review on biological importance of endoperoxides and their...

Indian Journal of Chemistry Vol. 53B, July 2014, pp 835-857

Advances in Contemporary Research

Review on biological importance of endoperoxides and their various routes of synthesis

Hitesh D Patel* & Dayena J Christian

School of Sciences, Chemistry Department, Gujarat University, Navrangpura, Ahmedabad 380 009, India

E-mail: [email protected]

Received 7 March 2013; accepted (revised) 28 April 2014

This review paper describes the synthesis of different endoperoxides, which exhibit anti-malarial, anti-cancer and other biological activity. This review is primarily based on artemisinine. Many researchers have proved that artemisinine is active in malaria and cancer. It is also proved that in artemisinine, the endoperoxide bond plays a key role in the fight against disease. It is expected that this review will provide first-hand information on endoperoxide chemistry to organic chemists, pharmacologists and medicinal chemists who are working on anti-malarial and anti-cancer drug development.

Keywords: Anti-bacterial, anti-malarial, anti-tumor, artemisinine, endoperoxide

The story of artemisinine began in China in the late 1960s. Artemisinine is extracted from the leaves of Artemisia annua and is now widely used against the treatment of multidrug resistant P. falciparum. Artemisia plant has been identified in traditional Chinese pharmacopoeia for the treatment of fevers. The research on this drug was prompted in China by the Vietnam War. China was supporting North Vietnam, and malaria greatly reduced the combat strength1. An effective insecticide, a vaccine, or a new anti-malarial drug seemed to be the only hope. Artemisia annua is a major milestone in malaria chemotherapy2.

Currently, the sesquiterpene lactone artemisinin 1 (Figure 1) and its derivatives are the only class of compounds consistently effective for multidrug resistant strains of P. falciparum. Artemisinins derivatives are now routinely recommended as first-line therapy for complicated and severe P. falciparum malaria. Interestingly, artemisinine derivatives also display a wide variety of biological activities, including cytotoxic, antibacterial, and antifungal activities3-7.

Nowadays, Artemisinine and its bioactive derivatives have been found to exhibit potent anticancer effects in a variety of human cancer cell systems8. The recent developments made on various kinds of artemisinine derivatives and their efficiency towards malarial parasites and different cancer cell lines were compared with artemisinine, and various other anti-malarial and anti-cancer drugs9.

Mechanism of Action

Mechanism of action of Artemisinine

The mechanism of action of any drug is very important in drug development. Generally, the drug compound binds with a specific target, a receptor, to mediate its effects. Therefore, suitable drug-receptor interactions are required for high activity. Although the mechanism of artemisinine as an anti-malarial is still in doubt, there is general agreement on the significance of the endoperoxide group of artemisinine to the anti-malarial activity. This is evident from the inactivity of the deoxyartemisinine compound that lacks the endoperoxide moiety10. In addition, in-vitro experiments reveal that heme iron is required for artemisinine to have antimalarial activity11-13.

The active principle of sweet wormwood herb is Artemisinine, a sesquiterpene, which exerts not only anti-malarial activity but also profound cytotoxicity against tumor cells14. The anti-tumor mechanism has similarities with the anti-malarial mechanism. Artemisinine molecule contains an endoperoxide bridge that reacts with an iron atom to form free radicals causing macromolecular damage and cell death15,16.

It has been proposed that heme iron attacks the endoperoxide linkage of artemisinine either at the O1 or O2 position17,18 (Figure 2). In pathway A, heme iron attacks the compound at the O2 position 6 and produces a free radical at the O1 position. Later, it rearranges to form the C4 free radical 7. In pathway

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INDIAN J. CHEM., SEC B, JULY 2014

836

B, heme iron attacks the compound at the O1 position 8 and produces a free radical at the O2 position. After that, the C3-C4 bond is cleaved to give a carbon radical at C4 9. It has been suggested that the C4 free radical in both the pathways is an important intermediate in anti-malarial activity19.

Although the Artemisinine ring system is complex and difficult to construct, more than 100 analogs have been synthesized. The essential part of the molecule appears to be the endoperoxide bridge. Consequently, simpler structures containing this bridge, such as the trioxanes and tetraoxanes, are far more accessible. Indeed, more than 1000 new endoperoxides belonging to several classes have been prepared. Not only do this derivatives offer new therapeutic possibilities, but they have been helpful in providing an understanding of the mode of action.

The above mode of action indicates that endoperoxide bond is an active part in artemisinine, with some limitations. Therefore, it has been planned to synthesize new compounds having endoperoxide

bond, which can provide antimalarial, anticancer, and other biological activity.

The mode of action appears to involve two distinct steps. In the first step, Endoperoxide bridge is catalyzed by intra parasitic iron and heme to generate unstable free radical intermediates20. The selective toxicity of the drug against the malarial parasites is probably due to this step, since the intra-erythrocytic parasite is rich in iron and heme. In the second step, the resulting free radical, or a further rearranged free radical or electrophile, then alkylates specific malaria proteins21 (Figure 3).

Experiments with [18O]-labeled trioxane analogs have permitted further details of the interaction between iron and the endoperoxide to be elucidated. The first event is the reduction of the endoperoxide bond by ferrous ion to form an O-centered radical that rearranges to a C-centered radical either through a 1,5-hydrogen atom shift or by homolytic cleavage of a C=C bond22. Evidence for the importance of the 1,5-H shift was obtained using a stereochemical probe23,24.

O

O

H

O H

R1 R2

O

3. R1=H, R2=OEt Arteether

2. R1=H, R2=OMe Artemether

1. R1=R2=O Artemisinine

4. R1=H, R2=OOCCH2CH2CO2Na Sodium artesunate

5. R1=H, R2=OCH2PhCO2Na Sodium artelinate

Figure 1 — Structure of Artemisinine and its derivative

O

O

OO

O

H

HH

O

O

O

H

HH

O

FeO

O

O

O

H

HH

FeOO

O

C

O

O

H

HH

OHFeO

H

B

Fe2+

Fe2+

1

6 7

8 9

AcO

CH2

O

O

H

HH

FeO

A

123

45 6

7

8

91011

1212a

5a

8a13

14

Figure 2 — Modes of action of Artimisinine

PATEL et al.: ENDOPEROXIDES AND THEIR VARIOUS ROUTES OF SYNTHESIS

837

Charles W. Jefford et al. first synthesized the peroxide 20 (Ref 25a) obtained by the Rose Bengal sensitized photooxygenation of 1,4-dimethoxy-naphthalene 19 in THF at ‒78oC (Ref 25b). To the resulting solution of 20, an excess of acetaldehyde together with amberlyst-15 resin as a catalyst was added. After the mixture was stirred at ‒78oC overnight, workup afforded three products. The first two 19 (24%) and 21 (37%) area consequence of the inherent thermal and chemical instability of the peroxide 20. However, the third product 22 is the cis-fused 1,2,4-trioxane (13%) consisting of a pair of epimers (Scheme I).

John A. Kepler et al. prepared 24a, which is described in literature26. They also prepared 24b by addition of singlet oxygen in tetrahydrobenzopyran27. Then by using potassium azodicarboxylate and acetic acid, this compound is converted into saturated form 25a (Ref 28). Compounds 29-35 were prepared from tetrahydrobenzopyran 28 as shown in Scheme II.

Reaction of β-ionone with LDA and acetaldehyde gave the condensation product 27. Photochemical cyclization of 27 in the presence of triethylamine29

gave tetrahydrobenzopyran 28. Rose Bengal sensitized photooxygenation of 28 gave a mixture of diastereomeric alcohols 29 and 30. The stereochemistry of the singlet oxygen addition to 28 was assigned by comparison of the 8a-methyl resonances of the olefins 30, 31 and 32 with their saturated analogues 33, 34 and 35 respectively. One of the alcohols, with the arbitrarily assigned stereochemistry depicted by structure 30, was isolated by crystallization. The second alcohol, 29, was purified through its crystalline benzoate 30. Esterification of 30 afforded the benzoate 32. The saturated compounds 33, 34 and 35 were prepared by reduction of the corresponding olefin with diimide30.

As shown in Scheme III, Gary H. Posner et al. synthesized Trioxane alcohol 42 in only six separate operations starting with inexpensive and

Fe(II)

Fe(II)O

PhFeO

Ph

OC

HH

Fe(II)

*

10 11 12

13 14 15

16 17 18

O

OH

HH

OO

OMeO

OH

HH

FeO

O

OMe

O

C

OH

HH

FeOOH

OMe

O

OTs

H

OO

OMe

O

OTs

H

FeO

OMe

O

O

CH2

OTs

HO

FeO

OMe

*

O

PhFeO

Ph

O

O

OO

Ph

Ph

Figure 3 — Mechanism of action of endoperoxide containing derivatives

OMe

OMe

OMe

OMe

O

O

hv, O2, Rose Bengal

THF, -78 Co

MeCHO

Amberlyst 15

O

O

+

O

O

O

O

MeO

Me19 20 2122

19 +

Scheme I


838

commercially available cyclohexanone. One-flask enamine alkylation with acrylonitrile, followed by in

situ formation of the less-substituted enamine, and finally alkylation with ethyl bromoacetate produced 2,6-disubstituted cyclohexanone 37 in a novel process31. Wittig methoxymethylenation gave enol ester 38 as a 4:l mixture of diastereomers32. Reduction of ester 38 gave mainly alcohol isomer 39 that underwent chemo selective addition of methyllithium to the nitrile group to afford keto olefin 40. Conversion of this electron-rich olefin into the corresponding ketodioxetane was achieved with both Et3SiOOOH (Red 33) and with lO2 generated photochemically34. Using the Et3SiOOOH procedure, dioxetane formation was complete in less than 1 min. at ‒78oC. Addition of tert −butyldimethylsilyl triflate to the solution of ketodioxetane at ‒78oC produced trioxane 41 that was desilylated to give the desired trioxane alcohol 42.

Gary H. Posner et al. prepared 4-monomethylated trioxanes 46a and 46b and 4,4-dimethylated trioxane 46c, as outlined in Scheme IV (Ref 35). These were

evaluated in vitro against both chloroquine-resistant and chloroquine-susceptible strains of Plasmodium

falciparum using the semidilution method of Desjardin et al.

36 as modified by Millrose et al.37 This

method is also mentioned in Scheme III. Jean-Marie Aubry et al. prepared endoperoxide

from 1,4-dimetylnapthalene and its derivatives by the [4+2] cycloaddition reaction of singlet oxygen38,39

(Scheme V). Steady State Photolysis: A solution of the

naphthalenic substrate 2.5 × 10-3 M and a photosensitizer (Rose Bengal) 3 × 10-5 M was saturated with oxygen and irradiated in a Pyrex cell at 5°C with a halogen lamp (600 W, Osram). Control experiments were performed to ensure that the naphthalenic substrate alone does not act as a photosensitizer under these conditions. The photochemical reaction was monitored by HPLC analysis on RP 18 columns. The solutions of the naphthalenic endoperoxides were then decomposed by heating for 1 hr at 50°C, and the quantitative regeneration of the starting compound was checked by HPLC. The rate of 1O2 production

O R

a = R = CH3

b = R = CH2COOCH3

hv, O2

Rose Bengal O R

OO

Potasium azodicarboxylate(PADA) / HOAC

O R

OO

2324 25

23a = R = CH3

b = R = CH2COOCH324

a = R = CH3

b = R = CH2COOCH325 O BuLi

Diisopropylamine

CH 3CHO

O OH

O

OH

hv, O 2Rose Bengal

C6H5COCl

O

OO

R1 R2O

OO

R1 R2 Potassium azodicarboxylate

HOAc

27 28

29) R 1 = H, R 2 = OH

30) R 1 = OH, R 2 = H

31) R 1 = H, R 2 = OCOC 6H5

32) R 1 = OCOC 6H5, R 2 = H

34) R 1 = OCOC 6H5, R 2 = H

35) R 1 = OCOC 6H5, R 2 = H

33) R 1 = OH, R 2 = H

hv

Et 3N

Py, CHCl 3

26

Scheme II


839

was determined by replacing the naphthalenic substrate with two efficient 1O2 scavengers, α-terpinene 5 × 10-2 M in organic solvents and CHDDE 2×10-2 M in D2O, which trap completely photo generated singlet oxygen.

Yoshihiro Ushigoe et al. synthesized trioxane by ozonolysis of unsaturated hydroperoxy acetals. To obtain information for the structural effect of allylic alcohols on the efficiency, they conducted ozonolysis of β-methoxystyrene 49a in the presence of a series of allylic alcohols 51a-c (3 equiv) in CH2Cl2 at ‒70°C. Treatment of 52a with ozone in MeOH-ether at ‒78°C gave the expected 6-hydroxy-1,2,4-trioxane 55a almost quantitatively40 (Scheme VI).

Emine Salamci et al. synthesized hydroperoxy endoperoxide by photooxygenation of 1,4-cyclohexa-diene41. To a stirred solution of 1,4-cyclohexadiene (1.0 g, 12.5 mmol) in 100 mL of CH2Cl2, 20 mg of tetraphenylporphyrin (TPP) was added. The resulting mixture was irradiated with a projection lamp (150 W) while oxygen was being passed through solution, and the mixture was stirred for 48 hr at RT. The 1H NMR spectrum of the mixture showed that the ratio of

3:4 was 88:12. Evaporation of the solvent at 30°C, 20 mmHg, and chromatography of the residue over a silica gel column (100 g) eluting with hexane/ether (1:1) gave the first fraction as endoperoxide 58a (1.15 g, 63%) and the second fraction as endoperoxide 58b (0.12 g, 7%) (Scheme VII).

Christel Pierlot and Jean-Marie Aubry mentioned that 1,4-endoperoxide 60 and 5,8-endoperoxide 61 were derived from 1,4-disubstituted naphthalenes 59 by photooxidation42 (Scheme VIII). A solution of 59 (30 mg) and methylene blue (1.6 × 10-5 M in 1 mL of deuterated water were irradiated with a sodium lamp 150 W) under continuous bubbling of oxygen at a constant temperature. During the reaction, some methylene blue was periodically added to compensate for its fading. HPLC analysis was used to determine the ratio of each product.

Gary H. Posner et al. prepared endoperoxide via formation of enones using easily available aryl methyl ketones43-45. These synthesized peroxides have shown good anti-malarial activity in comparison to clinically used natural trioxane artemisinin46 (Scheme IX).

O

NH1)

2) CN

3) Br - CH2COOEt

O

NC

EtOOC

NC

EtOOC

MeO

MeOCH=PPh3

LiB(sec Bu)3H

NC

MeO

OH

MeO

O

OH

MeLiO2 or Et3SiOOOH1)

2) t -BuMe2SiOTf

3) Et3N

n Bu4NF

36 37 38

394041

42

O

OSiMe2But

HO

O

OMe

H

O

OH

HO

O

OMe

Scheme III


840

Enone Synthesis (Aldol Condensation, Dehydration): LDA solution (1.1 equiv based on 1.0 equiv of acetophenone substrate) was prepared by treating diisopropylamine (1.1 equiv) in THF (volume needed to make final concentration of LDA 0.3-0.5 M) at ‒78°C with n-BuLi (1.7 M solution in hexanes, 1.1 equiv). The LDA solution was stirred at ‒78°C for 10 min and then at RT for 10 min, then re-cooled to ‒78°C. Acetophenone (1.0 equiv, either neat in the case of liquids or as a 0.5-1.0 M solution in THF) was added into the LDA solution and stirred at ‒78°C for

15 min and then at RT for 10 min. The reaction was cooled to ‒78°C, and aldehyde (1.0-1.2 equiv) was added. The reaction was stirred at ‒78°C for 1 hr and then at RT for 1 hr. The reaction was quenched (saturated aqueous NH4Cl), extracted (ether), washed (H2O, brine), dried (anhyd. Na2SO4), and concentrated at reduced pressure to give a crude product.

Peroxy Ketal Synthesis (Photoenolization, Oxygenation): In a 125 mL three-necked sulfonation flask equipped with a screw-cap, oxygen inlet, and a 13 cm Vigreux distilling column with a gas outlet to a

O

NH1)

2) CN

3) BrCH 2COOEt

O

NC

EtOOC

MeOCH=PPh 3NC

EtOOC

MeO

1) LiB(Sec Bu) 3H

2) TiO SiMe 2Bu-t

Et3N

NC

MeO

OEt

1) i Pr 2NLi

2) MeI

NC

MeO

OEt

Me

1) i Pr 2NLi

2) MeIMeO

OEt

NCMeMe

1) MeLi

2) 1O2

3) TiOSiMe 2Bu-t

4) Et 3N

5) n Bu 4NF

MeO

OH

O

OO

HR1

R2

a) R 1 = H, R 2 = Me

b) R 1 = Me, R 2 = H

c) R 1 = Me, R 2 = Me

36 3738

434445

46

Scheme IV

R

R'

+

R

R'

O

O

1O2

50oC, 1h

.

47 48

Scheme V


841

mineral oil bubbler, a solution of enone (75-350 mg) and CuSO4 (15-40 mg) in CH2Cl2 (100 mL) and MeOH (10 mL) was irradiated at RT by a 275 W sun lamp (placed ca. 10 cm from the reaction vessel) while ultra-high purity grade oxygen was bubbled through the solution at a rate of 20 mL/min. The flask was cooled by a fan, and solvent was refilled as required. After 14-17 hr the reaction was stopped, washed (water), dried (anhyd. Na2SO4), and concentrated to give a crude product.

Georgios Vassiliko Giannakis et al. prepared endoperoxides from 2,5-dimethyl-2,4-hexadiene by

photooxygenation. The reaction of singlet oxygen with the sterically hindered 2,5-dimethyl-2,4-hexadiene (DMHD, 66) forms a mixture of 1,2-dioxetane 67 and endoperoxide 68 in methanol solvent47 (Scheme X).

Jiro Motoyoshiya et al. prepared cis-endoperoxides by photo-oxygenation of 1-aryl-1,3-pentadienes48,49.

TPP-Sensitized Photooxygenation of Dienes: Photooxygenation was carried out with a 100 W tungsten lamp under bubbling oxygen for 15 hr as noted elswhere, and the reacting solutions were kept at 30°C. After irradiation of the solutions of the dienes 69a-c (1.89-4.85 mmol) and TPP (1/20 mol

PhCH=CHOMeO3 PhCHOO

OH

R1

R2

O

HHOO

Ph R1

R2

49 a 50 a

51a - c52 a - c

O3

R2

O

H

R1

O

O

O

Ph

HOO

R2

O

HHOO

Ph R1

O + H2COOO O

O

Ph OH

R1

R2 MeOH

H2C(OMe)OOH

R1

R2

% yield

a

b

c

H 51

43

13Me Me

Me

H

H

53

5455

Scheme VI

O2, TPP, hv

CH2Cl2, 48h, rt

OOH

OO

OOHOO

OOH

5657

58a 58b

Scheme VII


842

toward the dienes) in 60-100 mL of benzene, the solvent was removed using an evaporator, and the residue was chromatographed using benzene, hexane/ethylacetate (5-2/1), and hexane/methanol/ether (10/1/0.1) as eluants to give the endoperoxides 70a-c (Scheme XI).

Waldemar Adam et al. prepared the diastereomeric hydroperoxy endoperoxides exo-4 and endo-4 and the diastereomeric hydroperoxides trans-5 and cis-5 by the photooxygenation of 1,4-cyclohexadiene50.

Photooxygenation of 1,4-cyclohexadiene 55: A sample of 2.00 g (24.98 mmol) of the 1,4-cyclohexadiene 55 and 30 mg of mesotetraphenylporphinein in 80 mL of chloroform were photolyzed for 24 hr at ‒20°C with a 150-W sodium lamp while a slow stream of oxygen gas was passed through the solution. After removal of the solvent (25°C, 15 hr), the mixture was chromatographed over silica gel (100 g) at ‒20°C by elution with hexanes-Et2O (3:2) to afford 2.82 g of products exo-74, trans-75, and cis-75 and 0.27 g of (1.87 mmol, 7.5%) endo-74. The mixture of exo-74, trans-75, and cis-75 was recrystallized from chloroform-hexane (4:1) to give 110 mg (0.76 mmol,

3%) of the bishydroperoxide trans-75. The filtrate was diluted with hexane and kept in the freezer, and 2.48 g (17.22 mmol, 69%) of exo-74 was crystallized (Scheme XII).

exo-2,3-Dioxabicyclo[2.2.2]oct-7-en-5-ol (exo-77): To a stirred solution of 270 mg (1.87 mmol) of hydroperoxide exo-74 and 2 g of molecular sieves (4 Å) in 10 mL of dichloromethane at 5°C were added 200 mg (2.22 mmol) of Et2S and 26.0 mg (0.09 mmol) of titanium tetraisopropoxide. Five minutes later, the reaction was stopped by the addition of 40 mL of water, and the solids were removed by filtration. After removal of the solvent (ca. 20°C and 15 hr), the mixture was loaded on a short silica gel column (20 g), and elution with Et2O-hexane (4:1) gave 220 mg (1.71 mmol; 92%) of exo-77, which was recrystallized from Et2O-hexane.

endo-2,3-Dioxabicyclo[2.2.2]oct-7-en-5-ol (endo-77): To a stirred solution of 190 mg (1.31 mmol) of hydroperoxide endo-74 and 1 g of molecular sieves (4 Å) in 10 mL of dichloromethane at 5°C were added 142 mg (1.57 mmol) of Et2S and 19.0 mg (0.065 mmol) of titanium tetraisopropoxide. The reaction was

R

R

R O

O

R

R

R

O

O

+1O2

heat

59 60 61

Scheme VIII

ph

O 1) LDA

OHC H

R R

2) ph

O

H

R R

hv, CuSO4MeOH

ROH

Ph R

O2O O

R

R

Meo

ph

62 63 64 65 Scheme IX

1O2

[2 + 2]

[4 + 2]

O O

O

O

66

67

68

Scheme X


843

stopped by the addition of 30 mL of water and 5 min later, the solid material was removed by filtration. After evaporation of the solvent (20°C and 15 hr), the mixture was loaded on a short silica gel column (20 g) and elution with Et2O-hexane(4:1) gave 160 mg

(1.25 mmol, 95%) of solid endo-77, which was recrystallized from Et2O-hexane (Scheme XII).

Gary H. Posner et al. derived five-step preparation of synthetic trioxanes 85 which is outlined in Scheme XIII (Ref 51). Highlights of this streamlined

MeRO O

R MeO2, TPP

hv, Benzene

69 a R= H

69 b R= Me

69 c R= OMe

70 a - c

cis (and trans)

Scheme XI

OH OO

OH1O2

72 73

OO

O

71

O2, TPP, hv

CHCl3

O

O

OOH+ +

exo - 74 (87%) endo - 74 (9%)

OOH

OOH

OOH

OOH

+

trans - 75 (3.5) cis - 75 (0.5%)

PPh3

20o C

Et2S(1.3 eqi)

Ti(Oi - Pr)4 (5 mol%)

CH2Cl2

5o

C, 4Ao MS

Ti(Oi - Pr)4 (5 mol%)

CH2Cl2

5o C, 4A

o MS

Et2S(1.2eqi)

OH

OH

OH

OH

O

m CPBA

(1 equi)

CH2Cl2rt

exo - 77 (96%) endo - 77(96%)trans - 76 trans - 76a (70%)

PCC, CH2Cl2

Ca, 20o C

PCC, CH2Cl2

Ca, 20o

C

Yield 48%

( 52% yield)

O

O

OH

O

O

O

55

78

O

O

OOH

O

O

OH

OOH

1O2

ene

1O2

ene

[ 4+2]exo - 74 endo - 74+

trans - 75 cis - 75+

7980

Scheme XII


844

synthetic route include the following: (1) use of a styrene carbon-carbon double bond as a masked form of a water-solubilizing carboxyl group; (2) use of readily available and inexpensive air instead of expensive cylinders of purified molecular oxygen for IR lamp-induced formation of styryl trioxane 84; (3) optimization of the photooxygenation step after trying diverse silyl triflate and tertiary amines; and (4) final oxidative cleavage of the vinyl group in styryl trioxane 84 to form benzoic acid trioxanes 85 without disturbing the trioxane peroxide linkage that is the crucial anti-malarial pharmacophore. Noteworthy also is the formation of styryl ketone 83 using the corresponding styryllithium organometallic reagent formed in situ via tert-butyllithium reaction with commercial p-bromostyrene, without anionic polymerization of the styrene system52.

Alex G. Griesbeck et al. synthesized 1,2,4-trioxanes from allylic alcohol by photooxygenation53.

During their work on the photoinduced electron-transfer oxygenation of alkenes, they observed the formation of 1,2-dioxanes by trapping of arylated alkenes radical cations with triplet oxygen54. This reaction was also observed with prenol (2-methyl-2-buten-4-ol, 89), when irradiated in acetonitrile in the presence of catalytic amounts of 9,10-dicyanoanthracene (DCA) and oxygen, the 1,2,4-trioxane 90 was formed in low yield. They have recently developed the polystyrene (PS) microcontainer photooxygenation for the ene reaction of 86. In this solvent-free approach, the diastereoselectivity drops remarkably in comparison to the reaction in CCl4 due to the high (protic) substrate concentration. With this efficient source of α-hydroperoxyalcohol 87 in hand, they

investigated the peroxy-acetalization with a series of carbonyl components. Boron trifluoride etherate turned out to be the most efficient Lewis acid catalyst, and the trans-5,6-disubstituted trioxanes 88 were formed in good yield (Scheme XIV).

Takahiro Tokuyasu et al. derived 1,2-dioxolane derivatives via unsaturated peroxy radical, which was produced by the cyclopropylmethyl radical. They investigated the mechanism of the Co (II)-catalyzed peroxidation of alkenes with molecular oxygen and triethylsilane discovered by Isayama and Mukaiyama55,56

and found that the reaction of a vinylcyclopropane 96 provides the 1,2-dioxolane derivative 99 by the intramolecular cyclization of an unsaturated peroxyl radical 98, which is produced by the rapid ring opening of the cyclopropylmethyl radical 97 followed by reaction with O2 (Scheme XV)57.

Rainer Schobert et al. derived stable endoperoxide from 3 alkylidenedihydrofuran-2,4-diones58. A convenient access to pure hemiketal endoperoxide lactones 102 was eventually found in the photooxygenation of 101 with 1.5-2 equiv of oxygen in the presence of catalytic amounts of p-TsOH and CuSO4 (Scheme XVI).

Dannis K. Taylor et al. synthesized a series of epoxy endoperoxide compounds using simple starting materials. According to the generalized Scheme XVII key features include a [4 + 2] cycloaddition of singlet oxygen with the appropriate 1,3-butadiene 103a-n to generate the core of the endoperoxide ring and afford compounds of type 104a-n. Further oxidation with m-CPBA at ambient temperatures furnishes the epoxy endoperoxides 105 and 106 (Ref 59).

Paul M. O’neill et al. synthesized different trioxanes and endoperoxides from substituted allylic

ONC

O

NC NC

OMe

1)

2)

, H+ Li

OMe

O

2) Me3SioTf

3)air,hv, 1)

H

O

OMe

O

OKMnO4

H

O

OMe

OOHOOC

- 90o

C

NH

EtN

36 8182

83

8485

Methylene blue

Scheme XIII


845

alcohols. Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates α-hydroxy-peroxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trio-xanes in good yields. During the course of their work in the synthesis of new anti-malarial endoperoxides, they utilized a thiol-olefin co-oxygenation (TOCO) reaction to generate bicyclic peroxides structurally related to Yingzhaosu A60. In this letter they describe how, by replacement of a terpene with an allylic

alcohol, this methodology can be extended to a new method for the synthesis of functionalized spiro 1,2,4-trioxanes by a simple one-pot procedure. Scheme XVIII illustrates the synthesis of a formyl-substituted trioxane 115 via thiol oxidation using stoichiometric m-CPBA followed by exposure of the sulfoxide 114 to Pummerer conditions61. The resultant carbonyl group in 115 readily undergoes numerous condensation and nucleophilic substitution reactions, imparting a high degree of structural flexibility to a

hv

O2, Sons

R1R2C=O

BF3

R1=R2=Me,Et, C-pent,C-hex,

R1=Me R2=Et, OMe

R1=H, R2=Me, Et, Ph

86 87 88

OH OH

OOH

R1O

OO

H

R2H

OH hv

O2, DCA

33%89

90

O

O O

;

R2C=O

BF3, Et2O

CH2Cl291 92 93

OOH

OH

O O

OR

R O O

O ( )n

R1 CHO

BF3, Et2O

CH2Cl294 95

OOH

OH O

O O

R1

Scheme XIV

Ph

CH

Ph OO

Ph

OO OOSiEt3

Ph

O2

O2

Co(modep)2

O2, Et3SiH, 7h

conv 67%

38%

+OOH

Ph

16%

9697

98

99100

Scheme XV


846

pharmacophore that is of great interest in current medicinal chemistry. For example, Wittig reactions on 115 provide vinyl-substituted trioxane analogues 117 in excellent yields.

Chandan Singh and Heetika Malik reported a photooxygenation route for the 1,2,4-trioxanes synthesis62,63. From the preliminary experiments, it was clear that ketones could be protected as 1,2,4-trioxanes using easily accessible α-hydroxy-hydroperoxides and again regenerated under basic conditions at an ambient temperature. Having achieved this, they examined the stability of 1,2,4-trioxane moiety under conditions of a variety of reactions, an essential requirement of a good protecting group. Towards this end, they studied the chemistry of the carbonyl group of trioxanes 119a and 119b, easily accessible64 by monoprotection of 1,4-cyclohexanedione with α-hydroxyhydroperoxides 118a,b. Trioxane showed promising antimalarial activity against multi-drug-resistant malaria in a mice model65 (Scheme XIX).

Chandan Singh et al. prepared 1,2,4-trioxepanes from homoallylic alcohols via hydroxyl-

hydroperoxides66. They derived homoallylic alcohols from cyclopropyl methyl ketone by employing a two-step reaction process.

Hydroxyhydroperoxides from homoallylic alcohols: A solution of homoallylic alcohol 123a (2.5 g) and methylene blue (75 mg) in acetonitrile (250 mL) was irradiated with a 500 W tungsten-halogen lamp at −10°C, while a slow stream of O2 was bubbled through the reaction mixture. After 3 hr, the reaction mixture was concentrated under vacuum at RT, and the crude product was purified.

Photooxygenation of homoallylic alcohol: Photo-oxygenation of homoallylic alcohol 127, prepared from reduction of ester 126 by LiAlH4, exhibited regioselectivity of a different sort and furnished δ-hydroxyhydroperoxide 128 as the sole isolable product in 67% yield (Scheme XX).

Chandan Singh et al. synthesized adamantine-based trioxanes 132 by the preparation of β-hydroxy-hydroperoxides 131 by photooxygenation of allyl alcohols, and their acid-catalyzed reaction with aldehydes/ketones are the key steps to this method67.

O

OO

R2R1

OR1

R2

OOH

O

OCuSO4, p-ToSOH

2O2, hv, CH2Cl2

R1 R2 %

-(CH2)5 -(CH2)5- 67 a

b -(CH2)4 -(CH2)4- 60

Ph H 53 c

101 102

Scheme XVI

H

HH

H

R2

R1

O2, Rose Bengal

bis(triethyl ammonium salt)

CH2Cl2, 7h

m-CPBA

CH2Cl2, rt

O

O

R1 H

HR2

H

H

O+O

O

R1 H

HR2

H

HO

O

R1 H

HR2

H

H

O

a) R1=R2=cyclohexyl

b) R1=R2=cyclopentyl

c)R1=R2=cyclobutyl

d)R1=cyclohexyl,R2=H

e)R1=cyclopentyl,R2=H

f)R1=1-adamantyl,R2=H

g)R1=CH2-cyclohexyl,R2=H

h)R1=R2=n-propyl

i)R1=n-heptyl,R2=n-propyl

j)R1=R2=phenyl

k)R1=phenyl , R2=cyclohexyl

l)R1=ph, R2=Me

m)R1=CH2-OC(O)-1-adamentyl R2=methyl

n)R1=CH2CH2CH2OH, R2=Me

103 104 105 106

Scheme XVII


847

OHR

AlBN, ArSH, O2, hv

R1R2C=O, TsOH

O O

OR

Ars R1

R2107a R=ph

107b R=Me 108a -b, Ar = ph, P-Cl-ph

R

OH

Sph

R

O

O

1) AlBN, PhSH, O2 ,hv

2) PPh3, CH2Cl2

109 110

OHR1

1)AlBN, ArsH, O2, hv

2) cyclohexanone, TsOH

CH3CN111112

O

O O R3

R2Ars

R1

mCPBA

CH2Cl2

+

TFAA

2, 6, lut

P+(Ph)3 Br

-Ar

NHMDS,THF

Ar=Ph

Ar= p-Cl-Ph

TFAA=Triflluoroacetic anhydride

2, 6, lut 2, 6, lutidine

O O

O

Phs

O-

OO

O

R2

R3R1

Ars

O O

O

O

HO O

O

Ar

113 114

115117

116

Scheme XVIII

O-OH

OH

O

O

+H

+, CH3CN

OR1

R2

R1, R2 = H, OH, OH, CH2CO2Et, H, NHAr, OH, Me, OH, Ph,

OH, CH2CH2OH, H, OCOCH2CH2CO2Me

Tritone B, THF

O

OO

O

O

OOR1

R2

118 119

120

Scheme XIX


848

O

OH

ArCH3 Ar

OH

ArMgX

Anhyd ether

HClO 4.H2O

1,4-Dioxan

0o C

MeCN, 1O2

Methyleneblue

-10o C

R1

R2

O

H+ Ar

OH

OOH

O

O

O R1

R2 Ar

121122 123

124125

R1 R 2

O

O O

O

R1R 2

COOEt OHOH

O-OH

LiAlH 4

Anhyd ether

MeCN, 1O 2

Methylene blue

-10oC 126

127 128

129 Scheme XX

O2, Methylene blue, hv

-10-0o C, Keton/aldehyde

HCl, rt

R1 R2

O , H+ O O

O

R1

R2R4-6 hr

130

131132

OH

R

OOH

R OH

Scheme XXI

Some of these were assessed for anti-malarial activity68 (Scheme XXI).

Agustina La-Venia et al. prepared trioxane from resin-bound p-carboxybenzaldehydes by this typical procedure69: A solution of p-carboxybenzaldehyde (99.1 mg, 0.66 mmol, 3 equiv), DIC (0.10 mL, 0.66 mmol, 3 equiv), and DMAP (cat.) in anhydrous DCM (7 mL) was added to Wang resin (200 mg, 1.1 mmol/g) under nitrogen atmosphere. The mixture was stirred for 18 hr at RT. After filtration, the resulting resin 135b was successively washed with MeOH (3× 3 mL), DMF (3 × 3 mL), and DCM (3 × 3 mL) and dried under high vacuum. A solution of ionone 134a (0.90 mL, 4.4 mmol, 20 equiv) in anhydrous DME (2 mL) was added to resin 133b (0.22 mmol) under nitrogen atmosphere. Then, LiOH (105.4 mg, 4.4 mmol, 20 equiv.) was added with

stirring. The mixture was stirred for 18 hr under nitrogen atmosphere at RT, after which the resin was filtered, washed with AcOH (3×3 mL), H2O (2×3 mL), MeOH (2×3 mL), DMF (3×3 mL), MeOH (3×3 mL), and DCM (3×3 mL), and finally dried under high vacuum. The resin was then re-subjected to the same reaction conditions to ensure the formation of the product 136b. After that, a suspension of the resin 136b (0.22 mmol) in toluene (60 mL) contained in a transparent pyrex vessel was irradiated at λ=354 nm, while a stream of oxygen was passed through this suspension. After 2 hr the resin was filtered, washed with DCM (3 × 3 mL), and dried under high vacuum to give the resin-bound trioxane 138b (Scheme XXII). For the release of trioxanes from the solid support, two general protocols were used: (a) Resin 138b (131.1 mg, 0.10 mmol) was swelled in anhydrous


849

THF/MeOH (4:1) (3.5 mL) at RT for 1 hr. Then a solution of freshly prepared MeONa 0.5 N in anhydrous MeOH (0.20 mL, 0.10 mmol, 1 equiv) was added by syringe and the mixture was kept at RT for 50 min. The resin was filtered into a separating funnel containing a saturated NH4Cl solution and washed with AcOEt (3 × 5 mL) and DCM (1 × 3 mL). After it was dried in vacuo, the resin was subjected once more to the same reaction conditions. The collected phases were separated, and the organic phase was washed with saturated aqueous NH4Cl, brine, and dried over anhydrous Na2SO4. Evaporation of the solvent afforded the crude material, which was purified by column chromatography to give 12 mg of 4-[2-(2,2,6-trimethyl-7, 9, 10-trioxa-tricyclo[6.2.2.01,6]dodec-11-en-8-yl)vinyl]-benzoic acid methyl ester 138b (32% overall yield, based on the initial loading level of the Wang resin) and 1 mg of 4-[3-(2,2,6-trimethyl-7,9,10-trioxa-tricyclo-[6.2.2.01,6] dodec-11-en-8-yl)-oxiranyl]- benzoic acid methylester 137 (2% overall yield, based on the initial loading level of the Wang resin). (b) KCN (30 mg) and Et3N was added as a suspension of the resin 138b (147.0 mg, 0.11 mmol) in THF/EtOH (1:3) (12 mL). The mixture was stirred at 50°C for 26 hr, after this the resin was filtered and washed with MeOH (4 × 5 mL), DCM (4 × 5 mL), and saturated aqueous NaHCO3/H2O (1:1) (1 × 5 mL). The phases were

separated, and the organic phase was washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent afforded the crude material, which was purified by column chromatography to give 14.0 mg of 4-[2 (2,2,6-trimethyl-7,9,10-trioxatricyclo[6.2.2.01,6]-dodec-11-en-8-yl)vinyl]-benzoic acid ethyl ester 138c (31% overall yield, based on the initial loading level of the Wang resin70.

Zhixiong Liang et al. synthesized regioselective compounds 140 and 141 by the photooxidation of tetracenediamide 140 in solution and in crystalline form71 (Scheme XXIII).

Jason R. Harris et al. prepared 1,2-dioxanes from unsaturated tertiary hydro-peroxides using palladium(II) catalyst. Additional screening of reaction conditions with unsaturated hydroperoxide 149 provided a set of standard conditions for peroxycyclization (Scheme XXIV). From these studies, it was clear that employing catalytic Pd(OAc)2 afforded higher conversions and yields when using Pd(OCOCF3)2, [(NHC)Pd-(allyl)Cl]2, Pd(PPh3)2Cl2, Pt(PPh3)2Cl2, or PdCl2. Exchanging NaH2PO4 with pyridine suppressed furan formation, simplifying isolation of the endoperoxide. In contrast to the success with benzoquinone, some oxidants (N-chlorosuccinimide 2,3-dichloro-5,6-dicyanobenzoquinone, K2S2O8, O2, Re2O7, Ag2CO3/O2) gave mostly decomposition products,

.X

O

O

R

O

LiOH

X

R

O

O

X

O

R

O

O

O

KCN,Et3N

ROH/THF

hv,O2

NaOMeTHF/MeOH

R'O

O

R

O

OO

MeO

O

R

O

OO

133a X=NH135a X=NH, R=H

138b R=H

138c R=H, R'=Et

133b X=O135b X=O, R=H

135c X=O, R=OAc

136a X=NH, R=H

136b X=O, R=H

136c X=O, R=OAc

138d R=OH, R'=Me

+MeO

O

R

O

OO

O

137 R=H

134

Scheme XXII


850

while others (HOAc/MnO2, cumene hydroperoxide, Ag2O) provided the desired 1,2-dioxane, albeit in lower yields. When used as an oxidant in 1,4-dioxane, the combination of catalytic benzoquinone and stoichiometric Ag2CO3 (or AgOAc)22 gave comparable yields to the reaction using stoichiometric benzoquinone72.

Virginie Bernat et al. prepared hemeketal endoper-oxides from 2-alkylidene-1,3-cyclohexanediones by green process73 (Scheme XXV).

General procedure for the preparation of endoperoxides

To aldehyde (1 eq.) solubilised in anhydrous dichloromethane is added piperidine (1 eq.) at RT, under argon. Cycloalkanedione (1 eq.) is solubilised in anhydrous dichloromethane and piperidine (1 eq.) is added. After 25 min, the dione solution is slowly poured into the iminium solution. The mixture is shaken for 30 min, and then concentrated. The

Mannich base is obtained as a solid. The mixture is then dissolved in dichloromethane and treated with saturated NH4Cl in 1 M HCl solution. After 30 min, the organic phase is washed with water, then dried over magnesium sulfate, filtered and concentrated. The enone is solubilised in dichloromethane and left exposed to air. Thereafter, the raw mixture is concentrated and purified by silica gel column chromatography (petroleum ether–ethyl acetate). The desired endoperoxides are obtained as white solids.

Armando P. et al. discovered the synthesis of 1,2,4-trioxanes 159, when they attempted to form geminal-dihydroperoxides from unsaturated ketones 158. Treatment of γ,δ-unsaturated ketones with acidic hydrogen peroxide solutions74-77 gave trioxanes 159 and two identifiable decomposition products: peroxide oligomers78 and Baeyer-Villiger oxidation products79. Oligomerization was decreased by slow addition of the γ,δ-unsaturated ketone 158 into the

OH13C6HN

H13C6HN O

OO

OH13C6HN

H13C6HN O

OH13C6HN

H13C6HN O

OO

crystals solution in CHCl 3

hv, air hv, air

139 140141

Scheme XXIII

R 2

R 1

R 3OOH Cat Pd(OAc) 2

cat.pyr oxidantO O R 3

R 2

R 1

142 143

Me

OOH

R

Me O O

Me

+ Me

Me

R

OH

R=CH 2CH2Ph

5 mol% Pd(OAc) 2

20 mol% pyr

ClCH 2CH2Cl

80oC, 3h

31%yield 12%yield

1 equiv BQ

144145 146

OOHMe

R Me

5 mol% Pd(OAc)2

20 mol% pyr

10 mol% BQ

1 equiv Ag2CO3

Dioxane

80oC, 3h

33% yield

147148

OOR

Me

5 mol% Pd(OAc) 2

20 mol% pyr

80oC, 3h

Ag2CO3 or BQR1

R2

OOH

Me

R3 OO

R2

R1R3

149 150

Scheme XXIV


851

reaction mixture (Scheme XXVI). Lowering the reaction temperature reduced the amount of Baeyer-Villiger oxidation observed for a number of substrates80.

Salwa Elkazaz and Paul B. Jones prepared endoperoxide from anthraquinones derivatives under photochemical conditions81-84 (Scheme XXVII).

General procedure for photochemical hydroxylation

A 0.003M solution of the 1-methyl-9,10-anthraquinone derivative in benzene was prepared. Oxygen was bubbled through the solution for 20 min and then while the solution was irradiated at 419 nm. The reaction was followed on TLC until the starting anthraquinone was completely consumed. The solution was concentrated immediately in vacuo in the dark. The crude endoperoxide thus obtained was then reduced using one of the methods listed below.

Emine Salamci prepared endoperoxide from cis, cis-1,3-cyclooctadiene by this method85:

To a stirred solution of cis,cis-1,3-cyclooctadiene 166 (1.00 g, 9.26 mmol) in 230 mL of CCl4 was added 20 mg of tetraphenylporphyrin (TPP) (Scheme XXVIII). The resulting mixture was irradiated with a projection lamp (500 W) while oxygen was

being passed through solution and the mixture was stirred for 3 days at RT. The solvent was rota-evaporated (at 30°C, 20 mmHg), giving an oil, which was purified over a silica gel column (35 g, ether/hexane 40:60) to yield 167 (Scheme XXIX).

Latif Kelebekli et al. synthesized endoperoxide from cyclooctatetraene86. cis-Dichlorobicyclooctadiene 170 was synthesized from cyclooctatetraene 169 by the addition of chlorine following the literature procedure87. Photooxygenation of cis-dichlorobicylo-octadiene 170 with singlet oxygen gave the expected endoperoxide 171 (Ref 88-90) (Scheme XXIX).

Jeff A. Celaje et al. synthesized endoperoxide by cycloaddition reaction91,92. Endoperoxide 173 accounts for nearly 60% of the products from the reaction of 172 with singlet oxygen. In addition to the three products mentioned above, a very small amount (<5%) of an unidentified compound that is a secondary photoproduct was also formed upon prolonged irradiation of product 173 (Scheme XXX). It was reported that trans-resveratrol reacts with singlet oxygen via two entirely different pathways, both of which involve the trans-double bond, namely [2 + 2] addition and [4 +2] addition.

R1

O

H

R2

+NH

CH2Cl2R1

R2 N+

H

OH-

O

O

O

C5H11N, CH2Cl2

NH4Cl, HCl

CH2Cl2O2

O

O

OH

H

N

O

R1 R2

O

O

R1

N

R2

O

O

R1

R2

O O

O

R1

OH

R2

O

OO

O

R1

R2

OHO

O

151152

155a

155b

156a156b157

153

154

Scheme XXV

R1

Me

R2

O

H2O2, CF3CO2H

H2SO4, CH2Cl2

0o C

25-95% yield

O

O

H

R1

O

C

Me

R2

158159

Scheme XXVI


852

Nicole M. et al. prepared endoperoxide from 1,3-cyclohexadiene93 (Scheme XXXI). General procedure for the preparation of

endoperoxide To a solution of the requisite 1,3-cyclohexadiene

176 in dichloromethane (30 mL/g of 1,3-diene), in a custom-made pyrex flask fitted with a cooling jacket,

was added Rose Bengal, bis(triethylammonium) salt (100 mg). Ice water was pumped throughout the cooling jacket to maintain a temperature of ca 5-10°C within the reaction mixture at all times. Oxygen was bubbled through the solution, and the contents irradiated with 3 × 500 W tungsten halogen lamps until complete via TLC (1−8 hr). The mixture was

O

O

OO

O

OHhv

O2

160 161

O

O

R1

R2

OO

OR1

R2

OHhv ( 419 )

PhH, O2

R1=R2=H

R1=CH3 R2=H

R1=H R2=CH3

162163

O

OR2

OR1

O

OO

OOR2

OR1

OHhv ( 419 )

PhH, O2

R1=H, R2=CH3

R1=R2=H

R1=R2=C(O)C2H5

NaH,C2H5COCl

THF(45%)

164 165

Scheme XXVII

O

O

O2, TPP, hv

CCl4, 3 days, rt

166 167

Scheme XXVIII

Cl

Cl

Cl2

CCl4, 50 oC

1O2, TPP, hv

CH2Cl2, rt

Cl

Cl

OO

169 170 171

Scheme XXIX


853

then concentrated in vacuo and the residue purified by flash chromatography.

Bigyan Sharma et al. synthesized endoperoxide by irradiation of 4,5,6,8,12,13,15,16-octamethyl[2.2]MPCP 178 (MPCP = metaparacyclophane) in acetone, using a high pressure mercury lamp for 6 hr which led to photooxygenation to produce only the bis-endoperoxide179 (Ref 94) (Scheme XXXII).

Griesbeck and his co-workers have reported a one-pot [4+2] cycloaddition reaction for synthesis of 1,2-dioxane derivative (180) using E,E or E,Z α-methylated substrates in excellent yield by vinylogous gem effect. The product is obtained as diastereoisomeric mixture (Scheme XXXIII) (Ref 95).

Quinn et al. introduced the Swern oxidation of (E)-hex-4-en-1-ol followed by Wittig reaction with benzyl triphenylphosphoranylidene acetate in a one-pot procedure to get the desired product (2E,6E)-benzyl octa-2,6-dienoate in good yield and in presence of the singlet oxygen, the ene reaction was achieved by photo oxidation using two 300 W flood lamps in CDCl3 for 6 hr with a catalytic amount of tetraphenylporphine as sensitizer (Scheme XXXIV) (Ref 96)

Maimone and collogues have acquainted a novel method to synthesis endoperoxide derivative (181) using various metal pre-catalyst hydride in the presence of oxygen of air which was followed by treatment of tripheylphosphene (Scheme XXXV) (Ref 97)

OH

OH

OH

O2, Methylene blue,

CD3CN,

OO

OH

OH

OH

tautomerization

OO

OH

OH

O

O2, Methylene blue,

CD3CN,

[ 4 2 ] cycloaddition

[ 2 2 ]

cycloaddition

only endoperoxide observed

+

+

172173

174

175

O O

OH

OH

OH

hv, rt

hv, rt

Scheme XXX

R R1

R R1O

O

O2, DCM, hv

rose bengal

176 177

Scheme XXXI

Me

Me Me

MeMe Me

Me Me

Me

Me Me

Me

OO

Me Me

Me Me

OO

Irradiation with

high pressure

Hg lamp

in acetone room temp.for 6 h

178 179

Scheme XXXII


854

Scheme XXXIII

OH

Swern oxidation

Ph3PCHCOOBn

O

OBn

O2, PPh3300W

6h

O

OBn

O

OBn

O

O

OH

OH

Et2NH

CF3CH2OHOO OBn

O(CH3)3SnOH

OO

O

OH

Scheme XXXIV

Scheme XXXV

Scheme XXXVI

Scheme XXXVII


855

Inokuchi et al. reported a novel series of 1,2,4-trioxanes from 2,3,5-trioxabicyclo[2.2.2]oct-7-ene-8-carboxylate (182) by utilizing Rose Bengal in the presence of oxygen under photochemical radiation in methanol at 0°C for 1 hr (Scheme XXXVI) (Ref 98).

Baran and co-workers have introduced a novel photochemical method for bis-endoperoxides by utilizing oxygen from air. The method include diene as a precursor in the presence of triphenylphosphene at 0°C to afford endoperoxide in 25 min, with the extension of time the product is converted to bis-endoperoxide (Scheme XXXVII) (Ref 99).

Acknowledgements

The authors are thankful to the Department of Chemistry, Gujarat University, Ahmedabad, India for providing the necessary facilities and also thankful to UGC-Infonet and INFLIBNET Gujarat University for providing e-resource facilities. The authors are thankful to Rajesh H. Vekariya and Kinjal D. Patel for manuscript editing.

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