Synthesis of β-peroxy-lactones using 30% H2O2

Article abstract of DOI:10.1016/j.tetlet.2005.02.158

Cyclopropyl carbinols 1a-e react with H₂O₂ in the presence of concd H₂SO₄ at 0-5°C to furnish the corresponding hydroperoxides 2a-e in 45-82% yields. This efficient trapping of cyclopropylmethyl cations by the hydroperoxy group has been exploited to prepare compounds 14-23, a new series of cyclopropyl substituted β-peroxy- lactones.

Full text of DOI:10.1016/j.tetlet.2005.02.158

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2757–2759
q
Synthesis of b-peroxy-lactones using 30% H2O2
Chandan Singh,a,* Naveen Chandra Srivastav,a Nisha Srivastavaa and Sunil K. Purib
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received 13 October 2004;revised 15 January 2005;accepted 25 February 2005
Abstract—Cyclopropyl carbinols 1a–e react with H2O2 in the presence of concd H2SO4 at 0–5 ꢀC to furnish the corresponding
hydroperoxides 2a–e in 45–82% yields. This efficient trapping of cyclopropylmethyl cations by the hydroperoxy group has been
exploited to prepare compounds 14–23, a new series of cyclopropyl substituted b-peroxy-lactones.
ꢁ 2005 Elsevier Ltd. All rights reserved.
The cyclopropylmethyl cation and its rearrangement
have been extensively studied in the context of cyclopro-
pane chemistry. Cyclopropylmethyl substrates solvolyze
with abnormally high rates forming the cyclopropyl-
methyl cation as a key intermediate, that either rear-
ranges to the corresponding cyclobutyl cation or a
homoallylic cation. Thus the products of solvolysis often
include compounds not only derived from unrearranged
cyclopropylmethyl cations but also from cyclobutyl and
homoallylic cations.1 On the basis of solvolysis experi-
ments the order of stability of these cations follows
the order:2 cyclopropylmethyl cation > cyclobutyl cat-
ion ꢀ homoallylic cation.
Thus cyclopropyl carbinols 1a–e, easily accessible from
cyclopropyl methyl ketone by reaction with an appro-
priate Grignard reagent, reacted with 30% H2O2 in the
presence of concd H2SO4 at 0–5 ꢀC to furnish hydroper-
oxides 2a–e in 45–82% yields. A similar reaction of 1a
with t-BuOOH furnished the corresponding tert-butyl
peroxide 2f in 57% yield (Scheme 1).5,6 Thus, H2O2 acts
as an efficient trap for the cyclopropylmethyl cation
before it rearranges to cyclobutyl or homoallylic cations.
We have extended this observation to the preparation of
b-peroxy-lactones. Thus, b-hydroxy esters 4–13 pre-
pared by reaction of cyclopropyl ketones 3 with a-halo
esters/zinc were treated with 30% H2O2 in the presence
of concd H2SO4 in THF at 0–5 ꢀC to furnish b-per-
oxy-lactones 14–23 in 30–80% yields (Scheme 2, Table
1).7 Peroxy-lactones 15 and 21 were isolated as an insep-
arable mixture of diastereomers.8
The greater stability of the cyclopropylmethyl cation is
due to the presence of the cyclopropyl group. The bonds
in cyclopropane cannot be pure r bonds and have con-
siderable sp2 character and therefore provide a p cloud,
which stabilizes the positive charge on the adjacent car-
bon atom.3 The rearrangement of the cyclopropylmethyl
cation to a homoallylic cation has been exploited syn-
thetically to convert cyclopropyl carbinols into homo-
allylic alcohols, homoallylic acetates and homoallylic
halides.4 In the course of work designed to prepare
homoallylic hydroperoxides we discovered that cyclo-
propyl substituted carbinols react efficiently with 30%
H2O2 in the presence of concd H2SO4 to furnish cyclo-
propyl substituted hydroperoxides in good yields.
OH
OOH
30% H2O2/H+
THF, 0-5 o
Me
Me
R
C
R
1a-e
2a-e
a, R= Ph; b, R=4-ClC6H4; c, R=3-MeOC6H4;
d, R=n-pentyl; e, R=cyclohexyl
O
OH
O
70% t-BuOOH/H+
THF, 0-5 o
C
Me
Me
Ph
Ph
q CDRI communication no. 6666.
1a
2f
*
Corresponding author. Tel.: +91 522 2624273;fax: +91 522
2623405;e-mail: chandancdri@yahoo.com
Scheme 1.
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.158

2758
C. Singh et al. / Tetrahedron Letters 46 (2005) 2757–2759
Table 2. In vitro antimalarial activity of b-peroxy-lactones 14–23
R1
O
O
OH
O
O
(a)
R2
(b)
against P. falciparum (NF-54)
R1
O
OEt
MICa,b (lg/mL)
R1
R3
4-13
Compound
R3
R2
14-23
14
15
10.00
10.00
3
Scheme 2. Reagents and conditions: (a) a-bromo ester, Zn, benzene,
reflux, 2–7 h;(b) 30% H 2O2, concd H2SO4, THF, 0–5 ꢀC, 4–6 h.
16
17
>50.00
50.00
50.00
18
19
50.00
20
21
>50.00
>50.00
>50.00
>50.00
0.03
Table 1. Yields of b-peroxy-lactones 14–23
Compound
R1
R2
R3
Yield (%)
22
23
14
15
16
17
18
19
20
21
22
23
Me
Me
H
H
80
38
69
39
35
42
55
52
33
30
Artemisinin
Chloroquine
H
Me
H
0.04
Cyclopropyl
Cyclopropyl
Cyclopropyl
Phenyl
H
a MIC = Minimum concentration inhibiting development of ring stage
parasites into the schizonts.
b 50.00 lg/mL was the highest concentration used in this study.
H
Me
Et
H
H
H
4-Chlorophenyl
Me
Me
H
H
Et
H
Me
Me
Me
Me
Cyclopropyl
Table 3. In vivo antimalarial activity of compounds 14 and 15 against
P. yoelii in Swiss mice by the i.m. route
Compound Dose
% Suppression No. of surviving
mice on day 28
b-Peroxy-lactones have earlier been prepared from b-hy-
droxy acids using 90% H2O2.9 Since the preparation of
90% H2O2 is hazardous, the present method is advanta-
geous since commercially available 30% H2O2 is used.
However, the presence of the cyclopropyl group is essen-
tial for this reaction as b-hydroxy esters 24, 25 and 26
failed to react with 30% H2O2 under the same conditions
(Scheme 3).
(mg/kg/day) on day 4a
14
15
192
192
96
76.60
Toxic
77.52
0/5
0/5
0/5
a Percent suppression = [(C À T)/C] · 100;where C = parasitaemia in
the control group, and T = parasitaemia in the treated group.
etc. have been tested for antimalarial activity, to our
knowledge this is the first report on antimalarial activity
of b-peroxy-lactones.
Since there was no report on the antimalarial activity of
b-peroxy-lactones we also tested these easily accessible
b-peroxy-lactones against P. falciparum (NF-54) in
vitro10 (Table 2).
In conclusion, we have discovered that hydrogen perox-
ide is an efficient trap for cyclopropylmethyl cations and
have exploited this observation to develop a convenient
route for the preparation of b-cyclopropyl substituted
b-peroxy-lactones using 30% H2O2. Work related to
trapping of cyclopropylmethyl cations by other soft
nucleophiles such as thiols is currently in progress and
will be reported in our subsequent publications.
Compounds 14 and 15 which showed activity at 10 lg/
mL were also tested in vivo11 against multi-drug resis-
tant P. yoelii in mice by the intramuscular (i.m.) route
(Table 3). Both these compounds showed significant
suppression of parasitaemia. However, considering the
high order of activity shown by artemisinin and its
derivatives, the activity shown by these compounds is
weak.
Acknowledgements
While various classes of peroxides such as 1,2,4-triox-
anes,12 1,2,4,5-tetraoxanes,13 endoperoxides,14 H2O2,15
alkyl hydroperoxides,16 peroxyamines,17 peroxyketals,18
N.C.S. is grateful to the Council of Scientific and Indus-
trial Research (CSIR), New Delhi for the award of a Se-
nior Research Fellowship. Technical help from Mr.
Akhilesh Kumar Srivastava is gratefully acknowledged.
O
OH
(a)
(a)
No Reaction
No Reaction
OEt
OEt
24
References and notes
OH
O
1. Sarel, S.;Yovell, J.;Sarel-Imber, M. Angew. Chem., Int.
Ed. Engl. 1968, 7, 577–588.
2. Roberts, J. D.;Mazur, R. H. J. Am. Chem. Soc. 1951, 73,
2509–2520.
3. Wong, H. N. C.;Hon, M.-Y.;Tse, C.-W.;Yip, Y. C.
Chem. Rev. 1989, 89, 165–198.
R
Me
25 R= cyclohexyl
26 R= p-CH3C6H4
Scheme 3. Reagents and conditions: (a) 30% H2O2, concd H2SO4,
THF, 0–5 ꢀC, 7–9 h.
4. (a) Wagner, A. F.;Wolff, N. E.;Wallis, E. S. J. Org.
Chem. 1952, 17, 529–541;(b) Hoffsommer, R. D.;Taub,

C. Singh et al. / Tetrahedron Letters 46 (2005) 2757–2759
2759
D.;Wendler, N. L. J. Org. Chem. 1962, 27, 4134–4137;
(c) Biernacki, W.;Gdula, A. Synthesis 1979, 37–38;(d)
CDCl3) d 0.55–0.61 (m, 8H), 1.02–1.13 (m, 2H), 2.78 (s,
2H); 13C NMR (50 MHz, CDCl3) d 0.00, 0.23, 15.32,
39.20, 88.77, 173.95;FABMS ( m/z) 169 (M+H)+. Peroxy-
Kanemoto, S.;Shimizu, M.;Yoshioka, S.
Tetrahedron
Lett. 1987, 28, 663–666;(e) Madesclaire, M.;Ruche, D.;
Boucherle, A.;Carpy, A. Synthesis 1987, 834–835.
5. In sharp contrast to the reaction reported here, spiro-
cyclopropylcarbinols 27 have been reported to react with
90% H2O2 under acid catalysis to give exclusively bicyclic
hemiacetal peroxides 28. [Lillie, T. S.;Ronald, R. C.
J. Org. Chem. 1985, 50, 5084–5088.]
lactone 21 (mixture of diastereomers): oil;IR (neat, cm À1
)
1
1789; H NMR (200 MHz, CDCl3) d 0.50–0.65 (m, 4H),
0.87–1.04 (m, 1H), 1.09–1.20 (m, 6H), 1.50–2.04 (m, 2H),
2.79–2.88 (m, 1H); 13C NMR (50 MHz, CDCl3) d 1.41,
1.66, 2.27, 2.36, 12.14, 12.22, 14.24, 16.72, 17.98, 19.36,
19.59, 22.79, 54.27, 54.58, 90.57, 91.27, 177.94, 178.22;
FABMS (m/z) 171 (M+H)+.
9. Greene, F. D.;Adam, W.;Knudsen, G. A., Jr. J. Org.
Chem. 1966, 31, 2087–2090.
O OH
10. The compounds 14–23 were evaluated against P. falcipa-
rum (NF-54) using a minor modification of the technique
of Rieckmann et al.19 The asynchronous parasites
obtained from cultures of P. falciparum were synchronized
after 5% sorbitol treatment so as to contain only ring stage
parasites.20 A parasite suspension in medium RPMI 1640
at 1–2% parasitaemia and 3% hematocrit was dispensed
into the wells of sterile 96-well plates. Test compounds
were serially diluted in duplicate wells to obtain the final
test concentrations. The culture plates were incubated in a
candle jar at 37 ꢀC for 36–40 h. Thin blood smears from
each well prepared at the end of incubation period were
microscopically examined and the concentration, which
inhibited the maturation of rings into the schizont stage,
was recorded as the MIC.
11. The in vivo efficacy of compounds 14 and 15 was
evaluated against Plasmodium yoelii (MDR) in the Swiss
mice model. The colony bred Swiss mice (25 1 g) were
inoculated with 1 · 106 parasitized RBC on day zero and
treatment was administered to a group of five mice at each
dose, from days 0 to 3, in two divided doses daily. The
drug dilutions were prepared in groundnut oil, so as to
contain the required amount of the drug in 0.1 mL and
administered intramuscularly for each dose. Parasitaemia
levels were recorded from thin blood smears between days
4–28.21
90%H2O2/H+
OH
( )n
27
( )n
O
28
For other related studies see: (a) Ronald, R. C.;Lillie, T.
S. J. Am. Chem. Soc. 1983, 105, 5709–5710;(b) Ronald, R.
C.;Lillie, T. S. Tetrahedron Lett. 1986, 27, 5787–5790;
(c) Ronald, R. C.;Ruder, S. M.;Lillie, T. S. Tetrahedron
Lett. 1987, 28, 131–134.
6. Bourgeois, M. J.;Montaudon, E.;Maillard, B. Tetrahe-
dron 1993, 49, 2477–2484.
7. Typical procedure for the synthesis of b-peroxy-lactones:
To an ice-cooled (0–5 ꢀC) solution of 4 (0.5 g, 2.90 mmol)
in THF (15 mL) was added 30% H2O2 (2 mL) followed by
dropwise addition of concd H2SO4 (2 mL) with constant
stirring and then at 0–5 ꢀC for 5 h. The reaction mixture
was diluted with cold water (50 mL) and the aq layer
extracted with ether (3 · 50 mL). The combined organic
layers were washed with saturated aq NaHCO3 solution
(50 mL) and water (2 · 25 mL). The combined organic
layers were dried over anhyd Na2SO4 and the solvent was
evaporated under vacuum to give the crude product,
which on column chromatography over silica gel using
benzene–hexane (1:1) as eluant furnished 14 (0.33 g, 80%).
8. Selected spectral data: Compound 2a: oil;IR (neat, cm À1):
12. Bhattacharya, A. K.;Sharma, R. P. Heterocycles 1999,
51, 1681–1745.
1
3399; H NMR (200 MHz, CDCl3) d 0.35–0.40 (m, 2H),
0.50–0.58 (m, 2H), 1.28–1.41 (m, 1H), 1.45 (s, 3H), 7.24–
7.51 (m, 5H); 13C NMR (50 MHz, CDCl3) d 1.60, 2.79,
19.09, 21.99, 87.19, 126.55, 127.82, 128.75, 143.87;
FABMS (m/z) 179 (M+H)+. Compound 2f: oil;IR (neat,
cmÀ1): 762, 878, 1365, 1449; 1H NMR (200 MHz, CDCl3)
d 0.31–0.51 (m, 4H), 1.23 (s, 9H), 1.27–1.35 (m, 1H), 1.45
(s, 3H), 7.21–7.50 (m, 5H); 13C NMR (50 MHz, CDCl3) d
0.00, 0.88, 18.57, 20.99, 25.34, 77.33, 81.78, 125.00, 125.21,
126.13, 143.63;FABMS ( m/z) 235 (M+H)+. Peroxy-
13. Vennerstrom, J. L.;Dong, Y.;Anderson, S. L.;Ager, A.
L., Jr.;Fu, H.-N.;Miller, R. E.;Wesche, D. L.;Kyle, D.
E.;Gerena, L.;Watters, S. M.;Wood, J. K.;Edwards, G.;
Holme, A. D.;Maclean, W. G.;Milhous, W. K. J. Med.
Chem. 2000, 43, 2753–2758.
14. Kepler, J. A.;Philip, A.;Lee, Y. W.;Musallam, H. M.;
Caroll, F. I. J. Med. Chem. 1987, 30, 1505–1509.
15. Dockrell, H. M.;Playfair, J. H. L. Infect. Immun. 1983, 39,
456–459.
À1
lactone 14: oil;IR (neat, cm
)
1796; 1H NMR
16. Vennerstrom, J. L.;Eaton, J. W. J. Med. Chem. 1988, 31,
1269–1277.
(200 MHz, CDCl3) d 0.47–0.64 (m, 4H), 1.02–1.20 (m,
1H), 1.43 (s, 3H), 2.85 (s, 2H); 13C NMR (50 MHz,
CDCl3) d 0.00, 0.43, 16.05, 20.91, 41.19, 87.32, 173.89;
EIMS (m/z) 142 (M+). Peroxy-lactone 15 (mixture of
diastereomers): oil;IR (neat, cm À1) 1791; 1H NMR
(200 MHz, CDCl3) d 0.49–0.63 (m, 4H), 0.95–1.11 (m,
1H), 1.19 and 1.35 (2 · s, 3H), 1.22 and 1.34 (2 · d, 3H,
J = 7.4 Hz each), 3.01 and 3.05 (2 · q, 1H, J = 7.4 Hz
each); 13C NMR (50 MHz, CDCl3) d 0.00, 0.19, 0.35, 0.99,
8.52, 9.03, 12.94, 15.88, 16.21, 20.77, 46.23, 47.14, 89.40,
90.08, 177.07, 177.35;FABMS ( m/z) 157 (M+H)+. Peroxy-
lactone 16: oil;IR (neat, cm À1) 1798; 1H NMR (200 MHz,
17. Sunder, N.;Jacob, V. T.;Bhat, S. V.;Valecha, N.;Biswas,
S. Bioorg. Med. Chem. Lett. 2001, 11, 2269–2272.
18. Cointeaux, L.;Berrien, J.-F.;Peyrou, V.;Provot, O.;
Ciceron, L.;Danis, M.;Robert, A.;Meunier, B.;
Mayrargue, J. Bioorg. Med. Chem. Lett. 2003, 13, 75–
77.
19. Rieckmann, K. H.;Campbell, G. H.;Sax, L. J. U.;
Mrema, J. E. Lancet 1978, 1, 22–23.
20. Lambros, C.;Vanderberg, J. P. J. Parasitol. 1979, 65, 418–
420.
21. Puri, S. K.;Singh, N. Expl. Parasit. 2000, 94, 8–14.