SYNTHESIS OF ISOMERIC ll-HYDROXY ll-METHYL PROSTAGLANDINS'

Angel GusmAn, Miguel Vera and Pierre Crabbg2

Research Laboratories, Syntex S.A.

Apartado Postal 10-820, Mexico D.F., Mexico.

ABSTRACT

The synthesis of several novel 11-substituted

prostaglandins has been achieved from PGA, methyl ester

from the marine coral Plexaura homomalla. The configuration

of the substituents at position 11 is based on the nuclear

magnetic resonance properties.

Accepted September 16

PROSTAGLANDINS

OCTOBER 10, 1974 VOL. 8 NO. 1 85

PROSTAGLANDINS

In recent years, various laboratories have been

engaged in the chemical synthesis of modified prostaglan-

dins, as with steroids and antibiotics it is anticipated

that some modified entities will exhibit higher and/or

more selective biological properties than their natural

occurring counterparts3. Among the modified entities which

have already been prepared are 11-methyl4 and ll-hydroxy-

methyl5 prostaglandins. In this paper we wish to report

the synthesis of novel 11-hydroxy 11-methyl prostaglandins

using PGA2 methyl ester (1) from the marine coral Plexaura

homomalla6 as a starting material.

Pyrolysis of the pyrazoline (2)' in refluxing

xylene, in an argon atmosphere, provided 11-methyl PGA2

methyl ester (2)' in 47% yield. Epoxidation of the PGA2

derivative (z), with alkaline hydrogen peroxide in methanol

solution at -18', yields a mixture of lO,lla-and B-epoxides

(4) (oil ; IR v max 1740,1620,1600 cm'1 ; NMR 1.5 (s., ll-

methyl), 3.65 p.p.m. (s., l-Me ester)), in 98% yield.

Reduction of this mixture ($1 with aluminium amalgam

in dimethylformamide solution, under argon', affords the

lla-and 118-hydroxy-derivatives (5) and (5). The mixture of .

isomers, in which the latter predominates, was separated by

preparative thin layer chromatography (t.1.c.). The B-con-

figuration of the methyl group in the ll-methyl PGE2 methyl

ester (5) (colorless liquid : [a],., -55" ; IR vmax 3450,

1740,1720,970 cm -1 ; NMR 0.88 (C-20 Me), 1.24 (s.,llB-Me),

86 OCTOBER 10, 1974 VOL. 8 NO. 1

PROSTAGIANDINS

3.65 (s., l-Me ester), 4.1 (m., CEOH) ; 5.2 - 5.7 p.p.m.

(m., vinylic H) ; MS m/e 362 (M+-H20))' isolated in ca.lO% -

yield, is assigned on the basis of its NMR spectrum, since

the 11-methyl.group is shielded 10

by the cis-alkyl group.

Moreover, in flexible five-member rings such as in com-

pounds (2) and (5) the chemical shift of the 11-methyl

group in a quasi-axial configuration usually appears at

higher field than in the quasi-equatorial stereochemistry 11

In fact, whereas the chemical shift of the methyl group in

the 11(3-methyl compound (2) is 1.24 p.p.m., the signal

corresponding to the same group appears at 1.34 p.p.m. in

the llu-methyl isomer (a) (oil ; [alD -39’ ; IR wmax 3450,

1740,1725,970 cm -1 ; NMR 0.88 (C-20 Me), 1.34 (s., lla-Me),

3.64 (s., l-Me ester), 4.13 (m., CEOH), 5.2 - 5.75 p.p.m.

(m., vinylic H) ; MS m/e 362 (M+-H20)) (z. 70%). This

shows that epoxidation of the enone (3) occurs mainly from

the B-side giving the lO,lld-epoxide as the major component

of the mixture (Q).

Reduction of the carbonyl group at C-9 of the 118-

hydroxy-compound (6) with sodium borohydride in methanol

solution affords mainly the 9$-hydroxy-derivative (1)

{liquid ; [a]), +14' ; IR vmax 3500,1730,970 cm-l ; NMR 0.88

(C-20 Me), 1.22 (s., lla-Me), 3.65 (s., l-Me ester), 3.9

(m., 9a-H), 4.06 (m., CEOH), 5.3 - 5.7 p.p.m. (m., vinylic

H) ; MS m/e 364 (M+-H20)) (96%). The 9-hydroxyl is assigned

the (3-configuration in the major component, because the

OCTOBER 10, 1974 VOL. 8 NO. 1 87

PROSTAGLANDINS

Vu-proton appears at ca. 3.9 p.p.m., in agreement with a - 11

quasi-axial configuration .

Selective oxidation of the allylic alcohol at C-15

in compound (7) with DDQ in dioxane solution provides the _-

corresponding enone (8) {oil ; IaID +78' ; UV Xmax 232 nm

(E = 20.900) ; IR vmax 3400,1735,1650,970 cm-l ; NMR 0.88

(C-20 Me), 1.23 (s., lla-Me), 3.63 (s., l-Me ester), 3.97

(m., CIJOH), 5.3 - 5.5 (m., C-5,C-6 vinylic H), 6.05 (d, J

= 14Hz, vinylic H14), 6.76 and 6.95 (da., Jl = 14Hz, J2 =

~Hz, vinylic H13) ; MS m/e 380 (M+)). Grignard reaction

with methyl ma.gnesium bromide at -18", under argon, on the

enone (S) alkylates the carbonyl group4, thus affording a

mixture of isomeric alcohols (Va) and (z), separated by -

preparative t.1.c.. The configuration of the tertiary

methyl at c-15 in the isomeric dimethylated prostaglandins

(Va) {colorless liquid ; [aID +26’ ; IR vmax 3500,1735,980 -

cm -1 ; NMR 0.87 (C-20 Me), 1.18 (s., 15-Me), 1.24 (s., ll-

Me), 3.64 (s., l-Me ester), 3.88 (m., Vu-H), 5.32 - 5.65

p.p.m. (m., vinylic H)) and (Vb) foil ; IalD +25" ; IR -

vmax 3450,1730,970 cm-l ; NMR 0.86 (C-20 Me), 1.18 (s.,

15-Me), 1.25 (s., ll-Me), 3.64 (s., l-Me ester), 3.88 (m.,

Vu-H), 5.3 - 5.6 p.p.m. (m., vinylic H)) is still unknown.

OC'I'OBEK 10, 1974 VOL. 8 NO. 1

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References

1. Contribution No442 from the Syntex Institute of Organic

Chemistry. Studies in Prostaglandins N039.

2. Present address : C.E.R.M.O., UniversitB Scientifique

et MBdicale, B.P. 53, Grenoble 38, France.

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Chem. Sot., 95, 8483, 1973 ; S. Iguchi, F. Tanouchi,

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90 OCTOBER 10, 1974 VOL. 8 NO. 1

6.

7.

8.

9.

10.

11.

PROSTAGLANDINS

and J.H. Fried, Tetrahedron Letters, 5151, 1972.

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All rotations and infrared (IR) spectra in chloroform

solution. The NMR Spectra were recorded with Varian

A-100 and T-60 instruments, for 5-8 w/v solutions in

deuteriochloroform containing tetramethylsilane as

internal reference. Mass spectra (MS) were recorded

with an Atlas CH-4 spectrometer. Thanks are due to Dr.

M.L. Maddox, Syntex Research, Palo Alto (Calif.), for

various spectra and helpful comments.

L.M. Jackman and S. Sternhell, Applications of Nuclear

Magnetic Resonance Spectroscopy in Organic Chemistry,

2nd. edit., Pergamon Press, London, 1959, p. 234.

J.F. Bagli and T. Bogri, Tetrahedron Letters, 5,

1967 ; M. Miyano, C.R. Dorn, and R.A. Mueller, J. Org.

Chem., 37, 1810, 1972 ; M. Miyano and C.R. Dorn, J.

Org. Chem., 37, 1818, 1972.

OCTOBER 10, 1974 VOL. 8 NO. 1 91