First total synthesis of longimicin D

Article abstract of DOI:10.1002/ejoc.200500850

We have accomplished the first total synthesis of longimicin D (1), which displays potent cytotoxicity against human pancreatic carcinoma cells. The bis-THF core bearing congested stereocenters was constructed by our methodology for synthesis of poly-THF

Full text of DOI:10.1002/ejoc.200500850

FULL PAPER
DOI: 10.1002/ejoc.200500850
First Total Synthesis of Longimicin D
Hiroaki Tominaga,[a] Naoyoshi Maezaki,*[a] Minori Yanai,[a] Naoto Kojima,[a]
Daisuke Urabe,[a] Risa Ueki,[a] and Tetsuaki Tanaka*[a]
Keywords: Annonaceous acetogenins / Natural products / Total synthesis / Longimicin D
We have accomplished the first total synthesis of longim-
icin D (1), which displays potent cytotoxicity against human
pancreatic carcinoma cells. The bis-THF core bearing con-
gested stereocenters was constructed by our methodology for
synthesis of poly-THF cores, which consists of asymmetric
alkynylation with the C4 unit and stereodivergent THF ring
formation. Although we had planned to join the C9–C34 bis-
THF core segment 2 and the C1–C8 γ-lactone segment 3,
a model study revealed that the coupling was difficult. We
resolved the problem by applying asymmetric alkynylation
of bis-THF aldehyde 24 with functionalized alkyne 19 re-
spresenting the polymethylene chain from the C3 to C12 po-
sition.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
high cytotoxicity. In a previous paper we have reported a
systematic and stereoselective construction of the THF ring
moiety for acetogenins, and a library of mono- and bis-
THF ring moieties was synthesized by applying the meth-
odology.[5] On the basis of the preliminary study, we next
focused on a synthesis of longimicin D (1).
Introduction
Annonaceous acetogenins are polyketides containing one
to three tetrahydrofuran (THF) ring(s) with various stereo-
chemistries in the middle of a long hydrocarbon chain and
a butenolide moiety at the end. More than 400 acetogenins
have been isolated from nature so far.[1] They have attracted
considerable attention, due to their various biological ac-
tivities (antitumor, pesticidal, antimalarial, immunosup-
pressive, and antifeedant). Furthermore, it is known that
some acetogenins inhibit multidrug-resistant cancer cells.[1]
Their mode of action was suggested to be based on inhibi-
tory activity against complex I (NADH-ubiquinone oxido-
reductase) in the mammalian and insect mitochondrial elec-
tron transport system, and NADH oxidase, which is specifi-
cally active in the plasma membranes of tumors and is inac-
tive in normal cells. Many workers are engaged in syntheses
of members of the acetogenin family, due to their attractive
biological activities.[2,3]
Scheme 1. Structure of longimicin D.
Here we describe the first total synthesis of longimicin D,
with asymmetric alkynylation of an aldehyde neighboring a
bis-THF core with a functionalized alkyne as a key step.
Longimicin D (1) is a structural isomer of asimicin, iso-
lated by McLaughlin and co-workers from leaves and twigs
of Asimina longifolia K. (Annonaceae) in 1996 (Scheme 1).[4]
Longimicin D has a bis-THF ring moiety flanked by two
hydroxy groups (threo/trans/threo/trans/threo-type) and also
possesses an (R)-hydroxy group at the C10 position. Longi-
micin D exhibited selective cytotoxic activities against hu-
man lung carcinoma (A-549), human prostate adenocarci-
noma (PC-3), and human pancreatic carcinoma (PaCa-2),
with potency from 103 to 105 times that of adriamycin.
There is no total synthesis of longimicin D, in spite of its
Results and Discussion
We planned to synthesize longimicin D (1) by applying a
reiterative process based on asymmetric alkynylation of an
α-oxyaldehyde with the C4 unit followed by stereodivergent
THF ring formation as shown in Scheme 2.[5]
The reiterative process is advantageous in terms of econ-
omics (same reagents/solvents used) and technical effective-
ness. In addition, since our methodology is stereodivergent
in each step, a synthetic route for one stereoisomer will also
apply to other stereoisomers.
We noted the presence of three latent C4 units in the
C9–C20 THF core of the target molecule, and employed a
synthetic route involving a triple introduction of the C4 unit
for synthesis of the THF core. Longimicin D was thus dis-
connected into the THF core segment 2 and the γ-lactone
[a] Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax: +81-6-6879-8214
E-mail: maezaki@phs.osaka-u.ac.jp
t-tanaka@phs.osaka-u.ac.jp
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First Total Synthesis of Longimicin D
FULL PAPER
8.[5b] However, the reaction did not proceed and segment 3
decomposed under the reaction conditions (Scheme 3).
Scheme 3. Alkynylation of 9 with 3 or 11: a) Tf2O, 2,6-lutidine,
CH2Cl2, 0 °C, quant., b) n-BuLi, THF, –78 °C, c) n-BuLi, HMPA,
THF, –78 °C to room temp.
We assumed that the instability of 3 was a consequence
of the labile γ-lactone, and so alkynylation of the triflate 9
with alkyne 11, without the γ-lactone moiety,[8] was investi-
gated, but again no reaction took place. Attempts involving
the replacement of the alkylating agent with 2-(tert-butyldi-
methylsilyloxy)-1-iodotetradecane and 1,2-epoxytetrade-
acane also failed.
Since all attempts to connect the polymethylene chain at
the C9 position had been fruitless, we decided to try a new
synthetic route, in which the polymethylene chain would be
introduced by asymmetric alkynylation of the aldehyde 4
with alkyne 13 and the adduct coupled with the γ-lactone
segment 7 (Scheme 4). This route is attractive, since the
whole polymethylene chain might be introduced into the
bis-THF core accompanied by stereocontrol over the C13
stereogenic center. At the same time, the route involved
some risk of making the reaction sluggish, since alkynes
with bulky substituents regularly show poor reactivity in
Carreira’s asymmetric alkynylation.[9]
Scheme 2. Synthetic cycle for poly-THF cores and retrosynthetic
analysis of longimicin D.
segment 3. The segments 2 were to be synthesized from the
previously reported bis-THF aldehyde 4.[5a,5c]
The γ-lactone segment 3 was synthesized by alkylation
of γ-lactone 7[6] with alkyl iodide 6, bearing a terminal al-
kyne.[7] The results are summarized in Table 1. Segment 3
was obtained in 48% yield when KHMDS was employed
as a base (Entry 1), whilst addition of HMPA caused a de-
crease in the yield (Entries 2 and 3). Finally, we found that
use of LDA at low temperature dramatically improved the
yield (Entry 4), with the adduct 3 being obtained almost
quantitatively.
Table 1. Alkylation of γ-lactone 7 with 6.
Entry
Conditions[a]
Yield (%)
1
2
3
4
A
B
C
D
48
23
32
97
[a] Conditions (values in parenthesis are equivalents of reagents.)
A: 7 (1.0), KHMDS (1.0), 0 °C to room temp. B: 7 (1.0), KHMDS
(1.0), HMPA (1.0), 0 °C to room temp. C: 7 (1.0), KHMDS (1.0),
HMPA (5.0), 0 °C to room temp. D: 7 (1.1), LDA (1.1), HMPA
(6.0), –78 to 0 °C.
With the γ-lactone segment 3 to hand, we conducted a
model study for the coupling reaction between the THF
ring segment 2 and the triflate 9, prepared from alcohol Scheme 4. Alternate retrosynthetic analysis of longimicin D.
Eur. J. Org. Chem. 2006, 1422–1429
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The synthesis of the alkynes 18 and 19 is depicted in
Scheme 5. An attempted asymmetric alkynylation of 8-ben-
zyloxyoctanal (14)[10] with (trimethylsilyl)acetylene under
the conditions modified by Rein’s group[3l] provided the
alcohol 15 in moderate yield, albeit with unsatisfactory en-
antiomeric excess (ee) (58% yield and 89% ee). Alterna-
tively, we examined asymmetric reduction of the ynone 17,
prepared by oxidation of racemic propargyl alcohol rac-16
with Dess–Martin periodinane. Reduction with (R)-Me-
CBS-oxazaborolidine[11] furnished (R)-alcohol 16 in 56%
yield but with only 84% ee.[12] On the other hand, reduction
with (R)-Alpine-Borane®[13] gave 16 in 60% yield and with
97% ee. The absolute configuration of 16 was confirmed as
the desired (R) arrangement by the modified Mosher
method.[14] Protection of the alcohol with tert-butyldime-
thylsilyl and methoxymethyl groups afforded alkynes 18
and 19 in 94 and 96% yields, respectively.
Scheme 6. Asymmetric alkynylation of alkynes 18 and 19:
a) Zn(OTf)2, Et3N, (1R,2S)-(–)-N-methylephedrine, toluene, room
temp., 21 (0%), 22 (89%, β-OH/α-OH Ͼ 97:3).
Scheme 7. Asymmetric alkynylation of aldehyde 24 with alkyne 19:
a) SO3·pyridine, DMSO, Et3N, CH2Cl2, 0 °C to room temp., 90%,
b) Zn(OTf)2, Et3N, (1R,2S)-(–)-N-methylephedrine, toluene, room
temp., 65%, β-OH/α-OH Ͼ 97:3.
Scheme 5. Preparation of alkynes 18 and 19: a) (trimethylsilyl)acet-
ylene, n-BuLi, THF, –78 °C to room temp., b) K2CO3, MeOH, 0 °C
to room temp., 93% in two steps, c) Dess–Martin periodinane,
CH2Cl2, 0 °C to room temp., 98%, d) (R)-Me-CBS-oxazaborolid-
ine, BH3·SMe2, THF, 0 °C, 56%, 84% ee, e) (R)-Alpine-Borane®,
room temp., 60%, 97% ee, f) TBSCl, imidazole, DMF, 0 °C to
room temp., 94%, g) MOMCl, iPr2NEt, CH2Cl2, 0 °C to room
temp., 96%.
In order to evaluate which of the two alkynes, 18 or 19,
was more appropriate for asymmetric alkynylation of the α-
tetrahydrofurancarbaldehyde, we conducted asymmetric al-
kynylations of mono-THF aldehyde 20[5b] with alkynes 18
or 19 in a model study (Scheme 6), and found that the al-
kyne 19, bearing a small MOM group, was better than the
TBS-protected alkyne 18, with high steric demand. Whilst
no product was obtained from 18, the alkyne 19 afforded
adduct 22 in good yield and with excellent stereoselectiv-
ity.[15]
On the basis of this model study, the asymmetric alkynyl-
ation of bis-THF aldehyde 24 with the alkyne 19 was car-
ried out (Scheme 7). The bis-THF alcohol 23 prepared by
our reiterative THF ring formation[5a] was oxidized by
DMSO oxidation with SO3·pyridine to give aldehyde 24 in
90% yield. Introduction of the alkyne 19 into the bis-THF
core 24 proceeded successfully, exclusively giving the desired
propargyl alcohol 25 in 65% yield.[16]
Scheme 8. Preparation of bis-THF ring segment 28: a) MOMCl,
iPr2NEt, CH2Cl2, 0 °C to room temp., 94%, b) H2, 10% Pd/C,
EtOAc, room temp., 73%, c) I2, PPh3, imidazole, CH2Cl2, 0 °C to
room temp., 82%.
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First Total Synthesis of Longimicin D
FULL PAPER
After MOM protection of the secondary alcohol 25 in those reported, while the specific rotation of synthetic 1
94% yield, the resulting compound 26 was hydrogenated on {[α]2D5 = +23.2 (c = 0.48 in EtOH)} was higher than that
10% Pd/C to give alcohol 27 in 73% yield. The alcohol 27 reported in the literature {[α]D = +14 (c = 0.1 in
was converted into iodide 28 in 82% yield (Scheme 8).
The coupling of the bis-THF core 28 and the γ-lactone
7 is summarized in Table 2. When a small excess of the base
was used, very little of the coupling product 29 was ob-
tained and 85% of the iodide 28 was recovered (Entry 1).
Although addition of 1.1 equivalents of HMPA slightly im-
proved the yield (Entry 2), the yield of 29 was not increased
by further additional HMPA (Entry 3). Eventually we ob-
tained 29 in 76% yield by use of two equivalents of 7, LDA,
and HMPA (Entry 4).
EtOH)}.[3,17]
Conclusion
We have accomplished the first total synthesis of longim-
icin D by employing our systematic synthesis of the poly-
THF core of annonaceous acetogenins, with asymmetric al-
kynylation of the bis-THF aldehyde bearing congested ste-
reogenic centers with a functionalized alkyne as a key step.
Table 2. Coupling reaction between iodide 28 and γ-lactone 7.
Experimental Section
Optical rotations were measured with a JASCO DIP-360 digital
polarimeter. 1H NMR spectra were recorded in CDCl3 solution
with a JEOL JNM-GX-500 spectrometer (500 MHz). 13C NMR
spectra were recorded in CDCl3 solution with a JEOL JNM-AL300
spectrometer (75 MHz). All signals are expressed as δ values
in ppm downfield from the internal standard (tetramethylsilane).
The following abbreviations are used: broad = br., singlet = s,
doublet = d, triplet = t, quadruplet = q, quintet = qn, sextet = sext,
and multiplet = m. IR absorption spectra (FT = diffuse reflectance
spectroscopy) were recorded in KBr powder with a Horiba FT-210
IR spectrophotometer, and only noteworthy absorptions (in cm–1)
are listed. Mass spectra were obtained with JEOL JMS-600H and
JEOL JMS-700 mass spectrometers. Column chromatography was
carried out on Kanto Chemical silica gel 60N (spherical, neutral,
63–210 µm) and flash column chromatography was carried out on
Merck silica gel 60 (0.040–0.063 mm). All air- or moisture-sensitive
reactions were carried out in flame-dried glassware under Ar or
N2. All solvents were dried and distilled by standard procedures.
All organic extracts were dried with anhydrous MgSO4, filtered,
and concentrated under reduced pressure on a rotary evaporator.
Entry Conditions[a]
Yield (%)
29
28
1
2
3
4
A
B
C
D
trace
31
38
85
64
45
19
76
[a] Conditions (values in parenthesis are equivalents of reagents).
A: 7 (1.1), LDA (1.1). B: 7 (1.1), LDA (1.1), HMPA (1.1). C: 7
(1.1), LDA (1.1), HMPA (6.0). D: 7 (2.0), LDA (2.0), HMPA (2.0).
The total synthesis of longimicin D (1) (Scheme 9) was
accomplished from 29 by subsequent reactions – (1) oxi-
dation of the sulfide, (2) thermolytic elimination of the sulf-
oxide, and (3) global deprotection with acidic MeOH – to
give 1 in excellent yield.
(3RS,5S)-3-(Hex-5-ynyl)-5-methyl-3-(phenylthio)dihydrofuran-
2(3H)-one (3): (Table 1, Entry 4). n-BuLi (1.58  in hexane,
3.35 mL, 5.29 mmol) was added to a solution of iPr2NH
(0.741 mL, 5.29 mmol) in THF (8.8 mL) with stirring at –78 °C.
After the mixture had been stirred for 15 min, a solution of 7
(1.10 g, 5.29 mmol) in THF (8.8 mL) was added with stirring at
–78 °C. After this mixture had been stirred for 15 min, a solution
of 6 (1.00 g, 4.81 mmol) in HMPA (5.02 mL, 28.8 mmol) was added
with stirring at –78 °C for 1 h. After stirring at 0 °C for 30 min, the
reaction mixture was quenched with saturated NH4Cl and ex-
tracted with Et2O. The combined organic layers were washed with
saturated NH4Cl, water, and brine prior to drying and solvent
evaporation. Purification by column chromatography on silica gel
(hexane/EtOAc, 20:1) yielded 3 (1.35 g, 97%, 9:1 diastereomeric
mixture) as a colorless oil. [α]2D5 = –48.1 (c = 1.04 in CHCl3). 1H
NMR: δ = 1.23 (d, J = 6.1 Hz, 2.7 H), 1.39 (d, J = 6.1 Hz, 0.3 H),
1.47–1.58 (m, 3.1 H), 1.71–1.82 (m, 2.9 H), 1.96 (t, J = 2.7 Hz, 1
H), 1.98 (dd, J = 14.0, 6.7 Hz, 1 H), 2.19–2.22 (m, 2 H), 2.35 (dd,
J = 14.0, 5.5 Hz, 0.1 H), 2.54 (dd, J = 14.0, 7.3 Hz, 0.9 H), 4.51
(m, 0.9 H), 4.65 (m, 0.1 H), 7.34–7.42 (m, 3 H), 7.53–7.57 ppm (m,
2 H). 13C NMR: δ = 17.7, 20.3 (0.1 C), 21.1 (0.9 C), 22.9 (0.1 C),
23.2 (0.9 C), 27.8, 33.5 (0.1 C), 35.2 (0.9 C), 39.6 (0.9 C), 41.9 (0.1
C), 55.4 (0.1 C), 55.5 (0.9 C), 68.5 (0.1 C), 68.6 (0.9 C), 72.9 (0.9
Scheme 9. Synthesis of longimicin D: a) m-CPBA, CH2Cl2, 0 °C,
b) toluene, reflux, c) AcCl, MeOH, CH2Cl2, room temp., 71% in
three steps.
The spectroscopic and physical data of synthetic 1 (1H
NMR, 13C NMR, IR, MS) were in good agreement with C), 73.3 (0.1 C), 83.5 (0.9 C), 83.6 (0.1 C), 128.6 (2 C), 128.8 (0.1
Eur. J. Org. Chem. 2006, 1422–1429
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N. Maezaki, T. Tanaka et al.
FULL PAPER
C), 129.4 (0.9 C), 129.6 (0.1 C), 129.9 (0.9 C), 136.4 (1.8 C), 136.7
concentration of the commercially available 0.5  THF solution
(7.13 mmol, 14.3 mL). The resulting mixture was stirred at room
temp. for 6 h. After completion of the reaction, the mixture was
(0.2 C), 174.9 (0.1 C), 176.5 ppm (0.9 C). IR (KBr): ν = 3294, 3074,
˜
3060, 2978, 2943, 2864, 2116, 1763, 1190 cm–1. MS (FAB): m/z =
289 [M + H]+. HRMS (FAB): m/z calcd. for C17H21O2S: 289.1262; cooled to 0 °C and acetaldehyde (0.399 mL, 7.13 mmol) was added
found: 289.1292 [M + H]+.
to destroy the excess reagent (1 h reaction time). The mixture was
concentrated under reduced pressure and the residue was dissolved
in anhydrous ethyl ether (9.5 mL). The solution was cooled to 0 °C
and N-methylaminoethanol (0.573 mL, 7.13 mmol) was added to
remove 9-BBN. After 15 min, the 9-BBN-ethanolamine adduct was
filtered through a sintered glass funnel. The precipitated was
washed (2×5 mL) with cold ether. The combined filtrate and wash-
ings were dried and concentrated under reduced pressure. Purifica-
tion by flash column chromatography on silica gel (hexane/Et2O,
(2S)-2-(tert-Butyldimethylsilyloxy)tetradecanyl Trifluoromethane-
sulfonate (9): 2,6-Lutidine (0.0823 mL, 0.725 mmol) was added to
a solution of 8 (50.0 mg, 0.145 mmol) in CH2Cl2 (1.3 mL) with
stirring at room temp. After 5 min, trifluoromethanesulfonic anhy-
dride (0.0488 mL, 0.290 mmol) was added to the reaction mixture
with stirring at 0 °C and the stirring was continued for 25 min.
Water (0.1 mL) was added to the reaction mixture with stirring at
0 °C. After the mixture had been stirred at room temp. for 5 min,
saturated NaHCO3 was added and the mixture was extracted with
Et2O. The combined organic layers were washed with brine prior
to drying and solvent evaporation. Purification by flash column
chromatography on silica gel (hexane/EtOAc, 50:1) yielded 9
(69.5 mg, quant.) as a colorless oil. This compound was immedi-
ately used in the next reaction because of its instability.
4:1) yielded 16 (555 mg, 60%, 97% ee) as a colorless oil. [α]2D5
=
+1.7 (c = 1.07 in CHCl3). The spectroscopic data were identical to
those for rac-16.
(3R)-10-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)dec-1-yne (18):
Imidazole (52.3 mg, 0.768 mmol) was added with stirring at 0 °C
to a solution of 16 (100 mg, 0.384 mmol) in DMF (0.3 mL). After
5 min, TBSCl (116 mg, 0.768 mmol) was added to the mixture with
stirring at 0 °C. After 2 h at room temp., the reaction mixture was
quenched with water and extracted with EtOAc. The combined or-
ganic layers were washed with water and brine prior to drying and
solvent evaporation. Purification by column chromatography on
silica gel (hexane/EtOAc, 20:1) yielded 18 (136 mg, 94%) as a col-
orless oil. [α]2D8 = +24.4 (c = 1.31 in CHCl3). 1H NMR: δ = 0.11 (s,
3 H), 0.13 (s, 3 H), 0.90 (s, 9 H), 1.29–1.45 (m, 8 H), 1.61 (qn, J =
6.7 Hz, 2 H), 1.64–1.69 (m, 2 H), 2.36 (d, J = 1.8 Hz, 1 H), 3.46
(t, J = 6.7 Hz, 2 H), 4.33 (td, J = 6.7, 1.8 Hz, 1 H), 4.50 (s, 2 H),
7.26–7.34 ppm (m, 5 H). 13C NMR: δ = –5.1, –4.6, 18.2, 25.0, 25.7
(3 C), 26.1, 29.1, 29.3, 29.7, 38.5, 62.7, 70.4, 71.9, 72.8, 85.7, 127.4,
rac-10-(Benzyloxy)dec-1-yn-3-ol (rac-16): n-BuLi (1.60  in hexane,
13.7 mL, 21.9 mmol) was added with stirring at –78 °C to a solu-
tion of (trimethylsilyl)acetylene (3.03 mL, 21.9 mmol) in THF
(28 mL). After 15 min, a solution of 14 (3.42 g, 14.6 mmol) in THF
(28 mL) was added to the reaction mixture. After 15 min at the
same temperature, the whole was stirred for 1.75 h at room temp.
The reaction was quenched with saturated NH4Cl at 0 °C and the
mixture was extracted with EtOAc. The combined organic layers
were washed with saturated NH4Cl, water, and brine prior to dry-
ing and solvent evaporation. K2CO3 (4.64 g, 33.6 mmol) was added
to a solution of the residue in MeOH (30 mL) with stirring at room
temp. After 3.5 h, water was added to the reaction mixture, which
was then extracted with EtOAc. The combined organic layers were
washed with brine prior to drying and solvent evaporation. Purifi-
cation by column chromatography on silica gel (hexane/EtOAc,
6:1) yielded rac-16 (3.53 g, 93% in two steps) as a pale yellow oil.
1H NMR: δ = 1.32–1.50 (m, 8 H), 1.59–1.76 (m, 4 H), 1.84 (br.d,
J = 4.3 Hz, 1 H), 2.46 (d, J = 1.8 Hz, 1 H), 3.46 (t, J = 6.7 Hz, 2
H), 4.33–4.38 (m, 1 H), 4.50 (s, 2 H), 7.26–7.31 (m, 1 H), 7.33–
7.35 ppm (m, 4 H). 13C NMR: δ = 24.8, 25.8, 29.0, 29.1, 29.4, 37.4,
61.8, 70.2, 72.5, 72.6, 85.1, 127.3, 127.5 (2 C), 128.1 (2 C),
127.5 (2 C), 128.3 (2 C), 138.7 ppm. IR (KBr): ν = 3307, 3087,
˜
3068, 3030, 2113, 1471 cm–1. MS (FAB): m/z = 375 [M + H]+.
HRMS (FAB): m/z calcd. for C23H39O2Si: 375.2719; found:
375.2692 [M + H]+.
(3R)-10-(Benzyloxy)-3-(methoxymethoxy)dec-1-yne (19): MOMCl
(0.233 mL, 3.07 mmol) and iPr2NEt (0.527 mL, 3.07 mmol) were
added with stirring at 0 °C to a solution of 16 (400 mg, 1.54 mmol)
in CH2Cl2 (3.1 mL). After stirring for 2 h at room temp., the reac-
tion mixture was diluted with EtOAc and washed with water, satu-
rated NH4Cl, and brine prior to drying and solvent evaporation.
Purification by column chromatography on silica gel (hexane/
138.3 ppm. IR (KBr): ν = 3404, 3303, 3087, 3064, 3030, 1454 cm–1.
˜
MS (FAB): m/z = 283 [M + Na]+. HRMS (FAB): m/z calcd. for
C17H24NaO2: 283.1674; found: 283.1659 [M + Na]+.
EtOAc, 8:1) yielded 19 (448 mg, 96%) as a colorless oil. [α]2D7
=
+88.0 (c = 2.30 in CHCl3). 1H NMR: δ = 1.31–1.52 (m, 8 H), 1.61
(qn, J = 6.7 Hz, 2 H), 1.68–1.79 (m, 2 H), 2.40 (d, J = 1.8 Hz, 1
H), 3.38 (s, 3 H), 3.46 (t, J = 6.7 Hz, 2 H), 4.31 (td, J = 6.7, 1.8 Hz,
1 H), 4.50 (s, 2 H), 4.60 (d, J = 6.7 Hz, 1 H), 4.94 (d, J = 6.7 Hz,
1 H), 7.26–7.30 (m, 1 H), 7.31–7.37 ppm (m, 4 H). 13C NMR: δ =
24.9, 25.9, 29.0, 29.1, 29.6, 35.4, 55.4, 65.2, 70.2, 72.6, 73.3, 82.5,
10-(Benzyloxy)dec-1-yn-3-one (17): Dess–Martin periodinane
(3.05 g, 7.19 mmol) was added with stirring at 0 °C to a solution
of rac-16 (624 mg, 2.40 mmol) in CH2Cl2 (24 mL). After the mix-
ture had been stirred for 2 h at room temp., further Dess–Martin
periodinane (1.02 g, 2.40 mmol) was added with stirring at 0 °C.
After additional stirring for 1 h, the reaction mixture was filtered
through silica gel and the filtrate was concentrated under reduced
pressure. Purification by column chromatography on silica gel (hex-
ane/EtOAc, 10:1) yielded 17 (604 mg, 98%) as a colorless oil. 1H
NMR: δ = 1.31–1.41 (m, 6 H), 1.61 (qn, J = 6.7 Hz, 2 H), 1.65–
1.71 (m, 2 H), 2.58 (t, J = 7.3 Hz, 2 H), 3.19 (s, 1 H), 3.46 (t, J =
6.7 Hz, 2 H), 4.50 (s, 2 H), 7.26–7.30 (m, 1 H), 7.32–7.36 ppm (m,
4 H). 13C NMR: δ = 23.4, 25.7, 28.6, 28.9, 29.4, 45.1, 70.1, 72.6,
78.4, 81.2, 127.2, 127.4 (2 C), 128.1 (2 C), 138.4, 187.2 ppm. IR
93.9, 127.2, 127.4 (2 C), 128.1 (2 C), 138.5 ppm. IR (KBr): ν =
˜
3291, 3087, 3064, 3031, 2111, 1454 cm–1. MS (FAB): m/z = 327 [M
+ Na]+. HRMS (FAB): m/z calcd. for C19H28NaO3: 327.1936;
found: 327.1939 [M + Na]+.
(1R,4R)-11-(Benzyloxy)-1-[(1R,4R,5R)-5-(tert-butyldimethylsilyl-
oxy)-1,4-epoxyheptadecanyl]-4-(methoxymethoxy)undec-2-yn-1-ol
(22): A flask was charged with Zn(OTf)2 (262 mg, 0.720 mmol).
Vacuum (8 Torr) was applied and the flask was heated to 125 °C
for 8 h. The flask was allowed to cool to room temp. and the vac-
uum was then released. (1R,2S)-(–)-N-Methylephedrine (141 mg,
0.785 mmol) and toluene (0.7 mL) and Et3 N (0.110 mL,
0.785 mmol) were added to the flask with stirring at room temp. A
solution of 19 (199 mg, 0.654 mmol) in toluene (0.35 mL) was
(KBr): ν = 3263, 3087, 3062, 3030, 2029, 1684, 1454 cm–1. MS
˜
(FAB): m/z = 259 [M + H]+. HRMS (FAB): m/z calcd. for
C17H23O2: 259.1698; found: 259.1696 [M + H]+.
(3R)-10-(Benzyloxy)dec-1-yn-3-ol (16): The ketone 17 (922 mg,
3.57 mmol) was added to neat (R)-Alpine-Borane®, prepared by
1426
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1422–1429

First Total Synthesis of Longimicin D
FULL PAPER
added to the mixture with stirring at room temp. After 0.25 h, a
solution of 20 (135 mg, 0.327 mmol) in toluene (0.35 mL) was
added to the mixture with stirring at room temp. After stirring for
6 h, the reaction mixture was quenched with saturated NH4Cl and
extracted with EtOAc. The combined organic layers were washed
with brine prior to drying and solvent evaporation. Purification by
column chromatography on silica gel (hexane/EtOAc, 20:1) yielded
fication by column chromatography on silica gel (hexane/EtOAc,
5:1) yielded 26 (174 mg, 94%) as a colorless oil. [α]2D8 = +23.6 (c =
1
0.96 in CHCl3). H NMR: δ = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.85–
0.89 (m, 12 H), 1.26–1.48 (m, 30 H), 1.61 (tt, J = 7.6, 6.7 Hz, 2 H),
1.65–1.78 (m, 5 H), 1.86–1.99 (m, 4 H), 2.07–2.13 (m, 1 H), 3.36
(s, 3 H), 3.37 (s, 3 H), 3.48 (t, J = 6.7 Hz, 2 H), 3.59–3.62 (m, 1
H), 3.87–4.00 (m, 3 H), 4.17 (td, J = 6.7, 6.7 Hz, 1 H), 4.34 (td, J
= 6.7, 1.8 Hz, 1 H), 4.42 (dd, J = 6.7, 1.8 Hz, 1 H), 4.49 (s, 2 H),
4.56 (d, J = 6.7 Hz, 1 H), 4.63 (d, J = 6.7 Hz, 1 H), 4.88 (d, J =
22 (208 mg, 89%, β-OH/α-OH Ͼ 97:3) as a colorless oil. [α]2D6
=
1
+53.3 (c = 1.55 in CHCl3). H NMR: δ = 0.06 (s, 3 H), 0.07 (s, 3
H), 0.86–0.91 (m, 12 H), 1.26–1.79 (m, 36 H), 1.88–1.94 (m, 1 H), 6.7 Hz, 1 H), 4.91 (d, J = 6.7 Hz, 1 H), 7.25–7.34 ppm (m, 5 H).
2.02–2.08 (m, 1 H), 2.49 (br.s, 1 H), 3.36 (s, 3 H), 3.46 (t, J = 13C NMR: δ = –4.7, –4.3, 14.1, 18.2, 22.6, 25.2, 25.8, 25.9 (3 C),
6.4 Hz, 2 H), 3.57 (td, J = 6.1, 3.7 Hz, 1 H), 3.91 (dt, J = 7.9,
6.1 Hz, 1 H), 4.03 (q, J = 6.7 Hz, 1 H), 4.21 (dd, J = 6.7, 1.2 Hz,
1 H), 4.34 (td, J = 6.7, 1.2 Hz, 1 H), 4.50 (s, 2 H), 4.57 (d, J =
6.7 Hz, 1 H), 4.91 (d, J = 6.7 Hz, 1 H), 7.27–7.31 (m, 1 H), 7.32–
7.34 ppm (m, 4 H). 13C NMR: δ = –4.6, –4.2, 14.1, 18.2, 22.6, 25.2,
25.5, 25.9 (3 C), 26.1, 27.6, 28.3, 29.2, 29.3, 29.55 (2 C), 29.59 (3
C), 29.63, 29.7, 29.8, 31.9, 32.9, 35.6, 55.5, 65.3, 65.5, 70.4, 72.8,
74.8, 82.1, 82.7, 83.5, 84.2, 94.0, 127.4, 127.5 (2 C), 128.3 (2 C),
26.1, 27.2, 28.0, 28.1, 28.3, 29.2, 29.30, 29.32, 29.56 (2 C), 29.58 (2
C), 29.62, 29.7, 29.8, 31.9, 32.4, 35.6, 55.46, 55.52, 65.5, 68.5, 70.4,
72.8, 74.7, 80.5, 81.2, 81.9, 82.0, 82.3, 85.0, 94.0, 94.2, 127.4, 127.5
(2 C), 128.3 (2 C), 138.6 ppm. IR (KBr): ν = 2067, 2035, 1101,
˜
1032 cm–1. MS (FAB): m/z = 854 [M + Na]+. HRMS (FAB):
m/z calcd. for C49H86NaO8Si: 853.5990; found: 853.5981
[M + Na]+.
138.6 ppm. IR (KBr): ν = 3427, 3089, 3064, 3027, 1462 cm–1. MS
(8R,11R,12R,15R,16R,19R,20R)-20-(tert-Butyldimethylsilyloxy)-
12,15;16,19-diepoxy-8,11-bis(methoxymethoxy)dotriacontan-1-ol
(27): A solution of 26 (218 mg, 0.262 mmol) in EtOAc (2.6 mL)
was hydrogenated on 10% Pd/C (10.9 mg) with stirring at room
temp. for 11 h. The Pd/C was filtered off and the filtrate was con-
centrated under reduced pressure. Purification by flash column
chromatography on silica gel (hexane/EtOAc, 3:1) yielded 27
(142 mg, 73%) as a colorless oil. [α]2D7 = +24.9 (c = 0.98 in CHCl3).
1H NMR: δ = 0.049 (s, 3 H), 0.051 (s, 3 H), 0.85–0.87 (m, 12 H),
1.24–1.94 (m, 46 H), 3.35 (s, 3 H), 3.37 (s, 3 H), 3.34–3.56 (m, 3
H), 3.60 (t, J = 6.7 Hz, 2 H), 3.84–3.90 (m, 3 H), 3.99 (dt, J = 8.5,
6.1 Hz, 1 H), 4.64–4.61 (m, 2 H), 4.65 (d, J = 6.7 Hz, 1 H),
4.81 ppm (d, J = 6.7 Hz, 1 H). 13C NMR: δ = –4.7, –4.2, 14.1, 18.2,
22.6, 25.2, 25.6, 25.7, 25.9 (3 C), 26.7, 27.5, 28.1, 28.2, 28.4, 29.3
(2 C), 29.56 (2 C), 29.58 (2 C), 29.62, 29.7, 29.8, 30.2, 31.9, 32.6,
32.7, 34.2, 55.4, 55.7, 62.9, 75.0, 77.5, 79.7, 81.3 (2 C), 81.7, 82.5,
˜
(FAB): m/z = 740 [M + Na]+. HRMS (FAB): m/z calcd. for
C43H76NaO6Si: 739.5309; found: 739.5309 [M + Na]+.
(1R,4R)-11-(Benzyloxy)-1-[(1R,4R,5R,8R,9R)-9-(tert-butyldimeth-
ylsilyloxy)-1,4;5,8-diepoxyhenicosanyl]-4-(methoxymethoxy)undec-
2-yn-1-ol (25): DMSO (0.234 mL, 3.30 mmol) and Et3N (0.690 mL,
4.95 mmol) were added to a solution of 23 (200 mg, 0.413 mmol)
in CH2Cl2 (1.24 mL) with stirring at room temp., and then
SO3·pyridine (263 mg, 1.65 mmol) was added to the mixture with
stirring at 0 °C. The whole mixture was stirred at 0 °C for 10 min
and at room temp. for 1 h, quenched with water, and extracted with
EtOAc. The combined organic layers were washed with water and
brine prior to drying and solvent evaporation. Purification by col-
umn chromatography on silica gel (hexane/EtOAc, 5:1 Ǟ 1:1)
yielded 24 (180 mg, 90%). This aldehyde was immediately used in
the next reaction, due to its instability. The asymmetric alkynyl-
ation procedure was the same as that used for the preparation of
22. Compound 25 (188 mg, 65%, β-OH/α-OH Ͼ 97:3) was pre-
pared from 24 (177 mg, 0.367 mmol) and 19 (224 mg, 0.734 mmol)
95.2, 96.7 ppm. IR (KBr): ν = 2927, 2854, 1464, 1147, 1099 cm–1.
˜
MS (FAB): m/z = 768 [M + Na]+. HRMS (FAB): m/z calcd. for
C42H84NaO8Si: 767.5833; found: 767.5852 [M + Na]+.
1
as a colorless oil. [α]2D3 = +44.6 (c = 1.01 in CHCl3). H NMR: δ
(8R,11R,12R,15R,16R,19R,20R)-20-(tert-Butyldimethylsilyloxy)-
12,15;16,19-diepoxy-1-iodo-8,11-bis(methoxymethoxy)dotriacontane
(28): Imidazole (27.4 mg, 0.403 mmol) and iodine (40.9 mg,
0.161 mmol) were added with stirring (0.5 h) at 0 °C to a solution
of Ph3P (38.7 mg, 0.148 mmol) in CH2Cl2 (2.1 mL). A solution of
27 (100 mg, 0.135 mmol) in CH2Cl2 (0.29 mL) was added to the
reaction mixture with stirring at 0 °C. After the mixture had been
stirred at room temp. for 2 h, Ph3P (35.1 mg, 0.135 mmol) and iod-
ine (34.0 mg, 0.135 mmol) were added with stirring at 0 °C. After
additional stirring at room temp. for 0.5 h, saturated Na2S2O3 was
added to the reaction mixture with stirring until the brown color
of the solution had vanished. The mixture was extracted with Et2O
and the combined organic layers were washed with brine prior to
drying and solvent evaporation. Purification by flash column
chromatography on silica gel (hexane/EtOAc, 10:1) yielded 28
(94.6 mg, 82%) as a colorless oil. [α]2D5 = +23.1 (c = 0.97 in CHCl3).
1H NMR: δ = 0.05 (s, 3 H), 0.07 (s, 3 H), 0.85–0.89 (m, 12 H),
1.26–1.94 (m, 46 H), 3.18 (t, J = 6.7 Hz, 2 H), 3.37 (s, 3 H), 3.39
(s, 3 H), 3.46–3.58 (m, 3 H), 3.85–3.92 (m, 3 H), 4.01 (dt, J = 8.5,
6.1 Hz, 1 H), 4.03–4.66 (m, 2 H), 4.67 (d, J = 7.3 Hz, 1 H),
4.83 ppm (d, J = 7.3 Hz, 1 H). 13C NMR: δ = –4.7, –4.2, 7.11, 14.1,
18.2, 22.6, 25.2, 25.7, 25.9 (3 C), 26.7, 27.6, 28.1, 28.2, 28.4, 28.5,
29.3, 29.5, 29.57 (2 C), 29.59 (2 C), 29.64, 29.8, 30.2, 30.4, 31.9,
32.6, 33.5, 34.2, 55.5, 55.7, 75.0, 77.4, 79.7, 81.3 (2 C), 81.6, 82.5,
= 0.05 (s, 3 H), 0.07 (s, 3 H), 0.85–0.91 (m, 12 H), 1.22–1.47 (m,
30 H), 1.58–2.03 (m, 11 H), 2.06–2.11 (m, 1 H), 2.72 (s, 1 H), 3.35
(s, 3 H), 3.45 (t, J = 6.8 Hz, 2 H), 3.58–3.61 (m, 1 H), 3.84–3.95
(m, 3 H), 4.07 (q, J = 7.0, Hz, 1 H), 4.24 (d, J = 7.0 Hz, 1 H), 4.33
(t, J = 6.5 Hz, 1 H), 4.49 (s, 2 H), 4.56 (d, J = 6.5 Hz, 1 H), 4.91
(d, J = 6.5 Hz, 1 H), 7.25–7.33 ppm (m, 5 H). 13C NMR: δ =
–4.7, –4.3, 14.1, 18.2, 22.6, 25.2, 25.7, 25.9 (3 C), 26.1, 27.3, 28.1,
28.2, 28.5, 29.2, 29.3 (2 C), 29.58 (2 C), 29.59 (2 C), 29.64, 29.7,
29.8, 31.9, 32.5, 35.6, 55.6, 65.5 (2 C), 70.4, 72.8, 74.8, 81.4, 82.1,
82.4 (2 C), 83.4, 84.2, 94.0, 127.4, 127.5 (2 C), 128.3 (2 C),
138.6 ppm. IR (KBr): ν = 3425, 2058, 1101, 1066, 1032 cm–1. MS
˜
(FAB): m/z = 810 [M + Na]+. HRMS (FAB): m/z calcd. for
C47H82NaO7Si: 809.5727; found: 809.5760 [M + Na]+.
(8R,11R,12R,15R,16R,19R,20R)-1-(Benzyloxy)-20-(tert-butyldi-
methylsilyloxy)-12,15;16,19-diepoxy-8,11-bis(methoxymethoxy)-
dotriacont-9-yne (26): iPr2NEt (0.194 mL, 1.11 mmol) and MOMCl
(0.051 mL, 0.667 mmol) were added with stirring at 0 °C to a solu-
tion of 25 (175 mg, 0.222 mmol) in CH2Cl2 (2.2 mL). The whole
mixture was stirred at 0 °C for 10 min and at room temp. for 30.5 h.
MOMCl (0.017 mL, 0.222 mmol) was added to the reaction mix-
ture at 0 °C, with additional stirring at room temp. for 2 h. The
reaction mixture was quenched with saturated NH4Cl and ex-
tracted with EtOAc. The combined organic layers were washed
with water and brine prior to drying and solvent evaporation. Puri-
95.3, 96.7 ppm. IR (KBr): ν = 2927, 2856, 1464, 1250, 1147 cm–1.
˜
Eur. J. Org. Chem. 2006, 1422–1429
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1427

N. Maezaki, T. Tanaka et al.
FULL PAPER
MS (FAB): m/z = 877 [M + Na]+. HRMS (FAB): m/z calcd. for
= 623 [M + H]+. HRMS (FAB): m/z calcd. for C37H67O7: 623.4887;
found: 623.4940 [M + H]+.
C42H83INaO7Si: 877.4850; found: 877.4841 [M + Na]+.
(3RS,5S)-3-[(8R,11R,12R,15R,16R,19R,20R)-20-(tert-Butyldi-
methylsilyloxy)-12,15;16,19-diepoxy-8,11-bis(methoxymethoxy)-
dotriacontanyl]-5-methyl-3-(phenylsulfenyl)tetrahydrofuran-2-one
(29): (Table 2, Entry 4). n-BuLi (1.56  in hexane, 0.120 mL,
0.187 mmol) was added to a solution of iPr2NH (0.0263 mL,
0.187 mmol) in THF (0.30 mL) with stirring at –78 °C for 15 min.
A solution of 7 (39.0 mg, 0.187 mmol) in THF (0.30 mL) was
added to the reaction mixture with stirring at –78 °C. After the
mixture had been stirred for 15 min, a solution of 28 (80.1 mg,
0.0937 mmol) and HMPA (0.0326 mL, 0.187 mmol) in THF
(0.34 mL) was added with stirring at –78 °C for 1 h. After stirring
at 0 °C for 4 h, the mixture was quenched with saturated NH4Cl
and extracted with Et2O. The combined organic layers were washed
with saturated NH4Cl, water, and brine prior to drying and solvent
evaporation. After removal of excess 7 by column chromatography
on silica gel (CH2Cl2), purification by column chromatography on
silica gel (hexane/EtOAc, 4:1) yielded 29 (66.4 mg, 76%) as a color-
less oil along with recovered 28 (15.3 mg, 19%). [α]2D5 = +5.91 (c =
Acknowledgments
We acknowledge financial support in the forms of a Grant-in-Aid
for Scientific Research (C) from the Japan Society for the Pro-
motion of Science (No. 16590006), and a Grant-in-Aid for Scien-
tific Research on a Priority Area from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (No. 17035052).
We also thank the Research Foundation for Pharmaceutical Sci-
ences and the Suntory Institute for Bioorganic Research for finan-
cial support. N.K. and H.T. are grateful for a Research Fellowship
of the Japan Society for the Promotion of Science for Young Scien-
tists.
[1] For reviews for annonaceous acetogenins: a) A. Bermejo, B.
Figadère, M.-C. Zafra-Polo, I. Barrachina, E. Estornell, D.
Cortes, Nat. Prod. Rep. 2005, 22, 269–303; b) F. Q. Alali, X.-
X. Liu, J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504–540; c)
M.-C. Zafra-Polo, B. Figadère, T. Gallardo, J. R. Tormo, D.
Cortes, Phytochemistry 1998, 48, 1087–1117; d) “Acetogenins
from Annonaceae”: A. Cavé, B. Figadère, A. Laurens, D. Cor-
tes, in: Progress in the Chemistry of Organic Natural Products,
Vol. 70 (Ed.: W. Hertz), Springer-Verlag, New York, 1997,
pp. 81–288; e) L. Zeng, Q. Ye, N. H. Oberlies, G. Shi, Z.-M.
Gu, K. He, J. L. McLaughlin, Nat. Prod. Rep. 1996, 13, 275–
306; f) M. C. Zafra-Polo, M. C. González, E. Estornell, S. Sah-
paz, D. Cortes, Phytochemistry 1996, 42, 253–271; g) “Anna-
ceous Acetogenins”, Z.-M. Gu, G.-X. Zhao, N. H. Oberlies, L.
Zeng, J. L. McLaughlin, in: Recent Advances in Phytochemistry,
Vol. 29 (Eds.: J. T. Arnason, R. Mata, J. T. Romeo), Plenum
Press, New York, 1995, pp. 249–310; h) X.-P. Fang, M. J.
Rieser, Z.-M. Gu, G.-X. Zhao, J. L. McLaughlin, Phytochem.
Anal. 1993, 4, 27–67; i) J. K. Rupprecht, Y.-H. Hui, J. L.
McLaughlin, J. Nat. Prod. 1990, 53, 237–278.
1
0.95 in CHCl3). H NMR: δ = 0.05 (s, 3 H), 0.07 (s, 3 H), 0.87–
0.89 (m, 12 H), 1.19 (d, J = 6.7 Hz, 3 H), 1.25–1.82 (m, 44 H),
1.85–2.01 (m, 4 H), 1.96 (dd, J = 14.0, 6.7 Hz, 1 H), 2.51 (dd, J =
14.0, 6.7 Hz, 1 H), 3.37 (s, 3 H), 3.39 (s, 3 H), 3.46–3.58 (m, 3 H),
3.85–3.92 (m, 3 H), 4.01 (dt, J = 9.2, 6.1 Hz, 1 H), 4.49 (sext, J =
6.7 Hz, 1 H), 4.63 (d, J = 6.7 Hz, 1 H), 4.65 (d, J = 6.7 Hz, 1 H),
4.67 (d, J = 6.7 Hz, 1 H), 4.84 (d, J = 6.7 Hz, 1 H), 7.33–7.41 (m,
3 H), 7.51–7.56 ppm (m, 2 H). 13C NMR: δ = –4.7, –4.2, 14.1, 18.2,
21.5, 22.7, 24.6, 25.3, 25.7, 26.0 (3 C), 26.8, 27.6, 28.2, 28.3, 28.4,
29.3 (2 C), 29.3, 29.5, 29.6 (3 C), 29.7 (2 C), 29.8, 30.2, 31.9, 32.6,
34.3, 36.5, 40.1, 55.5, 55.7, 56.2, 73.2, 75.0, 77.5, 79.8, 81.3 (2 C),
81.7, 82.5, 95.3, 96.8, 129.0 (2 C), 129.7, 130.4, 136.8 (2 C),
175.5 ppm. IR (KBr): ν = 3073, 3060, 2925, 2854, 1768, 1720, 1464,
˜
1441, 1250 cm–1. MS (FAB): m/z = 957 [M + Na]+. HRMS (FAB):
m/z calcd. for C53H94NaO9SSi: 957.6285; found: 957.6306 [M +
Na]+
[2] For reviews of synthesis of annonaceous acetogenins: a) G. Ca-
siraghi, F. Zanardi, L. Battistini, G. Rassu, Chemtracts, Organic
Chemistry 1998, 11, 803–827; b) M. C. Elliott, J. Chem. Soc.,
Perkin Trans. 1 1998, 4175–4200; c) B. Figadère, Acc. Chem.
Res. 1995, 28, 359–365; d) R. Hoppe, H.-D. Scharf, Synthesis
1995, 1447–1464; e) U. Koert, Synthesis 1995, 115–132.
Longimicin D (1): A solution of m-CPBA (75% in water, 13.7 mg,
0.0597 mmol) in CH2Cl2 (0.49 mL) was added to a solution of 29
(46.5 mg, 0.0497 mmol) in CH2Cl2 (0.49 mL) with stirring at 0 °C
for 1.5 h. The reaction mixture was diluted with EtOAc and washed
with saturated Na2S2O3, water, and brine prior to drying and sol-
vent evaporation. The residue was diluted with toluene (1.50 mL)
and the solution was stirred under reflux for 2 h. After the solvent
evaporation, a low polar byproduct was removed by column
chromatography on silica gel (hexane/EtOAc, 4:1 Ǟ 1:1). After the
solvent evaporation, a solution of 5% AcCl in MeOH (1.0 mL) was
added to a solution of the residue in CH2Cl2 (0.80 mL) with stirring
at room temp. for 6 h. The reaction mixture was diluted with
CH2Cl2 and washed with saturated NaHCO3 and brine prior to
drying and solvent evaporation. Purification by column chromatog-
raphy on silica gel (CHCl3/MeOH, 50:1) yielded longimicin D
[3] Recent reports of syntheses of annonaceous acetogenins: a) Y.-
T. He, S. Xue, T.-S. Hu, Z.-J. Yao, Tetrahedron Lett. 2005, 46,
5393–5397; b) J. M. Tinsley, E. Mertz, P. Y. Chong, R.-A. F.
Rarig, W. R. Roush, Org. Lett. 2005, 7, 4245–4248; c) N. Mae-
zaki, H. Tominaga, N. Kojima, M. Yanai, D. Urabe, R. Ueki,
T. Tanaka, T. Yamori, Chem. Eur. J. 2005, 11, 6237–6245; d)
S. Hanessian, S. Giroux, M. Buffat, Org. Lett. 2005, 7, 3989–
3992; e) J. M. Tinsley, W. R. Roush, J. Am. Chem. Soc. 2005,
127, 10818–10819; f) G. Keum, C. H. Hwang, S. B. Kang, Y.
Kim, E. Lee, J. Am. Chem. Soc. 2005, 127, 10396–10399; g) S.
Takahashi, N. Ogawa, H. Koshino, T. Nakata, Org. Lett. 2005,
7, 2783–2786; h) D. Strand, T. Rein, Org. Lett. 2005, 7, 2779–
2781; i) L. Zhu, D. R. Mootoo, Org. Biomol. Chem. 2005, 3,
2750–2754; j) K. J. Quinn, A. K. Isaacs, B. A. DeChristopher,
S. C. Szklarz, R. A. Arvary, Org. Lett. 2005, 7, 1243–1245; k)
G. L. Nattrass, E. Díez, M. M. McLachlan, D. J. Dixon, S. V.
Ley, Angew. Chem. Int. Ed. 2005, 44, 580–584; l) D. Strand, T.
Rein, Org. Lett. 2005, 7, 199–202.
(22.0 mg, 71% in three steps) as a colorless, waxy solid. [α]2D5
=
1
+23.2 (c = 0.48 in EtOH). H NMR: δ = 0.88 (t, J = 6.7 Hz, 3 H),
1.25–1.46 (m, 36 H), 1.41 (d, J = 6.7 Hz, 3 H), 1.49–1.56 (m, 2 H),
1.60–1.74 (m, 4 H), 1.97–2.00 (m, 4 H), 2.26 (t, J = 7.9 Hz, 2 H),
2.45 (br., 3 H), 3.37–3.41 (m, 1 H), 3.45 (br., 1 H), 3.62 (br., 1 H),
3.83–3.88 (m, 4 H), 5.00 (br.q, J = 6.7 Hz, 1 H), 6.99 ppm (br.s, 1
H). 13C NMR: δ = 14.1, 19.2, 22.7, 25.1, 25.66, 25.70, 27.4, 28.4,
28.9, 29.0, 29.1, 29.25, 29.34, 29.5, 29.55, 29.61, 29.63 (3 C), 29.66
(2 C), 29.71, 31.9, 33.4, 33.6, 37.5, 71.7, 74.0, 74.2, 77.4, 81.7, 81.9,
[4] Q. Ye, K. He, N. H. Oberlies, L. Zeng, G. Shi, D. Evert, J. L.
McLaughlin, J. Med. Chem. 1996, 39, 1790–1796.
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T. Tanaka, Chem. Eur. J. 2004, 10, 672–680; b) N. Kojima, N.
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82.9, 83.2, 134.3, 148.9, 173.9 ppm. IR (KBr): ν = 3375, 2927, 2854,
˜
1755, 1653, 1466, 1319, 1198, 1068, 953, 874 cm–1. MS (FAB): m/z
1428
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Eur. J. Org. Chem. 2006, 1422–1429

First Total Synthesis of Longimicin D
FULL PAPER
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[12] ee was determined by HPLC analysis (CHIRALCEL OB, hex-
ane/iPrOH, 9:1) .
Received: October 31, 2005
Published Online: January 17, 2006
Eur. J. Org. Chem. 2006, 1422–1429
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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