Bifunctional Polyene Cyclizations: Synthetic Studies on Pimarane Natural Products

Article abstract of DOI:10.1002/chem.202101926

Polyene cyclizations generate molecular complexity from a linear polyene in a single step. While methods to initiate these cyclizations have been continuously expanded and improved over the years, the majority of polyene substrates are still limited to simple alkyl-substituted alkenes. In this study, we took advantage of the unique reactivity of higher-functionalized bifunctional alkenes. The realization of a polyene tetracyclization of a dual nucleophilic aryl enol ether involving a transannular endo-termination step enabled the total synthesis of the tricyclic diterpenoid pimara-15-en-3α-8α-diol. The highly flexible and modular route allowed for the preparation of a diverse library of cyclization precursors specifically designed for the total synthesis of the tetracyclic nor-diterpenoid norflickinflimiod C. The tetracyclization of three diversely substituted allenes enabled access to complex pentacyclic products and provided a detailed insight into the underlying reaction pathways.

Full text of DOI:10.1002/chem.202101926

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
Bifunctional Polyene Cyclizations: Synthetic Studies on
Pimarane Natural Products
Julian M. Feilner,[a] Immanuel Plangger,[a] Klaus Wurst,[b] and Thomas Magauer*[a]
In memory of Prof. Klaus Hafner
Abstract: Polyene cyclizations generate molecular complexity
from a linear polyene in a single step. While methods to
initiate these cyclizations have been continuously expanded
and improved over the years, the majority of polyene
substrates are still limited to simple alkyl-substituted alkenes.
In this study, we took advantage of the unique reactivity of
higher-functionalized bifunctional alkenes. The realization of
a polyene tetracyclization of a dual nucleophilic aryl enol
ether involving a transannular endo-termination step enabled
the total synthesis of the tricyclic diterpenoid pimara-15-en-
3α-8α-diol. The highly flexible and modular route allowed for
the preparation of a diverse library of cyclization precursors
specifically designed for the total synthesis of the tetracyclic
nor-diterpenoid norflickinflimiod C. The tetracyclization of
three diversely substituted allenes enabled access to complex
pentacyclic products and provided a detailed insight into the
underlying reaction pathways.
Introduction
of the cyclizations, numerous methods have been developed
and various functional groups were utilized to activate and
terminate the cascade.[4,5] Somewhat surprisingly, modifications
of the isoprene subunits are rare.[6] In seminal work by
Johnson,[7] it was shown that monofunctional modifications can
act as a cation stabilizing auxiliary and serve as a handle for
late-stage modifications (Scheme 1 B).
The cyclization of polyenes is one of the most fascinating
chemical reactions found in nature. Enabled by terpene
synthases (TS) molecular complexity is generated from a linear
precursor in a single step. Owing to the variety of cyclization
modes a wealth of terpene structures is available.[1] Pimaranes
belong to the family of diterpenoids (C20) and share a tricyclic
carbon skeleton that is biosynthetically derived from geranyl-
geranyl diphosphate (1) (Scheme 1 A). A type II terpene
synthase initiates a bicyclization by protonation of a double
bond followed by deprotonation of the cationic intermediate to
provide copalyl diphosphate (2) (Scheme 1 A). Ionization of the
allylic diphosphate group in 2 by a type I TS leads to a second
cyclization thus forming the tricyclic ring system as found in 3.[2]
Synthetic chemists have mimicked polyene cyclizations with
great success[3] and have demonstrated their efficiency in a
large number of natural product syntheses.[4] For the initiation
As an example, diene 4 provided the trans-fused tricycle 5
upon treatment with titanium(IV) chloride. The vinyl group
served as a masked carbonyl group, which enabled access to
the central lactone of neotripterifordin (6).[8] The cation-
stabilizing properties of the fluorine atom in 7 facilitated a
tetracyclization reaction in the presence of tin(IV) chloride. The
fluorinated product 8 set the stage for the total synthesis of 4β-
hydroxyandrostan-17-one (9).[9] For monofunctional modifica-
tions as found in 4 and 7, only the alkene participates in the
polyene cyclization and the residue is not directly involved in
the cyclization. For the synthesis of pimaranes 10 and 11, we
envisioned the cyclization of the dual nucleophilic aryl enol
ether 13.[10] For this system, the polyene was expected to first
undergo a linear cascade cyclization followed by an intra-
molecular transannular termination of the aryl unit of the aryl
enol ether. Hence, we consider the aryl enol ether to be a
bifunctional modification of the isoprene pattern. The realiza-
tion of a tetracyclization featuring a transannular endo-termi-
nation of such a bifunctional motif would enable divergent
access to pimarane natural products 10 and 11. The nor-
diterpenoid norflickinflimiod C (10) was first isolated from the
orchid Flickingeria fimbriata in 2014 together with 11 other
pimaranes. While 10 was only moderately biologically active,
other members of the family exhibited potent anticancer and
anti-inflammatory activities.[11]
[a] J. M. Feilner, I. Plangger, Prof. Dr. T. Magauer
Institute of Organic Chemistry and
Center for Molecular Biosciences
Leopold-Franzens-University Innsbruck
Innrain 80–82, 6020 Innsbruck (Austria)
E-mail: thomas.magauer@uibk.ac.at
[b] Dr. K. Wurst
Institute of General, Inorganic and Theoretical Chemistry
Leopold-Franzens-University Innsbruck
Innrain 80–82, 6020 Innsbruck (Austria)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101926
© 2021 The Authors. Chemistry - A European Journal published by Wiley-
VCH GmbH. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are made.
Retrosynthetically, we envisioned to unmask the lactone
motif within the tricyclic trans-fused carbon skeleton of 10
Chem. Eur. J. 2021, 27, 1–13
1
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
To date, the syntheses of only a few structurally simplified
members-all of which lack the axially-oriented tertiary alcohol-
have been reported.[14]
Results and Discussion
Total synthesis of pimara-15-en-3α,8α-diol
Geranyl bromide (14) provided a valuable starting point to
access bromoacetylene 16 via propargylation[15] with lithiated 1-
(trimethylsilyl)propyne (15) and subsequent silicon bromine
exchange[16] employing N-bromosuccinimide (NBS) in the pres-
ence of silver nitrate (AgNO3) (Scheme 2).
With decagram quantities of 16 in hand, we investigated
the phenol alkyne addition for the installation of the aryl enol
ether (Table 1). Following the reported conditions,[10b,c]
a
Scheme 2. Preparation of bromoacetylene 16 by propargylation of geranyl
bromide (14). Reagents and conditions: a) 1-(trimethylsilyl)propyne (15), t-
°
°
°
BuLi, THF, À 20 C to À 5 C, 70%; b) NBS, AgNO3, acetone, 0 C, 74%.
NBS=N-bromosuccinimide, THF=tetrahydrofuran.
Table 1. Investigation of the phenol alkyne addition for the preparation of
17a–e.[a]
Scheme 1. A) Biosynthesis of 3. B) Total synthesis of 6 and 9 by polyene
cyclization involving modified isoprenes. C) Retrosynthetic analysis of 10 and
11 based on a transannular polyene tetracyclization/endo-termination
sequence enabled by a bifunctional isoprene modification. Bn=benzyl,
OPP=diphosphate ester, TS=terpene synthase.
°
Entry Product ArOH (equiv.)
Base (equiv.) Temp. [ C] Yield [%]
1
17a
Cs2CO3 (1)
80
12
(10)
(10)
(3)
(10)
(10)
(10)
2
3
4
5
6
Cs2CO3 (3)
Cs2CO3 (3)
Na2CO3 (3)
NaH (3)
80
80
80
80
80
44
41
trace
30
36
upon oxidative scission of the bridging arene subunit of 12. The
axial secondary alcohol at C-14 would be introduced by
K3PO4 (3)
transformation of
a hydroxy-surrogate (R) for example
7
17b
17c
Cs2CO3 (3)
80
42
TamaoÀ Fleming oxidation of a dimethyl(phenyl)silyl group.[12]
From a total of seven stereocenters, six were envisioned to be
generated from the tetracyclization of aryl enol ether 13. A
pivotal transannular endo-termination step would install one of
the two quaternary stereocenters of the natural product.
Further CÀ O and CÀ C bond disconnections revealed geranyl
bromide (14) as the starting point of the synthesis.
(10)
(10)
8
Cs2CO3 (3)
80
44
9
17d
17e
Cs2CO3 (3)
Cs2CO3 (3)
80
80
27
51
Since pimara-15-en-3α-8α-diol (11)[13] features the same
tricyclic carbon skeleton as 10 only differing in the oxidation at
C-14 and the substituent at C-13, we envisioned its synthesis via
a similar tetracyclization strategy. The missing axial secondary
alcohol at C-14 would allow for structurally less complex
intermediates 12 and 13 with R representing a hydrogen atom.
(3)
(8)
10
[a] DMF=N,N-dimethylformamide.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
2
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
solution of 16 in N,N-dimethylformamide was heated at 80 C in
the presence of 10 equivalents (equiv) of 3-methoxyphenol and
cesium carbonate (1 equiv) for three days. The desired product
17a was isolated as a single isomer, but only in a disappointing
12% yield (Table 1, entry 1). We found that three equivalents of
base were crucial to increase the yield for 17a to 44% (Table 1,
entry 2). Lowering the excess of 3-methoxyphenol to three
equivalents gave 17a in almost identical yield (Table 1, entry 3).
Substitution of cesium carbonate by sodium carbonate, sodium
hydride or potassium phosphate was detrimental to the
reaction and provided 17a in less than 36% yield (Table 1,
entry 4–6).
Variation of the aromatic substitution pattern (Table 1,
entry 7–10) was also investigated. Similar yields were achieved
for 17b (42%) and 17c (44%). While enol ether 17d was
obtained in a significant lower yield of 27%, the best yield was
achieved for unsubstituted phenol 17e (51%).
For the regioselective installation of the epoxide we
resorted to the Corey–Noe–Lin[17] protocol. Standard
Sharpless[18] dihydroxylation or direct epoxidation with m-
chloroperoxybenzoic acid were impaired by poor regioselectiv-
ity and overoxidation (Scheme 3). The diol intermediate was
obtained in 73% yield and 94% ee[19] and converted to epoxide
19 by mesylation of the secondary alcohol followed by intra-
molecular nucleophilic substitution in the presence of K2CO3 in
80% yield. For the completion of the synthesis of the cyclization
precursor 21, a C(sp2)À C(sp3) Suzuki cross-coupling reaction
proved to be the method of choice.[20] For this purpose, a
boron-ate complex was first generated by sequential treatment
of alkyl iodide 20 with B-methoxy-9-BBN and t-butyllithium.[21]
In the presence of a second-generation SPhos precatalyst
(5 mol%) and SPhos (5 mol%), efficient cross-coupling with 19
took place to deliver 21 in 84% yield.[22] For the initiation of the
pivotal cyclization, a variety of reaction conditions was inves-
tigated. In an attempt to induce a radical cyclization, 21 was
°
treated with the Nugent-RajanBabu reagent (titanocene dichlor-
[23]
°
ide, Mn, THF, 22 C). Unfortunately, under these conditions
only a complex mixture of decomposition products was
°
obtained. Diethylaluminum chloride (Et2AlCl, CH2Cl2, À 78 C) did
not promote the cyclization at all and unreacted 21 was
recovered. The stronger[24] Lewis acid ethylaluminum
dichloride[25] (EtAlCl2, CH2Cl2, À 78 C) initiated a cationic polyene
°
cyclization, but only traces of the products 22a/b/c/d were
observed together with inseparable, unidentified side products.
°
We finally identified tin(IV) chloride (SnCl4, CH2Cl2, À 78 C) as a
suitable reagent to initiate the crucial polyene tetracyclization
and to promote the challenging transannular endo-termination
step. A mixture of pentacyclic products 22a/b/c/d was obtained
in more than 47% combined yield. The desired products 22a
and 22b—two inconsequential regioisomers which only differ
in the position of the methoxy group—were isolated after
purification by HPLC in 16% and 10% yield, respectively.[26] The
structures of 22a and 22b were validated by single-crystal X-
ray analysis.
Benzoylation of the remaining product fractions facilitated
the isolation of cis-decalin 23 in 9% yield over two steps. The
formation of 22c may be attributed to a low π-facial selectivity
of the enol ether and accounts for a stepwise mechanism
Scheme 3. Synthesis of 25a/b via polyene tetracyclization of 21. Reagents and conditions: a) Corey–Noe–Lin ligand 18, MeSO2NH2, K2OsO4 ·2H2O, K2CO3,
°
°
°
°
K3[Fe(CN)6], t-BuOH, H2O, 0 C, 73%, 94% ee; b) MsCl, pyridine, CH2Cl2, 22 C, then K2CO3, MeOH, 22 C, 80%; c) 20, t-BuLi, B-methoxy-9-BBN, THF, À 78 C to
°
°
°
°
22 C, then SPhos Pd GII, SPhos, Cs2CO3, DMF, H2O, 40 C, 84%; d) SnCl4, CH2Cl2, À 78 C, 16% 22a, 10% 22b; d) EtSH, NaH, DMF, 120 C, 94% of 25a, 84% of
°
25b; e) BzCl, DMAP, py, 22 C, 9% 23 over two steps, 12% 24 over two steps. B-methoxy-9-BBN=9-methoxy-9-borabicyclo[3.3.1]nonane, Bz=benzoyl,
DMAP=N,N-dimethylpyridin-4-amine, DMF=N,N-dimethylformamide, ee=enantiomeric excess, MsCl=methanesulfonyl chloride, py=pyridine, SPhos=2-
dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, SPhos Pd GII=chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]
palladium(II), THF=tetrahydrofuran.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
3
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
involving a boat-type transition state for the second ring
closure.[27] Isomerization of the (Z)-enol ether 21 prior to
cyclization, which would also explain the formation of 22c, was
found to be unlikely, as treatment of a model system lacking
the epoxide (see Supporting Information for details) with tin(IV)
chloride did not lead to any detectable isomerization. The
constitution of 24 (12% yield over two steps) was fully
supported by extensive 2D NMR studies, but the depicted
stereochemistry could not be validated at this point. NOE
experiments were inconclusive and crystals for single-crystal X-
ray analysis were not obtained.[28]
We also explored the impact of the aryl substitution pattern
on the cyclization reaction to further improve the yield and
diastereoselectivity of the process. The modular route allowed
to exchange the aryl group and investigate the tetracyclization
of several related aryl enol ethers. To our surprise, all derivatives
investigated proved to be inferior to 21, providing lower yields
and unidentified product mixtures.
Finally, demethylation of 22a/b was accomplished by treat-
°
ment with sodium ethanethiolate (EtSNa, DMF, 120 C) yielding
phenols 25a/b in excellent yields (94% and 84%).
For the installation of the axial vinyl group of 11, oxidative
scission of the aryl group was required. For initial studies, we
subjected cis-decalin 24 to a variety of oxidation protocols.
While potassium permanganate appeared to be ineffective to
promote any oxidation (Table 2, entry 1), ozonolysis of a
solution of 24 in methanol and chloroform (Table 2, entry 2) or
as adsorbate on silica gel (Table 2, entry 3) led to complete
decomposition of the material.[29] By applying the method of
°
Sharpless (RuCl3, NaIO4, CCl4, MeCN, H2O, 22 C), only traces of
ketolactone 26 were formed together with a complex mixture
of decomposition products (Table 2, entry 4).[30] While periodic
acid was described as a powerful substitute for sodium period-
ate in the literature, we did not observe any improvement
(Table 2, entry 5).[31] Subjecting pentacycle 24 to a solution of
cis-bis-(2,2’-bipyridine)-dichlororuthenium(II) and sodium peri-
Table 2. Attempted oxidation of 24.[a]
°
odate in a mixture of acetonitrile and water at 22 C did not
lead to any transformation (Table 2, entry 6).[32] The poor
solubility of 24 was addressed by replacing acetonitrile with
°
1,2-dichloroethane (DCE). Heating to 80 C facilitated the
oxidative scission of the aromatic ring and 26 was isolated in
24% yield (Table 2, entry 7). The structure of 26 was verified by
single-crystal X-ray analysis and also allowed for confirmation of
the proposed stereochemistry of 24. Since no satisfactory
results were achieved, we turned our focus on the oxidation of
phenol 25a (Scheme 4).
By treating phenol 25a with in situ generated ruthenium
tetroxide (RuCl3, H5IO6, CCl4, MeCN, H2O), traces of ketone 27
were isolated. While most of 25a decomposed in the presence
of potassium permanganate (KMnO4, acetone, H2O), the for-
Entry
Conditions
Yield [%]
°
1
2
3
4
5
6
7
KMnO4, CCl4, H2O, 75 C
0
0
0
°
O3, MeOH, CH2Cl2, À 78 C
°
O3, SiO2, À 78 C
°
RuCl3, NalO4, CCl4, MeCN, H2O, 22 C
traces
traces
0
°
RuCl3, H5lO6, CCl4, MeCN, H2O, 30 C
Ru(bpy)2Cl2, NalO4, MeCN, H2O, 22 C
Ru(bpy)2Cl2, NalO4, DCE, H2O, 80 C
°
°
24
[a] Bpy=2,2’-bipyridine, Bz=benzoyl, DCE=1,2-dichloroethane.
°
Scheme 4. Attempted oxidation of 25a/b and 22b and attempted reduction of 22b. Reagents and conditions: a) RuCl3, H5IO6, CCl4, MeCN, H2O, 30 C, traces;
°
°
°
°
b) KMnO4, acetone, H2O, 22 C, traces; c) PIDA, MeCN, H2O, 22 C, 33%; d) O3, CH2Cl2, MeOH, À 78 C, then dimethylsulfide; e) MeLi, THF, À 78 C; f) RuCl3, NaIO4,
°
°
°
°
CCl4, MeCN, H2O, 30 C, 24%; g) Na, NH3, THF, t-BuOH, À 78 C; h) Li, NH3, THF, t-BuOH, À 45 C; i1) O3, EtOAc, HOAc, 22 C, then H2O2; i2) RuCl3, H5IO6, CCl4,
°
°
°
MeCN, H2O, 30 C, traces; i3) RuCl3, H5IO6, CCl4, MeCN, H2O, 30 C, traces; i4) KMnO4, acetone, H2O, 22 C. Ac=acetyl, PIDA=phenyliodine(III) diacetate,
THF=tetrahydrofuran.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
4
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
1
mation of traces of 28 was indicated by H NMR. Exposing a
solution of 25a in acetonitrile and water to phenyliodine(III)
diacetate (PIDA) led to dearomatization. Dienone 29, whose
structure was verified by single-crystal X-ray analysis, was
isolated in 33% yield. The dienone motif proved to be resistant
to ozonolysis and only slow partial oxidation of the secondary
alcohol in 29 was observed.
excess of potassium permanganate (20 equiv) for 3.5 d, keto-
lactone 33 was isolated in 19% yield along with lactone 34 in
18% yield (Table 3, entry 1).[35] To prevent stalling of the
reaction, an aqueous solution of potassium permanganate had
to be added continuously to the reaction mixture via syringe
pump. Decreasing the concentration in the organic layer from
100 mM to 24 mM shifted the product ratio towards the desired
ketolactone 33 (27% yield, Table 3, entry 2). Increasing the
We attempted to increase the reactivity of the diene by
breaking the conjugation with the carbonyl group. However,
1,2-addition of methyllithium to 29 to give 30 was not observed
but a complex mixture was obtained instead. Finally, Sharpless
oxidation (RuCl3, NaIO4, CCl4, MeCN, H2O) of dienone 29
afforded the desired carbon skeleton 27, albeit in low yield
(24%). Due to the difficulties with the oxidative degradation,
we planned a Birch reduction of 22b to diene 31, as the latter
was envisioned to be more readily oxidized.[33] Unfortunately,
treatment of a solution of 22b in a mixture of ammonia,
tetrahydrofuran and t-butanol with sodium or lithium metal did
not provide diene 31 and solely 22b was reisolated. Ozonolysis
of 22b resulted in the formation of a complex product mixture.
Ruthenium catalyzed oxidation of 22b or 25b (RuCl3, H5IO6,
CCl4, MeCN, H2O) led to decomposition and only traces of
ketone 27 were isolated. We were unable to isolate any
products from the oxidation of phenol 25b with potassium
permanganate (KMnO4, acetone, H2O). We speculated that the
secondary alcohol might play a crucial role in the decomposi-
tion and therefore opted for selective acetylation of the
secondary alcohol. Transesterification with ethyl acetate cata-
lyzed by p-toluenesulfonic acid was indeed selective for the
secondary alcohol but was outcompeted by substrate decom-
position. Therefore, we developed a one-pot procedure for
double acetylation (Ac2O, DMAP, pyridine) and subsequent
selective deprotection of the phenol (KOt-Bu, t-BuOH) to
provide 32a in 85% yield (Table 3).[34]
°
temperature to 70 C allowed for a shorter reaction time (24 h)
and significantly improved the yield of 33 (38%) and provided
lactone 34 in 7% yield (Table 3, entry 3). We also found that a
shorter (Table 3, entry 4) or longer (Table 3, entry 5) reaction
time was detrimental to the reaction. Further increasing the
°
temperature (100 C in chlorobenzene) led to decomposition
and only traces of 33 and 34 were isolated (Table 3, entry 6).
The other regioisomer 32b turned out to be even more
reluctant to oxidation. Employing the optimized reaction
conditions and extending the reaction time to 48 h allowed for
the isolation of 33 in 20% yield along with 34 (7%) (Scheme 5).
Efforts to convert the lactone 34 into 11 by reduction to the
corresponding lactol and subsequent methylenation were
unsuccessful.
For the deprotection and reduction of 33 we initially
investigated a lithium aluminum hydride reduction. In this case,
we only observed incomplete reduction. In contrast, treatment
with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®)
reproducibly afforded tetraol 35 in excellent yield (89%). For
the final installation of the axial vinyl unit, direct vanadium[36] or
rhenium[37] catalyzed deoxydehydration (Bu4NReO4, P(o-tolyl)3;
H4NReO4, P(o-tolyl)3; MeReO4, P(o-tolyl)3) led to decomposition.
When employing Nicholas conditions (Bu4NReO4, Na2SO3, 15-
crown-5 or H4NReO4, indoline), traces of the diterpenoid 11
were obtained, but as an inseparable mixture with side
products.[38] Finally, the Corey–Winter protocol was found to be
the best option.[39] Thiocarbonate 36 was initially accessed by
When a solution of 32a in a biphasic mixture of ethyl
°
acetate and water was heated to 50 C in the presence of an
Table 3. Optimization of the oxidation of 32a.[a]
Entry Solvent Concentration
[mM]
Temp
Time
[h]
33
34
°
[ C]
1
2
3
4
5
6
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
C6H5Cl
100
24
24
24
24
24
50
50
70
70
70
100
84
72
24
12
48
12
19
27
38
25
29
18
12
7
3
13
Scheme 5. Completion of the synthesis of pimara-15-en-3α,8α-diol (11).
°
Reagents and conditions: a) KMnO4, ethyl acetate, H2O, 70 C, 38% from 32a,
traces traces
°
°
20% from 32b; b) Red-Al®, toluene, 22 C, then 80 C, 89%; c) TCDI, DMF,
°
[a] Reagents and conditions: a) Ac2O, DMAP, pyridine, CH2Cl2, 22 C, then
°
°
60 C, 55%; d) P(OMe)3, 110 C, 52%. Ac=acetyl, DMF=N,N-dimeth-
ylformamide, Red-Al®=sodium bis(2-methoxyethoxy)aluminum hydride,
TCDI=1,1’-thiocarbonyldiimidazole, THF=tetrahydrofuran.
°
KOt-Bu, THF, t-BuOH, 22 C, 85%. Ac=acetyl, DMAP=N,N-dimeth-
ylpyridin-4-amine, py=pyridine, THF=tetrahydrofuran.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
5
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
treating a solution of tetraol 35 in chloroform with thiophos-
gene and 4-(N,N-dimethylamino)pyridine. However, this proce-
dure was not reproducible and led to variable yields (0–58%).
We attribute this observation to the poor solubility of 35 in
chlorinated solvents. Performing the reaction with 1,1’-thiocar-
bonyldiimidazole (TCDI) in N,N-dimethylformamide at elevated
expected that the β-silicon effect would ensure the formation
of a six-membered carbocycle during the third ring-closure.[45]
We first planned the installation of a silacyclobutane unit
due to its small size and its capability to undergo the Tamao–
Fleming oxidation.[46] For the preparation of 45, we attempted
carbometallation of tetrahydropyranyl ether 44 (conditions g).
In the presence of methylmagnesium bromide and catalytic
amounts of nickel(II) bis(acetylacetonate) (Ni(acac)2) and
trimethylaluminum (AlMe3) decomposition occurred.[47] Treat-
ment of 44 with trimethylaluminum and zirconocene dichloride
(Cp2ZrCl2) led to the formation of 46 and 47 via nucleophilic
ring-opening of the tetrahydropyranyl group.[48] When alcohol
46 was treated under the same conditions, slow decomposition
over six days was observed. When silacyclobutane 46 was
exchanged with dimethyl(phenyl)silane 49, formation of traces
of 50 occurred upon treatment with Cp2ZrCl2 and AlMe3. In
contrast to 46, 49 proved to be stable under these conditions,
as unreacted 49 was reisolated. We found that the addition of
water (1 equiv) was crucial to promote the carbometallation
and to obtain vinyl silane 50 in 40% yield.[49] Alcohol 50 was
converted to alkyl iodide 51 in the presence of iodine,
triphenylphosphine and imidazole (60% yield). Borylation and
Suzuki cross-coupling with vinyl bromide 52 or 53 afforded the
cyclization precursors 54 (88% yield) and 55 (60% yield). When
a solution of precursor 54 or 55 in CH2Cl2 was treated with
ethylaluminum dichloride (EtAlCl2) or tin(IV) chloride (SnCl4) at
°
temperature (60 C) reproducibly afforded 36 in 55% yield.
°
Upon heating a solution of 36 in trimethyl phosphite to 110 C,
the final elimination was induced to complete the first total
synthesis of pimara-15-en-3α,8α-diol (11, 52%) in 0.2% overall
yield. The NMR and mass-spectroscopic data obtained for
synthetic 11 were in full agreement with those reported for the
natural enantiomer in the literature.[13]
Towards ent-Norflickinflimiod C
After the successful total synthesis of 11, we envisioned to
extend the application of the polyene tetracyclization/trans-
annular endo-termination step to the synthesis of ent-norflickin-
flimiod C (10). For the introduction of the secondary alcohol at
C-14, we attached various hydroxy-surrogates (=R) at the
corresponding C-14 position of the general cyclization precursor
37 (Scheme 6). Despite the potential propensity to form a 5-
membered ring during the third ring-closure, we wanted to
study the behavior of bis enol ether 42 under Lewis-acidic
conditions (Scheme 6A). Benzyl enol ether 40 was prepared by
Wittig olefination of ketone 39 employing ((benzyloxy)methyl)
triphenylphosphonium chloride (BnOCH2PPh3Cl) and n-
butyllithium.[40] Deprotection of the primary alcohol with
triethylamine trihydrofluoride afforded alcohol 40 in 72% yield
as a separable 1.6:1 mixture of 40a:40b. For the formation of
alkyl iodides 41a/b, a screen of reaction conditions was
performed (conditions c). Mesylation of 40a followed by
treatment with tetrabutylammonium iodide afforded alkyl
iodides 41a/b in 41% yield as a 1:1 mixture of double bond
isomers.[41] No isomerization was observed when 40b was
treated with iodine, triphenylphosphine and imidazole (imH),
but the product 41b was inseparable from residual triphenyl-
phosphine. Therefore, triphenylphosphine was replaced by
diphenylphosphinoÀ polystyrene (polÀ PPh3), a polymer-bound
variant.[42] This enabled the isolation of 41 as a mixture of
isomers (41a:41b=1:6) in 9% yield. Finally, a modified
Mitsunobu reaction (DEAD, PPh3, LiI) was able to deliver
isomerically pure 41a in 59% and 41b in 80% yield,
°
À 78 C, a complex mixture of unidentified decomposition
products was formed.
Since additional heteroatoms proved to be incompatible in
the tetracyclization reaction, we opted for an allyl group as a
hydroxy-surrogate in our third attempt (Scheme 6C). We
prepared 60 by allylation of vinyl iodide 58 (conditions l).[50]
Halogen lithium exchange was induced by treatment with t-
butyllithium. Upon addition of copper(I) cyanide di(lithium
chloride) complex 59 and allyl bromide, allylation was observed
and diene 60 was formed along with protodemetallation
product 61 and dimer 62 in a 7:3:1 ratio, which was
1
determined by H NMR analysis of the crude reaction mixture.
The use of allyl iodide instead of allyl bromide resulted in an
even larger amount of the protodemetallation product 61. We
found that the mixed magnesate (n-Bu)2i-PrMgLi was capable of
suppressing the formation of 61 (60:61:62=25:1:3) and the
desired product 60 was isolated in 66% yield.[51] Deprotection
of the tetrahydropyranyl ether with pyridinium p-toluenesulfo-
nate (PPTS) in methanol (85% yield) and treatment of the
resulting primary alcohol with iodine, triphenylphosphine and
imidazole afforded alkyl iodide 63 in 78% yield. Borylation and
Suzuki cross-coupling with either 19 or 53 yielded the
cyclization precursors 64 (63%) and 65 (79%). Exposing a
solution of 64 to ethylaluminum dichloride (EtAlCl2) or tin(IV)
respectively.[43] Fragments 41a/b were converted into
a
boronÀ ate complex by treatment with t-butyllithium in the
presence of B-methoxy-9-BBN. This enabled a Suzuki cross-
coupling reaction with vinyl bromide 19 to obtain polyenes
42a/b in 53% and 74% yield, respectively. Treatment of a
solution of 42a or 42b in dichloromethane with either ethyl-
aluminum dichloride (EtAlCl2) or tin(IV) chloride (SnCl4) at
°
chloride (SnCl4) at À 78 C led to the formation of a complex
product mixture. Treatment of 65 with tin(IV) chloride or
ethylaluminum dichloride under the same conditions led to a
complex mixture as well, but three major products were
isolated, which were inseparable from each other by normal
phase high performance liquid chromatography (HPLC). Exten-
sive NMR studies of the mixture indicated the formation of the
°
À 78 C resulted in the formation of a complex mixture of
unidentified decomposition products.
In the second approach, we decided to replace the benzyl
enol ether by a more stable vinyl silane, which would allow for
a late-stage Tamao–Fleming oxidation (Scheme 6B).[12,44] We
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
6
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
°
°
Scheme 6. Synthesis of cyclization precursors 42a/b, 54, 55, 64 and 65. Reagents and conditions: a) BnOCH2PPh3Cl, n-BuLi, THF, À 78 C to 22 C; b) NEt3 ·3HF,
°
°
°
°
°
MeCN, 22 C, 72% over two steps; c1) MsCl, NEt3, CH2Cl2, 0 C to 22 C, then TBAI, benzene, 80 C, 41% of 41a/b (1:1); c2) I2, PPh3, imH, CH2Cl2, 0 C, inseparable
°
°
°
°
mixture of 41b with PPh3; c3) I2, polÀ PPh3, imH, CH2Cl2, 0 C to 22 C, 9% of 41a/b (1:6); c4) DEAD, PPh3, LiI, THF, 0 C, 59%; c5) DEAD, PPh3, LiI, THF, 0 C, 80%;
°
°
°
°
d) t-BuLi, B-methoxy-9-BBN, THF, À 78 C to 22 C, then 19, SPhos Pd GII, SPhos, Cs2CO3, DMF, H2O, 40 C, 53% of 42a, 74% of 42b; e) EtAlCl2, CH2Cl2, À 78 C; f)
°
°
°
°
°
°
SnCl4, CH2Cl2, À 78 C; g1) 44, MeMgBr, Ni(acac)2, AlMe3, THF, 22 C; g2) 44, AlMe3, Cp2ZrCl2, CH2Cl2, 0 C to 22 C; g3) 46, AlMe3, Cp2ZrCl2, CH2Cl2, 0 C to 22 C;
°
°
°
°
°
g4) 49, AlMe3, Cp2ZrCl2, CH2Cl2, 22 C to 40 C, traces; g5) 49, AlMe3, Cp2ZrCl2, H2O, CH2Cl2, À 40 C to 40 C, 40%; h) I2, PPh3, imH, CH2Cl2, 0 C, 60%; i) t-BuLi, B-
°
°
°
°
methoxy-9-BBN, THF, À 78 C to 22 C, then 52 or 53, SPhos Pd GII, SPhos, Cs2CO3, DMF, H2O, 40 C, 88% of 54, 60% of 55; j) EtAlCl2, CH2Cl2, À 78 C; k) SnCl4,
1
°
°
CH2Cl2, À 78 C; l1) t-BuLi, CuCN·2LiCl (10 mol%), allyl bromide, THF, À 78 C, 60/61/62 (7:3:1) determined by H NMR analysis of the crude reaction mixture; l2)
1
°
t-BuLi, CuCN·2LiCl (10 mol%), allyl iodide, THF, À 78 C, 60/61/62 (10:10:1) determined by H NMR analysis of the crude reaction mixture; l3) i-PrMgBr, n-BuLi,
1
°
°
CuCN·2LiCl (10 mol%), allyl bromide, THF, À 78 C to 0 C, 60/61/62 (25:1:3) determined by H NMR analysis of the crude reaction mixture, 66% of 60; m)
°
°
°
°
PPTS, MeOH, 22 C, 85%; n) I2, PPh3, imH, CH2Cl2, 0 C, 78%; o) t-BuLi, B-methoxy-9-BBN, THF, À 78 C to 22 C, then 19 or 53, SPhos Pd GII, SPhos, Cs2CO3, DMF,
°
°
H2O, 40 C, 63% of 64, 79% of 65; p) EtAlCl2, CH2Cl2, À 78 C, traces. Acac=acetylacetone, B-methoxy-9-BBN=9-methoxy-9-borabicyclo[3.3.1]nonane,
Bn=benzyl, Cp=cyclopentadienyl, DEAD=diethyl azodicarboxylate, DMF=N,N-dimethylformamide, imH=imidazole, MsCl=methanesulfonyl chloride,
n.d.=not determined, polÀ PPh3 =diphenylphosphinoÀ polystyrene, PPTS=pyridinium p-toluenesulfonate, py=pyridine, SPhos=2-dicyclohexylphosphino-
2’,6’-dimethoxybiphenyl, SPhos Pd GII=chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II), TBAI=tetrabu-
tylammonium iodide, TBS=t-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran, THP=tetrahydropyranyl.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
7
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
putative pentacycle 67 as a mixture of diastereomers (1:1)
along with equimolar amounts of an unidentified incomplete
cyclization product. Variation of the temperature and reaction
time did neither alter the product ratio nor could the yield of
67 be improved. Oxidation of the product mixture by ozone or
osmium tetroxide and sodium periodate led to inseparable
mixtures as well.[52] As a result, verification of the proposed
structure 67 was not possible and we discontinued our efforts
on this approach.
avoiding additional heteroatoms in the cyclization precursor.
We decided to investigate the application of allenes as hydroxy-
surrogates, which are an underrepresented functional group in
the field of polyene cyclization (Scheme 7).[53]
Realization of a tetracyclization/endo-termination sequence
of an allene with the general structure 68 would give access to
pentacycle 69 via attack of C-14 and termination of the arene at
C-13. Oxidative cleavage of the exo-methylene group would
allow for unmasking of the hydroxy group at C-14. Alternatively,
exo-termination might occur at C-21, as a formal allylic cation
would be formed during the third ring-closure at C-14. Due to
the two electrophilic positions of the allylic cation, we decided
to investigate the impact of electronic and steric parameters on
the allene. For this purpose, we chose the four differently
substituted allenes 76, 81, 83 and 85, three of which differ only
in their alkyl substitution degree. The allene 81 features an
electron-withdrawing group to destabilize the developing
positive charge at the undesired C-21 position (Scheme 8).
Attempts to directly couple allene fragments with vinyl
bromide 19, failed (see Supporting Information for details).
Due to the results obtained for 65 and the lessons learned
from the alternative substrates, we planned a new route
Scheme 7. Envisioned tetracyclization/endo-termination sequence of allene
68 towards the total synthesis of ent-norflickinflimiod C (10).
°
°
Scheme 8. Synthesis of cyclization precursors 76, 81, 83 and 85. Reagents and conditions: a) n-BuLi, BF3 ·OEt2, THF, À 78 C to 0 C, 80%; b) I2, PPh3, imH, Et2O,
°
°
°
°
°
°
MeCN, 22 C, 78%; c) t-BuLi, B-methoxy-9-BBN, THF, À 78 C to 22 C, then 19, SPhos Pd GII, SPhos, Cs2CO3, DMF, H2O, 40 C, 76%; d) TBAF, THF, 0 C to 22 C,
°
°
°
°
°
82%; e) CuI, (CH2O)n, Cy2NH, 1,4-dioxane, 103 C, 57%; f) n-BuLi, THF, À 78 C to 22 C; g) TBSOTf, 2,6-lutidine, CH2Cl2, 0 C; h) p-TsOH·H2O, MeOH, 22 C, 56%
°
°
°
over three steps; i) I2, PPh3, imH, Et2O, MeCN, 22 C, 92%; j) t-BuLi, B-methoxy-9-BBN, THF, À 78 C to 22 C, then 19, SPhos Pd GII, SPhos, Cs2CO3, DMF, H2O,
°
°
°
°
°
°
40 C; k) TBAF, THF, 0 C to 22 C, 69% over two steps; l) PhSCl, NEt3, THF, À 78 C to 22 C, 98%; m) Ac2O, DMAP, NEt3, 22 C, 95%; n) [(Ph3P)CuH]6, toluene,
°
°
°
°
°
22 C, 46%; o) LiHMDS, MeI, THF, À 78 C to 22 C, 36%; p) CuI, LiBr, MeMgBr, THF, 0 C to 22 C, 91%. Ac=acetyl, B-methoxy-9-BBN=9-methoxy-9-borabicyclo
[3.3.1]nonane, Cy=cyclohexyl, DMAP=N,N-dimethylpyridin-4-amine, DMF=N,N-dimethylformamide, imH=imidazole, LiHMDS=lithium hexamethyldisilazide,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, SPhos Pd GII=chloro(2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-bi-
phenyl)]palladium(II), TBAF=tetra-n-butylammonium fluoride, TBS=t-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran, THP=tetrahy-
dropyranyl, TIPS=tri-iso-propylsilyl, Ts=toluenesulfonyl.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
8
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
Thus, we decided to install the allene after the C(sp2)À C(sp3)
coupling. The synthesis of allene 76 commenced with the
addition of lithiated alkyne 70 to oxirane (71) in the presence of
boron trifluoride diethyl etherate (BF3 ·OEt2) yielding primary
alcohol 72 in 80% yield (Scheme 8).[54] Treatment of 72 with
iodine, triphenylphosphine and imidazole afforded alkyl iodide
73 in 78% yield.
Borylation of 73 by exposure to t-butyllithium in the
presence of B-methoxy-9-BBN enabled a Suzuki cross-coupling
reaction with vinyl bromide 19. In the presence of a second-
generation SPhos precatalyst (5 mol%) and SPhos (5 mol%), 74
was obtained in 76% yield. Deprotection of alkynyl silane 74
was accomplished by treatment with tetra-n-butylammonium
fluoride in 82% yield. The resulting alkyne 75 underwent a
modified Crabbé homologation (CuI, (CH2O)n, Cy2NH) to provide
the cyclization precursor 76 in 57% yield.[55]
Formation of a chair-chair conformation 68a leads to the
generation of the trans-fused oxocarbenium ion 90. Subsequent
attack of the central carbon atom of the allene provides the
allyl cation 91a/b. A transannular endo-termination would
afford the desired product of the general structure 69.
Unfortunately, cyclization precursor 85 underwent an exo-
termination pathway via 91b to give pentacyclic products of
the general structure 92 (highlighted in green). The formation
of cis-fused products 86c/d (general structure 96) might be
explained by a chair-boat conformation 68b of the first two
rings at the beginning of the cyclization reaction (Scheme 9B).
A subsequent ring-flip results in the formation of oxocarbenium
ion 94a/b residing in a chair-chair conformation. The formation
of cis-fused [6,6,6,6,6]-pentacycles 96 (highlighted in red) is
consistent with an attack of the central carbon atom (C-14) of
the allene 94a followed by an exo-termination step of the
resulting allylic cation 95.
The higher substituted allenes 81, 83 and 85 were prepared
by a divergent strategy. Addition of lithiated alkyne 70 to
ketone 77 was followed by silylation of the resulting tertiary
alcohol under Corey’s conditions (TBSOTf, 2,6-lutidine).[56] Cleav-
age of the tetrahydropyranyl ether under acidic conditions (p-
TsOH, MeOH) afforded primary alcohol 78 in 56% yield over
three steps. Alkyl iodide 79 was provided in 92% yield by
treatment with iodine, triphenylphosphine and imidazole.
Borylation of 79 followed by a Suzuki cross-coupling reaction
with vinyl bromide 19 and subsequent desilylation of the
alkynyl silane and the silyl ether in the presence of tetra-n-
butylammonium fluoride afforded dienyne 80 in 69% yield over
two steps. Upon treatment of 80 with phenylsulfenyl chloride[57]
(PhSCl) in the presence of triethyl amine a Mislow-Evans
rearrangement[58] was induced to complete the synthesis of
cyclization precursor 81 in almost quantitative yield.[59] Acetyla-
tion of tertiary alcohol 80 (Ac2O, DMAP, NEt3) gave ester 82 in
95% yield. Employing Stryker’s reagent ([(Ph3P)CuH]6) to a
solution of 82 in degassed toluene delivered allene 83 in 46%
yield.[60] Alkyne 82 was lithiated by treatment with lithium bis
(trimethylsilyl)amide and alkylated with methyl iodide to give
84 in 36% yield. The low yield for 84 results from competing
alkylation of the acetyl group to form a propionyl group.
Introduction of the missing methyl group and completion of
the synthesis of allene precursor 85 was accomplished via a SN2’
reaction of the propargylic acetate. By subjecting 84 to a
mixture of copper(I) iodide, lithium bromide and meth-
ylmagnesium bromide in tetrahydrofuran 85 was formed in
91% yield.[61]
Owing to recent applications of HFIP as a cosolvent for
cationic polyene cyclization reactions, we decided to include it
in our screening.[62] Changing the solvent from dichloromethane
to a 17:1 mixture of dichloromethane and HFIP (conditions b)
°
and increasing the temperature to À 15 C led to a higher
overall yield of tetracyclization products (79%) and a change in
the product composition (Scheme 9A). The temperature had to
°
°
be increased from À 78 C up to À 15 C to prevent freezing of
HFIP. Instead of 86a and 86b, the regioisomers 86e and 86f
were formed in 14% and 25% yield. The structure of 86e was
verified by single-crystal X-ray analysis. The yield of cis-decalins
86c and 86d slightly increased to 17% and 23%, respectively.
The formation of the isomers 86e/f (general structure 93
highlighted in blue, Scheme 9B) is explained by the same
cyclization pathway as for 92 with a subsequent 1,3-phenolate
shift, which alleviates the unfavorable 1,3-diaxial interactions.
This reactivity was exclusively observed for the trans-decalins
but not for the cis-decalins.
DFT calculations revealed that exo-termination products are
considerably thermodynamically favored over the desired endo-
termination products (ΔG=10.0 kcal/mol for 86b). Neverthe-
less, we intended to investigate if the endo-termination product
could be obtained by variation of the stereoelectronic proper-
ties of the allene.
Exposure of a solution of disubstituted allene 83 in dichloro-
°
methane to tin(IV) chloride at À 78 C (conditions a) afforded a
mixture of four tetracyclization products in 59% overall yield.
The regioisomers 87a and 87b were isolated in 15% yield each,
which both originate from the undesired exo-termination.
Control experiments indicated that higher temperatures during
the work-up procedure caused the 1,3-phenolate shift (see
Supporting Information for details). Analysis of the 2D NMR
data revealed the opposite stereochemistry at C-13 when
compared to 86e and 86f. This was supported by single-crystal
X-ray analysis of 87b. The cis-fused regioisomers 87c and 87d
were isolated in 13% and 16% yield, respectively.
Upon treatment of a solution of tetrasubstituted allene 85
°
in dichloromethane with tin(IV) chloride at À 78 C (conditions
a), four tetracyclization products were isolated in 69% overall
yield. Trans-fused pentacycle 86a was obtained in 15% yield
along with regioisomer 86b (20% yield), which only differs in
the position of the methoxy group. The structure of 86b was
verified by single-crystal X-ray analysis. The cis-fused structures
86c and 86d were isolated in 13% and 21% yield, respectively
and represent epimers of 86a and 86b.
Addition of tin(IV) chloride to a solution of monosubstituted
°
We assume that the formation of cis- and trans-fused
products can be attributed to a low π-facial selectivity of the
enol ether involved in the second ring-closure (Scheme 9B).
allene 76 in dichloromethane at À 78 C (conditions a) afforded
only 32% of tetracyclization products and secondary products
thereof. Unfortunately, the decreased steric demand at C-13 did
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
9
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
Scheme 9. A) Cyclization of precursors 85, 83 and 76. B) Observed cyclization pathways. [a]: a mixture of double bond isomers was obtained, and the major
°
exo-methylene isomer spontaneously isomerized in a solution of CDCl3 to the endo-isomer while standing at 22 C; [b] only the endo-isomer was isolated.
°
°
°
Reagents and conditions: a) SnCl4, CH2Cl2, À 78 C; b) SnCl4, CH2Cl2, HFIP, À 15 C for 85, À 20 C for 76. HFIP=hexafluoro-iso-propanol.
not facilitate the formation of endo-termination products.
Instead, the trans-fused pentacyclic product 88a was isolated in
5% yield. The formation of regioisomer 88b was supported by
detailed NMR-studies of a sample containing copolar impurities.
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
10
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
Surprisingly, we observed the formation of cis-fused [6,6,5,6,6]-
pentacycle 88c, which was isolated as a mixture of double
bond isomers in 11% yield. For the exo-methylene unit, we
observed spontaneous isomerization to the endo-isomer in
deuterated chloroform. The structure of 88c was verified by
single crystal X-ray analysis. The formation of regioisomer 88d
was supported by NMR analysis of a sample containing copolar
impurities.
substituted allenes delivered novel pentacyclic structures, which
allowed insight into the underlying cyclization pathways. The
investigated allenes underwent an exo-termination pathway
instead of the transannular endo-termination pathway required
for the synthesis of ent-norflickinflimiod C (10). The use of
alternative cyclization precursors is currently investigated in our
laboratories and will be reported in due course.
The formation of cis-fused [6,6,5,6,6]-pentacycles 98 (high-
lighted in orange) originates from an unusual attack of C-13 of Experimental Section
the allene 94b and proceeds via an exo-termination at the
Crystal-structure analysis: Deposition Numbers 1987621 (for 22a),
intermediary vinyl cation 97 (Scheme 9B). DFT calculations
suggest kinetic reaction control, as the theoretical cis-fused
[6,6,6,6,6]-product (of the general structure 96) originating from
an exo-termination of an allylic cation would be thermodynami-
cally favored (ΔG=3.3 kcal/mol compared to exo-88c). While
the decreased steric demand of allene 76 furnished exo-88c as
a kinetic reaction product, still no endo-termination products
were observed. Additionally, we also isolated heterodimer 89 in
16% yield. We assume its formation by protonation of the exo-
1987622 (for 22b), 1987623 (for 23), 2082138 (for 26), 2082139 (for
29), 1987624 (for 35), 2082140 (for 86b), 2082141 (for 86e),
2082142 (for 87b) and 2082143 (for endo-88c) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access Struc-
tures service.
methylene group of exo-88c followed by a nucleophilic attack Acknowledgements
of the exo-methylene isomer of 88d at the intermediary tertiary
benzylic carbocation (conditions a).
This work was supported by the Tyrolean Science Fund TWF
When the cyclization reaction was conducted in a 21:1
mixture of dichloromethane and HFIP (conditions b) and at
(F.16646/5-2019 to J.M.F.), and the Center for Molecular
Biosciences CMBI. We are grateful to Assoc. Prof. Dr. Christoph
Kreutz, Assoc. Prof. Dr. Thomas Müller, and Dr. Christina
Meisenbichler (University of Innsbruck) for help with NMR and
HRMS studies. Furthermore, we thank Prof. Dr. Ulrich Griesser,
Larissa Feilner, Tobias Taibon and Elias Schmidhammer for
experimental support. T.M. acknowledges the European Re-
search Council under the European Union’s Horizon 2020
research and innovation program (grant agreement No
101000060).
°
elevated temperature (À 20 C), the formation of 88a and 88b
was not observed. Detailed NMR-studies of a sample containing
copolar impurities indicated the formation of 1,3-phenolate
shifted tetracyclization products of the general structure 93.
The yield of cis-fused [6,6,5,6,6]-pentacycle endo-88c was more
than doubled (23%) and exo-88c was not isolated due to
quantitative isomerization of the exo-methylene group subse-
quent to the cyclization event. Regioisomer 88d was obtained
in 21% yield. The presence of HFIP also prevented the
formation of heterodimer 89, which explains the higher yield of
the corresponding monomers 88c and 88d. We assume, that at Conflict of Interest
°
elevated temperatures (>À 20 C) in presence of tin(IV) chloride
and HFIP (conditions b) isomerization of exo-88c/d is faster
than dimerization and therefore the formation of 89 was not
observed.
The authors declare no conflict of interest.
Keywords: cationic cascades · natural products · polyene
cyclization · terpenoids · total synthesis
Sulfinyl allene 81 proved to be unreactive under conditions
a. However, under conditions b, sulfinyl allene 81 decomposed
to a complex product mixture and formation of tetracyclization
products was not observed.
In conclusion, we accomplished a polyene tetracyclization/
[1] a) F. Chen, D. Tholl, J. Bohlmann, E. Pichersky, Plant J. 2011, 66, 212–
229; b) E. Oldfield, F.-Y. Lin, Angew. Chem. Int. Ed. 2012, 51, 1124–1137;
Angew. Chem. 2011, 124, 1150–1163; c) F. Zhou, E. Pichersky, Curr. Opin.
Plant Biol. 2020, 55, 1–10.
[2] a) D. E. Hall, P. Zerbe, S. Jancsik, A. L. Quesada, H. Dullat, L. L. Madilao,
M. Yuen, J. Bohlmann, Plant Physiol. 2013, 161, 600–616; b) F. Chen, D.
Tholl, J. Bohlmann, E. Pichersky, Plant J. 2011, 66, 212–229.
[3] a) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77, 5068–5077;
b) A. Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni, Helv. Chim. Acta
1955, 38, 1890–1904.
[4] a) R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105, 4730–4756; b) W. S.
Johnson, Bioorg. Chem. 1976, 5, 51–98; c) C. N. Ungarean, E. H. South-
gate, D. Sarlah, Org. Biomol. Chem. 2016, 14, 5454–5467; d) A. Barrett, T.-
K. Ma, T. Mies, Synthesis 2019, 51, 67–82; e) M. Baunach, J. Franke, C.
Hertweck, Angew. Chem. Int. Ed. 2015, 54, 2604–2626; Angew. Chem.
2015, 127, 2640–2664.
transannular endo-termination sequence involving
a dual
nucleophilic aryl enol ether. Four carbonÀ carbon bonds and
five stereocenters were formed from a readily available polyene
by the key cyclization assembling the pimarane carbon skeleton
in a single step. Oxidative cleavage of the aryl group enabled
the first total synthesis of the diterpenoid pimara-15-en-3α-8α-
diol (11) in 13 steps from commercially available geranyl
bromide. The highly flexible and modular synthesis allowed for
rapid structural modifications of the substitution pattern along
the polyene backbone. A library of cyclization precursors aimed
at the total synthesis of the nor-diterpenoid ent-norflickinflimiod
C (10) was prepared. Polyene tetracyclization of three alkyl-
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
11
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202101926
Chemistry—A European Journal
[5] a) R. J. Felix, C. Munro-Leighton, M. R. Gagné, Acc. Chem. Res. 2014, 47,
2319–2331; b) K. Hung, X. Hu, T. J. Maimone, Nat. Prod. Rep. 2018, 35,
174–202.
[6] J. M. Feilner, F. Haut, T. Magauer, Chem. Eur. J. 2021, 27, 7017–7021.
[7] a) W. S. Johnson, S. J. Telfer, S. Cheng, U. Schubert, J. Am. Chem. Soc.
1987, 109, 2517–2518; b) W. S. Johnson, B. Chenera, F. S. Tham, R. K.
Kullnig, J. Am. Chem. Soc. 1993, 115, 493–497.
[8] E. J. Corey, K. Liu, J. Am. Chem. Soc. 1997, 119, 9929–9930.
[9] W. S. Johnson, V. R. Fletcher, B. Chenera, W. R. Bartlett, F. S. Tham, R. K.
Kullnig, J. Am. Chem. Soc. 1993, 115, 497–504.
[10] a) J. M. Feilner, K. Wurst, T. Magauer, Angew. Chem. Int. Ed. 2020, 59,
12436–12439; Angew. Chem. 2020, 132, 12536–12539; b) K. Speck, R.
Wildermuth, T. Magauer, Angew. Chem. Int. Ed. 2016, 55, 14131–14135;
Angew. Chem. 2016, 128, 14337–14341; c) K. Speck, T. Magauer, Chem.
Eur. J. 2017, 23, 1157–1165.
[37] a) G. K. Cook, M. A. Andrews, J. Am. Chem. Soc. 1996, 118, 9448–9449;
b) M. Shiramizu, F. D. Toste, Angew. Chem. Int. Ed. 2012, 51, 8082–8086;
Angew. Chem. 2012, 124, 8206–8210.
[38] a) I. Ahmad, G. Chapman, K. M. Nicholas, Organometallics 2011, 30,
2810–2818; b) C. Boucher-Jacobs, K. M. Nicholas, Organometallics 2015,
34, 1985–1990.
[39] E. J. Corey, R. A. E. Winter, J. Am. Chem. Soc. 1963, 85, 2677–2678.
[40] a) G. Wittig, G. Geissler, Justus Liebigs Ann. Chem. 1953, 580, 44–57; b) G.
Wittig, U. Schöllkopf, Chem. Ber. 1954, 87, 1318–1330; c) D. H. R. Barton,
S. D. Géro, J. Cléophax, A. S. Machado, B. Quiclet-Sire, J. Chem. Soc.
Chem. Commun. 1988, 1184–1186.
[41] a) J. Leroux, A. S. Perlin, Carbohydr. Res. 1978, 67, 163–178; b) R. W.
Binkley, M. G. Ambrose, D. G. Hehemann, J. Org. Chem. 1980, 45, 4387–
4391.
[42] G. Anilkumar, H. Nambu, Y. Kita, Org. Process Res. Dev. 2002, 6, 190–191.
[43] S. Manna, J. R. Falck, C. Mioskowski, Synth. Commun. 1985, 15, 663–668.
[44] K. Tamao, N. Ishida, T. Tanaka, M. Kumada, Organometallics 1983, 2,
1694–1696.
[45] a) L. H. Sommer, E. Dorfman, G. M. Goldberg, F. C. Whitmore, J. Am.
Chem. Soc. 1946, 68, 488–489; b) F. C. Whitmore, L. H. Sommer, J. Am.
Chem. Soc. 1946, 68, 481–484; c) L. H. Sommer, F. C. Whitmore, J. Am.
Chem. Soc. 1946, 68, 485–487; d) K. A. Nguyen, M. S. Gordon, G. T.
Wang, J. B. Lambert, Organometallics 1991, 10, 2798–2803.
[46] J. D. Sunderhaus, H. Lam, G. B. Dudley, Org. Lett. 2003, 5, 4571–4573.
[47] a) B. B. Snider, M. Karras, R. S. E. Conn, J. Am. Chem. Soc. 1978, 100,
4624–4626; b) B. B. Snider, R. S. E. Conn, M. Karras, Tetrahedron Lett.
1979, 20, 1679–1682.
[11] J.-L. Chen, Z.-M. Zhao, X. Xue, G.-H. Tang, L.-P. Zhu, D.-P. Yang, L. Jiang,
RSC Adv. 2014, 4, 14447–14456.
[12] I. Fleming, R. Henning, H. Plaut, J. Chem. Soc., Chem. Commun. 1984,
29–31.
[13] T. Meragelman, Phytochemistry 2003, 62, 569–572.
[14] a) R. F. Church, R. E. Ireland, J. A. Marshall, J. Org. Chem. 1962, 27, 1118–
1125; b) R. E. Ireland, P. W. Schiess, J. Org. Chem. 1963, 28, 6–16; c) R. F.
Church, R. E. Ireland, J. Org. Chem. 1963, 28, 17–23; d) E. E. Van Tamelen,
S. A. Marson, J. Am. Chem. Soc. 1975, 97, 5614–5616; e) K. Mori, M.
Waku, Tetrahedron 1985, 41, 5653–5660; f) B. J. M. Jansen, G. C.
Schepers, A. de Groot, Tetrahedron 1989, 45, 2773–2776; g) A. Yajima, K.
Toda, K. Okada, H. Yamane, M. Yamamoto, M. Hasegawa, R. Katsuta, T.
Nukada, Tetrahedron Lett. 2011, 52, 3212–3215; h) M. Zhao, J. Cheng, B.
Guo, J. Duan, C.-T. Che, J. Agric. Food Chem. 2018, 66, 7859–7872.
[15] E. J. Corey, H. A. Kirst, Tetrahedron Lett. 1968, 9, 5041–5043.
[16] T. Nishikawa, S. Shibuya, S. Hosokawa, M. Isobe, Synlett 1994, 1994, 485–
486.
[48] S. Ma, E. Negishi, J. Org. Chem. 1997, 62, 784–785.
[49] P. Wipf, S. Lim, Angew. Chem. Int. Ed. Engl. 1993, 32, 1068–1071; Angew.
Chem. 1993, 105, 1095–1097.
[50] M. Couturier, Y. L. Dory, D. Fortin, A. Rouillard, P. Deslongchamps,
Tetrahedron 1998, 54, 10089–10110.
[17] E. J. Corey, M. C. Noe, S. Lin, Tetrahedron Lett. 1995, 36, 8741–8744.
[18] E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroeder, K. B. Sharpless, J.
Am. Chem. Soc. 1988, 110, 1968–1970.
[19] The enantiomeric excess was determined by Mosher ester analysis: J. A.
Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512–519.
[20] a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437–
3440; b) N. Miyaura, A. Suzuki, J. Chem. Soc., Chem. Commun. 1979, 866–
867; c) N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Sato, A. Suzuki,
J. Am. Chem. Soc. 1989, 111, 314–321; d) T. Ohe, N. Miyaura, A. Suzuki, J.
Org. Chem. 1993, 58, 2201–2208.
[51] K. Kitagawa, A. Inoue, H. Shinokubo, K. Oshima, Angew. Chem. Int. Ed.
2000, 39, 2481–2483; Angew. Chem. 2000, 112, 2594–2596.
[52] R. Pappo, D. Allen, Jr., R. Lemieux, W. Johnson, J. Org. Chem. 1956, 21,
478–479.
[53] a) R. L. Snowden, J.-C. Eichenberger, S. Linder, P. Sonnay, Helv. Chim.
Acta 2004, 87, 1711–1723; b) R. L. Snowden, S. Linder, Helv. Chim. Acta
2005, 88, 3055–3068; c) R. L. Snowden, S. Linder, Helv. Chim. Acta 2006,
89, 3071–3086.
[54] R. Ma, J. Young, R. Promontorio, F. M. Dannheim, C. C. Pattillo, M. C.
White, J. Am. Chem. Soc. 2019, 141, 9468–9473.
[21] a) J. A. Marshall, B. A. Johns, J. Org. Chem. 1998, 63, 7885–7892; b) G.
Seidel, A. Fürstner, Chem. Commun. 2012, 48, 2055–2070.
[22] a) T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem.
Soc. 2005, 127, 4685–4696; b) T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am.
Chem. Soc. 2010, 132, 14073–14075; c) B. J. Reizman, Y.-M. Wang, S. L.
Buchwald, K. F. Jensen, React. Chem. Eng. 2016, 1, 658–666.
[23] a) W. A. Nugent, T. V. RajanBabu, J. Am. Chem. Soc. 1988, 110, 8561–
8562; b) T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116,
986–997.
[55] a) P. Crabbé, H. Fillion, D. André, J.-L. Luche, J. Chem. Soc. Chem.
Commun. 1979, 859–860; b) J. Kuang, S. Ma, J. Org. Chem. 2009, 74,
1763–1765.
[56] E. J. Corey, H. Cho, C. Rücker, D. H. Hua, Tetrahedron Lett. 1981, 22,
3455–3458.
[57] a) M. Behforouz, J. E. Kerwood, J. Org. Chem. 1969, 34, 51–55; b) X. Lei,
Y. Wang, E. Fan, Z. Sun, Org. Lett. 2019, 21, 1484–1487.
[58] a) P. Bickart, F. W. Carson, J. Jacobus, E. G. Miller, K. Mislow, J. Am. Chem.
Soc. 1968, 90, 4869–4876; b) D. A. Evans, G. C. Andrews, C. L. Sims, J.
Am. Chem. Soc. 1971, 93, 4956–4957.
[24] G. Hilt, F. Pünner, J. Möbus, V. Naseri, M. A. Bohn, Eur. J. Org. Chem.
2011, 2011, 5962–5966.
[25] E. J. Corey, M. Sodeoka, Tetrahedron Lett. 1991, 32, 7005–7008.
[26] a) The same overall yield was achieved by employing iron(III) chloride
[59] a) S. Braverman, Y. Stabinsky, Isr. J. Chem. 1967, 5, 125–126; b) S.
Braverman, H. Mechoulam, Isr. J. Chem. 1967, 5, 71–74; c) G. Smith,
C. J. M. Stirling, J. Chem. Soc. C 1971, 1530–1535.
°
(FeCl3, CH2Cl2, À 78 C) to initiate the cascade reaction, but with a 1:1
[60] J. F. Daeuble, C. McGettigan, J. M. Stryker, Tetrahedron Lett. 1990, 31,
ratio of 22a/b; b) S. E. Sen, S. L. Roach, S. M. Smith, Y. Z. Zhang,
Tetrahedron Lett. 1998, 39, 3969–3972.
2397–2400.
[61] T. L. Macdonald, D. R. Reagan, R. S. Brinkmeyer, J. Org. Chem. 1980, 45,
4740–4747.
[27] R. A. Shenvi, E. J. Corey, Org. Lett. 2010, 12, 3548–3551.
[28] However, the structure was later confirmed indirectly by single-crystal
X-ray analysis of an oxidative cleavage product (see below).
[29] H. Klein, A. Steinmetz, Tetrahedron Lett. 1975, 16, 4249–4250.
[30] P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem.
1981, 46, 3936–3938.
[31] M. T. Nunez, V. S. Martin, J. Org. Chem. 1990, 55, 1928–1932.
[32] A. K. Chakraborti, U. R. Ghatak, J. Chem. Soc. Perkin 1 1985, 2605–2609.
[33] A. J. Birch, J. Chem. Soc. Res. 1944, 430–436.
[62] a) S. J. Plamondon, J. M. Warnica, D. Kaldre, J. L. Gleason, Angew. Chem.
Int. Ed. 2020, 59, 253–258; Angew. Chem. 2020, 132, 259–264; b) A. M.
Arnold, A. Pöthig, M. Drees, T. Gulder, J. Am. Chem. Soc. 2018, 140,
4344–4353; c) Z. Tao, K. A. Robb, K. Zhao, S. E. Denmark, J. Am. Chem.
Soc. 2018, 140, 3569–3573; d) I. Shuklov, N. Dubrovina, A. Börner,
Synthesis 2007, 2007, 2925–2943; e) J.-P. Bégué, D. Bonnet-Delpon, B.
Crousse, Synlett 2004, 18–29.
[34] K. Iwasaki, M. Nakatani, M. Inoue, T. Katoh, Tetrahedron 2003, 59, 8763–
8773.
[35] a) O. Doebner, Ber. Dtsch. Chem. Ges. 1891, 24, 1753–1757; b) R.
Anschütz, G. Rauff, Justus Liebigs Ann. Chem. 1903, 327, 201–210.
[36] G. Chapman, K. M. Nicholas, Chem. Commun. 2013, 49, 8199–8201.
Manuscript received: June 1, 2021
Accepted manuscript online: July 2, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–13
www.chemeurj.org
12
© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
J. M. Feilner, I. Plangger, Dr. K. Wurst,
Prof. Dr. T. Magauer*
1 – 13
Bifunctional Polyene Cyclizations:
Synthetic Studies on Pimarane
Natural Products
The biosynthesis of pimaranes is
based on two consecutive cyclization
reactions of the linear polyene gera-
nylgeranyl diphosphate. In contrast,
our synthetic studies on pimaranes
involve a tetracyclization reaction of a
dual nucleophilic aryl enol ether. The
modified isoprene enabled a transan-
nular endo-termination step and rapid
assembly of the natural product
pimara-15-en-3α-8α-diol.