Tetrahedron Letters,Vo1.23,No.36,pp 3735-3736,1982 0040-4039/82/363735-02$03.00/O Printed In Great Brltaln 01982 Pergamon Press Ltd.

A TOTAL SYNTHESIS OF LEUKOTRIENE F4 (LTF4)

Frank Ellis, Lester S Mills and Peter C North*

Chemistry Research, Glaxo Group Research Ltd , Ware Hertfordshlre SC12 ODJ, England

Abstract The synthesis of LTF4 via the reaction of (+)-leukotrlene A4(LTA4), mett-il ester 1 with the protected glutamylcystelne 1 1s reported

The leukotrienes LTC4, D4 and E4 are a recently dlscovered family of arachldonlc acid

metabolltes which are thought to be involved in certain hypersensitlvlty reactlons including

allergic asthma ’ It was recently disclosed2 that incubation of LTE4 with Zf-glutamyl

transpeptldase, in the presence of glutathlone, produces a new leukotrlene (LTF4) possessing

a i -glutamylcystelne residue The biological activity of this new leukotrlene was,

however, not given We now wish to report a total synthesis of LTF4 via the reaction

of (t)-leukotrlene A4, methyl ester3 1 with the protected glutamylcjstelne 2, thds maklng

this new leukotrlene accessible for further study The ease or synthesis of 2 is particu- -

larly noteworthy, and the methods described herein should be applicable to other areas

of peptlde chemistry in which the formatlon of a 3 -glutamyl peptlde bond 1s required

LTC4. R=

R’=

LT& , R =

R’=

LTE4 , R =

R’=

CO -NH,

?02H

NHCH,CO,H

H

NHCH,CO.$i

H

OH

LTF4 . R = CO-NH,

I+= OH EO$i

C02CH3

HS w,NHCO y NHCOCF,

b&H3 C0fiH3

2

3735

3736

ROC L/‘k/NHCOCF3

EO*R’ SuNHC0wNH~~~~3

4, R=OH R’= CH3 8 C02CHB :02CH3 I 2

s, R=OCH, R’= H

6, R = Cl R’= CH, z

Treatment of L-glutamlc acid with an excess of trifluoroacetlc anhydrlde gave a 55% yzeld

of the anhydride A415 which was refluxed in dry methanol (ZOml/g, 2 mln) to afford a 5.2

mixture of the c-ester 2 [NMR/CDC13 6 3 8 CO2CH3] and the '1F -ester 2 [NMR/CDC13 6 3.7 CO2CH3] In 100% yield Without Further puriflcatlon, this mixture was dissolved UY ether

(tOml/g) and treated with 0.7 equivalents of dlcyclohexylamine at O” The resulting pre-

clpztate was recrystallzsed From dioxane to give the pure dicyclohexylamlne salt OF 2

[m.p. 193.5-1940, [$li-21 'lo, c=1.6 in H20] which was treated with 2M hydrochloric acid

to give, after extraction rnto ethyl acetate, the pure a-ester jj as a colourless Oil ln

36% overall yield from 2 [[c]iq -31 9’1 Co1 1 in &$I The preparation of 3 from glUtamlC

acid as described above can easily be accomplished in one day Exposure of 3 to 1 5 equl-

valents of thronyl chloride in ether-dlmethylFormamIde (lOO:l, lOml/g, 23O, 2h) gave the

acid chloride 5 which was treated with 0 5 equivalents of L-cystlne, dimethyl ester, dlhydro-

chloride which had previously been stlrred with 2 equivalents of triethylamine ln tetrahydro-

Furan For 15h at 2j0 The dlsulphlde 1 Cm p 167-1690, [a]:' -82 go, c:l.l In CH30H]

so obtained (60%) was reduced wrth an excess of zinc and acetle acid In ethyl acetate r ,23 to give the thloi 2 in 73% yleid irn p i2ii-i25o, talD +26.6o, c1i.2 In CHCi3]. The coupling

of 2 with 13 under standard conditions 6 gave a 1:l mxture of the trImethyl ester, N-trl-

Fluoroacetamlde of LTF4 together with its 5(R),6(S)-dlastereolsomer In 82% yield Hydrolysis

of thrs mixture 6 afforded the corresponding mixture of LTF& and rts diastereorsomer as

their trlpotas-_um salts rn QQ$ yleld7 Inltlal studres lndlcate that the mixture of LTF4

and its 5(R),6(S)-dlastereo,sorer* is 282 tines less active than LTD!J In contract:-g the

guinea pig Ileum and nas negliglbie contractile activity on the human bronchus ln Vlt"0

REFERENCES AND NOTES

1. 2. 3.

4 5.

6

7.

a,

For review see P. Borgeat and P. Sirols, J.Med.Chem,, 1981, ;", 121. M.E. Anderson, R.D. Allison and A. Melster, Proc.Natl Acad.Scl.USA., 1982, 2, 1088. Prepared essentially as described by I. Ernest, A.J. Maln and R. Menasse', Tetrahedron Letters, 1982, 2, 167 using racemlc epoxyaldehyde prepared as described by J.C. Gleason, D.B. Bryan and C.M. Kinzig, ibid, 7980, 21, 7129. C.M. Allen Jnr. and M.E. JonrArch.Blochem Blophys., 1966, 134, 115. All stable lntermedlates were characterised by mlcroanalysls,%, IR and, where applicable, UV spectroscopy. E.J. Corey, D.A Clark, G. Goto, A. Marfat and C. Mioskowskl, J.Amer.Chem SoC., 1980, 102, 1436 HPLC retention times were 5.3 and 6.0 mln on a 20x0 5cm Spherlsorb, 5i.1, Cl, column eluted at 2ml/mln with MeOH HZO*AcOH (65 35 0 01) buffered to pH 5 7 with NH+OH Under these condltlons LT& and its 5(R),6(S)dlastereolsomer eluted at 11.4 and 12 8 mln Experience has shown that in the case of LTG,, I&and Ej, this dlastereolsomer 1s as least two orders of magnitude less active than the natural dlastereolsomer.

(Recezved rn UK 5 July 1982)