β-Ketoesters as Mono- or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (?)-Englerin A and B

Article abstract of DOI:10.1002/anie.201900401

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring

Full text of DOI:10.1002/anie.201900401

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EnaneitꢁKlKceivK Tteal SynehKꢁiꢁ tf (ꢀ)ꢀEnglKꢂin A and B
Authors: BKꢂnd PliKekKꢂ and LKi Gut
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To be cited as: Angew. Chem. Int. Ed. 10.1002/aniK.201900401
Angew. Chem. 10.1002/angK.201900401
Link to VoR: heep://dx.dti.tꢂg/10.1002/aniK.201900401
heep://dx.dti.tꢂg/10.1002/angK.201900401

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COMMUNICATION

-Ketoesters as Mono- or Bisnucleophiles: A Concise
Enantioselective Total Synthesis of (-)-Englerin A and B
[
a]
[a]
Lei Guo , and Bernd Plietker*
Abstract: A short enantioselective total synthesis of englerin A, a
guaiane sesquiterpene with significant in vitro anti-tumor activity, is
reported. Key features of this total synthesis are an organocatalytic,
asymmetric decarboxylative aldol reaction, a neighboring group
participated [4+3] cycloaddition, a novel one-pot Heck coupling-
regioselective 1,4-hydrosilylation-Tamao-Fleming oxidation cascade,
and a kinetic CBS reduction to obtain the optically pure natural
products in 6.7 % overall yield within 12 steps starting from
methylglyoxal.
have spurred interest in developing efficient synthetic
strategies.[ In particular the complex tricyclic core represented
a severe synthetic challenge that needed to be addressed. Ring-
4-7]
closing olefin metathesis was successfully shown to be powerful
strategy to generate the core structure.[
5a,5c,5e,5f]
Alternatively, a
conjugate addition-reductive coupling sequence can be used to
assemble the tricyclic core in an efficient manner.[5d] However,
the majority of reported syntheses relied on the use of
cycloaddition as the key steps, e.g. a Au(I)-catalyzed enyne-
carbonyl [2+2+2]-cycloaddition,[
5b,6a]
an oxidopyrylium-based
4a]
[6c,7a]
[
5+2]-cycloaddition to acrylate,[ and a Rh-carbene-
or Pt-
Englerin
A and B (1 and 2, Figure 1) are guaiane
catalyzed[
6d]
[4+3]-cycloaddition.
As
the
majority
of
[5]
sesquiterpene type natural products originating from the shrub
tree Phyllanthus engleri common in East Africa, which were
isolated from its stem bark’s extraction by Beutler and co-
workers in 2009.[1] Biological evaluation revealed that englerin A
is a promising new lead compound in oncology as it targets
TRPC4/5, an essential part of the transient receptor potential
cation channels TRPC that regulate i.a. the Ca-concentration
within cells and controls endothelial permeability, vasodilation,
neurotransmitter release and cell proliferation. As such, englerin
A inhibits selectively renal cancer cell lines’ growth with GI50
enantioselective syntheses make use of chiral pool materials,
only four enantioselective total syntheses were reported in which
a catalytic asymmetric transformation of an achiral material was
employed.[6] We describe here
a conceptually novel total
synthesis of (-)-englerin A (1) and B (2) in which -ketoacid
derivatives play a pivotal role as either enolate surrogates in an
asymmetric organocatalytic aldol reaction or as 1,3-
bisnucleophiles in a [4+3]-cycloaddition.
[
1-3]
between 1-87 nM.
This unusual mode of action renders
englerin A to be a potent anti-cancer drug candidate and makes
it an interesting starting point for potential antitumor target
research.[3]
Figure 1. Guaiane sesequterpene natural products.
The englerins possess
a challenging tricyclic structure
featuring a trans-fused bicyclo[5.3.0]-guaiane-type moiety plus
the seven-membered ring is part of an oxabicyclo[3.2.1]-heptane
core system featuring six contiguous stereogenic centers. The
interesting molecular structure plus the reported bioactivities
Scheme 1. Retrosynthetic analysis (PG: protecting group).

-Ketoacids and their corresponding esters are essential
[
a]
M.Sc. Lei Guo, Prof. Dr. Bernd Plietker,
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring
building blocks in a variety of total syntheses.[ They can either
be considered as biological enol-surrogates in aldol-type C-C-
bond formations or as 1,3-dianion in cycloaddition chemistry.
Inspired by the latter type of transformation we hypothesized,
that these compounds could allow for a short straightforward
modular total synthesis of englerin A. The corresponding
8]
55, DE-70569, Stuttgart (Deutschland)
*
Corresponding author: Prof. Dr. Bernd Plietker,
e-mail:bernd.plietker@oc.uni-stuttgart.de
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
retrosynthetic strategy is depicted in Scheme 1. Accordingly, the
esterification of alcohol 3 in the final step would provide access
to englerin A (1), alcohol 3 might be accessible through an
oxidation-reduction sequence followed with a diastereoselective
olefin hydrogenation of allylic alcohol 4. The latter one was
envisaged to derive from Pd-catalyzed Heck-coupling followed
by a Pd-catalyzed 1,4-hydrosilylation of the formed 1,3-diene.
Tamao-Fleming oxidation of the allyl silane could provide access
to the desired alcohol 4. Cyclization precursor 5 can be obtained
in a straightforward manner from -ketoester 6, which might be
accessible through a neighboring group assisted formal [4+3]-
cycloaddition between dianion-surrogate -ketoester 7 and 1,4-
diketone 8. This aldol product 8 itself shall be synthesized
malonic acid half thioesters were used as enolate surrogates[10b]
.
Initial screening experiments indicated these catalysts to be
active, however, the products were isolated in low enantiopurity.
After an extensive screening of various organocatalysts we
found cinchona-dimers to catalyze this reaction in an
asymmetric manner at low temperature (Table 1). The linker
between two cinchona moieties had
a strong effect. A
phthalazine linker was found to be superior to both
anthraquinone- as well as pyrimidine-based linkers (Table 1,
entry 1-4). Whereas the temperature had only a minor effect on
the enantioselectivity (Table 1, entry 5-6), a strong solvent effect
was observed (Table 1, entry 7-10). Trifluoroethanol led to an
increase of the enantiomeric excess (ee) to 60% with 81% yield.
Despite intense efforts, a further increase proved to be difficult
(for details see supporting informations), hence we continued
the synthesis with the enantioenriched aldol product and
planned to increase the enantiomeric excess through a kinetic
asymmetric discrimination at a later stage.
enantioselectively through
a decarboxylative aldol-reaction
between enol-surrogate -ketoacid 9 and methylglyoxal hydrate
10 (Scheme 1).
The synthesis started with the decarboxylative aldol reaction
between methylglyoxal 10 and -ketoacid 9 which could be
performed smoothly in a non-enantioselective fashion in water at
room temperature without any catalysts (base, acid, metal etc.)
with 93% yield (see SI).[9]
Alcohol 8 was esterified with TBDPS-glycolic acid 11 under
Yamaguchi-conditions to afford ester 12 with 78% yield (Scheme
2).
Table 1. Development of the enantioselective decarboxylative aldol reaction.
Entry
Catalystb
Solventa
Temp.
Yieldc
(%)
Eed
(%)
o
(
C)
1
2
(DHQD)
(DHQD)
(DHQD)
(DHQ)
2
Pyr
THF
THF
-20
-20
83
67
-24
-28
2
AQN
3
4
5
6
7
8
9
2
PHAL
THF
THF
THF
THF
-20
-20
-40
-80
-20
-20
-20
-20
81
79
76
71
56
56
81
66
-52
51
2
PHAL
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
(DHQD)
2
PHAL
2
PHAL
2
PHAL
2
PHAL
2
PHAL
2
PHAL
-52
-52
-40
-43
-60
-47
CH
CH
2
Cl
2
3
CN
THF/TFEe
THF/HFIPe
10
[
a] Concentration: 0.1 M; [b] The structure of the catalysts are shown in the
supporting information; [c] Isolated yield; [d] Enantiomeric excess (ee) was
analyzed by chiral GC; [e] 10% of co-solvents were used. (THF:
tetrahydrofurane, TFE: trifluoroethanol; HFIP: hexafluoroisopropanol)
Ma[10a,c]
and
List/Song[10b]
reported
interesting
Scheme 2. TMSOTf-mediated [4+3]-cycloaddition. Reagents and conditions: a.
organocatalytic decarboxylative aldol reactions using chiral
bisoxazolines[
1
1 (1.05 equiv), 2,4,6-trichlorobenzoyl chloride (1.05 equiv), Et
DMAP (0.1 equiv), toluene, rt, 1 h, 78%; b. bis-silylenolether 15 (1.5 equiv),
TMSOTf (0.2 equiv), CH Cl
, -78 oC, 30 min, 83% overall yield. (TMSOTf:
3
N (1.2 equiv),
10a,c]
[10b]
or cinchona-type catalysts , however, in the
2
2
former case -ketoester reacted with highly reactive
trifluoroacetaldehyde hemiacetals[10a,c], in the latter case, only
trimethylsilyloxytrifluoromethansulfonate; DMAP: N,N-dimethylaminopyridine;
TBDPS: tert-butyldiphenylsilyl).
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COMMUNICATION
Subsequently, the [4+3]-cycloaddition was investigated using
methyl acetoacetate. Double deprotonation of the -ketoester to
the corresponding dianion followed by addition of ester 12
resulted in a complex product mixture. Inspired by Molander´s
pioneering report on methyl acetoacetate derived bis-
silylenolether 15 as active 1,3-dinucleophile in [4+3]-
[
11]
cycloadditions to 1,4-diketone, we treated ester 12 with diene
5 and were pleased to find that the desired oxa[3.2.1]heptane
1
core 17 was obtained with exclusive regioselectivity and
excellent control of diastereoselectivity of the C-O-bonds at C-3
and C-4 in 83% yield.[12] Silylation of the sterically less hindered
carbonyl oxygen atom leads to oxonium species 13 which
undergoes a fast hemiketal formation to 14. The adjacent
carboxyl group of the ester moiety eventually stabilizes the cyclic
oxonium structure thus forcing diene 15 to react trans to the
glyoxylic ester to give the first C-C-bond in 16 with correct
relative configuration. Intramolecular Mukaiyama-aldol reaction
results in the formation of 17, which was fully characterized
through extensive NMR-studies.
With oxabicyclic β-ketoester 17 in hand the synthesis was
pushed forward to explore the feasibility of the attempted
sequential Pd-catalysis. Alkylation of 17 plus decarboxylation
using microwave assisted Krapcho-condition led to the formation
of ketone 18 with full control of the diastereoselectivity (Scheme
3).
Scheme 3. Total synthesis of (-)-englerin A and B. Reagents and conditions: c.
4
7
7
9
-bromo-1-butene (1.5 equiv), LiHMDS (1.1 equiv), DMPU (2.0 equiv), THF, -
o
o
8
C to rt, 2 h, 86%; d. LiCl (1.5 equiv), wet DMSO, microwave, 150 C, 1 h,
o
4%; e. KHMDS (1.2 equiv), PhNTf
3%; f. Pd(PPh Cl (0.1 equiv), Et
H (2.5 equiv), 5 h, then: H
NMO (1.2 equiv), CH Cl /MeCN = 10:1, rt, 2 h, 86%; h. (S)-CBS (0.3 equiv),
2
(1.2 equiv), THF, -78 oC to 0 C over 3 h,
o
)
3 2
2
3
N (3.0 equiv), toluene, 80 C, 30 min,
then: MeSiCl
2
2 2
O , ethanol, 58%; g. TPAP (0.1 equiv),
Figure 2. Stereochemical models for Pd-catalyzed 1,4-hydrosilylation (top)
and CBS-catalyzed kinetic resolution (bottom).
2
2
o
3
2
BH (0.9 equiv), THF, -10 C, 2 h, 69%; i. Pd/C (10% w/w), 90 bar H , EtOH, rt,
4
1
K
8 h, 86%; i. cinnamoyl chloride (1.1 equiv), DMAP (0.2 equiv), CH
0/1, 40 oC, 2 h; k. TBAF (5.0 equiv), THF, rt, 6 h, 79% over 2 steps; m)
CO (3.0 equiv), MeOH/H
O = 2:1, 0 oC, 4 h, 71%. (LiHMDS: lithium
hexamethyldisalizide; DMPU: N,N-dimethylproypylenurea; DMSO:
2 2 3
Cl /Et N =
2
3
2
Formation of the enoltriflate 19 set the stage for the second
key transformation. Indeed the use of catalytic amounts of a
dimethylsulfoxide; NMO: N-methylmorpholine-N-oxide; TPAP: tetra-n-
propylammonium perruthenate; TBAF: tetra-n-butylammonium fluoride)
(
Ph
3
P)
2
PdCl
2
led to the formation of the diene 20 through an
SiH
intramolecular Heck-reaction. Subsequent addition of MeCl
2
to the reaction mixture paved the way for the second process in
this catalytic sequence, i.e. the Pd-catalyzed regio- and
diastereoselective 1,4-hydrosilylation of diene 20 to the
corresponding allylsilane 21 (Scheme 3).[13]
The high degree of regio- and diastereoselectivity can be
rationalized assuming that the Pd-H-species reacts with the less
hindered exocyclic methylene group from the less hindered
convex face of diene 20 (Figure 2). Fortunately, oxidative work-
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COMMUNICATION
up using H
2
O
2
under slightly basic conditions resulted in a clean
B. Trepel, J. A. Beutler, W. M. Linehan, L. Neckers, Cancer Cell 2013,
23, 228; (c) Y. Akbulut, J. Gaunt, K. Muraki, M. J. Ludlow, M. S. Amer,
oxidation of the C-Si-bond in 21 to give allylic alcohol 22 with
retention of the configuration. Starting from 19 alcohol 22 was
formed in diastereomerically pure form in 58 % yield. Up to this
point we were hoping to increase both the enantiopurity and to
install the hydroxy group in 23 with correct relative configuration
through the use of an asymmetric Corey-Bakshi-Shibata (CBS)
reduction after a Ley-oxidation of 22 (Scheme 3).[14] Indeed, this
strategy turned out to be particularly successful, the desired
alcohol 23 was isolated with 95% enantiomeric excess and an
overall yield of 60% starting from 22. Unfavourable steric
interactions between the catalyst and the undesired enantiomer
might explain the high degree of kinetic resolution (Figure 2). In
addition, the reduction of the intermediate ,-unsaturated
ketone using standard protocols with non-chiral reagents (e.g.
A. Burns, N. S. Vasudev, L. Radtke, M. Willot, S. Hahn, T. Seitz, S.
Ziegler, M. Christmann, D. J. Beech, H. Waldmann, Angew. Chem. Int.
Ed. 2015, 54, 3787 – 3791; Angew. Chem. 2015, 127, 3858 – 3862; (d)
T. Rodrigues, F. Sieglitz, V. J. Somovilla, P. M. S. D. Cal, A. Galione, F.
Corzana, G. J. L. Bernardes, Angew. Chem. Int. Ed. 2016, 55, 11077 –
11081; Angew. Chem. 2016, 128, 11243 – 11247.
[3]
[4]
http://dtp.nci.nih.gov/dtpstandard/cancerscreeningdata/index.jsp.
For total synthesis of (±)-englerin A, see: (a) K. C. Nicolaou, Q. Kang, S.
Y. Ng, D. Y. K. Chen, J. Am. Chem. Soc. 2010, 132, 8219 – 8222; (b) H.
Kusama, A. Tazawa, K. Ishida, N. Iwasawa, Chem, Asian J. 2016, 11,
64 – 67;
[
5]
For enantioselective total synthesis of englerins from chiral pool
materials, see: (a) M. Willot, L. Radtke, D. Könning, R. Fröhlich, V. H.
Gessner, C. Strohmann, M. Christmann, Angew. Chem. Int. Ed. 2009,
48, 9105 – 9108; Angew. Chem. 2009, 121, 9269 – 9272; (b) Q. Zhou,
X. Chen, D. Ma, Angew. Chem. Int. Ed. 2010, 49, 3513 – 3516; Angew.
Chem. 2010, 122, 3591 – 3594; (c) L. Radtke, M. Willot, H. Sun, S.
Ziegler, S. Sauerland, C. Strohmann, R. Fröhlich, P. Habenberger, H.
Waldmann, M. Christmann, Angew. Chem. Int. Ed. 2011, 50, 3998 –
3 4
CeCl /NaBH , etc.) gave alcohol 23 alongside with a variety of
side-products. As such, this example nicely illustrates the
privileged role of CBS-type Lewis-acids both with regard to
stereo-, but also to regio- and chemoselectivity in asymmetric
4002; Angew. Chem. 2011, 123, 4084 – 4088; (d) Z. Li, M. Nakashige,
catalysis.[
14]
Finally, diastereoselective hydrogenation of the
W.J. Chain, J. Am. Chem. Soc. 2011, 133, 6553 6556; (e) K.
-
endocyclic double bond following Ma´s elegant approach[5b] led
to fully saturated tricycle 24 in 86% yield. Esterification and
deprotection provided (-)-englerin A in 79% yield over both steps.
Selective saponification of the more reactive glycolic ester
moiety gave (-)-englerin B in another 71% yield.
Takahashi, K. Komine. Y. Yokoi, J. Ishihara, S. Hatakeyama, J. Org.
Chem. 2012, 77, 7364 – 7370; (f) M. Zahel, A. Kessberg, P. Metz,
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In summary we were able to develop a conceptually novel
[
6]
12 step synthesis of (-)-englerin A starting from methylglyoxal
and featuring an asymmetric organocatalytic decarboxylative
aldol reaction, a [4+3]-cycloaddition of β-ketoester-derived bis-
(c) T. Hanari, N. Shimada, Y. Kurosaki, N. Thrimurtulu, H. Nambu, M.
silylenolether to
a
1,4-diketone and formation of the
Anada, S. Hashimoto, Chem. Eur. J. 2015, 21, 11671 – 11676; (d) R.
Nelson, M. Gulias, J. L. Mascarenas, L. Lopez, Angew. Chem. Int. Ed.
cyclopentane motif through a sequential Pd-catalyzed Heck-
reaction-1,4-hydrosilylation-Tamao-Fleming oxidation. Kinetic
discrimination via a CBS-reduction step allowed to obtain an
advanced intermediate in more than 95% enantiomeric excess.
Overall, the synthesis allows the preparation of the natural
product in 6.7% overall yield starting from methylglyoxal. The
modularity of the synthesis which is based on the initial catalytic
decarboxylative aldol-reaction sets the stage for the preparation
of a potential englerin A-library to improve and study the mode-
of-action. Future work will concentrate on these aspects.
2016, 55, 14359 – 14363; Angew. Chem. 2016, 128, 14571 – 14575.
[
7]
For a selective formal synthesis of englerins, see: (a) J. Xu, E. J. E. C.
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Antibiot. 2018, 71, 257 – 262.
[
8]
9]
(a) N. Biber, K. Möws, B. Plietker, Nat. Chem. 2011, 3, 938 – 942; (b) K.
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Acknowledgements
12186; Angew. Chem. 2013, 125, 12405 – 12408; (c) F. Horeischi, N.
Financial support by the Deutsche Forschungsgemeinschaft and
the China Scholarship Council (Ph.D.-grant for L.G.) is gratefully
acknowledged.
Biber, B. Plietker, J. Am. Chem. Soc. 2014, 136, 4026 – 4030.
(a) N. Ren, J. Nie, J. Ma, Green Chem. 2016, 18, 6609 – 6617; (b)
details on the optimization of the non-enantioselective aldol reaction are
listed in the supporting information.
[
[
10] For organocatalytic decarboxlative aldol reaction using malonic acid
derivatives see: (a) Y. Zheng, H. Xiong, J. Nie, M. Hua, J. Ma, Chem.
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List, C. E. Song, Angew. Chem. Int. Ed. 2013, 52, 12143 – 12147;
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W. Meng, J. Nie, J. Ma, Org. Lett. 2016, 18, 6364 – 6367.
Keywords: organocatalysis • asymmetric catalysis • natural
product • antitumor • total synthesis
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[12] No enantiomeric excess erosion occurred in this cycloaddition, see SI.
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10.1002/anie.201900401
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13] T. Hayashi, S. Hengrasmee, Y. Matsumoto, Chem. Lett. 1990, 1377 –
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1380.
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Angewandte Chemie International Edition
10.1002/anie.201900401
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Lei Guo,and Bernd Plietker*
Page No. – Page No.
-Ketoesters as Mono- or

Bisnucleophiles: A Concise
Enantioselective Total Synthesis of
(
-)-Englerin A and B
Text for Table of Contents
A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro anti-tumor activity, is reported. Key
features are an organocatalytic, asymmetric decarboxylative aldol reaction, a neighboring group participated [4+3] cycloaddition, a one-pot
Heck coupling-regioselective 1,4-hydrosilylation-Tamao-Fleming oxidation cascade, and a kinetic CBS reduction.
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