A convergent total synthesis of ouabagenin

Article abstract of DOI:10.1039/c5sc00212e

A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved by assembly of the AB-ring, D-ring and butenolide moieties. The multiply oxygenated cis-decalin structure of the AB-ring was constructed from (R)-perillaldehyde through the Diels-Alder reaction and sequential oxidations. The intermolecular acetal formation of the AB-ring and D-ring fragments, and combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in a stereoselective fashion. Finally, stereoselective installation of the C17-butenolide via the Stille coupling and hydrogenation led to ouabagenin. This journal is

Full text of DOI:10.1039/c5sc00212e

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A Convergent Total Synthesis of Ouabagenin
Ken Mukai,a Satoshi Kasuya,a Yuki Nakagawa,a Daisuke Urabea and Masayuki
Inoue*a
Cite this: DOI: 10.1039/x0xx00000x
A convergent total synthesis of ouabagenin, an aglycon of cardenolide glycoside ouabain, was achieved
Received 00th January 2012,
Accepted 00th January 2012
by assembly of the ABꢀring, Dꢀring and butenolide moieties. The multiply oxygenated cisꢀdecalin
structure of the ABꢀring was constructed from (R)ꢀperillaldehyde through the DielsꢀAlder reaction and
sequential oxidations. The intermolecular acetal formation of the ABꢀring and Dꢀring fragments, and
combination of the intramolecular radical and aldol reactions, assembled the requisite steroidal skeleton in
a stereoselective fashion. Finally, stereoselective installation of the C17ꢀbutenolide via the Stille coupling
and hydrogenation led to ouabagenin.
DOI: 10.1039/x0xx00000x
www.rsc.org/
implicated in the regulation of diverse physiological and
pathological states. Importantly, cardenolides have received
considerable attention for their preventive actions of
proliferative diseases such as cancer.4
The steroidal skeleton of ouabagenin (
1, Scheme 1), an
aglycon of ouabain, possesses six hydroxy groups and the
β
ꢀ
oriented butenolide. This highly oxygenated structure of
1 has
posed a formidable synthetic challenge.5,6 Despite numerous
synthetic studies on cardenolides, only two successful total
syntheses of
1
have been reported to date. Deslongchamps
through a polyanionic cyclization methodology
to ouabain,7 while Baran designed the redox
constructed
1
and converted
1
relay strategy and efficiently transformed adrenosterone to 1 8
.
Motivated by the architectural complexity coupled with the
valuable bioactivities, we have launched synthetic studies of
cardenolides based on a distinctive convergent strategy.9 Here
we report the total synthesis of ouabagenin (1) by assembling
the ABꢀring fragment with the simple achiral Dꢀring and
butenolide moieties.
The threeꢀdimensional structure of
classical steroidal skeleton in that all the functional groups at
the ring junctions (C5, 10, 13, 14) are ꢀconfigured (Scheme 1).
This atypical ring fusion gives the nucleus a characteristic 'U'
shape. The ring framework of is further decorated by one
primary (C19) and three secondary (C1, 3 and 11) hydroxy
groups and an unsaturated lactone ring (C17). The congested
disposition of these functionalities creates synthetic problems.
To simplify the overall scheme, we retrosynthetically
1 is disparate from the
Scheme 1. Synthetic Plan of Ouabagenin (1)
β
Ouabain (Scheme 1), which belongs to a unique class of
steroids known as cardenolides, has been used for the treatment
of congestive heart failure for more than two centuries.1,2
Ouabain was isolated from the bark and roots of the ouabaio
tree, and was more recently identified as an adrenal hormone
that naturally occurs in mammals.3 The cardiac activity of
ouabain is attributed to a high affinity inhibitory interaction
with the membraneꢀbound sodium pump, Na+/K+ꢀATPase. As
functional modulation of Na+/K+ꢀATPase activates multiple
downstream signal transduction pathways, ouabain is
1
disassembled
. According to this plan, achiral A10 and meso
prepared, while introduction of only four out of ten
stereocenters of would be necessary for the synthesis of 5.
1
into ABꢀring
5
, Dꢀring meso
ꢀ
B
and butenolide
ꢀ
A
B9 were easily
1
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5SC00212E
The remaining six centers were planned to be installed en route
to
positions (C8, 9, 13, 14) was to be controlled by two and subjected to the aldol reactions (Scheme 2B).13 Despite
To experimentally examine the role of the linker (XꢀY), the
1
. Most importantly, the stereochemistry of the four angular synthetically more accessible models 3c and 3d were prepared
intramolecular reactions. After tethering
the acetal linkage, 6ꢀexo radical cyclization of
establish the C9ꢀstereochemistry. Aldol reaction of
then be employed for simultaneous introductions of the C8ꢀ, catalytic KN(TMS)2 in refluxing THF led to formation of
13ꢀ and 14ꢀcenters of . The two peripheral functional groups desired 2ca as the sole isolable isomer, whereas application of
5
and meso
ꢀ
B
through their abbreviated structures, the transꢀdecalin rings of 3c and 3d
4
would were assumed to mimic the rigid orthoesterꢀprotected ABꢀring
3
would of 3a and 3b, respectively. Treatment of acetal 3c with
2
at C11 and 17 were planned to be constructed from
stage of the total synthesis.
2
at the last the same conditions to vinyl ether 3d selectively afforded
undesired 2db. These results demonstrated the crucial function
It would be challenging to control the three stereocenters in of the linker in influencing the stereoselectivity, and permitted
the reaction from to : eight diastereomers would be us to target acetal 3a as the key intermediate for the total
synthesis.
Prior to the synthesis of 3a, ABꢀring
)ꢀperillaldehyde 614 in 15 steps (Scheme 3). The Diels–Alder
and Rawal’s diene C15 proceeded in regioꢀ
3
2
potentially generated through desymmetrization of the meso
ꢀ
substructure (Scheme 2A).11,12 We envisioned that the linker
structure (XꢀY) would affect the stereochemical outcome of the
5 was prepared from
(
R
aldol reaction, and accordingly designed the two possible reaction between
intermediates, acetal 3a and vinyl ether 3b, which would be and diastereoselective manners to afford the cisꢀdecalin, which
integrated in the planned scheme. To assess suitability of 3a or was treated with aqueous acid to provide as a single
3b as the precursor, the relative energies of the eight isomers of product.16 The two carbonyl groups of
were simultaneously
each aldol reaction were evaluated in silico. The PM6 reduced with LiAlH4 to produce diol , the allylic alcohol of
calculation indicated that two products (2aa and 2ab from 3a which was chemoselectively oxidized with MnO2 to ketone
2ba and 2bb from 3b) were thermodynamically more stable Treatment of with TBSOTf and Et3N then introduced the two
than the six other adducts.13 However, selectivity between TBS groups at the C3ꢀenol and C19ꢀhydroxy groups, resulting
desired 2aa 2ba and undesired 2ab
2bb was not clarified by the in 10. Pd(OAc)2ꢀmediated oxidation17 of 10 in turn provided
simulation due to their small energy difference (<0.5 kcal/mol). dienone 11 18
For introduction of the ꢀconfigured C1ꢀ and 5ꢀ
oxygen functional groups, the C3ꢀ ꢀalcohol was utilized as the
6
7
7
8
,
9.
9
/
/
.
β
β
A. Singleꢀstep introduction of C8, C13 and C14 stereocenters
directing group. Namely, ketone 11 was stereoselectively
reduced by the action of the chiral reductant D19 to produce 12
O
X11'
O
(dr = 3:1).20 Thus obtained 12 was treated with
m
ꢀCPBA to
ꢀepoxidation in addition to the
epoxidation at C7', leading to trisꢀepoxide 13 After Dessꢀ
11
Y
13
17
H
14
induce the requisite bisꢀ
β
8
O
mesoꢀsubstructure
H
OH
.
O
O
Martin oxidation21 of alcohol 13 to ketone 14, reductive
opening of the two epoxides of 14 proximal to the C3ꢀketone
was realized using Al/Hg6g,22 to generate 15. Next, DIBALꢀH
transformed 15 into tetraol 16 through stereoselective hydride
attack on the C3ꢀketone from the opposite side of the C1,5ꢀ
hydroxy groups and regioselective attack on the C7'ꢀepoxide.
Having established the C1,3,5ꢀstereocenters, the ABꢀring
O
O
X11'
11
Y
17
O
2aa: XꢀY = (MeO)CHꢀCH
2ba: XꢀY = CH=C
13
14 D
?
O
O
O
8
O
X11'
11
14
Y
13
H
O
H
17
O
O
8
O
H
OH
O
3a: XꢀY = (MeO)CHꢀCH
3b: XꢀY = CH=C
O
O
fragment
5 was prepared from 16 through fiveꢀstep functional
2ab: XꢀY = (MeO)CHꢀCH
2bb: XꢀY = CH=C
+ six other isomers (2acꢀ2ah, 2bcꢀ2bh)
group manipulations (Scheme 3). After the three cisꢀhydroxy
groups were protected as the orthoester, the remaining tertiary
hydroxy group of 17 was regioselectively dehydrated using
POCl3 to produce 18. Ozonolysis of tetrasubstituted olefin 18
gave rise to C7ꢀketone 19, the Xꢀray crystallographic analysis
B. Model study of the aldol reaction
O
OMe
H
OMe
H
O
KN(TMS)2
(30 mol%)
17
O
O
13
17
13
14
14
H
of which confirmed
C19ꢀhydroxy methyl groups. Finally, Pd(OCOCF3)2ꢀpromoted
dehydrogenation,23 followed by TBAFꢀtreatment, transformed
βꢀorientations of the three hydroxy and
O
O
8
THF
reflux
65%
H
OH
O
H
TBSO
TBSO
TBSO
H
H
3c
2ca
O
19 into the requisite 5.
O
KN(TMS)2
(30 mol%)
O
17
14
O
14
13
17
13
H
THF
reflux
74%
O
O
8
H
OH
O
H
TBSO
H
H
3d
2db
Scheme 2. Design of the Substrates of Aldol Reaction
2 | J. Name., 2012, 00, 1-3
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ARTICLE
DOI: 10.1039/C5SC00212E
remaining C11ꢀbromo group of
radical donor by treatment with Et3B/O2 and nꢀBu3SnH. The
4
was in turn utilized as a
24
acetal tether of
add from the
4
effectively constrained the generated radical to
β
ꢀface of the C9ꢀolefin to provide 21 (C11,11'ꢀ
diastereomixture).25 Saponification of the two acetates of 21
and subsequent Dess–Martin oxidation of 22 furnished the
diastereomerically pure triketone 3a after chromatographic
purification (26% yield from
5). As expected from the
computational simulation and the model experiments in
Scheme 2, the acetalꢀtethered 3a was selectively converted into
the desired isomer 2aa
.
Specifically, treatment of 3a with
KN(TMS)2 (30 mol%) in refluxing THF delivered desired 2aa
(65%) along with its minor diastereomer 2ab (8%).
Noteworthy, this mild fiveꢀstep sequence realized introduction
of four new stereocenters (C8, 9, 13 and 14) without affecting
the preexisting oxygen functionalities.
Having constructed the properly substituted steroid,
ouabagenin (1) was synthesized from 2aa through adjustments
of the C7,11ꢀfunctional groups, attachment of the C17ꢀ
butenolide and global deprotection. First, the C7ꢀoxygen
functionality was removed. Chemoselective NaBH4 reduction
at C7 of diketone 2aa afforded alcohol 23, which was
derivatized into thiocarbamate 24 by means of thioisocyanate
and NaH.26,27 Reductive cleavage of the C7ꢀthiocarbamate of
24 was realized by mixing with AIBN and (TMS)3SiH in
refluxing benzene, providing 25
. Next, the αꢀoriented C11ꢀ
hydroxy group was constructed from the C11ꢀbranched carbon
linker, which served as the stereocontrolling element. Before
doing so, the acetal of 25 was converted to the vinyl ether of 26
by acidꢀpromoted elimination of MeOH.28 Oxidative scission
of the resultant C11ꢀolefin of 26 with ozone, reductive workup
and the basic deformylation at C19ꢀOH gave hemiacetal 27
TBSOTf and Et3N then introduced TBS groups at both C19ꢀ
and C17ꢀoxygen atoms of 27, liberating the C11ꢀketone of 28
.
.
Subjection of 28 to Birch reduction conditions resulted in
formation of 29 with the thermodynamically favorable
equatorial C11ꢀOH group.
Scheme 3
. Stereoselective Synthesis of ABꢀRing 5. Reagents and
The
βꢀoriented C17ꢀbutenolide was incorporated through
Conditions: a) toluene, 110 °C; 1.2 M aqueous HCl, THF, 67%; b)
LiAlH4, Et2O, –78 °C, 80%; c) MnO2, CH2Cl2, 89%; d) TBSOTf, Et3N,
CH2Cl2, 0 °C; e) Pd(OAc)2, CH3CN, 0 °C, 81% (2 steps); f)
BuOMe, Et2O, –100 to –40 °C, 68% for 12 (dr = 3 : 1); g)
chloroperbenzoic acid (
DessꢀMartin reagent, NaHCO3, CH2Cl2, 0 °C, 100%; i) Al/Hg,
NaHCO3, THF, EtOH, H2O, 0 °C; j) diisobutylaluminum hydride
(DIBALꢀH), CH2Cl2, –40 °C; k)
the Stille coupling reaction29 and stereoselective hydrogenation
(Scheme 4). Treatment of bisꢀTBS ether 29 with TBAF at ꢀ78
°C resulted in formation of C17ꢀketone 30, which was in turn
transformed to vinyl iodide 31 via the hydrazone
D,
tꢀ
mꢀ
mꢀCPBA), NaHCO3, CH2Cl2, 0 °C, 82%; h)
intermediate.30
proceeded in the presence of Pd(PPh3)4 and CuCl in DMSO,31
leading to 32 bearing the entire carbon structure of To
achieve hydrogenation from the concave ꢀface of the 'U'ꢀshape
The Stille coupling between 31 and A
pꢀtolSO3Hꢁpyridine, HC(OMe)3, DMF,
0 °C; l) POCl3, pyridine, 0 °C; m) O3, CH2Cl2, –78 °C; Me2S, 22% (5
steps); n) Pd(OCOCF3)2, NaOAc, DMSO, 50 °C, 91%; o) tetraꢀ
butylammonium fluoride (TBAF), AcOH, THF, 50 °C, 91%.
1
.
nꢀ
α
skeleton, the C14ꢀhydroxy group of 32 was capped with the
We have thus reached a critical stage in the total synthesis,
i.e., unification of the two fragments ( meso ) and
bulky TMSꢀether to generate 33. Presumably because the C14ꢀ
5
,
ꢀB
OTMS blocked the approach of reagents from the
βꢀface, Pd/Cꢀ
stereoselective construction of the tetracyclic system by a
combination of intramolecular radical and aldol reactions
(Scheme 4). Before the coupling, the vinyl ether of Dꢀring
catalyzed hydrogenation of 33 occurred selectively from the
α
ꢀ
face to yield 34 as the major product. Finally, global
deprotection of 34 with 3M HCl in MeOH removed the two
TMS, one TBS and one methine groups, giving rise to
meso
ꢀ
B
was converted to dibromide
E
.
The C19ꢀhydroxy
ꢀactivated C11'ꢀ
in the presence of an acid scavenger
as a diastereomixture. The
group of ABꢀring
bromo group of
5 selectively displaced the O
E
ouabagenin (
optical rotation, IR, Hꢀ, 13CꢀNMR, and HRMS were identical
with those of authentic
1). The analytical data of synthetic 1 including the
1
PhNMe2, leading to acetal
4
1
.
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5SC00212E
OH
19
R1O
MeO
O
MeO
AcO
OMe
11'
b.Et3B, O2
nꢀBu3SnH
O
A
B
11
11
O
O
O
19
d. DessꢀMartin
; PhNMe2
a. Br2
D
e. KN(TMS)2
O
5
OAc
9
O
O
Br
8
OR1
O
O
AcO
O
O
O
A
B
H
Br
H
O
O
11
11'
O
O
O
O
MeO
O
O
D
Br
: R1 = Ac
: R1 = H
B
4
21
22
3a
mesoꢀ
AcO
c. NaOH
E
SO3H—pyridine
MeO
MeO
O
O
O
17
O
OH
H
H
h. AIBN
(TMS)3SiH
11
13
14
NO2
O
O
O
17
O
O
i.
j. O3; NH4OH
k. TBSOTf
F
11
C
C
H
H
H
H
19
8
O
O
O
O
H
OH
X1
H
OH
H
OH
H
OH
7
7
O
O
O
O
O
O
O
: X1 = O
2aa
23
24
25
26
27
O
f. NaBH4
g. NaH
PhNCS
: X1 = OH, H
: X1 = C(S)NHPh, H
O
OTBS
O
X3
R2O
R2O
TBSO
R3O
R4O
X2
19
17
HO
17
17
TBSO
TBSO
11 H
H
H
m. TBAF
n. (NH2)2; I2
q. Pd/C, H2
H
14
OR2
H
OR2
O
O
O
O
O
H
OH
H
H
OH
O
O
R4O
r. 3 M HCl
OR4
O
O
O
O
: X3 = I, R2 = H
O
31
34: R2 = TMS, R3 = TBS, R4 = CH
30
: X2 = O
: X
: R2 = R3 = R4 = H
28
29
1
l. Li/NH3
2
= ꢀOH, H
o.
A
nꢀBu3Sn , Pd(PPh3)4
O
3
, R2 = H
, R2 = TMS
32
33
: X
: X
=
=
p. TMSOTf
3
Scheme 4. Total Synthesis of Ouabagenin (
Et3B, ꢀBu3SnH, O2, toluene; c) NaOH, MeOH, H2O; d) DessꢀMartin reagent, NaHCO3, CH2Cl2, 26% for 3a (4 steps from
mol%), THF, reflux, 65% for 2aa, 8% for 2ab; f) NaBH4, THF; g) NaH, H2O, PhNCS, THF; h) AIBN, (TMS)3SiH, benzene, reflux, 39% (3 steps);
i) , toluene, reflux, 81%; j) O3, MeOH, –78 °C; Me2S; NH4OH; k) TBSOTf, Et3N, CH3CN, –35 to 0 °C, 68% (2 steps); l) Li, NH3, THF, –78 °C,
96%; m) TBAF, THF, –78 °C, 99%; n) (NH2)2, Et3N, EtOH, 50 °C; I2, Et3N, THF, 89%; o) (3.0 equiv), Pd(PPh3)4, LiCl, CuCl, DMSO, 60 °C; p)
TMSOTf, 2,6ꢀlutidine, CH2Cl2; SiO2, 58% (2 steps); q) H2, Pd/C, EtOAc; r) 3 M aqueous HCl, MeOH, 56% (2 steps).
1).
Reagents and Conditions: a) meso
ꢀB
(2.5 equiv), Br2, CH2Cl2, –78 °C;
5
(1.0 equiv), PhNMe2; b)
n
5); e) KN(TMS)2 (30
F
A
and Dr. Kimiko Hasegawa (Rigaku Corporation) for Xꢀray
crystallographic analyses.
In conclusion, we achieved the convergent total synthesis of
ouabagenin ( ) using highly functionalized ABꢀring together
with the simple achiral Dꢀring meso and butenolide (33
steps from ( )ꢀperillaldehyde ). After preinstalling the four
stereocenters of introduction of the six remaining
stereocenters and construction of the entire pentacyclic
structure of required only 18 steps, demonstrating the
1
5
ꢀ
B
A
Notes and references
R
6
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
5
,
Hongo, Bunkyoꢀku, Tokyo 113ꢀ0033 Japan.
Eꢀmail: inoue@mol.f.uꢀtokyo.ac.jp
1
†
Electronic
Supplementary
Information
(ESI)
available:
efficiency of the strategy . The key transformations that
enabled the convergent synthesis include: i) the mild acetal
Characterization data for all new compounds, experimental procedures.
See DOI: 10.1039/b000000x/
formation between ABꢀring
5
and dibromide
E; ii) the tetherꢀ
guided 6ꢀexo radical cyclization of
aldol reaction of triketone 3a that was judiciously designed
based on in silico and model experiments; iv) installation of the
C17ꢀbutenolide by the Stille coupling using
stereoselective hydrogenation of C17ꢀdouble bond; and vi) the
singleꢀstep global deprotection. Because of its flexibility and
robustness, the present route would be applicable for the
synthesis of a variety of bioactive cardenolides, and synthetic
and SAR studies of such molecules will be our next focus.
4
; iii) the stereoselective
1
L. F. Fieser and M. Fieser, Steroids, Reinhold, New York, 1959,
pp.727.
2
3
S. H. Rahimtoola and T. Tak, Curr. Probl. Cardiol., 1996, 21, 781.
A. Y. Bagrov, J. I. Shapiro and O. V. Fedorova, Pharmacol Rev.,
2009, 61, 9.
A; v) the
4
(a) I. Prassas and E. P. Diamandis, Nat. Rev. Drug Discovery, 2008,
7, 926; (b) R. A. Newman, P. Yang, A. D. Pawlus and K. I. Block,
Mol. Interv., 2008, , 36; (c) J. A. R. Salvador, J. F. S. Carvalho, M.
8
A. C. Neves, S. M. Silvestre, A. J. Leitão, M. M. C. Silva and M. L.
Sá e Melo, Nat. Prod. Rep., 2013, 30, 324.
Acknowledgements
5
For recent reviews on total synthesis of steroids, see: (a) F. C. E.
Sarabèr and A. de Groot, Tetrahedron, 2006, 62, 5363; (b) A.ꢀS.
Chapelon, D. Moraléda, R. Rodriguez, C. Ollivier and M. Santelli,
This research was financially supported by the Funding
Program for a GrantꢀinꢀAid for Scientific Research (A) (JSPS)
to M.I., and (C) (JSPS) and on Innovative Areas (MEXT) to
D.U. A fellowship to K.M. and S.K. from JSPS is gratefully
acknowledged. We thank Naoto Aoki for preparation of 2db
,
4 | J. Name., 2012, 00, 1-3
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18, 3092.
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6
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