Total Synthesis of Limonin

Article abstract of DOI:10.1002/anie.201503794

Limonoids are highly oxygenated C13α-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet-oxygen cycloaddition and a Baeyer-Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Surez reaction to construct the unique AA′ ring system.

Full text of DOI:10.1002/anie.201503794

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Angewandte
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International Edition: DOI: 10.1002/anie.201503794
German Edition: DOI: 10.1002/ange.201503794
Total Synthesis
Hot Paper
Total Synthesis of Limonin**
Shuji Yamashita,* Akito Naruko, Yuki Nakazawa, Le Zhao, Yujiro Hayashi, and
Masahiro Hirama
Abstract: Limonoids are highly oxygenated C13a-triterpenes
and common secondary metabolites. Several hundred con-
geners have been isolated to date. The first total synthesis of
(Æ)-limonin, the flagship congener of the limonoids, is now
reported and features 1) a tandem radical cyclization generat-
ing the BCD ring system with the C13a configuration that is
essential to the limonoids and a Robinson annulation to
construct the limonoid androstane framework, 2) a singlet-
oxygen cycloaddition and a Baeyer–Villiger oxidation to
synthesize the highly oxidized D ring, and 3) a Suµrez reaction
to construct the unique AA’ ring system.
L
imonin (1), the flagship congener of the limonoids (tetra-
nortriterpenoids), was first isolated in 1841 during studies on
the bitter components of the citrus fruit.[1] However, the
structure of 1 remained unknown until 1960, when a historic
collaboration between the Arigoni, Barton, Corey, Jeger, and
Robertson groups led to the determination of the exact
structure of 1 by chemical derivatization and X-ray diffraction
methods (Scheme 1).[2] Since then, several hundred limonoids
have been isolated.[3] The intact limonoid framework is
characterized by a 4,4,8-trimethyl-17-furyl-13a-androstane,
but this family encompasses a diverse array of structural
architectures as a result of oxidations and skeletal rearrange-
ments. Not surprisingly, the unique architectures and the wide
spectrum of biological properties of limonoids have attracted
keen interest from the synthesis community,[4] and for
example, azadiradione,[5] cipadonoid,[6a] mexicanolides,[6b]
and azadirachtin have been synthesized.[7] Herein, we de-
scribe the first total synthesis of (Æ)-limonin (1).
Scheme 1. Structure and brief retrosynthetic analysis of limonin (1).
Our retrosynthetic analysis of 1 is shown in Scheme 1. We
envisaged that installation of a furan moiety onto the
limonoid skeleton 2 followed by modification of the A and
D rings would give 1. Tetracyclic compound 2 could be
constructed by a Robinson annulation from the BCD ring
system 3, which would be synthesized by a tandem radical
cyclization from the derivative of geraniol (4) that is based on
processes developed by the Snider group. Control of the
stereochemistry at the C13a position is crucial in this
synthetic scheme.
Our synthesis commenced with the preparation of tricy-
clic compound 3 (Scheme 2). Chlorination of 4 followed by
regioselective epoxidation afforded epoxygeranyl chloride,
which was successively treated with lithiated 1-(trimethylsi-
lyl)propyne[8] and aluminum isopropoxide,[9] giving rise to
allylic alcohol 5 in 75% overall yield. Subsequent treatment
of 5 with thionyl chloride, the dianion of ethyl 2-chloroace-
toacetate,[10] and then TBAF afforded the requisite alkynyl
b-ketoester 7. Manganese-mediated tandem radical cycliza-
tion of 7 according to a method developed by the Snider
group[11,12] furnished the tricyclic BCD ring system 3 with
C13a configuration as the major product along with the C13b
epimer 3’ (d.r. = 2.2:1). The structure of 3 was confirmed by
X-ray crystallographic analysis (see the Supporting Informa-
tion). A similar radical cyclization of the corresponding
terminal vinyl analogue 10 afforded 3’ almost exclusively.
After reductive removal of chloride from 3, treatment of the
resultant b-ketoester with methyl vinyl ketone (MVK) in the
presence of a catalytic amount of potassium tert-butoxide
furnished the tetracyclic system with excellent diastereose-
lectivity at the C10 position. Lastly, installation of a dimethyl
group at the C4 position of 8 was realized by treating the
compound with iodomethane and tBuOK to furnish 9 in 80%
yield.[13]
[*] Dr. S. Yamashita, Dr. A. Naruko, Y. Nakazawa, Dr. L. Zhao,
Prof. Dr. Y. Hayashi, Prof. Dr. M. Hirama
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki-aza aoba, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: syamashita@fas.harvard.edu
Prof. Dr. M. Hirama
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki-aza aoba, Aoba-ku, Sendai 980-8578 (Japan)
[**] This work was financially supported by the JSPS (KAKENHI Grant
24590003), a Grant-in-Aid for Specially Promoted Research from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), a SUNBOR GRANT from the Suntory Institute for
Bioorganic Research, and a grant from the NOVARTIS Foundation
(Japan) for the Promotion of Science (12-106). We are grateful to Dr.
E. Kwon and Dr. S. Ishida of the Graduate School of Science, Tohoku
University, for their assistance with X-ray crystallographic analysis
and for helpful discussions. We are also grateful to Prof. M. Sodeoka
and co-workers at RIKEN for their support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503794.
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Scheme 2. Construction of the limonoid framework. Reagents and
conditions: a) PCl3, DMF, THF, RT; b) m-CPBA, K2CO3, CH2Cl2, À60 to
08C; c) 1-(trimethylsilyl)propyne, nBuLi, THF, À40 to 08C, 85%
(3 steps); d) Al(OiPr)3, toluene, reflux, 88%; e) SOCl2, Et2O, pentane,
08C; f) ethyl 2-chloroacetoacetate, NaH, nBuLi, DMPU, THF, 08C,
69% (2 steps); g) TBAF, THF, RT, 98%; h) Mn(OAc)3·2H2O, EtOH,
RT, 64% (d.r.=2.1:1); i) Zn, AcOH, RT; j) MVK, tBuOK, tBuOH, 358C,
62% (2 steps); k) MeI, tBuOK, tBuOH, 408C, 80%;
l) Mn(OAc)3·2H2O, Cu(OAc)2·H2O, EtOH, RT, 55% (d.r.=27:1).
DMPU=1,3-dimethylhexahydro-2-pyrimidinone, m-CPBA=meta-
chloroperbenzoic acid, MVK=methyl vinyl ketone, TBAF=tetrabutyl-
ammonium fluoride.
Scheme 3. Development of a method for the cleave of the exo
methylene group. Reagents and conditions: a) LiAlH4, THF, 08C to
reflux, 97%; b) TBSCl, NaH, THF, 08C to RT, 75%; c) Ac2O, pyridine,
DMAP, CH2Cl2, RT, quant.; d) m-CPBA, NaHCO3, CH2Cl2, À20 to
À58C, 63%; e) NaCN, DMSO, 1208C; f) Ac2O, pyridine, DMAP,
CH2Cl2, RT, 86% (2 steps); g) TBHP, CuBr, CH2Cl2, RT, 77% (after
2 cycles); h) Li, NH3, tBuOH, THF, À60 to À408C; i) Dess–Martin
periodinane, NaHCO3, CH2Cl2, RT, 86% (2 steps); j) TBAF, THF, 08C
to RT, 91%; k) LiAlH(OtBu)3, THF, À608C; l) TESOTf, 2,6-lutidine,
CH2Cl2, À40 to À208C, 69% (for 15 over 2 steps; 15% for the
C7 epimer over 2 steps); m) LiHMDS, TMSCl, Et3N, THF, À78 to
À608C; Pd(OAc)2, MeCN, RT, 92%. DMAP=4-dimethylaminopyridine,
LiHMDS=lithium hexamethyldisilazide, TBHP=tert-butyl hydroperox-
ide, TBS=tert-butyldimethylsilyl, TES=triethylsilyl, Tf =trifluorometha-
nesulfonyl, TMS=trimethylsilyl.
Having successfully constructed the limonoid C13a-
androstane framework, we turned our attention to cleavage
of the exo methylene group in 9. Owing to severe steric
hindrance around this moiety, conventional direct oxidative
cleavage procedures were unsuccessful.[14] Therefore, an
alternative stepwise method was developed (Scheme 3).
Reduction of 9 with LiAlH4 afforded the corresponding
diol, and the two hydroxy groups were protected as a TBS
ether and an acetate, respectively, to give compound 11.
Chemo- and stereoselective epoxidation of the exo methylene
group of 11 was achieved with m-CPBA to provide epoxide
caused a chemoselective reduction of the C7 ketone; TES
protection of the hydroxy groups then afforded compound 15
in 69% yield (along with the C7 epimer in 15% yield). Ito–
Saegusa oxidation of ketone 15 proceeded smoothly to give
enone 16.[18]
À
12. We observed an interesting C C bond-cleavage reaction
We next focused on the installation of the furan moiety
and the construction of the epoxylactone D ring (Scheme 4).
Treatment of 16 with Tf2O in the presence of 2,6-di-tert-butyl-
4-methylpyridine (DTBMP)[19] afforded the corresponding
vinylogous enol triflate; butenolide 17[20] was then attached to
this intermediate in a Stille coupling[21] to give 18 in 83%
overall yield. The [4+2] cycloaddition of singlet oxygen to
diene 18 smoothly provided the endoperoxide in a stereose-
lective manner.[22] Sequential treatment of the butenolide
with diisobutylaluminum hydride (DIBAL) and acetic anhy-
dride/DMAP led to the formation of furan 19 in 74% yield
from 18. Ruthenium-catalyzed isomerization of the endoper-
oxide in 19 according to Noyoriꢀs method[23] furnished bis-
(epoxide) 20, which smoothly underwent a 1,2-hydride shift
when 12 was heated to 1208C in the presence of NaCN in
DMSO, which is possibly due to nitrile addition to the epoxide
followed by elimination of acetonitrile.[15] This process
directly provided the desired ketone 13 along with the
corresponding deacetylated compound, which was re-acety-
lated to give 13.
Allylic oxidation of 13 by means of tert-butyl hydro-
peroxide (TBHP) in the presence of a catalytic amount of
CuBr[16] furnished enone 14 in 77% yield after two cycles.
Installation of the C5 stereocenter and removal of the acetyl
group were achieved by Birch reduction of 14. Dess–Martin
oxidation[17] and TBAF treatment afforded hemiacetal 2 in
78% overall yield. Reduction of 2 using LiAlH(OtBu)3
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Scheme 4. Total synthesis of limonin. Reagents and conditions: a) Tf2O, DTBMP, CH2Cl2, 08C; b) 17, [Pd(PPh3)4], CuCl, LiCl, DMSO, 408C, 83%
(2 steps); c) O2 (1 atm), methylene blue, NaHCO3, CH2Cl2, hn (sunlamp), 08C, 92%; d) DIBAL, CH2Cl2, À908C; Ac2O, DMAP, À908C to RT, 80%;
e) [(Ph3P)3RuCl2], CH2Cl2, RT; SiO2; f) DBU, toluene, 408C, 61% (2 steps, d.r. =5.4:1); g) H2O2/urea, aq. NaOH (6m), MeOH, DME, 458C;
h) TBAF, THF, À60 to À208C, 49% (2 steps); i) PhI(OAc)2, I2, O2 (10 atm), cyclohexane, CCl4, hn (sunlamp), 408C; j) TBAF, THF, RT; k) TPAP,
NMO, molecular sieves (4 Š), CH2Cl2, RT, 17% (3 steps). DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL=diisobutylaluminum hydride,
DTBMP=2,6-di-tert-butyl-4-methylpyridine, NMO=4-methylmorpholine N-oxide, TPAP=tetrapropylammonium perruthenate.
Keywords: cycloaddition · limonoids · oxidation ·
radical reactions · total synthesis
on silica gel to give epoxyketone 21a. This compound was
isomerized by heating at 408C in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to provide a 21b/
21a = 5.4:1 mixture in 61% overall yield. Baeyer–Villiger
oxidation of ketone 21b under basic conditions followed by
selective deprotection of the TES acetal afforded epoxylac-
tone 22.
The remaining task was the construction of the AA’ ring
system of 24, which was accomplished by a Suµrez reaction in
a single operation.[24] Specifically, treatment of 22 with
iodobenzene diacetate and iodine under an oxygen atmos-
phere with sunlamp irradiation likely caused homolytic
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Angew. Chem. 2015, 127, 8658–8661
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(Æ)-1 (17% over 3 steps). The H and 13C NMR spectra of
synthetic (Æ)-1 are identical to those of natural limonin.
In summary, we have achieved the first total synthesis of
(Æ)-limonin (1) in 35 steps from geraniol (4). Our synthesis
features 1) the efficient construction of the limonoid andros-
tane framework with C13a configuration by a tandem radical
cyclization and subsequent Robinson annulation (7!3!9),
2) a ketone formation from the hindered exo methylene
group, possibly through epoxidation and nitrile addition
followed by MeCN elimination (11!13), 3) the installation
of an epoxylactone moiety by singlet-oxygen cycloaddition,
ruthenium-catalyzed bis(epoxide) formation, and Baeyer–
Villiger oxidation (18!22), and 4) a Suµrez reaction to
construct the unique AA’ ring system from the hemiacetal
(22!24). We believe that the synthetic strategy developed
here will allow for the synthesis of diverse limonoid archi-
tectures.
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Received: April 25, 2015
Revised: May 16, 2015
Published online: June 3, 2015
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