An iterative acetylene-epoxide coupling strategy for the total synthesis of longimicin C

Article abstract of DOI:10.1016/j.tetlet.2005.05.145

Longimicin C, a naturally occurring annonaceous acetogenin possessing a C₂-symmetrical bis-THF moiety and a short hydrocarbon chain between its THF-containing region and a terminal γ-lactone, was synthesized for the first time. The total synthe

Full text of DOI:10.1016/j.tetlet.2005.05.145

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 5393–5397
An iterative acetylene–epoxide coupling strategy for the
total synthesis of longimicin C
Yan-Tao He, Song Xue, Tai-Shan Hu and Zhu-Jun Yao*
State Key Laboratory of Bioorganic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354Fenglin Road, Shanghai 200032, China
Received 21 April 2005; revised 27 May 2005; accepted 30 May 2005
Abstract—Longimicin C, a naturally occurring annonaceous acetogenin possessing a C2-symmetrical bis-THF moiety and a short
hydrocarbon chain between itsTHF-containing region and a terminal c-lactone, was synthesized for the first time. The total syn-
thesis was successfully achieved by an iterative acetylene–epoxide coupling strategy. D-Mannitol was used to establish the bis-THF-
containing segment, in which the additional stereochemistries were introduced by Sharpless dihydroxylations and intramolecular
Williamson etherifications. Regioselective epoxide-openings by the appropriate terminal acetylenes allowed coupling and elabora-
tion of all four fragments including the introduction of three essential hydroxyls into the proper sites of the target skeleton.
Ó 2005 Elsevier Ltd. All rights reserved.
Annonaceousacetogeninsare a family of natural poly-
ketidesof over 350 member,s which have been found
in 37 different species of annonaceous plants.1 A broad
spectrum of biological properties have been reported
for these agents including cytotoxic, antitumor, antima-
larial, pesticidal and antifeedant activities. Biogeneti-
cally, annonaceousacetogeninsare derivativesof long-
chain fatty acids, in which THF (tetrahydrofuran)
and/or THP (tetrahydropyran) ring(s) as well as buteno-
lide moieties act as key structural features. Diversity
within thisfamily ariessprincipally from variationsof
stereochemistry and location of the THF(s) and/or
THP aswell aswith variouspatternsof hydroxyl-
ation.1,2 Longimicin C (Fig. 1) wasioslated together
with other acetogeninsfrom the leavesand twigsof Asi-
mina longifolia K. These natural products present asim-
icin-like structures, where the THF rings are shifted
along their hydrocarbon chainsby four methylene units
relative to each other.3 Among these, the spacer for
longimicin C, that is, the distance from the hydroxyl-
flanked THF region to the c-lactone ring isquite short.
In comparing itsbioactivity with one of itstsructural
isomers parviflorin, longimicin C showed only moderate
cytotoxicity against several human tumor cell lines. The
only structural difference between these two acetogenins
liesin the above mentioned hydrocarbon spacer length.
3
Therefore, synthetic studies on longimicin C and parvi-
florin which could facilitate structural modifications
using the methods established during synthesis, would
be of great value for structure–activity relationship stud-
ies of these acetogenins. For example, it may be of inter-
est to examine the effects of hydrocarbon spacers.
Longimicin C possesses a buteneolide terminus contain-
ing a hydroxyl group at the C-4 position and a dihydr-
oxylated bis-THF unit within its chain. During the
past decade, significant effort by us4 and others5,6 has
been devoted to the total syntheses of annonaceous aceto-
genins, which has led to the establishment of many use-
ful and efficient synthetic methodologies. Herein, we
report the first synthesis of longimicin C through a
two-directional strategy in the synthesis of bis-THF core
aswell asiterative acetylene–epoxide openingsfor cou-
pling of all four fragments.
Our retrosynthetic analysis is outlined in Figure 1. In
consideration of synthetic efficiency, the structural skele-
ton wasdivided into four partswith the aid of FGA
(functional group addition) operations. As a result,
three triple bondsreplaced the corresponding C–C sin-
gle bonds. Further disconnections were made on the
above positions based on acetylene–epoxide opening
reactions, resulting in segments 2,7 3,8 4 and 5. One
Keywords: Annonaceous acetogenin; Longimicin C; Total synthesis;
Coupling strategy.
*
Corresponding author. Tel.: +86 21 54925133; fax: +86 21
64166128; e-mail: yaoz@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.145

5394
Y.-T. He et al. / Tetrahedron Letters 46 (2005) 5393–5397
OH
O
O
O
O
n
m
OH
OH
O
O
parviflorin: m=1, n=5
longimicin C: m=5, n=1 (1)
FGAs
acetylene-epoxide
acetylene-epoxide
OH
O
O
5
OH
OH
O
O
TMS
+
+
+
O
O
5
O
O
O
4
5
3
2
Jacobsen's
catalyst
O
O
OMOM
O
O
OMOM
OTs
6
OTs
10
O
Sharpless AEs or ADs
coupling
coupling
aldol
O
OH
TBSO
Br
OTBS
OH
7
11
O
O
+
O
HO
+
TBSO
OTBS
OTHP
O
8
9
12
13
D-mannitol
Figure 1. Structures of longimicin C and its isomer parviflorin, and retrosynthetic analysis of longimicin C.
key intermediate, the THF core 2, has C2 symmetry. It
could be stereoselectively and bi-directionally con-
structed by Sharpless ADs9 and intramolecular William-
son etherifications10 starting from structure 7 or its
equivalent. Symmetric allylic alcohol 7 wasfurther dis-
connected into chiral alkyn-diol 8 and two unitsof 3-
bromo-prop-2-en-1-ol 9, both of which could be coupled
by Sonogashiria reactions. The other key segment, c-lac-
tone 3, could be prepared easily from compounds 12 and
13 according to our previously established procedure,
where an aldol condensation and Jacobsen dynamic
hydrolysis resolution served as key operations.8
tol, a commercially available and inexpensive chemical
as starting material. A two-directional synthesis was
adapted to substantially reduce the number of chemical
operations. Development of such two-directional ap-
proacheswould also be advantageousto apply to certain
acetogenins in this family possessing similar C2 symme-
try in their bis-THFs central cores. Therefore symmetri-
cal ene–yne 7 wasenviasged asa pivotal intermediate.
As the key substrate in this synthesis, compound 7 has
two advantages: (1) its precursor compound 8 can be
readily prepared from natural productsin enantiomeri-
cally pure form (see Scheme 1) and (2) itsconstruction
from 8 can be easily achieved by Sonogashira reactions13
with 9 in a single step.
The bis-THF-containing region of longimicin C is a
major synthetic objective, in which multiple oxygenated
stereogenic centers must be elaborated. Similar THF
moietiesare found not only in the annonaceousaceto-
genins but also in many other natural products.11 There-
fore, a wide array of methodshave been established for
the synthesis of various THFs. However, they are con-
tinuously supplemented by additional novel and efficient
methods to prepare substituted and functionalized
THFs, in particular those THFs that are not readily
available through classical approaches. These methods
include acid-induced ring closure of an epoxy alcohol,
intramolecular hetero-Michael addition, metal-cata-
lyzed oxidative cyclization of a hydroxyalkene, reduc-
tion of bicyclic ketals, oxabicyclic systems or spiro
compounds, the intramolecular Williamson reaction,
and [3+2] annulation of allysilanes and aldehydes,
etc.12 Considering the C2 symmetry involved, our syn-
thesis of bis-THF-containing segment 2 used D-manni-
Because the absolute configurations of both hydroxyls
of hexa-1,5-diyne-3,4-diol 18 are consistent with those
of D-mannitol (C3 and C4), the synthesis started from
D-mannitol (Scheme 1). Treatment of D-mannitol 1,6-
dibenzoate 1414 with a catalytic quantity of p-toluene-
sulfonic acid in 2,2-dimethoxypropane resulted in the
formation of two cyclic acetals, 15a and 15b, which
could be easily separable by column chromatography.
Their structures were affirmed by their 1H and 13C
NMR spectra, which fully agreed with the literature.15
Of note, were the 13C chemical shifts of the quaternary
carbon at d 109.8 ppm for 15a and at d 101.1 ppm for
15b, respectively. The configuration of isomer 15a was
further confirmed by X-ray crystallographic analysis of
derivative 17a. Benzoatesof compound 15 (both of
15a and 15b) were removed with K2CO3 in MeOH to
afford diols 16a and 16b. Chlorination of 16a and 16b

Y.-T. He et al. / Tetrahedron Letters 46 (2005) 5393–5397
5395
O
O
OBz
OH
OBz
OH
BzO
O
O
OH
OH
DMOP
HO
HO
BzCl, pyr.
47%
HO
HO
pTsOH·H2O
15a (36%)
OH
O
O
64%
O
O
HO
D-mannitol
BzO
OBz
15b (28%)
14
BzO
O
O
O
O
Cl
OH
Cl
HO
O
O
O
PPh3, CCl4
O
O
O
K2CO3
LDA, THF
K2CO3, iPr2NEt
CH3OH-THF
17a
OH
16a
HO
76%
86-93%
65%
O
O
O
O
O
O
18
HO
OH
Cl
Cl
16b
17b
Scheme 1. Synthesis of hexa-1,5-diyne-3,4-diol 18.
wasthen studied for an optimum chemical yield under a
variety of conditions. Initial attempts using PPh3 and
CCl4 with and without NaHCO3 or K2CO3 asadditive
all led to lower yieldsof 17a and 17b. In contrast to
these results, use of PPh3 and CCl4 in the presence of
both K2CO3 and N,N-diisopropylethylamine greatly im-
proved the transformation and provided 17a and 17b in
a satisfactory yield. Diol 18 wasobtained by elimination
genation of the triple bondsof 20 followed by tosylation
provided 22 in good yield.19 It isnoteworthy here, that
hydrogenation of 20 catalyzed with 5% or 10% palla-
dium on activated carbon did not give any desired prod-
uct 21, but resulted in severe side reactions. PtO2
ultimately proved to be a good and effective catalyst
for thisreaction. Removal of TBS groupswith TBAF
and subsequent intramolecular Williamson reactions
using NaH in THF resulted in THF ring formation to
afford 6, whose 1H and 13C spectra unambiguously
showed its C2 symmetrical characteristics. The key
di-epoxide 2 wasobtained after hydrolyisof the
MOM etherswith aqueousHCl in MeOH–THF and
cyclization with K2CO3 in MeOH. Both 1H NMR spec-
trum and optical rotation of 2 are identical with those
reported.7
16
reactionsof chlorides 17 using YadavÕscondition.s
The enantiomeric purity of compound 18 wasdeter-
mined17 prior to subsequent steps, though it has been
stated that no epimerization takes place under YadavÕs
conditions.
The hydroxylsof diol 18 were protected asTBS ethers 8
before the coupling reaction. With both intermediatesin
hand, Sonogashira coupling of 8 and 9 (prepared from
18
propargyl alcohol in two steps by PoltÕsprotocol
wascarried out in the presence of catalytic amountsof
)
The remaining key epoxide 3 wassynthesized according
to our previously reported procedures.8 Excellent opti-
cal purity of epoxide 3 (dr >99:1, asdetermined by
HPLC using a chiral column) was achieved by kinetic
resolution of racemic epoxide 10 with JacobsenÕscata-
lyst, (S,S)-salen-Co(OAc).20 Thismethod proved to be
a useful approach for synthesizing the lactone unit of
acetogeninshaving a C-4 hydroxyl group.
Pd(PPh3)2Cl2 and CuI in Et2NH to afford the symmetric
E-allylic alcohol 7 in good yield (Scheme 2). Asa pivotal
intermediate, bis-allylic alcohol 7 isvery flexible. A vari-
ety of methodscould be chosen for itsfurther transfor-
mation, including dihydroxylation or epoxidation
protocols. Finally, we decided to use WilliamsonÕsethe-
rificationsto elaborate the bi-sTHF ringsand accord-
ingly Sharpless asymmetric dihydroxylation was
adopted to introduce the additional oxygenated centers
into olefin 7. MOM protected derivative 19 wasusb-
jected to Sharpless conditions using (DHQ)2PHAL as
ligand to give tetraol 20 with a stereoselectivity of 20:1
per double bond (asdetermined by HPLC using a chiral
column).
With all epoxidesin hand, the original iterative coupling
strategy was applied for segment assembly. The acetyl-
ene–epoxide coupling methodology isa powerful tool
that isadvantageousin termsof economics(identical re-
agents used) and ease of operation and duplication.
Based on our previous analysis of longimicin C, regio-
selective epoxide openings21 were devised not only to
couple the four segments, but also to generate three
new hydroxylsin the target molecule. The first operation
wasexecuted upon di-epoxide 2 using one-half equiva-
lent of the alkyne 4 in the presence of n-BuLi and boron
trifluoride etherate (Scheme 3). The triple bond of the
In order to obtain 22, direct tosylation of 20 followed by
reduction of the triple bond wasattempted. However,
thisapproach failed. Finally, reversing the order of the
reactions was found to be successful (Scheme 2). Hydro-

5396
Y.-T. He et al. / Tetrahedron Letters 46 (2005) 5393–5397
OR
TBSCl
imidizole
DMF, r.t.
9, diethylamine
OTBS
OTBS
cat. Pd(PPh)2Cl2, CuI
18
79%
81%
OTBS
OTBS
R=H
MOMCl, iPr2NEt
CH2Cl2, 81%
8
7
19 R=MOM
OR
K3Fe(CN)6, K2CO3
cat. K2OsO4·2H2O
(DHQ)2-PHAL
OR OH
OTBS
cat. PtO2, H2
MeOH
CH3SO2NH2
OH
OH
tBuOH-H2O
0 °C, 87%
OTBS
20 R=MOM
OR1
84%
OH OR
OR2 OR1
OR1
OTBS
(i) TBAF, THF
OR
OR
(ii) NaH, THF
OR1 OR2
OTBS
21 R1=H, R2=MOM
O
O
53%
OTs
OTs
TsCl, DMAP
6 R=MOM
22 R1=Ts, , R2=MOM
pyridine, 57%
(i) HCl, THF-MeOH
(ii) K2CO3, THF-MeOH
2
68%
Scheme 2. Synthesis of bis-THF-containing segment 2.
(i) n-BuLi, BF3·Et2O
THF, -78 °C, 47%.
+
4
2
( )8
O
O
(ii) H2, cat. 10% Pd/C
Et3N, EtOAc, rt, 84%
OH
O
23
(i) TMSC ≡CH, n-BuLi, BF3·Et2O
23, THF, -78 °C
n-BuLi, BF3·Et2O
3, THF, -78 °C
( )11
(ii) MOMCl, iPr2NEt
O
O
83%
OMOM
OMOM
CH2Cl2, rt
(iii) TBAF, THF, 63%
24
(i) TsNHNH2, NaOAc
DME, reflux
( )11
OH
O
O
1
O
OMOM
(ii) HCl, THF-MeOH
51%
OMOM
25
O
Scheme 3. Completion of total synthesis of longimicin C (1).
resulting product was immediately hydrogenated to pro-
vide mono-epoxide 23 (39% yield in two steps). Epoxide-
opening of 23 with excess of trimethylsilyl acetylene 5
served as the second coupling operation to afford a diol
intermediate. Protection of both free hydroxylsin this
diol with MOMCl followed by removal of TMS fur-
nished the desired terminal acetylene 24 in excellent
yield (63% in three steps). The fully elaborated skeleton
25 wasobtained by the same coupling protocol, in which
alkyne 24 and epoxide 3 were joined under the same
conditions. Finally, selective reduction of the triple bond
with diimide and hydrolysis of the MOM ethers com-
pleted the total synthesis of longimicin C. All spectro-
scopic data of synthetic longimicin C were in full
agreement with those reported for the natural
sample.3,22
material with Sharpless dihydroxylations and intra-
molecular Williamson etherifications serving as key
steps to establish additional stereochemistries. An itera-
tive acetylene–epoxide coupling protocol was success-
fully applied in the couplings of all key segments,
leading to the final construction of longimicin C. Expan-
sion of the developed synthetic strategies will be
explored in thislaboratory for the ysntheissof other
structurally related annonaceous acetogenins, as well
asfor the deisgn of new acetogenin mimeticsof bio-
logical interest.
Acknowledgements
Thiswork wasfinancially uspported by the Major
State Basic Research and Development Program
(G2000077500), NSFC (30271531, 20425205 and
20321202), the Chinese Academy of Sciences (KGCX2-
SW-209) and the Shanghai Municipal Commission of
In summary, the first total synthesis of longimicin C has
been achieved convergently. The bis-THF-containing
segment was elaborated using D-mannitol astsarting

Y.-T. He et al. / Tetrahedron Letters 46 (2005) 5393–5397
5397
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OBn
OH
BnBr, NaH, THF
92%
[α]D -135.6
[α]D +134.8
OBn
OBn
OH
18
HO
OH
HOOC
COOH
OBn
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22. Data for synthetic 1: [a]D 11.3 (c 0.13, EtOH); lit. 3 [a]D 14
1
(c 0.10, EtOH). H NMR (300 MHz, CDCl3): d 7.19 (q,
J = 1.8 Hz, 1H), 5.06 (qq, J = 6.9, 1.5 Hz, 1H), 3.86–3.88
(m, 1H), 3.81–3.86 (m, 4H), 3.37–3.41 (m, 2H), 2.52–2.54
(m, 1H), 2.40 (dd, J = 15.1, 8.1 Hz, 1H), 1.97–2.00 (m,
4H), 1.53–1.70 (m, 4H), 1.20–1.50 (m, 34H), 1.43 (d,
J = 6.5 Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d 174.56, 151.77, 131.16, 83.16, 83.00,
81.78, 81.73, 77.93, 74.09, 73.82, 69.76, 37.20, 33.42, 33.37,
31.89, 29.70, 29.65, 29.62, 29.60, 29.58, 29.32, 28.92, 28.36,
28.33, 25.62, 22.65, 19.07, 14.01 ppm. HRMS (ESI, m/z)
calcd for (C35H62O7+Na)+: 617.4388. Found: 617.4375.
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