Synthetic studies on chartelline C: Stereoselective construction of the core skeleton

Article abstract of DOI:10.1002/anie.201204726

What a core-ker! The title synthesis was achieved using a route featuring an intramolecular Mitsunobu reaction of a nosyl amide, stereoselective construction of the β-lactam, and formation of an enamide moiety by selenoxide elimination. The stereochemistry of the alkylation for the formation of the β-lactam was controlled by a secondary hydroxy group on the ten-membered ring. SEM=2-(trimethylsilyl)ethoxymethyl; TBS=tert- butyldimethylsilyl. Copyright

Full text of DOI:10.1002/anie.201204726

Angewandte
Chemie
DOI: 10.1002/anie.201204726
Natural Products
Synthetic Studies on Chartelline C: Stereoselective Construction of the
Core Skeleton**
Kotaro Iwasaki, Rentaro Kanno, Toshiharu Morimoto, Tohru Yamashita, Satoshi Yokoshima,
and Tohru Fukuyama*
The chartellines (1–3; Scheme 1) were isolated from the
marine bryozoan Chartella papyracea in the 1980s by
Christophersen and co-workers.[1] The core structure of the
Scheme 2. Retrosynthesis. Ns=nitrobenzenesulfonyl.
Scheme 1. Structure of chartellines.
chartellines includes a b-lactam, an indolenine, and 2-
bromoimidazole. In addition, these natural products have
a unique rigid, folded conformation resulting from p–p
stacking between the indolenine and imidazole. To date,
Baran et al. have reported the only a racemic total synthesis
of chartelline C,[2] and several other groups have reported
synthetic approaches to the chartellines.[3–6] Herein, we
disclose a stereoselective construction of the core skeleton
of chartelline C.
intermediate 4. The conformation would be affected by the
secondary hydroxy group on the ten-membered ring. The ten-
membered ring in 4 would be synthesized by an intra-
molecular Mitsunobu reaction of nosyl amide 5,[7] which could
be derived from 6 by introduction of a nitrogen atom at the
3-position of the indole through a diazo coupling reaction,[8]
Our retrosynthetic analysis is shown in Scheme 2. We
envisioned that the enamide moiety in 3 would be constructed
by elimination of a hydroxy group at the position b to the
lactam nitrogen on the ten-membered ring. Formation of the
b-lactam would be performed by a stereoselective alkylation
at the 3-position of the indole, with the stereochemistry
controlled by the conformation of the ten-membered ring in
[*] Dr. K. Iwasaki, R. Kanno, Dr. T. Morimoto, Dr. T. Yamashita,
Dr. S. Yokoshima,[+] Prof. T. Fukuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[+] Current address: Graduate School of Pharmaceutical Sciences,
Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
Scheme 3. a) NIS, ClCH2CH2Cl, RT; Na2SO3, EtOH/H2O (3:1), reflux;
b) SEMCl, iPr2NEt, TBAI, THF/ClCH2CH2Cl (1:1), reflux, 94%
(2 steps); c) tri-n-butyl(vinyl)tin, [Pd(PPh3)4], o-xylene, reflux, 97%;
d) OsO4, NMO, acetone/H2O (1:1), RT, 93%; e) TBSOTf, iPr2NEt,
CH2Cl2, 08C, 95%; f) DIBAL, CH2Cl2, À788C; g) 13, K2CO3, MeOH, RT,
96% (2 steps). DIBAL=diisobutylaluminum hydride, NIS=N-iodosuc-
cinimide , NMO=N-methylmorpholine N-oxide, SEM=2-(trimethylsi-
lyl)ethoxymethyl, TBAI=tetra-n-butylammonium iodide, TBS=tert-
butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
[**] This work was financially supported by Grants-in-Aid for Scientific
Research (20002004, 22590002) from the Japan Society for the
Promotion of Science (JSPS), the Research Foundation for Phar-
maceutical Sciences, the Mochida Memorial Foundation for
Medical and Pharmaceutical Research, and the Uehara Memorial
Foundation. K.I. was a Research Fellow of JSPS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204726.
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and partial reduction of the alkyne moiety. The key 2-
alkynylindole 6 could in turn be synthesized by a Sonogashira
coupling reaction.
the nitrogen atom at the 3-position of the indole was carried
out by treatment of 17 with sodium hydride and benzenedia-
zonium tetrafluoroborate[14] to afford diazo coupling product
18. Reduction of the azo group of 18 with zinc, followed by
nosylation of the resultant, unstable 3-aminoindole furnished
19 in good yield. After selective deprotection of the primary
hydroxy group, the crucial intramolecular Mitsunobu reaction
was investigated. Gratifyingly, treatment of 20 with TMAD
and nBu3P[15] in toluene, heated to reflux, resulted in
formation of the requisite ten-membered ring to give 21 in
good yield without appreciable dimerization.
Our synthesis commenced with preparation of an imida-
zole unit bearing an alkyne moiety (14; Scheme 3). Diiodi-
nation of known imidazole 7[9] with NIS followed by
regioselective deiodination with sodium sulfite[10] led to
formation of 5-iodoimidazole 8 in good yield. After protec-
tion of the imidazole with an SEM group,[11] the resultant
iodide 9 was coupled with tributyl(vinyl)tin under standard
Stille cross-coupling conditions to afford vinyl imidazole 10.
A subsequent osmium-mediated dihydroxylation provided
a diol, which was protected with TBS groups to give bis(TBS
ether) 11. Reduction of 11 with DIBAL, followed by treat-
ment of the resulting aldehyde 12 with the Ohira–Bestmann
reagent (13),[12] furnished terminal alkyne 14 in 96% yield
over two steps.
Having established an efficient route to 21, we next
focused on construction of the spiro b-lactam (Scheme 5).
Removal of the nosyl group, followed by condensation of the
The Sonogashira coupling between imidazole 14 and the
known indole 15[13] proceeded regioselectively to afford 16 in
good yield (Scheme 4). After removal of the Boc group under
basic conditions, a zinc-mediated partial reduction of the
alkyne was performed to generate cis-olefin 17. Installation of
Scheme 5. a) HSCH2CO2H, DBU, MeCN, RT; b) BrCH2CO2H,
EDCI·HCl, CH2Cl2, RT, 95% (2 steps); c) Cs2CO3, MeCN/THF (2:1),
508C; d) TBAF, THF, RT, 74% (2 steps). DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide, TBAF=tetra-n-butylammonium fluoride.
resultant amine with bromoacetic acid, gave bromoacetamide
22 in excellent yield. The requisite intramolecular alkylation
proceeded smoothly upon treatment of 22 with cesium
carbonate in MeCN/THF (2:1) at 508C, thus affording
a spiro b-lactam as a single diastereomer. Removal of the
TBS group with TBAF gave alcohol 23.
The stereochemistry of 23 was determined by a combina-
tion of NMR techniques and computational chemistry.[16] The
observed NOEs are shown in Scheme 6a. The coupling
constant between H2a and H3 was 12.8 Hz, thus indicating
that these two protons are oriented anti to each other. An
exhaustive conformational search of 24a and 24b using the
Conflex program generated 17 and 18 possible confomers of
24a and 24b, respectively (Scheme 6b). Among these con-
formers, only the conformers of 24a having folded structures
similar to those of natural chartellines could fully explain the
observed NMR data. In addition, DFT calculations for a set of
conformers of 24a suggested that energetically favorable
conformers have folded structures, which comprised > 99%
of the Boltzmann distribution. Thus, we concluded that 23 has
the structure shown in Scheme 6a. We also analyzed the
conformation of the key intermediate 21 based on NMR data.
The observed NOEs and the coupling constant between H2a
and H3 (10.3 Hz) strongly suggested that 21 also has a folded
Scheme 4. a) [Pd2(dba)3]·CHCl3, Ph3P, CuI, nBuNH2, toluene, reflux,
93%; b) NaOMe, THF/MeOH (5:1), 08C, 97%; c) Zn, conc. HCl,
MeOH, reflux, 72%; d) PhN2BF4, NaH, THF/DMF (3:1), 08C, 94%;
e) Zn, NH4Cl, EtOH, RT, 96%; f) p-NsCl, pyridine, CH2Cl2, 08C, 81%;
g) CSA, MeOH, 508C, 98%; h) TMAD, nBu3P, toluene, reflux, 75%.
Boc=tert-butoxycarbonyl, CSA=10-camphorsulfonic acid, dba=diben-
zylideneacetone, DMF=N,N’-dimethylformamide , THF=tetrahydro-
furan, TMAD=N,N,N’,N’-tetramethylazodicarboxamide.
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Scheme 8.
Scheme 6. Determination of the structure of 23. a) Observed NOEs.
b) Structures used for conformational analysis with the Conflex pro-
gramme.
introduced to the imidazole ring (Scheme 9). After cleavage
of the SEM group by treating compound 25d with triflic acid
in dichloromethane, a benzoyl group was introduced under
structure, as shown in Scheme 7. Taken together, these
analyses imply that the intramolecular alkylation was likely
to occur from the less-hindered convex side of the ten-
membered ring.
Scheme 7. Selected NOEs of 21.
Having established an efficient synthesis of the b-lactam
moiety, we turned our attention to construction of the
enamide moiety by elimination of the secondary hydroxy
group (Scheme 8). Although treatment of 23 with either MsCl
or SOCl2 afforded chloride 25a, any attempts to perform
dehydrochlorination under basic conditions proved unsuc-
cessful. Treatment of 23 with Martin sulfurane, a reagent used
for dehydration either through the E1 or E2 mechanism,[17]
resulted in formation of substitution product 25b. This
outcome might be attributed to the poor overlap of the
Scheme 9. a) o-NO2C6H4SeCN, nBu3P, THF, RT, 62%; b) TfOH,
CH2Cl2, À78 to 08C; c) BzCl, Et3N, DMAP, CH2Cl2/THF (2:1), RT, 72%
(2 steps); d) mCPBA, CH2Cl2, RT, 80%; e) Na2CO3, THF/H2O (2:1),
RT, 63%. Bz=benzoyl, DMAP=4-(dimethylamino)pyridine,
mCPBA=m-chloroperbenzoic acid.
À
À
orbitals of the carbocation and C H bond, or the C O and
C H bonds. Therefore, dehydration through a syn elimination
standard conditions to afford 26.[19] As expected, oxidation of
26 with mCPBA afforded enamide 27 in good yield. Removal
of the benzoyl group under basic conditions then furnished
28.[20]
In conclusion, we have developed an efficient synthetic
route to the core skeleton of chartelline C (3); this route
features an intramolecular Mitsunobu reaction of a nosyl
amide, stereoselective construction of a b-lactam, and for-
mation of an enamide moiety by a selenoxide elimination.
The stereochemistry of the alkylation for the formation of the
b-lactam was effectively controlled by the secondary alcohol
À
was next attempted. Upon treatment with Burgess reagent, 23
only underwent a substitution reaction, instead of formation
of the desired double bond. Although a 2-nitrophenylselenyl
group could be introduced using the Grieco–Nishizawa
protocol,[18] subsequent oxidation with H2O2 induced substi-
tution with water to give 23. This result suggested that the
imidazole ring participated in generation of a carbocation
upon activation of the leaving group.
To suppress the participation of the imidazole group in the
carbocation formation, an electron-withdrawing group was
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36, 6373 – 6374; d) T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai,
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preparation of the imidazole unit in an enantioselective
manner would lead to an asymmetric synthesis of optically
active chartelline.
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Received: June 16, 2012
Published online: && &&, &&&&
Keywords: imidazole · Mitsunobu reaction · natural products ·
.
spiro b-lactams · total synthesis
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4
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Communications
Natural Products
K. Iwasaki, R. Kanno, T. Morimoto,
T. Yamashita, S. Yokoshima,
T. Fukuyama*
&&&& — &&&&
Synthetic Studies on Chartelline C:
Stereoselective Construction of the Core
Skeleton
What a core-ker! The title synthesis was
achieved using a route featuring an
intramolecular Mitsunobu reaction of
a nosyl amide, stereoselective construc-
tion of the b-lactam, and formation of an
enamide moiety by selenoxide elimina-
tion. The stereochemistry of the alkylation
for the formation of the b-lactam was
controlled by a secondary hydroxy group
on the ten-membered ring. SEM=2-(tri-
methylsilyl)ethoxymethyl; TBS=tert-
butyldimethylsilyl.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!