A concise total synthesis of (+)-neopeltolide

Article abstract of DOI:10.1002/anie.201000624

(Figure Presented) Short and sweet: The highly potent antiproliferative marine macrolide (+)-neopeltolide has been synthesized based on the strategic application of olefin metathesis reactions. The total synthesis proceeded in only 13 steps from commercially available starting materials, and represents the shortest synthesis of (+)-neopeltolide reported to date.

Full text of DOI:10.1002/anie.201000624

Angewandte
Chemie
DOI: 10.1002/anie.201000624
Natural Product Synthesis
A Concise Total Synthesis of (+)-Neopeltolide**
Haruhiko Fuwa,* Asami Saito, and Makoto Sasaki
(+)-Neopeltolide (1) is a marine macrolide that belongs to the
family Neopeltidae, and was isolated from a deep-water
sponge collected off the northwest coast of Jamaica by Wright
et al.[1] Neopeltolide exhibits highly potent in vitro antiproli-
ferative activity against several cancer cell lines with nano-
molar IC50 values (IC50 = 1.2, 5.1, and 0.56 nmolLÀ1 against
the A-549 human lung adenocarcinoma, the NCI-ADR-RES
human ovarian sarcoma, and the P388 murine leukemia cells,
respectively) as well as potent antifungal activity against
pathogenic yeast Candida albicans. Kozmin and co-workers
reported that neopeltolide targets cytochrome bc1 complex
and may inhibit mitochondrial ATP synthesis.[2] The complex
molecular architecture coupled with the intriguing biological
activity of 1 have spurred the interest of the synthetic
community. A number of total syntheses of 1,[3,4] including
the studies from our research group,[5] have been reported.
metathesis reactions. The synthesis proceeds in only 13 linear
steps from commercially available (E)-cinnamaldehyde, and
represents the shortest synthesis of 1 reported to date.
Our retrosynthesis towards 1 is summarized in Scheme 1.
On designing the overall strategy, manipulations of oxygen
functionalities such as oxidation, reduction, protection, and
Our previous total synthesis of (+)-neopeltolide and its
analogues relied on our Suzuki–Miyaura coupling/ring-clos-
ing metathesis (RCM) strategy.[5] Unfortunately, our synthesis
of 1 necessitated 24 steps (longest linear sequence) owing to
the protective group manipulations and oxidation/reduction
steps involved. It was necessary to devise a more concise and
efficient synthetic entry to 1 and its analogues to facilitate
detailed investigations on its structure–activity relationship
and biological activity. Herein, we describe a concise total
synthesis of 1 based on the strategic application of olefin
Scheme 1. Retrosynthesis of (+)-neopeltolide (1). BOM=benzyloxy-
methyl, TBS=tert-butyldimethylsilyl.
deprotection steps have to be minimized to maximize the
overall efficiency of the plan. Olefin metathesis reactions are
particularly attractive in this context owing to the superb
chemoselectivity, bond-forming ability, and unnecessary
manipulation of oxygen functionalities. Although there was
no precedent that utilized RCM[6] for the construction of the
neopeltolide macrocycle, we envisioned that the 14-mem-
bered lactone 2 could be accessed by a RCM/hydrogenation
[*] Prof. Dr. H. Fuwa, A. Saito, Prof. Dr. M. Sasaki
Laboratory of Biostructural Chemistry
Graduate School of Life Sciences, Tohoku University
2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan)
Fax: (+81)22-717-8896
À
sequence of diene 3 to forge the C8 C9 bond and define the
stereogenic center at C9.[4c] This particular RCM would be
challenging because of the pronounced lower reactivity of 1,1-
disubstituted alkenes and styryl groups toward olefin meta-
thesis reactions.[6] Furthermore, 2-vinyl-substituted tetrahy-
dropyrans are known to be difficult substrates in RCM.[7] We
were also concerned about the stereochemical outcome of the
RCM, which would play a key role in determining the
E-mail: hfuwa@bios.tohoku.ac.jp
[**] This work was supported by the Tohoku University Global COE
program “International Center of Research and Education for
Molecular Complex Chemistry” from MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000624.
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Table 1: Chemoselective olefin cross-metathesis.
conformation of the RCM product and the facial selectivity of
subsequent hydrogenation. Diene 3 would be derived from an
esterification of acid 4 and alcohol 5. The acetic acid
appendage at the C3-position of 4 suggested an intramolec-
ular oxa-conjugate addition of 6 would be suitable for the
stereoselective construction of the 2,4,6-trisubstituted tetra-
hydropyran substructure. Enoate 6 would be formed from
olefin 7 by means of a chemoselective olefin cross-metathesis
(CM) reaction to allow introduction of the enoate function-
Entry Substrate Reagents and conditions
Yield [%]
ality, where the phenyl group at C9 and the OTBS group at C7
[8]
1
2
3
4
11
11
7
methyl acrylate (20 equiv), CH2Cl2 12a, 25 12b, 71
methyl acrylate/toluene (1:1)
methyl acrylate/CH2Cl2 (1:1)
À
would block initiation of CM at the C8 C9 double bond.
12a, 51 12b, 46
13a, 77 13b, 7
Nonetheless, the CM should still be challenging owing to an
À
intrinsically competitive RCM initiated at the C2 C3 double
7
methyl acrylate (30 equiv), CH2Cl2 13a, 82 13b, 7
bond to form a six-membered carbocycle. Finally, substrate 7
would be synthesized from the known homoallylic alcohol 8,[9]
which is available from (E)-cinnamaldehyde by an asymmet-
ric allylation.
The synthesis commenced with protection of 8 as its TBS
ether and gave olefin 9 (Scheme 2). Chemoselective dihy-
droxylation of 9 and concomitant oxidative cleavage[10]
afforded aldehyde 10. Asymmetric allylation[11] of 10 by
using the protocol developed by Brown and Jadav proceeded
with good diastereoselectivity, and led to an inseparable
mixture of homoallylic alcohol 7 and its diastereomer (d.r. =
10:1) in 96% yield. Protection of 7 as its BOM ether furnished
olefin 11.
12a was isolated in 51% yield along with RCM product 12b
in 46% yield under these conditions (entry 2). However, upon
scale-up (> 0.1 mmol), the reaction often stalled before
reaching completion (ca. 70%–80% conversion), and the
product selectivity proved to be capricious. Other conditions
examined resulted in lower yields, which could be a conse-
quence of the competitive RCM and/or insufficient conver-
sion of the starting material.
At this stage, we thought that the hydroxy group at C5 of 7
could be exploited as a “directing group” to render the
conformation of the molecule unfavorable for the competitive
RCM (Scheme 3). A recent report by Hoveyda et al.[14a] and
previous literature precedents[14b–h] suggested that the reac-
tion of a homoallylic alcohol with a Grubbs catalyst would
generate the corresponding ruthenium alkylidene species,
wherein hydrogen bonding between the hydroxy group and
the chlorine atom of the catalyst is formed (such as A). We
Scheme 2. Synthesis of olefins 7 and 11. a) TBSCl, imidazole, DMF,
RT, 98%; b) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O, 08C, 42%
(59% brsm); c) (+)-Ipc2BOMe, allylMgBr, Et2O, À788C; then aq
NaOH, 30 wt.% in H2O, RT, 96% (d.r.=10:1); d) BOMCl, iPr2NEt,
CH2Cl2, RT, 88%. brsm=based on recovered starting material,
DMF=N,N-dimethylformamide, Ipc=isopinocampheyl, PG=protect-
ing group.
Olefin CM of 11 with methyl acrylate (20 equiv) using
5 mol% of the Grubbs second-generation catalyst (G-II)[12] in
CH2Cl2 at room temperature gave the desired (E)-enoate 12a,
albeit in 25% yield together with RCM product 12b in 71%
yield (Table 1, entry 1). To overcome the intrinsically com-
petitive RCM, the CM of 11 was investigated under various
reaction conditions using G-II or the Hoveyda–Grubbs
second-generation catalyst (HG-II)[13] in CH2Cl2, toluene or
THF at room temperature. The best result was obtained when
11 was treated with 5 mol% of G-II in methyl acrylate/
toluene (1:1) at room temperature. The desired (E)-enoate
Scheme 3. Olefin metathesis reactions of 7. Cy=cyclohexyl,
Mes=mesityl.
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envisaged that the CM of 7 would be more facile than the
competitive RCM, because the latter process has to proceed
through energetically demanding pathway(s). Thus, forma-
tion of a ruthenacyclobutane B by breaking the hydrogen
bonding in A or a conformationally strained ruthenacyclo-
butane C would be necessary for the RCM of 7 to give 13b. In
the event, we were delighted to find that treatment of 7 with
G-II (5 mol%) in methyl acrylate/CH2Cl2 (1:1) at room
temperature afforded (E)-enoate 13a in a gratifying 77%
yield, and the cyclohexene-derivative RCM product 13b was
isolated in only 7% yield (entry 3). Moreover, we could lower
the amount of methyl acrylate used in the reaction without
affecting the product selectivity (entry 4). Therefore, the
intramolecular hydrogen bonding formed within ruthenium
alkylidene A plays a key role in determining the reaction
pathway. Consequently, we were able to reproducibly prepare
13a in good yield.
Completion of the total synthesis of 1 is illustrated in
Scheme 4. Protection of 13a as its BOM ether and subsequent
desilylation provided alcohol 6. The intramolecular oxa-
conjugate addition of 6 was best accomplished by treatment
with DBU in toluene at 1008C which afforded the thermo-
dynamically favored 14 in 73% yield (14/3-epi-14 = > 20:1).
At this stage, the minor C5 diastereoisomer could be
separated by flash chromatography on silica gel.[15] Hydrolysis
of 14 using TMSOK[16] provided acid 4 quantitatively.
Esterification of 4 with alcohol 5[17] under Yamaguchi
conditions[18] delivered ester 3 in 94% yield.
As expected, the construction of the 14-membered macro-
cycle 2 by the RCM of 3 was a significant challenge. After
extensive investigations, we eventually found that treatment
of 3 with G-II (30 mol%) in the presence of 1,4-benzoquino-
ne[7c,19] in toluene at 1008C afforded the 14-membered
macrocycle 15 in 85% yield. As a result of the high reaction
temperature, slow addition of the G-II complex was impor-
tant to achieve a satisfactory conversion.[20] Gratifyingly, 15
was isolated solely as the desired Z isomer, whose hydro-
genation was anticipated to occur from the less hindered
Re face of the molecule to give neopeltolide macrolactone 2
with the desired configuration at C9. This outcome was
suggested by molecular modeling and by a recent related
report by Tu and Floreancig.[4c,21] In the event, the stereose-
Scheme 4. Completion of the total synthesis of 1. a) BOMCl, iPr2NEt,
nBu4NI, 1,2-dichloroethane, 508C; b) TBAF, AcOH, THF, 358C, 90%
(over 2 steps); c) DBU, toluene, 1008C, 73% (d.r. >20:1); d) TMSOK,
Et2O, RT, 100%; e) 2,4,6-Cl3C6H2COCl, Et3N, THF, RT; then 5, DMAP,
toluene, RT, 94%; f) G-II (30 mol%), 1,4-benzoquinone, toluene,
1008C, 85%; g) H2 (0.8 MPa), Pd/C, Pd(OH)2/C, EtOH, RT, 93%.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP=4-dimethylamino-
pyridine, TBAF=tetrabutylammonium fluoride, THF=tetrahydrofuran,
TMS=trimethylsilyl.
pyran-containing macrolide natural products and their ana-
logues.
À
lective hydrogenation of the C8 C9 double bond with
concomitant hydrogenolysis of the BOM group afforded 2
in 93% yield as a single diastereomer, which has previously
been transformed into 1 by us[5] and other research groups.[3b–f]
In conclusion, we have completed a concise total synthesis
of (+)-neopeltolide (1), which proceeded in only 13 steps
(longest linear sequence) from commercially available
(E)-cinnamaldehyde. The present synthesis represents the
shortest asymmetric synthesis of 1 reported to date. High-
lights of the present synthesis are: 1) a highly chemoselective
CM of 7 by exploiting hydrogen bonding, 2) a stereoselective
intramolecular oxa-conjugate addition of 6 under thermody-
namic conditions to forge the 2,4,6-trisubstituted tetrahydro-
pyran subunit, and 3) a macrocyclization of 3 through a
stereoselective RCM/hydrogenation sequence. Significantly,
our newly developed olefin metathesis-based strategy should
be generally applicable to the rapid assembly of tetrahydro-
Received: February 2, 2010
Published online: March 22, 2010
Keywords: chemoselectivity · cyclization · macrolides ·
.
metathesis · natural products
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a more reactive and air-stable complex, was ineffective for the
present RCM, presumably as a result of the steric bulk.
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