Conversion of a cyclic α,β-unsaturated ketone into a tertiary dienyl hydroperoxide: Application to the first hemisynthesis of 15-hydroperoxyabietic acid

Article abstract of DOI:10.1055/s-2001-18089

The first hemisynthesis of 15-hydroperoxyabietic acid, a major contact allergen among the oxidation products of colophony, is reported. The key step includes a new approach to easily obtain a dienyl tertiary hydroperoxide from a cyclic α,β-unsaturated ketone. The procedure is based on the formation of a bromodiene using a Vilsmeier's reagent, followed by a halogen/metal exchange and alkylation with acetone, to afford the dienyl alcohol precursor of the hydroperoxide.

Full text of DOI:10.1055/s-2001-18089

LETTER
1723
Conversion of a Cyclic , -Unsaturated Ketone into a Tertiary Dienyl
Hydroperoxide: Application to the First Hemisynthesis of 15-
Hydroperoxyabietic Acid
The First
H
emis
a
ynthesis of
u
15-Hydrope
r
roxyabie
e
tic
A
cid Haberkorn, Vincent Mutterer, Elena Giménez Arnau, Jean-Pierre Lepoittevin*
Laboratoire de Dermatochimie, Université Louis Pasteur, Clinique Dermatologique, CHU, 67091 Strasbourg, France
Fax +33(3)88140447; E-mail: jplepoit@chimie.u-strasbg.fr
Received 11 July 2001
Abstract: The first hemisynthesis of 15-hydroperoxyabietic acid, a
major contact allergen among the oxidation products of colophony,
is reported. The key step includes a new approach to easily obtain a
C
dienyl tertiary hydroperoxide from a cyclic , -unsaturated ketone.
A
B
The procedure is based on the formation of a bromodiene using a
Vilsmeier’s reagent, followed by a halogen/metal exchange and
alkylation with acetone, to afford the dienyl alcohol precursor of the
hydroperoxide.
COOH
COOH
1
2
16
15
Key words: colophony, 15-hydroperoxyabietic acid, dienyl hydro-
peroxide , -unsaturated ketone, halo-diene alkylation
12
OOH
17
13
11
20
1
14
9
2
10
8
3
4
7
6
5
Colophony (rosin) is a widespread natural product ob-
tained from different species of coniferous trees either
from oleoresins, tapped from living trees, or by distillation
of tall oil, a by-product of the paper pulp industry. Due to
its tackifying, emulsifying, and insulating properties, it is
widely used in the production of many products (i. e. ad-
hesives, paints, cosmetics).1,2 Today, allergic contact der-
matitis (ACD) to colophony is one of the 10 most
commonly encountered allergic reactions.3 Colophony
has a complex chemical composition consisting mainly of
resin acids of which abietic acid 1 and dehydroabietic acid
2 (Figure 1) are the major components. It has been dem-
onstrated that 1 and 2 are not allergenic4,5 and that the al-
lergenic activity of colophony is caused by air oxidation
products of the resin acids.6 The dienyl hydroperoxide 15-
hydroperoxyabietic acid 3 (15-HPA; Figure 1) has been
identified as a major contact allergen.7
COOH
19
18
15-HPA
3
Figure 1 Structures of abietic acid 1, dehydroabietic acid 2 and 15-
hydroperoxyabietic acid 3
cate that radical reactions could be important in the case
of haptens containing hydroperoxide groups.10
In order to study the mechanisms leading to the formation
of radicals from 15-HPA, and their subsequent reaction
with skin proteins, relatively large quantities of the hydro-
peroxide are needed. The isolation of 15-HPA from sam-
ples of air oxidized colophony has been reported in a
process that is very time consuming and expensive.7 We
therefore decided to pursue a stepwise synthetic route to
access workable amounts of 15-HPA 3. This letter reports
a new synthetic method for the conversion of an , -un-
saturated ketone into a tertiary dienyl hydroperoxide that
has been successfully applied to the first hemisynthesis of
15-HPA from abietic acid.
Contact allergens are low molecular weight compounds
(haptens) that bind covalently to endogenous proteins in
the skin before they can be recognized as antigens and
thereby elicit the immune reaction characteristic of ACD.8
It is accepted that the main hapten-protein interaction
mechanism is the formation of a covalent bond between
the hapten and nucleophilic residues of proteins through a
nucleophile/electrophile reaction.9 However, the interac-
tion mechanism of allergenic allylic hydroperoxides de-
rived from the autoxidation of terpenes with skin proteins
does not fit this model and is still unknown. Mechanisms
involving radicals have been suggested in the discussion
of hapten-protein binding, and our previous studies indi-
A major problem for the synthesis of 15-HPA is the easy
aromatization of cycle C leading to the formation of dehy-
droabietic derivatives. For many years, and despite sever-
al attempts, this has been a major pitfall to the access to
15-HPA.11 We have successfully synthesized 15-HPA 3
from the known , -unsaturated ketone 4, a versatile start-
ing material for the synthesis of diterpenes, avoiding
isomerization of the conjugated system as well as aroma-
tization. Our synthetic approach is outlined in Scheme 1.
In order to build the tertiary dienyl alcohol 6, precursor of
the hydroperoxide 3, the , -unsaturated ketone 4 was
converted into bromodiene 5 using a Vilsmeier’s reagent.
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1723,1726,ftx,en;G14101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1724
L. Haberkorn et al.
LETTER
Br
O
b
a
a
b
1
COOH
COOH
COOCH3
5
4
7
O
OH
c
OOH
c, d, e
4
COOCH3
COOH
COOH
8
3
6
a) see reference (20); b) MCPBA, CH2Cl2, 0 °C, 2 h, 90%; c) H5IO6,
THF, –30 °C to –10 °C, 1 h, 87%; d) HCl, MeOH, 0 °C, 4 h, 96%; e)
t-BuOK, DMSO, r.t., 45 min, 80%.
a) (COBr)2, DMF, CH2Cl2, –78 °C to r.t., 5 h, 74%; b) t-BuLi, Et2O,
anhyd acetone, –78 °C to r.t., 2 h, 70%; c) H2O2/H2O (35%), H2SO4,
0 °C, 10 h, 63%.
Scheme 2 Synthesis of ketone 4 from commercial abietic acid
Scheme 1 Synthesis of 15-hydroperoxyabietic acid 3 from ketone 4
pound 7. We did find a useful alternative for the obtention
of a , -unsaturated ketone from 7, based in a selective
epoxidation of the exocyclic double bond, followed by an
oxidative cleavage of the epoxide. Indeed, treatment of
compound 7 with a stoechiometric amount of MCPBA in
anhydrous dichloromethane at 0 °C led to the formation of
epoxide 8 with a good yield (90%). Further cleavage of
the epoxide with periodic acid in tetrahydrofuran at low
temperature gave the desired , -unsaturated ketone (87%
yield), which was easily isomerized with HCl in metha-
nol, and converted into an , -unsaturated ketone (96%
yield).
It has been reported in the literature that treatment of 3-
oxo-4-ene steroids with a Vilsmeier’s reagent, typically
produced by reaction between N,N-dimethylformamide
and phosphorous oxychloride (DMF–POCl3), affords a
mixture of products of which 3-chloro-3,5-dienes are the
major components.12 Recently, Yu and Baine reported the
use of a Vilsmeier’s reagent, formed from oxalyl bromide
and DMF, for the production of a bromodiene in rings A
and B of a ketosteroidal acid.13 Based on these results, the
same experimental conditions were applied for the con-
version of ketone 4 to bromodiene 5. Treatment of 4 with
4 equivalents of DMF–(COBr)2 in dichloromethane gave,
after 5 hours stirring at room temperature, the diene 5 in
74% yield.14 Alcohol 6 was then synthesized (70% yield)
by alkylation, with an excess of anhydrous acetone, of the
alkenyllithium derivative obtained from 5 by a halogen/
metal exchange with tert-butyllithium in diethyl ether.15
Finally, one of the most classical methods for the prepara-
tion of tertiary allylic hydroperoxides is the quenching
with hydrogen peroxide of a carbocation generated from a
hydroxyl function under acidic conditions.16 Alcohol 6
was thus treated with a solution of H2O2 (35% in water)
under acidic conditions (H2SO4) at 0 °C to give 3 in 63%
yield.17,18
We considered convenient, at this stage of the synthesis,
to cleave the methyl ester in order to obtain the free car-
boxylic acid function of compound 4. A number of mild,
neutral methods of ester cleavage, such as LiOH, NaCN/
HMPA, NaCN/DMF, LiI/pyridine, LiI/lutidine LiI/DMF,
Ba(OH)2/MeOH, KOH/MeOH–H2O, were devised and
used without success.21 However, the use of potassium
tert-butoxide (4 equivalents) in dimethyl sulfoxide al-
lowed the ketone 4 to be obtained in 80% yield. These re-
action conditions have been used considerably with di-
and tri-terpenes, in particular, with methyl esters of diter-
penoids with the dehydroabietic skeleton.22
This first reported synthesis of 15-HPA 3 will enable fur-
ther fundamental studies, necessary for the understanding
of its allergenic activity. Studies concerning the formation
and the identification of reactive radicals derived from 15-
HPA, as well as their reactivity, will now be undertaken,
using a combination of chemical-trapping experiments
and electron paramagnetic resonance studies (EPR), that
have been already developed in the course of our investi-
gations on allylic hydroperoxides as potential sources for
radical intermediates.10c,d Understanding of mechanisms
leading to the formation of these radicals and their subse-
quent reaction with proteins will open new insights in our
understanding of antigen formation.
, -Unsaturated ketone 4 was obtained (Scheme 2) from
commercially available abietic acid 1 (technical grade 70–
80%) which was initially purified by way of its ethanola-
mine salt followed by treatment with glacial acetic acid
and recrystallization.19
Pure abietic acid was converted into the diene compound
7 following the procedure described by Arno and cowork-
ers.20 In their developed methodology to synthesize diter-
pene derivatives from abietic acid, the exocyclic carbon-
carbon double bond of 7 was cleaved by partial ozono-
lyzis to give a , -unsaturated ketone. It was then neces-
sary to carefully monitor the ozone flow in order to avoid
the cleavage of both tetrasubstituted double bonds in com-
Synlett 2001, No. 11, 1723–1726 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
The First Hemisynthesis of 15-Hydroperoxyabietic Acid
1725
cm–1 (C-H). Anal. Calcd for C17H23BrO2: C, 60.18; H, 6.83.
Found: C, 60.43; H, 6.80.
Acknowledgement
We thank the Ministère de l’Education Nationale (France) for sup-
port of this research through a fellowship to L. H.
(15) 7-(1-Hydroxy-1-methyl-ethyl)-1,4a-dimethyl-
1,2,3,4,4a,4b,5,6,10,10a-decahydro-phenantrene-1-
carboxylic Acid(6): To a solution of 5 (100 mg, 0.29 mmol)
in anhyd Et2O (15 mL) was added a solution of tert-
butyllithium (1.74 mL, 1.74 mmol, 1 M solution in pentane)
at –78 °C. The reaction was stirred at this temperature for 1.5
h and monitored by TLC (hexane–EtOAc 7:3). When the
bromide-lithium exchange was completed, an excess of
anhyd acetone (1 mL, 13.6 mmol) was added dropwise. To
obtain anhyd acetone, this was first distilled over potassium
permanganate, dried over K2CO3 for 48 h, filtered and
distilled a second time. The reaction mixture was allowed to
warm to r.t. and stirred for 2 h. The mixture was quenched
with an aq sat. soln NH4Cl (10 mL). The organic layer was
separated and the aq phase extracted with diethyl ether
(3 10 mL). The combined organic layers were washed with
brine (3 10 mL), dried (MgSO4), filtered and concentrated
under reduced pressure. The crude product was purified by
silica gel column chromatography (hexane–EtOAc 5.5:4.5)
to give 64.6 mg (0.2 mmol, 70% yield) of 6 as a white solid:
mp 147–149 °C; [ ]D –86 (c 1.1, acetone); 1H NMR
(CDCl3, 200 Mhz): 0.83 (s, 3 H, CCH3), 1.26 (s, 3 H,
C(CH3)(CO2H), 1.33 (s, 3 H, C(OH)(CH3)2), 1.35 (s, 3 H,
C(OH)(CH3)2), 1.18–2.36 (m, 14 H, 6 CH2, 2 CH), 5.48
(m, 1 H, =CHCH2), 6.07 (s, 1 H, =CHC); 13C NMR (CDCl3,
50 Mhz): 14.0, 16.7, 18.1, 22.6, 25.7, 25.8, 28.6, 28.7,
34.4, 37.2, 38.3, 44.8, 46.3, 50.7, 72.9, 122.5, 122.9, 135.0,
144.5, 184.3; IR (DMSO) 1705 (C=O), 2878 (C–H), 3230–
3620 cm–1 (broad, O–H). Anal. Calcd for C20H30O3: C,
75.43; H, 9.50. Found: C, 75.61; H, 9.48.
References and Notes
(1) Karlberg, A.-T. Acta Derm.-Venereol. (Suppl.) 1988, 139, 1.
(2) Karlberg, A.-T.; Lidén, C. Br. J. Dermatol. 1992, 126, 161.
(3) Downs, A. M. R.; Sansom, J. E. Contact Dermatitis 1999,
41, 305, and references cited therein.
(4) Karlberg, A.-T.; Bergstedt, E.; Boman, A. Contact
Dermatitis 1985, 13, 209.
(5) Hausen, B. M.; Kreuger, A.; Mohnert, J. Contact Dermatitis
1989, 20, 41.
(6) (a) Gäfvert, E. Acta Derm.-Venereol. (Suppl.) 1994, 184, 1.
(b) Sadhra, S.; Foulds, I. S.; Gray, C. N. Contact Dermatitis
1998, 39, 58. (c) Hausen, B. M.; Börries, M.; Budianto, E.;
Krohn, K. Contact Dermatitis 1993, 29, 234. (d) Gäfvert,
E.; Nilsson, U.; Karlberg, A.-T.; Magnusson, K.; Nilsson, J.
L. G. Arch. Derm. Res. 1992, 284, 409. (e) Khan, L.; Saeed,
M. A. J. Pharm. Sci. 1994, 83, 909.
(7) Karlberg, A.-T.; Bohlinder, K.; Boman, A.; Hacksell, U.;
Hermansson, J.; Jacobsson, S.; Nilsson, J. L. G. J. Pharm.
Pharmacol. 1988, 40, 42.
(8) Scheynius, A. In Allergic Contact Dermatitis: The
Molecular Basis; Lepoittevin, J.-P.; Basketter, D. A.;
Goossens, A.; Karlberg, A.-T., Eds.; Springer-Verlag:
Berlin, Heidelberg, 1998, 4.
(9) Roberts, D. W.; Lepoittevin, J.-P. In Allergic Contact
Dermatitis: The Molecular Basis; Lepoittevin, J.-P.;
Basketter, D. A.; Goossens, A.; Karlberg, A.-T., Eds.;
Springer-Verlag: Berlin, Heidelberg, 1998, 81.
(10) (a) Lepoittevin, J.-P.; Karlberg, A.-T. Chem. Res. Toxicol.
1994, 7, 130. (b) Gäfvert, E.; Shao, L. P.; Karlberg, A.-T.;
Nilsson, U.; Nilsson, J. L. G. Chem. Res. Toxicol. 1994, 7,
260. (c) Bezard, M.; Karlberg, A.-T.; Montelius, J.;
Lepoittevin, J.-P. Chem. Res. Toxicol. 1997, 10, 987.
(d) Mutterer, V.; Giménez Arnau, A.; Karlberg, A.-T.;
Lepoittevin, J.-P. Chem. Res. Toxicol. 2000, 13, 1028.
(11) Mutterer, V. Ph. D. Thesis; Université Louis Pasteur
Strasbourg: France, 1997.
(16) Porter, N. A. In Organic Peroxides; Ando, W., Ed.; Wiley:
Chichester, 1992, 101.
(17) 7-(1-Hydroperoxy-1-methyl-ethyl)-1,4a-dimethyl-
1,2,3,4,4a,4b,5,6,10,10a-decahydro-phenantrene-1-
carboxylic acid, 15-HPA(3): To an aq solution of H2O2 (16
mL, 35%) was added a drop of concentrated H2SO4 (97%).
The solution was cooled to 0 °C and stirred for 10 min. A
solution of 6 (40 mg, 0.12 mmol) in CH2Cl2 (10 mL) was
then added. The reaction mixture was vigorously stirred at
0 °C and monitored by TLC (hexane–EtOAc 5:5). When no
more significant evolution of the reaction (10–20 h) was
observed, the solution was treated with water (15 mL). The
organic layer was separated and the aq layer extracted with
CH2Cl2 (3 10 mL). The combined organic layers were
washed with a 50/50 aq sat. soln of NaCl and NaHCO3 (pH
= 8; 2 15 mL) and concentrated under reduced pressure to
give the crude hydroperoxide, which was recrystallized from
CH2Cl2/pentane. Recrystallization afforded 25.6 mg (0.076
mmol, 63% yield) of 3 as a white crystalline solid: CAS
registry number [113903-96-1]; mp 68–70 °C; [ ]D –34 (c
1.1, CHCl3); 1H NMR (DMSO-d6, 200 Mhz): 0.75 (s, 3 H,
CCH3), 1.11 (s, 3 H, C(CH3)(CO2H)), 1.19 (s, 3 H,
C(OOH)(CH3)2), 1.23 (s, 3 H, C(OOH)(CH3)2), 1.06–2.34
(m, 14 H, 6 CH2, 2 CH), 5.42 (m, 1 H, =CHCH2), 5.89
(s, 1 H, =CHC), 10.73 (s, 1 H, OOH), 12.13 (s, 1 H, COOH);
13C NMR (DMSO-d6, 50 Mhz): 13.6, 16.7, 17.6, 21.8,
23.4, 24.0, 24.4, 25.1, 33.8, 36.7, 37.8, 44.4, 45.2, 50.3, 81.9,
122.2, 124.4, 134.7, 141.9, 179.2; IR (CHCl3) 887 (O–O),
1694 (C=O), 2853 (C–H), 3100–3550 cm–1 (broad, O–H).
(18) Structures of the synthesized compounds were established
by a combination of 1H and 13C NMR data. The
(12) Schmitt, J.; Panouse, J. J.; Pluchet, H.; Hallot, A.; Cornu, P.-
J.; Comoy, P. Bull. Soc. Chim. Fr. 1964, 2768.
(13) Yu, M. S.; Baine, N. H. Tetrahedron Lett. 1999, 40, 3123.
(14) 7-Bromo-1,4a-dimethyl-1,2,3,4,4a,4b,5,6,10,10a-
decahydro-phenantrene-1-carboxylic Acid(5): To a
solution of 4 (200 mg, 0.72 mmol) in anhyd CH2Cl2 (60 mL)
was slowly added DMF (221.6 L, 2.9 mmol) and oxalyl
bromide (270.2 L, 2.9 mmol) at –78 °C. After 15 min
stirring at –78 °C the mixture was gradually warmed to r.t.
and stirred for 5 h. H2O (50 mL) was then added and the
stirring followed for 20 min. The organic layer was
separated and the aq phase extracted with CH2Cl2 (3 25
mL). The combined organic layers were washed with water
(2 45 mL) and brine (3 45 mL), dried (MgSO4), filtered
and concentrated under reduced pressure, to give a crude
residue, which was purified by column chromatography on
silica gel (hexane–EtOAc, 8:2). The purification afforded
181.6 mg (0.53 mmol, 74% yield) of 5 as a white solid: mp
168–170 °C; [ ]D –123 (c 1.4, CHCl3); 1H NMR (CDCl3,
200 Mhz): 0.81 (s, 3 H, CCH3), 1.24 (s, 3 H,
C(CH3)(CO2H)), 1.55–2.04 (m, 12 H, 5 CH2, 2 CH),
2.52–2.55 (m, 2 H, CH2), 5.44 (m, 1 H, =CHCH2), 6.32 (s, 1
H, =CHC); 13C NMR (CDCl3, 50 Mhz): 14.1, 16.7, 18.0,
23.6, 25.6, 34.5, 36.1, 37.1, 38.2, 44.6, 46.2, 49.0, 122.5,
123.9, 132.1, 134.8, 184.9; IR (CHCl3)1693 (C=O), 2935
stereochemical determination was based on observations of
nuclear Overhauser effects (NOE). In the case of compound
6, a NOE between H-7 (5.48 ppm)and H-14 (6.07 ppm)
Synlett 2001, No. 11, 1723–1726 ISSN 0936-5214 © Thieme Stuttgart · New York

1726
L. Haberkorn et al.
LETTER
confirmed the conformation of the double bond conjugated
system.
(19) Dupont, M. M. G.; Desalbres, L. Bull. Soc. Chim. Fr. 1926,
4, 492.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley & Sons, Inc.: New York, 1991, Chap.
5.
(22) Chang, F. C.; Wood, N. F. Tetrahedron Lett. 1964, 40, 2969.
(20) Abad, A.; Arno, M.; Domingo, L. R.; Zaragoza, R. J.
Tetrahedron 1985, 41, 4937.
Synlett 2001, No. 11, 1723–1726 ISSN 0936-5214 © Thieme Stuttgart · New York