The enantioselective total synthesis of (+)-clusianone

Article abstract of DOI:10.1039/c4cc09701g

(+)-Clusianone, an exo-type B PPAP with reported anti-HIV and chemoprotective activities, was synthesized in eleven steps with 97% ee starting from acetylacetone. An enantioselective decarboxylative Tsuji-Trost-allylation and a Ru-catalyzed ring-closing metathesis-decarboxylative allylation were used to control both diastereo- and enantioselectivity.

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ARTICLE TYPE
The Enantioselective Total Synthesis of (+)-Clusianone
a
a
a
Fiene Horeischi, Claudia Guttroff, and Bernd Plietker*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
(+)-Clusianone, an exo-type B PPAP with reported anti-HIV
and chemoprotective activities, was synthesized within eleven
transformations (Table 1).
Table 1. Preparation of enantiomerically enriched cyclohexenone (S,S)ꢀ6.
steps with 97
enantioselective decarboxylative Tsuji-Trost-allylation plus a
Ru-catalyzed ring-closing metathesis-decarboxylative
% ee starting from acetylacetone. An
1
0
allylation were used to control both diastereo- and
enantioselectivity.
[
1]
Within the past eight years reports on the isolation and total
[
2ꢀ4]
synthesis
of polyprenylated polycyclic acylphloroglucinols
(PPAP), a class of natural products consisting of more than 200
1
2
2
5
0
5
members with an unusual bicyclo[3.3.1]nonatrione core, have
been published. The broad range of biological activities and the
challenge to synthesize a product that, apart from its unusual
bicyclic structure, is densely substituted possessing only three
hydrogen atoms but up to four stereocenters (a minimum of up to
three of them are quarternary), spurred the interest in developing
new or evaluating existing methodologies. As a consequence
[5]
[6ꢀ10]
elegant approaches toward endoꢀ and exoꢀtype
accomplished by various groups. However, only
enantioselective total synthesis are published up to date. Apart
PPAPs were
a
few
[
11]
[12]
from the use of chiral auxiliaries
,
substituents
, or
45
[
13]
a
b
reagents only a few strategies that rely on asymmetric catalysis
entry
ligand
solvent
time
yield [%]
(trans:cis)
ee [%]d ee [%]
d
c
[
14]
[
h]
(trans)
(cis)
were reported.
Herein we describe a short total synthesis of
9
7
(
+)ꢀclusianone in which an enantioselective decarboxylative
1
2
3
4
5
6
7
L1
L1
L1
L2
L2
L3
L4
THF
toluene
pentane
pentane
toluene
THF
1
15
72
(84 : 16)
[
15,16]
TsujiꢀTrost allylation
was used as a keyꢀstep (Figure 1).
9
3
1
34
46
29
38
0
90
97
82
84
ꢀ
(73 : 27)
9
5
1
(
(
(
(
(
66 : 34)
9
3
24
24
73 : 27)
8
5
72 : 28)
9
7
3
0
0.5
0.5
100 : 0)
Figure 1. (+)ꢀClusianone.
+)ꢀClusianone was isolated from C. congestiflora and shows
8
9
THF
0
ꢀ
100 : 0)
(
interesting antiviral activities against HIVꢀ and EppsteinꢀBarr
virus infections. In particular the latter activity is interesting since
the inhibition of this virus is discussed as a keyꢀstrategy in the
[a] All reactions were performed on a 0.125 mmolꢀscale under N
atmosphere until full conversion. [b] Ligand structures:
2
ꢀ
3
4
5
0
[
17]
field of chemoprotection.
The challenging scaffold and the
reported bioactivities in combination with the difficulties to
isolate bigger amounts of natural (+)ꢀclusianone spurred our
interest in developing a short total synthesis toward this
interesting natural product.
Starting from acetylacetone cyclohexenenone rac-5 was obtained
within three steps using the previously established
1
[c] Isolated yield, trans-cis ratio determined by H NMRꢀintegration of
50
the crude product. [d] Determined by chiral HPLC.
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Cyclohexenone rac-5 was subsequently transferred into the
corresponding allylvinylcarbonate rac-6 which was subjected to
the decarboxylative TsujiꢀTrost allylation. A variety of chiral
ligands were evaluated amongst which diaminocyclohexane
derived ligand (R,R)-L1 proved to be the optimum. The
corresponding allylated cyclohexenones (S,R)-7, (R,S)-7 and
5
0
5
0
(
S,S)-7 were obtained in an excellent combined yield of 95 %
with a diastereomeric cis-transꢀratio of 1 : 1.9. Fortunately, the
cisꢀproduct (S,S)ꢀ7 was formed with an excellent enantiomeric
excess (ee) of 97 % whereas the transꢀisomer showed an ee of
1
1
2
[
18]
only 43 % (entry 3, Table 1).
Having in hand the highly enantioenriched cyclohexenone (S,S)-7
we set out to finish the synthesis. Fortunately, the addition of
MeCu using previously established conditions provided good
access to the anticipated cyclohexanone
8
which was
subsequently reacted into the corresponding allylvinylcarbonate 9
With this compound in hand we investigated the stereochemical
course of the second decarboxylative TsujiꢀTrost allylation,
however we were disappointed to see that the new CꢀCꢀbond was
formed with high diastereoselectivity to product 10 with the
undesired relative transꢀconfiguration of two exocyclic carbonylꢀ
groups (Scheme 1).
Figure 2. Directing the diastereoselective course of the final TsujiꢀTrost
allylation via RCMꢀROCM.
Gratifyingly, treatment of (S,S)-7 with Grubbs second generation
40 metathesis catalyst provided the desired bicyclo[4.3.1]decenone
core in 13 in excellent yield (Scheme 2). 13 was subjected to the
1
,4ꢀadditionꢀalloc formation to give allylvinylcarbonate 11 in
excellent yield as a single regioisomer.
SCHEME 1. Diastereoselective synthesis of cyclohexanone 10.
2
3
3
5
0
5
This diastereoselective course might be rationalized assuming
that the pseudoꢀequatorial arrangement of both the allyl and
isoprenyl sideꢀchains in 9 hinders the addition of the allylꢀPd
complex from the top face leading to the undesired product 10
(Figure 2). Looking at this model we anticipated that one of the
axialꢀoriented methyl groups would be the only way to overcome
this steric interaction if the two unsaturated sideꢀchains would be
tied
together
using
a
crossꢀmetathesis
within
a
bicyclo[4.3.1]undecenone in which the enolate is accessible from
the top face (Figure 2).
45
SCHEME 3. The total synthesis of (+)ꢀclusianone.
The subsequent Pdꢀcatalyzed decarboxylative allylation gave
product 12 as a mixture of two diastereomers in a ratio of 15:85
in favor of the desired diastereomer. Base mediated
intramolecular Claisenꢀcondensationꢀbenzoylation led to the
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75
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B. Tolon, P. Nuhant, B. Delpech, C. Marazano, Eur. J. Org. Chem., 2007,
formation of the tetracyclic intermediate 14 which reacted with
isoꢀamylene in the presence of a Ruꢀcarbene catalyst in a ROCM
sequence to give the perprenylated natural product (Scheme 2). In
total we finished the enantioselective total synthesis of (+)-
clusianone within 11 steps starting from acetylacetone in an
overall yield of 8 %. Spectroscopic data and optical rotation are in
perfect agreement with the data reported in the literature.
Moreover, we were able to assign the absolute configuration of
5
5
8
117. (c) G. Mehta, T. Dhanbal, M. K. Bera, Tetrahedron Lett., 2010, 51,
302. (d) V Rodeschini, N. M Ahmad, N. S. Simpkins, Org. Lett., 2006,
, 5283. (e) N. M. Ahmad, V. Rodeschini, N. S. Simpkins, S. E. Ward, A.
J. Blake, J. Org. Chem., 2007, 72, 4803. (f) P. Nuhant, M. David, T.
Pouplin, B. Delpech, C. Marazano, Org. Lett., 2007, 9, 287.
5
[7] (a) H. Usuda, M. Kanai, M. Shibasaki, Org. Lett. 2002, 4, 859. (b) H.
Usuda, M. Kanai, M. Shibasaki, Tetrahedron Lett. 2002, 43, 3621. (c) Y.
Shimizu, A. Kuramochi, H. Usuda, M. Kanai, M. Shibasaki, Tetrahedron
Lett. 2007, 48, 4173. (d) A. Kuramochi, H. Usuda, K. Yamatsugu, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 14200.
(+)ꢀclusianone through xꢀray analysis of bicycle 13 (Figure 3).
[8] (a) C. Tsukano, D. R. Siegel, S. J. Danishefsky, Angew. Chem. Int.
Ed., 2007, 46, 8840. (b) D. R. Siegel, S. J.; Danishefsky, J. Am. Chem.
Soc., 2006, 128, 1048.
[9] (a) J. Qi, J. A. Jr. Porco, J. Am. Chem. Soc., 2007, 129, 12682. (b) B.
Mitasev, J. A. Jr.; Porco, Org. Lett., 2009, 11, 2285. (c) M. Uwamori, M.
Nakada, Nat. Prod. Commun., 2013, 8, 955.
[
[
10] G. Bellavance , L. Barriault, Angew .Chem. Int. Ed., 2014, 53, 6701.
11] (a) M. R. Garnsey, D. Lim, J. M. Yost, D. M. Coltart, Org. Lett.,
2
010, 12, 5234. (b) M. R. Garnsey, J. A. Matous, J. J. Kwiek, M. D.
Coltart, Bioorg. Med. Chem. Lett., 2011, 21, 2406.
[
[
12] J. H. Boyce, J. A. Jr. Porco, Angew. Chem. Int. Ed., 2014, 53, 7832.
13] V. Rodeschini, N. S. Simpkins, C. Wilson, J. Org. Chem., 2007, 72,
4
265.
[14] (a) J. Qi, A. B. Beeler, Q. Zhang, J. A. Jr. Porco, J. Am. Chem. Soc.,
2010, 132, 13642. (b) Y. Shimizu, S. L. Shi, H. Usuda, M. Kanai, M.
Shibasaki, Angew. Chem. Int. Ed., 2010, 49, 1103. (c) B. A. Sparling, D.
C. Moebius, M. D. Shair, J. Am. Chem. Soc., 2013, 135, 644.
[15] J. A. Keith, D. C. Behenna, N. Sherden, J. T. Mohr, S. Ma, S. C.
Marinescu, R. J. Nielsen, J. Oxgaard, B. M. Stoltz, W. A. Goddard, J. Am.
Chem. Soc., 2012, 134, 19050.
[
1
[
16] (a) B. M. Trost, J. Xu, T. Schmidt, J. Am. Chem. Soc., 2009, 131,
8343. (b) B. M. Trost, J Xu, J. Am. Chem. Soc., 2005, 127, 2846.
17] (a) antiꢀHIVꢀactivity: A. L. Piccinelli, O. CuestaꢀRubio, M. B. Chica,
1
0
Figure 3. Xꢀray structure of enantiopure bicycle 13
N. Mahmood, B. Pagano, M. Pavone, V. Barone, L. Rastelli, Tetrahedron
Lett., 2005, 61, 8206. (b) antiꢀEpsteinꢀBarr virus: C. Ito, M. Itoigawa, Y.
Miyamoto, S. Onoda, K. S. Rao, T. Mukainaka, H. Tokuda, H. Nishino,
H. Furukawa, J. Nat. Prod., 2003, 66, 206.[18] For a rationale for the
stereoselective course of asymmetric TsujiꢀTrost allylation see
supportings part I.
In summary we report here a short and concise enantioselective
total synthesis of (+)ꢀclusianone, a cisꢀ(or exoꢀ)type B PPAP with
reported activities against HIV and EppsteinꢀBarr virus. An
asymmetric TsujiꢀTrost allylation, and a sequence of Ruꢀ
1
2
5
0
catalyzed
ring
closing
metathesis
plus
subsequent
diastereoselective TsujiꢀTrost allylation represent the key steps
within this synthetic route. The successful application of these
methods on complex functional substrates not only underlines the
advanced status of current organometallic catalysis, but it also
enabled us to extend our PPAPꢀsynthesis algorithm to the exoꢀ
type B PPAPs without alteration of the synthetic operations.
Notes and references
a
2
3
3
4
5
0
5
0
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring
5
5, D-70569 Stuttgart, Germany; Tel: +49-711-68564283; E-mail:
bernd.plietker@oc.uni-stuttgart.de
Electronic Supplementary Information (ESI) available: General
†
procedure for the preparation of all new compounds including full
characterization. See DOI: 10.1039/b000000x/
[
[
1] R. Ciochina, R. B. Grossman, Chem. Rev., 2006, 106, 3963.
2] (a) J.ꢀA. Richard, R. H. Pouwer, D. Y.ꢀK. Chen, Angew. Chem. Int.
Ed., 2012, 51, 4536. (b) J. T. Njardarson, Tetrahedron, 2011, 67, 7631.
[3] (a) I. P Singh, S. B. Bharate, Nat. Prod. Rep., 2006, 23, 558. (b) I. P.
Singh, J. Sidana, S. B. Bharate, W. Foley, Nat. Prod. Rep., 2010, 27, 393.
[
2
4] J. H. George, M. D. Hesse, J. E. Baldwin, R. M. Adlington, Org. Lett.,
010, 12, 3532.
5] (a) N. Biber, K. Möws, B. Plietker, Nature Chem., 2011, 3, 938. (b) K.
[
Lindermayr, B. Plietker, Angew. Chem. Int. Ed., 2013, 52, 12183. (c) F.
Horeischi, N. Biber, B. Plietker, J. Am. Chem. Soc., 2014, 136, 4026. (d)
Q. Zhang, J. A. Jr. Porco, Org. Lett., 2012, 14, 1796. (e) Q. Zhang, B.
Mitasev, J. Qi, J. A. Jr. Porco, J. Am. Chem. Soc., 2010, 132, 14212.[6]
(a) S. J. Spessard, B. M. Stoltz, Org. Lett., 2002, 4, 1943. (b) T. Pouplin,
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