Synthesis of cardamom peroxide analogues by radical cyclization of hydroperoxyalkenes

Article abstract of DOI:10.1016/S0040-4039(02)01122-X

Three pinenic hydroperoxides were synthesized according to the Dussault method. Two of them could cyclize under radical conditions to give the exo-trig isomer as a single regioisomer. Only five- and six-member ring peroxides were obtained, whereas none of

Full text of DOI:10.1016/S0040-4039(02)01122-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6275–6277
Synthesis of cardamom peroxide analogues by radical cyclization
of hydroperoxyalkenes
Laure Cointeaux, Jean-Franc¸ois Berrien* and Joe¨lle Mayrargue*
UPRES A 8076 BioCIS, Faculte´ de Pharmacie, rue J.-B. Cle´ment, F-92296 Chaˆtenay Malabry, France
Received 10 June 2002; accepted 13 June 2002
Abstract—Three pinenic hydroperoxides were synthesized according to the Dussault method. Two of them could cyclize under
radical conditions to give the exo-trig isomer as a single regioisomer. Only five- and six-member ring peroxides were obtained,
whereas none of the possible seven-member ones was observed. This strategy could be employed in the total synthesis of
cardamom peroxide. © 2002 Elsevier Science Ltd. All rights reserved.
The terpenic peroxide 1 was isolated from the spice
cardamom, the fruit of Amomum krervanh Pierre.1 As
many other natural peroxides2 like artemisinin, car-
damom peroxide exhibited an antimalarial activity as
was shown in vitro against Plasmodium falciparum
(IC50=170 nM).1 First its relative configuration was
elucidated with the help of X-ray diffractometry. Its
absolute configuration could then be deduced from
those of known monoterpenes isolated conjointly in
cardamom. In connection with our program on anti-
malarial peroxides,3 we envisaged the synthesis of this
natural product not only for establishing the absolute
configuration but also for searching derivatives with
better antimalarial activity. The strategy adopted here
was to introduce later the chemosensitive peroxide
function for stability reasons. Thus, an attractive strat-
egy to obtain cardamom peroxide could use a sequence
developed by Porter,4 cyclization of a peroxy radical on
double bond in the presence of oxygen, and oxidation
of the resulting a-peroxy hydroperoxide into the corre-
sponding a-peroxy ketone,4a using the functionalized
hydroperoxide 2 (Scheme 1). This crucial step required
a 7-exo-trig cyclization of a peroxy radical on a double
bond. Results from the literature showed that 5-exo-
trig was favored compared to 6-endo-trig and 6-exo-
trig is favored compared to 7-endo-trig.4,5 However, to
our best knowledge, this has never been reported for
seven-member cyclic peroxides. Furthermore, the corre-
sponding 7-exo-trig ring closure center appeared to be
the most hindered carbon of the double bond, therefore
possibly being responsible for an 8-endo-trig cyclization
enhancement.5b
In order to check the behavior of such a reaction before
starting the synthesis of precursor 2, we decided to
prepare the pinene hydroperoxides 8a–c (Scheme 3) as
models to study the regioselectivity of the cyclization as
a function of the size of the ring (five-, six- or seven-
membered rings).
We report herein the synthesis of these pinene
hydroperoxides 8a–c and the result of our study on
their radical cyclization.
In order to prepare the pinene hydroperoxide 8a–c we
first synthesized the corresponding bromides 4a–c
(Scheme 2). Thus, nopyl bromide 4a was prepared from
nopol 3a according to a known procedure: the corre-
sponding tosylate was substituted with sodium bromide
in DMSO at 70°C.6 The same sequence was used to
prepare the bromides 4b and 4c. However, the tosylate
derived from homonopol 3b was less stable so it could
not be obtained in good yields. Moreover, its substitu-
tion with sodium bromide had to be conducted in
DMSO at room temperature. Homonopol 3b was pre-
pared as previously reported as a condensation product
from formaldehyde with the Grignard reagent
O
O
OH
OH
7-exo-trig ?
O
O
O
HOO
1
2
Scheme 1.
* Corresponding author. Tel.: 33 1 46 83 56 86; fax: 33 1 46 83 53 23;
e-mail: jean-francois.berrien@chimorg.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01122-X

6276
L. Cointeaux et al. / Tetrahedron Letters 43 (2002) 6275–6277
OH
Br
OH
2
Br
2
i, ii
i, ii
iii
Ref 6
Ref 6
3a
4a
3b
4b
CHO
OH
3
Br
3
v
i, ii
iv
2
Ref 7
5
6
3c
4c
Scheme 2. Reagents and conditions: (i) TsCl, pyridine, 0°C then rt 3 h, 89% from 3a, 46% from 3b, 77% from 3c; (ii) NaBr,
DMSO, rt 20 min then 70°C 2 h for 4a and 4c, rt 18 h for 4b, 78% for 4a, 98% for 4b, 66% for 4c; (iii) Mg°, THF rfx, 3 h then
CH2O gas, 66%; (iv) acrolein, ZnBr2, Et2O, rt 96 h, 29%; (v) NaBH4, EtOH, rt 2 h, 79%.
derived from nopyl bromide 4a.6 As we experienced
some difficulties to obtain this alcohol in its pure form,
the higher homologue 3c was prepared in a quite
different manner: by NaBH4 reduction of the corre-
sponding aldehyde 6 previously obtained by a ZnBr2-
catalyzed ene reaction between b-pinene and acrolein.7
With the three bromides 4a–c in hand, we prepared the
corresponding hydroperoxides 8a–c using Dussault’s
procedure (Scheme 3).8
Concerning the peroxy radical cyclization, nopyl
hydroperoxide 8a was subjected to the Porter condi-
tions,4b e.g. O2, benzene and di-t-butyl peroxyoxalate
(DBPO, CAUTION)13 as a radical initiator. The
cyclized hydroperoxide 9a was formed together with the
ketone 10a14 in a 7:3 ratio and in a 36% global yield.
The transformation of a hydroperoxide into its corre-
sponding ketone was previously reported in these
conditions.15
Substitution with 2-methoxyprop-2-yl hydroperoxide
118a led to perketals 7a–c in moderate to good yields
for 7c. The reaction times were extremely long (1–3
weeks) compared to those of straight-chain primary
alkyl bromides (1–2 h).8a This could be attributed to
steric hindrance of proximal pinene bulky moiety, as
yields and reaction time improved by increasing the
length of the alkyl chain between the pinene and the
bromide function. Deprotection of perketals 7a–c with
aqueous acetic acid8 gave the corresponding hydroper-
oxides 8a–c. The difficulty to prepare the perketals 7a–c
and the rather poor stability of hydroperoxides 8a–c
can explain that no other method tried so far could give
the desired hydroperoxides 8a–c from either the bro-
mides 4a–c (KO2, DMSO or DMF;9 Mg then O210) or
their corresponding tosylates (H2O2, MeOH, KOH;4
A complete two-step transformation into ketone 10a
could be performed using Ac2O/pyridine16 in a 24%
global yield and none of the 6-endo-trig cyclized
product or any other stereoisomer could be detected,
pointing out the selectivity of this strategy. As was
reported for other radical additions to pinene,17 we
observed a cis addition anti to the bulky gem dimethyl
group. The configuration of the molecules was confi-
rmed by NMR analysis. Other radical initiators proved
disappointing. Under the same conditions, AIBN18 led
to the same result but in lower yield (17%) and SmI2/
19
O2 caused a fast degradation of the hydroperoxide 8a
without any cyclization. In the case of the higher
homologue homonopyl hydroperoxide 8b, DBPO radi-
cal cyclization gave directly the ketone 10b14 as a sole
regio- and stereoisomer in 14% yield. The spontaneous
transformation, in the same reaction conditions, of
hydroperoxide 9b into ketone 10b was easier than for
NH2NH2 or NH2NHTs11,12 then H2O2). In our case,
11
the Dussault procedure appeared far superior to the
others.
Br
n
OOH
n
O
n
ii
i
O
OMe
4a-c
7a-c
8a-c
n
n
O
iii
O
O
O
O
OOH
9a-b
10a-b
Scheme 3. n=1 (a), n=2 (b) or n=3 (c). Reagents and conditions: (i) HOOC(CH3)2OMe (11), CsOH, DMF, rt 7 days (7b and 7c)
to 20 days (7a), 44% for 7a, 69% for 7b, 87% for 7c; (ii) AcOH, H2O, BHT, 97% for 8a, 98% for 8b, 97% for 8c; (iii) DBPO, O2,
benzene, rt, then Ac2O, pyridine, 36% for 10a, 14% for 10b.

L. Cointeaux et al. / Tetrahedron Letters 43 (2002) 6275–6277
6277
the five-member cyclic hydroperoxide 9a. Similar results
8. (a) Dussault, P.; Sahli, A. J. Org. Chem. 1992, 57,
1009–1012; (b) Dussault, P. Synlett 1995, 997–1003.
9. Johnson, R. A.; Nidy, E. G.; Merritt, M. V. J. Am.
Chem. Soc. 1978, 100, 7960–7966.
10. Walling, C.; Buckler, S. A. J. Am. Chem. Soc. 1955, 77,
6032–6038.
were obtained with AIBN as radical initiator.
For the cyclization of the seven-member ring precursor
hydroperoxide 8c, we were not able to detect any trace
of 7-exo-trig or 8-endo-trig products using either
DBPO or AIBN. The increase of the degree of freedom
with the length of the alkyl chain was presumably too
unfavorable for the cyclization of the peroxy radical
that decomposed. However, we thought that the
entropic factor could be limited in retrosynthetic pre-
cursor 2, as a second ring could significantly reduce the
degree of freedom of the chain with the peroxy radical.
11. Casteel, D. A.; Jung, K.-E. J. Chem. Soc., Perkin Trans.
1 1991, 2597–2598.
12. Collazo, L.; Guziec, F. S.; Hu, W.-X.; Mun˜os, A.; Wei,
D.; Alvarado, M. J. Org. Chem. 1993, 58, 6169–6170.
13. DBPO explodes violently under a shock or by scratching
it. For its preparation see: Bartlett, P. D.; Benzing, E. P.;
Pincock, R. E. J. Am. Chem. Soc. 1960, 82, 1762–1768.
14. All new compounds reported here were characterized on
1
the basis of spectroscopic data (IR, H and 13C NMR),
As exo-trig cyclic isomers were the sole isolated prod-
ucts following our strategy with five- and six-membered
cyclic peroxides as starting materials, this encouraged
us to pursue this route for the later synthesis of car-
damom peroxide 1.
[h]D and elemental analyses. Selected spectral data: Com-
pound 7c: [h]D −17 (c 0.97, CH2Cl2); 1H NMR (200
MHz, CDCl3): 5.21–5.10 (m, 1H), 4.00 (t, J=6.5 Hz,
3H), 3.31 (s, 3H), 2.34 (dt, J=8.3, 5.6 Hz, 1H), 2.25–2.13
(m, 2H), 2.13–1.87 (m, 4H), 1.60 (q, J=6.6 Hz, 2H),
1.50–1.31 (m, 2H), 1.38 (s, 6H), 1.26 (s, 3H), 1.13 (d,
J=8.3 Hz, 1H), 0.82 (s, 3H). 13C NMR (50 MHz,
CDCl3): l 147.9, 116.0, 104.4, 74.8, 49.0, 45.7, 40.9, 37.8,
36.6, 31.6, 31.2, 27.6, 26.3, 23.7, 22.7, 21.1. Compound
8c: 1H NMR (200 MHz, C6D6): l 6.61 (bs, 1H), 5.33–
5.06 (m, 1H), 3.81 (t, J=6.3 Hz, 2H), 2.33 (dt, J=8.3, 5.6
Hz, 1H), 2.23–2.14 (m, 2H), 2.13–1.80 (m, 4H), 1.43–1.32
(m, 5H), 1.37 (s, 3H), 0.89 (s, 3H). 13C NMR (50 MHz,
CDCl3): l 148.5, 116.4, 76.9, 46.2, 41.3, 38.2, 37.1, 32.1,
31.7, 27.9, 26.6, 24.0, 21.4. Compound 10a: [h]D +17 (c
0.17, EtOH); 1H NMR (200 MHz, CDCl3): l 4.37 (dt,
J=7.9, 4.5 Hz, 1H), 4.11 (q, J=7.9 Hz, 1H), 2.96 (dt,
J=11.3, 7.5 Hz, 1H), 2.70–2.64 (m, 2H), 2.33–2.05 (m,
4H), 1.55 (d, J=11.3 Hz, 1H), 1.37 (s, 3H), 0.88 (s, 3H).
13C NMR (50 MHz, CDCl3): l 209.3, 88.8, 71.4, 48.1,
44.4, 43.3, 39.8, 38.1, 29.4, 26.5, 22.2. Compound 10b:
[h]D −7 (c 1.62, EtOH); 1H NMR (400 MHz, C6D6): l
4.05 (dt, J=12.2, 6.1 Hz, 1H), 3.70 (dt, J=12.2, 4.5 Hz,
1H), 2.46–2.35 (m, 2H), 2.35–2.29 (m, 2H), 2.23–2.11 (m,
1H), 1.84 (d, J=10.9 Hz, 1H), 1.60–1.49 (m, 1H), 1.49–
1.37 (m, 2H), 1.19 (dt, J=13.8, 5.0 Hz, 1H), 1.03 (s, 3H),
0.52 (s, 3H). 13C NMR (100 MHz, C6D6): l 207.5, 86.9,
72.0, 45.6, 43.7, 38.9, 38.5, 27.7, 27.3, 27.2, 22.2, 19.8.
15. Goosen, A.; Kindermans, S. S. Afr. J. Chem. 1997, 50,
1–8.
Acknowledgements
We thank Dr. Jacqueline Mahuteau and Mrs. Sophie
Mairesse-Lebrun for valuable assistance on NMR
study and elemental analyses.
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