Chemospecific deuteration of prostaglandin silyl ethers

PROSTAGLANDINS CHEMOSPECIFIC

DEUTERA’ITON OF PROSTAGLANDIN A. Harry Andrist*

SILYL ETHERS

and Joseph E. Graas

Department of Chemistry The Cleveland State University Cleveland, Ohio 44115 ABSTRACT Complete achieved

chemical

selectivity

in the homogeneous

prostaglandin

double

or CS-Cl2

c13-c14 utilizes protection protection

rearrangement

deuterium

(Wilkinson’s

catalyst)

been

to

or partial

reduction

of

reaction ether and

group as the methyl ester prior to reduction with

been

CIO-Cl1

deuteration

double bond as the Cl5 0-silyl

under

tris(triphenylphosphine)chlororhodium

in 60:40 acetone:benzene

prepare

has

and endocyclic

The homogeneous

of the C13-Cl4

six

specifically

5,6_dideuterio-PGEl,

hexadeuterio-PGFld

of C5-C6

bonds without

molecular

dideuterio-PGFld

deuteration

chemospecificity)

double bonds.

of the carboxyl

used

(i.e.,

at 25’C.

deuterated

(I)

The’reaction

prdstaglandins:

5,6_dideuterio-PGB1,

has 5,6-

3,3,4,4,5,6-

5,6,10,11-tetradeuterio-ll-deoxy-PGE1,

and

lO,ll-

dideuterio-11-deoxy-PGEl.

INTRODUCTION Naturally excellent

occurring

starting

prostaglandins

materials

for

prostaglandin

structures’

prostaglandin

group interconversions

quantities

of specifically

in a direct combined selected

one-step

synthesis

as well as isotopically

gas chromatography-mass technique

labeled

are particularly

labeled materials

high-yield

ion monitoring

have been shown repeatedly

the directed

reaction.

to be

of less accessible substrates.2

attractive

Such

when small

which are needed can be obtained For the development

spectromet

ry -computer

for the prostaglandins,3

of a new

(GC-MS-COM) we required just

such a reaction. Prior to this work it was known that certain

derivatives

of PGE2 and

hydrogenated or PGF2a as well as the parent PGE2 could be catalytically tritiated.4-6 Selective reduction of the C5-C6 double bond over the C13Cl4

double

OCTOBER

bond

was

reported

1979 VOL. 18 NO. 4

to be good

for

the sterically

conjested

631

PROSTAGLANDINS derivatives; carbon

although, the most common result was reduction

double bonds.‘l

small quantities Wilkinson’s

In 1970, Koch and Dalenberg2

the overreduction

Besides PGE1, which was isolated

and rearrangement

oxo-13,14_dihydro-PGE1, fully corroborated

Wilkinson’s alcohols alcohol 60:40

by Lincoln,

Schneider,

of

homogeneous

catalytic

phenylpropiophenone

series

simultaneous

isotopic

present,

corresponding

the steric

result was

we

sensitivity

found

(l_; E_1,3-diphenyl-2-propen-l-01)

functionality

that

allylic

and cinnamyl

be quantitatively saturated

of

reduced

alcohols;

in

however,

was protected

as the trimethylsilyl 10 as well as rearrangement tog-

hydrogenation

The present contribution

if

and 15-

were prevented.

prostaglandin

bonds

This experimental

catalyst,

E-3-phenyl-2-propen-l-01) could acetone:benzene to the corresponding

(2 and 9,

13,14-dihydro-PGE1

testing

(3

alcohol

(I), &,

in only 50% yield,

and Pike in 1973.9

experiments

hydrogenation

as chalcol

when the original ether

products,

were also obtained.

the course

such

were able to tritiate

of PGE2 using tris(triphenylphosphine)chlororhodium

catalyst.*

During

of both carbon-

as

describes

a

general

labeling

while

of C5-C6

protecting

C15-trimethylsilyl

the extension procedure

the

of this reaction

for

the

double bonds, and Clo-Cl1 C13-Cl4

double

to the

reduction

bonds

and double

as the

ethers.

H-CH=C

$R

1

2 =H,R =Si(CH3)3

METHODS Prostaglandin PGB2, PGEl,

632

Starting

PGE2, PGFti

Materials.

Pure

samples

of

and 3,3,4,4-tetradeuterio_PGFZcl

OCTOBER

PGAl,

PGA2,

were supplied

1979 VOL. 18 NO. 4

PROSTAGLANDINS

through the courtesy

of Drs. U. Axen and J. E. Pike of the Upjohn Company, 11 Michigan. PGBl was prepared by the known procedure.

Kalamazoo,

.

Solvents. ether

Reagent

were distilled

grade

cyclohexane,

under nitrogen,

Linde 4A Molecular

acetone,

thoroughly

catalyst

triphenylphosphine

was

prepared

as

A standard

described

the generator ethyl

to the sample

ether

diethyleneglycol

to the generator

(Diazald).

Dry

nitrogen

generator

and into

the

tube

as 1 mL of

hydroxide

was added

remained

was

to the Diazald

continued

followed

was transferred

followed

bubbled

60%

Nitrogen

the

A 5-mL

by 2 mL of

time

through

aqueous

the

potassium

transfer

of the

the sample

(0.05-5

A 1-mL sample containing

mg) was placed

by 1.5 mL of dry ethyl

described

above

nitrogen.

The sample

and bubbled

of nitrogen,

using an additional of nitrogen

in a 7.5-

solution

into

the

sample

was then concentrated

transferred

to a 25-mL

1 mL of ethyl at 5O’C.

X LO-cm

ether,

solution

at 25OC for 2 h.

entry stopcock

and transferring

(BSTFA).

of

of 1 mL in a

After

fitting

acetone:benzene.

was placed

gas-entry

over the end of the Teflon

an atmosphere

stopcock

99.5 atom % deuterium

1979 VOL. 18 NO. 4

gasof

(I) was added to A rubber septum before

to 180 torr through a syringe needle connection.

evacuation,

in a

added 200

the flask with a Teflon

to a glove box containing

25 mg of tris(triphenylphosphine)chlororhodium

was evacuated

flask

to dryness

The flask was stoppered

the flask in 5 mL of 60:40 (by volume)

OCTOBER

in a stream

round-bottom

and evaporated

tube as

to a volume one-neck

culture

was generated

To the dry residue was immediately

and maintained

dry nitrogen,

a known amount of

Diazomethane

ether.

& of bistrimethylsilyltrifluoroacetamide

after

was constructed

N-methyl-N*itroso-p-

was

solution.

1 m beyond

Procedure.

a prostaglandin

stream

using

faintly yellow in color.

Deuteration

stream

Wilkinson

of dry nitrogen.

ether , and 250 mg of

sample

homogeneous

Diazomethane

in a stream

was added

monobutyl

by

generator

toluenesulfonamide

diazomethane

over

from ethanol.

diazomethane

using a 15- X 2-cm test tube with a side-arm.

portion of

and stored

The

4.S

freshly recrystallized

Diazomethane.

from

degassed,

and ethyl

Sieves.

Tris( triphenylphosphine)chlororhodium hydrogenation

benzene,

the flask

Immediately

gas was added to the 25-mL flask

633

PROSTAGLANDINS from a 25-mL

Hamilton

gas-tight

from the glove box and allowed

syringe.

The reaction

flask was removed

to shake on a wrist-action

shaker for 20 h.

The sample was next taken to dryness under vacuum, slurried in 5 mL of dry cyclohexane,

and filtered

cyclohexane

eluant was analyzed

assigned

by

samples

spectral

of unlabeled

mass spectral

through 2 mm of Florisil in a Pasteur pipette.

and

by GC-MS-COM.

chromatographic

prostaglandins

Product

structures

comparisons

coupled

The

with

with a careful

were

authentic

analysis of the

data.

GC-MS-COM

Analyses.

Gas chromatographic

separations

were achieved

on a 1.5- X 0.002-m

I.D. glass U-shaped

3% OV-101 on Chromosorb

W-HP column with methane

as the carrier gas.

Following

the column temperature

programmed 1015D

to increase from 240’

mass spectrometer

computer

was used with

system.12

sample injection,

to a Texas

an in-house

All mass spectral 13

ionization

to 275OC at 20°C

interfaced

A Finnigan

Instruments

constructed

data were collected

per m.

was

960A

mini-

and programmed

data

using methane

chemical

conditions.

RESULTS As suggested (vide -a),

by the model

homogeneous

acetone:benzene ed quantitative

of prostaglandin reduction

without

rearrangement

bonds.

The following

studies

hydrogenation

on chalcol

and cinnamyl

over Wilkinson’s

methyl ester trimethylsilyl

of C5-C6

or partial

and endocyclic reduction

six individual

Clo-Cl1

of C13-Cl4

transformations

or CS-Cl2

double out

ether):

(2)

(&I

A

5,6-dideuterio-PGB1-ME-TMS

634

double bonds

A

5,6-dideuterio-PGEl-ME-(TMS)2 PGB2-ME-TMS

ethers produc-

_____;)

5,6-dideuterio-PGFfME-(TMS)3 PGE2-ME-(TMS)2

alcohol in 60:40

were then carried

(where ME and TMS signify methyl ester and trimethylsilyl PGF2wME-(TMS)3

catalyst

(1)

OCTOBER

1979 VOL. 18 NO. 4

PROSTAGLANDINS

4) 3,3,4,4-tetradeuterio_PGF2c+ME>

(TMS)~ 3,3,4,4,5,6-hexadeuterio-PGFlG ME-(TMS13

(El

5) PGA2-ME-TMS

-

5,6,10,11-tetradeuterio-ll-deoxyPGEl-ME-TMS

(9)

6) PGAl-ME-TMS

,A

lO,ll-dideuterio-1

l-deoxy-PGEl-

ME-TMS (10) The 9-keto

prostaglandins

converted

to methoxime

produced

in reactions

derivatives

before

21, 3), 5), and 6) above, were

analysis by GC-MS-COM.

DISCUSSION Mechanistic olefins

investigations

with rhodium complexes

of

the

suggest

homogeneous

that the reaction

the addition of the alkene to a transient coordinatively dihydride. l4 olefin

The collision

is well known to be sensitive

carbon-carbon

double

bond.

hydrogenated

before 15 the same alkene. Other

extensive

selectivity ester

over

the

stereochemistry

in the homogeneous even

ester

of l@-PGE2-15

since

bond

in the

disubstituted

Schneider,

methyl

unsaturated

more

rhodium and

double

-acetate

yield.

of the

bonds are together

steric

in

showed

of

effects. excellent

of PGE2-15-acetate

in 80%

the

hydrogenation

subtle

and Pike9

of

through

vicinity

bonds when present

methyl

Moderate-yield

and 15&PGE2-15-acetate

These workers have pointed out that the

of the metal dihydride

C13-Cl4

effects

in the reduction

esters were also achieved. selectivity

double

procedes

this metal dihydride

to steric

revealed

by Lincoln,

hydrogenations

observed bond

have

be obtained

PGEl-15-acetate

selective methyl

study

could

to

of selectivity

derivatives

between

For example,

trisubstituted

examples

prostaglandin The

complex

hydrogenation

is not

5,6-trans-PGE2

to react with the C5-C6

strictly

a matter

is also reduced

double

of E versus predominantly

z to

PGEl (at a slower rate).

OCTOBER

1979 VOL. 18 NO. 4

635

PROSTAGLANDINS

The results

of

our own experimental

studies

demonstrate

trimethylsilyl

ether protecting

group exerts an even more powerful

effect

the

between

upon

rhodium bonds

interaction

In this case

dihydride.

double bonds in the prostaglandin PGB’s,

have

been

CS-C6

x-bonds,

The

as reduction

of

a-bonds the C -C 16 17 8 l2 also

for

chemospecifically

The

deuteration17’18 chemically sensitivity

atoms.

species,

The

substitution

derivatization

species

gas

for

of the GC-MS-COM

of preparing

with

detector

the

aid

of

employing

analytical

and,

procedure.

of prosta-

PG1, where each bonds are tagged can

separate

the

sorts out the varying the

dedicated

such

double bonds reduces

analysis

This result

class

and C8-Cl2

chromatograph

scheme

for

each

the corresponding

of all g-disubstituted

distinct

as anticipated

the feasibility

reducing

while the mass spectrometric

isotopic

inert

of the stable isotope deuterium.

double bond other than C 13-Cl4

deuterium

computer.3

demonstrate

introduction

to a single chemical

of

are

’

findings

to a method3

degrees

for

is as facile

alkenes.

individual PGl’s

for PGA’s and C8-Cl2

which are z, and disubstituted,

present

two

carbon-carbon

of

leads

with

Cl3-Cl4

Reduction

with specific

carbon-carbon

over

encountered

CIO-Cl1

directing

intermediate

reactivities:

PGl’s

glandins

the

the

the expected

while

tetrasubstituted

and

for CS-C6

commonly

series,

shown to have

CIO-Cllv-bonds,

alkene

the selectivity

The two other

is complete.

the

that

therefore, 3, 19,20

mini-

chemospecific the number of increases

the

ACKNOWLEDGEMENTS The authors acknowledge Department

of Chemistry

with thanks the financial

and the Office

of Research

assistance

of the

Services at Cleveland

State University. LIST OF REFERENCES -1.

For example, see R. A. Johnson, F. H. Lincoln, J. L. Thompson, E. G. Nidy, S. A. Mizsak, and U. Axen, ---J. Am. Chem. Sot., B,4182 (1977).

2.

G. K. Koch and J. W. Dalenberg,

3.

R. G. Megargle, submitted.

636

L. E. Slivon,

J. Label. Compounds, --

VI, 395 (1970).

J. E. Graas, and A. H. Andrist,

OCTOBER

1979 VOL. 18 NO. 4

PROSTAGLANDINS 4.

B. Samuelsson, --J. Biol. Chem., 239, 4091 (1964).

5.

E. J. Corey, (1970).

6.

E. J. Corey and R. K. Varma, ---J. Am. Chem. Sot., 93, 7319 (1971).

7.

For instance, see footnote 15 in C. J. Sih and F.-C. Chem. Sot., 100, 643 (1978). --

8.

J. A. Osbom, F. H. Jardine, &., A, 1711 (1966).

9.

F. H. Lincoln, (1973).

R. Noyori, and T. K. Schaaf, ---J. Am. Chem. Sot., 92, 2586

Huang, -J. .4m.

J. F. Yound, and G. Wilkinson, -J. Chem.

W. P. Schneider,

and J. E. Pike, J. Org. Chem., 38, 951

10.

For our method of analysis in this reaction, see: A. H. Andrist, L. Slivon, and J. E. Graas, J. Org. Chem., 43, 634 (1978).

11.

B. J. Sweetman, (1973).

12.

R. G. Megargle and L. E. Slivon, to be submitted.

13.

E. 0. Oswald, D. Parks, T.Eling, and B. J. Corbett, 47 (1974).

14.

For example, see J. M. Brown and P. A. Chaloner, J. Chem. Chem. Commun., 321 (1978) and references cited therei;;.

15.

R. E. Ireland and P. Bey, cited in M. Fieser and L. F. Fieser, Reapents for Organic Synthesis, Vol. 4, p. 561, J. Wiley and Sons, New York, 1974.

16.

A. L. Augustine, 1965.

17.

B. R. James, York, 1973.

18.

Alkenes do not undergo E-Z isomerization during homogeneous hydrogenation with rhodium complexes: K. E. Koenig and W. S. Knowles, 175th National Meeting of the American Chemical Society, Anaheim, March 1978, Abstract No. ORGN 154.

19.

For descriptions of other computerized GC/MS methods for PG quantitation, see: a) U. Axen, K. G&en, D. H&lin, and B. Samuelsson, Biochem. Biophys. Res. Commun., 45, 519 (1971); b) B. Samuelsson, M. Hamberg, and C. C.xeeley, Anal.Biochem., 38, 301 (1970); and c) L. Baczynskyj, D. J. Duchamp, m. Zieserl, Jr., and U. Axen, &I& Chem., 451479 (1973).

20.

Supplementary material, consisting of the methane chemical ionization mass spectra of the deuterated PG derivatives, is available upon request from the authors.

OCTOBER

J. C. Frglich,

Catalytic

Homogeneous

1979 VOL. 18 NO. 4

and J. T. Watson, Prostaglandins,

Hydrogenation,

Hydrogenation,

i. Chromatog.,

E.

2, 75

fi,

c.,

Marcel Dekker, New York,

J. Wiley and Sons, New

637

PROSTAGLANDINS

@02c~3ezcH3 ‘I\

Y

\

Si(CH3)3

Si(CH3)3

:

d Si(CHS3

Si(CH3)3

a

s

.

&02cH3

&2c”3

I

; 6 Q

\

\ @3)3

Si(CH313

Si(CH313

8

1

-10

638

OCTOBER

1979 VOL. 18 NO. 4