A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic β-sulfonyl-endoperoxides

2516

J . Med. Chem. 2003, 46, 2516-2533

A Sh or t Syn th esis a n d Biologica l Eva lu a tion of P oten t a n d Non toxic

An tim a la r ia l Br id ged Bicyclic â-Su lfon yl-En d op er oxid es

Mario D. Bachi,*^,†Edward E. Korshin,^†Roland Hoos,^†Alex M. Szpilman,^†Poonsakdi Ploypradith,^‡Suji Xie,⁾

Theresa A. Shapiro,⁾and Gary H. Posner^‡

Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel, Department of Chemistry, School

of Arts and Sciences, The J ohns Hopkins University, Baltimore, Maryland 21218, and the Division of Clinical Pharmacology,

Department of Medicine, School of Medicine, The J ohns Hopkins University, Baltimore, Maryland 21205

Received December 27, 2002

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types

9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like

yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-

dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R¹) OH) are readily available through

a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation

(a TOCO reaction). â-Sulfenyl peroxides 9 and 10 (R¹) OH) are converted into â-sulfinyl and

â-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-

hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogena-

tion. Ten enantiopure â-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial

activity comparable to that of artemisinin (IC₅₀) 6-24 nM against Plasmodium falciparum

NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates

that the antimalarial efficacies of â-sulfonyl peroxides 39a , 46a , 46b, and 50a are comparable

to those of some of the best antimalarial drugs and are higher than artemisinin against

chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of â-sulfonyl

peroxides 39a , 46a , and 46b in mice, at high dosing, these compounds are regarded as promising

antimalarial drug candidates.

In tr od u ction

countries is arteether (2c), which was registered in the

year 2000 in The Netherlands for treatment of severe

malaria.¹⁵

Although a variety of new approaches for fighting

malaria are being investigated,^1,2chemotherapy is still

the most common method for treating malaria.^3-11The

continuing spread of malaria parasite strains resistant

to customary drugs is motivating a worldwide quest for

new, effective, and inexpensive therapeutic agents.^2,3

Various organic endoperoxides have been found to

exhibit antimalarial activity. The natural product ar-

temisinin (1), and its semisynthetic C(10) acetal deriva-

tives artemether (2b), arteether (2c), artesunic acid

(2d ), and artelinic acid (2e) have already been used for

treatment of malaria in endemic countries.^3-11No

serious side effects have been reported for the clinical

trials with artemisinin (1) and its acetal derivatives

2b-e in malaria-endemic areas. However, some indica-

tions of serious neurotoxicity and cardiac abnormalities

have been found in animal studies at high doses of 1

and its lactols 2b,c.¹²This neurotoxicity is very likely

to be associated with the nature of acetals 2b,c, which

are rapidly metabolized, hydrolyzed, or both to yield the

highly neurotoxic dihydroartemisinin (2a ) as a major

metabolite.¹³Thus, the data on adverse pharmacokinetic

and clinical properties, as well as the potentially harm-

ful biological side effects, have deferred approval of this

first generation of antimalarial artemisinin derivatives

2 in nonendemic countries.^3,4,14The first and so far the

only antimalarial peroxide to reach the market in those

The identification of the trioxane system 5 as the

pharmacophore of the natural product 1 and its semi-

synthetic derivatives 2 led to the development of a

variety of structurally simplified racemic trioxanes such

as tricyclic compounds 3^10,11,16and spirocyclic trioxanes

such as fenozan (4).^9,17,18The antimalarial potency

against chloroquine-resistant Plasmodium strains of

some of the synthetic compounds 3 and 4 was found to

be considerably higher than that of artemisinin (1) and

comparable to its derivatives 2b-e.

* To whom correspondence should be addressed. Tel: +972-8-

9342043. Fax: +972-8-9344142. E-mail: mario.bachi@weizmann.ac.il.

^†Department of Organic Chemistry, The Weizmann Institute of

Science.

^‡Department of Chemistry, The J ohns Hopkins University.

⁾Division of Clinical Pharmacology, The J ohns Hopkins University.

Published on Web 05/03/2003

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2517

Sch em e 1

Another, although a much less studied, group of

promising antimalarial peroxides consists of compounds

containing the 2,3-dioxabicyclo[3.3.1]nonane pharma-

cophore (6) in their molecular backbone. System 6 was

originally identified in yingzhaosu A (7), a natural

product isolated from a traditional Chinese herbal

antimalarial medicament¹⁹and subsequently obtained

by total syntheses.^20-22Although no data on the anti-

malarial activity of yingzhaosu A (7) was ever re-

ported,¹⁹it inspired a few research groups to design and

synthesize some simplified endoperoxides containing the

2,3-dioxabicyclo[3.3.1]nonane framework (6) and screen

them for antimalarial activity. In a pioneering work it

was shown that synthetic endoperoxides of type 8 do

exhibit potent antimalarial activity.²³Arteflene (8a ) was

identified as a lead drug candidate.^23,24It exhibits a

rapid onset of drug action, long-lasting high antima-

larial effect against drug-resistant strains of P. falci-

parum, and a very low toxicity.²⁴Essentially no side

effects were found for the treatment with arteflene (8a )

in preclinical and phase 2 clinical studies.^3,25,26The

reported procedure²³for the synthesis of antimalarials

of type 8 is laborious, and their further development as

drugs seems to have been interrupted.^6,14

Recently, we reported on an expedient synthesis of

endoperoxides of types 9-13 (R¹) OH)^27-29and on a

novel and efficient total synthesis of yingzhaosu A (5).²¹

In a preliminary screening, we found that some â-sul-

fonyl-endoperoxides of types 12 and 13 exhibit high

antimalarial activity.^29,30Moderate antimalarial activity

was observed also in synthetic acetal derivatives of 2,3-

dioxabicyclo[3.3.1]nonane,³¹whereas some similar â-iodo-

endoperoxides showed significant antimalarial activi-

ties.³²

liminary toxicological studies. â-Sulfonyl-bridged bicy-

clic endoperoxides 39a , 46a , and 46b (type 12), which

were synthesized in 3 to 4 steps from readily available

starting materials, were found to be highly potent and

nontoxic antimalarial agents.

Ch em istr y: Syn th esis of P olysu bstitu ted 2,3-

Dioxa bicyclo[3.3.1]n on a n es 9-13. On the basis of the

methodology reported in our previous papers, endoper-

oxides of types 9-13 were prepared in a few synthetic

steps from inexpensive, commercially available re-

agents.^27,28The first stage, leading to 4-sulfenylmethyl-

2,3-dioxabicyclo[3.3.1]nonan-8-ols of type 9, involves the

application of a free-radical sequential thiol-olefins co-

oxygenation (TOCO) reaction to monoterpenes, as ex-

emplified using R-(+)-limonene (14) in Scheme 1. The

TOCO reactions were initiated by AIBN and UV ir-

radiation or by di-tert-butylperoxalate (DBPO). In this

multicomponent reaction, five new bonds are formed in

one sequential, free-radical process. Upon completion

of the free-radical TOCO reaction, the hydroperoxide

function of the resulting hydroperoxide endoperoxides

15-18 is chemoselectively reduced in the same vessel,

yielding the corresponding â-sulfenyl-endoperoxides

19-22.²⁸â-Sulfenyl-endoperoxides 19-21 were easily

oxidized to the corresponding â-sulfonyl-endoperoxides

23-25.²⁸These compounds, which were obtained as

mixture of C(4) epimers, as well as additional com-

pounds obtained by further structural modifications, are

distinguished throughout this paper by subscripts a and

b in accordance with their absolute configuration on

In this paper, we give a detailed report on a short and

efficient synthesis of numerous â-sulfinyl- and â-sulfo-

nyl-endoperoxides of types 11-13, as well as on their

in vitro and in vivo antimalarial evaluation and pre-

2518 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

Sch em e 2^a

a

Reagents and conditions: (a) AcCl, DMAP, pyridine, CH₂Cl₂, 0 °C to rt; (b) TMSOTf, 2,6-lutidine, CH₂Cl₂, 5 °C; (c) AcCl, rt; (d) oxalyl

chloride, rt; (e) EtOH, 2,6-lutidine, CH₂Cl₂, 4 °C; (f) Bn₂NH, 2,6-lutidine, CH₂Cl₂, 0 °C.

Sch em e 3

stereogenic center C(4). Application of the same proce-

dure to the co-oxygenation of S-(-)-limonene or R-(-)-

carveol derivatives yielded endoperoxides 26-30 having

the opposite absolute configuration.

At an early stage of this research, it was recognized

that the potent and stable â-sulfonyl-endoperoxides 12

are more expedient candidates for further development

of antimalarials than their sulfenyl precursors, 9.³⁰

Additionally, chromatographic separation of â-sulfonyl-

endoperoxides 12 and 13 to their individual diastereo-

mers is more efficient.^27,28Therefore, our standard

protocol involves the isolation of the â-sulfenyl-endo-

peroxides 19-22 as a diastereomeric mixture of the C(4)

epimers a and b. Subsequent oxidation to the corre-

sponding â-sulfonyl-endoperoxides 23-25, followed by

their separation, affords individual epimers of â-sulfo-

nyl-endoperoxides of series a and series b. A few

â-sulfinyl-endoperoxides of type 11 were obtained by

controlled partial oxidation of the corresponding â-sulfe-

nyl-endoperoxides 9. This protocol allows the prepara-

tion of a variety of endoperoxides of types 9-13 (R¹)

OH) in which the nature of substituents R and R²is

predetermined by selection of the thiol and monoterpene

used in the TOCO reaction. Additional structural modi-

fications are feasible through manipulations with the

8-hydroxyl group such as acylation, alkylation, and

deoxygenation.

more expedient method for mono-acylation involves

silylation of hydroxy compound 19 with TMSOTf to give

the TMS derivative 33 (quantitative), followed by treat-

ment with excess acetyl chloride to give the acetoxy

derivative 31 (93%). A similar procedure was applied

for the preparation of oxalyl chloride derivative 34,

which on treatment with ethanol afforded ester 35

and, with dibenzylamine, amide 36 in good yield. The

8-hydroxy- and 8-acetoxy-â-sulfenyl-endoperoxides 19

and 31 were oxidized with one equivalent of mCPBA to

the corresponding â-sulfinyl-endoperoxides 37 and 38

(Scheme 3.1). Oxidation of the 8-acyloxy-â-sulfenyl-

endoperoxides 31, 32, 35, and 36 with an excess of

mCPBA afforded the corresponding â-sulfonyl-endo-

peroxides 39-42 (Scheme 3.2).

Stereochemistry assignment at stereogenic center

C(4) of â-sulfonyl-endoperoxides 39a , 42a , and 39b -

42b was based on their ¹H NMR spectra. It was

observed that a strong through-space deshielding effect

of electronegative O(2) atom on the syn-positioned C(12)

HH′ fragment in series a and the Me(11) group in series

Direct acylation with acyl chlorides and DMAP of the

sterically hindered hydroxyl group in peroxides 9, 10,

12, and 13 is slow and therefore subject to competitive

secondary reactions. Indeed, treatment of â-sulfenyl-

endoperoxide 19 with acetyl chloride and DMAP (Scheme

2) afforded, in addition to acetoxy derivative 31 (53%),

1

b, induces a significant downfield shift in the H NMR

spectra of all â-sulfonyl-endoperoxides 39-42. This

effect was previously^27,28formulated as an empirical rule

that holds also for other structurally related bicyclic

peroxides. Similarly, the configuration at C(4) in â-sulfi-

the diacetylated derivative acetoacetate 32 (13%).³⁰

A

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2519

Ta ble 1. Selected ¹H (400 MHz) and ¹³C (100 MHz) NMR Data for 8-Acetoxy-4,8-dimethyl-4-phenylsulfinylmethyl-2,3-

a

dioxabicyclo[3.3.1]nonanes 38 in CDCl₃

38a ′

38a ′′

38b′

38b′′

position

¹H

4.42 (m)

¹³C

¹H

¹³C

¹H

¹³C

¹H

¹³C

1

5

7

77.58 d

4.47 (br d, 3.6)

77.75 d 4.47 (br dd, 3.8, 1.8) 78.02 d 4.49 (br d, 3.3)

78.34 d

31.60 d

32.92 t

∼2.20 (m)

29.09 d ∼1.85 (m)

30.90 d 2.02 (br dddd)

33.20 t 2.18-2.29 (m)

2.18-2.29 (m)

30.55 d 1.90 (br dddd)

32.77 t 2.07 (ddd, ax)

2.31 (ddd, ax)

∼2.20 (m, eq)

1.65 (s)

32.98 t

2.30 (ddd, ax)

2.20 (br dd, 14.8, 6.2 eq)

1.68 (s)

1.56 (br s)

3.31 (AB quartet, 14.0)

3.36 (AB quartet, 14.0)

2.14 (br dd, 14.8, 6.6 eq)

22.45 q 1.62 (s)

22.88 q 1.89 (br s)

65.45 t 2.67 (br d, 13.6)

3.10 (br d, 13.6)

10

11

12

22.43 q

23.55 q

64.54 t

22.53 q 1.65 (s)

22.59 q

22.05 q

65.82 t

1.44 (br s)

3.08 (d, 13.8)

3.61 (dd, 13.8, 0.6)

22.23 q 1.80 (d, 0.6)

66.04 t 2.77 (dd, 13.4. 0.6)

2.92 (br d, 13.4)

a

For complete NMR data see Experimental Section. The values in brackets refer to a multiplicity of the signal and a coupling constant

J in Hz.

Sch em e 4^a

Sch em e 5

a

Reagents and conditions: (a) TMSOTf, 2,6-lutidine; (b) AcCl;

(c) PhOCH₂C(O)Cl, CsF.

PhSH using the sequence of transformations displayed

in Schemes 1, 2, and 3.2 was reported earlier.²⁸The

nyl-endoperoxides 37a , 38a and 37b, 38b was deter-

mined using 2D NMR techniques (COSY and HMQC)

and corroborated by NOE difference experiments. The

couples of sulfoxides a ′ and a ′′ as well as b′ and b′′ differ

only in the absolute configuration at the sulfur atom,

which was not determined in this work. Representative

1D NMR data, relevant for the structural differentiation

of all the C(4) diastereomers of 8-acetoxy-â-sulfinyl-

endoperoxides 38a ′, 38a ′′, 38b′, and 38b′′, are sum-

marized in Table 1.

As shown in Table 1, all four isomeric â-sulfinyl-

endoperoxides 38 reveal very similar NMR patterns for

atoms and groups attached to the C(8) stereogenic

center and different patterns for atoms and groups

juxtaposed to the C(4) stereogenic center. This indicates

that all the diastereomers have the same configuration

at C(8) and differ in their configurations at only C(4)

(series a and b) and on the sulfur atom. Stereochemical

assignment of â-sulfinyl-endoperoxides 38 was based on

major diastereomers 45a and 45b are enantiomeric to

39a and 39b, respectively. Alkylation of the tertiary C(8)

hydroxyl group in â-sulfonyl-endoperoxides 23 with

alkyl halides under basic conditions failed because of a

competitively fast Kornblum-De La Mare degradation

of the peroxidic function.^33,34Alkylation was therefore

performed with strong electrophiles under acidic condi-

tions. The O-benzylated derivatives 46a and 46b were

obtained in 85% yield by treatment of 23a and 23b,

respectively, with phenyldiazomethane in the presence

of a catalytic amount of TfOH.³⁵The trichloroacetimi-

1

their H NMR spectra. Structures 38a ′ and 38a ′′ were

assigned to the isomers in which the C(12) HH′SO group

is more deshielded and the Me(11) group is more

shielded relative to the other two isomers to which were

assigned structures 38b′ and 38b′′.²⁸Indeed, separate

oxidation of both individual sulfoxides 38a ′ and 38a ′′

with mCPBA (1.5 equiv) gave the same sulfone 39a

(>90%). As we reported previously, the b series of

4-sulfonylmethyl- and 4-sulfenylmethyl-2,3-dioxabicyclo-

[3.3.1]nonanes is characterized by the higher values of

the C(5) chemical shift in ¹³C NMR spectra (∆_b-aδ_Cca.

1.5 ppm) than the a series.²⁸Comparison of the δ_C

values within the diastereomeric pairs a ′/b′ and a ′′/b′′

indicates that this rule is applicable also for the sulfox-

ides 38 (Table 1) and 37 (Experimental Section).

8-Acylated-â-sulfonyl-endoperoxides 39a and 44a were

prepared from the 8-hydroxy-â-sulfonyl-endoperoxides

23a via its TMS derivative 43a (Scheme 4). This

procedure was used also in gram-scale preparations of

compound 39a (95% yield in two steps). The preparation

and characterization of all four individual 8-acetoxy-â-

sulfonyl-endoperoxides 45a -d from S-(-)-limonene and

dates 47-49, which were obtained from the correspond-

ing benzylic or allylic alcohols and trichloroacetoni-

trile,³⁶were found to be suitable alkylating agents.^36,37

Thus, treatment of 8-hydroxy sulfone 23a with trichlo-

roacetimidates 49-51 and TfOH afforded the corre-

sponding O-alkylated products 50a -52a . (Scheme 5).

8-Deoxygenated sulfone-endoperoxide 56 was ob-

tained from 8-hydroxysulfide-peroxide 19. The latter

was readily dehydrated with thionyl chloride and py-

2520 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

Sch em e 6^a

electrophiles, oxidants, and some reducing agents.

However, these peroxides are highly sensitive to strong

bases and iron salts.³⁴It is noted that working with

peroxides requires appropriate safety precautions.⁴¹

Biology

In Vitr o An tim a la r ia l Activity. In vitro antima-

larial activity of more than 50 2,3-dioxabicyclo[3.3.1]-

nonanes of types 9-13 were determined by modifica-

tion⁴²of the methods of Desjardins⁴³and Milhous.⁴⁴

Tables 2 and 3 summarize the IC₅₀values of these

compounds against a chloroquine-sensitive NF54 strain

of P. falciparum relative to the activity of artemisinin

(1). At an early stage of the screening, it was observed

that the carveol derivatives 27-30 (Table 2) possessing

substituents X at C(7) are less active than the corre-

sponding C(7)-unfunctionalized analogue 26, which is

readily obtained from S-limonene. Therefore, the study

was focused on C(7)-unsubstituted endoperoxides deriv-

ing from enantiomeric R-(+)- and S-(-)-limonenes.

Assessment of the possible influence of the sulfur-

containing appendages Y and Z on antimalarial activity

indicated that no difference in antimalarial activity was

detected by replacement of the standard phenyl group

in 27 with the n-Bu substituent as in 28 (Table 2). Also,

comparison of the antimalarial activity of p-fluorophenyl

sulfone 24 with that of the parent phenyl derivative 23

(Table 3) indicates that the frequently beneficial influ-

ence of fluorine is rather small in this case. The

carbmethoxymethyl derivative 25 is inactive.

The â-sulfonyl-endoperoxides 23 and 26, themselves

in vitro moderately active antimalarial agents, served

as intermediates for the preparation of a variety of much

more active â-sulfonyl-endoperoxides through structural

modifications on the C(8) hydroxyl group (Table 3,

compounds of the type A). Increasing lipophilicity of a

series of antimalarial trioxanes is usually accompanied

by enhancement of activity.⁴⁵Such an effect was ob-

tained by acetylation of C(8) hydroxyl in â-sulfonyl-

endoperoxides 26a and 26b to the more liphophilic and

active derivatives 45a and 45b (Table 2). It is noted that

the minor isomeric 8-acetoxy-â-sulfonyl-endoperoxides

45c and 45d are practically inactive. All the 8-acylated-

â-sulfonyl-endoperoxides 39-42 and 44a (Table 3) are

much less polar than the parent hydroxysulfones 23,

but only half of them are significantly more potent. The

moderate activity of peroxides 40a and 40b bearing a

distal acetoacetate group may be associated with the

ability of this function to effectively bind the free iron

ions, thus neutralizing the trigger for the activation of

endoperoxides.^46,47In contrast, the relatively polar

acetoxysulfoxide 38 showed significant antimalarial

activity. This may be due to the ability of its sulfoxide

function to ligate metal ions in proximity to the endo-

peroxide function. One of these sulfoxides, namely 38b′′

(IC₅₀) 14 nM), is similar in potency to corresponding

sulfones 39a and 39b (IC₅₀) 17 nM).

a

Reagents and conditions: (a) SOCl₂, pyridine, CH₂Cl₂, 0 °C

to rt; (b) Potassium azodicarboxilate, AcOH, MeOH, CH₂Cl₂, 0 °C

to rt; (c) mCPBA, EtOAc, rt.

ridine to give a mixture of cyclohexene-endoperoxide 53

and methylenecyclohexanes-endoperoxide 54 (ca. 85:15)

(Scheme 6). Treatment of this mixture with excess of

diimide (generated in situ from potassium azodicar-

boxylate, >10 equiv)³⁸resulted in the selective hydro-

genation of methylenecyclohexanes 54a ,b to give a

mixture of the four saturated sulfides 55a -d . The less

reactive endocyclic CdC bond in sulfides 53a ,b re-

mained unchanged. Attempts to hydrogenate the cyclo-

hexene-sulfide 53 with additional diimide or by catalytic

hydrogenation using PtO₂,^39aPd/C, and Rh/Al₂O₃cata-

lysts failed. Likewise unsuccessful were attempts to

hydrogenate sulfide 53 using a homogeneous Wilkinson^39b

and Crabtree^39ccatalyst. The pairs of saturated sulfide-

endoperoxides 55a ,b with an equatorially positioned

Me(10) group were separated by MPLC from the pair

55c,d having an axial Me(10) group. Diastereomers

55a ,b were oxidized with mCPBA to give a mixture of

sulfone-endoperoxides 56a and 56b (Scheme 6), which

was separated using semipreparative HPLC. The failure

of the above-mentioned catalytic hydrogenations was

probably due to the poisoning of the catalysts by the

divalent sulfur. To circumvent this obstacle, sulfone-

endoperoxides 56a and 56b were prepared by the

hydrogenolysis of unsaturated sulfones 57 and 58 as

described in Scheme 7. Thus, dehydration of the 8-hy-

droxysulfone 23a afforded a mixture of unsaturated

sulfone-endoperoxides 57a and 58a . This mixture of

unsaturated endoperoxides was hydrogenated over a

PtO₂catalyst at low temperature (-10 °C), giving

chemo- and diastereoselectively a single-saturated sul-

fone 56a in excellent yield (Scheme 7.1).⁴⁰Following the

same protocol, hydroxysulfone 23b was converted into

saturated sulfone 56b (Scheme 7.2). Additionally, un-

saturated sulfone 57a was diastereoselectively epoxi-

dized from the less-hindered side of the carbocycle to

give the epoxy endoperoxide 59a as a single diastere-

omer (Scheme 8). The transformations described in this

section indicate that the endoperoxide function in

compounds of types 9-13 is compatible with a wide

range of reaction conditions including strong acids,

Further increase of lipophilicity was obtained by

O-benzylation to compounds 46 and 50a , by O-allylation

to 51a and 52a , as well as by C(8) deoxygenation to

â-sulfonyl-endoperoxide 56. All these compounds were

found to exhibit in vitro antimalarial activity, close to

that of artemisinin (1). The most potent of them, namely

8-benzyloxy derivative 46a , is 140% as active as 1. The

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2521

Sch em e 7

Sch em e 8

Toxicology

The remarkable in vivo antimalarial efficacy of â-phe-

nylsulfonyl-endoperoxides 39a , 46a ,b, and 50a renders

them potential drug candidates. Although no significant

neuropathology was observed in the studies on arteflene

(8a ),^24,25other antimalarial peroxides, namely artemisi-

nin (1) and its acetal derivatives 2, were found to be

neurotoxic on repeated administration of high doses.¹²

This prompted us to submit â-phenylsulfonyl-endoper-

oxides 46a ,b and 39a to acute, sub-acute, and neural

toxicity tests, as well as to preliminary behavioral

observations in rodents. Preliminary in vivo acute

toxicity studies of the acetoxy derivative 39a in rodents

showed no toxicity at high dosage.⁵⁰Indeed, in a group

of six male CD-1 mice dosed with a single dose of 1140

mg/kg of 39a (solution in sesame oil) using an intra-

peritoneal (IP) route of treatment, all the animals

survived for at least 8 days after administration.

Moreover, this single high dose of 39a produced neither

any treatment-related adverse clinical signs nor any

dramatic changes in clinical chemistry and hematology.

Only a statistically significant decrease in liver weights

of mice treated with 285, 570, and 1140 mg/kg was

observed, whereas mice treated with 143 mg/kg had

normal mean organ weights. Additionally, histopathol-

ogy studies revealed some renal tubular regeneration,

hepatocellular cytomegaly, and increased mitoses, which

are considered responses to toxic effects of the compound

39a administration. For comparison of toxicity, in the

reference artemether (2b) groups, only 10 and 4 mice

(from 18 in each group) survived being treated IP with

a single dose of 500 and 1000 mg/kg, respectively. A

single dose of 250 mg/kg of 2b did not cause mice

mortality. Nevertheless, even upon this single dosage

of 2b, specific treatment-related adverse clinical signs

were noted, including ruffled fur, hypoactivity, and

hunched posture.

pronounced decrease in antimalarial activity of unsat-

urated sulfones 57a and 58a (Table 3, types B and C),

as compared to that of the parent hydroxysulfone 23a ,

may derive from the particular chemical properties of

the allylic peroxy system. A similar, but more moderate,

adverse influence was observed in the case of epoxide

59a .

In Vivo An tim a la r ia l Activity. In vitro antima-

larial assays have provided reliable guidelines for

selecting peroxides for in vivo antimalarial examina-

tion.⁴⁸On this basis, the in vitro, highly active 8-acetoxy

derivative 39a , the two 8-benzyloxy C(4) epimers 46a

and 46b, and the 8-(p-methoxybenzyl)oxy derivative 50a

were selected for in vivo biological evaluation. For

comparison, the parent 8-hydroxy-endoperoxide 23a was

also tested. All of these five 4-phenylsulfonylmethyl-2,3-

dioxabicyclo[3.3.1]nonanes were evaluated in mice

against chloroquine-sensitive P. berghei N and chloro-

quine-resistant P. yoelii ssp. NS. In Table 4, the data

obtained from this screening are compared to those of

the peroxidic antimalarial drugs or drug candidates

artemisinin (1), artemether (2b), arteether (2c), artelinic

acid (2e), and arteflene (8a ), as well as the widely used

chloroquine. The parent compound 23a , bearing a free

hydroxyl group and being moderately active in vitro,

showed no significant activity in vivo. The acetoxy

derivative 39a is approximately 50% as active as

arteflene (8a ) and 30% as active as artemisinin (1) vs

P. berghei and P. yoelii. It is noteworthy that compound

39a in subcutaneous (SC) administration is ca. two

times more active against P. berghei than one of the

currently leading antimalarial drug candidates, artelinic

acid (2e).⁴⁹Aralkylated derivatives 46a , 46b, and 50a

were found to exhibit potent in vivo activity. When

administrated SC, the antimalarial potency of endo-

peroxides 46a and 46b is ca. 200% that of artemisinin

(1) vs P. berghei and 300% vs chloroquine-resistant P.

yoelii. The most potent representative in this group,

namely benzyloxy derivative 46b, exhibits in vivo activ-

ity similar to that of artemether (2b) and arteether (2c)

and 10 times higher activity than artelinic acid (2e).

The endoperoxide 46b is also an efficacious antimalarial

on oral administration, being comparable to artemisinin

(1) and arteflene (8a ).

More detailed toxicity tests were performed on 8-benz-

yloxy derivatives 46a and 46b in a mouse model (see

Experimental Section). At the first stage of the study,

four groups of mice (g4 mice in each group) were treated

intramuscularly (IM) with a single dose of the test

articles 46a ,b, arteether (2c) as a reference, and sesame

oil as a vehicle. Solutions (5%) or suspensions of the test

articles 46a ,b and reference 2c in sesame oil were used

for injections. The test compounds 46a ,b and the

reference 2c were injected into one or more sites of the

musculature of the rear limb assembly so that the

volume injected per site did not exceed 0.05 mL. The

doses varied from 85 to about 400 mg/kg. After 14 days,

all the mice (from the four groups) treated with 380 (

2522 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

Ta ble 2. In Vitro Antimalarial Activity of (1S,5S)-4-(R-Sulfonyl)methyl-2,3-dioxabicyclo[3.3.1]nonanes Against Chloroquine-Sensitive

NF54 Strain of P. falciparum

compd

Y

Z

R¹

R²

X

IC₅₀(nM) ^a

26a

26b

27a

27b

28a

28b

29a

29b

30a

45a

45b

45c^b

PhSO₂

H

PhSO₂

H

n-BuSO₂

H

PhSO₂

H

PhSO₂

H

PhSO₂

H

OH

OAc

Me

OAc

H

120

95

170

>2500

100-500

500-2500

815

500-2500

>2500

20

PhSO₂

H

PhSO₂

H

n-BuSO₂

H

PhSO₂

H

â-OBz

R-OBz

R-OH

H

PhSO₂

H

PhSO₂

H

18

270

220

45d ^b

Me

Artemisinin(1)

8.7 ( 0.7

a

Antimalarial activity was determined as described in ref 42. The standard deviation for each set of quadruplicates was an average

of 8% (e38%) of the mean. R²values for the fitted curves were g0.985. Artemisinin (1) activity is mean ( standard deviation of concurrent

control (n ) 13). Ca. 93% pure.

b

Ta ble 3. In Vitro Antimalarial Activity of (1R,5R)-4-(R-Sulfenyl)methyl-, (R-Sulfinyl)methyl-, and (R-Sulfonyl)methyl-2,3-

dioxabicyclo[3.3.1]nonanes Against Chloroquine-Sensitive P. falciparum (NF 54)

IC₅₀

compd

type

Y

Z

R¹

(nM) ^a

compd type

Y

Z

R¹

(nM)^a

22a

22b

23a

23b

24a

24b

25a

25b

37a ′′

37b′

38a ′

38a ′′

38b′

38b′′

39a

39b

Artemisinin(1)

Arteflene(8a )

A

TrS

H

PhSO₂

H

4-FC₆H₄SO₂

H

TrS

H

PhSO₂

H

4-FC₆H₄SO₂

H

MeO₂CCH₂SO₂OH >2500

H

PhSO

H

OH 150

OH 72

40a

40b

41a

41b

42a

42b

44a

46a

46b

50a

51a

52a

56a

56b

53a

57a

A

B

C

D

PhSO₂

H

PhSO₂

H

PhSO₂

H

PhSO₂

H

PhSO₂

H

O₂CCH₂C(O)Me

46^b

73^b

170^b

140^b

21^b

81^b

37

6.5

9.4

14^b

35

PhSO₂O₂CCH₂C(O)Me

O₂CCO₂Et

PhSO₂O₂CCO₂Et

O₂CCONBn₂

PhSO₂O₂CCONBn₂

OH 55^b

OH 89^b

OH 49

H

OH 52

OH >2500

MeO₂CCH₂SO₂

H

O₂CCH₂OPh

OBn

PhSO

H

PhSO

H

OH 150

OH 820

OAc 62

OAc 54

OAc 40

OAc 14

OAc 17^b

PhSO₂OBn

H

OCH₂C₆H₄OMe-4

OCH₂CHdCMe₂

OCH₂CHdCHPh-E 32

H

PhSO

H

17

24

940

360

<3220

92

H

PhSO₂

H

PhS

H

PhSO₂

8.9 ( 1.6 58a ^c

71 59a

a

Antimalarial activity was determined as reported in ref 42. The standard deviation for each set of quadruplicates was an average of

10% (e53%) of the mean. R²values for the fitted curves were g0.975. Artemisinin (1) activity is mean ( standard deviation of concurrent

control (n ) 36). Data reported in ref 30. ^cA mixture containing 80% of 58a and 20% of 57a .

b

20 mg/kg of the test compounds 46a ,b or with 360 ( 10

mg/kg of the reference 2c (two animals) demonstrated

100% survival and normal expected body weight gain.

No gross pathological or behavioral findings were noted

in any of the treated animals.

In the next stage of the trial, the 7-day repeated IM

toxicity test in mice (five animals in each group) was

performed (see Experimental Section). The test articles

46a and 46b were administered IM daily in two differ-

ent doses (50 and 200 mg/kg/day). In the reference

group, the reference 2c was administered at the lower

dose (50 mg/kg/day), whereas in the control group, only

the vehicle sesame oil was injected. No animal mortality

occurred prior to the scheduled sacrifice at the 9th day.

Body weight determined on days 1, 5, and 8 failed to

reveal any significant differences between treated and

concurrent reference and control groups. Clinical signs

examined daily throughout the study period did not

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2523

Ta ble 4. In Vivo Antimalarial Activity of (1R,5R,8R)-4-Phenylsulfonyl-2,3-dioxabicyclo[3.3.1]nonane Against Chloroquine-Sensitive

Plasmodium berghei N and Chloroquine-Resistant Plasmodium yoelii ssp. NS in mg/kg/day × 4^a

P. berghei N

P. yoelii ssp. NS

ED₅₀ED₉₀

inactive at 30

compd

Y

Z

R¹

OH

OAc

OBn

OPMB

ED₅₀

ED₉₀

23a

39a

46a

46b

50a

PhSO₂

H

>30

3.7

>30

7.3

12.5

28.0

3.8

0.8 (10.5)

0.43 (4.2)

1.3

1.7 (115)

1.3 (23.5)

2.3

1.3

1.0

4.8

5.8^c

PhSO₂

H

3.1

PhSO₂

8.3

Artemisinin(1)^b

Artemether (2b)^b

Arteether (2c)

0.95 (5.0)

0.5 (3.1)

0.9

2.5 (14.0)

1.1 (5.0)

1.4

10.0^c

Artelinic acid (2e)

6.6

2.7 (10.4)

1.0 (1.9)

14.0

3.9 (18.0)

1.2 (2.3)

Arteflene (8a )^b

Chloroquine (base)^b

2.4^c

56.0^c

a

Substances were administered to mice subcutaneously. Data in brackets correspond to oral administration. Protocols of these tests

were previously described in ref 17a. These data were taken from ref 24. ^cThe values were taken from ref 18b.

b

reveal any abnormalities in any of the groups. The only

gross abnormality evident at sacrifice was an enlarge-

ment of the spleen observed in all animals of the

reference 2c group, high-dose 46b test group, and in

three of five animals in the 46a high-dose group.

Microscopic examination showed no toxicity-related

lesions in any of the examined organs. On the basis of

the reported information indicating a loss of neurons

and gliosis in rats treated with the 25 mg/kg/day of

arteether (2c),¹²particular attention was paid to any

potential treatment-related lesions in the brain section

of the cerebellum, the medulla oblongata nuclei, such

as the neuron of the trapezoid body. The microscopically

described enlarged spleens were found to consist of a

mild degree of extramedullary hematopoesis, but at this

stage of the study it was not possible to conclude that

splenomegaly is a treatment-related effect. Examination

of hematology and clinical chemistry parameters at

study termination did not reveal any differences among

test and control groups of animals.

IC₅₀values lower than 25 nM against P. falciparum (NF

54). Upon subcutaneous administration, four â-sulfonyl-

endoperoxides, namely 46a , 46b, 50a , and 39a are

highly active in vivo antimalarials against P. yoelii and

P. berghei strains of malaria parasites. Relative to

artemisinin (1), the most potent compounds 46a and

46b are about two times more efficacious against

chloroquine-sensitive P. berghei and 3-5 times more

efficacious against chloroquine-resistant P. yoelii. Thus,

the potency of the endoperoxides 46a and 46b is

comparable to those of some of the best currently used

antimalarial drugs, including artemether (2b) and ar-

teether (2c). The benzyloxy derivative 46b exhibits also

a reasonable oral antimalarial efficacy. â-Sulfonyl-

endoperoxides 46a and 46b were found to be nontoxic

and easily tolerable at high doses. Considering also the

ready accessibility by chemical synthesis (three to four

steps) from inexpensive starting materials, as well as

their high chemical stability (compounds 39 and 46 are

stable for at least 2 years at 4 °C), â-sulfonyl-endoper-

oxides 39a , 46a , and 46b constitute promising antima-

larial drug candidates.

Thus, on the basis of the experimental results, the

7-day, daily-repeated IM treatment of mice with 50 and

200 mg/kg of 8-benzyloxy-endoperoxides 46a and 46b

was well tolerated without any evidence of toxic effects.

Exp er im en ta l Section

Ch em istr y. Gen er a l.²⁸The compounds 19-30 and 45 were

synthesized and purified as described earlier.²⁸Arteether (2c)

was prepared according to the reported procedure⁵¹and

thoroughly purified using 3-times-repeated, low-temperature

(-20 °C) recrystallization from hexane shortly before testing.

Unless otherwise stated, the purity of all the in vitro-tested

compounds was judged to be g95% by 400 MHz H NMR and

analytical HPLC determination. The purity of the in vivo-

tested compounds was g97% according to the same criteria.

Dir ect Acetyla tion of Hyd r oxysu lfid es 19a ,b. To a

solution of sulfides 19a ,b (1.15 g, 3.91 mmol, a/b ca. 55:45),

pyridine (1.54 g, 19.5 mmol), and DMAP (49 mg, 0.4 mmol) in

dry CH₂Cl₂(30 mL) at 0 °C was added a solution of AcCl (1.22

g, 15.6 mmol) in CH₂Cl₂(5 mL). After stirring for 12 h at rt,

the reaction mixture was poured into water (100 mL), ex-

tracted with hexanes-EtOAc (7:3, 3 × 100 mL), dried (Na₂-

SO₄+ NaHCO₃), and evaporated. The residue was subjected

to flash chromatography (FC) on silica gel (gradient elution,

hexanes-EtOAc, from 9:1 to 7:3) to recover the unreacted

hydroxysulfides 19a ,b (292 mg, 0.99 mmol, 25.5%) and to give

Con clu sion

As shown in Tables 2 and 3, there are minor differ-

ences in the in vitro activity between 2,3-dioxabicyclo-

[3.3.1]nonanes of the a series and those of the b series.

These differences are not significant, particularly in

view of the fact that the relative activities can be

inverted in the in vivo test, as in the case of the

â-sulfonyl-endoperoxides 46a and 46b. Also, there are

no significant differences in potency between the acetoxy-

sulfone 45 (Table 2) and its enantiomer 39 (Table 3).

Noteworthy exceptions are the enantiomeric hydroxy-

sulfones 23a and 26a . Similar slight variations in the

antimalarial potency were reported for enantiomeric

fenozanes (4) derivatives.^18b

1

More than 50 compounds of types 9-13 were screened

in vitro. Ten of the â-sulfonyl-endoperoxides of types 12

and 13 and one â-sulfinyl-endoperoxides of type 11 have

2524 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

a mixture of diastereomeric acetoxy derivatives 31a ,b (518 mg,

1.54 mmol, 53% yield, a /b ca. 55:45) and a mixture of

diastereomeric acetoacetates 32a ,b (152 mg, 13%, a /b ca. 54:

46).

a mobile pale yellow oil, R_f) 0.55 (5% of EtOAc in hexane);

IR (neat): 2954, 2928, 1453, 1446, 1372, 1250, 1125, 1060,

1

1040 cm^-1; H NMR (400 MHz, CDCl₃): δ 0.108 and 0.111 (2

× s, Me₃Si), total 9H; 1.22 (br s, a ), 1.53 (d, J ) 0.5 Hz, Me-

(11), b), total 3H; 1.38 (s, b), 1.39 (s, Me(10), a ), total 3H; 1.58-

1.65 (m, 1H, H(7)eq), 1.67-1.82 (m, 3H), 1.84 (br dddd, J )

6.0, 6.0, 3.0, 3.0 Hz, H(5), a ), 1.97-1.99 (m, 1H); 2.06 (ddd, J

) 13.0, 3.0, 2.5 Hz, H(9)ax, a ), 2.13-2.25 (m), total 2H; 2.94

(d) and 3.02 (dd, J ) 0.5 Hz) (AB quartet, J ) 12.0 Hz, HH′-

(12), b), 3.32 (d, J ) 12.7 Hz, H(12), a ), 3.68 (dd, J ) 12.7, 0.6

Hz, H′(12), a ), total 2H; 3.59 (br dd, J ) 2.5, 2.5 Hz, a ), 3.63

(m, H(1), b), total 1H; 7.26-7.42 (m, 5H).

Acetyla tion of Hyd r oxysu lfid es 19a ,b via TMS Der iva -

tives 33a ,b. (a) To a cold (5 °C) solution of hydroxysulfides

19a ,b (305 mg, 1.04 mmol) and 2,6-lutidine (277 mg, 2.60

mmol) in dry CH₂Cl₂(5 mL) was added neat TfOTMS (491

mg, 2.08 mmol). The reaction mixture was stirred at 5 °C for

40 min, poured into a cold water (50 mL), extracted with

EtOAc-hexane (1:4, 2 × 50 mL), washed with cold saturated

NaHCO₃(25 mL) and brine (25 mL), and dried over Na₂SO₄.

Evaporation, followed by vacuumization overnight at 0.3

mmHg, afforded the crude TMS derivatives 33a ,b (377 mg,

quantitative yield) as colorless mobile oil, which was used in

the next steps without further purification.

(b) A mixture of crude TMS derivatives 33a ,b (377 mg) was

treated with a freshly distilled AcCl (2.5 mL). The mixture

was stirred for 50 h at rt and evaporated. The residue was

dissolved in EtOAc-hexane (1:4, 80 mL), washed with water

(2 × 20 mL), and dried over Na₂SO₄. Evaporation, followed

by FC (10% of EtOAc in hexane), afforded the acetoxysulfides

31a ,b (323 mg, 93% in two steps from 19a ,b).

Oxa lyla tion of Hyd r oxysu lfid es 19a ,b via TMS Der iva -

tives 33a ,b. (1) (a) A mixture of TMS derivatives 33a ,b (193

mg, ca. 0.52 mmol), prepared from hydroxysulfides 19a ,b (153

mg, 0.52 mmol) as described above, was treated with a freshly

distilled oxalyl chloride (3 mL). The mixture was stirred at rt

for 18 h and evaporated and vacuumized at 0.2 mmHg for 3 h

to yield the crude chloride 34a ,b (205 mg, a /b ca. 56:44), which

was used in the next steps without additional purification.

(b) To a solution of chloride 34a ,b in dry CH₂Cl₂(3 mL) at

0 °C was added a solution of dry EtOH (79 mg, 1.7 mmol) and

2,6-lutidine (214 mg, 2.0 mmol) in CH₂Cl₂(2 mL). The reaction

mixture was stirred at 4 °C overnight and poured into cold

water (50 mL), extracted with EtOAc-hexane (1:4, 2 × 50 mL),

dried (Na₂SO₄), and evaporated. FC (hexanes-EtOAc, 85:15)

of the residue gave the esters 35a ,b (140 mg, 68% in three

steps from 19a ,b; a /b ca. 57:43).

(2) To a solution of chloride 34a ,b, prepared from hydroxy-

sulfide 19a ,b (112 mg, 0.38 mmol) as described above, in CH₂-

Cl₂(3 mL) at 0 °C was added a solution of dibenzylamine (156

mg, 0.8 mmol) and 2,6-lutidine (160 mg, 1.5 mmol) in CH₂Cl₂

(2 mL). The mixture was stirred at 0°C for 8 h and poured

into cold water (50 mL). Extraction with hexanes-EtOAc (3:

1, 2 × 50 mL), washing with saturated KHSO₄(15 mL) and

NaHCO₃(15 mL), drying over Na₂SO₄, and evaporation

followed by FC (hexanes-EtOAc, 85:15) gave the amides 36a ,b

(a /b ca. 59:41) (160 mg, 77% in three steps from 19a ,b; a /b

ca. 59:41).

(1R,4R/S,5R,8R)-8-Acetoxy-4,8-d im eth yl-4-p h en ylsu lfe-

n ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (31a ,b): a color-

less mobile oil, R_f) 0.67 (30% of EtOAc in hexane); IR (neat):

2935, 1732, 1453, 1371, 1254, 1223, 1204, 1054 cm^-1; ¹H NMR

(400 MHz, CDCl₃): δ 1.24 (br s, a ), 1.56 (br s, Me(11), b), total

3H; 1.65 (s, b), 1.66 (s, Me(10), a ), total 3H; 1.67-1.89 (m,

3H); 1.74 (m, b), 1.90 (br dddd, J ) 6.6, 6.6, 3.3, 3.3 Hz, H(5),

a ), total 1H; 2.00 (s, 3H, MeC(O)); 2.07 (br ddd, J ) 14.1, 6.6,

3.4 Hz, a ), 2.27 (m, H(9)eq, b), total 1H; 2.12-2.20 (m, 1H,

H(7)eq); 2.25 (ddd, J ) 15.0, 13.2, 6.0 Hz, b), 2.28 (ddd, J )

14.3, 13.3, 6.0 Hz, H(7)ax, a ), total 1H; 2.95 (d) and 3.02 (dd,

J ) 0.4 Hz) (AB quartet, J ) 12.0 Hz, HH′(12), b), 3.30 (d, J

) 12.8 Hz, H(12), a), 3.72 (dd, J ) 12.8, 0.5 Hz, H′(12), a ),

total 2H; 4.40 (br dd, J ) 3.4, 1.0 Hz, a ), 4.44 (br dd, J ) 3.4,

0.8 Hz, H(1), b), total 1H; 7.17-7.23 (m, 1H), 7.29 (m, 2H),

7.37 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.03 (Me(11)),

22.42 (Me(10)), 22.55 (MeC(O)), 23.50 (CH₂), 23.97 (CH₂), 28.52

(C(5)H), 32.88 (CH₂), 40.71 (C(12)H₂), 77.46 (C(1)H), 82.76 (C),

83.85 (C), 126.24 (CH), 128.91 (2CH), 129.76 (2CH), 136.73

(C), 170.13 (CdO) (isomer 31a ); 21.77 (Me(11)), 22.53 (Me-

(10)), 22.55 (MeC(O)), 23.22 (CH₂), 24.09 (CH₂), 29.89 (C(5)H),

33.20 (CH₂), 40.81 (C(12)H₂), 77.91 (C(1)H), 82.67 (C), 83.73

(C), 126.43 (CH), 128.96 (2CH), 129.73 (2CH), 136.29 (C),

170.13 (CdO) (isomer 31b).

(1R,4R/S,5R,8R)-8-Acet yla cet oxy-4,8-d im et h yl-4-p h e-

n ylsu lfen ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (32a ,b):

a colorless oil, R_f) 0.40 (hexanes-EtOAc, 7:3); ¹H NMR (400

MHz, CDCl₃) (keto-enol ca. 91:9): δ 1.23 (br s, a ), 1.55 (br s,

Me(11), b), total 3H; 1.68 (s, b), 1.69 (s, Me(10), a ), total 3H;

1.70-1.93 (m, 4H); 2.08 (br ddd, J ) 14.0, 6.5, 3.5 Hz, H(9)eq,

a ), 2.15-2.33 (m), total 3H; 2.25 (s, a ), 2.26 (s, MeC(O)CH₂,

b), total 3H; 2.95 and 3.00 (AB quartet, J ) 12.6 Hz, HH′(12),

b), 3.31 (d, J ) 12.8 Hz, H(12), a ), 3.69 (br d, J ) 12.8 Hz,

H′(12), a ), total 2H; 3.40 (s, a ), 3.41 (s, MeC(O)CH₂, b), total

2H; 4.37 (br d, J ) 3.5 Hz, a -keto), 4.41 (br d, J ) 3.6 Hz,

b-keto), 4.45 (br d, J ) 3.5 Hz, a -enol), 4.49 (br d, J ) 3.5

Hz, H(1), b-enol), total 1H; 4.92 (br s, a ), 4.94 (br s, CHd,

b-enol), total ca. 0.09 H; 7.26-7.42 (m, 5H); 12.05 (br s, ca.

0.09 H, HO-enol); ¹³C NMR (100 MHz, CDCl₃): δ 21.89 (Me-

(11)), 22.48 (Me(10)), 23.28 (CH₂), 23.74 (CH₂), 28.43 (C(5)H),

30.15 (MeC(O)), 32.67 (CH₂), 40.59 (C(12)H₂), 51.18 (MeC(O)-

CH₂), 77.30 (C(1)H), 83.76 (C), 84.25 (C), 90.60 (HCd, enol),

126.16 (CH), 128.83 (2CH), 129.65 (2CH), 136.62 (C), 165.83

(OCdO), 200.57 (CdO) (isomer 32a ); 21.64 (Me(11)), 22.49

(Me(10)), 22.98 (CH₂), 23.85 (CH₂), 29.74 (C(5)H), 30.15 (MeC-

(O)), 33.02 (CH₂), 40.75 (C(12)H₂), 77.72 (C(1)H), 83.82 (C),

84.17 (C), 90.60 (HCd, enol), 126.37 (CH), 128.88 (2CH),

129.68 (2CH), 136.18 (C), 165.84 (OCdO), 200.57 (CdO)

(isomer 32b).

(1R,4R/S,5R,8R)-8-Ch lor ooxalyloxy-4,8-dim eth yl-4-ph e-

n ylsu lfen ylm eth yl-2,3-dioxabicyclo [3.3.1]n on an e (34a,b):

a pale brown immobile oil; IR (neat): 2965, 2937, 1796, 1754,

1481, 1452, 1441, 1376, 1275, 1224, 1118, 1053, 1015 cm^-1

;

¹H NMR (250 MHz, CDCl₃): δ 1.26 (br s, a ), 1.58 (br s, Me-

(11), b), total 3H; 1.78 (s, b), 1.79 (s, Me(10), a ), total 3H; 1.68-

2.02 (m, 4H); 2.15 (br ddd, J ) 13.8, 6.6, 3.4 Hz, H(9)eq, a ),

2.30-2.44 (m), total 3H; 2.965 and 3.02 (br) (AB quartet, J )

12.1 Hz, HH′(12), b), 3.33 (d, J ) 13.0 Hz, H(12), a ), 3.70 (dd,

J ) 13.0, 0.5 Hz, H′(12), a ), total 2H; 4.28 (br dd, J ) 3.4, 1.0

Hz, a ), 4.44 (br dd, J ) 3.4, 1.0 Hz, H(1), b), total 1H; 7.18-

7.45 (m, 5H).

(1R,4R/S,5R,8R)-4,8-Dim eth yl-8-eth oxyoxalyloxy-4-ph e-

n ylsu lfen ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (35a ,b):

a pale yellow oil, R_f) 0.41 (hexanes-EtOAc, 4:1); IR (neat):

2984, 2938, 1765, 1742, 1451, 1441, 1374, 1320, 1185, 1090,

1053, 1013 cm^-1; ¹H NMR (250 MHz, CDCl₃): δ 1.26 (br s, a ),

1.57 (br s, Me(11), b), total 3H; 1.373 and 1.378 (2 × t, 3H, J

) 7.1 Hz, MeCH₂O); 1.75 (s, b), 1.76 (s, Me(10), a), total 3H;

1.68-1.96 (m, 4H); 2.11 (br ddd, J ) 13.6, 6.4, 3.4 Hz, H(9)eq,

a ), 2.27-2.39 (m), total 3H; 2.96 and 3.02 (br) (AB quartet, J

) 12.1 Hz, HH′(12), b), 3.32 (d, J ) 12.9 Hz, H(12), a ), 3.71

(br d, J ) 12.9 Hz, H′(12), a ), total 2H; 4.325 and 4.331 (2 ×

q, 2H, J ) 7.1 Hz, MeCH₂O); 4.34 (m, a ), 4.38 (m, H(1), b),

total 1H; 7.17-7.44 (m, 5H).

(1R,4R/S,5R,8R)-8-Diben zyla m in ooxa lyloxy-4,8-d im e-

t h yl-4-p h en ylsu lfen ylm et h yl-2,3-d ioxa b icyclo[3.3.1]n o-

n a n e (36a ,b): a colorless immobile oil, R_f) 0.38 (hexanes-

EtOAc, 4:1); IR (neat): 2988, 2936, 1728, 1661, 1452, 1440,

1374, 1287, 1265, 1170, 1081, 1053, 1014 cm^-1; ¹H NMR (250

MHz, CDCl₃): δ 1.24 (br s, a ), 1.57 (br s, Me(11), b), total 3H;

1.62-1.90 (m, 4H), 1.71 (br s, 3H, Me(10)); 2.06 (br ddd, J )

13.4, 6.2, 3.4 Hz, H(9)eq, a ), 2.18-2.42 (m), total 3H; 2.95 and

3.00 (br) (AB quartet, J ) 12.1 Hz, HH′(12), b), 3.32 (d, J )

13.0 Hz, H(12), a ), 3.68 (br d, J ) 13.0 Hz, H′(12), a ), total

(1R,4R/S,5R,8R)-4,8-Dim eth yl-4-p h en ylsu lfen ylm eth yl-

8-tr im eth ylsilyloxy-2,3-dioxabicyclo[3.3.1]n on an es (33a,b):

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2525

2H; 4.33 (br d, J ) 3.4 Hz, a ), 4.39 (m, H(1), b), total 1H; 4.38

(br s, 2H) and 4.52 (br s, 2H, PhCH₂N), 7.22-7.41 (m, 15H).

m eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n es (38b′,b′′). A mix-

ture of title diastereomeric sulfoxides 38 (total 364 mg, 1.02

mmol, 91%) was prepared by oxidation of sulfides 31a ,b (376

mg, 1.12 mmol) according to the procedure described above

and completely separated by MPLC (hexanes-EtOAc, 1:1).

(1R,4R,5R,8R)-4,8-Dim et h yl-4-p h en ylsu lfin ylm et h yl-

2,3-dioxabicyclo[3.3.1]n on an -8-ols (37a′, 37a′′) an d (1R,4S,-

5R,8R)-4,8-Dim eth yl-4-p h en ylsu lfin ylm eth yl-2,3-d ioxa bi-

cyclo[3.3.1]n on a n -8-ols (37b′, 37b′′). To a solution of sulfides

19a ,b (468 mg, 1.59 mmol, ratio a /b ca. 55:45) in EtOAc (25

mL) at -50 °C was added a solution of mCPBA (478 mg of ca.

60%, ca. 1.65 mmol) in EtOAc (20 mL). The mixture was

stirred at -30 °C for 1 h (TLC monitoring), poured into

saturated NaHCO₃(75 mL), extracted with EtOAc (3 × 60

mL), dried (Na₂SO₄+ NaHCO₃), and evaporated. The residue

was purified by FC (hexanes-EtOAc, 1:4) to give the diaster-

eomeric sulfoxides 37a ′,a ′′,b′,b′′ (438 mg, total yield 89%, ratio

a ′/a ′′/b′/b′′ ca. 21:32:20: 27). The individual diastereomers of

the sulfoxides 37 were isolated by sequential medium-pressure

liquid chromatography (MPLC) on silica gel (hexanes-EtOAc,

22:78).

Th e isom er 38a ′ (78 mg, 0.221 mmol): a colorless oil, R_f)

0.40 (hexanes-EtOAc, 1:1); ¹H NMR (400 MHz, CDCl₃): δ 1.44

(br s, 3H, Me(11)), 1.65 (s, 3H, Me(10)), 1.86 (br dddd, 1H, J

) 14.0, 14.0, 6.0, 3.5 Hz, H(6)ax), 1.94-2.00 (m, 1H, H(6)eq),

1.96 (ddd, 1H, J ) 14.0, 4.0, 1.7 Hz, H(9)ax), 2.01 (s, 3H, MeC-

(O)), 2.18-2.25 (m, 3H), 2.31 (ddd, 1H, J ) 14.0, 14.0, 6.0 Hz,

H(7)ax), 3.08 (d, 1H, J ) 13.8 Hz, H(12)), 3.61 (dd, 1H, J )

13.8, 0.6 Hz, H′(12)), 4.52 (m, 1H, H(1)), 7.50-7.58 (m, 3H),

7.65-7.68 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.36 (MeC-

(O)), 22.43 (Me(10)), 23.36 (C(6)H₂), 23.55 (Me(11)), 24.16 (C(9)-

H₂), 29.09 (C(5)H), 32.98 (C(7)H₂), 64.54 (C(12)H₂), 77.58

(C(1)H), 82.37 (C(4)), 82.53 (C(8)), 123.65 (2CH), 129.35 (2CH),

131.10 (CH), 144.38 (C), 170.10 (CdO).

Th e isom er 37a ′: a colorless solid, mp 131-133 °C dec; R_f

Th e m ost p ola r isom er 38a ′′ (122 mg, 0.346 mmol): a

colorless solid, mp 98-100 °C; R_f) 0.29 (hexanes-EtOAc, 1:1);

¹H NMR (400 MHz, CDCl₃): δ 1.56 (br s, 3H, Me(11)), 1.68 (s,

3H, Me(10)), 1.78 (br dddd, 1H, J ) 14.0, 14.0, 6.0, 3.2 Hz,

H(6)ax), 1.80-1.88 (m, 2H), 1.92-1.98 (m, 1H, H(6)eq), 2.01

(s, 3H, MeC(O)), 2.17-2.24 (m, 1H, H(9)eq), 2.20 (br dd, 1H, J

) 14.8, 6.2 Hz, H(7)eq), 2.30 (ddd, 1H, J ) 14.8, 14.0, 5.9 Hz,

H(7)ax), 3.31 and 3.36 (AB quartet, 2H, J ) 14.0 Hz, HH′-

(12)), 4.47 (br d, 1H, J ) 3.6 Hz, H(1)), 7.48-7.57 (m, 3H),

7.66-7.69 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.23 (Me-

(11)), 22.48 (MeC(O)), 22.53 (Me(10)), 23.42 (C(6)H₂), 24.17

(C(9)H₂), 30.90 (C(5)H), 33.20 (C(7)H₂), 66.04 (C(12)H₂), 77.75

(C(1)H), 82.25 (C(4)), 82.67 (C(8)), 123.82 (2CH), 129.35 (2CH),

130.92 (CH), 144.86 (C), 170.22 (CdO).

1

) 0.35 (hexanes-EtOAc, 1:4); H NMR (400 MHz, CDCl₃): δ

1.39 (s, 3H, Me(10)), 1.45 (br s, 3H, Me(11)), 1.63 (br dd, 1H,

J ) 13.8, 5.3 Hz, H(7)eq), 1.65 (br s, 1H, OH), 1.88-2.02 (m,

2H), 2.16-2.21 (m, 3H), 2.39 (ddd, 1H, J ) 13.8, 13.8, 6.9 Hz,

H(7)ax), 3.12 (d, 1H, J ) 13.9 Hz, H(12)), 3.59 (br d, 1H, J )

13.9 Hz, H′(12)), 3.73 (br s, 1H, H(1)), 7.48-7.57 (m, 3H), 7.65-

7.69 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.53 (Me(11)),

23.60 (C(6)H₂), 24.47 (C(9)H₂), 28.11 (Me(10)), 29.88 (C(5)H),

35.75 (C(7)H₂), 64.87 (C(12)H₂), 71.43 (C(8)), 81.89 (C(1)H),

82.53 (C(4)), 123.83 (2CH), 129.42 (2CH), 131.13 (CH), 144.76

(C).

Th e m ost p ola r isom er 37a ′′: a colorless solid, mp 153-

1

155 °C; R_f) 0.32 (hexanes-EtOAc, 1:4); H NMR (400 MHz,

CDCl₃): δ 1.40 (s, 3H, Me(10)), 1.55 (br s, 3H, Me(11)), 1.63

(br dd, 1H, J ) 14.0, 5.6 Hz, H(7)eq), 1.83 (br dddd, 1H, J )

6.4, 6.4, 3.0, 3.0 Hz, H(5)), 1.86 (dddd, 1H, J ) 14.0, 14.0, 5.9,

3.4 Hz, H(6)ax), 1.91-1.99 (m, 1H, H(6)eq), 2.06 (ddd, 1H, J

) 13.8, 3.0, 2.0 Hz, H(9)ax), 2.18 (ddd, 1H, J ) 13.8, 6.4, 3.6

Hz, H(9)eq), 2.37 (br ddd, 1H, J ) 14.0, 14.0, 6.5 Hz, H(7)ax),

3.31 and 3.35 (AB quartet, 2H, J ) 14.0 Hz, HH′(12)), 3.70

(m, 1H, H(1)), 7.47-7.56 (m, 3H), 7.64-7.67 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 22.08 (Me(11)), 23.47 (C(6)H₂), 24.37

(C(9)H₂), 28.06 (Me(10)), 31.56 (C(5)H), 35.77 (C(7)H₂), 66.08

(C(12)H₂), 71.42 (C(8)), 81.94 (C(1)H), 82.25 (C(4)), 123.83

(2CH), 129.32 (2CH), 130.87 (CH), 144.91 (C).

Th e lea st p ola r isom er 37b′: a white foam; R_f) 0.38

(hexanes-EtOAc, 1:4); ¹H NMR (400 MHz, CDCl₃): δ 1.36 (s,

3H, Me(10)), 1.62 (br dd, 1H, J ) 13.9, 5.8 Hz, H(7)eq), 1.78-

1.85 (m, 1H, H(6)eq), 1.79 (br s, 3H, Me(11)), 1.96 (dddd, 1H,

J ) 13.9, 13.9, 6.0, 3.5 Hz, H(6)ax), 2.00 (br dddd, 1H, J )

6.4, 6.4, 3.0, 3.0 Hz, H(5)), 2.13 (ddd, 1H, J ) 13.5, 3.0, 2.0

Hz, H(9)ax), 2.29 (br ddd, 1H, J ) 13.9, 13.9, 6.2 Hz, H(7)ax),

2.35 (ddd, 1H, J ) 13.5, 6.4, 3.6 Hz, H(9)eq), 2.77 (dd, 1H, J )

13.5. 0.6 Hz, H(12)), 2.91 (br d, 1H, J ) 13.5 Hz, H′(12)), 3.73

(m, 1H, H(1)), 7.50-7.56 (m, 3H), 7.63-7.66 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 22.93 (Me(11)), 23.70 (C(6)H₂), 24.00

(C(9)H₂), 28.04 (Me(10)), 31.21 (C(5)H), 35.47 (C(7)H₂), 65.57

(C(12)H₂), 71.32 (C(8)), 82.20 (C(1)H), 82.61 (C(4)), 123.77

(2CH), 129.49 (2CH), 131.34 (CH), 144.73 (C).

Th e lea st p ola r isom er 38b ′ (68 mg, 0.193 mmol): a

colorless solid, mp 116-118 °C; R_f) 0.41 (hexanes-EtOAc,

1:1); IR (neat): 2980, 2929, 1734, 1445, 1372, 1257, 1232, 1186,

1

1153, 1086, 1056, 1022 cm^-1; H NMR (400 MHz, CDCl₃): δ

1.65 (s, 3H, Me(10)), 1.80 (d, 3H, J ) 0.6 Hz, Me(11)), 1.82-

1.89 (m, 2H), 1.89 (ddd, 1H, J ) 13.6, 3.2, 1.8 Hz, H(9)ax),

2.02 (br dddd, 1H, J ) 6.0, 6.0, 3.2, 3.2 Hz, H(5)), 2.03 (s, 3H,

MeC(O)), 2.18-2.29 (m, 2H), 2.39 (br ddd, 1H, J ) 13.6, 6.0,

3.8 Hz, H(9)eq), 2.77 (dd, 1H, J ) 13.4, 0.6 Hz, H(12)), 2.92

(br d, 1H, J ) 13.4 Hz, H′(12)), 4.47 (br dd, 1H, J ) 3.8, 1.8

Hz, H(1)), 7.52-7.57 (m, 3H), 7.64-7.67 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 22.38 (MeC(O)), 22.45 (Me(10)), 22.88

(Me(11)), 23.52 (C(6)H₂), 23.76 (C(9)H₂), 30.55 (C(5)H), 32.77

(C(7)H₂), 65.45 (C(12)H₂), 78.02 (C(1)H), 82.50 (C(8)), 82.57

(C(4)), 123.69 (2CH), 129.45 (2CH), 131.33 (CH), 144.57 (C),

170.08 (CdO).

Th e isom er 38b′′ (96 mg, 0.272 mmol): a colorless solid,

mp 105-107 °C; R_f) 0.36 (hexanes-EtOAc, 1:1); ¹H NMR

(400 MHz, CDCl₃): δ 1.62 (s, 3H, Me(10)), 1.76 (dddd, 1H, J

) 14.2, 12.5, 7.2, 3.3 Hz, H(6)ax), 1.83 (ddd, 1H, J ) 13.6, 3.3,

1.8 Hz, H(9)ax), 1.89 (br s, 3H, Me(11)), 1.90 (br dddd, 1H, J

) 6.4, 6.4, 3.3, 3.3 Hz, H(5)), 1.93-2.01 (m, 1H, H(6)eq), 2.02

(s, 3H, MeC(O)), 2.07 (ddd, 1H, J ) 14.8, 14.2, 5.6 Hz, H(7)-

ax), 2.14 (br dd, 1H, J ) 14.8, 6.6 Hz, H(7)eq), 2.35 (br ddd,

1H, J ) 13.6, 6.4, 3.3 Hz, H(9)eq), 2.67 (br d, 1H, J ) 13.6 Hz,

H(12)), 3.10 (br d, 1H, J ) 13.6 Hz, H′(12)), 4.49 (br d, 1H, J

) 3.3 Hz, H(1)), 7.48-7.57 (m, 3H), 7.63-7.67 (m, 2H); ¹³C

NMR (100 MHz, CDCl₃): δ 22.05 (Me(11)), 22.47 (MeC(O)),

22.59 (Me(10)), 23.46 (C(6)H₂), 23.80 (C(9)H₂), 31.60 (C(5)H),

32.92 (C(7)H₂), 65.82 (C(12)H₂), 78.34 (C(1)H), 82.64 (C(8)),

82.81 (C(4)), 123.81 (2CH), 129.42 (2CH), 131.16 (CH), 144.90

(C), 170.22 (CdO).

Th e isom er 37b′′: a colorless solid, mp 138-140 °C dec; R_f

1

) 0.34 (hexanes-EtOAc, 1:4); H NMR (400 MHz, CDCl₃): δ

1.34 (s, 3H, Me(10)), 1.55 (br dd, 1H, J ) 14.0, 5.7 Hz, H(7)-

eq), 1.83 (br dddd, 1H, J ) 14.2, 14.2, 5.8, 3.4 Hz, H(6)ax),

1.85-1.98 (m, 3H), 1.87 (br s, 3H, Me(11)), 2.06 (ddd, 1H, J )

13.5, 3.0, 1.9 Hz, H(9)ax), 2.15 (br ddd, 1H, J ) 14.2, 14.0, 6.2

Hz H(7)ax), 2.32 (ddd, 1H, J ) 13.5, 6.8, 3.3 Hz, H(9)eq), 2.70

(br d, 1H, J ) 13.7 Hz, H(12)), 3.09 (br d, 1H, J ) 13.7 Hz,

H′(12)), 3.73 (m, 1H, H(1)), 7.47-7.55 (m, 3H), 7.63-7.66 (m,

2H); ¹³C NMR (63 MHz, CDCl₃): δ 21.97 (Me(11)), 23.48 (C(6)-

H₂), 23.94 (C(9)H₂), 28.04 (Me(10)), 32.16 (C(5)H), 35.46 (C(7)-

H₂), 65.93 (C(12)H₂), 71.37 (C(8)), 82.35 (C(1)H), 82.73 (C(4)),

123.82 (2CH), 129.39 (2CH), 131.12 (CH), 144.84 (C).

Oxid a tion of Su lfid es to Su lfon es (Gen er a l P r oced u r e

1). A solution of sulfides (0.3 mmol, 1 equiv, a mixture of

diastereomers) and mCPBA (0.75-0.9 mmol, 2.5-3.0 equiv)

in EtOAc (5 mL) was stirred for 4-6 h at rt. After consumption

of the more polar intermediate sulfoxide (TLC monitoring), the

mixture was poured into a saturated solution of NaHCO₃,

extracted with EtOAc/hexane, dried over Na₂SO₄, and evapo-

rated. FC (hexanes-EtOAc) of the residue afforded the title

compounds as a mixture of diastereomers. An additional FC,

(1R,4R,5R,8R)-8-Acet oxy-4,8-d im et h yl-4-p h en ylsu lfi-

n ylm eth yl-2,3-dioxabicyclo[3.3.1]n on an es (38a′, 38a′′) an d

(1R,4S,5R,8R)-8-Acetoxy-4,8-d im eth yl-4-p h en ylsu lfin yl-

2526 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

MPLC, or HPLC provided a separation of a mixture of

diastereomers.

less oil; ¹H NMR (400 MHz, CDCl₃) (keto-enol ca. 95:5): δ

1.60 (s, 3H, Me(10)), 1.80 (br s, 3H, Me(11)), 1.81-1.88 (m,

2H) 1.91-1.98 (m, 1H), 1.93 (d, ca. 0.15H, J ) 0.4 Hz, MeCd

enol), 2.07 (br ddd, 1H, J ) 14.5, 14.5, 6.0 Hz, H(7)ax), 2.10

(br dddd, 1H, J ) 6.8, 6.8, 3.4, 3.4 Hz, H(5)), 2.18 (br dd, 1H,

J ) 14.5, 6.0 Hz, H(7)eq), 2.25 (s, 3H, MeC(O)CH₂), 2.30 (br

ddd, 1H, J ) 13.8, 6.8, 3.6 Hz, H(9)eq), 3.13 (d, 1H, J ) 14.0

Hz, H(12)); 3.32 (dd, J ) 14.0, 0.3 Hz, H′(12)-keto), 3.33 (br

d, J ) 14.0 Hz, H′(12)-enol), total 1H; 3.41 (s, 2H, MeC(O)-

CH₂); 4.39 (br d, J ) 3.6 Hz, H(1)-keto), 4.49 (br d, J ) 3.8

Hz, H(1)-enol), total 1H; 4.93 (br s, HCdenol), 7.58 (m, 2H),

7.66 (m, 1H), 7.92 (m, 2H), 12.04 (br s, HO-enol); ¹³C NMR

(100 MHz, CDCl₃): δ 21.89 (Me(11)), 22.56 (Me(10)), 23.25

(C(9)H₂), 23.65 (C(6)H₂), 30.30 (MeC(O)CH₂), 30.84 (C(5)H),

32.82 (C(7)H₂), 51.29 (MeC(O)CH₂), 60.51 (C(12)H₂), 78.35

(C(1)H), 83.03 (C(8)), 83.97 (C(4)), 127.62 (2CH), 129.38 (2CH),

133.91 (CH), 141.12 (C), 165.95 (OCdO), 200.58 (CdO); DCI

(CH₄) HRMS: obsd 411.1421, calcd for C₂₀H₂₇O₇S (MH⁺),

411.1478.

(1R,4R,5R,8R)-4,8-Dim eth yl-8-eth oxyoxa lyloxy-4-p h e-

n ylsu lfon ylm eth yl-2,3-d ioxa bicyclo [3.3.1]n on a n e (41a )

a n d (1R,4S,5R,8R)-4,8-Dim et h yl-8-et h oxyoxa lyloxy-4-

p h en ylsu lfon ylm et h yl-2,3-d ioxa b icyclo [3.3.1]n on a n e

(41b). A mixture of diastereomeric sulfones 41a ,b (120 mg,

94%, a /b ca. 57:43) was prepared by oxidation of a mixture of

sulfides 35a ,b (118 mg, 0.30 mmol) according to general

procedure 1 and separated by MPLC (hexanes-EtOAc, 3:1).

(1R,4R,5R,8R)-8-Acet oxy-4,8-d im et h yl-4-p h en ylsu lfo-

n ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n es (39a ) a n d (1R,-

4S,5R,8R)-8-Acetoxy-4,8-d im eth yl-4-p h en ylsu lfon ylm eth -

yl-2,3-d ioxa bicyclo[3.3.1]n on a n es (39b). The sulfones 39a

(31 mg) and 39b (26 mg) (total yield 97%) were prepared by

oxidation of a mixture of diastereomeric sulfides 31a ,b (55 mg,

0.163 mmol, a /b ca. 55:45) and separated by MPLC (hexanes-

EtOAc, 7:3).

Th e less p ola r isom er 39a :

a colorless solid, mp

97-98 °C; R_f) 0.37 (hexane-benzene-EtOAc, 11:6:3); [R]²⁰

D

-259.9° (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 1.51

(br s, 3H, Me(11)), 1.62 (s, 3H, Me(10)), 1.78 (br dddd, 1H, J

) 14.5, 13.4, 6.8, 3.4 Hz, H(6)ax), 1.88 (ddd, 1H, J ) 14.0, 3.4,

1.2 Hz, H(9)ax), 1.90 (dddd, 1H, J ) 14.5, 6.8, 2.8, 2.8 Hz, H(6)-

eq), 2.01 (s, 3H, MeC(O)), 2.14 (m, 1H, H(7)eq), 2.19 (m, 1H,

H(7)ax), 2.26 (ddd, 1H, J ) 14.0, 6.6, 3.2 Hz, H(9)eq), 2.30 (br

dddd, 1H, J ) 6.8, 6.8, 3.4, 3.4 Hz, H(5)), 3.25 (d, 1H, J ) 14.3

Hz, H(12)), 4.22 (dd, 1H, J ) 14.3, 0.4 Hz, H′(12)), 4.45 (br dd,

1H, J ) 3.2, 1.2 Hz, H(1)), 7.58 (m, 2H), 7.66 (m, 1H), 7.94 (m,

2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.42 (MeC(O)), 22.49 (Me-

(10)), 23.09 (Me(11)), 23.39 (C(6)H₂), 24.52 (C(9)H₂), 29.42

(C(5)H), 33.26 (C(7)H₂), 60.98 (C(12)H₂), 77.80 (C(1)H), 82.54

(C(8)), 82.72 (C(4)), 127.52 (2CH), 129.35 (2CH), 133.75 (CH),

141.08 (C), 170.20 (CdO); DCI (CH₄) HRMS: obsd 369.1354,

calcd for C₁₈H₂₅O₆S (MH⁺), 369.1372. Anal. Calcd for C₁₈H₂₄

-

O₆S: C, 58.68; H, 6.56; S, 8.70. Found: C, 58.64; H, 6.55; S,

8.34.

Th e less p ola r isom er 41a : a colorless oil; IR (neat): 2987,

2940, 1767, 1737, 1448, 1376, 1310, 1187, 1152, 1095, 1086,

1013 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 1.37 (t, 3H, J ) 7.1

Hz, MeCH₂O), 1.53 (br s, 3H, Me(11)), 1.72 (s, 3H, Me(10)),

1.82 (dddd, 1H, J ) 14.2, 13.2, 6.8, 3.5 Hz, H(6)ax), 1.94

(ddddd, 1H, J ) 14.2, 5.2, 2.6, 2.6, 2.6 Hz, H(6)eq), 1.97 (ddd,

1H, J ) 14.0, 2.6, 1.4 Hz, H(9)ax), 2.24-2.37 (m, 4H), 3.27 (d,

1H, J ) 14.3 Hz, H(12)), 4.21 (br d, 1H, J ) 14.3 Hz, H′(12)),

4.33 (q, 2H, J ) 7.1 Hz, CH₂O), 4.36 (br dd, 1H, J ) 3.6, 1.4

Hz, H(1)), 7.59 (m, 2H), 7.67 (m, 1H), 7.94 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 13.92 (MeCH₂O), 22.34 (Me(10)),23.05

(Me(11)), 23.23 (C(6)H₂), 24.46 (C(9)H₂), 29.32 (C(5)H), 32.49

(C(7)H₂), 60.96 (C(12)H₂), 63.03 (CH₂O), 77.74 (C(1)H), 82.91

(C(4)), 86.58 (C(8)), 127.57 (2CH), 129.41 (2CH), 133.83 (CH),

141.03 (C), 156.66 (OCdO), 158.08 (OCdO); DCI (CH₄)

HRMS: obsd 427.1407, calcd for C₂₀H₂₇O₈S (MH⁺), 427.1427.

Th e m or e p ola r isom er 41b: a colorless oil; IR (neat):

2986, 2942, 1763, 1740, 1448, 1376, 1322, 1197, 1181, 1154,

1087, 1014 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 1.36 (t, 3H, J

) 7.1 Hz, MeCH₂O), 1.66 (s, 3H, Me(10)), 1.80-1.89 (m, 1H,

H(6)ax), 1.82 (br s, 3H, Me(11)), 1.88 (ddd, 1H, J ) 14.2, 3.4,

1.8 Hz, H(9)ax), 1.94-2.02 (m, 1H, H(6)eq), 2.11-2.15 (m, 1H,

H(5)), 2.14 (ddd, 1H, J ) 14.5, 14.5, 6.0 Hz, H(7)ax), 2.33 (br

dd, 1H, J ) 14.5, 6.2 Hz, H(7)eq), 2.34 (ddd, 1H, J ) 14.2, 6.4,

3.6 Hz, H(9)eq), 3.12 (d, 1H, J ) 14.0 Hz, H(12)), 3.32 (br d,

1H, J ) 14.0 Hz, H′(12)), 4.32 (q, 2H, J ) 7.1 Hz, CH₂O), 4.35

(m, 1H, H(1)), 7.57 (m, 2H), 7.67 (m, 1H), 7.92 (m, 2H); ¹³C

NMR (63 MHz, CDCl₃): δ 13.87 (MeCH₂O), 21.87 (Me(11)),

22.29 (Me(10)), 23.30 (C(9)H₂), 23.53 (C(6)H₂), 30.70 (C(5)H),

32.14 (C(7)H₂), 60.41 (C(12)H₂), 63.01 (CH₂O), 78.26 (C(1)H),

83.12 (C(4)), 86.31 (C(8)), 127.58 (2CH), 129.37 (2CH), 133.92

(CH), 141.02 (C), 156.56 (OCdO), 158.00 (OCdO).

Th e m or e p ola r a cetoxysu lfon e 39b: a colorless solid,

mp 101-102 °C; R_f) 0.32 (hexane-benzene-EtOAc, 11:6:3);

¹H NMR (400 MHz, CDCl₃): δ 1.56 (s, 3H, Me(10)), 1.79 (ddd,

1H, J ) 13.6, 3.4, 1.4 Hz, H(9)ax), 1.80 (br s, 3H, Me(11)), 1.84

(br dddd, 1H, J ) 14.0, 14.0, 6.0, 3.4 Hz, H(6)ax), 1.96 (m, 1H,

H(6)eq), 2.00 (s, 3H, MeC(O)), 2.04 (m, 1H, H(7)ax), 2.10 (br

dddd, 1H, J ) 6.8, 6.8, 3.4, 3.4 Hz, H(5)), 2.16 (br dd, 1H, J )

14.5, 6.0 Hz, H(7)eq), 2.29 (ddd, 1H, J ) 13.6, 6.8, 3.6 Hz, H(9)-

eq), 3.12 (d, 1H, J ) 14.0 Hz, H(12)), 3.32 (br d, 1H, J ) 14.0

Hz, H′(12)), 4.42 (br dd, 1H, J ) 3.6, 1.4 Hz, H(1)), 7.57 (m,

2H), 7.66 (m, 1H), 7.92 (m, 2H); ¹³C NMR (100 MHz, CDCl₃):

δ 21.94 (Me(11)), 22.43 (MeC(O)), 22.53 (Me(10)), 23.40 (C(9)-

H₂), 23.78 (C(6)H₂), 30.92 (C(5)H), 32.92 (C(7)H₂), 60.50 (C(12)-

H₂), 78.45 (C(1)H), 82.35 (C(8)), 82.97 (C(4)), 127.61 (2CH),

129.37 (2CH), 133.89 (CH), 141.15 (C), 170.16 (CdO). Anal.

Calcd for C₁₈H₂₄O₆S: C, 58.68; H, 6.56; S, 8.70. Found: C,

58.72; H, 6.57; S, 8.51.

(1R,4R,5R,8R)-8-Acetyla cetoxy-4,8-d im eth yl-4-p h en yl-

su lfon ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (40a ) a n d

(1R,4S,5R,8R)-8-Acetyla cetoxy-4,8-d im eth yl-4-p h en ylsu l-

fon ylm eth yl-2,3-d ioxa bicyclo [3.3.1]n on a n e (40b). A mix-

ture of diastereomeric sulfones 40a ,b (94 mg, 67%, a /b ca. 55:

45) was prepared by oxidation of a mixture of sulfides 32a ,b

(130 mg, 0.34 mmol) according to general procedure 1 and

separated by MPLC (hexanes-EtOAc, 3:2).

1

Th e less p ola r isom er 40a : a colorless oil; H NMR (400

MHz, CDCl₃) (keto-enol ca. 93:7): δ 1.52 (br s, 3H, Me(11)),

1.66 (s, 3H, Me(10)), 1.80 (br dddd, 1H, J ) 14.0, 13.7, 6.5, 3.4

Hz, H(6)ax), 1.87-1.97 (m, 2H), 2.15-2.25 (m, 2H), 2.26 (s,

3H, MeC(O)CH₂), 2.28 (ddd, 1H, J ) 13.0, 6.4, 3.6 Hz, H(9)-

eq), 2.31 (br dddd, 1H, J ) 6.4, 6.4, 3.2, 3.2 Hz, H(5)), 3.27 (d,

1H, J ) 14.4 Hz, H(12)), 3.42 (s, 2H, MeC(O)CH₂); 4.20 (br d,

J ) 14.4 Hz, H′(12)-keto), 4.23 (br d, J ) 14.0 Hz, H′(12)-

enol), total 1H; 4.43 (br d, J ) 3.6 Hz, H(1)-keto), 4.50 (br d,

J ) 4.0 Hz, H(1)-enol), total 1H; 4.94 (br s, HCdenol), 7.58

(m, 2H), 7.67 (m, 1H), 7.94 (m, 2H), 12.05 (br s, HO-enol);

¹³C NMR (100 MHz, CDCl₃): δ 22.53 (Me(10)), 23.01 (Me(11)),

23.27 (C(6)H₂), 24.39 (C(9)H₂), 29.39 (C(5)H), 30.28 (MeC(O)-

CH₂), 33.13 (C(7)H₂), 51.29 (MeC(O)CH₂), 60.95 (C(12)H₂),

77.73 (C(1)H), 82.75 (C(8)), 84.17 (C(4)), 127.53 (2CH), 129.36

(2CH), 133.76 (CH), 141.05 (C), 165.99 (OCdO), 200.48

(CdO); DCI (CH₄) HRMS: obsd 411.1507, calcd for C₂₀H₂₇O₇S

(MH⁺), 411.1478.

(1R,4R,5R,8R)-8-Diben zylam in ooxalyloxy-4,8-dim eth yl-

4-p h en ylsu lfon ylm et h yl-2,3-d ioxa b icyclo[3.3.1]n on a n e

(42a ) a n d (1R,4S,5R,8R)-Dib en zyla m in ooxa lyloxy-4,8-

d im eth yl-4-p h en ylsu lfon ylm eth yl-2,3-d ioxa bicyclo[3.3.1]-

n on a n e (42b). A mixture of diastereomeric sulfones 42a ,b

(143.5 mg, 99%, a /b ca. 60:40) was prepared by oxidation of

sulfides 36a ,b (137 mg, 0.25 mmol) according to general

procedure 1 and separated by MPLC (hexanes-EtOAc, 7:3).

Th e less p ola r isom er 42a : a colorless oil; IR (neat): 2985,

2928, 1736, 1670, 1653, 1496, 1453, 1377, 1318, 1272, 1181,

1

1171, 1150, 1083, 1013 cm^-1; H NMR (400 MHz, CDCl₃): δ

1.50 (br s, 3H, Me(11)), 1.67 (s, 3H, Me(10)), 1.68-1.75 (m,

1H, H(6)ax), 1.82-1.92 (m, 2H), 2.18-2.28 (m, 4H), 3.27 (d,

1H, J ) 14.3 Hz, H(12)), 4.17 (br d, 1H, J ) 14.3 Hz, H′(12)),

4.35 (br s, 2H, PhCH₂N), 4.36 (m, 1H, H(1)), 4.50 (br s, 2H,

Th e m or e p ola r isom er 40b: 40b was finally purified by

semipreparative DP HPLC (hexanes-EtOAc, 65:35): a color-

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2527

PhCH₂N), 7.19-7.26 (m, 4H), 7.31-7.41 (m, 6H), 7.59 (m, 2H),

7.67 (m, 1H), 7.94 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ

22.46 (Me(10)), 22.93 (Me(11)), 23.12 (C(6)H₂), 24.33 (C(9)H₂),

29.25 (C(5)H), 32.90 (C(7)H₂), 46.22 (PhCH₂N), 50.02 (PhCH₂N),

60.89 (C(12)H₂), 77.60 (C(1)H), 82.78 (C(4)), 86.51 (C(8)),

127.38 (2CH), 127.53 (2CH), 127.87 (CH), 128.25 (CH), 128.46

(2CH), 128.78 (2CH), 128.93 (2CH), 129.36 (2CH), 133.79 (CH),

134.81 (C), 135.34 (C), 140.98 (C), 162.14 (CdO), 162.18 (Cd

O); DCI (CH₄) HRMS: obsd 578.2187, calcd for C₃₂H₃₆NO₇S

(MH⁺), 578.2212. Anal. Calcd for C₃₂H₃₅NO₇S: N, 2.42; S, 5.55.

Found: N, 2.10; S, 5.28.

Th e m or e p ola r isom er 42b: a colorless oil; IR (neat):

2982, 2935, 1733, 1663, 1654, 1450, 1379, 1322, 1312, 1176,

1153, 1084, 1015 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ 1.61 (s,

3H, Me(10)), 1.71-1.80 (m, 2H), 1.79 (br s, 3H, Me(11)), 1.87-

1.95 (m, 1H, H(6)eq), 2.03 (br dddd, 1H, J ) 6.4, 6.4, 3.2, 3.2

Hz, H(5)), 2.09 (br ddd, 1H, J ) 14.2, 14.2, 6.0 Hz, H(7)ax),

2.07 (br dd, 1H, J ) 14.2, 5.8 Hz, H(7)eq), 2.27 (br ddd, 1H, J

) 13.8, 6.4, 3.3 Hz, H(7)eq), 3.11 (d, 1H, J ) 14.0 Hz, H(12)),

3.29 (br d, 1H, J ) 14.3 Hz, H′(12)), 4.34 (m, 1H, H(1)), 4.35

(br s, 2H, PhCH₂N), 4.48 and 4.51 (AB quartet, 2H, J ) 14.0

Hz, PhCH₂N), 7.19-7.24 (m, 4H), 7.30-7.40 (m, 6H), 7.57 (m,

2H), 7.66 (m, 1H), 7.91 (m, 2H); ¹³C NMR (100 MHz, CDCl₃):

δ 21.84 (Me(11)), 22.49 (Me(10)), 23.24 (C(9)H₂), 23.50 (C(6)-

H₂), 30.71 (C(5)H), 32.71 (C(7)H₂), 46.27 (PhCH₂N), 50.04

(PhCH₂N), 60.49 (C(12)H₂), 78.19 (C(1)H), 83.11 (C(4)), 86.30

(C(8)), 127.36 (2CH), 127.63 (2CH), 127.90 (CH), 128.26 (CH),

128.48 (2CH), 128.80 (2CH), 128.95 (2CH), 129.38 (2CH),

133.93 (CH), 134.84 (C), 135.35 (C), 141.09 (C), 162.10 (Cd

O), 162.21 (CdO). Anal. Calcd for C₃₂H₃₅NO₇S: N, 2.42; S,

5.55. Found: N, 2.23; S, 5.17.

(C(5)H), 35.97 (C(7)H₂), 61.09 (C(12)H₂), 74.40 (C(8)), 82.45

(C(1)H), 82.65 (C(4)), 127.54 (2CH), 129.31 (2CH), 133.65 (CH),

141.22 (C).

(1R,4R,5R,8R)-4,8-Dim eth yl-8-(p h en oxy)a cetoxy-4-p h e-

n ylsu lfon ylm eth yl-2,3d ioxa bicyclo[3.3.1]n on a n e (44a ). A

mixture of TMS derivative 43a (prepared from 72 mg, 0.22

mmol of hydroxysulfone 23a as described above), phenoxy-

acetyl chloride (1.0 mL) and freshly oven-dried CsF (152 mg,

1.0 mmol) in dry acetonitrile (2.5 mL) was stirred at rt for a

week. The mixture was poured into saturated NaHCO₃(40

mL) and stirred for 2 h at rt. A mixture of hexanes-EtOAc

(3:1, 100 mL) was added, and the organic layer was separated

and washed with water (2 × 25 mL) and with saturated

NaHCO₃(25 mL). The organic extract was dried (Na₂SO₄

+

NaHCO₃) and evaporated. MPLC (hexanes-EtOAc, 4:1) of the

residue gave the title product 44a (57 mg, 56% yield) as a

colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 1.50 (br s, 3H, Me-

(11)), 1.58-1.66 (m, 1H, H(6)ax), 1.67 (s, 3H, Me(10)), 1.74

(ddd, 1H, J ) 14.0, 3.4, 1.4 Hz, H(9)ax), 1.82-1.90 (m, 1H,

H(6)eq), 2.16-2.27 (m, 4H), 3.24 (d, 1H, J ) 14.4 Hz, H(12)),

4.19 (br d, 1H, J ) 14.4 Hz, H′(12)), 4.36 (br d, 1H, J ) 3.2

Hz, H(1)), 6.89 (m, 2H), 7.00 (m, 1H), 7.30 (m, 2H), 7.58 (m,

2H), 7.66 (m, 1H), 7.94 (m, 2H); ¹³C NMR (100 MHz, CDCl₃):

δ 22.60 (Me(10)), 23.02 (Me(11)), 23.18 (C(6)H₂), 24.36 (C(9)-

H₂), 29.29 (C(5)H), 32.97 (C(7)H₂), 60.93 (C(12)H₂), 65.52

(PhOCH₂), 77.84 (C(1)H), 82.76 (C(4)), 84.47 (C(8)), 114.36

(2CH), 121.73 (CH), 127.53 (2CH), 129.37 (2CH), 129.58 (2CH),

133.78 (CH), 141.02 (C), 157.65 (C), 167.93 (CdO); DCI (CH₄)

HRMS: obsd 461.1617, calcd for C₂₄H₂₉O₇S (MH⁺), 461.1634.

(1R,4R,5R,8R)- 8-Ben zyloxy-4,8-d im eth yl-4-p h en ylsu l-

fon ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (46a ). Phenyl-

diazomethane was freshly prepared by dry pyrolysis of sodium

salt of benzaldehyde tosylhydrazone (11.87 g, 40.1 mmol).⁵²

To a vigorously stirred cold (-30 °C) solution of hydroxysulfone

23a (1.26 g, 3.86 mmol) and freshly distilled TfOH (0.1 mL)

in dry CH₂Cl₂(12 mL) was slowly cannulated over 1 h a cold

(-40 °C) solution of phenyldiazomethane in CH₂Cl₂(8 mL).

The rate of cannulation was regulated in the way to maintain

the reaction mixture colorless or very pale pink. When the

reaction mixture became reddish, the cannulation was inter-

rupted, and a new portion of TfOH (0.1 mL) was added,

followed by continuation of the cannulation. The cannulation

was interrupted five times, and new portions of TfOH (0.1 mL)

were added. After completion of the cannulation, the reaction

mixture was stirred at -30 °C for an additional 30 min and

quenched with pyridine (1 mL). A cold (0 °C) reaction mixture

was poured into cold water (100 mL) and extracted with

EtOAc-hexane (400 mL, 1:3). The organic extract was washed

with water (2 × 100 mL), saturated NaHCO₃(100 mL) and

brine (100 mL) and was dried over Na₂SO₄. Evaporation,

followed by FC (from 6% to 25% EtOAc in hexane) and MPLC

(EtOAc-hexane, 1:9) afforded the title product 46a (1.380 g,

86% yield, g98.5 purity) as a colorless solid: mp 85-86 °C

(tert-butyl methyl ether); [R]²⁰_D-237.0° (c 1.0, CHCl₃); ¹H NMR

(400 MHz, CDCl₃): δ 1.39 (s, 3H, Me(10)), 1.54 (d, 3H, J ) 0.5

Hz, Me(11)), 1.83 (dddd, 1H, J ) 14.0, 14.0, 5.6, 3.6 Hz, H(6)-

ax), 1.86-1.92 (m, 1H, H(6)eq), 1.97 (br dd, 1H, J ) 14.7, 5.2

Hz, H(7)eq), 2.13 (ddd, 1H, J ) 14.7, 14.0, 6.5 Hz, H(7)ax),

2.19-2.22 (m, 2H, H(9)ax + eq), 2.29 (br dddd, 1H, J ) 6.4,

6.4, 3.2, 3.2 Hz, H(5)), 3.31 (d, 1H, J ) 14.3 Hz, H(12)), 3.85

(br dd, 1H, J ) 2.8, 2.8 Hz, H(1)), 4.25 (dd, 1H, J ) 14.3, 0.5

Hz, H′(12)), 4.38 (d, 1H, J ) 11.2 Hz, PhCHH′O), 4.50 (d, 1H,

J ) 11.2 Hz, PhCHH′O), 7.26-7.30 (m, 1H), 7.33-7.38 (m,

4H), 7.57-7.62 (m, 2H), 7.65-7.70 (m, 1H), 7.95-7.98 (m, 2H);

¹³C NMR (100 MHz, CDCl₃): δ 22.15 (Me(10)), 22.94 (Μe(11)),

23.55 (C(6)H₂), 24.61 (C(9)H₂), 29.88 (C(5)H), 30.73 (C(7)H₂),

61.12 (C(12)H₂), 63.23 (PhCH₂O), 76.07 (C(8)), 80.89 (C(1)H),

82.76 (C(4)), 127.19 (2CH), 127.31 (CH), 127.58 (2CH), 128.35

(2CH), 129.35 (2CH), 133.71 (CH), 139.22 (C), 141.19 (C); DCI

(CH₄) HRMS: obsd 417.1746, calcd for C₂₃H₂₉O₅S (MH⁺),

417.1736. Anal. Calcd for C₂₃H₂₈O₅S: C, 66.32; H, 6.78; S, 7.70.

Found: C, 66.43; H, 6.78; S, 7.37.

Oxid a tion of (1R,4R,5R,8R)-8-Acetoxy-4,8-d im eth yl-4-

ph en ylsu lfin ylm eth yl-2,3-dioxabicyclo[3.3.1]n on an es (38a′

a n d 38a ′′). (i) A mixture of sulfoxide 38a ′ (14.2 mg, 0.040

mmol) and mCPBA (ca. 60%, 14.4 mg, 0.05 mmol) in EtOAc

(0.2 mL) was stirred for 6 h at rt. A workup as above, followed

by FC (EtOAc-hexane, 1:4), afforded the sulfone 39a (13.8

mg, 93%) as a colorless solid, mp 96-98 °C. (ii) Oxidation of

sulfoxide 38a ′′ (15.5 mg, 0.044 mmol) with mCPBA (ca. 60%,

15.8 mg, 0.055 mmol) as above yielded the same sulfone 39a

(15.3 mg, 94%).

Syn th esis of (1R,4R,5R,8R)-8-Acetoxy-4,8-d im eth yl-4-

p h en ylsu lfon ylm et h yl-2,3-d ioxa b icyclo[3.3.1]n on a n es

(38a ) fr om Hyd r oxysu lfon e 25a via TMS Der iva tive 42a .

(a) To a cold (0 °C) solution of hydroxysulfone 23a (230 mg,

0.705 mmol) and 2,6-lutidine (193 mg, 1.80 mmol) in dry CH₂-

Cl₂(5 mL) was added neat TfOTMS (354 mg, 1.50 mmol). The

reaction mixture was stirred at 0 °C for 1.5 h, poured into a

cold water (50 mL), extracted with EtOAc-hexane (1:4, 2 ×

75 mL), washed with cold saturated NaHCO₃(30 mL) and

brine (30 mL), and dried over Na₂SO₄. Evaporation, followed

by vacuumization overnight at 0.3 mmHg, afforded the crude

TMS derivative 43a (283 mg, quantitative yield) containing

traces of 2,6-lutidine. The TMS derivative 43a was used in

the next steps without additional purification.

(b) As prepared in the previous step, TMS derivative 43a

(283 mg) was treated with a freshly distilled AcCl (3.0 mL)

and stirred for 50 h at rt. The mixture was evaporated, the

residue was dissolved in EtOAc-hexane (1:2, 60 mL), washed

with saturated NaHCO₃(30 mL), and dried over MgSO₄.

Evaporation, followed by FC (EtOAc-hexane, 1:4), afforded

the acetoxysulfone 39a (247 mg, yield 95% in two steps) as a

colorless solid, mp 97-98 °C.

(1R,4R,5R,8R)-4,8-Dim eth yl-4-p h en ylsu lfon ylm eth yl-8-

tr im eth ylsilyloxy-2,3-d ioxa bicyclo[3.3.1]n on a n e (43a ): a

1

mobile colorless oil, R_f) 0.36 (15% of EtOAc in hexane); H

NMR (250 MHz, CDCl₃): δ 0.12 (br s, 9H), 1.37 (s, 3H, Me-

(10)), 1.51 (br s, 3H, Me(11)), 1.66 (ddd, 1H, J ) 13.6, 3.4, 3.4

Hz, H(9)ax), 1.79-1.90 (m, 2H), 2.11-2.22 (m, 3H), 2.25 (br

dddd, 1H, J ) 6.8, 6.8, 3.4, 3.4 Hz, H(5)), 3.27 (d, 1H, J ) 14.2

Hz, H(12)), 3.67 (br dd, 1H, J ) 3.4, 3.4 Hz, H(1)), 4.24 (br d,

1H, J ) 14.3 Hz, H′(12)), 7.59 (m, 2H), 7.68 (m, 1H), 7.96 (m,

2H); ¹³C NMR (63 MHz, CDCl₃): δ 2.46 (Me₃Si), 22.93 (Me-

(11)), 23.49 (C(6)H₂), 24.33 (C(9)H₂), 27.15 (Me(10)), 30.03

(1R,4S,5R,8R)- 8-Ben zyloxy-4,8-d im eth yl-4-p h en ylsu l-

fon ylm et h yl-2,3-d ioxa bicyclo-[3.3.1]n on a n e (46b ). The

2528 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

benzylated endoperoxide 46b (1.53 g, 85%, g98% purity) was

prepared from hydroxy endoperoxide 23b (1.418 g, 4.345 mmol)

according to the procedure for 46a . A colorless oil, [R]²⁰_D-62.5°

(c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 1.34 (s, 3H, Me-

(10)), 1.82 (d, 3H, J ) 0.3 Hz, Me(11)), 1.86-1.92 (m, 2H),

1.94-1.99 (m, 2H), 2.08 (br dddd, 1H, J ) 6.2, 6.2, 3.1, 3.1

Hz, H(5)), 2.09-2.13 (m, 1H), 2.23-2.28 (m, 1H), 3.18 (d, 1H,

J ) 14.0 Hz, H(12)), 3.38 (dd, 1H, J ) 14.0, 0.3 Hz, H′(12)),

3.87 (br dd, 1H, J ) 3.7, 2.0 Hz, H(1)), 4.37 (d, 1H, J ) 11.2

Hz, PhCHH′O), 4.48 (d, 1H, J ) 11.2 Hz, PhCHH′O), 7.26-

7.30 (m, 1H), 7.31-7.37 (m, 4H), 7.57-7.62 (m, 2H), 7.66-

7.70 (m, 1H), 7.93-7.96 (m, 2H); ¹³C NMR (100 MHz, CDCl₃):

δ 21.92 (Μe(11)), 22.12 (Me(10)), 23.43 (CH₂), 23.88 (CH₂),

30.70 (C(7)H₂), 31.37 (C(5)H), 60.60 (C(12)H₂), 63.27 (PhCH₂O),

75.88 (C(8)), 81.23 (C(1)H), 82.93(C(4)), 127.18 (2CH), 127.31

(CH), 127.66 (2CH), 128.34 (2CH), 129.33 (2CH), 133.82 (CH),

139.19 (C), 141.25 (C); DCI (CH₄) HRMS: obsd 417.1774, calcd

for C₂₃H₂₉O₅S (MH⁺), 417.1736.

3.0, 3.0 Hz, H(1)), 4.24 (br d, 1H, J ) 14.3 Hz, H′(12)), 4.29 (d,

1H, J ) 10.7 Hz, ArCHH′O), 4.41 (d, 1H, J ) 10.7 Hz,

ArCHH′O), 6.88 (m, 2H), 7.24 (m, 2H), 7.58 (m, 2H), 7.66 (m,

1H), 7.95 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.16 (Me-

(10)), 22.92 (Μe(11)), 23.53 (C(6)H₂), 24.57 (C(9)H₂), 29.86

(C(5)H), 30.76 (C(7)H₂), 61.10 (C(12)H₂), 62.91 (ArCH₂O), 75.94

(C(8)), 80.84 (C(1)H), 82.71 (C(4)), 113.78 (2CH), 127.55 (2CH),

128.72 (2CH), 129.33 (2CH), 131.26 (C), 133.68 (CH), 141.17

(C), 158.92 (C); DCI (CH₄) HRMS: obsd 447.1869, calcd for

C

₂₄H₃₁O₆S (MH⁺), 447.1841.

(1R,4R,5R,8R)-4,8-Dim eth yl-8-(3-m eth ylbu t-2-en yl)oxy-

4-p h en ylsu lfon ylm eth yl-2,3-d ioxa bicyclo [3.3.1]n on a n e

(51a ). The title compound 51a (58 mg, 51%) was prepared from

hydroxysulfone 23a (95 mg, 0.32 mmol) and imidate 48 (720

mg, 3.0 mmol) according to the procedure described for 50a

and purified by MPLC (hexanes-EtOAc, 84:16). A colorless

oil: R_f) 0.42 (hexanes-EtOAc, 4:1); ¹H NMR (400 MHz,

CDCl₃): δ 1.29 (s, 3H, Me(10)), 1.50 (br s, 3H, Me(11)), 1.65

(m, 3H, MeMe′Cd), 1.73 (m, 3H, MeMe′Cd),1.78 (dddd, 1H, J

) 14.0, 14.0, 6.0, 3.5 Hz, H(6)ax), 1.79-1.85 (m, 1H, H(6)eq),

1.85 (br dd, 1H, J ) 14.0, 5.5 Hz, H(7)eq), 2.06 (br ddd, 1H, J

) 14.0, 14.0, 6.1 Hz, H(7)ax), 2.10-2.18 (m, 2H, H(9)ax + eq),

2.27 (br dddd, 1H, J ) 6.0, 6.0, 3.0, 3.0 Hz, H(5)), 3.27 (d, 1H,

J ) 14.3 Hz, H(12)), 3.77 (br s, 1H, H(1)), 3.80 (br dd, 1H, J )

10.8, 6.8 Hz, dCHCHH′O), 3.90 (br dd, 1H, J ) 10.8, 6.8 Hz,

dCHCHH′O), 4.22 (dd, 1H, J ) 14.3, 0.3 Hz, H′(12)), 5.27

(ddqq, 1H, J ) 6.8, 6.8, 1.4, 1.4 Hz, dCHCHH′O), 7.56 (m,

2H), 7.65 (m, 1H), 7.94 (m, 2H); ¹³C NMR (100 MHz, CDCl₃):

δ 17.94 (MeMe′Cd), 22.04 (Me(10)), 22.87 (Μe(11)), 23.49 (C(6)-

H₂), 24.48 (C(9)H₂), 25.81 (MeMe′Cd), 29.84 (C(5)H), 30.97

(C(7)H₂), 57.58 (dCHCH₂O), 61.09 (C(12)H₂), 75.47 (C(8)),

80.70 (C(1)H), 82.63 (C(4)), 121.78 (dCHCH₂O), 127.53 (2CH),

129.29 (2CH), 133.64 (CH), 135.90 (Me₂Cd), 141.17 (C); DCI

(CH₄) HRMS: obsd 395.1859, calcd for C₂₁H₃₁O₅S (MH⁺),

395.1892.

O-(3-Meth ylbu t-2-en yl) Tr ich lor oa cetim id a te (48). To

a suspension of NaH (121 mg of 70% suspension in mineral

oil, 3.53 mmol) in dry ether (5 mL) was added dropwise over

10 min a solution of 3-methylbut-2-en-1-ol (3.015 g, 35.0 mmol)

in ether (5 mL). After stirring for an additional 20 min at rt,

a homogeneous mixture was cooled to -30 °C, and CCl₃CN

(4.90 g, 34.0 mmol) was added gradually. The mixture was

allowed to warm to rt (1 h) and was stirred at rt for an

additional 1 h. Ether and excess of alcohol were evaporated

under reduced pressure, and the residue was treated with a

solution of MeOH (112 mg, 0.14 mL, 3.5 mmol) in dry pentane

(25 mL). The resulting solution was filtered through a short

plug of Celite, evaporated, and vacuumized at 0.2 mmHg for

6 h to give the imidate 48 (7.315 g, 93%) as a pale yellow

viscous liquid of ca. 95% purity (according to the ¹H NMR

spectra). ¹H NMR (250 MHz, CDCl₃): δ 1.76 (br s, 3H, Me),

1.81 (br s, 3H, Me), 4.80 (d, 2H, J ) 6.5 Hz, CH₂O), 5.49 (m,

1H, CHd), 8.27 (br s, 1H, dNH).

(1R,4R,5R,8R)-4,8-Dim et h yl-8-(3-p h en ylp r op -2-en yl)-

oxy-4-p h en ylsu lfon ylm eth yl-2,3-d ioxa bicyclo [3.3.1]n o-

n a n e (52a ). The title compound 52a (49 mg, 32%, E/ Z ca.

9:1) was prepared from hydroxysulfone 23a (113 mg, 0.345

mmol) and imidate 49 (1.218 g, 4.23 mmol) according to the

procedure described above and purified by MPLC (hexanes-

EtOAc, 4:1). The final purification was achieved using semi-

preparative RP HPLC (MeCN-H₂O, 65:35). A pale yellow

O-(3-P h en ylp r op -2-en yl) Tr ich lor oa cetim id a te (49). A

treatment of trans-cinnamyl alcohol (3.414 g, 25.44 mmol) with

CCl₃CN (3.673 g, 25.44 mmol) as described above provided the

title imidate 49⁵³(6.719 g, 95%) as a yellow-orange oil of ca.

1

97% purity (according to the H NMR spectra). H NMR (250

MHz, CDCl₃): δ 5.01 (d, 2H, J ) 6.2 Hz, CH₂O), 6.43 (dt, 1H,

J ) 15.9, 6.5 Hz, CHd), 6.79 (d, 1H, J ) 15.9 Hz, PhCHd),

7.27-7.47 (m, 5H, Ph), 8.40 (br s, 1H, dNH). The imidates 48

and 49 were used for allylation without further purification.

1

immobile oil: R_f) 0.46 (hexanes-EtOAc, 3:1); H NMR (400

MHz, CDCl₃): δ 1.34 (s, 3H, Me(10)), 1.53 (br s, 3H, Me(11)),

1.84 (br dddd, 1H, J ) 14.0, 14.0, 5.6, 3.6 Hz, H(6)ax), 1.84-

1.93 (m, 2H), 2.10 (br ddd, 1H, J ) 14.0, 14.0, 6.4 Hz, H(7)ax),

2.15-2.22 (m, 2H), 2.27 (br dddd, 1H, J ) 6.0, 6.0, 3.0, 3.0

Hz, H(5)), 3.29 (d, 1H, J ) 14.3 Hz, H(12)), 3.82 (br s, 1H,

H(1)), 4.01 (ddd, 1H, J ) 12.6, 5.8, 1.5 Hz, dCHCHH′O), 4.12

(ddd, 1H, J ) 12.6, 5.8, 1.5 Hz, dCHCHH′O), 4.24 (br d, 1H,

J ) 14.3 Hz, H′(12)), 6.25 (ddd, 1H, J ) 15.9, 5.8, 5.8 Hz, CHd

CHCHH′O), 6.60 (br d, 1H, J ) 15.9 Hz, PhCHdCHCHH′O),

7.22-7.40 (m, 5H), 7.56-7.60 (m, 2H), 7.64-7.69 (m, 1H),

7.94-7.97 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 22.11 (Me-

(10)), 22.93 (Μe(11)), 23.53 (C(6)H₂), 24.58 (C(9)H₂), 29.90

(C(5)H), 31.00 (C(7)H₂), 61.15 (C(12)H₂), 61.94 (dCHCH₂O),

75.96 (C(8)), 80.78 (C(1)H), 82.75 (C(4)), 126.40 (2CH), 127.12

(CH), 127.52 (CH), 127.59 (2CH), 128.52 (2CH), 129.34 (2CH),

130.99 (CH), 133.69 (CH), 136.85 (C), 141.24 (C); DCI (CH₄)

HRMS: obsd 443.1915, calcd for C₂₅H₃₁O₅S (MH⁺), 443.1892.

(1R,4R,5R,8R)-4,8-Dim eth yl-8-(p-m eth oxyben zyl)oxy-

4-p h en ylsu lfon ylm et h yl-2,3-d ioxa b icyclo[3.3.1]n on a n e

(50a ). To a suspension of hydroxysulfone 23a (280 mg, 0.858

mmol) in dry diethyl ether (3 mL) at 0 °C was added a solution

of O-p-methoxybenzyl trichloroacetimidate 47^37b(1.287 g of ca.

93% purity, 4.20 mmol) in dry CH₂Cl₂(1.5 mL). The mixture

was stirred for 10 min until a homogeneous solution was

formed, and a solution of TfOH in ether (0.43 mL of 0.1 M

TfOH solution in ether, 0.043 mmol) was added. The mixture

was stirred for 1.5 h at 0 °C and for 10 h at rt. The second

portion of TfOH solution (0.25 mL, 0.025 mmol) was added,

and the mixture was stirred for additional 12 h. At that time,

the second portion of imidate 47 (772 mg, 2.51 mmol) and the

third portion of TfOH solution (0.25 mL, 0.025 mmol) were

added, and the resulting mixture was stirred for additional 8

h until consumption of starting alcohol 23a was detected (TLC

monitoring). The mixture was diluted with ether (15 mL) and

hexane (15 mL), and NaHCO₃(0.6 g) and Na₂SO₄(2.0 g) were

added. After being stirred overnight the mixture was filtered,

evaporated, fractionated by FC (hexanes-EtOAc, 3:1), and

purified by MPLC (hexanes-EtOAc, 78:22) to give the title

product 50a (175 mg, 46%) as a pale yellow oil: R_f) 0.40

P r ep a r a tion of Un sa tu r a ted Su lfid es 53a ,b a n d 54a ,b.

To a solution of SOCl₂(1.90 g, 16.0 mmol) and pyridine (3.165

g, 40.0 mmol) in dry CH₂Cl₂(150 mL) at 0 °C was added a

solution of hydroxysulfides 19a ,b (1.10 g, 3.74 mmol, ca. 55:

45) in CH₂Cl₂(30 mL) over 1.5 h. The reaction mixture was

allowed to warm to rt and stirred for an additional 2 h. At

that time, the mixture was poured into ice-cold 0.1 M HCl (100

mL) and extracted with hexanes-EtOAc (9:1, 2 × 300 mL).

The organic extract was washed with saturated NaHCO₃(2

× 80 mL), dried (Na₂SO₄+ NaHCO₃), and evaporated. The

residue was purified by FC (hexanes-EtOAc, 95:5) to give a

mixture of unsaturated sulfides 53a ,b and 54a ,b (955 mg, total

yield 92%; 53a /53b/54a /54b ca. 47:39:8:6 according to the

1

(hexanes-EtOAc, 3:1); H NMR (400 MHz, CDCl₃): δ 1.38 (s,

3H, Me(10)), 1.53 (br s, 3H, Me(11)), 1.81 (br dddd, 1H, J )

14.0, 14.0, 6.4, 3.3 Hz, H(6)ax), 1.82-1.89 (m, 1H, H(6)eq), 1.94

(br dd, 1H, J ) 14.6, 5.0 Hz, H(7)eq), 2.11 (br ddd, 1H, J )

14.6, 14.0, 6.4 Hz, H(7)ax), 2.15-2.19 (m, 2H, H(9)ax + eq),

2.27 (br dddd, 1H, J ) 6.4, 6.4, 3.2, 3.2 Hz, H(5)), 3.29 (d, 1H,

J ) 14.3 Hz, H(12)), 3.81 (s, 3H, MeO), 3.83 (br dd, 1H, J )

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2529

integration of the H(1) peaks in ¹H NMR spectrum at 400

MHz). A colorless oil: R_f) 0.29 (5% of EtOAc in hexane); H

(C(8)H), 40.91 (C(12)H₂), 79.23 (C(1)H), 83.36 (C(4)), 126.07

(CH), 128.90 (2CH), 129.59 (2CH), 136.90 (C) (isomer 55a ).

1

NMR (400 MHz, CDCl₃): δ 1.20 (d, J ) 0.7 Hz, 53a ), 1.29 (d,

J ) 0.6 Hz, 54a ), 1.57 (d, J ) 0.5 Hz, 54b), 1.58 (d, J ) 0.8

Hz, Me(11), 53b), total 3H; 1.55 (ddd, J ) 13.1, 3.0, 2.0 Hz,

53a ), 1.63 (dddd, J ) 13.0, 2.9, 2.4, 0.5 Hz, H(9)ax, 53b), total

ca. 1H; 1.79-1.81 (m, ca. 3H, Me(10), 53a ,b); 1.93 (m, 53b),

2.04 (m, H(5), 53a ), total ca. 1H; 2.15-2.37 (m), 2.48 (dddd, J

) 13.0, 3.6, 3.6, 1.6 Hz, H(9)eq, 53b), total 3H; 2.90 (d, J )

11.8 Hz, H(12), 53b) and 3.03 (dd, J ) 11.8, 0.8 Hz, H′(12),

53b), 3.00 (d, J ) 12.0 Hz, H(12), 54b) and 3.10 (dd, J ) 12.0,

0.5 Hz, H′(12), 54b), 3.30 (d, J ) 12.2 Hz, H(12), 54a ), 3.33 (d,

J ) 12.7 Hz, H(12), 53a ), and 3.79 (dd, J ) 12.7, 0.7 Hz, H′-

(12), 53a ), total 2H; 4.10 (br dd, J ) 3.6, 2.0 Hz, 53a ), 4.13 (br

dd, J ) 3.6, 2.4 Hz, 53b), 4.34 (br dd, J ) 4.0, 1.4 Hz, 54a ),

4.40 (br dd, J ) 4.3, 1.7 Hz, H(1), 54b ), total 1H; 4.89 (m,

HH′C(10)d, 54a ,b), 5.73 (m, 53b), 5.75 (m, H(7), 53a ), total

ca. 1H; 7.18-7.46 (m, 5H). The mixture of unsaturated sulfides

53a ,b and 54a ,b was used in the next step without further

separation or purification. For the characterization and bio-

logical evaluation, the major component 53a (ca. 97% purity)

was isolated by an additional preparative RP HPLC (column

LiChrosorb RP-8 (7 µm), 250-25 mm; MeCN-H₂O, 60:40).

(1R,4R,5R)-4,8-Dim et h yl-4-p h en ylsu lfen ylm et h yl-2,3-

d ioxa bicyclo[3.3.1]n on -7-en e (53a ). A colorless waxy solid:

mp 61-63 °C; ¹H NMR (400 MHz, CDCl₃): δ 1.20 (d, 3H, J )

0.7 Hz, Me(11)), 1.55 (ddd, 1H, J ) 13.1, 3.0, 2.0 Hz, H(9)ax),

1.80 (ddd, 3H, J ) 2.7, 1.6, 1.6 Hz, Me(10)), 2.04 (m, 1H, H(5)),

2.21 (dddq, 1H, J ) 19.0, 5.4, 2.7, 2.7 Hz, H(6)ax), 2.30 (dddd,

1H, J ) 13.1, 3.6, 3.6, 1.6 Hz, H(9)eq), 2.33 (dddq, 1H, J )

19.0, 6.4, 1.6, 1.6 Hz, H(6)eq), 3.34 (d, 1H, J ) 12.7 Hz, H(12)),

3.79 (d, 1H, J ) 12.7, 0.7 Hz, H′(12)), 4.10 (br dd, J ) 3.6, 2.0

Hz, H(1)), 5.76 (m, H(7)), 7.19 (m, 1H), 7.29 (m, 2H), 7.42 (m,

2H); ¹³C NMR (100 MHz, CDCl₃): δ 21.17 (Me(10)), 22.72 (Me-

(11)), 26.38 (C(9)H₂), 27.56 (C(6)H₂), 28.52 (C(5)H), 40.73

(C(12)H₂), 76.21 (C(1)H), 83.37 (C(4)), 126.15 (CH), 126.82

(C(7)H), 128.90 (2CH), 129.69 (2CH), 131.26 (C(8)), 136.96 (C);

DCI (CH₄) HRMS: obsd 277.1253, calcd for C₁₆H₂₁O₂S (MH⁺),

277.1262.

(1R,4R,5R,8R)-4,8-Dim et h yl-4-p h en ylsu lfen ylm et h yl-

2,3-d ioxa bicyclo [3.3.1]n on a n e (55c): a colorless waxy

substance; ¹H NMR (400 MHz, CDCl₃): δ 1.02 (d, 3H, J ) 7.4

Hz, Me(10)), 1.25 (d, 3H, J ) 0.6 Hz, Me(11)), 1.29 (br dd, 1H,

J ) 14.0, 5.8 Hz, H(7)eq), 1.62 (ddd, 1H, J ) 13.6, 3.2, 1.8 Hz,

H(9)ax), 1.74 (br dddd, 1H, J ) 14.0, 14.0, 6.2, 3.4 Hz, H(6)-

ax), 1.80-1.87 (m, 1H, H(6)eq), 1.87 (br dddd, 1H, J ) 6.3,

6.3, 3.2, 3.2 Hz, H(5)), 2.02 (dddd, J ) 13.6, 6.2, 3.6, 1.3 Hz,

H(9)eq), 2.38 (br qd, 1H, J ) 7.4, 7.2 Hz, H(8)eq), 2.55 (br dddd,

1H, J ) 14.0, 14.0, 7.2, 7.2 Hz, H(7)ax), 3.29 (d, 1H, J ) 12.8

Hz, H(12)), 3.75 (br dd, 1H, J ) 12.8, 0.7 Hz, H′(12)), 3.83 (br

ddd, 1H, J ) 3.6, 1.8, 1.8 Hz, H(1)), 7.18 (m, 1H), 7.28 (m,

2H), 7.41 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 19.18 (Me-

(10)), 22.06 (Me(11)), 23.38 (C(6)H₂), 24.02 (C(9)H₂), 27.17

(C(7)H₂), 29.61 (C(5)H), 32.98 (C(8)H), 40.83 (C(12)H₂), 80.32

(C(1)H), 83.66 (C(4)), 126.11 (CH), 128.90 (2CH), 129.66 (2CH),

136.92 (C).

(1R,4S,5R,8R)-4,8-Dim et h yl-4-p h en ylsu lfen ylm et h yl-

2,3-d ioxa bicyclo [3.3.1]n on a n e (55d ): a colorless oil; ¹H

NMR (400 MHz, CDCl₃): δ 1.03 (d, 3H, J ) 7.4 Hz, Me(10)),

1.29 (br dd, 1H, J ) 13.6, 6.0 Hz, H(7)eq), 1.54 (d, 3H, J ) 0.7

Hz, Me(11)), 1.64-1.82 (m, 4H), 2.20 (dddd, J ) 13.4, 6.6, 3.9,

1.3 Hz, H(9)eq), 2.37 (br qd, 1H, J ) 7.4, 6.8 Hz, H(8)eq), 2.53

(br dddd, 1H, J ) 13.6, 13.6, 6.8, 6.8 Hz, H(7)ax), 2.97 (d, 1H,

J ) 12.0 Hz, H(12)), 3.09 (br dd, 1H, J ) 12.0, 0.7 Hz, H′(12)),

3.84 (br ddd, 1H, J ) 3.9, 1.8, 1.8 Hz, H(1)), 7.19 (m, 1H), 7.28

(m, 2H), 7.37 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 19.02

(Me(10)), 21.96 (Me(11)), 23.05 (C(6)H₂), 24.05 (C(9)H₂), 27.51

(C(7)H₂), 31.14 (C(5)H), 32.89 (C(8)H), 40.78 (C(12)H₂), 80.76

(C(1)H), 83.65 (C(4)), 126.29 (CH), 128.97 (2CH), 129.62 (2CH),

136.86 (C).

(1R,4R,5R)-4,8-Dim eth yl-4-p h en ylsu lfon ylm eth yl-2,3-

d ioxa b icyclo [3.3.1]n on -7-en e (57a ) a n d (1R,4R,5R)-4-

Met h yl-8-m et h ylid en e-4-p h en ylsu lfon ylm et h yl-2,3-d i-

oxa bicyclo[3.3.1]n on a n e (58a ). To a mixture of SOCl₂(395

mg, 3.32 mmol) and pyridine (656 mg, 8.30 mmol) in CH₂Cl₂

(40 mL) at 0 °C was added a solution of hydroxysulfone 23a

(270 mg, 0.827 mmol) in CH₂Cl₂(15 mL) over 30 min. The

mixture was stirred at 0 °C for 2 h and for 4 h at rt, poured

into ice-cold 0.2 N HCl (100 mL), and extracted with hexanes-

EtOAc (3:1, 2 × 200 mL). The combined organic extract was

washed with saturated NaHCO₃(30 mL), dried (Na₂SO₄),

filtered, and evaporated. FC (hexanes-EtOAc, 4:1) afforded

a colorless solid mixture of 57a and 58a (243 mg, 95.5%, 57a /

58a ca. 86:14). More polar isomer 57a (ca. 97.5% purity) was

isolated using sequential MPLC (hexanes-EtOAc, 85:15) as

a colorless solid, mp 111-112 °C; ¹H NMR (400 MHz, CDCl₃):

δ 1.47 (d, 3H, J ) 0.6 Hz, Me(11)), 1.72 (ddd, 1H, J ) 13.3,

2.8, 2.0 Hz, H(9)ax), 1.78 (ddd, 3H, J ) 2.7, 1.7, 1.7 Hz, Me-

(10)), 2.26 (dddq, 1H, J ) 19.1, 5.4, 1.7, 1.7 Hz, H(6)ax), 2.39

(dddq, 1H, J ) 19.1, 3.2, 1.7, 1.7 Hz, H(6)eq), 2.46 (m, 1H,

H(5)), 2.50 (dddd, 1H, J ) 13.3, 3.5, 3.5, 1.6 Hz, H(9)eq), 3.29

(d, 1H, J ) 14.3 Hz, H(12)), 4.12 (m, 1H, H(1)), 4.31 (dd, 1H,

J ) 14.3, 0.6 Hz, H′(12)), 5.77 (m, 1H, H(7)), 7.58 (m, 2H),

7.66 (m, 1H), 7.95 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 21.16

(Me(10)), 23.62 (Me(11)), 26.83 (C(9)H₂), 27.48 (C(6)H₂), 29.54

(C(5)H), 61.23 (C(12)H₂), 76.70 (C(1)H), 82.35 (C(4)), 127.28

(C(7)H), 127.55 (2CH), 129.35 (2CH), 131.15 (dC(8)), 133.71

(CH), 141.20 (C). Anal. Calcd for C₁₆H₂₀O₄S: C, 62.31; H, 6.54;

S, 10.40. Found: C, 62.17; H, 6.57; S, 10.47.

Hyd r ogen a tion of Un sa tu r a ted Su lfid es 53a ,b a n d

54a ,b w ith Diim id e.³⁸To a mixture of unsaturated sulfides

53a ,b and 54a ,b (120 mg, total 0.43 mmol; 53a /53b/54a /54b

ca. 54:34: 6.5:5.5) and potassium azodicarboxilate (1.00 g, 5.15

mmol) in MeOH-CH₂Cl₂(5 mL, 3:2) at 0 °C over 45 min was

added a solution of AcOH (620 mg, 10.3 mmol) in CH₂Cl₂(2

mL). The reaction mixture was allowed to warm to ambient

temperature and stirred for an additional 48 h. The mixture

was diluted with ether (50 mL), filtered through Celite, and

evaporated. The residue was fractionated by sequential MPLC

(hexanes-EtOAc, 98: 2) to recover the starting unsaturated

sulfides 53a ,b (70 mg, 0.25 mmol; a /b ca. 61: 39), and to give

the saturated sulfides 55c (4 mg) and 55d (3 mg) (both ca.

95% purity), as well as two fractions consisting of the mixtures

of 55a ,b with a different ratio of isomers: (4 mg, a /b ca. 83:

17) and (19 mg, a /b ca. 53: 47). Total yield of hydrogenated

sulfides 55a -d : 30 mg (60% based on consumed, unsaturated

sulfides).

(1R,4R/S,5R,8S)-4,8-Dim eth yl-4-p h en ylsu lfen ylm eth yl-

1

2,3-d ioxa bicyclo[3.3.1]n on a n es (55a ,b): a colorless oil; H

NMR (400 MHz, CDCl₃): δ 1.09 (d, J ) 6.7 Hz, b), 1.10 (d, J

) 6.7 Hz, Me(10), a ), total 3H; 1.24 (br s, a ), 1.55 (d, J ) 0.7

Hz, Me(11), b), total 3H; 1.41 (ddd, J ) 13.3, 3.0, 1.7 Hz, a ),

1.48 (ddd, J ) 13.1, 3.2, 1.7 Hz, H(9)ax, b), total 1H; 1.58-

1.69 (m, 2H, H(6)ax + eq, a + b), 1.75-1.85 (m, 1H, H(8)ax, a

+ b); 1.90-1.94 (m, 1H, H(5), a + b), 1.94-2.05 (m, 2H, H(7)-

ax + eq, a + b); 2.28 (dddd, J ) 13.3, 4.0, 4.0, 2.6 Hz, a ), 2.45

(dddd, J ) 13.1, 3.8, 3.8, 2.9 Hz, H(9)eq, b), total 1H; 2.94 (d,

J ) 11.9 Hz, H(12), b), 3.05 (dd, J ) 11.9, 0.7 Hz, H′(12), b),

3.31 (d, J ) 12.7 Hz, H(12), a ), 3.73 (dd, J ) 12.7, 0.7 Hz,

H′(12), a ), total 2H; 3.83 (br dd, J ) 4.0, 1.7 Hz, a ), 3.71 (br

Th e less p ola r isom er 58a : 58a (ca. 95% purity) was

isolated by semipreparative DP HPLC (i-PrOH-hexane, 2:98)

1

as a colorless waxy substance; H NMR (400 MHz, CDCl₃): δ

1.57 (d, 3H, J ) 0.6 Hz, Me(11)), 1.65 (ddd, 1H, J ) 13.7, 3.2,

1.7 Hz, H(9)ax), 1.73 (dddd, 1H, J ) 14.2, 14.2, 6.4, 3.8 Hz,

H(6)ax), 2.15 (br ddd, 1H, J ) 14.2, 6.6, 3.2 Hz, H(6)eq), 2.39

(br dd, 1H, J ) 14.2, 6.6 Hz, H(7)eq), 2.46 (dddd, 1H, J ) 6.4,

6.4, 3.2, 3.2 Hz, H(5)), 2.57 (ddd, 1H, J ) 13.7, 6.4, 3.6 Hz,

H(9)eq), 2.99 (m, 1H, H(7)ax), 3.29 (d, 1H, J ) 14.3 Hz, H(12)),

4.30 (br dd, 1H, J ) 14.3, 0.6 Hz, H′(12)), 4.36 (br dd, 1H, J )

3.6, 1.7 Hz, H(1)), 4.92 (br dd, 1H, J ) 2.2, 2.2 Hz, dCHH′),

4.95 (br ddd, 1H, J ) 2.2, 2.2, 0.6 Hz, dCHH′),7.59 (m, 2H),

dd, J ) 3.8, 1.7 Hz, H(1), b), total 1H; 7.17-7.43 (m, 5H); ¹³

C

NMR (100 MHz, CDCl₃): δ 18.56 (Me(10)), 22.05 (Me(11)),

27.06 (CH₂), 29.19 (C(5)H), 29.56 (CH₂), 29.59 (CH₂), 35.62

2530 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12

Bachi et al.

7.67 (m, 1H), 7.96 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 23.32

(Me(11)), 27.02 (C(6)H₂), 30.39 (C(5)H), 30.50 (C(9)H₂), 30.52

(C(7)H₂), 61.27 (C(12)H₂), 80.77 (C(1)H), 82.96 (C(4)), 113.59

(dC(10)H₂), 127.57 (2CH), 129.36 (2CH), 133.74 (CH), 141.18

(C), 146.21 (dC(8)); DCI (CH₄) HRMS: obsd 309.1193, calcd

for C₁₆H₂₁O₄S (MH⁺), 309.1161.

2H, H(8)ax + H(5)), 2.47 (dddd, 1H, J ) 13.3, 4.4, 3.2, 3.2 Hz,

H(9)eq), 3.14 (d, 1H, J ) 14.0 Hz, H(12)), 3.37 (br dd, 1H, J )

14.0, 0.5 Hz, H′(12)), 3.85 (br dd, 1H, J ) 4.4, 2.0 Hz, H(1)),

7.57 (m, 2H), 7.66 (m, 1H), 7.93 (m, 2H); ¹³C NMR (100 MHz,

CDCl₃): δ 18.49 (Me(10)), 22.06 (Me(11)), 27.33 (C(9)H₂), 28.96

(C(6)H₂), 29.61 (C(7)H₂), 31.56 (C(5)H), 35.53 (C(8)H), 60.60

(C(12)H₂), 80.06 (C(1)H), 82.53 (C(4)), 127.64 (2CH), 129.32

(2CH), 133.76 (CH), 141.37 (C); DCI(CH₄) HRMS: obsd

311.1265, calcd for C₁₆H₂₃O₄S (MH⁺), 311.1317. Anal. Calcd

for C₁₆H₂₂O₄S: C, 61.91; H, 7.14; S, 10.33. Found: C, 62.31;

H, 7.16; S, 10.58.

P r ep a r a tion of Sa tu r a ted Su lfon e-En d op er oxid es 56a

a n d 56b by Oxid a tion of Su lfid es 55a ,b. A mixture of

diastereomers 56a ,b (18.0 mg, 90%, a /b ca. 55:45) was

prepared by oxidation of sulfides 55 a ,b (18.0 mg, 0.065 mmol,

a /b ca. 54:46) according to the general procedure 1 and purified

by FC (hexanes-EtOAc, 4:1). The isomers 56a and 56b were

separated by semipreparative DP HPLC (i-PrOH-hexane, 2:

98).

(1R,4S,5R)-4,8-Dim et h yl-4-p h en ylsu lfon ylm et h yl-2,3-

d ioxa b icyclo [3.3.1]n on -7-en e (57b ) a n d (1R,4S,5R)-4-

Met h yl-8-m et h ylid en e-4-p h en ylsu lfon ylm et h yl-2,3-d i-

oxa bicyclo[3.3.1]n on a n e (58b). With the same procedure as

above, 23b (780 mg, 2.39 mmol) was transformed into a

mixture of 57b and 58b (total 692 mg, 94%, 57b/58b ca. 84:

16), which was obtained as a colorless solid, mp 121-124 °C.

Recrystallization from EtOAc-hexane (5:95) afforded a single

isomer 57b (g97% purity): a colorless solid, mp 133-134 °C;

¹H NMR (400 MHz, CDCl₃): δ 1.63 (br ddd, 1H, J ) 13.1, 2.8,

2.2 Hz, H(9)ax), 1.77 (m, 3H, Me(10)), 1.86 (d, 3H, J ) 0.7 Hz,

Me(11)), 2.31 (m, 1H, H(5)), 2.34 (ddq, 1H, J ) 18.5, 2.6, 2.6

Hz, H(6)ax), 2.45 (m, 1H, J ) 18.5 Hz, H(6)eq), 2.54 (dddd,

1H, J ) 13.1, 3.4, 3.4, 1.7 Hz, H(9)eq), 3.02 (d, 1H, J ) 14.0

Hz, H(12)), 3.37 (br d, 1H, J ) 14.0 Hz, H′(12)), 4.14 (m, 1H,

H(1)), 5.74 (m, 1H, H(7)), 7.58 (m, 2H), 7.68 (m, 1H), 7.93 (m,

2H); ¹³C NMR (100 MHz, CDCl₃): δ 21.11 (Me(10)), 22.30 (Μe-

(11)), 25.97 (CH₂), 28.52 (CH₂), 30.67 (C(5)H), 60.70 (C(12)-

H₂), 77.43 (C(1)H), 82.70 (C(4)), 126.74 (C(7)H), 127.49 (2CH),

129.41(2CH), 131.17 (dC(8)), 133.88 (CH), 141.20 (C). Anal.

Calcd for C₁₆H₂₀O₄S: C, 62.31; H, 6.54. Found: C, 62.37; H,

6.58.

Selected NMR d a ta for 58b: ¹H NMR (400 MHz, CDCl₃):

δ 1.52 (br ddd, 1H, J ) 13.6, 3.1, 1.5 Hz, H(9)ax), 1.78 (br s,

3H, Me(11)), 2.15-2.25 (m, 3H), 2.52-2.57 (m, 1H), 2.76-2.87

(m, 1H, H(7)ax), 3.21 (d, 1H, J ) 14.0 Hz, H(12)), 3.41 (br d,

1H, J ) 14.0 Hz, H′(12)), 4.37 (br d, 1H, J ) 3.4 Hz, H(1)),

4.85-4.90 (m, 2H, dCHH′); ¹³C NMR (100 MHz, CDCl₃): δ

21.95 (Μe(11)), 27.24 (CH₂), 29.23 (CH₂), 30.12 (CH₂), 32.02

(C(5)H), 60.39 (C(12)H₂), 80.96 (C(1)H), 82.96 (C(4)), 112.92

(dC(10)H₂), 145.97 (dC(8)).

(1R,4R,5R,7R,8R)-4,8-Dim eth yl-7,8-ep oxy-4-p h en ylsu l-

fon ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (59a ). A mix-

ture of unsaturated sulfone 57a (36.0 mg, 0.114 mmol) and

mCPBA (38.0 mg of ca. 60%, 0.13 mmol) in CH₂Cl₂(2 mL) was

stirred at rt for 12 h. The reaction mixture was diluted with

hexanes-EtOAc (40 mL, 3:1), washed with saturated NaHCO₃

(2 × 5 mL), and the aqueous washings were extracted with

hexanes-EtOAc (20 mL, 3:1). The combined organic extract

was dried (Na₂SO₄+ NaHCO₃) and evaporated. The residue

was purified by FC (hexanes-EtOAc, 4:1) to afford the epoxide

1

59a (35.5 mg, 96%) as a colorless solid: mp 130-131 °C; H

NMR (400 MHz, CDCl₃): δ 1.44 (s, 3H, Me(10)), 1.50 (d, 3H, J

) 0.5 Hz, Me(11)), 1.91 (ddd, 1H, J ) 14.0, 2.3, 1.8 Hz, H(9)-

ax), 2.01 (br dd, 1H, J ) 16.5, 2.3 Hz, H(6)ax), 2.15 (ddd, 1H,

J ) 14.0, 6.6, 3.8 Hz, H(9)eq), 2.21-2.32 (m, 2H), 3.19 (br d,

1H, J ) 5.5 Hz, H(7)eq), 3.29 (d, 1H, J ) 14.3 Hz, H(12)), 4.18

(br dd, 1H, J ) 3.8, 1.8 Hz, H(1)), 4.22 (dd, 1H, J ) 14.3, 0.5

Hz, H′(12)), 7.59 (m, 2H), 7.68 (m, 1H), 7.94 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 18.64 (Me(10)), 22.57 (C(9)H₂), 23.38 (Me-

(11)), 25.27 (C(6)H₂), 28.74 (C(5)H), 57.10 (C(8)), 59.00 (C(7)H),

60.93 (C(12)H₂), 78.29 (C(1)H), 82.15 (C(4)), 127.50 (2CH),

129.36 (2CH), 133.79 (CH), 140.99 (C). Anal. Calcd for

Syn th esis of (1R,4R,5R,8S)-4,8-Dim eth yl-4-p h en ylsu l-

fon ylm eth yl-2,3-d ioxa bicyclo[3.3.1]n on a n e (56a ) by Hy-

d r ogen a tion of Un sa tu r a ted Su lfon es 57a a n d 58a . A

mixture of unsaturated sulfones 57a and 58a (37.0 mg, 0.120

mmol, 57a /58a ca. 86:14) in EtOAc (7 mL) was hydrogenated

over PtO₂‚H₂O (4.0 mg) at -10 °C ( 2 °C for 40 min

(atmospheric pressure of hydrogen). After completion of hy-

drogenation, excess hydrogen was removed in vacuo. The

mixture was filtered through a plug of cotton, washed with

EtOAc, and evaporated. FC (EtOAc-hexane, 1:4) of the residue

afforded the hydrogenated endoperoxide 56a (33.2 mg, 90%)

C

₁₆H₂₀O₅S: C, 59.24; H, 6.21; S, 9.88. Found: C, 59.54; H, 6.21;

S, 9.46.

Biology

In Vitr o An tim a la r ia l Activity. Antimalarial activities

in vitro were determined in the Department of Medicine, J HU,

by a modification⁴²of the 48-h sensitivity assay of Desjardins⁴³

and Milhous,⁴⁴based on a measuring the incorporation of [³H]-

hypoxanthine as an assessment of parasite growth.

In Vivo An tim a la r ia l Activity. In vivo antimalarial

activity was determined by W. Peters and B. L. Robinson (the

Tropical Parasitic Diseases Unit, Northwick Park Institute for

Medical Research, U.K.) according to the previously reported

4-d test protocol in a mice model.^17a

Toxicology. The studies were carried out at Harlan Biotech

Israel, Ltd., Rehovot, Israel, in compliance with good labora-

tory practice (GLP). The potential toxic effects of the test

articles 46a and 46b were assessed following 7-d repeated

intramuscular injections in equally sized groups, comprising

5 male healthy 5-week-old ICR/CD-1 mice. During acclimation

and following dosing, the animals were housed within a

limited-access rodent facility and kept in groups of five mice

per cage. Automatically controlled environmental conditions

were set to maintain temperature at 20-24 °C with a relative

humidity of 30-70%. Sufficient air changes and 12-h light/

12-h dark cycles were provided in the study room. Animals

were provided a commercial rodent diet and were allowed free

access to drinking water.

as a colorless solid: mp 112-113 °C; [R]²⁰-246.7° (c 0.5,

D

CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 1.08 (d, 3H, J ) 6.6

Hz, Me(10)), 1.52 (d, 3H, J ) 0.7 Hz, Me(11)), 1.57 (ddd, 1H,

J ) 13.5, 3.1, 1.7 Hz, H(9)ax), 1.64-1.74 (m, 2H), 1.79-1.88

(m, 1H, H(8)ax), 1.89-1.98 (m, 1H), 2.04-2.10 (m, 1H), 2.35

(br dddd, 1H, J ) 6.0, 6.0, 3.2, 3.2 Hz, H(5)), 2.46 (dddd, 1H,

J ) 13.5, 6.0, 3.2, 3.2 Hz, H(9)eq), 3.24 (d, 1H, J ) 14.2 Hz,

H(12)), 3.85 (br s, 1H, H(1)), 4.31 (dd, 1H, J ) 14.2, 0.7 Hz,

H′(12)), 7.59 (m, 2H), 7.67 (m, 1H), 7.95 (m, 2H); ¹³C NMR

(100 MHz, CDCl₃): δ 18.50 (Me(10)), 23.06 (Μe(11)), 26.88

(C(9)H₂), 29.69 (C(6)H₂), 30.00 (C(5)H), 30.02 (C(7)H₂), 35.54

(C(8)H), 61.31 (C(12)H₂), 79.78 (C(1)H), 82.42 (C(4)), 127.55

(2CH), 129.34 (2CH), 133.67 (CH), 141.26 (C); DCI (CH₄)

HRMS: obsd 311.1294, calcd for C₁₆H₂₃O₄S (MH⁺), 311.1317.

Anal. Calcd for C₁₆H₂₂O₄S: C, 61.91; H, 7.14; S, 10.33. Found:

C, 62.20; H, 7.24; S, 9.99.

(1R,4S,5R,8S)-4,8-Dim et h yl-4-p h en ylsu lfon ylm et h yl-

2,3-d ioxa bicyclo[3.3.1]n on a n e (56b). The saturated endo-

peroxide 56b (48.6 mg, 88%) was synthesized from a mixture

of unsaturated endoperoxides 57b and 58b (55.0 mg, 0.178

mmol; 57b/58b ca. 84:16) according to the procedure described

above for 56a . A colorless solid, mp 134-135 °C (hexane-tert-

butyl methyl ether); [R]²⁰-147.8° (c 0.5, CHCl₃); ¹H NMR

Animals were treated by injecting at one or more sites into

the musculature of the rear limb assemblies (thigh or leg

muscles) the maximal volume of injection, which was limited

to 0.05 mL/site. Compound 46b and arteether (2c) were freshly

D

(400 MHz, CDCl₃): δ 1.01 (d, 3H, J ) 6.4 Hz, Me(10)), 1.46

(ddd, 1H, J ) 13.3, 3.1, 2.0 Hz, H(9)ax), 1.65 (m, 1H), 1.68-

1.82 (m, 3H), 1.80 (d, 3H, J ) 0.5 Hz, Me(11)), 2.07-2.14 (m,

Evaluation of Antimalarial Bicyclic Endoperoxides

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2531

dissolved daily, while compound 46a was freshly finely sus-

pended using ultrasound technique in sesame oil (vehicle,

Sigma Chemical Co.) at 45-50 °C to prepare 5% (50 mg/mL)

stock solutions (suspensions) for injections. The solutions were

thermostated at 37 °C before injections. Variable volumes

appropriate for the selected dose level were injected. The same

dose of vehicle was administered under identical conditions.

Refer en ces

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Soisson, L.; Carucci, D. J .; Hoffman, S. L. A Multilateral Effort

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Assessment of toxicity was based on a comparison of effects

between the test groups, and both a reference and a control

group were administered the reference article arteether (2b)

and the vehicle, respectively. During the 7-d study, careful

clinical examinations were carried out daily, including obser-

vations of potentially induced changes in the skin, fur, eyes,

mucous membranes, respiratory, circulatory, autonomic and

CNS, somatomotor activity, and behavior pattern. Particular

attention was paid to the possible appearance of tremors,

convulsions, salivation, diarrhea, lethargy, sleep, and coma.

Changes in gait, posture, and response to handling, as well

as stereotypes, such as excessive grooming, repetitive circling,

or otherwise bizarre behaviors were also monitored. Morbidity

and mortality were monitored and recorded twice every day.

Individual body weights of animals were determined just prior

to dosing (day 1). Thereafter, the animals were weighed also

on day 5 and at study termination prior to sacrifice (day 8).

At the end of the study, surviving animals were sacrificed by

CO₂asphyxiation. Hematology and clinical chemistry param-

eters for all animals of the vehicle control, arteether (2c)

reference, and the high-dose groups of both test articles 46a

and 46b were determined in blood samples, collected at the

time of the scheduled terminal sacrifice (day 8 of the study).

All animals were subjected to a full necropsy, including

examination of the external surface of the body, all orifices,

and the cranial, thoracic, and abdominal cavities and their

contents. The heart, liver, kidneys, and spleens from the

animals were trimmed of any adherent tissue, as appropriate,

weighed wet as soon as possible after dissection, and then

preserved in 4% formaldehyde solution. The brain was not

trimmed but rather excised following in situ perfusion. Per-

fusion was carried out through the left ventricle and by an

appropriate fixative (a mixture of concentrated 37% formal-

dehyde (100 mL), distilled water (900 mL), NaHPO₃(4 g), and

Na₂PO₃(65 g)). The brains were further preserved in the same

medium and submitted as such to further processing. Tissue

processing and slide preparations were performed by Pathology

International Associates (U.S.A.), a GLP-approved laboratory.

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Final assessment of the test articles 46a and 46b effects

was based on the results of clinical observations, as well as

on the body weights, clinical pathology, necropsy findings,

organ weights, and histopathology results as compared to those

of the vehicle (sesame oil) and the reference article (arteether

(2c)) treated groups. Where applicable (i.e., the data of body

weights, organ weights, and clinical pathology results), sta-

tistical analysis of the data was performed (software: Graph-

Pad Instat, version 3.02; Statistical method: One-Way ANOVA-

Dunnet Multiple Comparison Test).

Ack n ow led gm en t. We gratefully acknowledge the

financial support by the United States-Israel Bina-

tional Science Foundation (BSF), J erusalem, Israel,

Grant 94-102; Keren Lewin, the Weizmann Institute of

Science; the J ohns Hopkins University-Weizmann

Institute of Science Exchange Program; the NIH Grant

RR-00052 at the J ohns Hopkins University; and the

Burroughs Wellcome Fund. We thank also the Israel

Ministry of Absorption for a fellowship to E.E.K; the

Swiss Society of the Friends of the Weizmann Institute

of Science for a fellowship to R.H; Dr. Leonid Konstan-

tinovski (WIS) for his help in the NMR studies, and Dr.

Yona Grunfeld (Harlan Biotech Israel, Ltd.) for his

advice in planning the toxicological tests.

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J M020584A

Article Doi

A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic β-sulfonyl-endoperoxides

DOI: 10.1021/jm020584a

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