A stable rearrangement product of humulene-4,5-epoxide

Article abstract of DOI:10.1021/np0501839

Humulene-4,5-monoepoxide, 1, may rearrange to the cyclopropyl diol 2 during chromatography over silica. The rearrangement can be reversed with acid.

Full text of DOI:10.1021/np0501839

J. Nat. Prod. 2005, 68, 1441-1442
1441
A Stable Rearrangement Product of Humulene-4,5-epoxide
Raymond M. Carman*
Chemistry, The University of Queensland, Brisbane, Queensland, Australia 4072
Received May 26, 2005
Humulene-4,5-monoepoxide, 1, may rearrange to the cyclopropyl diol 2 during chromatography over silica.
The rearrangement can be reversed with acid.
The epoxides of humulene are naturally occurring and
are of special concern to the brewing industry.1 The
interesting interconversion of epoxide 1 to epoxide 3,
proceeding through the cyclopropyl diol 2, has already been
observed.2 Treatment of either epoxide 1 or 3 with refluxing
acid (pH 4) gave in each case a mixture of more than 30
products, from which compound 2 was isolated, and,
although its structure was later revised,3 its melting point
has never been disclosed.
We now report that chromatography of epoxide 1 over
silica affords diol 2. Thus, diol 2 may appear as an artifact
in the purification of epoxide 1 or 3, and so this report also
serves as a warning to workers in the field.
quent chromatography of purified epoxide 1 also yielded
diol 2. Yields of diol 2 were variable, ranging up to 15%,
depending upon the time the epoxide was in contact with
the silica and upon the quantity of acid and water present.
The structure 2 was not immediately obvious. Elemental
analysis was troublesome due to avid retention of water,
but finally C15H26O2, m/z 238, was obtained. From its
polarity, both oxygen atoms in the compound were hydroxyl
groups, yet the 1H NMR spectrum showed no protons
geminal to hydroxyls downfield of δ 3.0, with only a single
vinyl proton in this region, so these two hydroxyls were
tentatively assumed to be tertiary. However the 13C NMR
spectrum provided two methine carbons (δ 82.5, 74.8)
attached to oxygen, and since these values are too far
downfield to be associated with an epoxide,5 they were
assigned to secondary hydroxyls. High-field cyclopropyl
protons were consistent with structure 2, and H-2 (δ 2.78)
and H-9 (δ 2.95) could be assigned on the basis of their
coupling patterns.
The diol 2 cleanly oxidized to a diketone 4, which showed
no infrared hydroxyl absorption but which gave bands at
1680 and 1675 cm-1, consistent with the presence of two
carbonyls both adjacent to a cyclopropane moiety.6 The diol
2 could also be hydrogenated to a mixture of diastereomers,
from which a single isomer, the saturated diol 5, was
isolated following extensive recrystallization. Compound 5
retained the protons H-2 (δ 2.75) and H-9 (δ 3.18) at high-
field, and so it is the cyclopropane ring in these compounds
which contributes to the upfield shift, rather than the
double bonds.
Acetylation of diol 2 gave a diacetate showing the
expected downfield shift of the protons geminal to the
acetate group at δ 4.23 (H-2) and 5.65 (H-9). The diacetate
gave a consistent melting point and provided NMR spectra
similar to those reported7 for a diacetate obtained from
epoxide 1 on treatment with BF3/Ac2O and for which an
X-ray structure is available to establish the configuration,
which also follows from mechanistic considerations.
The reversible nature of the reaction 2 to 1 became
apparent when the proximity of the two hydroxyl groups
in diol 2 was explored through attempted acetonide forma-
tion. Diol 2 is stable in refluxing acetone, but the addition
of a trace of p-toluenesulfonic acid converted the diol at
room temperature within 2 h into epoxide 1 in more than
90% yield. Both hydroxyl groups in conformer 2a of
compound 2 are pseudoequatorial, both suitably placed
antiperiplanar to the C10-C1 bond of the cyclopropyl ring
to permit facile conversion into epoxide 1 after protonation
of the C2 hydroxyl.
Epoxide 1, synthesized from humulene through humu-
lene triepoxide by the method of Roberts,4 was contami-
nated with various diepoxides and a triepoxide of humu-
lene. Chromatography over silica gave elution of the
compounds in the order of the number of oxygen atoms they
contain. After triepoxide had been washed off, the column
was cleaned with ether, whereupon product 2 eluted to
form glistening crystals on the tip of the column. Subse-
* To whom correspondence should be addressed. E-mail: carman@
chemistry.uq.edu.au.
10.1021/np0501839 CCC: $30.25
© 2005 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/09/2005

1442 Journal of Natural Products, 2005, Vol. 68, No. 9
Notes
Experimental Section
General Experimental Procedures. 1H (220 Mz) and 13
76.9%, H 9.7%, calcd for C15H22O2, C 76.9%, H 9.5%). IR (Nujol)
1
νmax no OH, 1680, 1675, 1105, 1090, 1075, 975, 930 cm-1; H
C
NMR δ 5.52 (br dd, H-6), 3.27 (X region of an ABCX system,
H-3a), 2.4 (m, H-3b and H-7a), 2.5-2.1 (m, two H-4), 2.26
(obscured, H-7b), 2.20 (dd, H-10), 1.98 (dd, H-11a), 1.75 (s, C5-
Me), 1.35 (dd, H-11b), 1.40, 1.26, 1.16 (three s, Me); with J6,7a
) small, J6,7b ) 10, J10,11a)7, J10,11b ) 9, J11a,11b ) -3 Hz. EIMS
m/z 234 (M, 7%), 219 (M - Me, 5), 206 (M - CO, 2), 191 (M -
Me - CO, 3), 151 (35), 124 (32), 123 (35), 109 (100), 95 (67).
Diol 5. Diol 2 (103 mg) in EtOH was hydrogenated (5 h,
atmospheric pressure and room temperature) over Pd/C.
Numerous recrystallizations (petroleum/diethyl ether) and
careful drying gave [1RS,2RS,5RS,9SR,10RS]-1,5,8,8-tetra-
methylbicyclo[8.1.0]undecane-2,9-diol, 5 (78 mg). The C-5
configuration is uncertain, but follows if it is assumed that
the conformation depicted in 2a hydrogenates from the
external face. Compound 5 as the racemate had mp 81-83 °C
(ether/petroleum) (anal. C 75.2%, H 12.0%, calcd for C15H28O2,
C 75.0%, H 11.7%). IR (Nujol) νmax 3310 s, no CdC, 1030, 935
NMR (25.1 Mz) spectra were recorded in CDCl3 solution. 13C
multiplicities were assigned by off-resonance decoupling.
Diol 2. Humulene-4,5-monoepoxide 1 was prepared from
humulene triepoxide by the Stirling4 method. The oil showed
(analytical TLC, petroleum/EtOAc, 9:1) predominantly mo-
noepoxide 1 (Rf 0.49), with minor amounts of humulene (Rf
0.68), humulene-1,2-monoepoxide (Rf 0.39), humulene diep-
oxides (Rf ∼0.24), and unreacted humulene triepoxide (Rf 0.06).
In this relatively nonpolar analytical system, compound 2 has
Rf 0.0. Column chromatography (petroleum/diethyl ether, 49:
1) afforded the monoepoxide 1. Further elution with increasing
amounts of ether afforded the di- and triepoxides. Elution with
ether then afforded compound 2 (typically 7-15%), which
crystallized at the column tip. [1RS,2RS,5E,9SR,10RS]-1,5,8,8-
Tetramethylbicyclo[8.1.0]undec-5-ene-2,9-diol, 2, as the race-
mate, had mp 109-111 °C (ether/petroleum). The compound
retained water tenaciously (anal. for a sample dried overnight
over P2O5 and high vacuum: C 75.4%, H 11.3%, calcd for
C15H26O2, C 75.6%, H 11.0%). IR (Nujol) νmax 3320 s, 1660 w,
1
cm-1; H NMR δ 3.18 (d, J ) 7 Hz, H-9), 2.75 (X region of an
ABX system, H-2), 1.15, 1.08, 0.92 (three s, Me; obscuring
H-10), 0.90 (d, Me), 0.7-0.3 (m, two H-11). This spectrum
showed a small impurity doublet (J ) 7 Hz) at δ 3.35, which
may be H-9 of a conformer or of the C-5 configurational isomer.
EIMS m/z 248 (M, 6%), 222 (M - H2O, 7), 141 (37), 123 (35),
109 (27), 95 (100), with a metastable at 107.3 (141 - H2O f
123).
Acid Treatment of Diol 2. Diol 2 was unchanged by
boiling in acetone. Diol 2 dissolved in anhydrous acetone with
a crystal of p-toluenesulfonic acid at room temperature had
completely reacted overnight to give a one-spot oil (Rf 0.73 in
EtOAc, compared with compound 2, Rf 0.29). Subsequent runs
showed that starting material was completely gone after 2 h.
Normal workup followed by elution off a short column provided
humulene 4,5-epoxide, 1 (yield >90%), with characteristic odor,
identical retention times (silica and AgNO3 impregnated
plates), and superimposable spectra (1H NMR, IR, MS) to
authentic epoxide 1. The analytical methodology available did
not allow the detection of very minor amounts of the alterna-
tive 1,2-epoxide of humulene, which could have been a byprod-
uct of this reaction.2,3
1095, 1022, 925 cm-1 1H NMR δ 5.26 (br dd, H-6), 2.95 (d,
;
H-9), 2.78 (dd, H-2), 2.12 (dd, H-7a), 1.87 (dd, H-7b), 1.6-2.2
(4H, m, H-3 and H-4), 1.63 (s, C5-Me), 1.09 (ddd, H-10), 0.95,
0.95, 1.05 (three 3H s, Me), 0.56 (dd, H-11a), 0.36 (dd, H-11b);
with J2,3a ) 3, J2,3b ) 10, J6,7a ) 4, J6,7b ) 11, J7a,7b )-14, J9,10
) 7, J10,11a ) 6, J10,11b ) 10, J11a,11b ) -4.5 Hz. Decoupling at
δ 1.63 converted the δ 5.26 system into a sharp dd, J ) 11
and 4 Hz. Irradiation at δ 1.8 converted the δ 2.78 system into
a broad singlet. Irradiation at δ 2.0 converted the δ 5.26 system
into a broad doublet, J ) 11 Hz. 13C NMR δ 132.6 (C-5), 124.9
(C-6), 82.5 (C-2), 74.8 (C-9), 40.2 and 38.4 (C-4 & C-7), 39.8
(C-8), 31.8 (C-3), 31.2 (C-10), 30.2 (Me), 28.3 (C-1), 18.5 (Me),
17.8 (C-11), 16.4 (Me), 13.7 (Me). These 13C values are all
within 0.2 ppm of those listed3 for a compound obtained (no
mp reported) by hydrolysis of a diacetate, and they agree well
(except for one peak, δ 23.2 rather than 31.8 for C-3, believed
to be a typographical error) with data2 for a compound (no mp
reported) isolated as one of more than 30 products from
aqueous acid treatment of humulene monoepoxide 1 or 3.
EIMS m/z 238 (M, 2%), 220 (M - H2O, 2), 205 (M - H2O -
Me, 2), 202 (M - 2H2O, 3), 192 (2), 191 (2), 187 (4), 178 (35),
138 (30), 135 (25), 125 (35), 121 (20), 111 (100), 109 (45).
Compound 2 was also obtained in similar yield during the
chromatographic purification of monoepoxide 1.
The diacetate of compound 2 (Ac2O/pyridine, 4 h, quantita-
tive yield) gave chunky crystals, mp 144 °C (ether/petroleum)
(lit.7 140-142 °C) (anal. C 70.7%, H 9.5%, calcd for C19H30O4
C 70.8%, H 9.4%). IR (Nujol) νmax no OH, 1725 s br, 1240 s br,
1035, 1018, 950 cm-1; 1H NMR δ 5.45 (br d, H-6), 4.65 (d, H-9),
4.23 (dd, H-2), 2.36 (dd, H-7a), 2.08 and 2.08 (two acetate Me),
1.93 (dd, H-7b), 2.3-1.7 (4H, m, H-3 and H-4), 1.74 (s, C9-
Me), 1.22 (ddd, H-10), 1.20, 1.14, 0.95 (three s, Me), 0.70 (dd,
H-11a), 0.14 (dd, H11b); with J2,3a ) 3, J2,3b ) 10, J6,7a ) small,
J6,7b ) 11, J7a,7b)-15, J9,10 ) 8, J10,11a ) 6, J10,11b ) 10, J11a,11b
) -5 Hz, similar to the literature values.7
Compound 2 showed signs of decomposition after some time
on an AgNO3 impregnated plate, to give a spot with the same
Rf as humulene 4,5-epoxide, 1.
Acknowledgment. J. Mlotkiewicz and J. Roberts are
thanked for practical advice.
References and Notes
(1) Over 340 hits for ‘humulene epoxide’ in Scifinder Scholar, with ∼145
since 2000. See in particular: Lermusieau, G.; Collin, S. J. Am. Soc.
Brewing Chem. 2001, 59, 39-43.
(2) Yang, X.; Deinzer, M. L. J. Org. Chem. 1992, 57, 4717-4722.
(3) Hayano, K.; Shirahama, H. Chem. Lett. 1993, 1151-1152.
(4) Sattar, A.; Forrester, J.; Moir, M.; Roberts, J. S.; Parker, W.
Tetrahedron Lett. 1976, 1403-1406.
(5) Davies, S. G.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 2 1975,
861-863.
(6) Cross, A. D.; Jones, R. A. An Introduction to Practical Infrared
Spectroscopy, 3rd ed.; Butterworths: London, 1969; pp 54 and 84.
(7) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Misumi, S.; Ohtsuka, T.;
Hashibta, N.; Furusaki, A.; Murata, S.; Noyori, R.; Matsumoto, T.
Tetrahedron Lett. 1980, 4835-4838.
Diketone 4. Diol 2 (130 mg) was oxidized (5 h, RT) with
pyridinium chlorochromate in CH2Cl2 containing NaOAc as
buffer.8 The oily product (134 mg) partly crystallized overnight.
Elution from a short silica column (petroleum/diethyl ether,
9:1) gave [1RS,5E,10RS]-1,5,8,8-tetramethylbicyclo[8.1.0]-
undec-5-ene-2,9-dione, 4, mp 75-76 °C (petroleum) (anal. C
(8) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647-2650.
NP0501839