Structural diversity from the transannular cyclizations of natural germacrone and epoxy derivatives: A theoretical-experimental study

Article abstract of DOI:10.1002/chem.201300662

Treatment of germacrone (1) with different electrophiles, and of its epoxy derivatives germacrone-4,5-epoxide (2), germacrone-1,10-epoxide (3) and isogermacrone-4,5-epoxide (4) with Br?nsted/Lewis acids and Ti ^III, gives rise to a great structural diversity. Thus, by using a maximum of two steps, the production of more than 40 compounds corresponding to 14 skeletons is described. Computational calculations rationalizing the structural divergence produced are also described. Finally, since some of the compounds generated are bioactive natural sesquiterpenes, the mechanisms of formation of these substances will provide new insights in their biosynthesis. Copyright

Full text of DOI:10.1002/chem.201300662

DOI: 10.1002/chem.201300662
Structural Diversity from the Transannular Cyclizations of Natural
Germacrone and Epoxy Derivatives: A Theoretical–Experimental Study
M. Carmen Pꢀrez Morales,[a] Julieta V. Catalꢁn,[a] Victoriano Domingo,[a]
Martꢂn Jaraꢂz,[b] M. Mar Herrador,[a] Josꢀ F. Quꢂlez del Moral,[a]
Josꢀ-Luis Lꢃpez-Pꢀrez,*[c] and Alejandro F. Barrero*[a]
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FULL PAPER
Abstract: Treatment of germacrone (1)
with different electrophiles, and of its
epoxy derivatives germacrone-4,5-ep-
oxide (2), germacrone-1,10-epoxide (3)
and isogermacrone-4,5-epoxide (4)
with Brçnsted/Lewis acids and TiIII,
gives rise to a great structural diversity.
Thus, by using a maximum of two
steps, the production of more than 40
compounds corresponding to 14 skele-
tons is described. Computational calcu-
lations rationalizing the structural di-
vergence produced are also described.
Finally, since some of the compounds
generated are bioactive natural sesqui-
terpenes, the mechanisms of formation
of these substances will provide new in-
sights in their biosynthesis.
Keywords: biosynthesis · conforma-
tional analysis · density functional
calculations · ring closure · terpenes
Introduction
Biologically active small molecules have always attracted
great interest due to their capability to modulate the func-
tions of macromolecules in living systems.[1] In this sense,
the efficient generation of a library of compounds possessing
a high degree of structural and functional diversity entails a
major challenge.[2] Since Schreiberꢁs seminal works in the
early 2000s,[3] the use of diversity-oriented synthesis (DOS,
defined as the deliberate, simultaneous and efficient synthe-
sis of more than one target compound in a diversity-driven
approach) is increasing in number and sophistication.[4] Out-
standing studies very recently reported by Winssinger and
Baran[5] prove the current relevance of this strategy. The bi-
osynthesis of natural products, especially that of terpenes
(from which an amazing number of skeletons are produced
from simple substrates), in some ways parallels the key prin-
ciples of the diversity-oriented synthesis. Thus, germacra-
dienes, are postulated to be biosynthetic intermediates of an
extensive group of different sesquiterpenic structures.[6]
With the final aim of developing a synthetic strategy allow-
ing the efficient generation of many structurally diverse
compounds, we conceived that natural germacrone (1)[7]
could well be used in a reagent-based approach to produce
the targeted scaffold diversity (Scheme 1).
Scheme 1. Germacrone-based approach to skeleton diversity.
Germacrone can be isolated on a multigram scale from
the essential oils of Bacharis latifolia[8] and Geranium mac-
rorrhizum.[9] To assure the availability of this starting mate-
rial, we are optimizing Geranium macrorrhizum cultures for
the sustainable production of germacrone.[10] Some transan-
nular cyclization reactions of 1 mediated by different elec-
trophiles have also been described, leading fundamentally to
bicyclic compounds with eudesmane and occasionally
guaiane and cadinane structures.[11] In this regard, we have
recently reported the first results showing a new type of
transannular cyclization of germacrone mediated by
HSO3Cl at low temperature.[12] Easily available from germa-
crone,[13] epoxides 2–4 also possess a latent reactivity that
gives these molecules the potential to be converted into dif-
ferent molecular skeletons only by varying the reagents
used. Epoxides 2–4 are also natural products isolated mainly
from the rhizomes of different species of Curcuma.[14] Some
examples of the reactivity of epoxides 2–4 against different
acid media were also described. Thus, epoxide 2 was report-
ed to lead mainly to guaianes, whereas eudesmanes were
the major products resulting from the transannular cycliza-
tions of 3 and 4.[7,15]
[a] M. C. Pꢂrez Morales, Dr. J. V. Catalꢃn, Dr. V. Domingo,
Dr. M. M. Herrador, Dr. J. F. Quꢄlez del Moral, Prof. A. F. Barrero
Department of Organic Chemistry
Institute of Biotechnology, University of Granada
Avda. Fuente Nueva, s/n, 18071 Granada (Spain)
Fax : (+34)958243318
E-mail: afbarre@ugr.es
[b] Prof. M. Jaraꢄz
Department of Electronics, ETSIT, University of Valladolid
Paseo de Belꢂn 15, 47011 Valladolid (Spain)
[c] Prof. J.-L. Lꢅpez-Pꢂrez
The present study intends to prove the usefulness of 1–4
as a source of structural diversity and also as starting materi-
als in natural product synthesis. Thus, we report here the
cyclization reactions of 1 mediated by electrophiles, such as
Brønsted and Lewis acids, and those of epoxides 2–4, trig-
gered either by Lewis acids or [TiCl(Cp)2] (Cp=cyclopenta-
dienyl). In the event, these studies will also permit us to
Department of Pharmaceutical Chemistry
Faculty of Pharmacy, University of Salamanca
Avda. Campo Charro, s/n, 37007 Salamanca (Spain)
E-mail: lopez@usal.es
Supporting information for this article (including experimental proce-
dures of all the reactions performed, spectroscopic data, NMR spec-
tra, computational details, coordinates and energies for all computed
structures, and IRC) is available on the WWW under http://
dx.doi.org/10.1002/chem.201300662.
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
compare the behavior of the corresponding radical inter-
mediates with that of their cationic equivalents.
Additionally, we have performed theoretical studies,[16–19]
not only to rationalize the formation of the sesquiterpenic
structures generated, but also to provide new insights in the
mechanisms of formation of these sesquiterpenes. In this
sense, theoretical studies providing relevant insights into the
mechanisms of sesquiterpene-forming reactions have been
reviewed very recently.[20]
Results and Discussion
Figure 2. Energy diagram for the formation of carbocations I–III (ammo-
Cyclizations of germacrone: Transannular cyclization reac-
tions from medium-sized cycles are usually governed by the
geometry of the most stable conformation or conforma-
tions.[21] The adopted conformation capable of undergoing a
transannular interaction accounts for the regio- and stereo-
specificity of this reaction. In this sense, germacrone (1)
presents two major conformations in solution as can be
found in variable-temperature NMR spectra confirmed by
DFT calculations by using the B3LYP 6-31+G* method
(Figure 1).[12,22]
nium ion was included in the calculation to emulate the acidic medium in
the experimental conditions, see ref. [23]). Relative energies [kcalmolꢀ1
,
UB3LYP/6-31G(d)]. Selected distances in ꢆ. The IUPAC numbering is
in magenta.
These results led us to study the possibility of selecting
the experimental conditions that would lead with a certain
degree of selectivity over one cyclization type to another.[11]
Thus, as we recently reported,[12] when germacrone 1 was
treated with chlorosulphonic acid (4 equiv) in nitropropane
at low temperatures (ꢀ788C) for 10 min, only products de-
rived from intermediate III are obtained, namely spirane 5
(24%), together with the tricyclic compound 6 (35%), the
bicyclic compound 7 (8%), and minor compounds 8 (2%)
and 9 (1%) (Scheme 2). Compounds 5–9 possess new ses-
quiterpenoid skeletons.
On the other hand, when the reaction was carried out
with chlorosulphonic acid at room temperature, we observed
a rapid decomposition of the products, which prevented a
Figure 1. Major (1a) and minor (1b) solution conformations of germa-
crone (1). Relative energies [kcalmolꢀ1, uB3LYP/6-31G(d)] in blue. The
IUPAC numbering is in black.
In the predominant confor-
mation (1a) the distance be-
tween C-1 and C-4 is quite
short (2.80 ꢆ), which favors a
transannular cyclization proc-
esses.[12] Theoretical compara-
tive calculations at the DFT
level have been carried out on
the activation and reaction en- Scheme 2. Formation of compounds 5–9 from 1.
ergies from the major conform-
er 1a to the bicyclic carboca-
tionic intermediates II and III, resulting from the initial pro-
tonation–cyclization of the double bonds 1,10 and 4,5, re-
spectively (Figure 2). These studies have shown that the for-
mation of cation III is concerted, whereas that of
eudesmanic carbocation II, originated through 1,10 protona-
tion, is not a concerted process, involving the initial produc-
tion of carbocation I, which subsequently cyclizes to II.[23]
This two-step transformation has an activation energy of
3.3 kcalmolꢀ1, higher than the 2.2 kcalmolꢀ1 leading to the
cyclobutanic derivative carbocation III. Moreover, II is con-
siderably more stable than III (12.0 kcalmolꢀ1) (Figure 2).
conclusive analysis of the results. Nevertheless, when sulphu-
ric acid in CHCl3 was used at room temperature, eudes-
manes 10–13, produced through intermediate II, were ob-
tained (Scheme 3).
When the cyclization of 1 was stopped after 60 min, 94%
of the more stable eudesmane 13[24] was obtained. If the re-
action was stopped at shorter times, the proportion of 13
fell and that of 10–12 increased. Consequently, compound
13 should be formed after acid-mediated isomerization of
compound 12 through stereoselective protonation of the 4,5-
double bond by the convex face. For eudesmanes 10 and 11,
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Cyclizations of Natural Germacrone and Epoxy Derivatives
FULL PAPER
14, and 6%, respectively. The
relative stereochemistry of 19
and 20 was demonstrated by re-
ducing them to 10 and 11 in
identical conditions to those
employed for 15 and 16. On the
other hand, compounds 21 and
22 showed eudesmane proper-
ties in the NMR spectrum. The
Scheme 3. Formation of compounds 10–14 from 1.
which possess a known structure,[25,26] the stereochemistry of
interannular junction is trans as a result of the participation
of the major conformation 1a in the cyclization process. In
all these cases, only 1,10 double bond protonation products
were obtained. Compound 13 can be easily transformed into
the natural product coralloidin A (14).[24]
By following our reagent-based skeletal diversity ap-
proach, the behavior of 1 versus softer electrophiles, such as
N-bromosuccinimide (NBS), PhSeCl, and N-chlorosuccini-
mide (NCS) was also examined. Initially, compound 1 was
reacted with NBS (1.1 equiv) in CH2Cl2 at room tempera-
ture. After 15 min the reaction was complete, yielding 78%
of a mixture of eudesmanes 15 and 16 (Scheme 4) in a 3:1
Scheme 5. Mechanism for the preparation of compounds 18–22 from 1.
cis interannular junction was determined from the observed
nuclear Overhauser effect (NOE) between Me14 and H5. In
this case, the reaction mechanism involves the formation of
both the trans- and cis-eudesmane carbocations VII and
VIII, resulting from the participation of the conformers 1a
and 1b in the process (Scheme 5). The formation of cis-eu-
desmanes constitutes an outstanding novelty on germacra-
1(10),4-diene cyclizations, since they derived from transan-
nular cyclizations involving the minor conformer 1b.
The treatment of 1 with NCS (1.1 equiv) in CH2Cl2 at
room temperature led, after 30 h, to the formation of the
unstable allyl chloride 23 as the major product, together
with guaiane 25 and the bicyclic compound 24. All these
products resulted from the initial reaction of NCS with the
4,5 double bond, yielding the chloronium ion IX,[27] with the
last two compounds being formed as a result of different
transannular cyclizations from IX (Scheme 6).
The structural elucidation of compound 24 was carried
out by an exhaustive analysis of its 1D and 2D NMR spec-
tra. The molecular formula C15H21ClO, established by
HRMS, confirmed the presence of chlorine as well as five
degrees of unsaturation. Combined analysis of its COSY
and HMBC spectra allowed the presence of the connectivi-
ties shown in Figure 3 to be determined. Study of the long-
range correlations in its HMBC spectrum led us to the struc-
ture of this compound. The relative stereochemistry was de-
termined on the basis of the NOE-difference experiments
(Figure 3), with the NOE effects observed between Me15
and H2b, H6b, and between H1a and H5, H2a confirming
Scheme 4. Mechanism for the preparation of compounds 15–17 from 1.
ratio. Trans-decaline structures of 15 and 16 were confirmed
through radical reduction with Bu3SnH/azobisisobutyroni-
trile (AIBN) to the above mentioned compounds 10 and 11.
This regioselective and stereospecific cyclization started by
interaction of NBS with the double bond 1,10 present in the
major conformation 1a. This interaction originated the bro-
monium ion IV[27] on the a face of the double bond. The
transannular cyclization gave rise to the bicyclic carbocation
V, which after deprotonation, yielded the bromine deriva-
tives 15 and 16 (Scheme 4).
The preparation of compound 10 in two steps from 1 con-
stitutes a formal synthesis of natural cuauhtemone (17;
Scheme 4).[28]
The result of the cyclization of 1 with PhSeCl in CH2Cl2
at room temperature was similar to the previous one, and
eudesmanic-phenylseleno derivatives 18–22 (Scheme 5)
were formed exclusively after 30 min with yields of 37, 20, 7,
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
Scheme 6. Synthesis and mechanism for the preparation of compounds
23–25 stemming from 1.
Figure 4. Local ionization potential (LIP) mapped onto the electron den-
sity surface. The red spot (lowest LIP value) over the 4,5 double bond
corresponds to the most favorable site for an electrophilic attack. The
representation was obtained with Spartan ’08.[29]
was carried out, and the energies of the different conforma-
tions were calculated in vacuum (Figure 5).
Figure 3. Key COSY and HMBC correlations, and NOE effects of 24.
the trans interannular junction and the syn relationship be-
tween Me15 and the chlorine atom. Finally, the trans inter-
annular junction is in agreement with the participation of
the major conformation 1a in the cyclization process.
The above results on the reaction of 1 with the softer elec-
trophilic reagents, NBS and PhSeCl at room temperature,
follow the general guideline for germacra-1(10),4-dienes and
led only to eudesmanes, again as a consequence of the large
difference in stability of the bicyclic intermediates. Only
NCS, due to its lower reactivity as an electrophile (since
chlorine hardly accommodates a positive charge), could
react selectively with the more reactive 4,5 double bond,
leading to the cyclobutadiene derivative 24 and guaiane 25
as products of the transannular cyclization. The higher reac-
tivity of the 4,5 double bond towards an electrophilic attack
stems from its low local ionization potential, as shown in
Figure 4.
Figure 5. Main conformations of epoxigermacrones 2 and 3 and epoxyiso-
germacrone 4. The relative energies (kcalmolꢀ1, UB3LYP/6-31G(d)) are
given.
Up to now, we have shown how germacrone can be con-
verted through transannular cyclizations into more than 20
different products with different molecular skeletons
through the variation of reagents and conditions and, quite
remarkably, after only one chemical step.
Epoxygermacrones can adopt eight low-energy conform-
ers; four diastereomers and their respective enantiomers
(see the Supporting Information and Figure 1). The two
major conformers of the three products are represented in
Figure 5. These results are in agreement with the NMR
spectroscopic studies performed for some germacranolides
showing the existence of different conformer ratios depend-
ing on the solvent.[30] To test the solvent effect, the calcula-
tions were performed also by applying the polarizable con-
tinuum model (PCM),[31] to reproduce the experimental con-
ditions. In this sense, THF was considered as a solvent. The
results obtained with solvent were almost identical to those
Cyclizations of epoxides of germacrone and isogermacrone:
Once we had confirmed the diversity of skeletons available
from germacrone, we focused our efforts on analyzing the
Lewis acid and/or TiIII-mediated radical cyclization of epox-
ides of germacrone and isogermacrone, with the ultimate
goal of further widening the variety of structures derived
from germacrone. As with germacrone 1, an exhaustive con-
formational study of germacrone-4,5-epoxide (2), germa-
crone-1,10-epoxide (3), and isogermacrone-4-epoxide (4)
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Cyclizations of Natural Germacrone and Epoxy Derivatives
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Table 1. 1H (400 for 24 and 500 MHz for 28) and 13C NMR (100 for 24 and 125 MHz for 28) data (d, ppm) of
compounds 24 and 28.
in vacuum. Consequently, the
rest of the calculations per-
formed in this study were car-
ried out only in the gas phase.
We began our study by treat-
ing germacrone-4,5-epoxide (2)
with [TiIIICl(Cp)2], a mild and
highly chemoselective single-
electron transfer (SET) reagent
that has been used in the radi-
cal cyclization of epoxides.[32] In
the event, two main tricyclic
compounds possessing a new
sesquiterpenic skeleton, 26 and
27, were obtained after a cas-
cade cyclization that could be
rationalized by considering the
intermediacy of radicals X–XII
(Scheme 7). No eudesmane or
guaiane formation was detect-
ed, although these are the main
compounds found in previously
reported acid or basic cycliza-
tions of 2.[15]
24
28
24
28
1H NMR
1H NMR
13C NMR
13C NMR
3.48 (brt, J=9.7 Hz, H1)
2.17 (q, J=10.5 Hz, H2b)
1.39–1.35 (m, H1)
44.8 (C1)
19.8 (C2)
48.4 (C1)
21.7 (C2)
2.16–2.08 (m, H2b
)
2.02–1.94 (m, H2a
1.82–1.78 (m, H3b
)
)
1.77–1.72 (m, H2a)
1.62–1.57 (m, H3b)
1.50–1.45 (m, H3a)
31.8 (C3)
33.3 (C3)
1.73 (dt, J=11.3, 1.7 Hz, H3a
)
–
–
47.2 (C4)
70.9 (C5)
46.5 (C4)
81.8 (C5)
4.14 (dd, J=12.3, 4.0 Hz, H5)
4.42 (dd, J=11.6, 3.1 Hz, H5)
2.86 (dd, J=14.0, 3.9 Hz, H6b)
2.29 (dd, J=14.0, 12.6 Hz, H6a
2.78 (t, J=12.5 Hz, H6b)
2.42 (dd, J=13.2, 3.1 Hz, H6a)
33.4 (C6)
33.8 (C6)
)
–
–
–
–
133.5 (C7)
201.4 (C8)
127.5 (C7)
66.8 (C8)
0.93 (d, J=5.9 Hz, 1H, H9b
0.91 (d, J=5.8 Hz, 1H, H9a)
)
6.01 (brs, H9)
129.0 (C9)
32.5 (C9)
–
–
–
–
156.8 (C10)
133.8 (C11)
21.8 (C12)
20.1 (C13)
25.4 (C14)
13.7 (C15)
25.3 (C10)
140.2 (C11)
21.2 (C12)[a]
22.5 (C13)[a]
16.5 (C14)
14.9 (C15)
1.62 (s, H12)
1.82 (s, H13)
1.92 (s, H14)
1.06 (s, H15)
1.95 (s, H12)[a]
1.79 (s, H13)[a]
1.19 (s, H14)
1.41 (s, H15)
[a] Interchangeable assignments.
The connectivities deduced from its COSY spectrum to-
gether with some of the long-range correlations observed in
the HMBC spectrum (Figure 6) confirmed the proposed
Figure 6. Key COSY and HMBC correlations, and NOE effects of 28.
structure for 28. Finally, the correlations found in its
NOESY spectrum between H5 and H1 and between Me15
and Me14 established the relative stereochemistry. Com-
pound 29 was assigned to be a diastereomer of diacetate 28
(see the Supporting Information), in which the existence of
NOE effects between H5 and Me14 and between H1 and
Me15 determined its relative stereochemistry.
Theoretical calculations let us propose the pathway for
the formation of these compounds, shown in Figure 7. We
began these calculations without reagent, but the energy
barriers of transition states were very high and the latest
cyclization in both cases did not converge with the B3LYP
method recommended for this type of calculation.[20] We
therefore performed these calculations considering TiCl3 as
the electron-transfer reagent for the transannular cycliza-
tions of both low-energy conformations (2a and 2b) of ger-
macrone-4,5-epoxide 2.[34] In the presence of this reagent,
germacrone adopts preferred conformations with the sub-
stituents at C7 and C8 disposed in a planar disposition,
Scheme 7. Radical cyclization of 2 leading to 26–27.
Due to the marked instability of compounds 26 and 27,[33]
their structures were elucidated through extensive studies of
the spectroscopic data of their corresponding diacetate de-
rivatives, 28 and 29. Thus, compound 28 possesses the mo-
lecular formula C19H28O4 (HRFABMS). Taking into account
the presence of the two acetoxy groups and only one double
bond, the molecule must possess a tricyclic skeleton. Com-
1
parison of its H and 13C NMR spectroscopic data with those
of compound 24 (Table 1) showed a similarity in many of
the signals, with the two main differences found in the
moiety C8–C10, apart from the change of the substituent at
C5, which is Cl in 24 and AcO in 28. The presence of a cy-
ꢀ
ꢀ
clopropane ring located at C8 C9 C10 was deduced from
the shielded AB system corresponding to the two C9 pro-
tons (H9a, d=0.91 ppm, d, J=5.8 Hz; H9b, d=0.93 ppm, d,
J=5.8 Hz).
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
Figure 7. Mechanism proposed for the radical-mediated formation of tricycles 26 and 27. The relative energies (kcalmolꢀ1, UB3LYP/6-31G(d)). Selected
distances in TSs are shown in ꢆ. The IUPAC numbering is in magenta.
which facilitates the second cyclization step in both cases.
The transition states were verified by IRC calculations. The
potential energy surface is a little more favorable for 26-
been reported, but as far as we know, there are no prece-
dents for a transformation involving the consecutive genera-
tion of a four- and then a three-membered cycle.
A
E
We continued our study by treating germacrone-1,10-ep-
oxide (3) with the same [TiIIICl(Cp)2] reagent. In this case,
only one eudesmane alcohol was obtained (31) in an excel-
lent (89%) yield. The stereochemistry of 31 is rationalized
by considering that the most stable conformation of epoxide
3, that is 3a, is the reactive conformer (Scheme 8). Com-
pound 31 was previously reported,[15c] together with its D3-
regioisomer, as a product of the reaction of epoxide 3 with
BF3 in ether (27% yield).
We concluded these radical-triggered cyclizations of
epoxy-derivatives of germacrone by treating isogermacrone-
4,5-epoxide (4) with [TiIIICl(Cp)2]. In the event, three main
structures were produced after the homolytic opening of the
epoxide present in 4, namely 32–34 (Scheme 9).
ratio of compounds 28 and 29 found in the experimental
conditions. The radicals resulting from the epoxide opening,
Xa and Xb (both derived from the two lower energy confor-
mations 2a and 2b of germacrone-4,5-epoxide, respectively),
underwent a 4,1-closure to yield [4+8]-bicyclic-ring systems
(radicals XI and XII). These processes were predicted to be
exothermic by only 0.5 and 0.2 kcalmolꢀ1, respectively, and
with activation barriers of about 10 kcalmolꢀ1. At this point,
the proximity between C10 and the carbonyl carbon atom
C8 (2.44 ꢆ in XI, and 2.40 ꢆ in XII) together with their ap-
propriate spatial arrangement, allows a second cyclization
process to take place with a low barrier in both cases (3.2
and 1.2 kcalmolꢀ1, respectively). The data are consistent
with the fact that minor geometric changes are required for
this attack to occur. The tricy-
clic intermediates 26
ACHTUNGTNER[NUNG 2TiCl3]
and 27[2TiCl3] are thus gener-
ACHTUNGTRENNUNG
ated, and their formation pre-
dicted to be exothermic by 21.3
and 19.2 kcalmolꢀ1.
It should be noted that com-
pounds 26 and 27 were formed
as a result of a radical 4-exo-
trig,3-exo-trig domino process.
Individual 3-exo-trig[35] or 4-
exo-trig[36] cyclizations have Scheme 8. Radical cyclization of 3 leading to 31.
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Cyclizations of Natural Germacrone and Epoxy Derivatives
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Figure 8. Key COSY and HMBC correlations, and NOE effects of 34.
firmed the tricyclic core for compound 34. The existence of
NOE effects between H9 and Me14 and Me15 indicated
their syn relative stereochemistry (Figure 8). Furthermore,
after noticing on the one hand the geometric requirements
of the cyclopropane ring fused to the decalin, and on the
other the NOE effects observed between H5 and H3b and
H6b, the relative stereochemistries at C8 and C5 were also
unambiguously assigned.
Theoretical studies were carried out to find a plausible
mechanism for the formation of 33 and 34 (Figure 9). Ac-
cordingly, the homolytic opening of isogermacrone-4,5-epox-
ide (4) leads to radical XIII, with XIIIa as the most stable
conformation for this intermediate—a conformation that
differs from the most stable one found for the starting epox-
ide 4. Intermediate XIIIa then evolves to conformation
XIIIb, which is less stable by 1.9 kcalmolꢀ1, but the only one
able to cyclize to eudesmane 33 through the bicyclic radical
XIV. This radical evolved through a 3-exo cyclization to the
tricyclic compound 34. The formation of this structure was
the result of a new domino 6-endo-trig, 3-exo-trig process,
the calculated activation energies of which were predicted
to be only 3.0 and 2.2 kcalmolꢀ1, as can be seen in the com-
puted pathway for compounds 33 and 34 in Figure 9. The
global process was predicted to
Scheme 9. Radical cyclization of 4 leading to 32–34.
The 5 +7 skeleton present in compound 32 was originated
after the addition of the initially formed tertiary radical
XIII to the C10 carbon atom (Scheme 9, pathway a). The
same bicyclic scaffold was already found in 7, a compound
produced in the low-temperature protic-induced cyclization
of germacrone; however, to our knowledge, natural hedera-
cines A and B[37] and jasomontanone[38] were the only natu-
ral precedents reported to possess this skeleton. The struc-
ture assigned to compound 33 (Scheme 9, pathway b) was
confirmed by the basic isomerization of 33 into its known
tetrasubstituted isomer 35.[39] The structural elucidation of
compound 34 was carried out by an exhaustive analysis of
its 1D and 2D NMR spectra and by comparison of its spec-
troscopic data with those of 33. In Table 2, significant
ꢀ
changes were observed in the signals corresponding to C8
ꢀ
C9 C10, in which the presence of a cyclopropane ring is in-
ferred from the chemical shifts of H9 and C9 (Table 2). The
selected bidimensional correlations shown in Figure 8 con-
be exothermic by 36.8 kcal
molꢀ1.
Table 2. 1H (500 MHz) and 13C NMR (125 MHz) data (d, ppm) of compounds 33 and 34.
Being aware of the recent
33
34
33
34
1H NMR
1H NMR
13C NMR
13C NMR
papers reporting promising re-
sults on the InIII-promoted cyc-
lization of epoxyalkenes,[40] as
well as the use of Et2AlCl by
Corey et al. to trigger cascade
cyclizations of monoepoxypoly-
prenes,[41] we decided to treat
the three epoxides deriving
from germacrone with these
Lewis acids. With these experi-
ments we aimed not only to
compare the behavior of these
epoxides under radical and cati-
onic conditions, but also we an-
ticipated that new structural va-
riety could emerge from these
experiences. Thus, treatment of
2.17–2.11 (m, H1a)
2.27–2.19 (m, H1b
1.66–1.60 (m, H2a)
1.74–1.68 (m, H2b),
1.26–1.17 (m, H3a)
1.27–1.21 (m, H1a)
1.47–1.41 (m, H1b)
33.8 (C1)
22.1 (C2)
33.3 (C3)
29.6 (C1)
20.7 (C2)
33.4 (C3)
)
1.14–1.09 (m, H2b, H2a),
0.89–0.83 (m, H3a)
1.66–1.60 (m, H3b
)
0.98–0.94 (m, H3b
)
41.8 (C4)
70.5 (C5)
32.1 (C4)
75.0 (C5)
3.94 (t, J=6.0 Hz, H5),
2.59 (dd, J=15.8, 6.6 Hz, H6a)
2.87 (brd, J=15.6 Hz, H6b
3.50 (brs, H5)
2.38 (d, J=18.3 Hz, H6a)
2.47 (brd, J=17.5 Hz, H6b)
34.0 (C6)
35.9 (C6)
)
128.4 (C7)
203.1 (C8)
62.5 (C9)
145.0 (C10)
145.9 (C11)
23.3 (C12)
22.6 (C13)
126.4 (C7)
58.5 (C8)
31.5 (C9)
25.2 (C10)
133.3 (C11)
19.9 (C12)[a]
22.2 (C13)[a]
2.93 (s, H9)
0.38 (s, H9)
2.03 (s, H12)
1.83 (s, 3H, H13)
4.50 (s, 1H, H14a
4.92 (s, 1H, H14b
1.03 (s, 3H, H15)
1.78 (s, H12)[a]
1.59 (s, H13)[a]
)
)
1.28 (s, H14)[b]
1.17 (s, H15)[b]
112.0 (C14)
20.8 (C15)
23.1 (C14)
23.1 (C15)
germacrone-4,5-epoxide
(2)
[a] and [b] Interchangeable assignments.
with InBr3 resulted in the gen-
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
was reported to be produced by biotransformation of ger-
macrone-4,5-epoxide with Cichorium intybus,[15b] although in
the same work it was claimed that conversion of 2 into 38
appeared to be an uncatalyzed process. Curcumenone is a
bioactive cyclopropane-sesquiterpene with hepatoprotective
effects, antidiabetes activity,[44] and was also found to inhibit
nitric oxide production.[42] Diketone 39 is a new compound.
Only one precedent of a natural compound possessing the
[4+8] bicyclic skeleton present in 39 has been reported.[45]
Remarkably, the interannular junction of the natural com-
pound was reported to be cis, contrary to that reported for
39. This stereochemical dissimilarity constituted another ex-
ample of the capability of these Lewis acid mediated cycliza-
tions to generate diversity. Compound 40 showed the spec-
troscopic features of the natural product curcumadione. This
seco-guaiane derivative has been isolated from different
Curcuma species.[46]
Quantum mechanics calculations were undertaken to
reveal the role played by the Lewis acid species in the
whole process. Lewis acids were included in the calculations
to emulate experimental conditions. The proposed pathways
from 4,5-epoxygermacrone (2) to gajutsulactone A (37) and
curcumenone carbocation XVII are shown in Figure 10.[47] It
was then observed that the interaction of epoxide 2 with the
Lewis acid caused this germacrone derivative to adopt a
Figure 9. Mechanism proposed for the radical-mediated formation of tri-
cycle 34. The relative energies (kcalmolꢀ1, UB3LYP/6-31G(d)) are in
blue for intermediates and in green for TS. Selected distances in TSs are
shown in ꢆ. The IUPAC numbering is in magenta.
eration of two main structures, 37 (30%) and 38 (35%), to-
gether with minor guaiane 36 (8%) (Scheme 10). When the
same epoxide 2 was exposed to Et2AlCl, 36–38 were again
obtained (4, 31, and 22%, respectively), although now ac-
companied by two new diketones, 39 (11%) and 40 (18%).
A reasonable mechanistic proposal for the formation of
these compounds is shown in Scheme 10. Thus, the type a
cyclization leads to 36–38 and 40 through guaiane carboca-
tion XV, whereas the opening of the epoxide through path b
produces 39 through intermediate XVIII.
Compound 37 possesses identical spectroscopic data to
those reported for gajutsulactone A, which, together with its
epimer at C1, possesses a unique seco-guaiane-type skeleton
isolated from the rhizome of Curcuma zeodaria.[42] Gajutsu-
lactone A was found to inhibit nitric oxide (NO) production
in lipopolysaccharide (LPS)-activated mouse peritoneal
macrophages.[43] Compound 38 was identified as curcume-
none, again as a result of a domino process. This compound
productive conformer 2eACHTNUTRGENNG[U AlBr3], in which the methyl
groups are disposed anti, contrary to their disposition in the
most stable conformer of the starting epoxide 2a. This pro-
ductive conformer also presented a planar disposition for
both carbonyl and isopropilidene so as to overcome the
transition-state barrier (7.0 kcalmolꢀ1) of the transannular
cyclization leading to intermediate XV. Interestingly, the
generation of XV involves a concerted asynchronous rear-
rangement reaction in which the portion of the reaction co-
ordinate that precedes the transition structure shows a sub-
stantial degree of synchrony between the opening of the
epoxy group and the approximation of the generated carbo-
cation to the double bond, whereas the portion of the reac-
tion coordinate following the transition-state structure
shows that the epoxide is already fully opened, whereas the
[48]
ꢀ
C5 C1 bond-formation is still under progress.
At this
point, it should be noted that a
mechanistic proposal for com-
pound 37 was reported and this
involved the attack of the
oxygen atom derived from the
epoxide opening to the carbon-
yl carbon atom.[43] However,
this proposal seems unlikely
since a secondary carbocation
would be generated as an inter-
mediate.[49,20] Apart from this,
the axial H at C5 would prevent
the approach of the oxygen to
the carbonyl group.
Theoretical calculations on
the intermediate guaiane carbo-
Scheme 10. Treatment of 2 with Lewis acids (LA).
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Cyclizations of Natural Germacrone and Epoxy Derivatives
FULL PAPER
Figure 10. Mechanism proposed for the formation of 37 and 38. The relative energies (kcalmolꢀ1, UB3LYP/6-31G(d)) are in blue for intermediates and
in green for TS. Selected distances in TSs are shown in ꢆ. The IUPAC numbering is in magenta.
ꢀ
cation XV revealed an elongation of the C8 C9 bond
(1.66 ꢆ), which should be caused by a hyperconjugative
effect since the carbocation is located at an allylic position.
This elongation facilitated the cycle opening through a tran-
portion of the reaction coordinate following the transition
state structure shows a high degree of synchrony.
The formation of compound 39 could be rationalized by
considering an acid-mediated concerted cyclization process
of the germacrone-4,5-epoxide leading to a 4+8 bicyclic in-
termediate XVIII, which would progress to 39 through a
transannular 1,4 hydride-transfer process from XVIII to
XX.[50] Nevertheless, our computational studies showed that
the very high activation energy for this 1,4-hydride transfer
(40.5 kcalmolꢀ1) can be alternatively avoided through two
sequential hydride-transfer reactions, 1,2- and 1,3-hydride
from XVIII to XIX and from XIX to XX, respectively. The
calculated activation energies for these processes are 12.6
and 8.4 kcalmolꢀ1, which are substantially lower than the
corresponding 1,4-hydride transfer (Figure 11). It should be
pointed that although compound 39 could not be detected
when InBr3 was used as a Lewis acid, this compound ap-
pears in the reaction of 2 with the harder Lewis acid
Et2AlCl.[51] This fact indicates that the coordination of this
Lewis acid with 2 somehow also provokes the formation of
the carbocationic intermediate XVIII instead of only XV. In
ꢀ
sition state TXV!XVI, which presents a distance between C8
C9 of 2.36 ꢆ. The opening of the cycle leads to intermediate
XVIa, which, by rotation of the C5,6 bond, originates a new
rotamer (XVIb) that is 0.1 kcalmolꢀ1 more stable. In this in-
termediate, an approximation between the oxygen deriving
from the epoxide opening to the carbonyl carbon atom
takes place. Finally, the nucleophilic attack to the carbonyl
group (through a barrier of 3.2 kcalmolꢀ1) produces com-
pound 37 through a clearly exothermic process.
On the other hand, the rearrangement step leading to the
formation of curcumene carbocation XVII from XV in-
volves a second concerted asynchronous rearrangement re-
action with a low barrier of only 3.6 kcalmolꢀ1. This second
concerted process evolves just as the opposite of the genera-
tion of XV: the portion of the reaction coordinate that pre-
cedes the transition structure takes place asynchronously,
with the closure of the three-membered ring; whereas the
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
Figure 11. Mechanism proposed for the formation of 39. The relative energies (kcalmolꢀ1, UB3LYP/6-31G(d)) are in blue for intermediates and in green
for TS. Selected distances in TSs are shown in ꢆ. The IUPAC numbering is in magenta.
this sense, theoretical calculations emulating the experimen-
tal procedure by using AlBr3 as a Lewis acid show that the
oxyrane opening and subsequent formation of 39 is not pos-
sible. However, when the harder AlBr2 species is included in
the computational studies, the formation of 39 turned into a
straightforward process.
We continued our study by analyzing the behavior of ger-
macrone-1,10-epoxide (3) under the presence of InIII and
AlIII species (Scheme 11).
two spiro derivatives 43 and 44 were also new sesquiterpenic
compounds. In fact, we found only two precedents of natural
compounds presenting this skeleton, namely spirojatamol, a
sesquiterpene alcohol of Nardostachys jatamansi,[52] and spi-
rolepechinene, from Lepechinia bullata.[53] The obtention of
diketone 45 after Dess–Martin oxidation of a mixture of 43
and 44 confirmed that these two compounds are epimers at
C1. As we did with many of the compounds obtained, we
studied theoretically the mechanistic aspects of their forma-
tion. Computational studies led us to propose the formation
of aldehyde 42 and spirojatamanes 43 (Figure 12). In these
calculations, AlBr3/AlBr2 were considered to emulate exper-
imental conditions. In the presence of the Lewis acid AlBr3,
the preferred conformation of the starting epoxide coincides
with that found when the acid is not considered. The com-
putations gave an activation energy of 14.3 kcalmolꢀ1 to
lead to the trans-eudesmanyl intermediate XXI, an exother-
mic cyclization by 10.3 kcalmolꢀ1. After the ring closure, the
process continues with a typical hydride-shift step from C5
to C4 to produce species XXII, a process that is predicted to
be exothermic by 1.4 kcalmolꢀ1. The opening of the cycle,
an unusual process favored by the stability of the resulting
carbonyl group, led to monocycle XXIIIa and its lower
energy rotamer XXIIIb, which are direct precursors of alde-
hyde 42. However, intermediates XXIIIa and XXIIIb can
further evolve, with remarkably low energetic barriers of 2.8
and 1.8 kcalmolꢀ1, through an intramolecular Prins reac-
tion[54] to intermediates XXIV and XXV, which are direct
precursors of compounds 43 and 44. In this sense, the physi-
cal basis for the rearrangement of the eudesm-5-yl carboca-
tion leading to the spirojatamane skeleton (Scheme 12
path a), among others, was reported very recently.[55] It
should be noted that the herein-described mechanism for
the formation of spirojatames 43 and 44 involves an alterna-
tive route to these sesquiterpenes (Scheme 12, path b). With
Scheme 11. Treatment of 3 with Lewis acids.
When InBr3 was used as Lewis acid, we obtained the mix-
ture of eudesmanes 41, aldehyde 42, and alcohols 43 and 44
(a pair of epimers found to possess a rare spiroACHTNUTRGNE[UNG 4.5]decane
carbon framework), which constituted a new proof of the
singular role of these Lewis acids. On the other hand, the
use of Et2AlCl led to the formation of aldehyde 42 as a
major compound.
Eudesmanes 41 were previously reported to be obtained
after treating 3 with BF3 etherate.[15c] With respect to alde-
hyde 42, no natural compound possessing this skeleton has
been previously reported to our knowledge, whereas the
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Cyclizations of Natural Germacrone and Epoxy Derivatives
FULL PAPER
Figure 12. Mechanism proposed for the formation of 42, 43, and 44. The energies (kcalmolꢀ1, relative to 3a, UB3LYP/6-31G(d)) are shown in blue for in-
termediates and in green for TS. The selected distances in the TSs are shown in ꢆ in black. The IUPAC numbering is in magenta.
Scheme 13. Treatment of 4 with Et2AlCl.
chemistry of 46 reveals that this product is derived from the
cyclization of the less-stable conformation of 4, that is, from
4b, which indicates that the coordination of the Lewis acid
alters the energies of the corresponding conformers.
Since no redox changes can be inferred from these cycli-
zation processes, we devoted our final efforts to studying the
Scheme 12. Different pathways towards the spirojatamane skeleton from
eudesm-5-yl cation.
feasibility of achieving these transformations catalytically. In
this sense, some examples of cyclizations of polyprenes or
a view to contributing to gain more insights into the biosyn-
thesis of these sesquiterpenes, we performed new theoretical
calculations, which on the one hand, confirmed that the non-
functionalized eudesm-5-yl cation evolves directly to the spi-
rojatame skeleton as described by Hess.[55] On the other
hand, they also revealed that this direct pathway could not
be found when an extra hydroxyl group is incorporated in
the parent eudesm-5-yl cation. Consequently, the herein-de-
scribed mechanism should not be ruled out a priori when
addressing the biosynthetic origin of new natural products
showing this skeleton.
epoxypolyprenes catalyzed by metallic triflates can be found
in the literature.[56] Thus, our preliminary studies revealed
that the cyclization of not only germacrone (1) but also of
its epoxy derivatives 2 and 4 can be very efficiently cata-
lyzed by using bismuth triflate (BiACHTUNGRTEN(NUNG OTf)3, 0.1 mol%) at
room temperature (Scheme 14).
Conclusion
In the reactions of germacrone (1) with electrophiles, the
type of electrophile and the reaction conditions used in each
case allow the selection of the trisubstituted double bond to
start the reaction, and subsequently the type of transannular
cyclization. Furthermore, the processes of the opening of
We continued our study by analyzing the behavior of iso-
germacrone epoxide 4 in the presence of Lewis acids. In the
event, treatment of 4 with Et2AlCl led mainly to the cis-eu-
desmane 46 (Scheme 13). It should be noted that the stereo-
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J.-L. Lꢅpez-Pꢂrez, A. F. Barrero et al.
not only limited to the presence of different skeletons, but
also includes functional and stereochemical variations, cov-
ering thus the main types of structural diversity.[58] In this
sense, it should be mentioned that these compounds contain
peripheral functional groups, which further increases the
possibilities of diversification. For instance, the structures
generated could incorporate (by using branching reaction
sequences) well-established privileged substructures[59] or
other molecular features that aid the conversion of the mol-
ecule into a therapeutic agent. It is also remarkable that this
diversity has been reached only after a minimum number of
steps (1–2), which should facilitate the large-scale prepara-
tion of these compounds.
We are aware that the ultimate goal of a DOS is the dis-
covery of biologically active molecules. In this regard, the
fact that some of the compounds obtained are natural prod-
ucts already proven to possess biological activity could be
considered a good starting point in this research.
Scheme 14. Treatment of compounds 1, 2, and
(0.1 mol%).
4 with BiACHTNUTGNRUEGN(OTf)3
Regarding the mechanistic studies, it can be concluded
that the initial conformation of the starting materials can be
modified by their interaction with the electrophilic reagents,
thus justifying the structural diversity found. We have also
found that the acid-mediated cyclizations of germacrone ep-
oxides are all concerted processes. In our opinion, this con-
formational alteration caused by the reagents resembles
somehow the action of the enzymes in the biosynthesis of
terpenes.[49a]
the three monoepoxy derivatives of germacrone (2–4),
either homo- or heterolytic, turned out to be complexity-
generating reactions. Thus, selective transformations have
been achieved to originate a set of products showing a
broad structural diversity, including several compounds that
possess new mono-, bi-, and tricyclic sesquiterpene skeletons
(Scheme 15). This fact should be highlighted since the exist-
ing correlation between skeletal variations and biorelevant
diversity is widely accepted.[57] Furthermore, this diversity is
Finally, we have also performed preliminary tests in which
nontoxic and readily available BiACTHNUTRGNENUG(OTf)3 (0.1 mol%) proved
to catalyze the cyclizations of
germacrone and derivatives
with high efficiency.
Acknowledgements
We thank the Spanish Ministry of Sci-
ence and Technology (projects CTQ
2010-16818 BQ) and the Junta de An-
dalucia (project of Excellence P08-
FQM-3596) for supporting this re-
search. We also thank the Spanish
Ministry of Science and Technology
for a predoctoral grant to M.C.P.M.
and to Prof. E. DuÇach (Institut de
Chimie de Nice, Universitꢂ Nice-
Sophia Antipolis, France) for the kind
donation of BiACHTNUTRGNE(UNG OTf)3. We also thank
Antonio Diu for the frontispiece
design.
Scheme 15. Summary of compounds obtained from germacrone. Compounds in red were obtained after only
one step. Compounds in blue were obtained after two steps.
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Cyclizations of Natural Germacrone and Epoxy Derivatives
FULL PAPER
plots are shown in the Supporting Information. The energies in
Figure 1 and throughout the paper are expressed in kcalmolꢀ1 and
include the ZPE correction.
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[7] A remarkable characteristic of this natural product is the spatial
proximity observed between C1 and C4, both in the model obtained
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www.chemeurj.org
6611

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Received: February 20, 2013
Published online: April 16, 2013
6612
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Chem. Eur. J. 2013, 19, 6598 – 6612