Total Synthesis of the Diterpene Waihoensene

Article abstract of DOI:10.1002/anie.202011298

A racemic and scalable enantioselective total synthesis of (+)-waihoensene was accomplished. (+)-Waihoensene belongs to the diterpene natural product family, and it features an angular triquinane substructure motif. Its tetracyclic [6.5.5.5]backbone is al

Full text of DOI:10.1002/anie.202011298

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Accepted Article
Title: Total Synthesis of the Diterpene Waihoensene
Authors: Tanja Gaich, Lisa-Catherine Rosenbaum, and Maximilian
Häfner
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Total Synthesis of the Diterpene Waihoensene
Lisa-Catherine Rosenbaum‡, Maximilian Häfner‡, and Tanja Gaich* [a]
[a]
M. Sc. L.-C. Rosenbaum+, M. Sc. M. Häfner+, Prof. Dr. T. Gaich
Department of Chemistry
University of Konstanz
Universitätsstrasse 10, 78464 Konstanz, Germany
E-mail: tanja.gaich@uni-konstanz.de
‡
[ ]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: A racemic and scalable enantioselective total synthesis of
(+)-waihoensene was accomplished. (+)-Waihoensene belongs to the
diterpene natural product family, and features an angular triquinane
substructure motif. Its tetracyclic [6.5.5.5]backbone is all-cis-fused,
containing six contiguous stereocenters, four of which are quaternary.
These structural features were efficiently installed by means of a
diastereoselective radical cyclization, followed by an intramolecular
Pauson–Khand reaction, a diastereoselective a-alkylation, and a
diastereoselective 1,4-addition reaction. Enantioselectivity was
introduced at an early stage, by asymmetric palladium catalyzed
decarboxylative allylation reaction on gram-scale.
functional groups beside a single double bond thus representing
a pure hydrocarbon. This specific feature might look innocent in
the first place, but upon synthetic planning it turns out to represent
one of the greatest synthetic obstacles for an efficient synthesis—
besides the four quaternary stereocenters present in the natural
product. Since most C-C-bond forming reactions require
functional groups, the lack of functionalization (or in biosynthetic
terms — lack of oxygenation of the natural product) inevitably
entails over-functionalization of synthetic intermediates
(overshooting molecular complexity), and eventually requires
application of additional de-functionalization reactions (FGIs),
lengthening the overall synthetic route. Waihoensene (1) has
been synthesized previously by three groups, who devised
different synthetic strategies depicted in Figure 2. [4-7]
Terpene natural products containing polyquinane structure motifs
constitute a diverse structural subclass prominent in sesqui;- di;-
as well as sesterterpenes, and ever since have attracted great
attention from the synthetic community.[1] Angular triquinanes 2
in particular pose a synthetic challenge, since their principal
Previous works:
Tandem [3+2] cycloaddition strategy:
H.-Y. Lee et al.
structure element implies the existence of
a
quaternary
Me
Me
O
Me
stereocenter[2] (blue dot structure 2 in Figure 1), as opposed to
linear triquinanes 3, where a quaternary stereocenter is not a
prerequisite.
NHTs
N
tandem
[3+2]-CA
Me
Me
Me
Me
(+)-waihoensene (1)
4
5
Conia-ene/Pauson–Khand strategy:
a) J. Huang & Z. Yang et al.
Me
Me
O
O
7
Conia-ene
reaction
O
8
Pauson–Khand
reaction
O
(1)
Me
Me
Me
Me
Me
6
Pauson–Khand
reaction
(+)-waihoensene (1)
linear
triquinane 3
angular
triquinane 2
b) S. A. Snyder et al.
Lee: 21 steps (racemic)
Huang & Yang: 15 steps
Snyder: 16 steps
O
R
O
Figure 1. Comparison of the linear and angular triquinane structure element.
MeO2C
Conia–ene
reaction
Me
Me
Waihoensene (1) harbors such an angular triquinane substructure,
9
10 R: = CO2Me
and moreover contains altogether four quaternary stereocenters
which are aligned in
a contiguous fashion across the
Figure 2. Synthetic strategies of previous syntheses.
carboskeleton. The diterpene waihoensene (1) has been isolated
from the plant Podocarpus totara var. waihoensis native to New
Zealand in 1997 by the Weavers group.[3] Structural analysis of
waihoensene (1) reveals a tetracyclic fused ring-skeleton with six
stereocenters embedded of which four are quaternary
stereocenters. All stereocenters are contiguously arranged,
making it a very densely packed molecule sterically utmost
encumbered. In addition, waihoensene (1) does not contain any
The first accomplished total synthesis in racemic form followed a
tandem-[3+2]-cycloaddition strategy, and was published in 2017
by Lee and coworkers.[5] Recently, in 2020 two further syntheses
were published involving a Conia–Ene/Pauson–Khand strategy
by the groups of Huang & Zhang [6] and the group of Snyder.[7]
Both latter synthetic approaches are enantioselective with a step
1
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10.1002/anie.202011298
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COMMUNICATION
2. t-BuLi, 17 , then 16
Et2O, -78 °C to
-60 °C, then 2M HCl
Me
OBn
count ranging of 15 and 16 steps. By contrast Lee’s racemic
synthesis required 21 steps.
Me
Me
1. LiTMP, DMPU
then 15, THF,
O
EtO
O
EtO
O
I
OBn
Herein we report both, an enantioselective synthesis of
waihoensene (1) and in racemic form, with an overall step count
of 14 (racemic) and 19 (enantioselective) steps. Our strategy was
guided by first establishing one of the four quaternary
stereocenters via an asymmetric allylation reaction to give
compound 27 (Scheme 3).[8] We then assembled the hydrindane
part 18 of waihoensene (1) by a radical cyclization reaction
together with establishing the methyl-group at C7 at the same
time.[9] By contrast, all other syntheses do not tie these two
transformations together. This bicycle 18 served as rigid template
for the Pauson–Khand reaction [10] to give the carboskeleton of
1. Compound 11 was eventually converted to waihoensene (1) in
a three-step sequence.
-78 °C - r.t.,
80%
17
Me
Me
Me
16
13
89%
14 (commercially
available)
3. HSnBu3, AIBN
PhH, 80 °C,
95%
OTf
15
OBn
OBn
4. PPTS, DCM, r.t.
OBn
Me
Me
Me
SnBu3
6. NH2NHTs,
EtOH, 0 °C - r.t.
TsHNN
O
O
5. MeOH, NaOH,
7
7
50 °C, 33.3:1 d.r.
88% over 2 steps
94%
20
18
Me
Me
19
Me
7. catechol borane,
CHCl3, -10 °C - r.t.
then NaOAc·3H2O,
reflux, 62%
OH
OBn
Me
Me
Me
9. SO3·pyr, NEt3
8. Na, NH3(l)
-78 °C to -60 °C
7
DMSO, r.t.
10.Ohira–Bestmann
reag. K2CO3, MeOH,
r.t., 65% over 2 steps
91%
Me
Me
Me
21
12
22
Strategy of this work:
Scheme 1. Synthesis of the Pauson–Khand precursor 12.
Me
FGIs and
Methylation
Me
Me
Pauson-Khand
O
The high preference for the desired configuration of the C-7-
methyl-group in 19 is attributed to minimization of 1,3-allyl-strain.
Defunctionalization of the ketone in 19 was accomplished by
conversion to hydrazone 20 followed by reduction with catechol
borane to give compound 21. This was converted to alkyne 12 by
deprotection under Birch conditions, Parikh–Doering oxidation to
the corresponding aldehyde, and Ohira–Bestmann alkynylation.
The intermediate aldehyde tends to undergo acid-mediated Prins
cyclization and was therefore used in the next step without
purification. Alkyne 12 poses the precursor for the Pauson–Khand
reaction, and was treated with dicobalt-octacarbonyl to give the
corresponding cobalt-alkyne complex. This intermediate
underwent cyclization and CO-insertion under forcing conditions
to yield 46% of the desired product 11, and thus delivering the
fully established core of waihoensene (1) (Scheme 2).
Fortuitously, we obtained a single crystal [12] of this key
intermediate and therefore we were able to unambiguously
establish the correct configuration of 11.
Me
Me
Me
11
Me
(+)-waihoensene (1)
OBn
Radical cycl.
Me
O
Enantioselective
Allylation
Me
12
13
Me
Figure 3. Retrosynthetic analysis this work’s synthesis.
On the outset, we started our synthetic racemic sequence from
commercially available compound 14 (Scheme 1). Introduction of
the quaternary center to 14 was accomplished by an alkylation
reaction with homopropargylic triflate to yield 16 in 80%. This was
followed by an addition of lithiated 17 to the vinylogous ester in 16
and in-situ elimination reaction to afford enone 13 in 89% yield. At
this point the radical cyclization reaction established the desired
hydrindane scaffold 18 in 95% yield as an inconsequential
diastereomeric mixture at C-7. Destannylation of 18 and
consecutive treatment with sodium hydroxide in methanol
established the desired configuration of the C-7 methyl-group by
equilibration to give 97% of desired all-cis 19 in 88% yield. The
correct configuration of the methyl-group and the cis-fusion of the
hydrindane system was confirmed by single crystal X-ray analysis
after converting the ketone into the 2,4-di-nitrophenyl hydrazone.
[11]
2
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10.1002/anie.202011298
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COMMUNICATION
(+)-13 in full accordance with the racemic route. The
enantioselective route is very robust and was executed on gram
scale with no loss of yields and optical activity. Therefore, the
enantioselective material was funneled into the racemic route and
eventually delivered (+)-waihoensene (1) in analogous fashion
and 19 overall steps.
Me
11. Co2(CO)8
xylene, reflux
O
12
46%
Me
11
ORTEP
of 11
12. LiTMP, DMPU
then MeI, THF,
-78 °C - r.t. 63%
(96% brsm)
O
OAllyl
O
O
O
OAllyl
O
Me
Me
Me
2. 31 (8 mol%), Pd2(dba)3
(4 mol%), 1,4-dioxane, r.t.
Me
Me
1. NaH, MeI, THF
83%
gram scale
87%
96% ee
gram scale
PhS
PhS
PhS
13. MeLi, CuCN,
BF3·OEt2, Et2O,
-78 °C to -55 °C
ORTEP
25
27
26
Me
3. Na, MeOH,
reflux, 7h
O
93%
gram scale
OH
Me
of 23
70%
O
4. [Rh(PPh3)3Cl], catechol-borane,
THF, 0 °C to r.t., 1h;
then H2O2, pH 7 phosphate buffer,
EtOH, THF, 0°C to r.t., overnight
O
5. SO3·pyr, NEt3, DMSO,
O
Me
23
Me
Me
Me
Me
r.t., 4 h
Me
Me
6. Ohira–Bestmann reag.,
MeO
K2CO3, MeOH, r.t., 4 h.
70% over 2 steps
29
MeO
30
80%
gram scale
28
MeO
Me
Me
Me
Me
gram scale
7. step 2
from
Me
Ph2
P
PPh2
14. Ph3PCH2Br,
KOtBu, PhMe, 110 °C
Me
Scheme 1
O
H
N
12 steps
H
N
(+)-13
O
O
Me
Me
Me
91%
Me
(+)-waihoensene (1)
Me
(±)-waihoensene (1)
(11S, 12S) 31
Me
24
Scheme 3. Enantioselective approach to (+)-waihoensene (1) via an
asymmetric allylation reaction.
Scheme 2. Pauson–Khand reaction of 12 and endgame to waihoensene (1).
The endgame of the synthesis consisted of a three-step sequence
starting with a-alkylation of Pauson–Khand product 11 to give 23
as a single diastereomer. From this point onward, our synthesis
deviates from all previously published ones, who share a common
endgame consisting sequentially of a 1,4-addition of the methyl-
group to enone 11, subsequent a-alkylation, and final olefination
to give waihoensene (1). By contrast to these reports,[5] we
encountered no difficulties upon first performing an a-alkylation of
11, and were able to confirm the desired stereochemistry of the
newly formed stereocenter by single crystal X-ray analysis of
product 23.[13] The choice of base and additive in this a-alkylation
of 11 is crucial with regard to the competing formation of kinetic
and thermodynamic enolates. Strong bases, i.e. LDA (lithium
diisopropylamide), LiTMP (Lithium 2,2,6,6-tetramethylpiperidid)
and LiICA (lithium isopropylcyclohexylamide) in combination with
DMPU give desired methylated 23 as the only product, however
incomplete conversion lead to concurrent re-isolation of starting
material in all cases. The use of weaker bases such as LiHMDS
lead to the formation of the thermodynamic enolate
(deprotonation in g-position of the enone moiety). 1,4-Addition of
methyl cuprate to 23 delivered 24 in 70% yield, and again
exclusively gave a single stereoisomer. The synthesis was
concluded by Wittig olefination to deliver the natural product
waihoensene (1) in 91 % yield and a very concise overall 14 step
sequence. For obtaining optically active material, we decided to
proceed via an enantioselective allylation reaction [14] to
introduce the first of the four quaternary stereocenters (Scheme
3). We thereby started from vinylogous thioester 25,[15] which
was required in order to obtain excellent enantioselectivity.
Quaternarization of 25 with methyl iodide delivered 26 [14] and
palladium catalyzed decarboxylative allylation using Trost’s ligand
[16] furnished the desired optically active 27 with 96% ee and 87%
yield. Conversion of the vinylogous thioester to its corresponding
methylester, manipulation of the allyl side chain in three steps
(hydroboration/oxidation and Ohira–Bestman reaction), and
addition elimination reaction of 30 gave synthetic intermediate
In conclusion, we have developed the so far shortest route to (±)-
waihoensene (1) consisting of only 14 steps and delivering
racemic material. For the enantioselective route we require 19
steps and are able to produce optical active material 30 on gram
scale. Our synthetic strategy to assemble the carboskeleton
features a radical cyclization to form the hydrindane part 18 of
waihoensene as a rigid template for further C-C-bond forming
reactions. The skeleton is constructed via the Pauson–Khand
reaction to deliver the final product (+)-waihoensene (1) in a three-
steps containing endgame which introduces two additional
stereocenters.
Acknowledgements
We thank the NMR department of the University of Konstanz (A.
Friemel and U. Haunz) for extensive analyses, and Heiko
Rebmann and Dr. Thomas Huhn for X-ray analysis and structure
refinement. We thank Dr. Gerald Dräger from the Institute of
Organic Chemistry of the Leibniz University Hannover and Malin
Bein from the University of Konstanz for mass spectroscopic
analysis.
Keywords: Angular triquinane • Total Synthesis • Quaternary
stereocenter • Diterpene • Pauson-Khand reaction
[1]
[2]
[1] G. Mehta, G. Srikrishna, Chem. Rev. 1997, 97, 671−720. (b) Y. Qiu,
W.-J. Lan, H.-J. Li, L.-P. Chen, Molecules 2018, 23, 2095−2127.
For a recent review on syntheses of natural products with contiguous all-
carbon quaternary stereocenters, see: M. Büschleb, S. Dorich, S.
Hanessian, D. Tao, K. B. Schenthal, L. E. Overman, Angew. Chem. Int.
Ed. 2016, 55, 4156 – 4186; Angew. Chem. 2016, 128, 4226 – 4258.
D. B. Clarke, S. F. R. Hinkley, R. T. Weavers, Tetrahedron Lett. 1997,
38, 4297 – 4300.
[3]
3
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10.1002/anie.202011298
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COMMUNICATION
[4]
Previous synthesis and synthetic approaches: a) Ergüden, J.-K.; Moore,
H. W. Org. Lett. 1999, 1, 375−378; b) Li, S.; Zhang, P.-P.; Li, Y.-H.; Lu,
S. M.; Gong, J. X.; Yang, Z. Org. Lett. 2017, 19, 4416−4419.
H. Lee, T. Kang, H.-Y. Lee, Angew. Chem. Int. Ed. 2017, 56, 8254 –
8257; Angew. Chem. 2017, 129, 8366 – 8369.
[5]
[6]
[7]
Y. Qu, Z. Wang, Z. Zhang, W. Zhang, J. Huang, and Z. Yang J. Am.
Chem. Soc. 2020, 142, 6511-6515.
C. Peng, P. Arya, Z. Zhou, and S. A. Snyder Angew. Chem. Int. Ed. 2020,
59, doi.org/10.1002/anie.202004177; Angew. Chem. 2020, 132,
doi.org/10.1002/ange.202004177.
[8]
[9]
For a recent review on the asymmetric allylation reaction see: J. D.
Weaver, A. Recio, III, A. J. Grenning, and J. A. Tunge, Chem.Rev. 2011,
111, 1846–1913.
a) S. Janardhanam, P. Shanmugam, K. Rajagopalan, J. Org. Chem.
1993, 58, 7782-7788; b) For a review see: C. P. Jasperse, D. P. Curran,
and T. L. Fevig Chem. Rev. 1991 91 (6), 1237-1286; c) K. J. Romero, M.
S. Galliher, D. A. Pratt, C. R. J. Stephenson Chem. Soc. Rev. 2018,
47(21), 7851-7866; d) K. Hung, X. Hu, T. J. Maimone, Nat. Prod. Rep.
2018, 35(2), 174-202.
[10] I. U. Khand P. L. Pauson, J. Chem. Soc., Perkin Trans. 1, 1976, 1, 30-
32.
[11] CCDC number: 2016640 For an X-ray data analysis, see experimental
section.
[12] CCDC number: 2016641 For an X-ray data analysis, see experimental
section.
[13] CCDC number: 2016642 For an X-ray data analysis, see experimental
section.
[14] B. M. Trost, R. N. Bream, and J. Xu, Angew. Chem. Int. Ed. 2006, 45,
3109 –3112.
[15] K. V. Petrova, J. T. Mohr, and B. M. Stoltz, Org. Lett. 2009, 11, 293–295.
[16] a) B. M. Trost, D.L. Van Vranken, and C. Bingel, J. Am. Chem. Soc. 1992,
114, 9327–9343; For resolution with brucine see: b) M. Passarello, S.
Abbate, G. Longhi, S. Lepri, R. Ruzziconi, and V. P. Nicu, J. Phys. Chem.
A 2014, 118, 4339−4350.
4
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Entry for the Table of Contents
AAA-reaction
radical cyclization
Pauson-Khand reaction
Me
Me
Me
EtO
O
Me
Me
racemic: 14 steps
asymmetric: 19 steps
Me
(+)-waihoensene
commercial
available
Insert text for Table of Contents here. An efficient, racemic and enantioselective total synthesis of the diterpene waihoensene is
presented. Key steps are a radical cyclization, a Pauson–Khand reaction, and an asymmetric allylic decarboxylative allylation
reaction to obtain optical active material.
5
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