hydroxycodeinone-2.pdf

J. Org. Chem. 2000, 65, 4671-4678

4671

The [4

2] Addition of Singlet Oxygen to Thebaine: New Access

to Highly Functionalized Morphine Derivatives via Opioid

Endoperoxides

Dolores Lpez, Emilio Qui ˜o , and Ricardo Riguera*

Departamento de Qu mica Org nica, Facultad de Qu mica, and Instituto de Acuicultura,

Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain

ricardo@usc.es

Received March 2, 2000

The photooxidation of thebaine ( 3 ) with a sun lamp affords two main products: hydrodibenzofuran

10 (major) and benzofuran 11 (minor). The latter compound becomes predominant if a Hg lamp is

used instead of a sun lamp. The formation of 10 proceeds via an endoperoxide intermediate that

undergoes oxidation at the nitrogen atom. Protection of the nitrogen either by protonation or

quaternization prevents its oxidation and thus the photooxidation of 3 in acid media constitutes a

one-pot procedure for the preparation of 14-hydroxycodeinone 35 . Photooxidation of the thebaine

ammonium salt 31 allows the isolation in good yields of the corresponding to thebaine endoperoxide

32 . The selective protection and reduction of the keto, aldehyde, and olefinic groups of hydro-

dibenzofuran 10 allowed the preparation of several diol and keto alcohol derivatives. This is the

first report on the use of photooxidation to functionalize thebaine at C(6) and C(14) and also the

first on the isolation of opioid endoperoxides.

Introduction

Surprisingly, no references are found in the literature

on the cycloaddition to thebaine ( 3 ) of the well-known

dienophile singlet oxygen ( 1 O 2 ). This is despite the fact

that the expected cycloaddition, if it were to take place,

would open a direct way for the introduction of oxygen

atoms at C(6) and C(14) via the corresponding endo-

peroxide. These positions are especially relevant to

analgesic activity, 4 as indicated by the clinical use of

oxycodone (Eucodal, 14-hydroxydihydrocodeinone, 6 ),

oxymorphone (Numorphan, 14-hydroxydihydromorphone,

7 ), and (

The search for new opioid derivatives that act on the

CNS and have pain-relieving properties and are devoid

of undesired side effects, such as addiction, has been the

goal of a large number of scientists for many years.

Consequently, a wide variety of modifications of the well-

known alkaloids morphine ( 1 ), codeine ( 2 ) and thebaine

( 3 ) have been described. As a result, a large number of

compounds with pharmacological properties (antitusive,

analgesic, sedative, etc.) have been obtained, and many

of them are commercially available and employed in a

large number of diverse therapies. 1

In previous investigations, thebaine ( 3 ) has played a

very important role as a starting material for a number

of reasons: it is readily available, its cost is lower than

other opiates and, in addition, it contains a conjugated

diene system at ring C, which has allowed the prepara-

tion of many pharmaceutical products by Diels-Alder

cycloadditions with a large number of dienophiles. Clas-

sical examples of drugs prepared using this approach are

etorphine 1e (Immobilon, 4 ), buprenorphine 2 (temgesic,

buprenex, Buprex, Prefin, 5 ) and many other adducts

(Chart 1), reported mainly by Bentley. 3

)-naloxone ( 8 ), as analgetics. 1 This gap in the

chemistry of thebaine may well be attributed either to

the difficulties usually associated with photooxygena-

tion processes (i.e. complex mixtures and difficult work

up due to the presence of the colored sensitizer) or to

the high reactivity of the electron-rich methoxydiene

moiety.

Nevertheless, a few reports have been published that

describe the photooxidation of other morphine derivatives

and these reactions have different outcomes. One ex-

ample is the N -demethylation of codeine ( 2 ) to norcodeine

( 9 ). 5 The photooxidations of N -acyl morphine derivatives

bearing a diene moiety in ring C ( N -methoxycarbonyl-

9,17-secothebaine, N -(ethoxycarbonyl)norcodeinone pyr-

rolidine dienamine and N -(ethoxycarbonyl)norcodeinone

dienol acetate) have also been described. 6,7 In these cases,

the photooxidation products were not isolated. Instead,

the reaction mixtures were immediately submitted to

reduction yielding 14-hydroxy derivatives.

* To whom correspondence should be addressed. FAX/Phone: 34-

81-591091.

(1) (a) Lenz, G. R.; Evans, S. M.; Walters, D. E.; Hopfinger, A. J.;

Hammond, D. L. Opiat es; Academic Press: Orlando, 1986. (b) Casy,

A. F.; Parfitt, R. T. Opioid Analgesics: Chemistry and Receptors ;

Plenum Press: New York, 1986. (c) Central Analgetics ; Lednicer, D.,

Ed.; John Wiley & Sons: New York, 1982. (d) Zimmerman, D. M.;

Leander J. D. J. Med. Chem . 1990 , 33 , 895. (e) Bentley, K. W. The

Alkaloids, Chemistry and Pharmacology ; Manske, R. H. F., Holmes,

H. L., Eds.; Academic Press: New York, 1971; Vol. XIII, p 75, and

references therein. (f) The Merck Index ; 12th ed. on CD-ROM, ver. 12:

2; Chapman & Hall/CRCnetBASE.

(2) Lewis, J. W. Discovery of Buprenorphine, a Potent Antagonist

Analgesic. In Medicinal Chemistry. The Role of Organic Chemistry in

Drug Research ; Roberts, S. M., Price, B. J., Eds.; Academic Press:

London, 1985; p 119, and references therein.

(3) (a) Bentley, K. W.; Hardy, D. G.; Meek, B. J. Am. Chem. Soc.

1967 ,89 , 3273. (b) id. J. Am. Chem. Soc 1967 , 89 , 3293. (c) id. J. Am.

Chem. Soc . 1967 , 89 , 3312.

(4) Schmidhammer, H.; Schratz, A.; Schmidt, C.; Patel, D.; Traynor,

J. R. Helv. Chim. Acta 1993 , 76 , 476.

(5) Lindner, J. H. E.; Kuhn, H. J.; Gollnick, K. Tetrahedron Lett.

1972 , 1705.

(6) Schwartz, M. A.; Wallace, R. A. J. Med. Chem. 1981 , 24 , 1525.

(7) Schwartz, M. A.; Wallace, R. A. Tetrahedron Lett. 1979 , 3257.

Published on Web 07/01/2000

4672

J. Org. Chem., Vol. 65, No. 15, 2000

Lpez et al.

Chart 1

1 H and 13 C Chemical Shifts for the Two Rotamers in Equilibrium of Compound 10 in CDCl 3 at Room

Temperature

Table 1.

1 H NMR

13 C NMR

1 H NMR

13 C NMR

atom no.

major

minor

major/minor

atom no.

major

minor

major/minor

7.59 (d, J

)

8.5 Hz)

7.57 (d, J

)

8.5 Hz)

112.8/112.8

10.21 (s)

10.06 (s)

189.5/189.4

6.94 (d, J ) 8.5 Hz)

128.1/126.0

127.0/127.3

150.0/150.3

128.1/128.5

147.9/148.0

61.6/61.4

5.29 (s)

4.98 (s)

85.7/86.8

191.0/191.0

194.3/193.8

2.30-2.38 (m)

2.39-2.50 (m)

35.4/34.6

2.64-2.72 (m)

2.52-2.60 (m)

6.96 (d, J ) 10.4 Hz)

6.92 (d, J ) 11.1 Hz)

140.5/140.0

3.02-3.18 (m)

3.18-3.32 (m)

40.5/45.3

3.45-3.75 (m)

6.87 (d, J ) 10.4 Hz)

6.88 (d, J ) 11.1 Hz)

142.6/142.9

3-OMe

3.97 (s)

3.91 (s)

56.3/56.2

7.87 (s)

7.89 (s)

162.8/162.6

NMe

2.93 (s)

2.80 (s)

34.4/29.5

In a previous communication 8 we gave a short account

of the photooxidative transformation of thebaine ( 3 )to

hydrodibenzofuran 10 . We wish to report here full details

of this photooxidation under different conditions as well

as the modifications performed on the photooxidation

products.

lished on the basis of spectroscopic data and chemical

transformations.

Structure of the Photooxygenation Products.

Compound 10 , a pale yellow solid, showed a molecular

ion (HRMS) at m / z 343.1055, indicating the molecular

formula C 18 H 17 NO 6 . The 1 H and 13 C NMR spectra of this

compound (Table 1) were complicated by the fact that a

pair of signals was observed for each hydrogen and each

carbon present in the molecule. The ratio between the

two sets of signals varied with the solvent (2:1 in CDCl 3

and C 6 D 6 ; 1:1 in DMSO- d 6 at 298 K) and also with the

temperature. A complete coalescence to a single set of

signals in 1 H NMR was observed at 393 K. These results

could be attributed to the presence of two rotamers in

equilibrium, generated by the presence of a formamide

group.

Analysis of the 1D- and 2D-NMR spectra of 10 allowed

the assignment of all the signals in the spectra and the

identification of all the spin systems. These data, along

with a comparison of the chemical shifts with those of

thebaine and other opiates, helped to establish that rings

AandBof 10 remained unchanged, that rings D and E

were opened, and that ring C included a but-2-ene-1,4-

dione moiety. The two remaining carbonyl groups were

assigned to a benzaldehyde on ring A and to a formamide

group that completed the structure. The IR and UV

spectra showed bands that are in agreement with the

Results and Discussion

Our initial attempts to find a practical use for the

photooxidation of thebaine consisted of a number of

experiments in which oxygen was bubbled through solu-

tions of thebaine ( 3 ) in different solvents (dioxane, ethyl

acetate, butan-1-ol). The solutions were then submitted

to irradiation with a 300 W sun lamp in the presence of

methylene blue or rose bengal as photosensitizers and

monitored by TLC. Complex mixtures of compounds

resulted in all cases, the isolated yields of 10 and 11 were

very low and the photosensitizers were found particularly

difficult to separate from the reaction mixture.

Nevertheless, when the reaction was performed with

meso -tetraphenylporphyrin (5, 10, 15, 20-tetraphenyl-21

H ,23 H -porphine; TPP) as sensitizer and dichloromethane

as solvent, the reaction was much cleaner by TLC, TPP

could be easily recovered from the reaction mixture and

compounds 10 and 11 could be isolated in reasonable

yields (62% and 5%, respectively) by column chromatog-

raphy. The structures of the two products were estab-

[4 + 2] Addition of Singlet Oxygen to Thebaine

J. Org. Chem., Vol. 65, No. 15, 2000

4673

Scheme 1

functional groups and chromophores assigned to the

molecule. The carbon framework and functional groups

proposed for 10 were further confirmed by a series of

hydrogenation reactions, which are summarized in Scheme

The Formation of 10 from Thebaine. The mecha-

nism of the formation of 10 from 3 was investigated next.

Inspection of the structure of 10 indicated that any

mechanism proposed should justify the incorporation of

two molecules of O 2 into the thebaine framework and also

the breaking of rings D and E along with the concomitant

functionalization, suggesting that a multistep transfor-

mation is involved.

The well-known dienophile character of singlet oxygen

together with the presence of the electron-rich 1,3-diene

on ring C of thebaine strongly suggested a [4+2] cycload-

dition to be the most likely starting point for the process.

The fact that the resulting endoperoxide ( 20 ) is also part

of a ketal moiety (at C-6) must make it more labile than

usual endoperoxides: the methoxy group can act as a

leaving group and, if the peroxide bridge were broken, a

ketone would be formed at C-6. The oxidation of the

tertiary nitrogen to an amino radical cation ( 21 )bya

second molecule of oxygen could be the trigger for such

a transformation through the cleavage of the C-9/C-14

bond. The immonium intermediate 22 already has the

correct functionalization for ring C. The isomerization of

the immonium double bond to give the styrene/enamine

23 leads to an extremely electron rich double bond due

to the presence of both the nitrogen and the p -methoxy-

phenyl group. This double bond can subsequently un-

dergo a [2+2] cycloaddition with a third molecule of 1 O 2

to form a 1,2-dioxetane intermediate ( 24 ). Finally, the

opening of the four-membered ring causes the cleavage

of the C-9/C-10 bond and the formation of the two formyl

groups that are present in 10 . The overall transformation

is depicted in Scheme 2. 9

To demonstrate the plausibility of the above mecha-

nistic pathway, a number of experiments were performed.

First, in an attempt to detect the intermediates involved,

for example endoperoxide 20 , the reaction was carried

Smooth catalytic hydrogenation of 10 (Adams, 1 atm,

rt) allowed the selective reduction of the carbonyl at C(6)

to yield keto alcohol 13 , as a single isomer, in quantitative

yield. Compound 13 was further transformed into its

acetate 14 . Diketone 12 , an intermediate in this reaction,

can be isolated if the reaction is stopped before comple-

tion, confirming that the double bond is hydrogenated

first.

At higher hydrogen pressures (4 atm, rt) the carbonyl

groups at C(10) and C(14) also undergo hydrogenation

to give 6,10,14-triol 16 as single product, which can be

transformed into its triacetate 17 by standard treatment.

6,10-Diol 15 can be isolated during the course of the

reaction, indicating that the benzaldehyde group is

reduced before the carbonyl group at C(14), which is less

prone to hydrogenation.

These experiments show that in this polyfunctionalized

structure the ¢ 7 double bond is the most sensitive to

hydrogenation followed, in order, by the carbonyl groups

at C(6), C(10), and C(14). In addition, it is interesting to

note that both keto groups at ring C are hydrogenated

in a highly stereoselective way to give exclusively one of

the four possible stereoisomers (the cis -1,4-diol 16 ),

indicating that the acyclic ethylamine chain does not

impede the approach of the molecule to the catalyst

surface. The regio- and stereochemistry of the reductions

were determined by extensive use of 1D and 2D NMR

studies of the products and their corresponding acetates,

including selective decouplings and analysis of the J

values.

The second product formed in the photooxygenation of

thebaine was obtained in low yield and identified as the

benzofuran 11 . This is an optically inactive compound;

its NMR spectra suggest a much simpler structure than

the major reaction product 10 , although it still showed

two sets of signals for hydrogen and carbon atoms in a

similar way to those due to rings A and B of the starting

material. Spectroscopic data and hydride reductions to

18 and 19 confirmed the structure proposed.

(8) Lpez, D.; Qui ˜o , E.; Riguera, R. Tetrahedron Lett. 1994 , 35 ,

5727. Three patents have been issued: Riguera, R.; Qui ˜o , E.; Lpez,

D., Patents P9602716, P9602717 and P9602718, 1996.

(9) For a general reference on peroxides see: Clennan, E. L.; Foot,

C. S. Endoperoxides. In Organic Peroxides ; Ando, W., Ed.; Wiley: New

York, 1992. See also: Akaeshi, T.; Ando, W. Peroxides from Photo-

sentitized Oxidation of Hetero Atom Compounds. In Organic Peroxides ;

Ando, W., Ed.; Wiley: New York, 1992.

4674

J. Org. Chem., Vol. 65, No. 15, 2000

Lpez et al.

Scheme 2

out at low temperature (243 K). However, no intermedi-

ates were isolated or detected by NMR.

As already indicated above, the two most likely reasons

for the instability of endoperoxide 20 , if it is indeed

generated, are the presence of the ketal function at C-6

and the nitrogen lone pair. We therefore decided to block

alternately the two possible sites of reaction (the diene

and the amine) and then to assess the course of the

transformation in each case.

Thus, reaction of thebaine with methyl vinyl ketone

yielded the Diels-Alder adduct thevinone 25 , 10 which

was submitted to the standard photooxidation conditions

and afforded the N -demethylated derivative (northevi-

none, 26 ) in 73% yield. This result confirms that the

nitrogen does undergo oxidation to the amine radical

cation. When ring C is blocked, the reaction leads to the

loss of the N -methyl group by hydrolysis of the resulting

immonium ion. An alternative mechanism for the trans-

formation of thebaine into 10 , based on the involvement

of the lone pair of the amine group to open the endop-

eroxide in a retro-Mannich-like reaction with methoxy

as the leaving group, does not now seem reasonable.

We proceeded to investigate the effect of the deactiva-

tion of the lone pair of the thebaine nitrogen atom

through quaternization with a methylating agent (such

as methyl iodide) or by its transformation into an N -oxide

with MCPBA. 11 The products (thebaine methylammo-

nium iodide 27 and thebaine N- oxides 28 and 29 ) were

submitted to photooxygenation. However, the corre-

sponding endoperoxides were not detected and complex

mixtures of products were obtained instead. Only the salt

30 was identified in the reaction of 27 , suggesting that

the endoperoxide was actually formed but then rapidly

transformed into 30 .

Thebaine Peroxides. Finally, treatment of thebaine

with methyl triflate gave 31 as a crystalline salt that,

when submitted to photooxygenation, gave endoperoxide

32 in almost quantitative yield. 12 In contrast to the

elusive endoperoxide 20 , compound 32 is perfectly stable

for several weeks. When dissolved in dilute TFA at 25

°C, 32 does not decompose for several hours, but if this

solution is gently heated, 32 is transformed into keto

alcohol 33 in 7 h. If this transformation is carried out in

an NMR tube and monitored by 1 Hor 13 C NMR spec-

troscopy, the presence of hydroperoxide 34 as an inter-

mediate is observed. Indeed, if the reaction is stopped

after 90 min, 34 can be isolated from the reaction mixture

as the sole product. Hydroperoxide 34 shows NMR data

that are almost identical to those of keto alcohol 33 . The

main difference is found in the chemical shift of C(14):

81.1 ppm in 34 versus 70.0 ppm in 33 . Addition of Ph 3 P

to 34 in the NMR tube led, as one would expect, to the

disappearance of the signals corresponding to the hydro-

peroxide and its rapid transformation into keto alcohol

33 .(+)-FAB and EIMS further confirmed the difference

of one oxygen between the two compounds.

One-Pot Procedure to 14-Hydroxycodeinone. In

a practical extension of these studies, we tried to trans-

form thebaine directly into the keto alcohol by carrying

out the photooxidation in acid media. Thus, when the-

baine was photooxygenated in a 1% TFA/CH 2 Cl 2 solution,

14-hydroxycodeinone (oxycodone) 1a,b salt 35 was isolated

as the sole reaction product in 61% yield. This constitutes

an excellent one-pot method for the simultaneous func-

tionalization at C(6) and C(14) of thebaine and its

analogues (Chart 2).

On the Origin of 11. Once a reasonable mechanistic

pathway had been established to explain the generation

of 10 from thebaine, our next goal was to determine the

mechanistic relationship between thebaine, 10 and 11 .

To this end, a series of experiments with thebaine ( 3 )

and hydrodibenzofuran 10 as starting materials was

carried out. These experiments indicated 10 to be the

precursor of 11 and ruled out a direct transformation of

(10) Bentley, K. W.; Hardy, D. G.; Meek, B. J. Am. Chem. Soc. 1967 ,

89 , 3267.

(11) (a) Phillipson, J. D.; Handa, S. S.; El-Dabbas, S. W. Phytochem-

istry 1976 , 15 , 1297. (b) Theus, H. G.; Jansen, R. H. A. M.; Biessels,

H. N. A.; Salemink, C. A. J. Chem. Soc., Perkin Trans . 1984 , 1701. (c)

Caldwell, G. W.; Gautier, A. D.; Mills, J. E. Magn. Reson. Chem. 1996 ,

34 , 505.

Alder reactions of thebaine is

known to produce exclusively the adducts formed at the less hindered

face of the diene (see ref 1e). The transformation of 32 into 35 (a known

compound), confirmed the assigned stereochemistry of 32 .

(12) The stereoselectivity of Diels

[4 + 2] Addition of Singlet Oxygen to Thebaine

J. Org. Chem., Vol. 65, No. 15, 2000

4675

Chart 2

Table 2. Photooxidative, Photochemical, and Thermal Experiments Carried out To Determine the Origin of Compound

conditions a

light source

entry substrate atmosphere b sun lamp Hg lamp sensitizer (TPP) T (°C) products (yields, %)

1 3 O 2 yes yes 40 10 (62) + 11 (<5)

2 3 Ar yes 40 complex mixture c

3 3 O 2 yes yes 20 11 (57) d

4 10 O 2 yes yes 40 11 (85)

5 10 O 2 yes 40 11 (87)

6 10 Ar yes 40 11 (88)

7 10 Ar yes 40 11 (95)

8 10 O 2 20 no reaction

9 10 O 2 40 no reaction

10 10 Ar 20 no reaction

11 10 Ar 40 no reaction

12 10 Ar 66 e no reaction

13 10 Ar 120 f decomposition c

14 10 110 g no reaction

a All the reactions were carried out in CH 2 Cl 2 as solvent except entries 12, 13, and 14. b The reaction was carried out under continuous

gas bubbling. c Neither 10 nor 11 was detected. d The formation of compound 10 as intermediate and its convertion into 11 can be observed

while monitoring this reaction. e In THF. f In DMSO. g In a sealed tube with toluene as solvent.

thebaine into 11 (Table 2). In these experiments, the roles

played by different reaction variables (the photoirradia-

tion source, oxygen, the nature of the photosintetizer and

the temperature) were investigated in order to decide

which of the three plausible possibilities was most likely

to account for the formation of 11 . The three main

possibilities are (a) a thermal retro Diels

or the presence of a sensitizer ( 1 O 2 addition, entries 5

are necessary for this reaction to take place. Entries 6

and 7 show that only light is necessary, clearly indicating

that the photochemical R-cleavage of the carbonyl groups

(Norrish type I reaction, route c) is a satisfactory expla-

nation for the conversion of 10 into 11 . In fact, the sun

lamp photooxidation of thebaine to 10 and the photo-

chemical cleavage of 10 to give 11 can be conveniently

represented as a single chemical operation: photooxida-

tion of thebaine with a mercury lamp and TPP as a

sensitizer in CH 2 Cl 2 under argon afforded 11 in 57% yield

(entry 3, Table 2).

Structural Modifications on 10. Once the structure

of the products and the mechanistic pathways were

Alder reaction

(retro [4+2]), (b) a direct photooxygenation of the double

bond (photochemical [2+2]) followed by the breaking of

ring C, and (c) a double Norrish type I photochemical

reaction (routes a, b and c in Scheme 3, respectively).

Pathways a and b can be discounted on the basis of

experiments that showed that neither heating (thermal

process, entries 8-14, Table 2), oxygen (entries 6 and 7)

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