The Total Synthesis of (±)-Naupliolide: A Tetracyclic Sesquiterpene Lactone

Article abstract of DOI:10.1002/anie.201600055

The first total synthesis of (±)-naupliolide has been achieved. The synthetic method includes a Simmons-Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight-membered ring by ring-closing metathesis.

Full text of DOI:10.1002/anie.201600055

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International Edition: DOI: 10.1002/anie.201600055
German Edition: DOI: 10.1002/ange.201600055
Total Synthesis
The Total Synthesis of (Æ)-Naupliolide: A Tetracyclic Sesquiterpene
Lactone
Hideki Abe, Tomoyuki Morishita, Toshihiro Yoshie, KØrya Long, Toyoharu Kobayashi, and
Hisanaka Ito*
Abstract: The first total synthesis of (Æ)-naupliolide has been
achieved. The synthetic method includes a Simmons–Smith
cyclopropanation of an allyl alcohol, diastereoselective cleav-
age of a benzylidene acetal group, radical cyclization of an
aldehyde with a cyclopropane ring, and construction of an
eight-membered ring by ring-closing metathesis.
neoplastic cell lines, including the human cancer cells A-549,
HT-20, and MEL-28.[4]
Although many examples of the total synthesis of related
sesquiterpene lactones 6,7,9,10-tetradehydroasteriscanolide
(2),[5] asteriscunolides A–D (3a–3d),[6] asteriscanolide (4),[7]
and aquatolide (5)[8] have been reported, to our knowledge no
publication has reported the total synthesis of naupliolide (1).
There has been only one reported attempt to synthesize
naupliolide (1), specifically by Li et al. in 2014 through an
acid-mediated cyclization of asteriscunolide,[5] but this effort
was unsuccessful. The structural features of 1 provided the
motivation for this synthesis study of tetracyclic sesquiterpene
lactones. Herein, we report the first total synthesis of (Æ)-
naupliolide employing radical cyclization as the key step.
Our retrosynthetic analysis for the total synthesis of 1 is
shown in Figure 2. The final compound would be obtained
from diene derivative 6 by a ring-closing metathesis step. The
diene derivative 6 would be derived from tricyclic lactone 7.
The stereoselective construction of tricyclic lactone 7 would
be achieved by radical cyclization of aldehyde 8, which has an
unsaturated ester and a cyclopropane ring, using SmI2 as the
reagent. Aldehyde 8 would be prepared from the known
N
aupliolide (1), isolated from the aerial parts of Nauplius
graveolens subsp. oborus (Schousb) Wikl. in 2006 by Barrero
et al., is a sesquiterpene lactone possessing a three-membered
ring, a five-membered ring, an eight-membered ring, and a g-
lactone.[1] The structure of naupliolide (1), assigned based on
1D NOE and 2D NMR spectra (specifically HSQC, HMBC,
and H–1H COSY), is depicted in Figure 1. This compound
1
was isolated along with 6,7,9,10-tetradehydroasteriscanolide
(2)[2] and asteriscunolides A–D (3a–3d),[3] and a biosynthetic
pathway towards 1 and 2 was proposed that included an acid-
induced cyclization of asteriscunolide C (3c). Biological
activities of novel sesquiterpene lactones 1 and 2 have not
been reported yet, but those of asteriscunolides A–D (3a–3d)
have been investigated. In particular, asteriscunolide D (3d)
exhibits moderate cytotoxic activities (IC50 = 1–4 mm) against
alcohol 10 through
a Z-selected Horner–Wadsworth–
Emmons reaction and a Simmons–Smith cyclopropanation.
Figure 1. Structures of naupliolide (1) and related sesquiterpenes 2–5.
[*] Dr. H. Abe, T. Morishita, T. Yoshie, K. Long, Dr. T. Kobayashi,
Prof. H. Ito
School of Life Sciences
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
E-mail: itohisa@toyaku.ac.jp
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201600055.
Figure 2. Retrosynthetic analysis for the total synthesis of naupliolide
(1). Bn=benzyl; TBDPS=tert-butyldiphenylsilyl.
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Stereoselective construction of the tricyclic lactone was
the first aim of this synthetic project. The synthesis began
from the known cyclic acetal 10,[9] as shown in Scheme 1.
Oxidation of 10 with Dess–Martin periodinane,[10] followed by
Z-selective Horner–Wadsworth–Emmons olefination[11] of
the resulting aldehyde, gave the unsaturated ester 11 as an
inseparable mixture of cis and trans isomers at the phenyl
group on the benzylidene acetal. This mixture could be
separated after reduction of ethyl ester 11 with DIBALH,
affording cis isomer 12a and trans isomer 12b in 43% and
42% yields, respectively.[12] The Simmons–Smith cyclopropa-
nation[13] of cis-12a tethering the Z-olefin afforded cis-13a
and trans-13b in 18% and 54% yields, respectively. Under
these cyclopropanation reaction conditions, epimerization of
the phenyl group at the C2 position in the 1,3-dioxolane to the
thermodynamically more stable trans isomer occurred. Cyclo-
propanation of trans-12b gave the same result to afford cis-
13a and trans-13b in 18% and 79% yields, respectively.
Protection of the hydroxy group of 13a and 13b with
a TBDPS group gave 14a and 14b, respectively. Diastereo-
selective ring opening at the benzylidene acetal of 14a and
14b was achieved by reduction with DIBALH to afford 15 in
82 and 92% yield, respectively.[14] Two-step operations
including Swern oxidation of 15, followed by Z-selective
olefination of the resulting aldehyde, produced the unsatu-
rated ester 9 in 74% yield as a single isomer. Cleavage of the
TBDPS group in 9 using hydrogen fluoride, and oxidation of
the resulting alcohol 16 by Swern oxidation gave the radical-
cyclization precursor 8 in excellent yield. The construction of
the
perhydrocyclopropa[4,5]cyclopenta[1,2-b]furan-2-one
framework was achieved by radical cyclization of 8 using
[15]
SmI2 and t-BuOH as a proton source, affording tricyclic
lactone 7 as a single isomer in 61% yield. The relative
configuration of the resulting tricyclic compound 7 was
confirmed by extensive spectroscopic analysis including
NOESY experiments. Selected NOESY correlations of 7 are
presented in Scheme 1. Clear NOE interactions between the
a-hydrogen (H5a) at the C5 position and both H3a and
H5b protons were detected. In addition, a NOE interaction
between H5a and the methylene of the C4 side-chain was also
detected. These results indicate that the stereochemical
relationship between the bridgehead protons at the C5b po-
sition and the methyl group at C5a was anti, and that the
relationship between the proton at C4 and the proton at the
C4a position was syn.
The stereoselectivity of the radical cyclization of 8 was
explained by chelation control as depicted in Figure 3. After
the single-electron reduction of the aldehyde group of 8 with
SmI2, a seven-membered cyclic transition state was formed
with the oxygen atom at the aldehyde group and the oxygen
atom at the ester carbonyl group tethering the Sm atom.
Transition state (TS) A was more stable than TS B, in which
steric hindrance existed between the benzyloxymethyl group
and the ethyl ester unit of the Z-unsaturated ester group.
Having obtained the desired tricyclic compound 7, our
interest turned to the synthesis of target molecule 1. After the
Scheme 1. Synthesis of the tricyclic lactone 7. a) Dess–Martin period-
inane, NaHCO3, CH2Cl2, 08C, 1 h, 65%; b) (PhO)2P(O)CH(Me)CO2Et,
NaH, THF, À508C, 2 h, 91%; c) DIBALH, Et2O, À788C, 2 h, 43% for
cis-12a and 42% for trans-12b; d) Et2Zn, CH2I2, CH2Cl2, RT, 1 h, 18%
for cis-13a and 54% for trans-13b from cis-12a, 18% for cis-13a and
79% for trans-13b from trans-12b; e) TBDPSCl, imidazole, DMF, RT,
2 h, 94% for 14a from 13a, and 92% for 14b from 13b; f) DIBALH,
CH2Cl2, À788C then À208C, 24 h, 82% [+8% diastereoisomer] from
14a, and 92% [+5% diastereoisomer] from 14b; g) (COCl)2, DMSO,
Et3N, CH2Cl2, À788C then RT, 1 h; h) (PhO)2P(O)CH2CO2Et, NaH,
THF, À508C, 2 h, 74% over 2 steps; i) HF·pyridine, pyridine, RT, 18 h,
92%; j) (COCl)2, DMSO, Et3N, CH2Cl2, À788C then RT, 1 h, 85%;
k) SmI2, t-BuOH, THF, 08C, 1 h, 61%. DIBALH=diisobutylaluminum
hydride, DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide.
Figure 3. Stereoselectivity of the radical cyclization of 8.
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benzyl group of 7 was removed, butenylation at the a position
following features: a) Simmons–Smith cyclopropanation of
to the carbonyl group of the resulting alcohol 18 gave alcohol
19 (d.r. = 19:1) in 56% yield. The obtained configuration at
the C3 position in 19 was not desired, therefore many
different sets of conditions (LDA and a proton source, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), t-BuOK) for epime-
rization of the C3 position to the desired configuration were
examined. Finally, combining the formation of the enolate
with LDA and protonation with solid silica gel gave the best
result, forming desired 20 and the undesired 19 in a 5:1 ratio.
After the resulting mixture was separated by HPLC, Swern
oxidation of 20, followed by Grignard reaction of the resulting
aldehyde with isopropenylmagnesium bromide, gave two
separable diastereoisomers 6a[16] and 6b[17] (ratio of 2:1) at
the secondary hydroxy group in 58% total yield over two
steps. Ring-closing metathesis[18] of the mixture of 6a and 6b
using Grubbs second-generation reagent achieved construc-
tion of the 8-membered ring and the Z-olefin moiety,
affording the tetracyclic compounds 21a and 21b in 50%
yield in a 2:1 ratio. Finally, Swern oxidation of 21 resulted in
the formation of (Æ)-naupliolide (1) in 76% yield. Spectro-
scopic data (1H and 13C NMR spectra, IR, and mass spectra)
of synthetic naupliolide were identical with those of the
reported natural product.[1] Additionally, the stereochemistry
of (Æ)-1 was confirmed using X-ray crystallographic analysis
(stereochemistry of (Æ)-1 shown in Scheme 2).[19]
an allyl alcohol; b) diastereoselective cleavage of a benzyli-
dene acetal group; c) construction of the tricyclic core of 1 by
radical cyclization by using the reagent SmI2; and d) ring-
closing metathesis of diene compound 6 yielding tetracyclic
compound 21 having an 8-membered ring and Z-olefin
moieties. This synthetic strategy will be applicable to the
synthesis of (+)-naupliolide, the natural enantiomer, which is
now in progress in our laboratory.
Acknowledgements
This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Keywords: cyclopropanation · lactones · radicals ·
ring-closing metathesis · total synthesis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3795–3798
Angew. Chem. 2016, 128, 3859–3862
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Scheme 2. Total synthesis of naupliolide 1. a) H2, Pd(OH)2/C, MeOH,
RT, 1 h, 83%; b) LDA, 4-iodo-1-butene, THF, À788C then À108C, 6 h,
56%, d.r.=19:1; c) LDA, THF, À788C, 1 h, then silica gel, À788C,
0.5 h, 90%, d.r.=5:1 for 20:19; d) (COCl)2, DMSO, Et3N, CH2Cl2,
À788C then RT, 1 h; e) isopropenylmagnesium bromide, THF, À788C,
2 h, 40% for 6a and 18% for 6b, over 2 steps; f) Grubbs 2nd
generation catalyst, toluene, 608C, 16 h, 50% yield, 2:1 mixture of 21a
and 21b; g) (COCl)2, DMSO, Et3N, CH2Cl2, À788C then RT, 1 h, 76%.
LDA=lithium diisopropylamide.
[12] The configuration of 2-phenyl-5-substituted-1,3-dioxane deriva-
tives was presumed from the comparison of chemical shifts at the
C2 and C5 positions in the 1H NMR spectrum: see Ref. [9b].
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benzylidene acetal of 14 is described in the Supporting
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[19] CCDC 1439961 contains the supplemental crystallographic data
for compound 1.
[16] CCDC 1439959 contains the supplemental crystallographic data
for compound 6a. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
[17] CCDC 1439960 contains the supplemental crystallographic data
for compound 6b..
Received: January 4, 2016
Published online: February 10, 2016
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