Where is the Oxygen? Structural Analysis of α-Humulene Oxidation Products by the Crystalline Sponge Method

Article abstract of DOI:10.1002/anie.201502302

Crystal structures of α-humulene, a cyclic sesquiterpene, and its oxidized subproducts, were analyzed by the crystalline sponge method. Regio- and stereochemistry, including absolute configuration when a chiral oxidant was applied, and the stable conformations of all the scaffold-related compounds were successfully determined for samples on a 5-50 μg scale.

Full text of DOI:10.1002/anie.201502302

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502302
German Edition: DOI: 10.1002/ange.201502302
Host–Guest Systems
Where is the Oxygen? Structural Analysis of a-Humulene Oxidation
Products by the Crystalline Sponge Method**
Nicolas Zigon, Manabu Hoshino, Shota Yoshioka, Yasuhide Inokuma, and Makoto Fujita*
Abstract: Crystal structures of a-humulene, a cyclic sesquiter-
pene, and its oxidized subproducts, were analyzed by the
crystalline sponge method. Regio- and stereochemistry, includ-
ing absolute configuration when a chiral oxidant was applied,
and the stable conformations of all the scaffold-related
compounds were successfully determined for samples on a
5–50 mg scale.
a-Humulene (1, Figure 1a) is a cyclic sesquiterpene
(formula C15H24) with three double bonds and six allylic
positions, all of them theoretically able to be oxidized. This
unique molecule has previously been used as a precursor for
biosynthesis-mimicking natural product synthesis through
transannular cyclization.[4] Additionally, there are several
reports on the site-selective oxidation of 1 using various
oxidation methods.[5] Herein, a series of oxidation products
are derived from 1 under various oxidation conditions and all
of the products are analyzed using the crystalline sponge
method. We show that all of the structural information,
including absolute configuration, can be univocally estab-
lished by single-crystal X-ray analysis using the crystalline
sponge method. Our results demonstrate that the crystalline
sponge method is a powerful tool for the structural analysis of
T
he direct oxidation of nonfunctionalized hydrocarbons is
a subject of current interest in synthetic chemistry because of
increasing demand for the development of highly efficient,
atom-economical synthetic processes.[1] In these reactions
however, substrates often carry similar oxidation sites within
the molecules and thus the determination of the regio- and
stereochemistry arising at the reaction sites is not always easy.
The same problems occur in pharmaceutical studies in which
drugs are metabolized into oxygenated derivatives.[2] In the
case of pharmaceuticals, the structure analysis is even more
demanding because, in addition to the need for determining
absolute stereochemistry at newly formed stereogenic cen-
ters, the analysis must often be carried out with only a trace
amount of the products (typically on a microgram scale).
The crystalline sponge method is a recently developed
X-ray technique that does not require crystallization of the
samples.[3] A porous metal complex absorbs a target molecule
into its pores, rendering the target molecule ordered and
detectable by X-rays. In this method, it is presumed that the
successful structural analysis of one parent compound prom-
ises the facile analysis of a series of its derivatives owing to the
capture of these derivatives at the same (or better) binding
sites in the crystalline sponge. This great advantage is
expected to enable us to provide a solution to the question
“where is the oxygen?”, a question which researchers often
encounter when studying hydrocarbon substrates that are
subjected to direct oxidation.
[*] Dr. N. Zigon, Dr. M. Hoshino, S. Yoshioka, Dr. Y. Inokuma,
Prof. Dr. M. Fujita
Department of Applied Chemistry
Graduate School of Engineering, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: mfujita@appchem.t.u-tokyo.ac.jp
[**] This research was promoted as a part of the JST-ACCEL project in
which M.F. is a principle investigator. We thank Prof. Phil S. Baran
and Dr. Dane Holte at Scripps Research Institute for providing us
with the information about their results on a-humulene trans-
annular reactions, as well as for helpful discussions. N.Z. thanks the
JSPS for a postdoctoral fellowship for North American and Euro-
pean researchers.
Figure 1. Structure determination of a-humulene by the crystalline
sponge method. a) Structure of 1; b) Superimposition of the Fo-map
(s=0.5) and the X-ray crystal structure (left), and side view of the X-
ray structure (right); c) X-ray structure of crystalline sponge 2·1. In (c),
the host framework is given as a light-gray stick model, 1 is shown in
blue as a space-filling model, and cyclohexane molecules are shown as
an orange stick model.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502302.
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a series of oxidized derivatives from a parent molecule, and
will be useful in total synthesis as well as in drug discovery.
Throughout the study, network complex [(ZnI2)3-
(tpt)2·x(cyclohexane)]n (2; tpt = 1,3,5-tris(4-pyridyl)triazine)
was used as the crystalline sponge.[6] First, parent compound
1 was analyzed. A tiny crystal of 2 (230 ” 170 ” 80 mm) was
treated with a small amount of 1 (5 mg) dissolved in
cyclohexane (5 mL) in a capped, pierced vial at 508C for 2 d
to give a guest-absorbed crystal (2·1), which was investigated
by X-ray diffraction.[7] Because of the presence of three E-
configured double bonds in the
components were formed and isolated in a ratio of circa
80:15:5 (Table 1, entry 1). Each component has a molecular
formula of C15H24O according to mass spectrometric meas-
urements. These products are expected to be three regioiso-
meric monoepoxides with different oxidation sites. However,
specifying the reaction site and especially elucidating the most
stable conformation of each product is difficult using only
NMR spectroscopic analysis. These structural concerns were
easily addressed with the crystalline sponge method. After
column chromatographic separation, the three components
cyclic scaffold, 1 is expected to
adopt
a
rigid conformation. Table 1: Preparation and crystallographic analysis of a-humulene oxidation products.
However, apart from an Ag+–
1 adduct,[5c] the native conforma-
tion of 1 has never been analyzed
by crystallography because it is
an oil at around room temper-
ature. The crystallographic anal-
ysis of the 2·1 complex clearly
showed the inclusion of one mol-
ecule of 1 per asymmetric unit
within the pores of the network
along with disordered cyclohex-
ane molecules (Figure 1b,c). The
three E-configured double bonds
are perpendicular to the cyclic
framework, and this pushes the 2-
and 9-methyl groups down and
up, respectively, in good agree-
ment with the Ag+–1 structure[5c]
as well as with the computer-
simulated stable conformation of
1.[8] This coincidence explains the
conformational rigidity of 1 as
the guest conformation in the
sponge pores is often influenced
by host–guest interactions and is
not always the most stable. Note
that conformationally fixed cyclic
E-alkenes are chiral; 1Rp*, 4Sp*,
and 8Rp* relative planar chirality
is defined for the three E-config-
ured double bonds. Thus, in this
case, the crystalline sponge
method clearly revealed both
the chemical structure and the
most stable conformation of 1.
With satisfactory X-ray data
for parent molecule 1 in hand, we
synthesized several oxidized
derivatives of
1 to examine
whether the same scaffolds
could fit into the pores of the
crystalline sponge after oxida-
tion. When 1 was oxidized with
one equivalent of m-CPBA [a] Left: Wire framework presentation overlaid with Fo maps. Values in parentheses are s levels. Right:
Stick presentation. [b] A mixture of 3–5 was obtained. [c] See the discussion in the text and the
Supporting Information. [d] Two conformers a and b are found in the crystal structure.
CHCl3 at À108C, three major
(meta-chloroperbenzoic acid) in
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were treated with crystalline sponge 2 and the guest-absorbed
crystals were subjected to single-crystal X-ray analysis.
The crystallographic analysis showed the major product
(isolated in 75% yield) to be (1R*,2R*)-1,2-epoxy humulene
(3; Table 1, entry 1). In the crystallographic analysis, one
molecule of 3 (occupancy 48%; the position is shared with
a disordered cyclohexane molecule (occupancy 52%)) was
refined.[9] Four disordered solvent molecules fill the remain-
ing pore voids. The conformation of the cyclic scaffold of 3 is
the same as that of parent 1 with 4Sp* and 8Rp* configurations.
In this conformer, the epoxy oxygen is located outside of the
cyclic framework. Selective formation of this conformer is
explained by the exo attack of m-CPBA on the 1,2-double
bond of 1.
The second product (14%) was determined to be 8,9-
epoxidized 4 (for convenience, scaffold carbons are numbered
using the same scheme as those of parent 1 throughout this
study).[10] Interestingly, the 9-methyl group of 4 is pointed
downward and thus the observed conformation of the 11-
membered cycle is diastereomeric to that of 1. Presumably,
the initial product is exo-attacked 4’, and this turns into
conformer 4 by flipping of the two double bonds [Eq. (1)].
The observed (and presumably the most stable) conformation
has 1Sp*4Rp* planar chirality for the two double bonds and
8R*9R* central chirality for the epoxy carbons. The third
component (5%) was identified as the 4,5-epoxidized com-
pound (5), a stable conformer with 1Sp*8Rp* planar chirality
and 4S*5S* central chirality.[11]
planar chirality on the 4,5-olefinic moiety was R*p. Further-
more, triepoxide 7 with three exo-epoxy oxygen atoms was
isolated as a major product when 3.5 equiv of m-CPBA were
applied (Table 1, entry 3). The scaffold conformations of both
diepoxide 6 and triepoxide 7 were the same as that of parent
1.[13]
The six allylic carbons in 1 are also theoretically active
toward oxidation. We studied the site selectivity in SeO2
oxidation by the crystalline sponge method and observed
that addition of SeO2 (1.0 equiv) to a solution of 1 in refluxing
tBuOH provided allylic aldehyde 8 in 15% yield (Table 1,
entry 4). The other aldehydes or alcohols that could result
from oxidation at different reaction sites were not isolated. In
the crystallographic analysis, despite a good R1 value (0.0397),
unnatural bond lengths and angles were detected for the guest
framework because of low guest occupancy and the thermal
motion of the guest, and we could only elucidate a rough
molecular framework for the guest. Nevertheless, oxidation at
the 2-methyl group was strongly suggested by the new
appearance of an electron-density peak, assignable as
À
a formyl oxygen, near the 2-methyl carbon (C O distance =
1.39(6) Š; see the Supporting Information).[14]
Dialdehyde 9 was obtained in 36% yield when 3.0 equiv
of SeO2 were applied to 1 (Table 1, entry 5).[15] In the
crystallographic analysis, two conformers (a and b) of 9 are
found in the asymmetric unit. Surprisingly, the molecular
structure of both conformers revealed that the E configura-
=
=
tions of the C1 C2 and C8 C9 double bonds were inverted to
the opposite configurations in the isolated product. The
isomerization may take place via bond rotation in the
SeO2–ene reaction intermediate, in which the double bond
is temporarily lost. The E/Z stereochemistry of trisubstituted
olefins is in general hard to determine by NMR spectroscopy,
yet can be easily visualized by crystallography. This example
further demonstrates the great potential of the crystalline
sponge method for the full determination of the stereochem-
istry of the target molecules.
It is noteworthy that the binding sites of the epoxide
moieties are substantially different for 3, 4, and 5, despite
their closely related scaffold and functional groups. Com-
pounds 3 and 4 are involved in hydrogen bonding with the
network and are placed at better binding sites: the oxygen
Finally, we applied our method to the absolute structure
determination of chiral humulene mono- and diepoxides
prepared with a chiral oxidation reagent. Using the asym-
metric epoxidation conditions of Shi and co-workers with
sugar derivative 10 (33 mol%) and oxone (1.1 equiv) as co-
oxidant in a buffered solution at À108C, monoepoxide 3 was
obtained in 41% yield.[16] Analysis by HPLC on a chiral
stationary phase showed the enantiomeric excess of 3 to be
85%. Thus-obtained 3 (85% ee) was included within the
crystalline sponge and the guest-soaked network structure
was crystallographically analyzed. As a result of the host–
guest interaction with the chiral guest, the network was
distorted in a chiral manner and the space group C2/c became
C2. The anomalous scattering from the host iodine atoms
allowed us to speculate the absolute structure of 3 to be 1R,2R
(Flack parameter= 0.215(13)).[17] Upon treatment of 1 with 10
(3.2 equiv) and oxone (5 equiv) at À108C, we obtained
a mixture of two diepoxides (circa 50% yield, obtained in
a 1:1 ratio as determined by NMR spectroscopy). From this
mixture, we isolated two major isomers, diepoxide 6 and its
diastereomer 11 with ee values of 40% and more than 99%,
respectively (Figure 2a). The absolute structure of 11 was
À
À
atom of 3 forms two CH···O bonds with two b CH moieties
of two adjacent pyridine moieties of a tpt ligand in the
À
network structure; 4 is maintained by two CH···O bonds
À
between the two a and b CH units of one pyridyl group of
a tpt core and the epoxide oxygen atom. Compound 5 is not
hydrogen bonded with the host framework.
Upon oxidation of 1 with two equivalents of m-CPBA,
a single isomer of the diepoxide with a formula of C15H24O2
(based on mass spectrometric measurements) was isolated
(Table 1, entry 2). In addition to the regioselectivity, we were
also interested in determining the relative stereochemistry
between the two epoxide moieties, but this is very difficult
using only spectroscopy. The stereochemical issues can only
be addressed by crystallography. After purification by recrys-
tallization, major product 6 was treated with crystalline
sponge 2 and the guest-absorbed crystal was subjected to X-
ray diffraction.[12] The crystallographic analysis showed the
reaction sites to be the 1,2- and 8,9-olefinic parts of 6 and the
relative stereochemistry to be 1R*2R*8S*9S*. The relative
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AgNO3-SiO2 column chromatography for 3, 4, and 5, and by
recrystallization from petroleum ether for 6 and 7.
General procedure for SeO2 oxidation: SeO2 (1–3 equiv) was
added portionwise to a solution of 1 in tBuOH (circa 0.2m) and the
solution was refluxed for 1 day. The resulting mixture was filtered,
extracted using cyclohexane and washed with H2O several times,
dried, and evaporated to dryness. Column chromatography and
preparative TLC (SiO2, cyclohexane/AcOEt) afforded aldehydes 8
and 9.
General procedure for chiral epoxidation: Two aqueous solutions
of oxone (1–5 equiv) and K2CO3 were added dropwise and simulta-
neously at À108C over 2 h to a flask charged with 1, Shiꢀs catalyst
(0.33–3.2 equiv), Bu4NHSO4 (0.1 equiv), CH3CN/MeOCH2OMe (1:2
ratio) and an aqueous solution of Na2B4O7/Na2EDTA (Na2EDTA =
disodium ethylenediaminetetraacetate). At the end of the addition,
the flask was allowed to stand at À108C for 1 h. Cyclohexane was
added, the mixture was filtered, and the phases were separated. After
extractions, drying, and evaporation to dryness, successive column
chromatographies (SiO2/AgNO3-SiO2, cyclohexane/AcOEt) and
recrystallizations (MeOH/H2O) yielded epoxides 3*, 6*, and 11*.
General procedure for guest inclusion into crystalline sponge: To
a micro vial containing a piece of single crystal of 1 and cyclohexane
(45 mL) was added 5–50 mL of a cyclohexane solution of the target
compound (1 mg/1 mL). Then, the micro vial was allowed to stand at
5–508C and the solvent was gradually evaporated over 2–7 d,
according to a previously reported procedure.[3a,b] For details, see
the Supporting Information.
X-ray crystallographic analysis: The guest-included crystalline
sponges were subjected to single-crystal X-ray diffraction. All the
data were collected using MoKa (l = 0.71073 Š) or CuKa X-ray
radiation (l = 1.54184 Š). All crystal structures were solved using
SHELXT[19] and refined using SHELXL.[20] For compounds 3, 6 (one
of two independent molecules), 7, 9, and 11*, no restraints were
applied for the guest frameworks. For compounds 1, 4, 5, 6 (the other
independent molecule), 8, and 3*, minimum numbers of restraints
(SIMU, DFIX, and/or SAME) were applied. Highly disordered
solvent molecules were refined by appropriately applying restraints
(DFIX, DANG, SIMU, and ISOR).
Figure 2. Asymmetric epoxidation of a-humulene 1. a) Reaction
scheme. b,c) Crystal structures of b) (1R,2R)-3 and c) (1R,2R,8R,9R)-
11. For the bottom structures in (b) and (c), the left images show the
superimposition of the Fo-map and the X-ray structure and the right
images show the side view of the X-ray structure. Atom colors:
C=blue; O=red.
determined to be 1R,2R,8R,9R with Flack parameter=
0.092(11)[18] (Figure 2c). We did not try to determine the
absolute structure of diastereomer 6 because of its low
ee value.
In summary, all the structures of the oxidation products of
parent compound 1, including their relative and absolute
stereochemical configurations, were successfully determined
using the crystalline sponge method. All the measurements
were performed with only microgram quantities of the
compounds. These experiments brought us not only structural
information but also several lessons on using the crystalline
sponge method for analysis. First, we clearly demonstrated
that if a parent compound fits the sponge pore, its scaffold-
related derivatives are also likely to be good substrates.
Second, we found that the guest-binding site for the deriva-
tives may be different from that of the original molecule if the
derivatives find better binding sites as a result of additional
host–guest interactions in the pore (for example, by hydrogen
bonding with the host framework). Third, it is clear that
careful consideration is necessary when discussing stable
conformations based on these crystal structures because the
guest conformation is biased by host–guest interactions in the
crystalline sponge. Our method can provide highly valuable
information on incorporated molecular scaffolds, such as
functional group position, stereochemistry, and the 3D
molecular arrangement. We expect that the crystalline
sponge method, even considering its limitations, will signifi-
cantly accelerate both synthetic research and drug discovery.
Keywords: configuration determination · crystalline sponge ·
host–guest systems · sesquiterpenes · structure elucidation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9033–9037
Angew. Chem. 2015, 127, 9161–9165
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Experimental Section
General procedure for m-CPBA epoxidation: m-CPBA (1–3.5 equiv)
was added portionwise to a solution of 1 in CHCl3 (circa 0.1m)
maintained at À108C. After 10 h at À108C, the mixture was allowed
to reach RT over 5 h. After addition of pentane, washing with H2O,
and evaporation to dryness, the products were purified using SiO2/
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[13] Crystallographic data for 2·7: C67.04H82.49I6.03N12O1.35Zn3.02 M =
2040.22, monoclinic C2/c, a = 34.651(4), b = 14.9888(15), c =
30.113(3) Š, b = 100.7353(19)8, V= 15366(3) Š3, Z = 8, Dcalc
1.764 gcmÀ3
GoF = 1.041, R1 = 0.0436, and wR2 = 0.1427.
CCDC number: 1053231.
=
,
[14] Crystallographic data for 2·8: C66.18H81.06I6.04N12O0.41Zn3.02 M =
2014.90, monoclinic C2/c, a = 34.7076(8), b = 15.0136(4), c =
29.9475(8) Š, b = 100.783(2)8, V= 15329.7(7) Š3, Z = 8, Dcalc
=
1.746 gcmÀ3, GoF = 1.025, R1 = 0.0397, and wR2 = 0.1100. CCDC
number: 1053222.
[7] Crystallographic data for 2·1: C58.04H65.65I6N12Zn3 M = 1888.83,
monoclinic
31.0584(7) Š, b = 101.437(2)8, V= 15759.7(5) Š3, Z = 8, Dcalc
1.592 gcmÀ3
GoF = 1.052, R1 = 0.0539, and wR2 = 0.1789.
C2/c,
a = 34.7408(7),
b = 14.9018(2),
c =
=
[15] Crystallographic data for 2·9: C75H82I6N12O4Zn3 M = 2173.03,
monoclinic C2/c, a = 34.307(7), b = 14.392(3), c = 34.931(7) Š,
,
b = 106.22(3)8, V= 16560(6) Š3, Z = 8,
D ,
calc = 1.743 gcmÀ3
CCDC-1053230 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
GoF = 1.064, R1 = 0.0725, and wR2 = 0.2268. CCDC number:
1053225.
[16] Z.-X. Wang, L. Shu, M. Frohn, Y. Tu, Y. Shi, Org. Synth. 2003, 9 –
17.
[8] a) H. Shirahama, E. Osawa, T. Matsumoto, J. Am. Chem. Soc.
1980, 102, 3208 – 3213; b) U. Neuenschwander, B. Czarniecki, I.
Hermans, J. Org. Chem. 2012, 77, 2865 – 2869; CCDC number:
1051619.
[17] Crystallographic data for 2·3*: C110.55H118.45I11.68N24OZn6 M =
3673.11, monoclinic C2, a = 34.5793(12), b = 14.9292(5), c =
30.6203(11) Š, b = 101.179(7)8, V= 15507.5(10) Š3, Z = 4,
D
calc = 1.573 gcmÀ3
,
GoF = 0.998, R1 = 0.0523, and wR2 =
[9] Crystallographic data for 2·3: C67.35H83.80I6N12O0.48Zn3 M =
2026.70, monoclinic C2/c, a = 34.5900(4), b = 14.92734(18), c =
30.1552(5) Š, b = 100.9231(13)8, V= 15288.1(4) Š3, Z = 8,
0.1680, Flack (Parsons) = 0.215(13). This Flack parameter
value is below the IUCr regulation criteria (0.3), but is not
sufficient to fully convince the absolute stereochemistry. The
1R,2R configuration of 3* was thus confirmed by converting it
into 11* whose configuration was determined with a reasonable
Flack parameter (see Ref. [19] and the Supporting Information).
CCDC number: 1053224.
D
calc = 1.761 gcmÀ3
,
GoF = 1.072, R1 = 0.0528, and wR2 =
0.1592. CCDC number: 1053227.
[10] Crystallographic data for 2·4: C58.08H62.94I6N12O1.45Zn3 M =
1909.79, monoclinic C2/c, a = 34.9245(6), b = 14.9263(2), c =
29.7839(5) Š, b = 101.228(2)8, V= 15229.0(4) Š3, Z = 8, Dcalc
=
[18] Crystallographic data for 2·11*: C105H108I12N24O2Zn6 M =
3653.17, monoclinic C2, a = 34.814(3), b = 14.9103(11), c =
1.666 gcmÀ3, GoF = 1.074, R1 = 0.0556, and wR2 = 0.1807. CCDC
number: 1053228.
30.057(3) Š, b = 101.500(2)8, V= 15289(2) Š3, Z = 4, Dcalc
=
[11] Crystallographic data for 2·5: C57.60H63.36I6N12O0.59Zn3 M =
1890.76, monoclinic C2/c, a = 34.9032(8), b = 14.8011(2), c =
1.587 gcmÀ3, GoF = 1.046, R1 = 0.0483, and wR2 = 0.1568, Flack
(Parsons) = 0.092(11). CCDC number: 1053223.
31.0811(7) Š, b = 101.564(2)8, V= 15730.7(6) Š3, Z = 8, Dcalc
=
[19] G. M. Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3 – 8.
[20] G. M. Sheldrick, Acta Crystallogr. Sect. C 2015, 71, 3 – 8.
1.597 gcmÀ3, GoF = 1.063, R1 = 0.0606, and wR2 = 0.1964. CCDC
number: 1053229.
[12] Crystallographic data for 2·6: C60H66I6N12O2Zn3 M = 1944.75,
monoclinic
C2/c,
a = 34.8531(7),
b = 14.7838(3),
c =
=
31.0339(8) Š, b = 101.296(2)8, V= 15680.8(6) Š3, Z = 8, Dcalc
Received: March 11, 2015
Revised: May 7, 2015
1.648 gcmÀ3, GoF = 1.045, R1 = 0.0624, and wR2 = 0.2055. CCDC
number: 1053226.
Published online: June 12, 2015
Angew. Chem. Int. Ed. 2015, 54, 9033 –9037
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9037