An efficient synthesis of bridged-bicyclic peroxides structurally related to antimalarial yingzhaosu A based on radical co-oxygenation of thiols and monoterpenes

TETRAHEDRON

Pergamon

Tetrahedron 58 72002) 2449±2469

An ef®cient synthesis of bridged-bicyclic peroxides structurally

related to antimalarial yingzhaosu A based on radical

co-oxygenation of thiols and monoterpenes

Edward E. Korshin,^aRoland Hoos,^aAlex M. Szpilman,^aLeonid Konstantinovski,^a

Gary H. Posner^band Mario D. Bachi^a,p

^aDepartment of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel

^bDepartment of Chemistry, Schoolof Arts and Sciences, The Johns Hopkins University, Batlimore, MD 21218, USA

Received 24 October 2001; revised 2 January 2002; accepted 31 January 2002

AbstractÐSynthesis of b-sulfenyl endoperoxides 9 was achieved by a four component sequential free radical reaction based on the

application of the thiol-ole®n-co-oxygenation reaction to monoterpenes, followed by in situ treatment with triphenylphosphine. b-Sulfenyl

endoperoxides 9 were oxidized with m-CPBA to b-sulfonyl endoperoxides 10. This process provides an ef®cient method for the preparation

of peroxides containing the 2,3-dioxabicyclo[3.3.1]nonane system 72) characteristic of antimalarial agents of the yingzhaosu A 73) family. A

1. Introduction

evaluation of yingzhaosu A 73) as an antimalarial agent

were ever reported, the role of the 2,3-dioxabicyclo[3.3.1]-

nonane system 2 as a pharmacophore was established

through the synthesis and antimalarial screening of

synthetic peroxides of type 4. Compounds of type 4

7RAr, Het or long chain alkyl) were found to exhibit

high antimalarial activity,⁷and arte¯ene 74a) proved to be

a reasonable drug candidate.^1,3e,7,8It seems that one of the

factors that may have halted the further development of

natural yingzhaosu A 73) and synthetic endoperoxides 4 as

antimalarial drug candidates derived from the scant supply

of 3 from natural sources and the low-yielding syntheses of

3 and 4. Recently, syntheses of acetal-peroxides of types 5⁹

and 6¹⁰based on the construction of the endoperoxide

system 2 by a heterolytic cyclization involving the inter-

mediacy of transient carbonyl-oxide and hydroperoxide

derivatives were reported.

A promising approach for the treatment of malaria caused

by Plasmodia resistant to customary drugs like the quinoline

derivatives, chloroquine and me¯oquine, involves the use of

peroxides.^1,2Indeed, naturally occurring artemisinin

7qinghaosu) and semisynthetic derivatives thereof have

been used, on a limited scale, for treating malaria.³The

development of this ®rst generation of antimalarial peroxide

drugs was followed by a world-wide intensive quest for

better antimalarial peroxides. Major efforts were directed

towards the development of new compounds that, like

artemisinin, contain a trioxane system 1 as a pharmaco-

phore.^1,4Among other investigated cyclic peroxides, par-

ticular attention was given to compounds containing, as

putative pharmacophore, the 2,3-dioxabicyclo[3.3.1]nonane

system 2. The 2,3-dioxabicyclo[3.3.1]nonane system 2 was

®rst identi®ed in yingzhaosu A 73) isolated from an extract

of Artabotrys Uncinatums that was used in Chinese folk

medicine for treating malaria.⁵Yingzhaosu A was subse-

quently obtained by a low yield 15-step total synthesis.⁶In

this synthesis the bicyclic peroxide system is formed on the

sixth step through an intramolecular Michael addition of an

hydroperoxide group to a carbonyl-conjugated carbon±

carbon double bond.⁶A similar synthetic strategy was

applied for the synthesis of more readily accessible endo-

peroxides of type 4.⁷While no suf®cient data required for

Keywords: antimalarial peroxides; free radicals; multi-component reaction;

sequential reactions; thiol ole®n co-oxygenation reaction.

p

Corresponding author. Tel.: 1972-8-934-2043; fax: 1972-8-934-4142;

e-mail: mario.bachi@weizmann.ac.il

PII: S0040-4020702)00126-6

2450

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

In the mid 1990's we initiated a research project directed

towards the design, synthesis, and antimalarial screening of

new endoperoxides 7, 8 containing the 2,3-dioxabicyclo-

[3.3.1]nonane system 2.^11,12This was followed by the

elaboration of a new total synthesis of yingzhaosu A 73).¹³

We now present a full account on the synthesis and structure

determination of b-sulfenyl- and b-sulfonyl-endoperoxides

9 and 10, which served as precursors in the synthesis of

potent antimalarial agents.^12,14,15Additionally, we showed

that 4-sulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonanes 9⁰⁰

7n0, RPh, R¹R²H) can function as a key intermediate

in a total synthesis of yingzhaosu A 73).¹³

Scheme 1.

18, phenylthiol and two equivalents of molecular oxygen.

A straightforward approach to the synthesis of 2,3-dioxa-

bicyclo[3.3.1]nonane 20a,b would thus require a one

operation process by which these four components would

interact through a sequential free-radical reaction following

the pattern described in Scheme 3. This would require that

PhSÇ, obtained in the initiation step from PhSH and the radi-

cal initiator 7InÇ), would add regioselectively to the terminal

end of the isopropenyl double bond of limonene 18. The

emerging carbon centered radicals 21 should be rapidly

trapped by molecular oxygen to give peroxy-radicals 22,

which should undergo a 6-exo intramolecular addition to

endocyclic double bond generating tertiary carbon-centered

radicals 23. Radicals 23 should be trapped by a second

equivalent of oxygen, thus giving peroxy radicals 24. In

turn, peroxy-radicals 24 should abstract a hydrogen atom

2. Synthesis design

Enantiomeric 2,3-dioxabicyclo[3.3.1]nonanes of type 7 and

8 were de®ned as synthetic targets in which X, Y, Z and W

represent a hydrogen atom, or functional groups that can be

modi®ed as deemed necessary from structure±activity

studies. Following the development of reactions based on

thiol-mediated free radical cyclizations, useful for the

synthesis of nitrogen-containing heterocycles,¹⁶we

examined the application of a similar strategy to the

synthesis of the dioxygen-containing heterocycles of type

7 and 8.^11,12Additional support for using a methodology

based on free radical reactions came from two directions:

71) studies by Porter on the synthesis of monocyclic

peroxides by a method involving a 6-exo intramolecular

addition of peroxyradicals to carbon±carbon double

bonds;¹⁷72) studies by Beckwith on the application of

Thiol Ole®n Co-Oxygenation 7TOCO reaction) to 1,4-

dienes for the synthesis of 1,2-dioxolanes like 16, 17

7Scheme 1).^19,20

As exempli®ed in Scheme 1, monocyclic peroxides like 16

were obtained through a highly favored 5-exo-trig addition

of a peroxy radical intermediate 13. Application of the

TOCO reaction to the synthesis of bridged bicyclic

peroxides of type 7 and 8 posed a few questions that

required careful consideration. Scheme 2 represents a retro-

synthesis of the prototypic b-phenylsulfenyl-endoperoxides

20a,b which leads to endoperoxide±hydroperoxide 19a,b

and then, through homolytic bond cleavage to limonene

Scheme 2.

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2451

Scheme 3.

from PhSH, giving the target bicyclic hydroperoxides 19a,b

and PhSÇthat continues the chain reaction. In this sequential

process every step, except the last one, is reversible. The

viability of such a process depends on a particular series of

rate constants.^21±26A major concern during the planning

stage derived from the notion that 6-exo addition of peroxy

radical 22 requires an axial conformation as in 22ax. The

predominance of the equatorial conformation 22eq could

result in an excessive reduction in the rate of cyclization

of 22, e.g. in comparison to the 5-exo-cyclization of 13 to

the corresponding dioxolanyl-radicals 14 7Scheme 1).

Under such circumstances radical 22 7Scheme 3)

could take undesired reaction paths resulting from intra-

molecular hydrogen atom abstraction from allylic

positions, and premature intermolecular hydrogen atom

abstraction from phenylthiol leading to monocyclic hydro-

peroxide 25.

radical reaction of limonene 18, a thiol and two equivalents

of molecular oxygen are described in Scheme 4 7see also

Scheme 5). In this scheme the major reaction products,

which were obtained in all the studied reactions, are

separated from the minor reaction products that were

deliberately sought, isolated and characterized only in a

few experiments with limonene 18 and phenylthiol. Due

to the instability of the hydroperoxide function in

compounds 19⁰, 27⁰±32⁰and 25⁰the crude reaction mixture

was treated, in the same vessel, with PPh₃to give a mixture

of the bicyclic 8-hydroxy-endoperoxides 20⁰, 33⁰±38⁰and

monocyclic b-hydroxysul®des of type 26⁰. Trapping of the

carbon-centered radical 21 by molecular oxygen 7Scheme 3)

was found to be non-diastereoselective. Indeed, diastereo-

meric mixtures of endoperoxides 20⁰a, 33⁰a±38⁰a and 20⁰b,

33⁰b±38⁰b were isolated and characterized as the two major

peroxides 7Scheme 4). The ratios of the isomers a/b in most

experiments and in all the high-yielding experiments

7.40%) described in Table 1 and detailed in Section 6,

are 55:45 7^3%). A slightly higher, though still insigni®-

cant diastereoselectivity was observed in some of the low-

yielding experiments. In contrast trapping of the carbon-

centered radical 23 7Scheme 3) is highly diastereoselective.

Molecular oxygen adds preferentially from the less hindered

side of radical 23 to form the axially-oriented peroxy-

radical 24, and after subsequent reduction the major

hydroxy peroxides 20⁰a, 33⁰a±38⁰a and 20⁰b, 33⁰b±38⁰b

7Scheme 4). In some large-scale experiments with limonene

and PhSH, a few percent of equatorially positioned hydroxy

peroxides 20c and 20d were isolated and characterized by

derivatization as shown in Scheme 6. Since preliminary

screening indicated that b-sulfonyl-endoperoxides 39⁰are

much better antimalarial agents than the corresponding

b-sulfenyl-endoperoxides 20⁰,^12,14and since they are also

more amenable to chromatographic separation into indi-

vidual diastereomers of types a and b, diastereomeric

mixtures of sul®des 20⁰, 33⁰±38⁰were usually oxidized to

the corresponding sulfones 39⁰±44⁰and then separated into

individual diastereomers 7Scheme 4). Exceptions are the

b-sulfenyl-endoperoxides 35⁰a,b; 38⁰a,b which were sepa-

rated to their individual two diastereomers 35⁰a, 38⁰a and

35⁰b, 38⁰b, respectively.

3. Synthesis of 4-sulfenylmethyl- and 4-sulfonylmethyl-

2,3-dioxabicyclo[3.3.1]nonan-8-ols 9 and 10

Due to the interest in the antimalarial properties of

target compounds 9 and 10,^12,14,15some of the experiments

described in this paper were performed with R-71)-

limonene 718⁰), some with S-72)-limonene 718⁰⁰), and

some individually with both of them. To avoid unnecessary

repetitions, where discussions are accompanied by

3-dimensional formulas as in Schemes 2 and 3, the

structures of S-72)-limonene 18⁰⁰and reaction products

of it are drawn. Numbering of compounds originating

from, or relating, to both S-72)- and R-71)-limonene

718) are denoted mn, while compounds originating

from experiments in which only R-71)-limonene 718⁰)

was used are denoted mn⁰and those from experiments

in which only S-72)-limonene 718⁰⁰) was used are

denoted mn⁰⁰.

Following the synthetic plan shown in Scheme 3, the thiol±

limonene co-oxygenation was studied under a variety of

conditions and with a number of different thiols. The

products of the designed four-component sequential free

2452

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

Scheme 4.

The data related to the optimization of the TOCO reaction

when applied to the co-oxygenation of limonene 18 and

phenylthiol are summarized in Table 1 along with a few

examples of co-oxygenation involving other representative

thiols. The feasibility of the reaction described in Scheme 4

was ®rst examined with PhSH, under conditions 7method

1A) similar to those reported^19a7Scheme 1) for the prepara-

tion of 1,2-dioxolane 17 from 1,4-diene 11. Thus, limonene

18⁰, PhSH 7equimolar amount) and free radical initiator [di-

tert-butylperoxalate 7DBPO),²⁷catalytic amount] were

dissolved in benzene, and oxygen gas was bubbled through

the solution for 15 h. After ¯ushing with argon to remove

excess oxygen, the resulting endoperoxide±hydroperoxide

19⁰a,b 7RPh) was chemoselectively reduced with PPh₃to

give hydroxy-endoperoxides 20⁰a,b 714%) as a mixture of

two diastereomers 7a/b, 55:45), PhS±SPh 725%) and

hydroxysul®de 26⁰732%). These results 7Scheme 4 and

Table 1, entry 1; see also Scheme 3) indicated that: 7a)

PhSÇdimerization competes with PhSÇaddition to limonene;

7b) intermolecular hydrogen atom transfer from PhSH to

peroxyradical 22 to give hydroperoxy-sul®de 25 7and,

after PPh₃reduction, hydroxy-sul®de 26) competes with

the intramolecular 6-exo-addition of peroxy radical 22 to

the trisubstituted endocyclic CvC bond. The ®rst problem

was handled by increasing the limonene/thiol ratio. Indeed,

at a 3:1 ratio 7Table 1, entry 2) the yield of endoperoxide

Scheme 5.

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

Table 1. Co-oxygenation of limonene 18 and thiols 7Schemes 4 and 5).

2453

Entry

Procedure^a

Scheme

RSH

Ratio of

limonene/thiol

T 78C)

Initiator

7mol %)^b

Solvent^c

Reaction

time 7h)^d

Product

Yield 7%)

1

2

3

4

1A

1B

1C

1D

1E

4

4, 5

4

4, 5

5

4

5

4, 5

4

5

4

PhSH

4-FC₆H₄SH

PhSH

n-BuSH

MeO₂CCH₂SH

Cyclo-HexSH

tr-BuSH

TrSH

1:1

3:1

1:1

3:1

1:1

3:1

rt

65

40

rt

4

210

4

DBPO 75)

DBPO 73)

AIBN 7313)

AIBN 73)

AIBN 7313)

AIBN 7616)

AIBN 7414)

AIBN 7616)

AIBN 73115)

AIBN 7313)

AIBN 7616)

AIBN 7313)

AIBN 7616)

Benzene

HP±BN

MeCN

MeOH

MeCN

15

12

10110

10

10110

10

18

36

12

30

18

25

48

20⁰a,b

20a,b

20⁰a,b

33⁰a,b

20a,b

20⁰⁰a,b

20⁰a,b

20⁰₀a,b

20 a,b

20⁰⁰a,b

20a,b

14

29

31

55

54

26

47

18

47

16

7

50

42

52

49

31

48

34

44

34

18

25

18

16

29

41

5

6^e

7

8

9^e

10

11

12^e

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

20a,b

20⁰a,b

20⁰₀a,b

20 a,b

20⁰⁰a,b

20⁰a,b

34⁰a,b

35⁰a,b

36⁰a,b

37⁰a,b

38⁰a,b

4

30

a

Procedures are recorded in the text and detailed in Section 6.

b

DBPO is an abbreviation for di-tert-butylperoxalate. The ®rst value in brackets refers to the portion of initiator initially placed into the reaction mixture; the

second value refers to the portion of initiator, which was slowly added simultaneously with the thiol.

HP±BN refers to a mixture of n-heptane±benzene 7ca. 2.5:1).

The ®rst value refers to the time of the thiol addition, the second value refers to additional exposure to oxygen.

Air was used instead of oxygen.

c

d

e

20⁰a,b was doubled while the yield of PhS±SPh was

reduced to 10%. A corollary to increasing the rate of

generation of radicals 21 and consequently 22, is the

increase in the yield of formation of hydroperoxide 25⁰,

and consequently of hydroxy-sul®de 26⁰746%). To

decrease the rate of hydroxy-sul®de 26⁰formation, the

concentration of PhSH should be decreased throughout the

duration of the reaction. Indeed, by adding PhSH to the

reaction mixture through a syringe pump over 10 h 7method

1B) the yield of hydroxy-endoperoxide 20 was doubled

7compare entries 1 and 3, Table 1). When the two modi-

®cations which are described in entries 2 and 3, were

employed at once, the yield of the endoperoxide 20 was

augmented to 55% 7entries 4 and 5, method B). No

difference was observed between reactions that were

terminated immediately after completion of thiol addition

and those in which oxygen was bubbled through the reaction

mixture for an additional 10 h 7compare entries 4 and 5).

Substitution of pure oxygen by air resulted in a signi®cant

yield diminution 7compare entries 4±6, and 8±9). Usually,

experiments were directed towards the preparation of

endoperoxides like 20a,b, while by-products were not

examined. However, when the overall mass balance was

examined 7Table 1, entry 5) the following compounds

were accounted for: 7i) excess of limonene 18 772%); 7ii)

b-phenylsulfenyl-endoperoxides 20a±d 7ca. 57%, a/b/c/d,

ca. 52:42:3:3)²⁸; 7iii) hydroxy-endoperoxides 26 725%);

and 7iv) PhS±SPh 710%), thus accounting for a mass

balance of 90% of sulfur-containing products. Fluoro-

phenylsulphenyl-endoperoxides 33⁰a,b were obtained in

similar yield 7entry 7) using 4-¯uorothiophenol instead of

thiophenol.

Procedure 1B, under the conditions speci®ed in entry 5, was

found to be highly reproducible and was used in our labora-

tory for the preparation of endoperoxides 20a,b on 2±4 g

scale. 7See Ref. 29 for SAFETY PRECAUTIONS). In order

to minimize the generation of hazardous mixtures of oxygen

and organic solvents vapors, and in order to allow testing

reactions in a wider range of temperature, the procedure of

bubbling oxygen through the reaction mixture 7methods 1A

and 1B) was substituted by vigorous stirring of the reaction

mixtures under a measured volume of pure oxygen

7methods 1C±1E). An additional advantage of this modi-

®cation is the possibility of monitoring oxygen consump-

tion. Applying method 1C did not result in a signi®cant

decrease in yield 7compare entries 5 and 8). Also, for safety

reasons, the hazardous DBPO initiator was substituted by

AIBN and the heptane±benzene solvent was substituted by

acetonitrile. In these experiments one portion of AIBN

initiator was added at the start of the reaction and a second

portion was introduced through a syringe pump simul-

taneously with the thiol. Following this procedure 7method

1D) endoperoxides 20⁰a,b were obtained in a good yield at

658C 7entry 10) and in a modest yield at 408C 7entry 11),

substitution of oxygen by air reduced the yield even further

7entry 12). To allow an effective use of AIBN at moderate

temperatures the reaction mixture was irradiated 7l310±

400 nm; l_max365 nm; Pyrex glassware) 7method 1E).

Indeed at 408C 7entry 13), at room temperature 7entries 14

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E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

and 15), as well as at 48C 7entry 16) endoperoxides 20a,b

were obtained in good yields. Further decrease of

reaction temperature 7entry 21), increase in amount of

initiator 7entry 18), prolongation of reaction time 7entry

20), and using methanol as a solvent 7entry 17) were

counterproductive.

the corresponding individual sulfones 39⁰a±44⁰a and

39⁰b±44⁰b 7Scheme 4), 39⁰⁰a, 52⁰⁰a±55⁰⁰a and 39⁰⁰b,

52⁰⁰b±54⁰⁰b 7Scheme 5).³¹Sterically hindered tritylsul®des

38⁰couldn't be oxidized under these conditions.

For structural determination 7next section) and for pre-

liminary biological screening^12,14,15a mixture of diastereo-

meric 8-hydroxy-b-phenylsulfenyl-endoperoxides 20⁰⁰a±d

was converted into 8-acetoxy-b-sulfonylendoperoxides

58⁰⁰a±d 7Scheme 6). Our best procedure involves O-silyla-

tion of hydroxyl function in 20⁰⁰a±d to give the TMS-

derivatives 56⁰⁰a±d, followed by acetylation with neat

AcCl to the corresponding 8-acetoxy-b-phenylsulfenyl-

endoperoxides 57⁰⁰a±d.³²The resulting crude mixture of

b-phenylsulfenyl-endoperoxides 57⁰⁰a±d was oxidized

with m-CPBA to yield, after repeated chromatography, the

four individual diastereomeric 8-acetoxy-b-phenylsulfonyl-

endoperoxides 58⁰⁰a 747% from 20⁰⁰a±d), 58⁰⁰b 740%), 58⁰⁰c

7ca. 1.5%), and 58⁰⁰d 7ca. 2.5%). The major isomers 58a and

58b were also prepared from the single hydroxysulfones

39a and 39b respectively.^12,15

Due to safety considerations²⁹we recommend the use of

method 1E, at 48C, 7entry 16) for the synthesis of b-phenyl-

sulfenyl-endoperoxides 20a,b, although method 1B 7entry

5) affords the same products in slightly higher yield.

Procedure 1E was repeatedly used for the preparation of

endoperoxides 20a,b in up to 5 g scale.

Co-oxygenation of R-71)-limonene 718⁰) with aliphatic

thiols, namely n-butylthiol, methylthioglycolate, cyclo-

hexylthiol, tert-butylthiol,and tritylthiol afforded the corre-

sponding b-sulfenyl-endoperoxides 34⁰±38⁰7Table 1,

entries 22±27).³⁰The tested primary and secondary

alkylthiols were found to be considerably less effective

than thiophenol 7entries 22±25). A modest increase in

yield was observed for tert-butylthiol 7entry 26), and a

considerable improvement for the bulky tritylthiol 7entry

27). An improvement in the yields of the target endo-

peroxide in the TOCO reactions with aliphatic thiols was

obtained by a prolonging the thiol addition time and by

increasing the amount of AIBN 7compare the entries 22

and 23). These factors partially compensate for the

decreased reactivity of aliphatic thiyl radicals and the

lower hydrogen donation ability of alkylthiols as compared

to phenylthiol.

Pure endoperoxides of type 10 are highly stable. For

example, no change was observed in the NMR spectra of

the samples 39⁰⁰a 7crystals) and 39⁰⁰b 7oil) that were kept for

four years at room temperature.

4. Structure determination

In the thiol±terpene co-oxygenation reaction, described in

the previous section, the three new stereogenic centers at

C71), C74) and C78) are generated in a single operation. The

fourth, stereocenter at C75), originating from the unaltered

stereocenter at C74) of the parent monoterpenes 18, 45±47,

was used as a reference for the determination of the absolute

con®guration of all the other stereocenters.

In Scheme 5 the co-oxygenation 7procedure 1B) of

phenylthiol with S-72)-limonene 718⁰⁰) is compared to that

of O-benzoylcarveols 45⁰⁰, 46⁰⁰and cis-carveol 747⁰⁰). It was

found that the reaction yields signi®cantly decrease with the

introduction of substituents at position 7. An atypical high

diastereoselectivity at C74) was observed in the TOCO

reaction with carveol 47⁰⁰which afforded exclusively isomer

51⁰⁰a.

Single crystal X-ray analysis of 4,8-dimethyl-4-phenyl-

39⁰⁰a

sulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

provided the 3D-structure shown in Fig. 1. The absolute

con®guration of stereocenters 1S, 4S, and 5S in the bicyclic

system is the same as that reported for the corresponding

stereocenters in yingzhaosu A 73).^6aAlso, the methyl710)

Each mixture of diastereomeric sul®des 20⁰a,b; 33⁰a,b±

37⁰a,b; 20⁰⁰a,b and 48⁰⁰a,b±51⁰⁰a was oxidized with

m-CPBA at rt to give, after chromatographic separation,

Scheme 6. Reagents and conditions: 7a) 7i) O₂, DBPO, heptane±benzene 7general procedure 1B); 7ii) Ph₃P; 7b) TMSOTf, 2-6-lutidine, CH₂Cl₂, 08C, 1 h;

7c) AcCl 7neat), rt, 48 h; 7d) 7i) m-CPBA, EtOAc, rt, 6 h; 7ii) FC and HPLC separation.

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2455

Figure 1. The X-ray crystal structure of the bicyclic endoperoxide 39⁰⁰a 7ORTEP).⁴³

group on the 8S-carbon is equatorially positioned as the

analogous methyl group in 3.^6aBoth of the 1,2-dioxane

and the cyclohexane rings adopt chair conformations, form-

ing a low energy 2,3-dioxabicyclo[3.3.1]nonane system. A

chair conformation of the endoperoxide ring has been

previously reported for other 2,3-dioxabicyclo[3.3.1]nonane

systems^6a,9as well as for monocyclic 1,2-dioxanes.³³In

contrast to that, the 1,2-dioxane fragment in the peroxide±

acetals of type 6 adopts a boat-like conformation.^10a

difference in through space distances between the dia-

stereotopic C712)HH⁰protons and the electronegative

O72)-atom is bound to be re¯ected in the H NMR spectra.

1

The additional deshielding effect of O72)-atom should be

stronger on the H⁰712)-proton than on its geminal H712)-

proton. In contrast, due to the anti-arrangement between

O72) and C712)HH⁰in diastereomeric b-sulfonyl-endo-

peroxide 39b both protons of the C712)HH⁰group are

more remote through space from O72) than in diastereomer

39a and therefore should be less deshielded. Accordingly, in

isomer 39b, that has a syn-arrangement of the O72) and

Me711), the protons of the Me711) group are closer to the

O72)-atom than Me711)-protons in the isomer 39a. Conse-

quently, the effect of additional deshielding by O72)-atom

on Me711) group should be inverted between the isomers

39a and 39b. The viability of this analysis was corroborated,

as described below by NMR studies on b-sulfonyl-endo-

peroxides 39±44 and 52±55 as well as b-sulfenyl-endo-

peroxides 20, 33±38, and 48±51, thus providing a simple

NMR method for differentiation between diastereomers of

series a and b.

Since no simple method for the determination of con®gura-

tion at the quaternary C74) and C78)-stereocenters of 2,3-

dioxabicyclo[3.3.1]nonanes has been reported, a thorough

NMR study on the new 4,8-dimethyl-4-phenylsulfonyl-

methyl-2,3-dioxabicyclo[3.3.1]nonane derivatives was

performed, and is detailed herein. b-Sulfonyl-endo-

peroxides 39a as well as other diastereomers of series a

are characterized by a syn-arrangement of the O72)±O73)±

C74)±C712) bonds, while b-sulfonyl-endoperoxides 39b as

well as the other diastereomers of series b are characterized

b y ananti-arrangement of the O72)±O73)±C74)±C712)

bonds. Analysis of the X-ray data of b-sulfonyl-endo-

peroxides 39⁰⁰a revealed a signi®cant difference in the

through space distances between the nonequivalent

hydrogen atoms of the C712)HH⁰moiety and the oxygen

atoms. For the C712)H-proton the calculated through

A detailed analysis of the ¹H and ¹³C/DEPT NMR spectra of

all the b-sulfonyl-endoperoxides 39±44, 52±55, 58 and

b-sulfenyl-endoperoxides 20, 33±38 and 48±51, supported

by the COSY, HMQC and NOE difference experiments for

the key compounds 20, 35, 38, 39, 51±55 and 58 enabled a

full assignment of the resonance signals 7see Section 5).

Ê

space distances are 3.175 A for H712)±O72) and 2.528 A

for H712)±O73), while for the C712)H⁰-proton the corre-

sponding distances are shorter and almost identical, namely

1

Representative signals in the H and ¹³C spectra required

0

Ê

2.431 A for H 712)±O72) and 2.491 A for H 712)±O73). The

for structural discrimination between diastereomers a and

b are given in Table 2 for the b-sulfenyl-endoperoxides

20a,b and b-sulfonyl-endoperoxides 39a,b. Diastereomers

a and b exhibit very similar NMR patterns for stereocenter

C78) and adjacent atoms. In contrast, the NMR patterns

related to atoms adjacent to the stereocenter C74) are signi®-

cantly different for the a and b diastereomers. Therefore,

diastereomers a and b differ in their con®guration at C74),

but not at C78). Thus, a typical AB quartet attributed to

1

the C712)HH⁰group appears in the H NMR spectra of

2456

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

1

Table 2. Selected H 7400 MHz) and ¹³C 7100 MHz) NMR data for 4-phenylsulfenylmethyl- 20a,b and 4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabi-

cyclo[3.3.1]nonan-8-ols 39a,b in CDCl₃

Position

20a

20b

39a

39b

¹H

¹³C

¹H

¹³C

¹H

¹³C

¹H

¹³C

1

4

5

10

11

12

3.68 m

81.57 d

83.77 s

29.23 d

28.04 q

21.89 q

40.68 t

3.71 m

82.02 d

83.83 s

30.50 d

28.04 q

21.76 q

40.73 t

3.67 br dd 73.5, 2.5)

81.96 d

82.71 s

30.05 d

27.97 q

22.87 q

61.02 t

3.68 br dd 73.3, 1.8)

82.35 d

82.84 s

31.53 d

27.83 q

21.71 q

60.55 t

1.91 br dddd

1.40 s

1.25 br s

3.35 d 712.8)

3.71 dd 712.8, 0.5)

1.81 m

1.39 s

1.56 d 70.6)

2.96 d 712.0)

3.03 dd 712.0, 0.6)

2.30 m

1.35 s

1.51 br s

3.27 d 714.3)

4.23 dd 714.3, 0.5)

2.09 br dddd

1.29 s

1.80 br s

3.14 d 714.0)

3.33 br d 714.0)

Chemical shifts 7ppm), multiplicity of the signal and coupling constants 7Hz) are recorded. For the full record of the NMR data see Section 6.

b-sulfonyl-endoperoxide 39a at d 3.27 and 4.23 ppm

7²J14.3 Hz), the low ®eld component of the quartet is

additionally split 7⁴J0.5 Hz) by the Me711) protons. In

the spectra of the diastereomeric b-sulfonyl-endoperoxides

39b the corresponding AB quartet was observed at d 3.14

and 3.33 ppm 7²J14.0 Hz), the low ®eld signal is

broadened by a long-range coupling with the Me711)-

protons. The difference in the chemical shifts D7dH⁰2dH)

is about 1.0 ppm for 39a and about 0.2 ppm for its diastereo-

mer 39b. This conforms with the differences in deshielding

magnitude of diastereotopic C712)HH⁰protons, by O72) in

the isomers a and b, discussed above. A long-range coupling

was always observed as a cross-peak of the H⁰712)-proton

and Me711) in the COSY spectra in all the examined 2,3-

dioxabicyclo[3.3.1]nonanes. This interaction usually results

in the broadening of the Me711) singlet and the down®eld

component of the C712)HH⁰pattern. In many cases a split-

in the b series than in the corresponding a diastereomers

7see Table 2 and Section 5). These empirical rules for the

quick determination of the con®guration at C74)-stereo-

center in 2,3-dioxabicyclo[3.3.1]nonanes by NMR were

proved to be valid not only for the b-sulfonyl-endo-

peroxides and b-sulfenyl-endoperoxides,¹¹but also for the

corresponding b-sul®nyl-endoperoxides.¹⁵

The con®guration of the substituents on the stereogenic

atoms C74) and C78) of the 2,3-dioxabicyclo[3.3.1]nonane

system was corroborated by the ¹H NOE difference experi-

ments. Upon irradiation of H71) at 3.68 ppm in 39⁰b a NOE

enhancement of the signals Me710) 4.2%, Me711) 0.8%,

H79)eq 7.4% and H79)ax 3.2% was detected. The magnitude

of the NOE correlation between the equatorial H71) and

Me711) is in accordance with the axial orientation of the

latter. Irradiation of the distinctively situated H77)ax signal

of both b-benzoates 52⁰⁰a and 52⁰⁰b provided a simple

unambiguous elucidation of the con®gurations at C74) and

C78)-stereocenters 7Fig. 2). Irradiation of H77) in 52⁰⁰a

resulted in a strong NOE response for both the Me710)

and Me711) signals, indicating that H77) and the two methyl

groups are situated in spatial proximity on the same side of

both the 1,2-dioxane and of the carbocyclic rings. In

contrast, irradiation of the H77) signal in 52⁰⁰b resulted in

4

ting of the signals with J0.3±0.7 Hz could be directly

1

detected in H NMR spectra. The broadened singlet or

doublet of Me711) is clearly distinguished from the narrow

singlet of Me710). The chemical shift values of Me710) are

always very similar for both a and b diastereomers and are

not in¯uenced by the oxidation state of a sulfur atom.

As expected, a low ®eld shift of Me711) at d 1.80 was

observed in the ¹H NMR spectra of b-sulfonyl-endo-

peroxide 39b as compared to d 1.51 in its C74)-isomer

39a. The same tendency in the chemical shifts of

C712)HH⁰and Me711) were noticed in the ¹H NMR spectra

of the diastereomeric b-sulfenyl-endoperoxides 20a,b

7Table 2) and all the other bicyclic endoperoxides studied

in this work 7see Section 5). Thus, down®eld chemical shifts

for C712)HH⁰AB quartet of D7d H⁰±H) values of about

1.0 ppm for b-sulfonyl-endoperoxides and 0.4 ppm for

b-sulfenyl-endoperoxides, as well as a chemical shift of

Me711) at d 1.5 ppm for b-sulfonyl-endoperoxides and

1

1.25 ppm for b-sulfenyl-endoperoxides are distinctive H

NMR features for endoperoxides of the a series. For the b

series the usual chemical shifts difference for C712)HH⁰AB

quartet D7d H⁰±H) is about 0.2 ppm for b-sulfonyl-endo-

peroxides and 0.1 ppm for b-sulfenyl-endoperoxides.

Typically, a low ®eld signal at about 1.8 ppm is observed

for the Me711) of b-sulfonyl-endoperoxides and at ca.

1.55 ppm for b-sulfenyl-endoperoxides. Additional

diagnostic indications for the a and bseries of 2,3-dioxa-

bicyclo[3.3.1]nonanes were found in the ¹³C NMR spectra.

In all the examined compounds the values of d_Cfor C71) and

C75) were always higher by ca. 0.4 and 1.5 ppm respectively

Figure 2. Distinctive ¹H NMR and NOE difference data for 52⁰⁰a and 52⁰⁰b.

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2457

a signi®cant NOE enhancement of the Me710) and H⁰712)

patterns and no response at the Me711) signal.

compounds 51⁰⁰a and 55⁰⁰a sustains this particular intra-

molecular hydrogen bonding through two bridged

7-membered rings 7Fig. 3).

Analysis of the coupling constants indicated the conserva-

tion of the chair conformation for both 1,2-dioxane and

cyclohexane rings of the 2,3-dioxabicyclo[3.3.1]nonane

system in CDCl₃solutions.^34,35In agreement with the

chair conformation, the splitting pattern of H77) in the

b-benzoates 52⁰⁰, 53⁰⁰corresponds to the axial orientation

of the proton 7J_7ax,6ax11.8 Hz, J_7ax,6eq6.2 Hz), whereas in

the a-benzoates 54⁰⁰a,b the H77) is equatorial

Representative NMR data for the four diastereomeric

8-acetoxy-b-sulfonyl-endoperoxides 58⁰⁰a±d 7Scheme 6)

are summarized in the Table 3. The NMR spectra of the

minor diastereomers 58⁰⁰c and 58⁰⁰d differ extensively

from the spectra of the major diastereomers 58⁰⁰a and

58⁰⁰b in the pattern attributed to the C78)-stereocenter frag-

ment, but not of the C74)-stereocenter moiety. This indicates

that in these two pairs the C78)-stereocenter has the opposite

con®guration. Thus, the acetoxy-group at C78) occupies an

equatorial position in the minor diastereomers 58⁰⁰c,d.

Indeed, the bridgehead H71) protons were observed at d

4.7 ppm in the diastereomers 58⁰⁰c,d and at 4.45 ppm in

the diastereomers 58⁰⁰a,b. The axial H77) protons in the

minor diastereomers 58⁰⁰c,d shifted down®eld by 0.3±

0.4 ppm because of the deshielding effect of the neighboring

acetoxy-group, while for the equatorial H77) the opposite,

albeit less pronounced effect, was observed. In the ¹H NMR

spectra of both minor diastereomers 58⁰⁰c,d the Me710)

signal appeared as two singlets of about equal intensity

7total 3H), which indicated a restricted rotation of the

acetoxy group with two energetically favored conforma-

tions of similar population. A marked difference in the ¹³C

NMR spectra of the minor diastereomers 58⁰⁰c,d with

respect to those of major diastereomers 58⁰⁰a,b is the down-

®eld shift of C77) and Me710) signals by ca. 1.7 and 0.8±

1.0 ppm respectively. The similarity of the NMR patterns

attributed to the C74)-stereocenter in the pairs of diastereo-

mers 58⁰⁰a and 58⁰⁰c as well as diastereomers 58⁰⁰b and 58⁰⁰d

proves that the con®guration at C74) is identical for each of

these couples. The criteria described above for the differ-

entiation between a and b series of 2,3-dioxabicyclo[3.3.1]-

nonanes can be applied also for the differentiation between c

and d series of endoperoxides.

1

7J_7eq,6eq6.5 Hz, J_7eq,6ax1.6 Hz). In the H NMR spectra

of the related 7a-hydroxy-b-sulfonyl-endoperoxides 55⁰⁰a

the H77)eq pattern was observed as a doublet with 2

coupling constants similar to the previous ones

7J_7eq,6eq5.4 Hz, J_7eq,6ax0.9 Hz), and the third, larger one

7J13.2 Hz). Similar values of coupling constants

7J13.2 Hz and J_7eq,6eq5.5 Hz, J_7eq,6ax<0 Hz) were

observed for H77)eq in b-sulfenyl-endoperoxides 51⁰⁰a.

COSY experiments revealed a strong interrelationship of

H77)eq and the doublets 7J13.2 Hz) at d 4.09 and

3.89 ppm in 51⁰⁰a and 55⁰⁰a respectively. These doublets

lack the cross-peaks in the HMQC-spectra. The doublets

1

disappeared in the H NMR spectra upon deuteration with

excess of CD₃CO₂D, but not with CD₃OD or D₂O. Thus, the

doublets at d 4.09 and 3.89 ppm were attributed to the

secondary OH protons at C77), coupled with the H77)eq.

The unusually high value of the vicinal coupling

³J_OH,7eq13.2 Hz is consonant with the nearly 1808 dihedral

angle between H±C77)±O and H±O±C77) planes.³⁶This

angle could be stabilized by the intramolecular hydrogen

bonding of C77)±OH with O73) of the endoperoxide

bridge.^37,38Presumably, the rigid 3D structure of

5. Conclusion

New hydroperoxide±endoperoxides of type 9 7R²OH),

containing the 2,3-dioxabicyclo[3.3.1]nonane system were

obtained from monoterpenes by a 4-component, one

operation free radical process, in which ®ve new bonds

are sequentially formed. These compounds were

Figure 3. Selected NMR data, evidence for intramolecular hydrogen

bonding in 55⁰⁰a.

Table 3. Selected ¹H 7400 MHz) and ¹³C 7100 MHz) NMR data for 8-acetoxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonanes 58⁰⁰a±d

in CDCl₃

Position

58⁰⁰a

58⁰⁰b

58⁰⁰c

58⁰⁰d

¹H

¹³C

¹H

¹³C

¹H

¹³C

¹H

¹³C

1

4

5

7 ax

7 eq

8

10

11

4.45 br dd 73.2, 1.2)

77.80 d

82.72 s

29.42 d

33.26 t

4.42 br dd 73.6, 1.4)

78.45 d

82.97 s

30.92 d

32.92 t

4.71 br d 74.2)

77.96 d

82.61 s

29.73 d

34.99 t

4.68 br dd 74.3)

78.52 d

82.82 s

31.14 d

34.74 t

2.30 br dddd

2.19 m

2.14 m

2.10 br dddd

2.04 m

2.16 br dd 714.5, 6.0)

2.35 br dddd

2.56 br ddd

1.92 br dd 713.8, 6.7)

2.14±2.23 m

2.39±2.47 m

1.94 br dd 713.7, 5.8)

82.54 s

22.49 q

23.09 q

60.98 t

82.35 s

22.53 q

21.94 q

60.50 t

82.61 s

23.58 q

23.06 q

61.06 t

81.65 s

23.25 q

22.00 q

60.29 t

1.62 s

1.51 br s

3.25 d 714.3)

4.22 dd 714.3, 0.4)

1.56 s

1.80 br s

3.12 d 714.0)

3.32 br d 714.0)

1.602, 1.604 72£s)

1.54 d 70.6)

3.21 d 714.3)

1.584, 1.586 72£s)

1.80 br s

3.12 d 714.0)

3.39 br d 714.0)

12H

12H⁰

4.27 dd 714.3, 0.6)

Chemical shifts 7ppm), multiplicity of the signal and coupling constants 7Hz) are recorded. For the full record of the NMR data see Section 6.

2458

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

selectively reduced 7PPh₃) in the same vessel to give 4,8-

dimethyl-4-sulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonan-

8-ols 9 7R²H) and, after oxidation, 4,8-dimethyl-4-sul-

fonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols 10 7R²H).

Compounds 9 and 10 served as precursors for the prepara-

tion of new potent antimalarial agents³⁹and in the total

synthesis of natural antimalarial endoperoxide yingzhaosu

A 73).¹³Compounds of type 9, 10 share with naturally

occurring yingzhaosu A 73) and synthetic arte¯ene 74a)

the 2,3-dioxabicyclo[3.3.1]nonane system 2, which is

considered to account for the antimalarial activity of these

compounds. The present study opens an avenue for the

preparation of an expanding class of antimalarial peroxide

agents and provides a comprehensive NMR analysis, that

allows a simple determination of the con®guration at the

four stereogenic centers of compounds 9 and 10.

given for analytical HPLC, eluents are speci®ed in the

single examples.

7R)-71)-Limonene 7Aldrich, # 18,316-4) 718⁰) and 7S)-72)-

Limonene 7Aldrich, # 21,836-7) 718⁰⁰) were used as starting

materials. Di-tert-butyl peroxalate 7DBPO)^27a7Caution!Ða

potentially explosive compound),²⁹trans-carveol benzoate

45⁰⁰,⁴¹and cis-carveol 47⁰⁰⁴²were prepared according to the

reported procedures. Other reagents are available from

Aldrich and Merck, and were puri®ed if necessary by

conventional methods. The following commercial solvents

were used for the TOCO reactions: n-heptane 7991%,

Aldrich), benzene 7puriss, Merck), acetonitrile and

methanol 7HPLC grade, BioLab, Israel); for oxidationsÐ

dichloromethane 7puriss, Merck) and ethyl acetate 7analyti-

cal, BDH or BioLab). For silylation and benzoylation

commercial CH₂Cl₂was distilled over CaH₂or P₂O₅,

pyridine was distilled over KOH pellets.

6. Experimental

6.1. General

Unless otherwise stated the purity of all the title compounds

was estimated to be $95% by H NMR and analytical

1

HPLC determination. The ratios of diastereomers were

determined by integration of the relevant separated signals

in H NMR spectra.

¹H, COSY, NOE-difference, ¹³C, DEPT and 2D-HMQC

NMR spectra were recorded on a Bruker Avance DRX-

400 spectrometer or on a Bruker Avance DPX-250 spectro-

meter 7¹H and ¹³C/DEPT only) in CDCl₃. Residual CHCl₃

1

6.1.1. R-cis-Carveol benzoate 046⁰⁰). A solution of cis-

carveol 47⁰⁰7480 mg, 3.15 mmol) in dry pyridine 78 mL)

at 08C was treated with BzCl 7496 mg, 3.53 mmol). The

mixture was stirred at 08C for 5 h and at rt overnight, poured

into a cold 10% H₂SO₄7100 mL), extracted with EtOAc±

hexane 71:9, 2£100 mL), dried 7Na₂SO₄1Na₂CO₃) and

concentrated under reduced pressure. FC 7EtOAc±hexane,

1:24) afforded the benzoate 46⁰⁰7656 mg, 81%) as a color-

less oil: R_f0.48 7EtOAc±hexane 7:93); IR 7neat): 2970,

2920, 1717 7vs), 1452, 1315, 1270 7s), 1112 7s),

1

77.26 ppm for H NMR) and CDCl₃777.00 ppm for ¹³C

NMR) peaks were used as internal standards. IR spectra

Â Â

were obtained with a Protege 460 FT-IR instrument.

Speci®c rotations were determined on a Perkin±Elmer 341

polarimeter using a microaperture mode. HRMS was

recorded on an AutoSpec mass-spectrometer at 70 eV with

direct probe insertion unit using a DCI 7desorption chemical

ionization) technique 7Bar Ilan University, Ramat Gan).

Microanalyses were conducted by Microanalysis Labora-

tory of Hebrew University 7Jerusalem). Melting points

were determined on a BuÈchi apparatus and are uncorrected.

For UV irradiation was used a 100 W BLAK-RAY^wUV

lamp B-100AP 7UVP), l310±400 nm 7l_max365 nm)

and a Pyrex glassware. TLC analysis was performed on E.

Merck 0.25 mm precoated silica gel 60 F-254 plates 7UV

detection) followed by charring with either alkaline KMnO₄

7stain 1) or N,N-dimethyl-p-phenylenediamine dihydro-

chloride in water±MeOH±AcOH 7stain 2, speci®c for

peroxides),⁴⁰stabilized by 2±3 mL of conc. HCl per

150 mL of the stain solution. Such stabilization provides

stability of the stain solution for at least 2±3 months at rt

without a signi®cant decrease in effectiveness. Flash column

chromatography 7FC) was performed on silica gel 60 7230±

400 mesh ASTM) from Merck. Medium pressure liquid

chromatography 7MPLC) was performed on glass columns

7BuÈchi-B-685, l460 mm, d26 or 43 mm, ®lled with

LiChroprep silica gel 715±25 mm particle size). For

analytical and semipreparative HPLC a LaChrom HPLC

instrument 7Merck-Hitachi) with UV detector was used.

DP refers to direct-phase HPLC [semipreparative using

LiChrospher Si-60 710 mm), 250£10 mm²column, ¯ow

rate: 2.5±3 mL/min; analyticalÐLiChrospher Si-60

75 mm), 250£4 mm²column, 1 mL/min]. RP refers to

reversed-phase HPLC [semipreparativeÐLiChrospher 100

RP-18 75 mm), 250£10 mm²column, ¯ow rate 2±2.5 mL/

min; analyticalÐLiChrospher 100 RP-18 75 mm),

250£4 mm²column, 1 mL/min]. Retention times t_Rare

1

711 cm²¹; H NMR 7400 MHz, CDCl₃): d 1.64 7ddd, 1H,

J12.3, 12.3, 10.0 Hz), 1.72 7m, 3H, Me), 1.74 7br s, 3H,

Me), 2.05 7m, 1H), 2.16 7m, 1H), 2.30±2.43 7m, 2H), 4.74

7br s, 2H), 5.67 7m, 1H), 5.70 7m, 1H), 7.45 7ddd, 2H, J7.9,

1.2, 1.2 Hz), 7.56 7m, 1H), 8.07 7m, 2H); ¹³C NMR

7100 MHz, CDCl₃): d 19.00, 20.51, 30.79, 33.99, 40.25,

73.80, 109.38, 125.99, 128.34, 129.59, 132.85, 133.08,

148.26, 166.40.

6.2. General procedures for the synthesis of 2,3-dioxa-

bicyclo[3.3.1]nonanes by the TOCO reactions.²⁹

Preparation of 01R,4R/S,5R,8R)- and 01S,4S/R,5S,8S)-

4,8-dimethyl-4-phenylsulfenylmethyl-2,3-dioxabicyclo-

[3.3.1]nonan-8-ols 020a,b)

6.2.1. Procedure 1A^19a0entry 1, Table 1). Through a

vigorously stirred solution of R-71)-limonene 718⁰)

7409 mg, 3.0 mmol, 1 equiv.), PhSH 7330 mg, 3 mmol,

1 equiv.) and DBPO 735 mg, 0.15 mmol, 0.05 equiv.) in

benzene 7100 mL) at rt is passed a slow stream of oxygen

gas for 15 h. Reaction mixture is cooled to 58C, ¯ushed with

argon, diluted with CH₂Cl₂720 mL), and Ph₃P 7786 mg,

3 mmol, 1 equiv.) is added. The mixture is stirred for an

additional 1 h at 58C and for 1 h at rt. Evaporation in

vacuum at rt 7Caution!ÐSafety screen is commonly recom-

mended to use for evaporation of peroxide-containing

solutions)²⁹followed by FC 7gradient elution, EtOAc±

hexane, from 1:49 to 3:7) affords the 71R,4R/S,5R,8R)-endo-

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2459

peroxides 20⁰a,b 7123 mg, 0.42 mmol, 14%, a/b ca. 55:45),

and unsaturated hydroxysul®des 26⁰a,b 7233 g, 0.96 mmol,

32%, a/b ca. 60:40). Evaporation of the least polar fraction

from FC followed by treatment of the residue with hexane,

®ltration and recrystallization from MeOH gives diphenyl

disul®de 782 mg, 0.376 mmol, 25%), mp 608C.

thiol addition the reaction mixture is cooled and worked-

up as described above to give the endoperoxides 20⁰a,b

7137 mg, 0.47 mmol, 47%) as a mixture of diastereomers

7ca. 58:42).

6.2.5. General procedure 1E 0entry 16, Table 1). A solu-

tion of R-71)-limonene 718⁰) 76.13 g, 45 mmol, 3 equiv.)

and AIBN 777 mg, 0.45 mmol, 0.03 equiv.) in acetonitrile

7700 mL) is placed into a Pyrex 3-necked round-bottom

¯ask equipped as described above for the procedure 1C

and kept under small positive pressure of pure oxygen.

The reaction mixture is vigorously stirred and UV irradiated

7from a distance ca. 5±7 cm) at 48C with simultaneous addi-

tion of solutions of thiophenol 71.65 g, 15 mmol, 1 equiv.)

and AIBN 777 mg, 0.45 mmol, 0.03 equiv.) in acetonitrile

710 mL each) over a period of 10 h 7syringe pump). After

completion of the addition, the reaction mixture is worked-

up as described above to yield endoperoxides 20⁰a,b

72.17 g, 7.38 mmol, 49%) as a mixture of diastereomers

7ca. 55:45).

6.2.2. General procedure 1B 0entry 5, Table 1). Oxygen

gas is bubbled at rt through a vigorously stirred solution of

R-71)-limonene 718⁰) 76.13 g, 45 mmol, 3 equiv.) and

DBPO 7105 mg, 0.45 mmol, 0.03 equiv.) in n-heptane±

benzene mixture 7500 mL/200 mL) with simultaneous addi-

tion of thiophenol 71.65 g, 15 mmol, 1 equiv.) in heptane

720 mL) over a period of 10 h 7syringe pump). After the

addition of thiol is completed, the mixture is cooled to

0±58C, ¯ushed with argon, diluted with CH₂Cl₂7100 mL),

and powdered Ph₃P 73.93 g, 15 mmol, 1 equiv.) is added.

The mixture is stirred for an additional 2 h at 0±58C, for

1 h at rt and evaporated at rt. FC 7gradient elution, EtOAc±

hexane, from 1:49 to 3:7) affords the title 71R,4R/S,5R,8R)-

endoperoxides 20⁰a,b 72.41 g, 8.20 mmol, 54%) as a

mixture of diastereomers 7a/b ca. 55:45), and unsaturated

hydroxysul®des 26⁰a,b 70.975 g, 4.03 mmol, 25%, a/b ca.

60:40). Evaporation of the least polar fraction from FC

followed by dilution with hexane, cooling 72208C) and

®ltration gives 7PhS)₂7162 mg, 0.743 mmol, 10%).

Evaporation of the ®ltrate followed by distillation affords

72.93 g, 21.5 mmol, 72% recovery) of R-71)-limonene

718⁰), bp 175±1768C.

Procedures 1B, 1C and 1E gave essentially the same results

when applied to the preparation of 71S,4S/R,5S,8S)-4,8-

dimethyl-4-phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]-

nonan-8-ols 720⁰⁰a,b) from S-72)-limonene 718⁰⁰). NMR and

IR spectra of 20⁰a,b and 20⁰⁰a,b coincided. Three-fold

scaling up of these TOCO reactions according to the proce-

dures 1C and 1E does not signi®cantly affect yields and

purity of endoperoxides 20.

6.2.3. General procedure 1C 0entry 8, Table 1). A

solution of R-71)-limonene 718⁰) 76.13 g, 45 mmol,

3 equiv.) and DBPO 7105 mg, 0.45 mmol, 0.03 equiv.) in

n-heptane±benzene mixture 7500 mL/200 mL) is placed

into 2 L 3-necked round-bottomed ¯ask, equipped with an

ef®cient egg-shaped magnetic stirring bar. A central neck of

the reaction ¯ask is connected to a big 72 L) external

graduated reservoir ®lled with oxygen and joined from its

bottom through a ¯exible tube to a leveling bulb 72 L) ®lled

with brine. The two side necks of the reaction ¯ask are

equipped with septums. The reaction vessel is thoroughly

¯ashed with pure oxygen and oxygen pressure is adjusted to

15±20 cm of brine. To a vigorously stirred under oxygen at

rt reaction mixture, a solution of thiophenol 71.65 g,

15 mmol, 1 equiv.) in heptane 720 mL) is added over a

period of 10 h 7syringe pump). Since no additional

consumption of oxygen occurs after completion of thiol

addition 7up to 10 h monitoring), the reaction mixture is

worked-up as described in the procedure 1B to give the

endoperoxides 20⁰a,b 72.09 g, 7.11 mmol, 47%) as a

mixture of diastereomers 7ca. 55:45).

6.2.6. Endoperoxides 20a,b. A colorless oil, R_f0.29

7EtOAc±hexane, 3:7); IR 7neat): 3420, 2964, 2928, 1584,

1480, 1454, 1440, 1373, 1055, 1015 cm²^{1 1}H NMR

;

7400 MHz, CDCl₃): d 1.25 7br s, Me711), a), 1.56 7d,

J0.6 Hz, Me711), b), total 3H; 1.39 7s, Me710), b), 1.40

7s, Me710), a), total 3H; 1.58 7m, 1H, H77)eq, a1b); 1.76±

1.85 7m, 2H, H76)ax1eq, a1b); 1.81 7m, H75), b), 1.91

7dddd, J6.4, 6.4, 3.2, 3.2 Hz, H75), a), total 1H; 1.98

7ddd, J13.6, 3.2, 2.0 Hz, H79)ax, a), 2.01 7ddd, J14.2,

3.2, 1.9 Hz, H79)ax, b), total 1H; 2.10 7ddd, J13.6, 5.5,

3.2 Hz, H79)eq, a), 2.26 7ddd, J14.2, 4.4, 3.0 Hz, H79)eq,

b), total 1H; 2.31±2.41 7m, 1H, H77)ax, a1b); 2.96 7d,

J12.0 Hz, H712), b), 3.35 7d, J12.8 Hz, H712), a), total

1H; 3.03 7dd, J12.0, 0.6 Hz, H⁰712), b), 3.71 7dd, J12.8,

0.5 Hz, H⁰712), a), total 1H; 3.68 7m, H71), a), 3.71 7m, H71),

b), total 1H; 7.17±7.23 7m, 1H), 7.27±7.33 7m, 2H), 7.36±

7.43 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d 21.89

7Me711)), 23.58 7C76)H₂), 24.17 7C79)H₂), 28.04

7Me710)), 29.23 7C75)H), 35.51 7C77)H₂), 40.68

7C712)H₂), 71.40 7C78)), 81.57 7C71)H), 83.77 7C74)),

126.14 7CH), 128.87 72CH), 129.63 72CH), 136.84 7C)

7isomer 20a); 21.76 7Me711)), 23.30 7C76)H₂), 24.26

7C79)H₂), 28.04 7Me710)), 30.50 7C75)H), 35.84 7C77)H₂),

40.73 7C712)H₂), 71.35 7C78)), 82.02 7C71)H), 83.83 7C74)),

126.33 7CH), 128.93 72CH), 129.63 72CH), 136.42 7C)

7isomer 20b).

6.2.4. Procedure 1D 0entry 10, Table 1). In this procedure

the same equipment is used as in the procedure 1C, except

that oxygen ®lled external reservoir was connected with the

reaction ¯ask via a bulb type vertically positioned

condenser. To a vigorously stirred under oxygen solution

of R-71)-limonene 718⁰) 7409 mg, 3.0 mmol, 3 equiv.) and

AIBN 75.0 mg, 0.03 mmol, 0.03 equiv.) in acetonitrile

7120 mL) at 658C solutions of thiophenol 7110 mg,

1.0 mmol, 1 equiv.) in MeCN 710 mL) and AIBN 75.0 mg,

0.03 mmol, 0.03 equiv.) in MeCN 710 mL) are added simul-

taneously over 10 h 7syringe pump). After completion of

Unsaturated hydroxysul®des 26⁰a,b: a colorless oil, R_f0.53

7EtOAc±hexane, 1:4); IR 7neat): 3420, 2977, 2935, 1584,

1

1480, 1438, 1377, 1089, 1025 cm²¹; H NMR 7400 MHz,

CDCl₃): d 1.19 7s, Me, a), 1.20 7s, Me, b), total 3H; 1.20±

1.33 7m, 1H); 1.64 7br s, MeCv, b), 1.65 7br s, MeCv, a),

total 3H; 1.68±1.83 7m, 2H), 1.87±1.93 7m, 1H), 1.94±2.19

2460

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

7m, 3H); 3.11 and 3.20 7AB quartet, J13.1 Hz, CHH⁰S, a),

3.13 and 3.24 7AB quartet, J13.4 Hz, CHH⁰S, b), total 2H;

5.33±5.37 7m, HCv, a), 5.37±5.41 7m, HCv, b), total 1H;

7.15±7.21 7m, 1H), 7.24±7.30 7m, 2H), 7.38±7.43 7m, 2H);

¹³C NMR 7100 MHz, CDCl₃): d 22.58 7Me), 23.26 7CH₂),

23.29 7Me), 27.00 7CH₂), 30.75 7CH₂), 42.79 7CH), 46.27

7CH₂), 74.02 7C), 119.95 7HCv), 126.11 7CH), 128.88

72CH), 129.50 72CH), 134.20 7MeCv), 137.01 7C) 7isomer

26⁰a); 22.58 7Me), 23.50 7Me), 24.25 7CH₂), 26.04 7CH₂),

30.71 7CH₂), 42.63 7CH), 45.62 7CH₂), 74.02 7C), 120.43

7HCv), 126.14 7CH), 128.88 72CH), 129.54 72CH), 133.70

7MeCv), 137.01 7C) 7isomer 26⁰b).

7MeCH₂CH₂CH₂S), 21.66 7Me711)), 21.92 7CH₂), 23.43

7C76)H₂), 24.44 7C79)H₂), 28.12 7Me710)), 30.61

7C75)H), 31.68 7CH₂), 33.74 7CH₂), 35.99 7C77)H₂), 38.93

7C712)H₂), 71.48 7C78)), 82.01 7C71)H), 84.17 7C74))

7isomer 34⁰b).

6.2.9. 01R,4R,5R,8R)-4,8-Dimethyl-4-0methoxycarbonyl-

methylsulfenyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

035⁰a) and 01R,4S,5R,8R)-4,8-dimethyl-4-0methoxycar-

bonylmethylsulfenyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-

8-ol 035⁰b). A mixture of diastereomers 35⁰⁰a,b 7178.5 mg,

18%, a/b ca. 50:50) was prepared from R-limonene 18⁰

71.36 g, 10 mmol), methyl thioglycolate 7353 mg,

3.33 mmol) and AIBN 734 mg, 0.20 mmol) according to

the general procedure 1E 7thiol addition time 18 h). The

diastereomers were separated by additional MPLC

7EtOAc±hexane, 1:2). More polar isomer 35⁰a: a colorless

6.2.7. 01R,4R/S,5R,8R)-4,8-Dimethyl-4-04-¯uorophenyl)-

sulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols 033⁰a,b).

A mixture of endoperoxides 33⁰a,b 7248.5 mg, 47%, a/b ca.

52:48) was prepared from R-71)-limonene 718⁰) 7695 mg,

5.10 mmol) and 4-FC₆H₄SH 7217 mg, 1.69 mmol) accord-

ing to the general procedure 1B 7thiol addition time 10 h). A

1

oil, R_f0.20 7EtOAc±hexane, 1:2); H NMR 7400 MHz,

CDCl₃): d 1.25 7br s, 3H, Me711)), 1.38 7s, 3H, Me710)),

1.57±1.61 7m, 1H, H77)eq), 1.70 7br dddd, 1H, J6.4, 6.4,

3.2, 3.2 Hz, H75)), 1.81±1.88 7m, 2H), 2.04 7ddd, 1H,

J13.6, 3.2, 2.0 Hz, H79)ax), 2.22 7br ddd, 1H, J13.6,

6.4, 3.6 Hz, H79)eq), 2.36 7ddd, 1H, J14.2, 12.7, 7.6 Hz,

H77)ax), 2.99 7d, 1H, J13.4 Hz, H712)), 3.29 7d, 1H,

J14.9 Hz, SCHH⁰CO₂Me), 3.37 7br d, 1H, J13.4 Hz,

H⁰712)), 3.44 7d, 1H, J14.9 Hz, SCHH⁰CO₂Me), 3.69

7br d, 1H, J3.6 Hz, H71)), 3.74 7s, 3H, MeO); ¹³C

1

pale yellow oil, R_f0.23 7EtOAc±hexane, 1:2); H NMR

7400 MHz, CDCl₃): d 1.22 7br s, Me711), a), 1.53 7br s,

Me711), b), total 3H; 1.36 7s, Me710), b), 1.38 7s, Me710),

a), total 3H; 1.55±1.67 7m, 1H, H77)eq, a1b), 1.72±1.86

7m, 3H); 1.96 7ddd, J13.5, 3.2, 2.0 Hz, H79)ax, a), 2.04

7ddd, J14.0, 3.2, 1.8 Hz, H79)ax, b), total 1H; 2.03±2.07

7m, H79)eq, a), 2.22±2.38 7m), total 2H; 2.89 7d, J12.2 Hz,

H712), b), 3.31 7d, J12.9 Hz, H712), a), total 1H; 2.97 7br

d, J12.2 Hz, H⁰712), b), 3.60 7br d, J12.9 Hz, H⁰712), a),

total 1H; 3.66 7m, H71), a), 3.69 7m, H71), b), total 1H;

6.97±7.01 7m, 2H), 7.36±7.43 7m, 2H); ¹³C NMR

763 MHz, CDCl₃): d 21.78, 21.91 7Me711)); 23.37, 23.67

7C76)H₂); 24.24, 24.34 7C79)H₂); 28.12 7Me710)), 29.35

7C75)H, a), 30.57 7C75)H, b); 35.59, 35.89 7C77)H₂);

42.12, 42.24 7C712)H₂); 71.45, 71.50 7C78)); 81.62, 82.06

7C71)H); 83.78, 83.89 7C74)); 116.08 7J_C±F21.9 Hz),

116.15 7J_C±F22.1 Hz)72CH); 131.33 7J_C±F3.6 Hz),

131.77 7J_C±F3.1 Hz)7C); 132.60 7J_C±F8.3 Hz), 132.73

7J_C±F8.4 Hz)72CH); 161.78 7J_C±F246.6 Hz), 161.91

7J_C±F246.8 Hz)7C±F).

NMR 763 MHz, CDCl₃):

d

21.32 7Me711)), 23.80

7C76)H₂), 24.26 7C79)H₂), 27.95 7Me710)), 30.29 7C75)H),

34.28 7CH₂), 35.45 7C77)H₂), 38.46 7C712)H₂), 52.32

7MeO), 71.35 7C78)), 81.61 7C71)H), 83.34 7C74)), 171.05

7CvO).

Less polar isomer 35⁰b: a colorless oil, R_f0.23 7EtOAc±

hexane, 1:2); H NMR 7400 MHz, CDCl₃): d 1.37 7s, 3H,

1

Me710)), 1.57 7br s, 3H, Me711)), 1.58±1.62 7m, 1H,

H77)eq), 1.66 7br dddd, 1H, J6.4, 6.4, 3.2, 3.2 Hz, H75)),

1.77±1.88 7m, 2H), 2.04 7ddd, 1H, J13.4, 3.2, 1.8 Hz,

H79)ax), 2.24 7br ddd, 1H, J13.4, 6.4, 3.2 Hz, H79)eq),

2.34 7ddd, 1H, J14.0, 14.0, 7.0 Hz, H77)ax), 2.68 7br d,

1H, J12.7 Hz, H712)), 2.81 7d, 1H, J12.7 Hz, H⁰712)),

3.23 and 3.32 7AB quartet, 2H, J14.8 Hz, SCHH⁰CO₂Me),

3.69 7br d, 1H, J3.2 Hz, H71)), 3.74 7s, 3H, MeO); ¹³C

6.2.8. 01R,4R/S,5R,8R)-4-n-Butylsulfenylmethyl-4,8-di-

methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 034⁰a,b).

A

diastereomeric mixture 34⁰a,b 7229 mg, 25%, a/b ca.

60:40) was prepared from R-limonene 18⁰71.36 g,

10 mmol), n-BuSH 7300 mg, 3.33 mmol) and AIBN

768 mg, 0.40 mmol) according to the general procedure 1E

7thiol addition time 30 h). A pale yellow oil, R_f0.23

7EtOAc±hexane, 3:7); ¹H NMR 7400 MHz, CDCl₃): d

0.90 t, J7.3 Hz, MeCH₂CH₂CH₂S, a), 0.91 7t, J7.3 Hz,

MeCH₂CH₂CH₂S, b), total 3H; 1.23 7br s, Me711), a), 1.56

7d, J0.3 Hz, Me711), b), total 3H; 1.36 7s, Me710), b), 1.37

7s, Me710), a), total 3H; 1.38±1.46 7m, 2H), 1.54±1.63 7m,

3H), 1.70±1.85 7m, 4H), 1.99±2.04 7m, 2H), 2.13±2.26 7m,

2H), 2.28±2.42 7m, 2H); 2.47 7d, J12.2 Hz, H712), b), 2.95

7d, J13.0 Hz, H712), a), total 1H; 2.54 7br t, J7.2 Hz,

C₃H₇CH₂S, b), 2.59 7br t, J7.2 Hz, C₃H₇CH₂S, a), total

2H; 2.62 7br d, J12.0 Hz, H⁰712), b), 3.14 7br d,

J13.0 Hz, H⁰712), a), total 1H; 3.67 7m, 1H, H71), a1b);

¹³C NMR 7100 MHz, CDCl₃): d 13.67 7MeCH₂CH₂CH₂S),

21.76 7Me711)), 21.87 7CH₂), 23.80 7C76)H₂), 24.40

7C79)H₂), 28.12 7Me710)), 29.59 7C75)H), 31.89 7CH₂),

33.46 7CH₂), 35.66 7C77)H₂), 38.60 7C712)H₂), 71.54

7C78)), 81.63 7C71)H), 83.90 7C74)) 7isomer 34⁰a); 13.63

NMR 763 MHz, CDCl₃):

d

21.19 7Me711)), 23.23

7C76)H₂), 24.41 7C79)H₂), 28.01 7Me710)), 31.14 7C75)H),

34.74 7CH₂), 35.64 7C77)H₂), 39.17 7C712)H₂), 52.38

7MeO), 71.32 7C78)), 81.92 7C71)H), 83.98 7C74)), 170.65

7CvO).

6.2.10. 01R,4R/S,5R,8R)-4-Cyclohexylsulfenylmethyl-4,8-

dimethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 036⁰a,b). A

mixture of diastereomers 36⁰a,b 7200 mg of ca. 75% purity,

ca. 16% yield, a/b ca. 55:45) was prepared from R-limonene

18⁰71.36 g, 10 mmol), cyclohexylthiol 7387 mg,

3.33 mmol) and AIBN 768 mg, 0.40 mmol) according to

the general procedure 1E 7addition time 25 h). A pale-

yellow oil, R_f0.24 7EtOAc±hexane, 3:7); ¹H NMR

7400 MHz, CDCl₃): d 1.22 br s, Me711), a), 1.54 7br s,

Me711), b), total 3H; 1.21±1.39 7m, 6H); 1.36 7s,

Me710)), 1.37 7s, Me710)), total 3H; 1.58±1.68 7m, 1H),

1.70±1.90 7m, 4H), 1.91±2.07 7m, 2H), 2.16±2.26 7m,

1H), 2.27±2.39 7m, 1H); 2.47 7d, J11.8 Hz), 2.62 7br d,

J11.8 Hz), 2.90 7d, J12.6 Hz), 3.16 7d, J13.4 Hz), 3.23

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2461

7br d, J12.6 Hz), 3.52 7d, J13.4 Hz), 7C712)HH⁰S) total

2H; 3.67 7br s, 1H, H71)); ¹³C NMR 7100 MHz, CDCl₃): d

21.74, 21.82 7Me711)); 23.44, 23.72, 24.39, 24.43, 25.78,

25.84, 25.97, 26.04 7CH₂); 28.13 7Me710)); 29.42 7C75)H,

a), 30.52 7C75)H, b); 33.56, 33.65, 33.73, 33.81, 35.69,

36.10, 36.31, 36.50 7CH₂); 44.66, 44.93 7CH); 71.48,

71.55 7C78)); 81.63 7C71)H, a), 82.07 7C71)H, b), 83.83

7C74), a), 84.03 7C74), b).

C712)HH⁰), 2.16 7ddd, 1H, J13.4, 6.5, 3.4 Hz, H79)eq),

3.62 7br d, 1H, J3.4 Hz, H71)), 7.18±7.23 7m, 3H),

7.26±7.30 7m, 6H), 7.42±7.46 7m, 6H); ¹³C NMR

763 MHz, CDCl₃): d 21.80 7Me711)), 23.26 7C76)H₂),

24.11 7C79)H₂), 28.01 7Me710)), 30.98 7C75)H), 35.76

7C77)H₂), 37.98 7C712)H₂), 66.45 7Ph₃CS), 71.36 7C78)),

82.04 7C71)H), 83.53 7C74)), 126.69 73CH), 127.87 76CH),

129.50 76CH), 144.28 73C).

6.2.11. 01R,4R/S,5R,8R)-4-tert-Butylsulfenylmethyl-4,8-

dimethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 037⁰a,b). A

mixture of diastereomers 37⁰a,b 7264 mg, 29%, a/b ca.

52:48) was prepared from R-limonene 18⁰71.36 g,

10 mmol), tert-BuSH 7300 mg, 3.33 mmol) and AIBN

768 mg, 0.40 mmol) according to the general procedure 1E

7thiol addition time 48 h). A colorless oil, R_f0.42 7EtOAc±

6.2.13. 01S,4S,5S,7S,8S)-7-Benzoyloxy-4,8-dimethyl-4-

phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols

048⁰⁰a) and 01S,4R,5S,7S,8S)-7-benzoyloxy-4,8-dimethyl-

4-phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-

ols 048⁰⁰b). A mixture of endoperoxides 48⁰⁰a,b 742 mg,

22%, a/b ca. 1:1) was synthesized from b-benzoate 45⁰⁰

7350 mg, 1.36 mmol) and PhSH 750 mg, 0.45 mmol)

according to the general procedure 1B 7thiol addition time

12 h). A colorless waxy solid, R_f0.25±0.26 7EtOAc±

hexane, 1:3); IR 7neat): 3547, 1713,1271, 711 cm²¹. Addi-

tional FC 7EtOAc±hexane, 1:4) afforded a sample of a solid

48⁰⁰a 7less polar isomer): mp 139±1408C; R_f0.26 7EtOAc±

hexane, 1:3); ¹H NMR 7400 MHz, CDCl₃): d 1.37 br s, 3H,

Me711)), 1.44 7s, 3H, Me710)), 1.83 7ddd, 1H, J13.1, 11.6,

3.3 Hz, H76)ax), 2.08 7m, 2H, H79)ax1eq), 2.20 7m, 1H,

H75)), 2.37 7m, 1H, H76)eq), 3.35 7d, 1H, J12.9 Hz,

H712)), 3.73 7br d, 1H, J12.9 Hz, H⁰712)), 3.96 7dd, 1H,

J2.4, 2.4 Hz, H71)), 5.76 7dd, 1H, J11.6, 6.3 Hz,

H77)ax), 7.20 7m, 1H), 7.30 7m, 2H), 7.42 7m, 2H), 7.48

7m, 2H), 7.60 7m, 1H), 8.03 7m, 2H^.); ¹³C NMR

7100 MHz, CDCl₃): d 22.30 7Me711)), 23.68 7C79)H₂),

24.46 7Me710)), 29.23 7C76)H₂), 31.31 7C75)H), 40.54

7C712)H₂), 72.81 7C78)), 74.75 7C77)H), 82.75 7C71)H),

83.79 7C74)), 126.43 7CH), 128.54 72CH), 129.03 72CH),

129.48 72CH), 129.94 72CH), 130.07 7C), 133.24 7CH),

1

hexane, 3:7); H NMR 7400 MHz, CDCl₃): d 1.22 7br s,

Me711), a), 1.55 7br s, Me711), b), total 3H; 1.31 7s,

Me₃C, b), 1.34 7s, Me₃C, a), total 9H; 1.369 7s, Me710),

b), 1.373 7s, Me710), a), total 3H; 1.53±1.91 7m, 4H);

1.97±1.99 7m, H75), b), 2.00±2.03 7m, H75), a), total 1H;

2.16±2.25 7m, 1H, H79)eq, a1b), 2.30±2.41 7m, 1H,

H77)ax, a1b); 2.39 7d, J10.7 Hz, H712), b), 2.63 7br

d, J10.7 Hz, H⁰712), b), 2.76 7d, J11.5 Hz, H712), a),

3.36 7br d, J11.5 Hz, H⁰712), a), total 2H; 3.67±3.68

7m, 1H, H71), a1b); ¹³C NMR 7100 MHz, CDCl₃): d

21.98, 22.04 7Me711)); 23.37, 23.59 7C76)H₂,);

24.25 7C79)H₂), 28.12 7Me710)), 29.34 7C75)H, a), 30.52

7C75)H, b); 30.67, 30.84 7Me₃CS); 34.42, 34.45

7C712)H₂); 35.67, 36.17 7C77)H₂); 41.95, 41.99 7Me₃CS);

71.47, 71.55 7C78)); 81.61, 82.15 7C71)H); 83.57, 83.72

7C74).

6.2.12. 01R,4R,5R,8R)-4,8-Dimethyl-4-0triphenylmethyl-

sulfenyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 038⁰a)

and 01R,4S,5R,8R)-4,8-dimethyl-4-0triphenylmethylsul-

fenyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 038⁰b).

A mixture of diastereomers 38⁰a,b 7630 mg, 41%, a/b ca.

57:43) was prepared from R-limonene 18⁰71.36 g,

10 mmol), TrSH 7919 mg, 3.33 mmol) and AIBN 768 mg,

0.40 mmol) according to the general procedure 1E 7thiol

addition time 30 h). The diastereomers were separated by

MPLC 7hexane±EtOAc, 7:3) and puri®ed by semiprepara-

tive DP HPLC 7hexane±EtOAc, 7:3). Less polar isomer

1

136.56 7C), 165.69 7CvO). More polar isomer 48⁰⁰b: H

NMR 7400 MHz, CDCl₃): d 1.43 7s, 3H, Me710)), 1.58 br

s, 3H, Me711)), 1.77 7ddd, 1H, J12.8, 11.2, 3.4 Hz,

H76)ax), 2.07±2.36 7m, 4H), 3.03 7d, 1H, J12.3 Hz,

H712)), 3.24 7br d, 1H, J12.3 Hz, H⁰712)), 3.99 7m, 1H,

H71)), 5.78 7dd, 1H, J11.2, 6.3 Hz, H77)ax), 7.21 7m, 1H),

7.30 7m, 2H), 7.42 7m, 2H), 7.48 7m, 2H), 7.59 7m, 1H), 8.03

7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d 21.40 7Me711)),

23.80 7C79)H₂), 24.46 7Me710)), 28.99 7C76)H₂), 32.53

7C75)H), 40.70 7C712)H₂), 72.83 7C78)), 74.81 7C77)H),

83.23 7C71)H), 83.88 7C74)), 126.51 7CH), 128.52 72CH),

129.03 72CH), 129.48 72CH), 129.90 72CH), 130.08 7C),

133.20 7CH), 135.99 7C), 165.52 7CvO).

1

38⁰a: a pale yellow oil, R_f0.23 7EtOAc±hexane, 3:7); H

NMR 7400 MHz, CDCl₃): d 1.08 7br s, 3H, Me711)), 1.32 7s,

3H, Me710)), 1.49±1.54 7m, 1H, H77)eq), 1.68±1.87 7m,

5H), 2.27 7ddd, 1H, J14.8, 11.8, 8.4 Hz, H77)ax), 2.52

7d, 1H, J11.5 Hz, H712)), 2.88 7br d, 1H, J11.5 Hz,

H⁰712)), 3.57 7br s, 1H, H71)), 7.19±7.22 7m, 3H), 7.26±

7.30 7m, 6H), 7.45±7.48 7m, 6H); ¹³C NMR 763 MHz,

6.2.14. 01S,4S/R,5S,7S,8S)-7-Benzoyloxy-4-n-butylsul-

fenylmethyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-

8-ols 049⁰⁰a,b). A mixture of endoperoxides 49⁰⁰a,b 759 mg

of ca. 85% purity, ca. 6.5% yield, a/b ca. 55:45) was

prepared from b-benzoate 45⁰⁰7993 mg, 3.87 mmol) and

n-BuSH 7180 mg, 2.0 mmol) according to the general pro-

cedure 1B 7thiol addition time 12 h). A pale yellow oil: R_f

0.26 7EtOAc±hexane, 1:4); ¹H NMR 7400 MHz, CDCl₃): d

0.91 t, J7.3 Hz, MeCH₂CH₂CH₂S, b), 0.92 7t, J7.3 Hz,

MeCH₂CH₂CH₂S, a), total 3H;?1.36 7s, Me711), a), 1.58 7s,

Me711), b), total 3H; 1.42 7m, 2H), 1.43 7s, Me710), b), 1.44

7s, Me710), b), total 3H; 1.60 7m, 2H), 1.78 7ddd, J13.3,

11.6, 3.4 Hz, H76)ax, b), 1.82 7ddd, J13.2, 11.8, 3.5 Hz,

H76)ax, a), total 1H; 1.96±2.52 7m, 4H); 2.59 7br t,

J7.3 Hz, C₃H₇CH₂S, a), 2.61 7br t, J7.3 Hz,

CDCl₃):

d

21.85 7Me711)), 23.44 7C76)H₂), 24.15

7C79)H₂), 28.04 7Me710)), 29.54 7C75)H), 35.56 7C77)H₂),

37.74 7C712)H₂), 66.54 7Ph₃CS), 71.42 7C78)), 81.40

7C71)H), 83.45 7C74)), 126.63 73CH), 127.83 76CH),

129.59 76CH), 144.59 73C). DCI 7CH₄) HRMS: obsd

461.2090, calcd for C₂₉H₃₃O₃S 7MH¹) 461.2150. More

polar isomer 38⁰b: a pale yellow oil, R_f0.21 7EtOAc±

1

hexane, 3:7); H NMR 7400 MHz, CDCl₃): d 1.30 7s, 3H,

Me710)), 1.42 7dd, 1H, J14.0, 5.7 Hz, H77)eq), 1.47 br s,

3H, Me711)), 1.49±1.65 7m, 3H), 1.93 7ddd, 1H, J13.4,

3.2, 1.9 Hz, H79)ax), 2.04 7ddd, 1H, J14.0, 14.0, 6.4 Hz,

H77)ax), 2.12 and 2.13 7AB quartet, 2H, J11.4 Hz,

2462

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

C₃H₇CH₂S, b), total 2H; 2.60 7br d, J12.2 Hz, H712), b),

2.80 7br d, J12.2 Hz, H⁰712), b), 2.96 7br d, J13.2 Hz,

H712), a), 3.20 7br d, J13.2 Hz, H⁰712), a), total 2H; 3.97

7m, 1H, H71), a1b), 5.76 7m, 1H, H77)ax, a1b), 7.46 7m,

2H), 7.59 7m, 1H), 8.03 7m, 2H^.); ¹³C NMR 7100 MHz,

CDCl₃): d 13.67 7MeCH₂CH₂CH₂S), 21.89 7CH₂), 22.09

7Me711)), 23.79 7C79)H₂), 24.44 7Me710)), 29.33

7C76)H₂), 31.58 7C75)H), 31.82 7CH₂), 33.47 7CH₂), 38.16

7C712)H₂), 72.81 7C78)), 74.79 7C77)H), 82.73 7C71)H),

83.81 7C74)), 128.50 72CH), 129.46 72CH), 130.05 7C),

133.20 7CH), 165.58 7CvO) 7isomer 49⁰⁰a); 13.62

7MeCH₂CH₂CH₂S), 20.66 7Me711)), 21.85 7CH₂), 23.89

7C79)H₂), 24.44 7Me710)), 28.99 7C76)H₂), 31.54 7CH₂),

32.59 7C75)H), 33.67 7CH₂), 38.88 7C712)H₂), 72.80

7C78)), 74.96 7C77)H), 83.15 7C71)H), 83.92 7C74)),

128.50 72CH), 129.46 72CH), 130.09 7C), 133.17 7CH),

165.58 7CvO) 7isomer 49⁰⁰b).

4.09 7d, 1H, J13.2 Hz, C77)OH, exch. with CD₃CO₂D),

7.22 7m, 1H), 7.32 7m, 2H), 7.42 7m, 2H); ¹³C NMR

7100 MHz, CDCl₃): d 22.22 7Me711)), 22.91 7C79)H₂),

24.57 7Me710)), 29.95 7C75)H), 30.92 7C76)H₂), 40.55

7C712)H₂), 72.98 7C77)H), 74.21 7C78)), 82.19 7C71)H),

83.86 7C74)), 126.56 7CH), 129.03 72CH), 130.07 72CH),

136.35 7C). Anal. Calcd for C₁₆H₂₂O₄S´H₂O: C, 58.51; H,

7.36; S, 9.76. Found: C, 58.48; H, 7.34; S, 9.27.

6.3. General procedure 2 for oxidation of sul®des to

sulfones by m-CPBA

A solution of sul®des 70.3 mmol, 1 equiv., a mixture of

diastereomers or single isomer) and m-CPBA 70.75±

0.9 mmol, 2.5±3.0 equiv.) in 5 mL of EtOAc 7procedure

2A) or CH₂Cl₂7procedure 2B) is stirred for 4±6 h at rt.

After consumption of the more polar intermediate sulfoxide

7TLC monitoring), the mixture is poured into a saturated

solution of NaHCO₃72A) or cold 5% K₂CO₃72B), extracted

with EtOAc±hexane 72A) or CH₂Cl₂72B), dried 7Na₂SO₄

and NaHCO₃) and evaporated. FC of the residue affords the

title compounds as a mixture of diastereomers. The mixture

of diastereomeric sulfones is separated by additional FC,

MPLC or HPLC. The reactions can be scaled up by a factor

of 20 without signi®cant affect on the yields.

6.2.15. 01S,4S/R,5S,7R,8S)-7-Benzoyloxy-4,8-dimethyl-4-

phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols

050⁰⁰a,b). A mixture of endoperoxides 50⁰⁰a,b 724 mg, 6%,

a/b ca. 65:35) was prepared from a-benzoate 46⁰⁰7690 mg,

2.70 mmol) and PhSH 799 mg, 0.90 mmol) according to the

general procedure 1B 7thiol addition time 12 h). A pale

yellow oil, R_f0.42 7EtOAc±hexane, 35:65); ¹H NMR

7400 MHz, CDCl₃): d 1.23 br s, Me711), a), 1.59 br s,

Me711), b), total 3H; 1.41 7s, Me710), b), 1.42 7s, Me710),

a), total 3H; 1.91±2.37 7m, 5H); 3.00 7d, J12.1 Hz, H712),

b), 3.14 7br d, J12.1 Hz, H⁰712), b), 3.39 7d, J12.8 Hz,

H712), a), 3.80 7br d, J12.8 Hz, H⁰712), a), total 2H; 3.82

7m, H71), a), 3.88 7dd, J4.1, 1.5 Hz, H71), b), total 1H;

5.26 7dd, J5.0, 1.7 Hz, H77)eq, b), 5.27 7dd, J5.0,

1.5 Hz, H77)eq, a), total 1H; 7.09 7m, 1H); 7.22 7m, b),

7.29 7m, a), total 2H; 7.41±7.47 7m), 7.54±7.58 7m), total

5H; 8.13 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d 22.30

7Me711)), 23.42 7C79)H₂), 23.47 7Me710)), 28.81 7C76)H₂),

29.36 7C75)H), 40.78 7C712)H₂), 73.83 7C78)), 74.36

7C77)H), 80.85 7C71)H), 82.74 7C74)), 126.36 7CH),

128.48 72CH), 129.00 72CH), 129.81 72CH), 129.90

72CH), 130.15 7C), 133.11 7CH), 136.71 7C), 166.33

7CvO) 7isomer 50⁰⁰a); 21.68 7Me711)), 23.35 7Me710)),

23.56 7C79)H₂), 28.68 7C76)H₂), 30.86 7C75)H), 40.37

7C712)H₂), 73.68 7C78)), 74.51 7C77)H), 81.38 7C71)H),

82.83 7C74)), 126.12 7CH), 128.52 72CH), 128.88 72CH),

129.06 72CH), 129.81 7C), 129.90 72CH), 133.18 7CH),

136.25 7C), 166.25 7CvO) 7isomer 50⁰⁰b).

6.3.1. 01S,4S,5S,8S)-4,8-Dimethyl-4-phenylsulfonylmethyl-

2,3-dioxabicyclo[3.3.1]nonan-8-ol 039⁰⁰a) and 01S,4R,

5S,8S)-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxa-

bicyclo[3.3.1]nonan-8-ol 039⁰⁰b). A mixture of diastereo-

mers 39⁰⁰a,b 7877 mg, 94%) was prepared from the

sul®des 20⁰⁰a,b 7840 mg, 2.85 mmol) and m-CPBA 7ca.

60%, 2.05 g, 7.12 mmol) according to the general procedure

2A 7reaction time 5 h). The diastereomers were separated by

MPLC 7EtOAc±hexane, 1:1). Less polar sulfone 39⁰⁰a: a

colorless solid 7plates), mp 112±1138C 7EtOAc±hexane,

20

1:5); R_f0.38 7EtOAc±hexane, 1:1); [a]_D1236.7

7c1.0, CHCl₃); IR 7CHCl₃): 3300±3500, 2960, 2928,

1602, 1448, 1318 7s), 1308 7s), 1228, 1151 7s), 1086,

1

1014 cm²¹; H NMR 7400 MHz, CDCl₃): d 1.35 7s, 3H,

Me710)), 1.51 7br s, 3H, Me711)), 1.60 7br dd, 1H,

J14.2, 5.6 Hz, H77)eq), 1.86 7br dddd, 1H, J14.2, 14.2,

6.0, 3.6 Hz, H76)ax), 1.93 7m, 1H, H76)eq), 2.11 7ddd, 1H,

J13.9, 3.0, 2.0 Hz, H79)ax), 2.23 7br ddd, 1H, J13.9, 6.0,

3.5 Hz, H79)eq), 2.30 7m, 1H, H75)), 2.30 7ddd, 1H, J14.2,

14.2, 6.7 Hz, H77)ax), 3.27 7d, 1H, J14.3 Hz, H712)), 3.67

7br dd, 1H, J3.5, 2.5 Hz, H71)), 4.23 7dd, 1H, J14.3,

0.5 Hz, H⁰712)), 7.58 7m, 2H), 7.67 7m, 1H), 7.95 7m,

2H); ¹³C NMR 7100 MHz, CDCl₃): d 22.87 7Me711)),

23.45 7C76)H₂), 24.64 7C79)H₂), 27.97 7Me710)), 30.05

7C75)H), 35.70 7C77)H₂), 61.02 7C712)H₂), 71.30 7C78)),

81.96 7C71)H), 82.71 7C74)), 127.51 72CH), 129.33 72CH),

133.71 7CH), 141.08 7C). DCI 7CH₄) HRMS: obsd

327.1255, calcd for C₁₆H₂₃O₅S 7MH¹) 327.1266. Anal.

Calcd for C₁₆H₂₂O₅S: C, 58.87; H, 6.79; S, 9.82. Found:

C, 58.94; H, 6.86; S, 9.75. The molecular structure of

39⁰⁰a was con®rmed by single crystal X-ray analysis.

6.2.16. 01S,4S,5S,7R,8S)-4,8-Dimethyl-4-phenylsulfenyl-

methyl-2,3-dioxabicyclo[3.3.1] nonan-7,8-diol 051⁰⁰a).

The endoperoxide 51⁰⁰a 7222 mg, 13.5%, a single isomer)

was synthesized from cis-carveol 47⁰⁰72.284 g, 15 mmol)

and PhSH 7550 mg, 5 mmol) according to general procedure

1B 7thiol addition time 12 h) and isolated as a monohydrate.

A colorless solid 7needles), mp 108±1098C 7EtOAc±

20

hexane), R_f0.20 7EtOAc±hexane, 1:1); [a]_D1177.2

7c0.5, CHCl₃); IR 7CHCl₃): 3490 7br, s), 3006, 2957,

2930, 1602, 1480, 1458, 1439, 1418, 1378, 1229, 1075

1

7s), 1041 7s) cm²¹; H NMR 7400 MHz, CDCl₃): d 1.36 br

More polar sulfone 39⁰⁰b: a colorless oil, R_f0.34 7EtOAc±

s, 3H, Me711)), 1.45 7s, 3H, Me710)), 1.96±2.06 7m, 3H),

2.09 7ddd, 1H, J16.0, 3.7, 1.4 Hz, H76)ax), 2.18 7ddd, 1H,

J16.0, 5.5, 4.4 Hz, H76)eq), 3.37 7d, 1H, J12.9 Hz,

H712)), 3.55 7br dd, 1H, J13.2, 5.5 Hz, H77)eq), 3.76

7dd, 1H, J12.9, 0.6 Hz, H⁰712)), 3.76 7m, 1H, H71)),

20

hexane, 1:1); [a]_D1107.8 7c1.0, CHCl₃); IR 7CHCl₃):

3300±3500, 2962, 2929, 1602, 1448, 1321 7s), 1310, 1154

1

7s), 1086, 1016 cm²¹; H NMR 7400 MHz, CDCl₃): d 1.29

7s, 3H, Me710)), 1.58 7br dd, 1H, J14.2, 5.4 Hz, H77)eq),

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2463

1.80 7br s, 3H, Me711)), 1.86±2.00 7m, 2H, H76)ax1eq),

2.03 7ddd, 1H, J13.6, 3.2, 1.8 Hz, H79)ax), 2.09 7br dddd,

1H, J6.4, 6.4, 3.2, 3.2 Hz, H75)), 2.14 7br ddd, 1H, J14.0,

14.0, 6.6 Hz, H77)ax), 2.27 7br ddd, 1H, J13.6, 6.4, 3.3 Hz,

H79)eq), 3.14 7d, 1H, J14.0 Hz, H712)), 3.33 7br d, 1H,

J14.0 Hz, H⁰712)), 3.68 7br dd, 1H, J3.3, 1.8 Hz, H71)),

7.58 7m, 2H), 7.67 7m, 1H), 7.93 7m, 2H); ¹³C NMR

7100 MHz, CDCl₃): d 21.71 7Me711)), 23.46 7C79)H₂),

23.72 7C76)H₂), 27.83 7Me710)), 31.53 7C75)H), 35.35

7C77)H₂), 60.55 7C712)H₂), 71.02 7C78)), 82.35 7C71)H),

82.84 7C74)), 127.52 72CH), 129.25 72CH), 133.76 7CH),

141.13 7C). DCI 7CH₄) HRMS: obsd 327.1247, calcd for

C₁₆H₂₃O₅S 7MH¹) 327.1266.

2.01±2.13 7m, 3H, H75)1H77)ax1H79)ax), 2.26 7br ddd,

1H, J14.0, 4.0, 4.0 Hz, H79)eq), 3.16 7d, 1H, J14.0 Hz,

H712)), 3.31 7br d, 1H, J14.0 Hz, H⁰712)), 3.68 7br d, 1H,

J4.0 Hz, H71)), 7.21±7.27 7m, 2H), 7.91±7.98 7m, 2H);

¹³C NMR 7100 MHz, CDCl₃): d 21.76 7Me711)), 23.54

7C79)H₂), 23.80 7C76)H₂), 28.00 7Me710)), 31.73 7C75)H),

35.49 7C77)H₂), 60.91 7C712)H₂), 71.13 7C78)), 82.40

7C71)H), 82.85 7C74)), 116.58 72CH, J_C±F22.7 Hz),

130.62 72CH, J_C±F9.6 Hz), 133.37 7C, J_C±F2.8 Hz),

165.82 7C±F, J_C±F256.8 Hz). DCI 7CH₄) HRMS: obsd

345.1167, calcd for C₁₄H₂₁FO₅S 7MH¹) 345.1172.

6.3.4. 01R,4R,5R,8R)-4-0n-Butylsulfonyl)methyl-4,8-di-

methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 041⁰a) and

01R,4S,5R,8R)-4-0n-butylsulfonyl)methyl-4,8-dimethyl-

2,3-dioxabicyclo[3.3.1]nonan-8-ol 041⁰b). A mixture of

diastereomers 41⁰a,b 734.2 mg, 88% yield, a/b ca. 63:37)

was prepared by oxidation of sul®des 34⁰a,b 734.7 mg,

0.127 mmol, a/b ca. 60:40) according to procedure 2B and

puri®ed by FC 7hexane±EtOAc, 1:1) to give a colorless oil,

R_f0.23 7EtOAc±hexane, 1:1). A single more polar isomer

41⁰a 7ca. 95% purity, containing 5% of 41⁰b) was isolated

by semipreparative DP HPLC 7hexane±EtOAc, 3:2). A

6.3.2.

01R,4R,5R,8R)-4,8-Dimethyl-4-phenylsulfonyl-

methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 039⁰a) and

01R,4S,5R,8R)-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-

dioxabicyclo[3.3.1]nonan-8-ol 039⁰b).

A mixture of

diastereomers 39⁰a,b 72.128 g, 91%) was prepared by oxida-

tion of sul®des 20⁰a,b 72.10 g, 7.13 mmol) according to

procedure 2A. The diastereomers were separated by

MPLC 7hexane±EtOAc, 1:1). Less polar isomer 39⁰a: a

colorless solid 7plates), mp 112±1138C 7hexane±EtOAc,

20

1

5:1); R_f0.38 7EtOAc±hexane, 1:1); [a]_D2247.5

colorless oil, H NMR 7400 MHz, CDCl₃): d 0.96 7t, 3H,

7c1.0, CHCl₃). Anal. Calcd for C₁₆H₂₂O₅S: C, 58.87; H,

6.79; S, 9.82. Found: C, 58.87; H, 6.84; S, 9.73. More polar

isomer 39⁰b: a colorless oil, R_f0.34 7EtOAc±hexane, 1:1);

J7.4 Hz, MeCH₂CH₂CHH⁰SO₂), 1.36 7s, 3H, Me710)),

1.48 7tq, 3H, J7.4, 7.4 Hz, MeCH₂CH₂CHH⁰SO₂), 1.50

7br s, 3H, Me711)), 1.60 7br dd, 1H, J14.2, 5.4 Hz,

H77)eq), 1.78±1.96 7m, 5H, MeCH₂CH₂CHH⁰SO₂1

H75)1H76)ax1eq), 2.13 7ddd, 1H, J13.9, 2.4, 2.4 Hz,

H79)ax), 2.25 7br ddd, 1H, J13.9, 6.8, 3.3 Hz, H79)eq),

2.31 7ddd, 1H, J14.2, 14.2, 6.4 Hz, H77)ax), 3.01±3.13

7m, 2H, MeCH₂CH₂CHH⁰SO₂), 3.56 and 3.62 7AB quartet,

2H, J14.4 Hz, C712)HH⁰), 3.67 7br s, 1H, H71)); ¹³C NMR

7100 MHz, CDCl₃): d 13.54 7MeCH₂CH₂CH₂SO₂), 21.73

7MeCH₂CH₂CH₂SO₂), 21.96 7Me711)), 23.48 7C76)H₂),

23.86 7MeCH₂CH₂CH₂SO₂), 24.69 7C79)H₂), 28.06

7Me710)), 31.05 7C75)H), 35.74 7C77)H₂), 55.36

7MeCH₂CH₂CH₂SO₂), 57.00 7C712)H₂), 71.40 7C78)),

82.04 7C71)H), 82.09 7C74)). DCI 7CH₄) HRMS: obsd

307.1543, calcd for C₁₄H₂₇O₅S 7MH¹) 307.1579. Selected

NMR data for the sulfon 41⁰b: ¹H NMR 7400 MHz, CDCl₃):

d 1.33 7s, 3H, Me710)), 1.76 br s, 3H, Me711)), 3.04 7d, 1H,

J14.1 Hz, H712)), 3.23 7br d, 1H, J14.1 Hz, H⁰712)),

3.71 7br d, 1H, J3.8 Hz, H71)); ¹³C NMR 7100 MHz,

CDCl₃): d 13.54 7MeCH₂CH₂CH₂SO₂), 21.07 7Me711)),

21.59 7MeCH₂CH₂CH₂SO₂), 23.41 7CH₂), 23.49 7CH₂),

24.05 7CH₂), 28.08 7Me710)), 32.48 7C75)H), 35.38

7C77)H₂), 55.77 7MeCH₂CH₂CH₂SO₂), 57.58 7C712)H₂),

70.98 7C78)), 81.97 7C74)), 82.27 7C71)H).

20

[a]_D2111.9 7c1.0, CHCl₃). DCI 7CH₄) HRMS: obsd

327.1258, calcd for C₁₆H₂₃O₅S 7MH¹) 327.1266. The NMR

spectra of sulfones 39⁰a and 39⁰b coincide with that of

enantiomers 39⁰⁰a and 39⁰⁰b respectively 7see above).

6.3.3. 01R,4R,5R,8R)-4,8-Dimethyl-4-04-¯uorophenylsul-

040⁰a)

fonyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

and 01R,4S,5R,8R)-4,8-dimethyl-4-04-¯uorophenylsul-

fonyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 040⁰b).

A 56:44 mixture of diastereomers 40⁰a,b 7177 mg, 90%)

was prepared by oxidation of sul®des 33⁰a,b 7179.5 mg,

0.57 mmol) according to procedure 2B 7reaction time 6 h)

and isolated by FC 7hexane±EtOAc, 1:1). The diastereo-

mers were separated by MPLC 7hexane±EtOAc, 3:2).

Less polar isomer 40⁰a: a colorless oil, R_f0.44 7EtOAc±

1

hexane, 1:1); H NMR 7400 MHz, CDCl₃): d 1.33 7s, 3H,

Me710)), 1.50 br s, 3H, Me711)), 1.58 7br dd, 1H, J14.0,

5.5 Hz, H77)eq), 1.81±1.93 7m, 2H, H76)ax1eq), 2.11 7ddd,

1H, J13.0, 2.4, 2.4 Hz, H79)ax), 2.20 7br ddd, 1H, J13.0,

6.0, 3.4 Hz, H79)eq), 2.22 7m, 1H, H75)), 2.27 7ddd, 1H,

J14.0, 14.0, 6.8 Hz, H77)ax), 3.30 7d, 1H, J14.3 Hz,

H712)), 3.66 7br d, 1H, J3.4 Hz, H71)), 4.15 7br d, 1H,

J14.3 Hz, H⁰712)), 7.22±7.27 7m, 2H), 7.92±7.98 7m,

2H); ¹³C NMR 7100 MHz, CDCl₃): d 22.76 7Me711)),

23.47 7C76)H₂), 24.68 7C79)H₂), 27.97 7Me710)), 30.25

7C75)H), 35.72 7C77)H₂), 61.20 7C712)H₂), 71.31 7C78)),

6.3.5. 01R,4R,5R,8R)-4,8-Dimethyl-4-0methoxycarbonyl-

methylsulfonyl)methyl-2,3-dioxabicyclo[3.3.1]nonan-8-

ol 042⁰a) and 01R,4S,5R,8R)-4,8-dimethyl-4-0methoxy-

carbonylmethylsulfonyl)methyl-2,3-dioxabicyclo[3.3.1]-

nonan-8-ol 042⁰b). Oxidation of sul®de 35⁰a 742.4 mg,

0.146 mmol) according to procedure 2B afforded after FC

puri®cation 7hexane±EtOAc, 1:1) the title sulfone 42⁰a

741.5 mg, 88%). A colorless oil, R_f0.11 7EtOAc±hexane,

81.98 7C71)H), 82.64 7C74)), 116.60 72CH, J_C±F

22.7 Hz), 130.51 72CH, J_C±F9.6 Hz), 133.27 7C, J_C±F

2.7 Hz), 165.77 7C±F, J_C±F256.5 Hz). DCI 7CH₄)

HRMS: obsd 345.1154, calcd for C₁₄H₂₁FO₅S 7MH¹)

345.1172.

1

1:1); H NMR 7400 MHz, CDCl₃): d 1.38 7s, 3H, Me710)),

More polar isomer 40⁰b: a colorless oil, R_f0.41 7EtOAc±

hexane, 1:1); H NMR 7400 MHz, CDCl₃): d 1.27 7s, 3H,

1.53 br s, 3H, Me711)), 1.58±1.64 7m, 1H, H77)eq), 1.79±

1.96 7m, 3H, H75)1H76)ax1eq), 2.14 7ddd, 1H, J13.8,

2.2, 2.2 Hz, H79)ax), 2.25±2.30 7m, 1H, H79)eq), 2.30

7ddd, 1H, J13.5, 13.5, 6.6 Hz, H77)ax), 3.65 7br d, 1H,

1

Me710)), 1.57 7ddd, 1H, J14.0, 3.3, 3.3 Hz, H77)eq), 1.79

7d, 3H, J0.3 Hz, Me711)), 1.88±1.95 7m, 2H, H76)ax1eq),

2464

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

J14.7 Hz, H712)), 3.73 7br d, 1H, J3.5 Hz, H71)), 3.82 7s,

3H, MeO), 3.98 7br d, 1H, J15.2 Hz, MeO₂CCHH⁰SO₂),

4.21 7d, 1H, J14.7 Hz, H⁰712)), 4.31 7d, 1H, J15.2 Hz,

MeO₂CCHH⁰SO₂); ¹³C NMR 763 MHz, CDCl₃): d 21.96

7Me711)), 23.23 7C76)H₂), 24.31 7C79)H₂), 27.92

7Me710)), 31.11 7C75)H), 35.44 7C77)H₂), 53.14 7MeO),

57.38 7C712)H₂), 59.06 7MeO₂CCH₂SO₂), 71.24 7C78)),

81.94 7C71)H), 81.99 7C74)), 163.79 7CvO). DCI 7CH₄)

HRMS: obsd 323.1187, calcd for C₁₃H₂₃O₇S 7MH¹)

323.1165.

2B followed by FC 7hexane±EtOAc, 1:1) afforded a mixture

of diastereomeric sulfones 44⁰a,b 7149 mg, 74% yield, a/b

ca. 58:42) as a colorless oil: R_f0.22 7EtOAc±hexane, 1:1).

Recrystallization from EtOAc±hexane 71:9) gave a single

isomer 44⁰a: a colorless solid, mp 89±918C; ¹H NMR

7400 MHz, CDCl₃): d 1.38 7s, 3H, Me710)), 1.44 7s, 9H,

Me₃CS), 1.49 br s, 3H, Me711)), 1.68 7br dd, 1H, J13.8,

6.0 Hz, H77)eq), 1.84 7dddd, 1H, J14.3, 14.3, 5.8, 3.5 Hz,

H76)ax), 1.89±1.95 7m, 1H, H76)eq), 2.12 7ddd, 1H, J13.8,

3.1, 1.9 Hz, H79)ax), 2.24±2.36 7m, 3H, H75)1

H77)ax1H79)eq), 3.05 7d, 1H, J13.6 Hz, H712)), 3.72

7br s, 1H, H71)), 4.14 7br d, 1H, J13.6 Hz, H⁰712)); ¹³C

NMR 7100 MHz, CDCl₃): d 22.99 7Me711)), 23.29

7Me₃CS), 23.54 7C76)H₂), 24.80 7C79)H₂), 28.08 7Me710)),

29.74 7C75)H), 35.89 7C77)H₂), 49.50 7C712)H₂), 60.33

7Me₃CS), 71.42 7C78)), 82.15 7C71)H), 83.05 7C74)). DCI

7CH₄) HRMS: obsd 307.1615, calcd for C₁₄H₂₇O₅S 7MH¹)

307.1579. Sulfon 44⁰b: ¹H NMR 7400 MHz, CDCl₃): d 1.35

7s, 3H, Me710)), 1.42 7s, 9H, Me₃CS), 1.57±1.66 7m, 1H,

H77)eq), 1.81 br s, 3H, Me711)), 1.86±1.98 7m, 2H,

H76)ax1eq), 2.02 7ddd, 1H, J13.8, 3.2, 1.9 Hz, H79)ax),

2.15 7br dddd, 1H, J6.4, 6.4, 3.2, 3.2 Hz, H75)), 2.19±2.29

7m, 2H, H77)ax1H79)eq), 2.83 7d, 1H, J13.0 Hz, H712)),

3.18 7br d, 1H, J13.0 Hz, H⁰712)), 3.72 7br s, 1H, H71));

¹³C NMR 7100 MHz, CDCl₃): d 22.18 7Me711)), 23.29

7Me₃CS), 23.61 7C76)H₂), 23.85 7C79)H₂), 28.10 7Me710)),

31.18 7C75)H), 35.73 7C77)H₂), 49.02 7C712)H₂), 60.83

7Me₃CS), 71.20 7C78)), 82.73 7C71)H), 83.46 7C74)).

Similarly, oxidation of the sul®de 35⁰b 760.0 mg,

0.207 mmol) 7procedure 2B) afforded the sulfone 42⁰b

759.4 mg, 89%). A colorless oil, R_f0.13 7EtOAc±hexane,

1

1:1); H NMR 7400 MHz, CDCl₃): d 1.33 7s, 3H, Me710)),

1.59±1.66 7m, 1H, H77) eq), 1.78 br s, 3H, Me711)), 1.79±

1.93 7m, 3H, H75)1H76)ax1eq), 2.08 7ddd, 1H, J13.6,

3.3, 1.7 Hz, H79)ax), 2.26±2.35 7m, 2H, H77)ax1H79)eq),

3.21 7dd, 1H, J14.6, 1.6 Hz, H712)), 3.78 7br d, 1H,

J4.2 Hz, H71)), 3.81 7s, 3H, MeO), 3.89 7br d, 1H,

J14.6 Hz, H⁰712)), 3.94 7dd, 1H, J15.3, 1.8 Hz,

MeO₂CCHH⁰SO₂),

4.31

7d,

1H,

J15.3 Hz,

MeO₂CCHH⁰SO₂); ¹³C NMR 763 MHz, CDCl₃): d 21.07

7Me711)), 23.24 7C76)H₂), 23.41 7C79)H₂), 28.11

7Me710)), 32.89 7C75)H), 34.83 7C77)H₂), 53.19 7MeO),

58.02 7C712)H₂), 59.57 7MeO₂CCH₂SO₂), 71.00 7C78)),

82.22 7C71)H), 81.42 7C74)), 163.74 7CvO). DCI 7CH₄)

HRMS: obsd 323.1158, calcd for C₁₃H₂₃O₇S 7MH¹)

323.1165.

6.3.8.

01S,4S,5S,7S,8S)-7-Benzoyloxy-4,8-dimethyl-4-

6.3.6. 01R,4R/S,5R,8R)-4-Cyclohexylsulfonylmethyl-4,8-

dimethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ols 043⁰a,b). A

mixture of diastereomeric sulfones 43⁰a,b 770.5 mg, ca.

85% yield, a/b ca. 60:40) was prepared by oxidation of

sul®des 36⁰a,b 7100 mg of ca. 75% purity, ca. 0.25 mmol)

7procedure 2B) and isolated by FC 7hexane±EtOAc, 1:1). A

colorless oil, R_f0.24 7EtOAc±hexane, 1:1); ¹H NMR

7400 MHz, CDCl₃): d 1.20±1.35 7m, 2H); 1.35 7s,

Me710), b), 1.37 7s, Me710), a), total 3H; 1.49 br s,

Me711), a), 1.79 br s, Me711), a), total 3H; 1.50±1.75 7m,

6H); 1.83±1.98 7m, ca. 5H), 1.99 7br dddd, J6.4, 6.4, 3.2,

3.2 Hz, H75)), 2.04 7ddd, 1H, J13.5, 3.2, 1.8 Hz, H79)ax),

total 7H; 2.10±2.30 7m, ca. 5H), 2.31 7ddd, 1H, J114.0,

114.0, 6.5 Hz, H77)ax), total 6H; 2.86±2.98 7m, 1H,

CHSO₂); 3.03 and 3.10 7AB quartet, J13.9 Hz,

C712)HH⁰, b), 3.27 7d, J14.0 Hz, H712), a), 3.83 7d, 1H,

J14.0 Hz, H⁰712)), total 2H; 3.71 7br d, J3.3 Hz, H71),

a), 3.74 7br d, J4.0 Hz, H71), b); ¹³C NMR 7100 MHz,

CDCl₃): d 21.56 7Me711), b), 22.51 7Me711), a); 23.44,

23.55, 23.60, 24.26, 24.55, 24.67, 24.94, 24.99, 25.03,

25.09, 25.66, 25.91 7CH₂); 27.98 7Me710), a), 28.10

7Me710), b); 30.43 7C75)H, a), 32.01 7C75)H, b); 35.58

7C77)H₂, b), 35.71 7C77)H₂, a); 53.29 7C712)H₂, a), 53.58

7C712)H₂, a); 63.45 7CHSO₂, a), 63.76 7CHSO₂, b); 71.08

7C78), b), 71.32 7C78), a); 82.00 7C71)H, a), 82.41 7C71)H,

b); 82.47 7C74), a), 82.83 7C74), b). DCI 7CH₄) HRMS: obsd

333.1752, calcd for C₁₆H₂₉O₅S 7MH¹) 333.1736.

phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

052⁰⁰a) and 01S,4R,5S,7S,8S)-7-benzoyloxy-4,8-dimethyl-

4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-

ol 052⁰⁰b). A diastereomeric mixture of sulfones 52⁰⁰a,b

780.5 mg, 93%) was prepared by oxidation of sul®des

48⁰⁰a,b 780 mg, 0.193 mmol) 7protocol 2A) and puri®ed by

FC 7hexane±EtOAc, 65:35). The diastereomers were sepa-

rated by MPLC 7hexane±EtOAc, 3:2). More polar isomer

52⁰⁰a: a colorless solid, mp 182±1838C; R_f0.36 7hexane±

20

EtOAc, 3:2); [a]_D1164 7c0.25, CHCl₃); IR 7CHCl₃):

3400±3550, 2989, 2973, 2934, 1717 7s), 1448, 1316 7s),

1310, 1270 7s), 1151 7s), 1087, 1070 cm²^{1 1}H NMR

;

7400 MHz, CDCl₃): d 1.41 7s, 3H, Me710)), 1.64 br s, 3H,

Me711)), 1.88 7ddd, 1H, J13.3, 11.8, 3.6 Hz, H76)ax), 2.25

7ddd, 1H, J14.0, 2.8, 2.8 Hz, H79)ax), 2.28 7dddd, 1H,

J14.0, 3.2, 2.8, 2.2 Hz, H79)eq), 2.38 7br s, 1H, OH),

2.39 7dddd, 1H, J13.3, 6.2, 3.2, 2.2 Hz, H76)eq), 2.61

7br dddd, 1H, J6.2, 6.2, 3.6, 3.2 Hz, H75)), 3.31 7d, 1H,

J14.3 Hz, H712)), 3.97 7br dd, 1H, J2.8, 2.8 Hz, H71)),

4.23 7br d, 1H, J14.3 Hz, H⁰712)), 5.71 7dd, 1H, J11.8,

6.2 Hz, H77)ax), 7.48 7m, 2H), 7.58±7.62 7m, 3H), 7.68 7m,

1H), 7.96 7m, 2H), 8.04 7m, 2H); ¹³C NMR 7100 MHz,

CDCl₃):

d

23.28 7Me711)), 24.19 7C79)H₂), 24.41

7Me710)), 29.13 7C76)H₂), 32.10 7C75)H), 60.87

7C712)H₂), 72.71 7C78)), 74.51 7C77)H), 82.51 7C74)),

83.14 7C71)H), 127.59 72CH), 128.56 72CH), 129.42

72CH), 129.51 72CH), 129.93 7C), 133.31 7CH), 133.87

7CH), 140.96 7C), 165.61 7CvO). Anal. Calcd for

C₂₃H₂₆O₇S: C, 61.87; H, 5.87; S 7.18. Found: C, 61.60; H

5.81; S 6.87.

6.3.7. 01R,4R,5R,8R)-4-0tert-Butylsulfonyl)methyl-4,8-

dimethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 044⁰a) and

01R,4S,5R,8R)-4-0tert-butylsulfonyl)methyl-4,8-dimethyl-

2,3-dioxabicyclo[3.3.1]nonan-8-ol 044⁰b). Oxidation of

sul®des 37⁰a,b 7180 mg, 0.66 mmol) according to procedure

Less polar isomer 52⁰⁰b: a colorless solid, mp 132±1338C; R_f

20

0.42 7hexane±EtOAc, 3:2); [a]_D157.2 7c0.5, CHCl₃);

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2465

IR 7CHCl₃): 3300±3550, 3013, 2986, 2973, 2933, 1716 7s),

1602, 1448, 1321 7s), 1270 7s), 1154 7s), 1105, 1088 cm²¹

J3.5, 2.5, 1.8 Hz, H71)), 5.68 7dd, 1H, J12.0, 6.1 Hz,

H77)ax), 7.48 7m, 2H), 7.61 7m, 1H), 8.02 7m, 2H); ¹³C

NMR 7100 MHz, CDCl₃): d 13.52 7MeCH₂CH₂CH₂SO₂),

21.16 7Me711)), 21.68 7MeCH₂CH₂CH₂SO₂), 23.23

7C79)H₂), 24.13 7MeCH₂CH₂CH₂SO₂), 24.36 7Me710)),

;

¹H NMR 7400 MHz, CDCl₃): d 1.36 7s, 3H, Me710)), 1.90 br

s, 3H, Me711)), 1.93 7ddd, 1H, J13.8, 12.0, 3.5 Hz,

H76)ax), 2.16 7ddd, 1H, J13.8, 3.3, 2.0 Hz, H79)ax), 2.30

7dddd, 1H, J13.8, 3.6, 3.6, 2.9 Hz, H79)eq), 2.34 7br s, 1H,

OH), 2.43 7m, 1H, H75)), 2.57 7dddd, 1H, J13.8, 6.1, 2.9,

2.9 Hz, H76)eq), 3.16 7d, 1H, J13.9 Hz, H712)), 3.58 7br d,

1H, J14.3 Hz, H⁰712)), 3.97 7ddd, 1H, J3.6, 2.0, 1.5 Hz,

H71)), 5.57 7dd, 1H, J12.0, 6.1 Hz, H77)ax), 7.50 7m, 2H),

7.58±7.63 7m, 3H), 7.67 7m, 1H), 7.97±8.05 7m, 4H); ¹³C

NMR 7100 MHz, CDCl₃): d 21.71 7Me711)), 23.27

7C79)H₂), 24.31 7Me710)), 29.49 7C76)H₂), 33.61 7C75)H),

60.24 7C712)H₂), 72.70 7C78)), 74.58 7C77)H), 82.91 7C74)),

83.80 7C71)H), 127.79 72CH), 128.55 72CH), 129.39 72CH),

129.49 72CH), 129.97 7C), 133.30 7CH), 133.91 7CH),

141.02 7C), 165.69 7CvO). Anal. Calcd for C₂₃H₂₆O₇S:

C, 61.87; H, 5.87; S 7.18. Found: C, 61.60; H 5.91; S

7.43.

29.33

7C76)H₂),

33.79

7C75)H),

56.19

7MeCH₂CH₂CH₂SO₂), 56.57 7C712)H₂), 72.71 7C78)),

74.44 7C77)H), 82.53 7C74)), 83.73 7C71)H), 128.60

72CH), 129.49 72CH), 129.87 7C), 133.36 7CH), 165.79

7CvO).

6.3.10. 01S,4S,5S,7R,8S)-7-Benzoyloxy-4,8-dimethyl-4-

phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

054⁰⁰a) and 01S,4R,5S,7R,8S)-7-benzoyloxy-4,8-dimethyl-

4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonan-8-

ol 054⁰⁰b). A mixture of the title sulfones 54⁰⁰a,b was

prepared by oxidation of the sul®des 50⁰⁰a,b 719.0 mg,

0.0435 mmol, ca. 65:35) according to protocol 2A. The

mixture was separated by MPLC 7hexane±EtOAc, 3:2) to

give individual sulfones 54⁰⁰a 711.0 mg) and 54⁰⁰b 76.3 mg)

7total yield 89%). More polar isomer 54⁰⁰a: a colorless solid,

mp 71±738C; IR 7CHCl₃): 3504 7br), 3405 7br), 2960, 2930,

1709 7s), 1600, 1448, 1377, 1317 7s), 1308 7s), 1283 7s),

6.3.9. 01S,4S,5S,7S,8S)-7-Benzoyloxy-4-0n-butylsulfonyl)-

methyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol

053⁰⁰a) and 01S,4R,5S,7S,8S)-7-benzoyloxy-4-0n-butylsul-

fonyl)methyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-

8-ol 053⁰⁰b). Oxidation of sul®des 49⁰⁰a,b 737.5 mg,

0.095 mmol, ca. 55:45) according to protocol 2A 7reaction

time 5 h) followed by FC 7hexane±EtOAc, 7:3) afforded the

individual diastereomeric sulfones 53⁰⁰a 719.5 mg) and 53⁰⁰b

717.2 mg) 7total yield 91%). More polar isomer 53⁰⁰a: a

colorless solid, mp 140±1428C, R_f0.25 7hexane±EtOAc,

3:2); ¹H NMR 7400 MHz, CDCl₃): d 0.98 7t, 3H,

J7.4 Hz, MeCH₂CH₂CHH⁰SO₂), 1.43 7s, 3H, Me710)),

1.49 7tq, 2H, J7.4, 7.4 Hz, CH₃CH₂CH₂CHH⁰SO₂), 1.64

1

1274 7s), 1149 7s), 1116 7s), 1086, 1033 cm²¹; H NMR

7400 MHz, CDCl₃): d 1.39 7s, 3H, Me710)), 1.51 7br s,

3H, Me711)), 1.94 7br s, 1H, OH), 2.14 7ddd, 1H, J14.0,

5.0, 2.4 Hz, H79)ax), 2.15 7ddd, 1H, J16.0, 4.7, 1.6 Hz,

H76)ax), 2.35 7ddd, 1H, J16.0, 6.5, 5.0 Hz, H76)eq), 2.36

7m, 1H, H79)eq), 2.50 7m, 1H, H75)), 3.36 7d, 1H,

J14.3 Hz, H712)), 3.83 7br dd, 1H, J3.6, 2.4 Hz, H71)),

4.34 7br d, 1H, J14.3 Hz, H⁰712)), 5.29 7dd, 1H, J6.5,

1.6 Hz, H77)eq), 7.44 7m, 2H), 7.55±7.62 7m, 3H), 7.68 7m,

1H), 7.97 7m, 2H), 8.10 7m, 2H); ¹³C NMR 7100 MHz,

7br

s,

3H,

Me711)),

1.83±1.91

7m,

2H,

CDCl₃):

d

23.23 7Me711)), 23.41 7Me710)), 23.97

CH₃CH₂CH₂CHH⁰SO₂), 1.85 7ddd, 1H, J13.5, 11.7,

3.3 Hz, H76)ax), 2.25 7m, 2H, H79)ax1eq), 2.31 7br dddd,

1H, J6.4, 6.4, 3.3, 3.3 Hz, H75)), 2.38 7ddddd, 1H, J13.5,

6.2, 3.3, 1.6, 1.6 Hz, H76)eq), 2.40 7br s, 1H, OH), 3.08 7m,

2H, CH₃CH₂CH₂CHH⁰SO₂), 3.50 7d, 1H, J14.2 Hz,

H712)), 3.76 7br d, 1H, J14.2 Hz, H⁰712)), 4.01 7br dd,

1H, J2.5, 2.5 Hz, H71)), 5.72 7dd, 1H, J11.7, 6.2 Hz,

H77)ax), 7.48 7m, 2H), 7.60 7m, 1H), 8.03 7m, 2H); ¹³C

NMR 7100 MHz, CDCl₃): d 13.55 7MeCH₂CH₂CH₂SO₂),

21.70 7MeCH₂CH₂CH₂SO₂), 22.46 7Me711)), 23.86

7MeCH₂CH₂CH₂SO₂), 24.12 7C79)H₂), 24.40 7Me710)),

7C79)H₂), 28.71 7C76)H₂), 30.15 7C75)H), 60.89 7C712)H₂),

73.75 7C78)), 74.14 7C77)H), 81.21 7C71)H), 81.71 7C74)),

127.58 72CH), 128.48 72CH), 129.42 72CH), 129.90 72CH),

130.11 7C), 133.15 7CH), 133.83 7CH), 141.10 7C), 166.20

7CvO). DCI 7CH₄) HRMS: obsd 447.1510, calcd for

C₂₃H₂₇O₇S 7MH¹) 447.1478.

Less polar isomer 54⁰⁰b: a colorless solid, mp 160±1628C

7dec.); ¹H NMR 7400 MHz, CDCl₃): d 1.37 7s, 3H, Me710)),

1.86 7br s, 3H, Me711)), 1.97 7br s, 1H, OH), 2.08 7ddd, 1H,

J13.6, 3.0, 1.6 Hz, H79)ax), 2.21 7ddd, 1H, J16.0, 4.4,

2.0 Hz, H76)ax), 2.32 7m, 1H, H75)), 2.34±2.42 7m, 2H,

H76)eq1H79)eq), 3.11 7d, 1H, J14.0 Hz, H712)), 3.58

7br d, 1H, J14.0 Hz, H⁰712)), 3.94 7br dd, 1H, J3.6,

1.6 Hz, H71)), 5.27 7dd, 1H, J6.3, 2.0 Hz, H77)eq), 7.34

7m, 3H), 7.49 7m, 2H), 7.68 7m, 1H), 7.97 7m, 2H), 8.08 7m,

2H); ¹³C NMR 7100 MHz, CDCl₃): d 21.89 7Me711)), 22.83

7C79)H₂), 23.33 7Me710)), 29.32 7C76)H₂), 32.20 7C75)H),

60.85 7C712)H₂), 73.33 7C78)), 74.80 7C77)H), 81.87

7C71)H), 82.04 7C74)), 127.02 72CH), 128.48 72CH),

129.17 72CH), 129.65 72CH), 129.83 7C), 133.18 7CH),

133.55 7CH), 140.88 7C), 166.08 7CvO). DCI 7CH₄)

HRMS: obsd 447.1591, calcd for C₂₃H₂₇O₇S 7MH¹)

447.1478.

29.06

7C76)H₂),

32.84

7C75)H),

55.41

7MeCH₂CH₂CH₂SO₂), 56.64 7C712)H₂), 72.71 7C78)),

74.36 7C77)H), 81.95 7C74)), 83.12 7C71)H), 128.57

72CH), 129.51 72CH), 129.90 7C), 133.33 7CH), 165.58

7CvO). Anal. Calcd for C₂₁H₃₀O₇S: C, 59.14; H, 7.09; S,

7.52. Found: C, 59.34; H, 7.17; S, 7.22.

Less polar isomer 53⁰⁰b: a colorless oil, R_f0.36 7hexane±

1

EtOAc, 3:2); H NMR 7400 MHz, CDCl₃): d 0.99 7t, 3H,

J7.4 Hz, MeCH₂CH₂CHH⁰SO₂), 1.44 7s, 3H, Me710)),

1.50 7tq, 2H, J7.4, 7.4 Hz, CH₃CH₂CH₂CHH⁰SO₂),

1.86±1.95 7m, 3H, H76)ax1MeCH₂CH₂CHH⁰SO₂), 1.88

7br s, 3H, Me711)), 2.16 7ddd, 1H, J13.0, 2.5, 1.9 Hz,

H79)ax), 2.28 7m, 1H, H75)), 2.31 7dddd, 1H, J13.0, 3.5,

3.3, 2.9 Hz, H79)eq), 2.32 7br s, 1H, OH), 2.42 7dddd, 1H,

J13.8, 6.1, 2.9, 2.9 Hz, H76)eq), 3.08 7m, 2H,

MeCH₂CH₂CHH⁰SO₂), 3.17 7d, 1H, J13.8 Hz, H712)),

3.37 7br d, 1H, J13.8 Hz, H⁰712)), 4.00 7br ddd, 1H,

6.3.11. 01S,4S,5S,7R,8S)-4,8-Dimethyl-4-phenylsulfonyl-

mono-

methyl-2,3-dioxabicyclo[3.3.1]nonan-7,8-diol

hydrate 055⁰⁰a). The title sulfone 55⁰⁰a 783 mg, 92% yield)

was prepared by oxidation of sul®de 51⁰⁰a 782 mg,

2466

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

0.25 mmol) according to protocol 2A and puri®ed by FC

7hexane±EtOAc, 2:3). A colorless solid: mp 132±1338C

7needles from hexane±EtOAc, 2:1); R_f0.20 7EtOAc±

total 2H; 3.63 7br dd, J2.5, 2.5 Hz, H71), a), 3.63 7m, H71),

b), total 1H; 7.26±7.42 7m, 5H).

20

hexane, 1: 1); [a]_D1142.8 7c0.5, CHCl₃); IR

7c) A diastereomeric mixture of TMS-derivatives 56⁰⁰a±d

7313 mg) was treated with freshly distilled AcCl 72.5 mL)

and stirred for 48 h at rt. The mixture was evaporated and

dried under vacuum 70.05 mm Hg) to give the crude acet-

oxysul®des 57⁰⁰a±d 7283 mg). A pale brown oil: R_f0.67

730% of EtOAc in hexane); IR 7neat): 2935, 1732, 1453,

7CHCl₃): 3510 7br, s), 3300±3550, 3006, 2959, 2930,

1602, 1448, 1381, 1319 7s), 1309 7s), 1151 7s), 1085,

1

1076, 1042 7s) cm²¹; H NMR 7400 MHz, CDCl₃): d 1.42

7s, 3H, Me710)), 1.64 7br s, 3H, Me711)), 2.16 7ddd, 1H,

J14.0, 3.4, 1.9 Hz, H79)ax), 2.17±2.25 7m, 2H,

H76)ax1eq), 2.27 7ddd, 1H, J14.0, 6.8, 3.4 Hz, H79)eq),

2.42 7br dddd, J6.4, 6.4, 3.4, 3.4 Hz, H75)), 3.36 7d, 1H,

J14.3 Hz, H712)), 3.57 7ddd, 1H, J13.2, 5.4, 0.9 Hz,

H77)eq), 3.78 7br dd, 1H, J3.4, 1.9 Hz, 1H, H71)), 3.89

7br d, 1H, J13.2 Hz, C77)OH, exch. with CD₃CO₂D), 4.25

7dd, 1H, J14.3, 0.5 Hz, H⁰712)), 7.60 7m, 2H), 7.68 7m,

1H), 7.96 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d 23.19

7Me711)), 23.65 7C79)H₂), 24.53 7Me710)), 30.86 7C75)H),

30.92 7C76)H₂), 60.70 7C712)H₂), 73.02 7C77)H), 74.25

7C78)), 82.63 7C71)H), 82.72 7C74)), 127.63 72CH), 129.46

72CH), 133.90 7CH), 141.09 7C). Anal. Calcd for

C₁₆H₂₂O₆S´ H₂O: C, 53.32; H, 6.71; S, 8.90. Found: C,

53.08; H, 6.82; S, 8.54.

1

1371, 1254, 1223, 1204, 1054 cm²¹; H NMR 7400 MHz,

CDCl₃): d 1.24 7br s, Me711), a), 1.56 7br s, Me711), b), total

3H; 1.65 7s, Me710), b), 1.66 7s, Me710), a), total 3H; 1.67±

1.89 7m, 3H); 1.74 7m, H75), b), 1.90 7br dddd, J6.6, 6.6,

3.3, 3.3 Hz, H75), a), total 1H; 2.00 7s, 3H, MeC7O)); 2.07

7br ddd, J14.1, 6.6, 3.4 Hz, H79)eq, a), 2.27 7m, H79)eq,

b), total 1H; 2.12±2.20 7m, 1H, H77)eq, a1b); 2.25 7ddd,

J15.0, 13.2, 6.0 Hz, H77)ax, b), 2.28 7ddd, J14.3, 13.3,

6.0 Hz, H77)ax, a), total 1H; 2.95 7d) and 3.02 7dd,

J0.4 Hz) 7AB quartet, J12.0 Hz, HH⁰712), b), 3.30 7d,

J12.8 Hz, H712), a), 3.72 7dd, J12.8, 0.5 Hz, H⁰712), a),

total 2H; 4.40 7br dd, J3.4, 1.0 Hz, H71), a), 4.44 7br dd,

J3.4, 0.8 Hz, H71), b), total 1H; 7.17±7.23 7m, 1H), 7.29

7m, 2H), 7.37 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d

22.03 7Me711)), 22.42 7Me710)), 22.55 7MeC7O)), 23.50

7C76)H₂), 23.97 7C79)H₂), 28.52 7C75)H), 32.88 7C77)H₂),

40.71 7C712)H₂), 77.46 7C71)H), 82.76 7C78)), 83.85 7C74)),

126.24 7CH), 128.91 72CH), 129.76 72CH), 136.73 7C),

170.13 7CvO) 7isomer 57⁰⁰a); 21.77 7Me711)), 22.53

7Me710)), 22.55 7MeC7O)), 23.22 7C76)H₂), 24.09

7C79)H₂), 29.89 7C75)H), 33.20 7C77)H₂), 40.81 7C712)H₂),

77.91 7C71)H), 82.67 7C78)), 83.73 7C74)), 126.43 7CH),

128.96 72CH), 129.73 72CH), 136.29 7C), 170.13 7CvO)

7isomer 57⁰⁰b).

6.3.12. 01S,4S,5S,8S)-8-Acetoxy-4,8-dimethyl-4-phenyl-

058⁰⁰a),

sulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonane

01S,4R,5S,8S)-8-acetoxy-4,8-dimethyl-4-phenylsulfonyl-

methyl-2,3-dioxabicyclo[3.3.1]nonane 058⁰⁰b), 01S,4S,5S,

8R)-8-acetoxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-

dioxabicyclo[3.3.1]nonane 058⁰⁰c), and 01S,4R,5S,8R)-8-

acetoxy-4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxa-

bicyclo[3.3.1]nonane 058⁰⁰d). 7a) A mixture of hydroxysul-

®des 20⁰⁰a±d 72.657 g, about 57% yield) was prepared

applying the TOCO reaction to S-limonene 18⁰⁰76.13 g,

45.0 mmol) and PhSH 71.653 g, 15 mmol) according to

general procedure 1B. A crude reaction mixture was frac-

tionated by FC 7EtOAc±hexane, 3:7) with collection of the

peroxidic fractions 7TLC monitoring using the stain 2) of R_f

0.23±0.29 7EtOAc±hexane, 3:7). The hydroxysul®des

20⁰⁰a±d isolated by this method were contaminated by

unidenti®ed nonperoxidic impurities 73±4%). Hydroxy-

sul®des 20⁰⁰a±d were used in the next steps without

additional puri®cation.

7d) A mixture of acetoxysul®des 57⁰⁰a±d 7283 mg) was

dissolved in EtOAc 78 mL) and oxidized by m-CPBA

7526 mg of ca. 70%, 2.135 mmol) 7protocol 2A, 6 h). A

conventional work-up followed by FC 7hexane±EtOAc,

3:1) afforded a solid mixture of sulfones 58⁰⁰a,b 7265 mg,

84%, a/b ca. 56:44) and more polar semisolid fraction

744 mg) consisted of the sulfones 58⁰⁰b±d and some non-

peroxidic impurities. The mixture of sulfones 58⁰⁰a,b was

separated by MPLC 7hexane±EtOAc, 3:1) to give the indi-

vidual diastereomers 58⁰⁰a 7the least polar component), and

58⁰⁰b, both as a colorless solid 7see below). The fraction

consisted of 58⁰⁰b±d was separated by semipreparative DP

HPLC 7EtOAc±hexane, 40:60) to give the sulfone 58⁰⁰b

78 mg), the sulfone 58⁰⁰d 78 mg of ca. 93% purity) as a

colorless oil 7the most polar component), and a fraction

containing the sulfone 58⁰⁰c 712 mg). The middle fraction

containing 58⁰⁰c was subjected to semipreparative RP HPLC

7methanol±water, 70:30) to afford the sulfone 58⁰⁰c 75 mg of

ca. 93% purity) as a colorless semisolid. Analytical HPLC

data 7EtOAc±hexane, 25:75) for 58⁰⁰a±d: t_R11.9 758⁰⁰a),

12.8 758⁰⁰b), 16.1 758⁰⁰c) and 17.5 758⁰⁰d) min. Analytical RP

HPLC 7methanol±water, 70:30, ¯ow rate 0.5 mL/min): t_R

8.1 min for 58⁰⁰c.

7b) To a cold 708C) solution of hydroxysul®des 20⁰⁰a±d

7250 mg, ca. 0.84 mmol) and 2,6-lutidine 7250 mg,

2.34 mmol) in dry CH₂Cl₂75 mL) was added neat TfOTMS

7422 mg, 1.79 mmol) and the reaction mixture was stirred at

08C for 1 h 7TLC monitoring). The mixture was then poured

into cold water 750 mL), extracted with EtOAc±hexane

71:4, 2£50 mL), washed with cold saturated NaHCO₃

725 mL), dried 7Na₂SO₄), and evaporated to give the crude

TMS-derivative 56⁰⁰a±d 7313 mg, quantitative yield). A

mobile pale yellow oil, R_f0.55 75% of EtOAc in hexane);

IR 7neat): 2954, 2928, 1453, 1446, 1372, 1250, 1125, 1060,

1040 cm²¹; ¹H NMR 7400 MHz, CDCl₃): d 0.108 and 0.111

72£s, Me₃Si), total 9H; 1.22 7br s, Me711), a), 1.53 7d,

J0.5 Hz, Me711), b), total 3H; 1.38 7s, Me710), b), 1.39

7s, Me710), a), total 3H; 1.58±1.65 7m, 1H, H77)eq, a1b),

1.67±1.82 7m, 3H), 1.84 7br dddd, J6.0, 6.0, 3.0, 3.0 Hz,

H75), a), 1.97±1.99 7m, 1H); 2.06 7ddd, J13.0, 3.0, 2.5 Hz,

H79)ax, a), 2.13±2.25 7m), total 2H; 2.94 7d) and 3.02 7dd,

J0.5 Hz) 7AB quartet, J12.0 Hz, HH⁰712), b), 3.32 7d,

J12.7 Hz, H712), a), 3.68 7dd, J12.7, 0.6 Hz, H⁰712), a),

The least polar major isomer 58⁰⁰a: a colorless solid, mp

97±988C; R_f0.37 7hexane±benzene±EtOAc, 11:6:3); H

1

NMR 7400 MHz, CDCl₃): d 1.51 7br s, 3H, Me711)), 1.62

7s, 3H, Me710)), 1.78 7br dddd, 1H, J14.5, 13.4, 6.8,

3.4 Hz, H76)ax), 1.88 7ddd, 1H, J14.0, 3.4, 1.2 Hz,

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2467

H79)ax), 1.90 7dddd, 1H, J14.5, 6.8, 2.8, 2.8 Hz, H76)eq),

2.01 7s, 3H, MeC7O)), 2.14 7m, 1H, H77)eq), 2.19 7m, 1H,

H77)ax), 2.26 7ddd, 1H, J14.0, 6.6, 3.2 Hz, H79)eq), 2.30

7br dddd, 1H, J6.8, 6.8, 3.4, 3.4 Hz, H75)), 3.25 7d, 1H,

J14.3 Hz, H712)), 4.22 7dd, 1H, J14.3, 0.4 Hz, H⁰712)),

4.45 7br dd, 1H, J3.2, 1.2 Hz, H71)), 7.58 7m, 2H), 7.66

7m, 1H), 7.94 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d

22.42 7MeC7O)), 22.49 7Me710)), 23.09 7Me711)), 23.39

7C76)H₂), 24.52 7C79)H₂), 29.42 7C75)H), 33.26 7C77)H₂),

60.98 7C712)H₂), 77.80 7C71)H), 82.54 7C78)), 82.72 7C74)),

127.52 72CH), 129.35 72CH), 133.75 7CH), 141.08 7C),

170.20 7CvO). DCI 7CH₄) HRMS: obsd 369.1354, calcd

for C₁₈H₂₅O₆S 7MH¹) 369.1372. Anal. Calcd for

C₁₈H₂₄O₆S: C, 58.68; H, 6.56; S, 8.70. Found: C, 58.73;

H, 6.49; S, 8.41.

23.25 7Me710)), 25.00 7C76)H₂), 25.11 7C79)H₂), 31.14

7C75)H), 34.74 7C77)H₂), 60.29 7C712)H₂), 78.52 7C71)H),

81.65 7C78)), 82.82 7C74)), 127.57 72CH), 129.42 72CH),

133.91 7CH), 141.19 7C), 170.39 7CvO). DCI 7CH₄)

HRMS: obsd 369.1396, calcd for C₁₈H₂₅O₆S 7MH¹)

369.1372.

6.4. X-Ray analysis of the structure of endoperoxide

39⁰⁰a⁴³

Endoperoxide 39⁰⁰a was crystallized from hexane±EtOAc

74:1) at room temperature.

Crystaldata : C₁₆H₂₂O₅S, colorless transparent, prismatic,

0.3£0.3£0.3 mm³, monoclinic, P271)/c 7No. 4), a

Ê

6.06071) A, b14.12673) A, c18.84474) A, b92.6873)8

The middle major acetoxysulfone 58⁰⁰b: a colorless solid,

mp 101±1028C; R_f0.32 7hexane±benzene±EtOAc, 11:6:3);

¹H NMR 7400 MHz, CDCl₃): d 1.56 7s, 3H, Me710)), 1.79

7ddd, 1H, J13.6, 3.4, 1.4 Hz, H79)ax), 1.80 br s, 3H,

Me711)), 1.84 7br dddd, 1H, J14.0, 14.0, 6.0, 3.4 Hz,

H76)ax), 1.96 7m, 1H, H76)eq), 2.00 7s, 3H, MeC7O)),

2.04 7m, 1H, H77)ax), 2.10 7br dddd, 1H, J6.8, 6.8, 3.4,

3.4 Hz, H75)), 2.16 7br dd, 1H, J14.5, 6.0 Hz, H77)eq),

2.29 7ddd, 1H, J13.6, 6.8, 3.6 Hz, H79)eq), 3.12 7d, 1H,

J14.0 Hz, H712)), 3.32 7br d, 1H, J14.0 Hz, H⁰712)),

4.42 7br dd, 1H, J3.6, 1.4 Hz, H71)), 7.57 7m, 2H), 7.66

7m, 1H), 7.92 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃): d

21.94 7Me711)), 22.43 7MeC7O)), 22.53 7Me710)), 23.40

7C79)H₂), 23.78 7C76)H₂), 30.92 7C75)H), 32.92 7C77)H₂),

60.50 7C712)H₂), 78.45 7C71)H), 82.35 7C78)), 82.97 7C74)),

127.61 72CH), 129.37 72CH), 133.89 7CH), 141.15 7C),

170.16 7CvO). Anal. Calcd for C₁₈H₂₄O₆S: C, 58.68; H,

6.56; S, 8.70. Found: C, 58.72; H, 6.57; S, 8.51.

Ê ³

from 25 re¯ections, T293 K, V1611.376) A , Z2,

Fw326.40, D_c1.345 g/cm³, m0.221 mm²¹

.

Data

collection and treatment: AFC5R diffractometer, Mo,

Ê

graphite monochromator 7l0.70173 A), 7798 re¯ections

collected, 1.088#Q#27.518, 27#h#7, 0#k#18,

224#l#24, v scan method, scan width1.28, scan speed

88/min, typical half-height width0.358, three standards

collected 40 times, 2% change in intensity, 3847 indepen-

dent re¯ections 7R_int0.0243). Solution and re®nement: the

structure was solved by direct methods with SHELXL-97.

Full-matrix least-squares re®nement was based on F²with

SHELXL-97. Hydrogens were calculated and re®ned in a

riding mode, 400 parameters with 0 restraints, ®nal

R₁0.0594 7based on F²) for all data, goodness-on-®t on

2

Ê ²³

F 1.065, largest residual electron density0.351 e/A

.

Acknowledgements

The middle minor acetoxysulfone 58⁰⁰c: a colorless waxy

solid; ¹H NMR 7400 MHz, CDCl₃): d 1.54 7d, 3H,

J0.6 Hz, Me711)), 1.602 and 1.604 72£s, 3H, Me710)),

1.63±1.73 7m, 2H, H76)ax1H79)ax), 1.92 7br dd, 1H,

J13.8, 6.7 Hz, H77)eq), 2.03 7s, 3H, MeC7O)), 2.04±2.12

7m, 1H, H76)eq), 2.35 7br dddd, 1H, J6.4, 6.4, 3.2, 3.2 Hz,

H75)), 2.43 7dddd, 1H, J14.4, 4.3, 3.2, 3.2 Hz, H79)eq),

2.56 7br ddd, 1H, J13.8, 13.8, 6.5 Hz, H77)ax), 3.21 7d,

1H, J14.3 Hz, H712)), 4.27 7dd, 1H, J14.3, 0.6 Hz,

H⁰712)), 4.71 7br d, 1H, J4.3 Hz, H71)), 7.59 7m, 2H),

7.67 7m, 1H), 7.94 7m, 2H); ¹³C NMR 7100 MHz, CDCl₃):

d 22.21 7MeC7O)), 23.06 7Me711)), 23.58 7Me710)), 24.60

7C76)H₂), 26.33 7C79)H₂), 29.73 7C75)H), 34.99 7C77)H₂),

61.06 7C712)H₂), 77.96 7C71)H), 82.61 7C74)1C78)), 127.55

72CH), 129.41 72CH), 133.78 7CH), 141.42 7C). DCI 7CH₄)

HRMS: obsd 369.1349, calcd for C₁₈H₂₅O₆S 7MH¹)

369.1372.

This research was supported by grant No. 94-102 from the

United StatesÐIsrael Binational Science Foundation

7BSF), Jerusalem, Israel. E. E. K. and L. K. are grateful to

the Israel Ministry of Absorption for ®nancial support. R. H.

thanks the Swiss Society of the Friends of the Weizmann

Institute of Science for a generous fellowship. We gratefully

acknowledge Dr L. Shimon for X-ray analysis.

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enylperoxy-radicals to form monocyclic 1,2-dioxane system

was reported to be k₃<10⁵s²¹while the reverse process of the

ring opening is much slower, k₂₃<10²s²¹; see Refs. 17,25.

The irreversible hydrogen transfer from thiophenol to peroxy-

radical has a value of k₄<5£10³M²¹s²¹7Refs. 23,26).

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5735. 7b) Ito, O.; Matsuda, M. J. Am. Chem. Soc. 1979, 101,

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J. Am. Chem. Soc. 1978, 100, 2579±2580.

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Med. Parasitol. 1994, 45, 266±271. 7b) Weidekamm, E.;

Dumont, E.; Jaquet, C. Trop. Med. Parasitol. 1994, 45,

278±283. 7c) Salako, L. A.; Guiguemde, R.; Mittelholzer,

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9. O'Neill, P. M.; Searle, N. L.; Raynes, K. J.; Maggs, J. L.;

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5989. 7b) Tokuyasu, T.; Masuyama, A.; Nojima, M.; Kim,

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122±124.

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3638±3645.

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Chichester, 1999; pp 193±224.

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12. Patented in: Bachi, M. D.; Posner, G. H.; Korshin, E. E. PCT

Int. Appl. WO 99/12900 A2, 1999; Chem. Abstr. 1999, 130,

237573.

13. Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.

J. Heterocycl. Chem. 2000, 37, 639±646.

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P.; Cumming, J. N.; Xie, S. J.; Shapiro, T. A.; Posner, G. H.

Bioorg. Med. Chem. Lett. 1998, 8, 903±908.

15. Full account on in vivo/in vitro antimalarial activity and toxi-

cology of potent b-sulfonyl-endoperoxides of type 10 will be

published soon elsewhere: Bachi, M. D.; Korshin, E. E.; Hoos,

R.; Szpilman, A. M.; Cumming, J. N.; Ploypradith, P.; Xie, S.

J.; Shapiro, T. A.; Posner, G. H. Manuscript in preparation.

16. See, for example: 7a) Bachi, M. D.; Balanov, A.; Bar-Ner, N.

J. Org. Chem. 1994, 59, 7752±7758. 7b) Bachi, M. D.; Bar-

Ner, N.; Melman, A. J. Org. Chem. 1996, 61, 7116±7124.

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Soc. 1976, 98, 6000±6005. See also Ref. 18.

28. While the major isomers 20a, and 20b were isolated in pure

state by FC, the minor isomers were separated and character-

ized as their derivatives 58⁰⁰c and 58⁰⁰d in the experiment

described in Scheme 6.

29. CAUTION! Although no accidents occurred in this laboratory,

it is mandatory to observe appropriate precautions for working

with potentially explosive materials. Particular attention

should be given to potentially explosive mixtures of oxygen

and vapors of organic solvents, to the potentially explosive

DBPO as well as to evaporation of peroxide containing

solutions. Ph₃P is expected to reduce the most reactive peroxy-

component. Reaction mixtures, prior to treatment with PPh₃,

may contain unidenti®ed explosive by-products

30. To the best of our knowledge, there are no reports on the use of

aliphatic mercaptans in a TOCO reaction yielding cyclic

peroxides. For early studies on co-oxygenation of aliphatic

mercaptans with 1,3-dienes or with monoole®ns leading to

open-chain hydroxy-sul®des or sulfoxides, see: Oswald, A.

A.; Wallace, T. J. The Chemistry of Organic Sulfur

Compounds; Kharasch, N., Meyers, C. V., Eds.; Pergamon:

18. For an application of 6-exo-trig cyclization of unsaturated

peroxy-radicals in the total synthesis of monocyclic natural

endoperoxide yingzhaosu C, see: Boukouvalas, J.; Pouliot,

R.; Frechette, Y. Tetrahedron Lett. 1995, 36, 4167±4170.

19. 7a) Beckwith, A. L. J.; Wagner, R. D. J. Am. Chem. Soc. 1979,

E. E. Korshin et al. / Tetrahedron 58 22002) 2449±2469

2469

Oxford, 1966; Vol. 2, pp 205±232 and the references cited

therein. For more recent applied studies, see e.g.: 7a) Muller,

U.; Kunze, A.; Herzig, C.; Weis, J. J. Macromol. Sci., Pure

Appl. Chem. A 1996, 33, 439±457.

36. Jackman, L. M.; Sternhell, S. Application of Nuclear Magnetic

Resonance Spectroscopy in Organic Chemistry; 2nd ed.;

Pergamon: Oxford, 1969; pp 280±301.

37. Intramolecular hydrogen bonding using oxygen atoms as

proton acceptors in endoperoxides was not extensively

studied. For the only available data obtained by the IR method,

see: 7a) Richardson, W. H.; Smith, R. S. J. Org. Chem. 1968,

33, 3882±3885. 7b) Richardson, W. H. In The Chemistry of

Peroxides; Patai, S., Ed.; Wiley: Chichester, 1983; pp 129±

160.

31. In the case of sul®des 35⁰a, 35⁰b and 51⁰⁰a isolation of indi-

vidual isomers preceded the oxidation step.

32. Direct acetylation of the sterically hindered tertiary hydroxyl

of endoperoxides 20a,b with AcCl in the presence of base was

found to be far less effective. See Refs. 12,14,15.

33. The chair conformation of the 1,2-dioxane system has been

previously determined by X-ray diffraction analysis and

reported in 7a) Tanaka, J.; Higa, T.; Suwanborirux, K.;

Kokpol, U.; Bernardinelli, G.; Jefford, C. W. J. Org. Chem.

1993, 58, 2999±3002. 7b) Piccinni-Leopardi, C.; Germain, G.;

Van Meerssche, M.; Albericci, M.; Braekman, J. C.; Daloze,

D.; Turch, B. J. Chem. Soc., Perkin Trans. 2 1982, 1523±

1526. 7c) Jefford, C. W.; Eschenhof, H.; Bernardinelli, G.

Heterocycles 1998, 47, 283±288. 7d) Albericci, M.; Collart-

Lempereur, M.; Braekman, J. C.; Dalcze, D.; Tursch, B.;

Declercq, J. P.; Germain, G.; Van Meerssche, M. Tetrahedron

Lett. 1979, 2687±2690.

38. Intramolecular hydrogen bonding of the hydroperoxy proton

to a dioxolane oxygen in 3-hydroperoxy-1,2-dioxolanes was

proposed to in¯uence the oxidative properties of these

compounds. See: Baumstark, A.; Chen, Y. X.; Rodriguez, A.

J. Heterocycl. Chem. 1996, 33, 1399±1402.

39. Compounds of type 10, e.g. 10⁰7RPh, R²p-MeOC₆H₄CH₂)

exhibit antimalarial activity comparable to that of artemisinin.

For preliminary communications see Refs. 12,14. Comprehen-

sive results will be published elsewhere 7Ref. 15).

40. 7a) Mair, R. D.; Hall, R. T. Organic Peroxides; Swern, D., Ed.;

Wiley: London, 1971; Vol. 2, p 553. 7b) Knappe, E.; Peteri, D.

Z. Anal. Chem. 1962, 190, 386±389.

34. For the chair conformation of the 1,2-dioxane ring in solutions

determined by the NMR technique, see: 7a) Capon, R. J.;

Macleod, J. K. Tetrahedron 1985, 41, 3391±3404. 7b) Xu,

X. X.; Dong, H. Q. J. Org. Chem. 1995, 60, 3039±3044.

7c) Fontana, A.; Ishibashi, M.; Kobayashi, J. Tetrahedron

1998, 54, 2041±2048. 7d) Compagnone, R. S.; Pina, I. C.;

Rangel, H. R.; Dagger, F.; Suarez, A. I.; Reddy, M. V. R.;

Faulkner, D. J. Tetrahedron 1998, 54, 3057±3068. See also

Refs. 17,32a.

41. Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.;

Date, T. J. Org. Chem. 1994, 59, 5633±5642.

42. Mascarenas, J. L.; Sarandeses, L. A.; Castedo, L.; Mourino, A.

Tetrahedron 1991, 47, 3485±3498.

43. Crystallographic data 7excluding structure factors) for the

structure 39⁰⁰a have been deposited with the Cambridge

Crystallographic Data Center 7CCDC) as supplementary

publication number CCDC 172269. Copies of the data can

be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge, CB2 1EZ, UK 7fax: 144-1223-

336033 or e-mail: deposit@ccdc.cam.ca.uk).

35. The conformational studies on the endoperoxides were

reviewed in 7a) Gougoutas, J. Z. In The Chemistry of

Peroxides; Patai, S., Ed.; Wiley: Chichester, 1983; pp 375±

415. 7b) Clennan, E. L.; Foote, C. S. In Organic Peroxides;

Ando, W., Ed.; Wiley: Chichester, 1992; pp 255±318.

Article Doi

An efficient synthesis of bridged-bicyclic peroxides structurally related to antimalarial yingzhaosu A based on radical co-oxygenation of thiols and monoterpenes

DOI: 10.1016/S0040-4020(02)00126-6

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