Four-Step Access to the Sesquiterpene Natural Product Presilphiperfolan-1β-ol and Unnatural Derivatives via Supramolecular Catalysis

Article abstract of DOI:10.1021/jacs.0c01464

Terpenes constitute one of the most structurally varied classes of natural products. A wide range of these structures are produced in nature by type I terpene cyclase enzymes from one single substrate. However, such reactivity has proven difficult to reproduce in solution with man-made systems. Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first experimental evidence consistent with the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

Full text of DOI:10.1021/jacs.0c01464

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Article
Four-step access to the sesquiterpene natural product presilphiperfolan-1#-
ol and unnatural derivatives via supramolecular catalysis
Leonidas-Dimitrios Syntrivanis, Ivana Némethová, Dario Schmid, Shani Levi, Alessandro
Prescimone, Fabian Bissegger, Dan Thomas Major, and Konrad Tiefenbacher
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01464 • Publication Date (Web): 05 Mar 2020
Downloaded from pubs.acs.org on March 6, 2020
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Four-step access to the sesquiterpene natural product
presilphiperfolan-1β-ol and unnatural derivatives via supramolecular
catalysis
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Leonidas-Dimitrios Syntrivanis,† Ivana Némethová,† Dario Schmid,† Shani Levi,§ Alessandro
Prescimone,† Fabian Bissegger,† Dan T. Major,§ Konrad Tiefenbacher*,†,‡
† Department of Chemistry, University of Basel, Mattenstrasse 24a, 4058 Basel, Switzerland
‡ Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 24, 4058 Basel, Switzerland
§ Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Supporting Information Placeholder
complex, biologically active terpenes, hard to synthesize by other
means, would be highly desirable and showcase the applicability of
supramolecular catalysis.
ABSTRACT: Terpenes constitute one of the most structurally
varied classes of natural products. A wide range of these structures
are produced in nature by type I terpene cyclase enzymes from one
single substrate. However, such reactivity has proven difficult to
reproduce in solution with man-made systems. Herein we report the
shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-
1β-ol to date, utilizing the supramolecular resorcinarene capsule as
catalyst for the key step. This synthetic approach also allows access
to unnatural derivatives of the natural product, which would not be
accessible through the biosynthetic machinery. Additionally, this
study provides useful insight into the biosynthesis of the
presilphiperfolanol natural products, including the first
experimental evidence consistent with the proposed biosynthetic
connection between caryophyllene and the presilphiperfolanols.
Cyclase enzymes exercise control over the terpene cyclization
pathway via their cavity shape, which facilitates specific substrate
folding,8 as well as via specific interactions with active site amino
acid residues and cofactors.9 However, as recently argued by
Tantillo,10 evidence from gas-phase computational studies
indicates that not every step is enzyme catalysed, as the intrinsic
gas-phase reactivity of the cation itself can dictate the reaction
outcome in some cases. We recognized that the resorcinarene
capsule I could be utilized to exploit this inherent reactivity:
identifying a key cationic intermediate and generating it within its
confines should enable the downstream reactions, while preventing
premature quenching of the reactive intermediates. To probe this
possibility in practice, we chose to investigate the postulated
biosynthetic connection between caryophyllene and the
presilphiperfolanol family of natural products.11 Three members of
this family have been isolated to date: (−)-presilphiperfolan-9α-ol
[(−)-2],12 (−)-presilphiperfolan-8α-ol [(−)-3],13 and (−)-
presilphiperfolan-1β-ol [(−)-4] (Figure 1 b).14,15 These natural
products hold significant importance in the study of terpene
biosynthesis, as their strained framework16 is believed to represent
a branching point that links together a number of different
biosynthetic pathways.11 They also exhibit interesting biological
activities like antimycobacterial and insect antifeedant
properties.17,18 Their complex tricyclic skeleton has proven to be a
challenging target for total synthesis; hitherto reported total
syntheses of the presilphiperfolanols have required 13-17 linear
steps from commercially available materials.15,19,20
INTRODUCTION
The tail-to-head terpene (THT) cyclization is one of the most
complex reactions observed in nature, giving rise to a vast amount
of complex terpene structures starting from a handful of linear
precursors.1 Despite its great synthetic potential, the THT
cyclization has proven very difficult to reproduce in solution, as
premature quenching of reactive intermediates, for instance by the
cleaved leaving group, gives rise to complex mixtures mainly
favoring monocyclic products.2 The Shenvi group succeeded in
forming a few polycyclic sesquiterpene structures by covalently
linking the leaving group to the molecule.3 Our group employed a
different approach, by using the hexameric resorcinarene capsule
I,4,5 formed from the assembly of monomers 1, as a reaction
chamber (Figure 1a). This supramolecular container is able to
catalyse the THT cyclization, likely via the stabilization of cationic
transition states within its cavity.6 We also demonstrated that the
limited selectivity encountered in the capsule-catalysed
cyclizations of linear sesquiterpene precursors could be overcome
through the use of a conformationally restricted substrate, in this
way achieving the selective preparation of the natural product
The current proposal for the presilphiperfolanol biosynthesis
(Figure 1b)21,22 posits that the initial cyclization of farnesyl
pyrophosphate, according to density functional theory (DFT)
calculations via its allylic isomer nerolidyl pyrophosphate,23 leads
to the humulenyl cation 5. After cyclization to the caryophyllenyl
cation 6, a concerted 1,2-alkyl shift/cyclization cascade leads to
structure 8, the direct precursor to presilphiperfolan-9α-ol (2).
From here, isotopic labelling22 and computational studies23 support
a 1,3-hydride shift (path a, red) as the path that leads to cation 11;
capture of this intermediate by water leads to presilphiperfolan-8α-
ol (3), while further rearrangements are believed to generate a
number of other sesquiterpene classes.13,21,24 The reassignment of
isolongifolene.7 However, isolongifolene is
a commercially
available compound, and it is not known to possess any biological
activity. Identifying capsule-catalyzed cyclizations that lead to
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Page 2 of 8
the C9 methyl configuration by Stoltz et al.15 allowed an alternative
(a)
HO
OH
1
2
3
4
5
6
7
8
1,2-hydride shift (path b, blue) to be proposed as the pathway that
leads to presilphiperfolan-1β-ol (4), however so far no further
evidence to support this has appeared in the literature.
R
R
self-
HO
OH
OH
assembly
in apolar
solvents
The proposed intermediacy of the caryophyllenyl cation 624c,25 in
the biosynthesis of the presilphiperfolanols has led to a number of
studies aimed at their biomimetic synthesis from caryophyllene and
related compounds in solution; however no such approach has so
far provided a natural presilphiperfolanol. Coates et al. carried out
solvolysis studies of caryophyllenyl alcohol derivatives.26 These
were only successful when performed on the simplified system 12
(Scheme 1a) lacking the methyl group present on C4 of the natural
product. The main product formed was compound 13, a derivative
of presilphiperfolan-9α-ol (2). When the solvolysis was attempted
on derivatized caryophyllenyl alcohol 14, the main product
(caryophyllene, 15), resulted from a simple elimination, while no
presilphiperfolanol structures were formed. Acidic treatment of
caryophyllene (15) itself has been shown to lead to unrelated
compounds.27 For instance, treatment with sulphuric acid furnished
-caryolanol (16) as the main product (Scheme 1b).27g
Rearrangement of isocaryophyllene (17), containing a Z-alkene
instead of the E-isomer, in acidic media has also been studied and
has only led to stereochemical isomers of the presilphiperfolanol
skeleton. Specifically, Robertson and coworkers reported the
formation of compound 18 in 35% yield as part of a mixture of
products by using sulfuric acid in diethyl ether (Scheme 1c); this
compound bears the opposite configuration on C1 to that observed
in the natural products.28 Collado et al. improved the yield to 60%
by employing FeCl3/SiO2 instead.29 Khomenko and coworkers
reported the formation of alcohol 19, bearing the opposite
configuration on C9 to that observed in the natural product, in 16%
yield by using superacid conditions (Scheme 1d).30
HO
R
R
HO
OH
(R = C11H23
I
1
6(H2O)8
=
1
)
(b)
H
H
H
H
9
rearranged
terpene
skeletons
H2O
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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H
H
PPO
(–)-presilphiperfolan-8-ol
11
(2E, 6E)-Farnesyl
pyrophosphate
3
[(–)-
]
path a: 1,3-hydride shift
b
H
H
a
H
H
(E or Z)
H
H
8
5
6
7
concerted
H2O
path b: 1,2-hydride shift
2
6
H
H
1
OH
9
H
OH H
15
3
5
H+
H2O
14
4
10
H
H
H
H
8
7
11
H
H
H
H
13
12
(–)-presilphi-
perfolan-1-ol
(–)-presilphiper-
folan-9-ol
10
9
4
]
2
]
[(–)-
[(–)-
H2O
Figure 1. a. Self-assembly of monomer 1 into hexameric capsule
I; b. Proposed biosynthesis of the presilphiperfolanol family of
natural products.
With this context in mind, we theorized that generation of the
caryophyllenyl cation 6 within the stabilizing environment of the
resorcinarene capsule may allow the reproduction of the so far
elusive natural cyclization cascade in a non-enzymatic setting.
However, the exact reaction product was not predictable at the
outset. This supramolecular approach led to several important
results, which are all reported in this article: (1) The shortest
synthesis of the sesquiterpene natural product presilphiperfolan-1β-
ol (4) to date (four steps), (2) the isolation and identification of a
novel hydrocarbon skeleton, (3) the facile access to
presilphiperfolan-1β-ol derivatives not available via the
biomachinery.
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O
O
Scheme 1. Overview of the literature on attempted
1
2
biomimetic synthesis of the presilphiperfolanol framework
from caryophyllene or its derivatives.
O3, DCM
Zn-Cu couple
O
O
EtOH, reflux
80%
then Zn dust,
AcOH
H
H
H
H
H
H
3
4
5
6
7
8
9
78 C  rt
98%
(a)
Coates et al.: Rearrangement only successful for nor-caryophyllenyl precursor
20
21
22
(Ts = tosyl, PNB = p-nitrobenzoyl)
(–)-caryophyllene
oxide
H
OH
$0.40 /g
H2O,
OH
H
4
acetone
H
H
I
10 mol%
TsO
75 ºC
MeMgBr
2.5 mol% HCl
H
H
H
H
Et2O
97%
H2O-satd. CHCl3,
30 °C
HO
H
H
13
61%
H
12
35%
(–)-presilphiperfolan-1-ol
23
4
(–)-
X-ray structure
4
[(–)-
]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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60
H2O,
acetone
PNBO
125 ºC
H
H
H
H
Optimization of the reaction conditions
14
15
)
caryophyllene (
70%
We next sought to identify optimal conditions for the formation
of presilphiperfolan-1β-ol (4) and its derivatives. Pleasingly, it was
found that carrying out the reaction in H2O-saturated CDCl3 slowed
down the formation of rearranged alkene 26, while at the same time
increasing the yield of desired presilphiperfolan-1β-ol (4) to
synthetically very useful 42% (Figure 2b). The reaction rate was
slower than with untreated CDCl3, with conversion reaching a
plateau at ~85%; addition of further HCl at this point was
ineffective as it increased the rate of formation of rearranged alkene
26. Carrying out the reaction with higher amounts of HCl favoured
formation of the rearranged alkene 26 and of caryophyllene (15).
Aromatic media (benzene and toluene) were also assayed but
proved inferior to CDCl3. Interestingly when H2O-saturated DCM
was used, the main byproduct observed was the elimination product
10; only traces of rearrangement product 26 were formed, while the
yield of presilphiperfolan-1β-ol was comparable to that observed in
the reaction in CDCl3. Under these conditions, prolonging the
reaction time eventually led to complete conversion of
presilphiperfolan-1β-ol into elimination product 10 (39% GC yield
after 20 d). Lastly, rearranged alkene 26 could be obtained as the
main product by prolonging the reaction time when using untreated
CDCl3 as the solvent, with complete conversion observed after 15
days at room temperature (21% GC yield) or 2 days at 50 °C (29%
GC yield).
(b)
Acid treatment of caryophyllene: Products derive from protonation of endocyclic double bond
H2SO4,
various
other
products
Et2O
HO
+
0 ºC
H
H
H
H
-caryolanol (16)
15
caryophyllene (
)
26%
(c)
Robertson et al., Collado et al.:
Reaction produces unnatural isomer
(d)
Khomenko et al.:
Reaction produces unnatural isomer
H
OH
1
H2SO4,
Et2O
H
9
FSO3H,
SO2ClF
various
other
products
various
other
products
+
H
H
+
–100 ºC
H
H
H
H
18
35%
19
16%
isocaryophyllene
17
(
)
RESULTS AND DISCUSSION
Initial cyclization studies
Alcohol 23 (Scheme 2) was chosen as the substrate for our
experiments. This was prepared in three steps from inexpensive
($0.4 /g)31 commercially available (−)-caryophyllene oxide (20)
following literature procedures;26 multigram quantities of this
alcohol can be readily accessed. In a first experiment, 23 was
subjected to reaction with 10 mol% of capsule I and 3 mol% of HCl
in CDCl3, conditions previously identified by us as optimal for the
capsule-catalyzed THT cyclization of sesquiterpenes.6a-d
Gratifyingly the formation of presilphiperfolan-1β-ol (4) as a major
product (13% GC yield after 4 days) was observed, along with
rearranged alkene 26 (11% GC yield, Figure 2a). The latter is
presumably formed through a 1,3-hydride shift of cation 9 (Figure
2c), followed by a methyl shift and elimination. To confirm the
structure of the rearranged alkene 26, a sample isolated after
preparative scale reaction (see SI) was subjected to allylic
oxidation; further oxidation to the aldehyde and formation of the
corresponding semicarbazone gave a crystalline derivative 28,
which provided further proof of the compound’s structure via X-
ray crystallography (Figure 2c). Interestingly, this compound
presents, to our knowledge, a novel hydrocarbon skeleton. It
remains to be seen if it also occurs in nature. Other components of
the reaction mixture were identified as elimination product 10 and
caryophyllene (15), the latter presumably deriving from
dehydration of the starting material.
(a)
(b)
4
4
SM
26
(23)
SM
(23)
15
15
10
26
10
(c)
H
H
1,3-hydride
shift
methyl shift
H
H
H
H
9
24
25
1. MnO2
DCM, rt
77%
H
H
H
H+
SeO2
H
DCM, 39 C
40%
(+ 30%
2. semicarbazide
hydrochloride,
NaOAc
EtOH/H2O 1:1,
50 C
aldehyde)
HO
26
27
84%
28
X-ray structure
Figure 2. a. Gas chromatogram of reaction in untreated CDCl3 after
4 d; b. Gas chromatogram of reaction in H2O-satd. CDCl3 after 7 d;
c. Proposed mechanism for the formation of rearranged alkene 26,
and synthesis of the crystalline derivative 28.
Scheme 2. Synthesis of (−)-presilphiperfolan-1β-ol utilizing
the capsule-catalysed cyclization cascade as the key step.
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Total synthesis on preparative scale
(a) capsule I catalysis
4
SM
23
1
2
3
4
5
6
7
8
15
To demonstrate the applicability of this approach to a total
synthesis of the natural product, a preparative scale reaction was
carried out, using optimized conditions (Scheme 2). A slightly
lower (2.5 mol%) loading of HCl was used as this was found to
provide a better reaction profile with regards to formation of
rearranged alkene 26 on this scale. H2O-saturated CHCl3 was
chosen as the solvent over H2O-saturated DCM since it provided a
less complex reaction mixture. However, concerning reaction time
DCM is clearly superior. The reaction was stopped after 7 days
(approximately 90% conversion), providing presilphiperfolan-1β-
ol in 35% isolated yield. Optical rotation measurement was
consistent with the literature value15 (within experimental error), as
expected given enantiomerically pure starting material was
utilized. This constitutes the shortest synthesis of (−)-
presilphiperfolan-1β-ol to date, in four steps from inexpensive
commercially available caryophyllene oxide. Additionally, X-ray
crystallographic analysis of crystals of the natural product thus
obtained (Scheme 2) confirmed that its structure is identical to that
of 9-epi-presilphiperfolan-1-ol reported by Joseph-Nathan et al.,14c
therefore supporting Stoltz’s structural reassignment.15
26
(
)
(b)
BF3.Et2O, Et2O, 0 °C
BCl3, DCM, - 80 °C
BBr3, DCM, - 22 °C
H2SO4, THF, 20 °C
(c)
(d)
(e)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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42
43
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45
46
47
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50
51
52
53
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57
58
59
60
(f)
H2SO4, DCM, 20 °C
(g)
HCOOH, 0 °C
Control experiments
Control experiments were carried out to confirm that the reaction
was taking place inside the cavity of capsule I. No product
formation was observed when the reaction was carried out in the
absence of capsule, or without any added HCl. Similarly, no
reaction was observed when the cavity of the capsule was blocked
with a strong-binding guest (Bu4NBr, 1.5 eq with respect to
capsule). Taken together, these results indicate that the synergistic
action between capsule and acid is essential for the catalytic
activity, in accordance with what was observed in our previous
studies.6a-d Interestingly, conversion of presilphiperfolan-1β-ol (4)
to either 10 or 26 also failed to take place in the absence of capsule,
indicating that these are also capsule catalysed processes.
Figure 3. Gas chromatograms for the cyclizations of compound
X under different conditions. (the full list is depicted in Fig. S-3 –
S-5).
Access to unnatural derivatives of presilphiperfolan-1β-ol
One potential advantage of resorcinarene capsule I over natural
enzymes is its capability to convert unnatural substrates; we
therefore decided to also investigate the potential of this
methodology to provide unnatural, hitherto unknown
presilphiperfolanol analogues. It was found that ethyl substituted
precursor 29 (Scheme 3) was tolerated by the supramolecular
catalyst system, providing the C4 ethyl analogue of
presilphiperfolan-1β-ol 30 in 27% isolated yield (32% GC yield)
after 10 days. To probe the limitations of the catalyst with regards
to the size of the substituent at C4, we synthesised several
cyclisation precursors that varied in the length of the incorporated
side-chain. Conversion of the linear butyl and hexyl substituted
precursors 31 and 35 proceeded smoothly. The desired derivatives
32 and 36 were isolated in 24% (33% GC yield after 22d) and 27%
(35% GC yield after 19d), respectively. However, a decrease in the
reaction rate was observed in both cases. For the branched i-butyl
substrate 33, the GC-yield dropped significantly (24%). However,
the targeted natural product derivative 34 was still isolated in 20%
yield. The octyl substrate 37 converted much slower (ca. 60%
conversion after two weeks), and product 38 was isolated in only
9% yield (12% GC yield). The decyl substrate 39 failed to convert
to an appreciable extent. The observed trend is consistent with a
specific size limit for the conversion on the inside of the
supramolecular capsule.
In order to better judge the importance of the supramolecular
catalyst (Figure 3a), further control experiments with a variety of
acidic conditions were tested. Emphasis was put on conditions
previously employed for the cyclization of caryophyllene or its
derivatives. A small selection of control experiments is displayed
in Figure 3 (the whole selection is displayed in Fig. S-3 – S-4). For
instance, BX3 Lewis acids29b,32 did not form any traces of the
natural product 4 (entries b-d). The same holds true for Bronsted
acids under a variety of conditions (entries e and g, see also Fig-
S-3 – S-4).33 Only in one case (H2SO4, DCM, 1:4) a minor peak
close in retention time to the one of the natural product 4 was
formed (entry f). However, NMR analysis (see SI Fig. S-5), did
not indicate formation of the natural product. These control
experiments highlight the extraordinary chemical environment
present inside the supramolecular catalyst system.
Scheme 3. Synthesis of (−)-presilphiperfolan-1β-ol C4-
derivatives.
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members of the presilphiperfolanol family. Computational studies
OH
H
I
10 mol%
1
2
3
4
5
6
7
8
point to the pathway that leads to presilphiperfolan-1β-ol as being
energetically preferred in the gas phase over the one that leads to
presilphiperfolan-8α-ol. This is in agreement with the observed
reactivity in the capsule catalyst. Rightfully, one could ask why the
development of man-made terpene cyclase mimics would be
required, when natural enzymes could be utilized instead. It is
certainly conceivable that if the enzyme that produces
presilphiperfolan-1β-ol in nature was identified, it could be used
for this purpose. However, access to the hitherto unknown
rearranged product 26 and to the unnatural C4 derivatives of
presilphiperfolan-1β-ol is only possible via the supramolecular
catalyst I so far, demonstrating for the first time the potential
advantage of supramolecular catalysis over natural enzymes for
terpene synthesis. Further work is required to clarify if the concept
of mimicking terpene biosynthesis by generating key biosynthetic
intermediates inside the capsule can be expanded to other natural
products.
RMgBr
Et2O
R
2.5 mol% HCl
R
22
HO
H2O-satd. CHCl3,
30 °C
H
H
H
29
31
33
35
37
39
30: R = Et (27%)
: R = Et (95%)
32: R = n-Bu (24%)
34: R = i-Bu (20%)
36: R = n-Hex (27%)
38: R = n-Oct (9%)
40: R = n-Dec (nd)
: R = n-Bu (85%)
: R = i-Bu (90%)
: R = n-Hex (68%)
: R = n-Oct (84%)
: R = n-Dec (89%)
Reaction pathway: Computational study
9
This study reports the first formation of a presilphiperfolanol
natural product from the caryophyllenyl cation 6, thereby providing
experimental evidence that is consistent with its intermediacy in the
biosynthesis of this family of natural products. Additionally, we
recognized that no presilphiperfolan-8α-ol 3, or any products
presumed to derive from it, were identified in the reaction mixture.
This suggests that in the cavity of the capsule, the 1,2-hydride shift
that leads to 9 (Figure 1b, path b) is favored over the 1,3-hydride
shift that leads to 11 (path a). To our knowledge the 1,2-hydride
shift pathway had not been computationally investigated before, in
contrast to the 1,3-hydride shift.23 Therefore, to probe this issue, the
relative energies of the two pathways were calculated (Figure 4,
Table S-1). In agreement with our experimental observations,
transition state TSb was found to be lower in free energy to
transition state TSa by 3.3 kcal/mol, while the resulting carbocation
9 was also found to be more stable than carbocation 11 by 7.8
kcal/mol. Also the final product 4 is more stable than its counterpart
3 from path a (Table S-2). This supports our hypothesis that the
resorcinarene capsule can be used to exploit the inherent gas-phase
reactivity of terpene frameworks, and in this way find application
in the biomimetic synthesis of complex terpenes.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications
website.
Experimental details and NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*konrad.tiefenbacher@unibas.ch; tkonrad@ethz.ch
H
H
H
Notes
The authors declare no competing financial interests.
TSa
TSb
+10.7
ACKNOWLEDGMENT
H
This work was supported by funding from the European Research
Council Horizon 2020 Programme [ERC Starting Grant 714620-
TERPENECAT] and the Swiss National Science Foundation as
part of the NCCR Molecular Systems Engineering.
+7.4
H
H
H
H
H
H
H
0.0
8
H
-3.8
11
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H
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for 5 Kg of compound
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TOC
1
key step:
2
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supramolecular catalysis
OH
H
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6
HO
H
H
H
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 Facile synthesis of
unnatural C4 derivatives
 novel hydrocarbon
skeleton discovered
Shortest
synthesis
to date
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