Thiol-oxygen cooxidation of monoterpenes. Synthesis of endoperoxides structurally related to antimalarial yingzhaosu A

Article abstract of DOI:10.1055/s-1998-1587

The first application of thiol-oxygen cooxidation of 1,5-dienes for the preparation of 6-membered ring endoperoxides is described. Treatment of S-(-)-limonene and related monoterpenes with PhSH, dioxygen and a radical initiator, followed by selective reduction of intermediate hydroperoxide-endoperoxides afforded 4,8-dimethyl-4-phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols.

Full text of DOI:10.1055/s-1998-1587

122
SYNLETT
LETTERS
Thiol-Oxygen Cooxidation of Monoterpenes. Synthesis of Endoperoxides Structurally Related
to Antimalarial Yingzhaosu A
Mario D. Bachi* and Edward E. Korshin
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
Fax: + 972-8-9344142; E-mail cobachi@weizmann.weizmann.ac.il
Received 8 October 1997
Abstract: The first application of thiol-oxygen cooxidation of 1,5-
dienes for the preparation of 6-membered ring endoperoxides is
described. Treatment of S-(–)-limonene and related monoterpenes with
PhSH, dioxygen and a radical initiator, followed by selective reduction
of intermediate hydroperoxide-endoperoxides afforded 4,8-dimethyl-4-
phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols.
A variety of cyclic peroxides have been studied as potential candidates
for the treatment of malaria caused by chloroquine-resistant parasites.
Figure 2
1
Our attention has been given to yingzhaosu A (1) and to arteflene (2),
two endoperoxides characterized by a 2,3-dioxabicyclo[3.3.1]nonane
system as a central molecular feature (Figure 1). Yingzhaosu A was
A simple retrosynthetic analysis of compound 12a leads initially to the
endoperoxide-hydroperoxide 11, and then by homolytic cleavage to a
monoterpene 6, benzenethiol, and molecular oxygen (Scheme 2). It was
isolated from an extract of Artabotris uncinatus (Annonaceae) which
2
was used in China as a folk remedy for the treatment of malaria and
anticipated that the application of the classical thiol-oxygen cooxidation
3
was subsequently obtained by total synthesis. Arteflene is
a
8
(TOCO) of olefins to substrate 6 may induce a sequential free radical
representative example of
dioxabicyclo[3.3.1]nonan-7-ones, which exhibit potent antimalarial
activity against Plasmodium falciparum and Plasmodium berghei.
a group of synthetic 4-arylvinyl-2,3-
reaction leading to endoperoxide-hydroperoxide 11 in one operation
(Scheme 3). Previous studies of the TOCO reaction for the synthesis of
4
5
cyclic endoperoxides were restricted to five-membered monocyclic 1,2-
9-14
dioxolane derivatives.
The formation of endoperoxide 11 in one
operation from monoterpenes 6, PhSH, and O , relies on the viability of
2
each step in the sequential process shown in Scheme 3. The
unprecedented 6-exo addition of peroxy radical 8 to form the 2,3-
dioxabicyclo[3.3.1]nonanyl radical 9 was viewed as a potential obstacle
in the synthetic plan. A protocol for the synthesis of endoperoxides 17-
20 which minimizes undesired competitive reactions of peroxy radical 8
was therefore developed (Scheme 4).
Figure 1
It was postulated that other endoperoxides, which like yingzhaosu A (1)
and arteflene (2), contain the 2,3-dioxabicyclo[3.3.1]nonane system in
their molecular backbone may also exhibit antimalarial activity. The
only reported synthetic approach to the 2,3-dioxabicyclo[3.3.1]nonane
system is based on the transformation of (-)-carvone into a derivative 3
(4 steps), followed by formation of an hydroperoxide
4
and
intramolecular Michael addition to give an endoperoxide 5 (Scheme
Scheme 2
3-4
1).
In an ongoing study directed toward the development of new
6
antimalarial drugs, a versatile method for the synthesis of new 2,3-
dioxabicyclo[3.3.1]nonanes of type 12 was required (Figure 2). The
singular array of substituents at positions 7,8, and 12 makes these
compounds amenable to chemical manipulations, and thus suitable for
The following general procedure was applied for the preparation of
compounds of type 12a: Oxygen gas is slowly bubbled through a stirred
solution of a monoterpene 13-16 (ca. 3 equivalents, concentration:
0.02-0.1 M) and di-tert- butyl peroxalate radical initiator (DBPO) (0.02-
0.04 equivalents) in n-heptane-benzene mixture (ca. 2:1), at rt, with
simultaneous addition of benzenethiol (1 equivalent) in benzene or
heptane (concentration: ca. 1M) over a period of 12 h (syringe pump).
After the addition of thiol is completed, the mixture is kept under
oxygen for an additional 12-14 h. It is then cooled to 0-5°C and diluted
15
7
structural activities studies.
with CH Cl , and powdered Ph P (1 equivalent) is added. The mixture
2
2
3
is stirred for an additional 2 h at 0-5°C and then 1 h at rt. Concentration
and flash chromatography affords the corresponding endoperoxides
Scheme 1

February 1998
SYNLETT
123
Scheme 3
Scheme 4
16-19
17a,b-20a.
Reactions were performed using 0.5-15 mmole thiol.
isomer b is further downfield than that of isomer a, while the chemical
12
12
shift of C H' and C H for isomer a is further downfield than that of
isomer b, also ∆ (δH' - δH) > ∆ (δH' - δH). This pattern
Sulfones 21a-24a and 21b-23b were obtained by oxidation of the
corresponding sulfides 17a,b-20a with MCPBA (2.5 equivalents,
EtOAc, rt, 4-8 h, monitored by TLC), followed by chromatographic
isomer a
isomer b
which derives from the deshielding effect of the O atom on the
2
16-19
juxtaposed CH or CH H-atoms, is common to all sulfone-peroxides
separation into diastereomers a and b.
2
3
21-24 and sulfide-peroxides 17-20 and constitutes a simple diagnostic
tool to differentiate between epimers a and b at position-4.
The one-pot, five-step conversion of S–(–)-limonene (13) into 2,3-
dioxabicyclo[3.3.1]nonan-8-ols (17a,b) and their subsequent oxidation
to (1S,4S,5S,8S)-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicy-
clo[3.3.1]nonan-8-ol (21a) (mp 112°C) and (1S,4R,5S,8S)-4,8-
dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol
(21b) (oil) (Scheme 4) is a rather efficient process. The decrease in
yields observed in the reactions with carveol and benzoyl carveols 14-
16 probably derives from steric interference, at one of the transition
states, by substituents at position 7.
19
In conclusion, expansion of the scope of thiol-oxygen cooxidation of
dienes opens
a
new avenue for the synthesis of 2,3-
dioxabicyclo[3.3.1]nonanes structurally related to antimalarial
endoperoxides like 1 and 2. Compounds of type 12 were found to
7
exhibit significant antimalarial activity.
Acknowledgments. This research was supported by grant No. 94-102
from the United States-Israel Binational Science Foundation (BSF),
Jerusalem, Israel. The authors are grateful to Professor Gary H. Posner
of the Johns Hopkins University for his collaboration.
1
The H NMR spectrum of isomer 21a exhibits characteristic signals:
11
12
CH
at 1.51 ppm and
C
H'H at 3.27 and 4.23 ppm. The
3
11
corresponding signals for isomer 21b are for CH at 1.80 ppm and for
3
12
11
C
H'H at 3.14 and 3.33 ppm. Thus the chemical shift of CH
of
3

124
LETTERS
SYNLETT
11
11
References and Notes
MHz): δ 1.23 (br s, Me , 17a), 1.55 (br s, Me , 17b), total 3H;
10
10
1.37 (s, Me , 17b ), 1.38 (s, Me , 17a), total 3H; 1.58 (m, 1H,
(1) Cumming, J. N.; Ploypradith, P.; Posner, G. H. Advances in
Pharmacology 1997, 37, 253.
7
6
6
5
H
, 17a + 17b); 1.75-1.87 (m, 2H, H + H , 17a+ 17b; H
,
e
e
a
e
3
3
3
3
17b), 1.91 (dddd, J
5
≈ J
= 6.4 Hz, J
≈ J
= 3.2 Hz,
5e6e
5e9e
5e6a
5e9a
(2) Liang, X. T.; Yu, D. Q.; Wu, W. L.; Deng, H. C. Acta Chim. Sin.
1979, 37, 215.
2
3
H
, 17a), total 3H ; 1.97 (ddd, J
= 13.6 Hz, J
= 3.2 Hz,
3
e
9a9e
9a5e
3
9
2
J
= 2.0 Hz, H , 17a) , 2.05 (ddd, J
= 13.4 Hz, J
=
=
9a1e
a
9a9e
9a5e
(3) Xu, X.; Zhu, J.; Huang, D.; Zhou, W. Tetrahedron Lett. 1991, 32,
3
9
2
3.0 Hz,
J
= 1.8 Hz, H , 17b), total 1H; 2.08 (ddd,
J
9a1e
a
9e9a
5785.
3
3
9
13.6 Hz,
J
= 6.4 Hz,
J
= 3.6 Hz, H , 17a), 2.25 (m,
9e5e
9e1e
e
(4) Hofheinz, W.; Bürgin, H.; Gocke, E.; Jaquet, C.; Masciadri, R.;
Schmid, G.; Stohler, H.; Urwyler, H. Trop. Med. Parasitol. 1994,
45, 261.
2
9
7
J
≈ 13.4 Hz, H , 17b), total 1H; 2.29-2.39 (m, 1H, H , 17a
9e9a
e
a
2
12
2
+ 17b); 2.95 (d, J = 12.0 Hz, H , 17b), 3.33 (d, J = 12.8 Hz,
12
2
12
H
2
, 17a), total 1H; 3.02 (br.d, J = 12.0 Hz, H' , 17b), 3.69 (dd,
4
12
1
(5) Jaquet, C.; Stohler, H. R.; Chollet, J.; Peters, W. Trop. Med.
Parasitol. 1994, 45, 266.
J = 12.8 Hz, J
= 0.4 Hz, H' , 17a), total 1H; 3.67 (m, H ,
12,11
1
16
17a), 3.70 (m, H , 17b), total 1H; 7.18-7.24 (m, 1H, H , 17a +
15
14
17b); 7.26-7.32 (m, 2H, H , 17a + 17b); 7.35-7.42 (m, 2H, H
,
(6) Bachi, M. D.; Korshin, E. E.; Ploypradith, P.; Cumming, J. N.;
13
17a + 17b). C NMR (CDCl , 100 MHz) (δ): Isomer 17a: 21.94
Xie, S.; Shapiro, T. A.; Posner, G. H. 1997, in preparation.
3
11
6
9
10
5
(Me ), 23.66 (C H ), 24.25 (C H ), 28.10 (Me ), 29.32 (C H),
2
2
(7) Preliminary SAR results will be given in reference 6.
7
12
8
1
35.63 (C H ), 40.81 (C H ), 71.47 (C ), 81.65 (C H), 83.83
2
2
(8) Oswald, A. A.; Wallace, T. J. In The Chemistry of Organic Sulfur
Compounds; N. Kharasch and C. Y. Meyers, Ed.; Pergamon
Press: Oxford, 1966; Vol. 2; pp 205.
4
16
14
15
(C ), 126.20 (C H), 128.92 (2C H), 129.75 (2C H), 136.93
13
11
6
9
(C ); Isomer 17b: 21.81 (Me ), 23.38 (C H ), 24.35 (C H ),
2
2
10
5
7
12
28.10 (Me ), 30.61 (C H), 35.96 (C H ), 40.86 (C H ), 71.42
2
2
(9) Beckwith, A. L. J.; Wagner, R. D. J. Am. Chem. Soc. 1979, 101,
8
1
4
16
14
(C ), 82.09 (C H), 83.89 (C ), 126.40 (C H), 128.98 (2C H),
7099.
15
13
129.75 (2C H), 136.50 (C ). (1S,4S,5S,8S)-4,8-Dimethyl-4-
(10) Beckwith, A. L. J.; Wagner, R. D. J. Chem. Soc., Chem. Commun.
1980, 485.
phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol, 21a)
1
10
H NMR (400 MHz, CDCl , δ): 1.35 (s, 3H, Me ), 1.51 (br s,
3
11
2
3
7
(11) Barker, P. J.; Beckwith, A. L. J.; Fung, Y. Tetrahedron Lett. 1983,
24, 97.
3H, Me ), 1.60 (br dd, 1H, J = 14.2 Hz, J
= 5.6 Hz, H ),
7e6e
e
2
3
3
3
1.86 (dddd, 1H, J ≈ J
= 14.2 Hz, J
= 6.0 Hz, J
= 3.6
6a7a
6
6a5e
6a7e
3
6
2
Hz, H ), 1.93 (m, 1H, H ), 2.11 (ddd, 1H, J = 13.9 Hz, J
=
(12) Beckwith, A. L. J.; Wagner, R. D. J. Org. Chem. 1981, 46, 3638.
a
e
9a5e
3
9
2
3
3.0Hz, J
= 2.0 Hz, H ), 2.23 (br ddd, 1H, J = 13.9 Hz, J
9a1e
3
a
9e5e
(13) (a) Feldman, K. S.; Simpson, R. E. J. Am. Chem. Soc. 1986, 108,
1328. (b) Feldman, K. S.; Simpson, R. E. J. Am. Chem. Soc. 1989,
111, 4878.
9
5
= 6.0 Hz, J
= 3.5 Hz, H ), 2.30 (m, 1H, H ), 2.30 (ddd, 1H,
e e
9e1e
2
3
3
7
2
J _ J
= 14.2 Hz, J
= 6.7 Hz, H ), 3.27 (d, 1H, J = 14.3
7a6a
12
7a6e a
3
3
1
Hz, H ), 3.67 (m, 1H, J
= 3.5 Hz, J
= 2.0 Hz, H ), 4.23
1e9e
1e9a
12
e
(14) Feldman, K. S. Synlett 1995, 217.
2
4
15,
(dd, 1H, J = 14.3 Hz, J
= 0.5 Hz, H' ), 7.58 (m, 2H, H
12',11
(15) S-(-)-Limonene (13) and (-)-carvone are commercially available,
derivatives 14-16 were obtained by standard methods from (-)-
carvone.
15'
16
14, 14' 13
), 7.67 (m, 1H, H ), 7.95 (m, 2H, H
); C NMR (63 MHz,
11
6
9
CDCl , δ): 22.81 (Me ), 23.38 (C H ), 24.57 (C H ), 27.89
3
2
2
10
5
7
12
8
(Me ), 30.01 (C H), 35.59 (C H ), 60.95 (C H ), 71.22 (C ),
2
2
1
4
14'
15
(16) Endoperoxides 17-24 are thermally stable at rt for at least 6
months and in solutions of inert organic solvents at 60 °C for at
least 5 h.
81.90 (C H), 82.65 (C ), 127.46 (2C H), 129.30 (2C H),
16
13
133.70 (C H), 140.97 (C ). (1S,4R,5S, 8S)-4,8-Dimethyl-4-
phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol,
1
10
21b). H NMR (400 MHz, CDCl , δ): 1.29 (s, 3H, Me ), 1.58 (br
(17) Caution is to be taken in handling potentially explosive di-tert-
3
2
3
7
11
dd, 1H, J = 14.2 Hz, J
= 5.4 Hz, H ), 1.80 (br.s, 3H, Me ),
e
butyl peroxalate and mixtures of organic solvents and oxygen.
7e6e
6
6
2
3
1.86-2.00 (m, 2H, H + H ), 2.03 (ddd, 1H, J = 13.6 Hz, J
e
a
9a5e
(18) All new compounds were fully characterized by detailed NMR
3
9
3
3
1
= 3.2 Hz, J
= 1.8 Hz, H ), 2.09 (br dddd, 1H, J
≈ J
9a1e
a
5e6e
5e9e
2
analysis which included NOE difference experiments, 1D - ( H,
3
3
5
13
1
1
1
13
= 6.4 Hz,
J
≈
3
J
= 3.2 Hz, H ), 2.14 (br ddd, 1H, J ≈
5e9a e
5e6a
C/DEPT), and 2D-NMR spectra ( H/ H COSY, H/
C
3
7
2
J
= 14.2 Hz, J
= 6.6 Hz, H ), 2.27 (ddd, 1H, J = 13.6
a
7a6a
3
7a6e
3
HMQC). All sulfones (21a,b-24a) were additionally characterized
by elemental microanalysis or CI HRMS. The 3D-structure of
endoperoxide 20a (crystallized as monohydrate) was determined
by X-ray diffraction analysis. The 3D-structure of all other
endoperoxides described in this paper was further corroborated by
correlation of their NMR spectra with those of 20a monohydrate.
9
2
Hz, J
= 6.4 Hz, J
= 3.3 Hz, H ), 3.14 (d, 1H, J = 14.0
e
9e5e
12
9e1e
2
12
3
Hz, H ), 3.33 (br.d, 1H, J = 14.0 Hz, H' ), 3.68 (m, 1H, J
=
1e9e
3
1
15, 15'
3.3 Hz, J
= 1.8 Hz, H ), 7.58 (m, 2H, H
), 7.67 (m, 1H,
1e9a
e
16
14,14' 13
H
), 7.93 (m, 2H, H
); C NMR (100 MHz, CDCl , δ):
3
11
9
6
10
21.71(Μe ), 23.46 (C H ), 23.72 (C H ), 27.83 (Me ), 31.53
2
2
5
7
12
8
1
(C H), 35.35 (C H ), 60.55 (C H ), 71.02 (C ), 82.35 (C H),
2
2
(19) Selected
NMR
spectra:
(1S,4S,5S,8S)-4,8-dimethyl-4-
(17a)
(1S,4R,5S,8S)-4,8-dimethyl-4-phenylthiomethyl-2,3-di-
4
14
15
16
82.82 (C ), 127.52 (2C H), 129.25 (2C H), 133.76 (C H),
phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol
13
141.13 (C ).
and
1
oxabicyclo[3.3.1]nonan-8-ol (17b):
H NMR (CDCl , 400
3