.
with CH2Cl2, and washed with brine. The organic phase was dried
with Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography on silica (2% MeOH in CH2Cl2)
to give 25 (724 mg, 94%) as a yellow waxy solid, m.p. 56.5–57.9 °C.
1H NMR (400.1 MHz, CDCl3): δ = 8.13 (m, 1 H), 7.87 (m, 1 H),
7.75–7.68 (m, 2 H), 5.74 (dd, J = 7.1, 5.0 Hz, 1 H), 3.74 (m, 1 H),
3.24 (ddd, J = 12.9, 7.1, 3.2 Hz, 1 H), 2.94 (ddd, J = 12.9, 8.0,
5.0 Hz, 1 H), 1.88 (br. s, 1 H), 1.46–1.20 (m, 18 H), 0.88 (vt, 3 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 148.1, 133.60, 133.59,
132.7, 131.1, 125.4, 70.4, 49.2, 34.7, 31.9, 29.56, 29.53, 29.46, 29.44,
K2CO3 (275 mg, 1.99 mmol) was added to a cooled (0 °C) solution
of the tosylated compound (681 mg, 0.94 mmol) in MeOH
(15 mL). The reaction mixture was stirred for 10 h, and HCl (1 m)
was then added until neutral pH was reached. The mixture was
diluted with EtOAc, and NaHCO3 (satd. aq.) was added. The
phases were separated, and the aqueous phase was extracted three
times with EtOAc. The combined organic extracts were dried with
MgSO4, filtered, and concentrated in vacuo to dryness. The residue
was purified by flash chromatography (5% EtOAc in petroleum
ether) to give product 16 (403 mg, 73% over three steps from 23)
as a beige oil.
29.3, 25.3, 22.7, 14.1 ppm. IR: ν = 3540, 3350, 2930, 2857, 1545,
˜
1367, 1168 cm–1. HRMS: calcd. for C18H30N2O5S [M + Na]+
409.1768; found 409.1762.
N-{(2S,13R)-13-[(tert-Butyldimethylsilyl)oxy]-2-hydroxy-14-[(5S)-5-
methyl-2-oxo-3-(phenylthio)tetrahydrofuran-3-yl]tetradecyl}-N-
[(S)-2-hydroxydodecyl]-2-nitrobenzenesulfonamide (26): K2CO3
(23 mg, 166 μmol) was added to a solution of nosylamide 25
(51 mg, 133 μmol) and epoxide 7 (36 mg, 66 μmol) in 1,4-dioxane
(0.4 mL), and the reaction mixture was stirred at 90 °C for 12 d.
Then the mixture was concentrated to dryness in vacuo. The resi-
due was purified by flash chromatography on silica (50% EtOAc
in petroleum ether) to give product 26 (28 mg, 45%) as a beige oil.
1H NMR (400.1 MHz, CDCl3): δ = 7.97 (m, 1 H), 7.76–7.66 (m, 2
H), 7.62 (m, 1 H), 7.59–7.50 (m, 2 H), 7.41–7.29 (m, 3 H), 4.60 (m,
0.2 H, minor isomer), 4.51 (m, 0.8 H, major isomer), 4.24 (m, 0.8
H), 4.03–3.92 (m, 2 H), 3.65–3.55 (m, 2 H), 3.09–2.97 (m, 3 H),
2.11–1.79 (m, 3 H), 1.49–1.16 (m, 41 H), 0.89 (br. s, 7 H), 0.86 (m,
5 H), 0.15 (br. s, 2 H), 0.11 (br. s, 2 H), –0.03 (br. s, 1 H), –0.02
(br. s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 177.6, 175.1
(minor), 148.4, 137.0, 136.6, 133.7, 132.1, 131.6, 130.7, 130.4,
129.9, 129.6 (minor), 129.5, 128.96, 128.91, 124.2, 73.6 (minor),
73.3, 71.64, 71.63, 70.3 (minor), 70.2, 69.5, 57.4, 55.4, 55.0 (minor),
42.4 (minor), 41.7 (minor), 41.2, 39.5, 38.5, 37.9 (minor), 34.7, 34.6
(minor), 31.8, 29.7, 29.6, 29.5–29.4 (overlapping signals), 29.2,
25.99, 25.97, 25.3, 25.2, 24.4, 22.6, 21.3, 20.3 (minor), 18.0, 14.0,
(S)-1-[(2-Aminoethyl)amino]dodecan-2-ol (24):[26] A solution of ep-
oxide (S)-9 (105 mg, 0.57 mmol) and ethylene-1,2-diamine (196 mg,
3.25 mmol) in EtOH (10 mL) was stirred at 50 °C for 4 h. Then the
reaction mixture was diluted with CH2Cl2, and brine was added.
The phases were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were dried with
MgSO4, filtered, and concentrated in vacuo to dryness. The residue
was purified by flash chromatography on silica (10:2:0.5 of CHCl3/
MeOH/NH4OH) to give 24 (137 mg, 99%). 1H NMR (400.1 MHz,
CDCl3, CD3OD): δ = 3.39 (m, 1 H), 2.56–2.33 (m, 7 H), 2.23 (dd,
J = 12.0, 9.2 Hz, 1 H), 1.23–0.93 (m, 18 H), 0.61 (vt, 3 H) ppm.
13C NMR (100.6 MHz, CDCl3, CD3OD): δ = 70.2, 55.6, 51.7, 41.1,
35.8, 32.3, 30.1, 30.0 (overlapping signals), 29.7, 26.0, 23.0,
14.2 ppm. IR: ν = 3113, 2916, 2846, 1465, 1114, 925, 837 cm–1.
˜
HRMS: calcd. for C14H32N2O [M + H]+ 245.2587; found 245.2581.
(S)-3-{(2R,13S)-2,13-Dihydroxy-14-[(2-{[(S)-2-hydroxydodecyl]-
amino}ethyl)amino]tetradecyl}-5-methylfuran-2(5H)-one (1): A mix-
ture of epoxide 8 (36 mg, 82 μmol), amine 24 (40 mg, 164 μmol),
and La(OTf)3 hydrate (5 mg, 8.5 μmol) in iPrOH (0.7 mL) was
stirred at 40 °C for 2 d, and the reaction was monitored by TLC
analysis. Then the mixture was concentrated to dryness in vacuo,
and the residue was purified by flash chromatography (5–10%
MeOH in CH2Cl2) to give the coupled product as a clear oil
(37 mg, 65%).
–3.7 (minor), –3.8, –4.1 (minor) ppm. IR: ν = 3344, 2924, 2854,
˜
1762, 1543, 1350, 1165, 1002, 833 cm–1. HRMS: calcd. for
C49H82N2O9S2Si [M + H]+ 935.5303; found 935.5302.
(5S)-3-((2R,13S)-2-[(tert-Butyldimethylsilyl)oxy]-13-hydroxy-14-
{[(S)-2-hydroxydodecyl]amino}tetradecyl)-5-methyl-3-(phenylthio)di-
hydrofuran-2(3H)-one (27): 1-Decanethiol (32 μL, 149 μmol) and
DBU (23 μL, 149 μmol) were added to a solution of 26 (27 mg,
29 μmol) in DMF (0.4 mL). The reaction mixture was stirred over-
night, then it was diluted with EtOAc, and brine was added. The
phases were separated, and the aqueous phase was extracted three
times with EtOAc. The combined organic extracts were dried with
MgSO4, filtered, and concentrated to dryness in vacuo. The residue
was purified by flash chromatoghraphy on silica (3% MeOH in
CH2Cl2) to give 27 (21 mg, 95 %) as a yellow oil. 1H NMR
(400.1 MHz, CDCl3): δ = 7.58–7.52 (m, 2 H), 7.39–7.30 (m, 3 H),
5.24 (br. s, 3 H), 4.60 (m, 0.2 H), 4.51 (m, 0.8 H), 4.25 (m, 0.8 H),
4.04–3.88 (m, 2 H), 3.04 (dd, J = 14.2, 7.7 Hz, 1 H), 3.00–2.71 (m,
4 H), 2.14–1.78 (m, 3 H), 1.56–1.14 (m, 41 H), 0.89 (br. s, 7 H),
0.86 (vt, 5 H), 0.15 (br. s, 2 H), 0.11 (br. s, 2 H), 0.03 (br. s, 1 H),
0.02 (br. s, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 177.6,
175.1 (minor), 137.0, 136.6, 130.4, 129.6, 128.9, 73.6 (minor), 73.3,
70.2 (minor), 69.5, 67.8, 55.5, 54.5, 54.4, 41.1, 39.4, 38.5, 35.0, 31.9,
29.8–29.5, 29.3, 25.9, 25.4, 24.4, 22.7, 21.3, 18.0, 14.1, –3.8 ppm.
The product (20 mg, 30 μmol) was then dissolved in MeOH (1 mL),
and AcCl (22 μL, 300 μmol) was added. The reaction mixture was
stirred overnight, and then excess NaHCO3 was added. The mix-
ture was filtered through a Celite plug, and the filtrate was concen-
trated to dryness in vacuo. The residue was purified by flash
chromatography on silica (10–30% MeOH in CH2Cl2) to give 1
(12 mg, 73%) as a beige waxy solid. 1H NMR (400.1 MHz, CDCl3,
CD3OD): δ = 6.96 (m, 1 H), 4.74 (m, 1 H), 3.52–3.40 (m, 2 H),
3.33 (m, 1 H), 2.90–2.49 (m, 6 H), 2.15–1.95 (m, 2 H), 1.17–0.86
(m, 41 H), 0.53 (vt, 3 H) ppm. 13C NMR (201.2 MHz, CDCl3): δ
= 174.9, 152.0, 130.9, 78.2, 70.5, 69.9, 69.9, 51.4, 44.9, 37.3, 34.8,
33.3, 31.9, 29.6–29.3, 25.6, 25.4, 22.6, 19.0, 14.1 ppm. IR: ν = 3329,
˜
2920, 2850, 1747, 1458, 1080, 1026 cm–1. HRMS: calcd. for
C33H64N2O5 [M + H]+ 569.4888; found 569.4875.
(S)-N-(2-Hydroxydodecyl)-2-nitrobenzenesulfonamide (25): A solu-
tion of epoxide (S)-9 (369 mg, 2.0 mmol), 2-nitrobenzenesulfon-
amide (809 mg, 4.0 mmol), TEBA (46 mg, 0.2 mmol), and K2CO3
IR: ν = 3357, 2911, 2849, 1762, 1462, 1439, 1379, 1341, 1253, 1182,
˜
1020, 845, 760, 752 cm–1. HRMS: calcd. for C43H79NO5SSi [M +
H]+ 750.5521; found 750.5517.
Eur. J. Org. Chem. 2013, 6886–6899
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6895

P. Villo, L. Toom, E. Eriste, L. Vares
FULL PAPER
(S)-3-((2R,13S)-2,13-Dihydroxy-14-{[(S)-2-hydroxydodecyl]-
amino}tetradecyl)-5-methylfuran-2(5H)-one (2): Compound 27
(29 mg, 39 μmol) was dissolved in CH2Cl2 (2.5 mL), and MeSO3H
(5 μL, 77 μmol) was added. The mixture was stirred for 20 min,
and then it was concentrated to dryness in vacuo. The residue was
redissolved in CH2Cl2 (2 mL), the solution was cooled to –20 °C,
and a solution of mCPBA (11 mg, 47 μmol, Ͼ77 % purity) in
CH2Cl2 (0.5 mL) was added. The reaction mixture was stirred for
1.5 h at –20 °C, then it was quenched with Na2S2O3 (20 % aq.;
5 mL). The mixture was brought to room temp. and stirred for a
further 15 min. The phases were separated, and the aqueous phase
was extracted three times with CH2Cl2. The combined organic ex-
tracts were dried with MgSO4, filtered, and concentrated in vacuo.
The residue was then redissolved in toluene (2 mL) and heated at
reflux for 3.5 h. Then the reaction mixture was brought to room
temperature and concentrated to dryness. The residue was purified
by flash chromatography (3–10% MeOH in CH2Cl2) to give the
unsaturated product (12 mg) as a beige oil, and final product 2
(13 mg, 63%). Data for 2: 1H NMR (400.1 MHz, CDCl3): δ = 7.19
(m, 1 H), 5.06 (m, 0.3 H), 4.95 (m, 0.7 H), 4.13–3.96 (m, 2 H), 3.84
(m, 0.7 H), 3.16–2.87 (m, 4 H), 2.56–2.37 (m, 2 H), 1.53–1.11 (m,
(S)-3-{(2R,13R)-2,13-Dihydroxy-14-[(2-{[(R)-2-hydroxydodecyl]-
(methyl)amino}ethyl)(methyl)amino]tetradecyl}-5-methylfuran-
2(5H)-one (3): MeSO3H (10 μL, 154 μmol) was added to a solution
of 29 (43 mg, 52 μmol) in CH2Cl2 (1.0 mL). The mixture was
stirred for 15 min, then it was concentrated to dryness in vacuo.
The residue was redissolved in CH2Cl2 (1.5 mL), the solution was
cooled to –20 °C, and a solution of mCPBA (14 mg, 63 μmol, Ͼ77
purity) in CH2Cl2 (0.5 mL) was added. The reaction mixture was
stirred for 2 h at –20 °C, then it was quenched with Na2S2O3 (20%
aq.). The mixture was brought to room temp. and stirred for a
further 15 min. The phases were separated, and the aqueous phase
was extracted three times with CH2Cl2. The combined organic ex-
tracts were dried with MgSO4, filtered, and concentrated in vacuo.
The residue was then redissolved in toluene (1.5 mL) and heated at
reflux for 4 h. Then the reaction mixture was brought to room
temp. and concentrated to dryness. The residue was purified by
flash chromatography (5–10% MeOH in CH2Cl2) to give the prod-
uct with an α,β-unsaturated lactone ring and an intact silyl group
(26 mg), and also final product 3 (6 mg). The silyl-ether-bearing
compound (26 mg, 37 μmol) was dissolved in MeOH (1.5 mL), and
AcCl (20 μL, 281 μmol) in MeOH (1.0 mL) was added. The mix-
38 H), 0.87 (vt, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = ture was stirred for 16 h under argon. The reaction was quenched
174.7, 151.9, 151.0, 131.2, 128.2, 81.8, 78.0, 70.5, 69.9, 68.5, 67.0,
54.7, 37.4, 34.9, 33.3, 31.9, 29.6–29.3, 25.4, 25.3, 24.9, 23.3, 22.6,
by the addition of solid NaHCO3, then the mixture was filtered,
and the filtrate was concentrated to dryness in vacuo. The residue
was purified by flash chromatography (2–10% MeOH in CH2Cl2)
to give 3 (combined yield: 27 mg, 87%) as a beige oil. 1H NMR
(400.1 MHz, CDCl3): δ = 7.16 (m, 1 H), 4.98 (m, 0.4 H), 4.88 (m,
0.6 H), 3.93 (m, 0.7 H), 3.81–3.72 (m, 2 H), 3.11–2.84 (m, 4 H),
2.76–2.63 (m, 4 H), 2.60 (br. s, 6 H), 2.35 (m, 1 H), 1.44–1.06 (m,
43 H), 0.78 (vt, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
175.0, 152.2, 151.2, 130.7, 81.9, 78.1, 69.3, 66.6, 65.5, 62.2, 61.9,
52.8, 42.1, 41.7, 37.0, 34.4, 33.1, 32.7, 31.7, 29.4–29.0, 25.3, 25.2,
19.0, 14.1 ppm. IR: ν = 3352, 2909, 2847, 1742, 1462, 1211, 1041,
˜
753 cm–1. HRMS: calcd. for C31H59NO5 [M + H]+ 526.4466; found
526.4467.
(R)-1-{Methyl[2-(methylamino)ethyl]amino}dodecan-2-ol (28): Ep-
oxide (R)-9 (306 mg, 1.66 mmol) was dissolved in iPrOH (0.5 mL),
and N,NЈ-dimethylethylene-1,2-diamine (900 μL, 8.30 mmol) was
added. The reaction mixture was warmed to 40 °C, and stirred for
18 h. The mixture was concentrated in vacuo, and the residue was
purified by flash chromatography (2% MeOH in CH2Cl2) to give
product 28 (295 mg, 65 %) as a colourless waxy substance. 1H
NMR (400.1 MHz, CDCl3): δ = 3.61 (m, 1 H), 2.83 (br. s, 2 H),
2.72–2.58 (m, 3 H), 2.46 (m, 1 H), 2.42 (br. s, 3 H), 2.28 (m, 1 H),
2.26 (br. s, 3 H), 1.50–1.16 (m, 18 H), 0.85 (vt, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 67.5, 63.8, 56.9, 49.3, 42.8, 36.1,
25.1, 24.7, 22.7, 22.4, 18.6, 13.8 ppm. IR: ν = 3387, 2924, 2854,
˜
1747, 1458, 1199, 1072 cm–1. HRMS: calcd. for C35H68N2O5 [M +
H]+ 597.5201; found 597.5195.
(R)-1-(Methylamino)dodecan-2-ol (30): A solution of epoxide (R)-
9 (273 mg, 1.48 mmol) and methylamine (8 m in EtOH; 930 μL,
7.44 mmol) was heated at 50 °C for 9 h. Then the mixture was con-
centated in vacuo, and the residue was purified by flash chromatog-
raphy (10% MeOH in CH2Cl2) to give product 30 (209 mg, 65%)
34.8, 31.8, 29.7, 29.5, 29.2, 25.6, 22.6, 14.0 ppm. IR: ν = 3410,
˜
2920, 2850, 2796, 1462, 1361, 1303, 1064, 1045, 1022, 960, 867,
779 cm–1. HRMS: calcd. for C16H36N2O [M + H]+ 273.2900; found
273.2900.
1
as a white solid. H NMR (400.1 MHz, CDCl3): δ = 3.63–3.50 (m,
3 H), 2.53 (d, J = 11.9, 3.2 Hz, 1 H), 2.41 (d, J = 11.9, 9.2 Hz, 1
H), 2.35 (br. s, 3 H), 1.43–1.10 (m, 18 H), 0.79 (vt, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 68.9, 68.8, 57.4, 35.8, 35.2, 31.7,
(5S)-3-{(2R,13R)-2-[(tert-Butyldimethylsilyl)oxy]-13-hydroxy-14-
[(2-{[(R)-2-hydroxydodecyl](methyl)amino}ethyl)(methyl)amino]-
tetradecyl}-5-methyl-3-(phenylthio)dihydrofuran-2(3H)-one (29): Ep-
oxide 16 (74 mg, 136 μmol) and amine 28 (44 mg, 163 μmol) were
dissolved in iPrOH (0.3 mL), and the mixture was heated at 50 °C
for 4 d. The mixture was concentrated in vacuo, and the residue
was purified by flash chromatography (2% MeOH in CH2Cl2) to
give product 29 (73 mg, 65%) as a beige oil. 1H NMR (400.1 MHz,
29.6, 29.4, 29.1, 25.6, 22.5, 13.9 ppm. IR: ν = 3417, 3286, 2916,
˜
2846, 1469, 910, 891, 864, 717 cm–1. HRMS: calcd. for C13H29NO
[M + H]+ 216.2321; found 216.2320.
(5S)-3-((2R,13R)-2-[(tert-Butyldimethylsilyl)oxy]-13-hydroxy-14-
{[(R)-2-hydroxydodecyl](methyl)amino}tetradecyl)-5-methyl-3-(phen-
ylthio)dihydrofuran-2(3H)-one (31): A solution of epoxide 16
(100 mg, 182 μmol) and amine 30 (109 mg, 506 μmol) in iPrOH
CDCl3): δ = 7.59–7.51 (m, 2 H), 7.40–7.29 (m, 3 H), 4.59 (m, 0.3 (2 mL) was heated at 50 °C for 19 h. Then the reaction mixture
H), 4.51 (m, 1 H), 4.24 (m, 1 H), 3.72–3.60 (m, 2 H), 3.03 (dd, J was concentrated in vacuo, and the residue was purified by flash
= 13.9, 7.6 Hz,1 H), 2.75–2.64 (m, 2 H), 2.42–2.24 (m, 10 H), 2.09–
1.78 (m, 3 H), 1.51–1.06 (m, 41 H), 0.89 (br. s, 7 H), 0.87–0.83 (m,
5 H), 0.14 (br. s, 2 H), 0.10 (br. s, 2 H), 0.02 (m, 1 H), 0.01 (m, 1
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 177.5, 175.0 (minor
isomer), 136.9, 136.6, 129.5, 128.9, 128.8, 73.6 (minor), 73.2, 70.2
(minor), 69.4, 68.0 (minor), 67.8, 63.3, 55.3, 54.5, 43.6, 42.8, 42.4,
41.1, 39.4, 38.5, 34.7, 31.8, 29.7–29.4, 29.2, 25.9–25.9, 25.6, 24.4,
chromatography (2% MeOH in petroleum ether) to give product
31 (128 mg, 92%) as a beige oil. H NMR (400.1 MHz, CDCl3): δ
1
= 7.57–7.51 (m, 2 H), 7.42–7.29 (m, 3 H), 4.60 (m, 0.2 H), 4.51 (m,
0.8 H), 4.25 (m, 0.8 H), 3.73–3.62 (m, 2 H), 3.04 (dd, J = 14.1,
7.6 Hz, 0.8 H), 2.84 (br. s, 2 H), 2.48–2.25 (m, 8 H), 2.09–1.78 (m,
3 H), 1.50–1.17 (m, 41 H), 0.89 (br. s, 7 H), 0.87–0.84 (m, 5 H,
overlap), 0.14 (br. s, 2 H), 0.11 (br. s, 2 H), 0.04–0.01 (m, 2 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 177.5, 175.1 (minor iso-
mer), 137.0, 136.6, 130.3, 129.5, 128.9, 128.8, 73.6, 73.3, 70.2, 69.4,
68.0, 67.5, 65.4, 63.8, 55.4, 55.0, 43.6, 42.3, 41.8, 41.6, 41.1, 39.4,
22.6, 21.2, 17.9, 14.0, –3.8 ppm. IR: ν = 3402, 2922, 2851, 1764,
˜
1462, 1250, 1180, 1061, 833, 773 cm–1. HRMS: calcd. for
C47H88N2O5SSi [M + H]+ 822.6289; found 822.6272.
6896
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6886–6899

Aza- and Thio-Analogues of Acetogenins
38.5, 37.9, 34.9, 34.9, 31.8, 29.7, 29.5–29.4, 29.3, 25.9, 25.6, 25.5,
= 13.7, 8.8 Hz, 2 H), 2.41 (m, 2 H), 1.53–1.19 (m, 48 H), 0.89–0.83
(m, 12 H), 0.04 (br. s, 3 H), 0.01 (br. s, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 173.9, 151.4, 130.8, 77.4, 70.2, 69.7, 40.3,
36.9, 36.2, 32.7, 32.6, 31.8, 29.6, 29.59–29.51, 29.2, 25.8, 25.7, 25.1,
22.6, 18.9, 18.0, 14.0, –4.4 ppm. HRMS: calcd. for C39H76O5S2Si
[M + H]+ 717.4976; found 717.4971.
24.4, 22.6, 21.3, 17.9, 14.0, –3.8 ppm. IR: ν = 3410, 2924, 2854,
˜
1766, 1462, 1253, 1184, 1053, 1006, 833, 775 cm–1. HRMS: calcd.
for C44H81NO5SSi [M + H]+ 764.5677; found 764.5672.
(S)-3-((2R,13R)-2,13-Dihydroxy-14-{[(R)-2-hydroxydodecyl]-
(methyl)amino}tetradecyl)-5-methylfuran-2(5H)-one (4): MeSO3H
(8 μL, 120 μmol) was added to a solution of amine 31 (51 mg,
67 μmol) in CH2Cl2 (1.0 mL). The mixture was stirred for 15 min,
and then it was concentrated to dryness in vacuo. Then the solid
was redissolved in CH2Cl2 (2.0 mL), the solution was cooled to
–20 °C, and a solution of mCPBA (18 mg, 81 μmol, Ͼ77% purity)
in CH2Cl2 (1.0 mL) was added. The reaction mixture was stirred
30 min at –20 °C, and then it was quenched with Na2S2O3 (20%
aq.). The mixture was brought to room temp. and stirred for a
further 15 min. The phases were separated, and the aqueous phase
was extracted three times with CH2Cl2. The combined organic ex-
tracts were dried with MgSO4, filtered, and concentrated in vacuo.
The residue was then redissolved in toluene (4.0 mL) and heated at
reflux for 2 h. Then the reaction mixture was brought to room
temp. and concentrated to dryness. The residue was purified by
flash chromatography (2% MeOH in CH2Cl2) to give the unsatu-
rated product still containing a silyl ether (20 mg), and also final
product 4 (9 mg). The silyl-ether-bearing compound (20 mg,
31 μmol) was dissolved in MeOH (1 mL), and AcCl (11 μL,
155 μmol) was added. The mixture was stirred for 12 h under ar-
gon. The reaction was quenched by the addition of solid NaHCO3,
then the mixture was filtered, and the filtrate was concentrated to
dryness in vacuo. The residue was purified by flash chromatog-
raphy (10% MeOH in CH2Cl2) to give 4 (13 mg; combined yield:
22 mg, 60%) as a beige oil. 1H NMR (400.1 MHz, CDCl3): δ =
7.18 (m, 1 H), 5.05 (m, 0.3 H), 4.95 (m, 0.7 H), 4.06 (m, 1 H),
3.92–3.79 (m, 2 H), 2.85–2.35 (m, 7 H), 1.53–1.17 (m, 41 H), 0.87
(vt, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 174.6, 174.6,
151.8, 150.9, 131.2, 131.1, 81.8, 77.9, 69.9, 67.0, 66.7, 66.1, 65.3,
64.1, 43.5, 37.3, 35.0–34.8, 33.3, 33.3, 31.8, 30.9, 29.6–29.1, 25.5–
(S)-3-{(2R,13S)-2,13-Dihydroxy-14-[(2-{[(S)-2-hydroxydodecyl]-
thio}ethyl)thio]tetradecyl}-5-methylfuran-2(5H)-one (5): Compound
33 (33 mg, 46 μmol) was dissolved in MeOH (0.3 mL), and AcCl
(33 μL, 464 μmol) in MeOH (0.2 mL) was added at room temp.
under an argon atmosphere. The mixture was stirred for 50 min,
and the reaction progress was monitored by TLC analysis. When
the starting material had been consumed, solid NaHCO3 was
added, and after stirring for 5 min, the mixture was filtered through
a silica plug. The filtrate was concentrated in vacuo to dryness.
The residue was purified by flash chromatography (2% MeOH in
CH2Cl2) to give 5 (24 mg, 89 %) as a white solid. 1H NMR
(400.1 MHz, CDCl3): δ = 7.18 (m, 1 H), 5.06 (qd, J = 6.8, 1.4 Hz,
1 H), 3.84 (m, 1 H), 3.65 (m, 2 H), 2.77 (m, 5 H), 2.57–2.32 (m, 5
H), 1.53–1.39 (m, 6 H), 1.43 (d, J = 6.8 Hz, 3 H), 1.36–1.22 (m, 32
H), 0.87 (vt, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 174.6,
151.8, 131.2, 77.9, 70.0, 69.7, 69.7, 40.3, 37.3, 36.3, 33.3, 32.5, 31.9,
29.6–29.3, 25.7, 25.5, 22.6, 19.1, 14.1 ppm. IR: ν = 3421, 2916,
˜
2850, 1739, 1465, 1323, 1199, 1080, 1026, 721 cm–1. HRMS: calcd.
for C33H62O5S2 [M + H]+ 603.4111; found 603.4113.
(S)-1-({2-[(2-Mercaptoethyl)thio]ethyl}thio)dodecan-2-ol (34): 2,2Ј-
Thiodiethanethiol (332 μL, 2.54 mmol) was added to a solution of
epoxide (S)-9 (156 mg, 0.84 mmol) and InCl3 (18 mg, 84 μmol) in
iPrOH (2 mL), and the mixture was stirred at room temp. for 1.5 d.
Then the mixture was concentrated in vacuo, and the residue was
purified by flash chromatography (5% EtOAc in petroleum ether)
to give 34 (153 mg, 53 %) as an opaque waxy solid. 1H NMR
(400.1 MHz, CDCl3): δ = 3.64 (m, 1 H), 2.82–2.67 (m, 9 H), 2.48
(dd, J = 13.6, 8.6 Hz, 1 H), 2.38 (br. s, 1 H), 1.72 (m, 1 H), 1.54–
1.18 (m, 18 H), 0.86 (vt, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 69.6, 40.3, 36.2, 32.5, 32.2, 31.8, 29.56, 29.54, 29.53, 29.50,
25.4, 24.8, 23.3, 22.6, 19.0, 14.0 ppm. IR: ν = 3363, 2924, 2854,
˜
1751, 1458, 1373, 1056, 732 cm–1. HRMS: calcd. for C32H61NO5
[M + H]+ 540.4622; found 540.4605.
29.2, 25.6, 24.7, 22.6, 14.0 ppm. IR: ν = 3433, 2916, 2846, 1465,
˜
1423, 1199, 1087, 1049, 721, 678 cm–1. HRMS: calcd. for
C16H34OS3 [M + H]+ 339.1844; found 339.1838.
(S)-1-[(2-Mercaptoethyl)thio]dodecan-2-ol (32): InCl3 (43 mg,
0.19 mmol) and 1,2-ethanedithiol (822 μL, 9.77 mmol) were added
to a solution of epoxide (S)-9 (360 mg, 1.95 mmol) in iPrOH
(1.5 mL). The reaction mixture was stirred for 1 h, then after TLC
indicated that the epoxide had been consumed the mixture was
concentrated to dryness in vacuo. The residue was purified by flash
chromatography (2 % EtOAc in petroleum ether) to give 32
(S)-3-[(2R,13S)-2-[(tert-Butyldimethylsilyl)oxy]-13-hydroxy-14-({2-
[(2-{[(S)-2-hydroxydodecyl]thio}ethyl)thio]ethyl}thio)tetradecyl]-
5-methylfuran-2(5H)-one (35): Sulfide 34 (32 mg, 95 μmol) was
added to a solution of 8 (27 mg, 63 μmol) and InCl3 (2 mg,
12 μmol) in CH2Cl2 (0.6 mL), and the mixture was stirred over-
night at room temp. Then the mixture was concentrated in vacuo,
and the residue was purified by flash chromatography (20% EtOAc
in petroleum ether) to give 35 (33 mg, 68%) as an opaque waxy
solid. 1H NMR (400.1 MHz, CDCl3): δ = 7.12 (m, 1 H, major
isomer), 7.10 (m, 0.06 H, minor isomer), 5.00 (m, 1 H), 3.94 (m, 1
H), 3.70–3.61 (m, 2 H), 2.80–2.73 (m, 10 H), 2.50 (dd, J = 13.6,
8.6 Hz, 2 H), 2.42 (m, 2 H), 1.53–1.19 (m, 52 H), 0.90–0.83 (m, 14
H), 0.05 (br. s, 3 H), 0.02 (br. s, 3 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 174.0, 151.4, 130.8, 77.4, 70.2, 69.8, 40.3, 36.9, 36.3,
32.7, 32.5, 32.4, 31.8, 29.69, 29.62–29.5 (overlapping signals), 29.3,
1
(334 mg, 61%) as a white solid. H NMR (400.1 MHz, CDCl3): δ
= 3.62 (m, 1 H), 2.79–2.66 (m, 5 H), 2.54 (br. s, 1 H), 2.41 (dd, J
= 13.6, 8.7 Hz, 1 H), 1.52–1.17 (m, 18 H), 0.85 (vt, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 69.6, 40.0, 36.2, 36.1, 31.8, 29.5,
29.5–29.4, 29.2, 28.6 25.6, 24.7, 22.5, 14.0 ppm. IR: ν = 3360, 2916,
˜
2850, 1465, 1087, 1049, 721 cm–1. HRMS: calcd. C14H30OS2 [M +
Na]+ 301.1630; found 301.1626 ppm.
(S)-3-{(2R,13S)-2-[(tert-Butyldimethylsilyl)oxy]-13-hydroxy-14-[(2-
{[(S)-2-hydroxydodecyl]thio}ethyl)thio]tetradecyl}-5-methylfuran-
2(5H)-one (33): A mixture of epoxide 8 (41 mg, 94 μmol), sulfide
32 (52 mg, 189 μmol), and InCl3 (2 mg, 9.4 μmol) in iPrOH
(0.5 mL) was stirred at room temp. for 21 h, and then the mixture
was concentrated in vacuo. The residue was purified by flash
chromatography (20% EtOAc in petroleum ether) to give product
25.8, 25.7, 25.1, 22.6, 18.9, 18.0, 14.0, –4.44, –4.45 ppm. IR: ν =
˜
3448, 2924, 2854, 1751, 1462, 1253, 1076, 1026, 837, 775 cm–1
.
HRMS: calcd. for C41H80O5S3Si [M + H]+ 777.5009; found
777.5016.
(S)-3-[(2R,13S)-2,13-Dihydroxy-14-({2-[(2-{[(S)-2-hydroxy-
dodecyl]thio}ethyl)thio]ethyl}thio)tetradecyl]-5-methylfuran-2(5H)-
one (6): Compound 35 (18 mg, 23 μmol) was dissolved in MeOH
(1 mL), and AcCl (16 μL, 0.23 mmol) was added. The mixture was
1
33 (39 mg, 58%) as a clear oil. H NMR (400.1 MHz, CDCl3): δ
= 7.11 (m, 1 H), 4.99 (m, 1 H), 3.94 (m, 1 H), 3.70–3.61 (m, 2 H),
2.79–2.72 (dd, J = 13.7, 3.4 Hz, 2 H), 2.76 (br. s, 4 H), 2.48 (dd, J
Eur. J. Org. Chem. 2013, 6886–6899
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6897

P. Villo, L. Toom, E. Eriste, L. Vares
FULL PAPER
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stirred overnight at room temp. Solid NaHCO3 was added, the mix-
ture was filtered through Celite, and the filtrate was concentrated
in vacuo. The residue was purified by flash chromatography (2%
MeOH in CH2Cl2) to give 6 (12 mg, 77%) as a white solid. 1H
NMR (400.1 MHz, CDCl3): δ = 7.17 (m, 1 H), 5.05 (m, 1 H), 3.84
(m, 1 H), 3.70–3.60 (m, 2 H), 2.79–2.73 (m, 10 H), 2.53–2.45 (m,
2 H), 2.27 (br. s, 3 H), 1.54–1.20 (m, 43 H), 0.87 (vt, 3 H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 174.5, 151.7, 131.2, 77.9, 69.9,
69.83, 69.82, 40.3, 37.4, 36.3, 36.2, 33.3, 32.5, 32.4, 31.8, 29.6,
29.59, 29.58, 29.55, 29.49, 29.48, 29.46, 29.3, 25.7, 25.6, 25.5, 22.6,
[10]
[11]
[12]
19.1, 14.0 ppm. IR: ν = 3425, 2916, 2846, 1739, 1465, 1423, 1319,
˜
1195, 1083, 1029, 736, 721 cm–1. HRMS: calcd. for C35H66O5S3 [M
+ H]+ 663.4145; found 663.4141.
Supporting Information (see footnote on the first page of this arti-
cle): Determination of enantiomeric ratio for (S)-9, determination
of enantiomeric and diastereomeric ratios for epoxy-diol 13, 1H
and 13C NMR spectra for compounds 1–8, 11 and 22–35, HRMS
spectra for aza and thio analogues 1–6.
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Received: May 24, 2013
Published Online: September 9, 2013
Eur. J. Org. Chem. 2013, 6886–6899
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6899