Pergamon

0040-4039(95)01271-0

Tetrahedron Letters, Vol. 36, No. 36. pp. 6437-6438, 1995 Elsevier Science Ltd

Printed in Great Britain 0041)-4039/95 $9.50+0.00

Total Synthesis of 19(RS)-F-LTA 4 Methyl Ester

Myl~ne Garcia +, Thierry Durand +*, Jean Pierre Girard +, Jean Claude Rossl +, Igor Serkov #,

Dmitry Kuklevl and Vladimir Bezuglov §

+Laboratoire de Chimie des M6diateurs et Physicochimie des Int6h'actions Biologiques associ6 au C.N.R.S.

Universit6 Montpellier I, Faeult~ de Phannacie, 15 Av. Ch. Flahault, F-34060 Montpellier, France.

#Department of Prostaglandin Chemistry, Institute of Physiologically Active Substances

The Russian Academy of Sciences, 142432 Chemogolovka, Moscow district, Russia.

§Department of PG & LT, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry

The Russian Academy of Sciences, uI.Miklukho-Maldaya 16/10; 117871 GSP 7 Moscow, Russia.

Abstract. The first total synthesis o f 19(RS)-fluoroleukotriene A 4 methyl ester 8 is presented. The strategy

focuses on oJ-1 functionalized phosphonium salt as (3(Z)-8-fluorononenyl)triphenyl phosphonium iodide 6 and its

coupling with epoxydienal 7.

The main metabolic pathway of leukotrienes is oxidation of their co-chain 1,2. In search for chemically and

metabolically stable leukotrienes mimics, we started the preparation of ¢o-1 functionalized leukotriene A 4

analogs 3,4. Recently we reported the synthesis of 19(RS)-OTBDMS-LTA43 and 19(RS)-NHCHO-LTA 4 methyl

esters 4. We describe herein the first total synthesis of 19(RS)-F-LTA 4 methyl ester 8 (Scheme 1).

The starting synthon 1 was prepared from commercial 3-butyn-l-ol and 5-chloropentan-2-one according

to the procedure published in our previous paper 3.

1 O 2 OH 3 F

4 F S F F

0

O H C ~ . , , ~ C O O M e F a 7

a: NaBH4/MeOH 100%, b: MSTF/CH2CI2/5 rain. 75%, e: HCI 10%/THF 82%, d: PPh3/12/'tmidazole/xylene 80°C 5 min. 85% e: PPh3/toluene 900C 24 hrs. 87%, f: BuLi/rHF/HMPT -78qC 15 rain. 68%.

Scheme 1

6437

6438

Ketone 1 after treatment by sodium borohydride in dry methanol gave the alcohol 2 in quantitative yield.

Reaction of the hydroxy compound 2 with MSTF 5 in dry CH2CI 2 generated the fluoro derivative 3 in 75% yield

and the defluoro derivative in 15% yield. Deprotection of the tetrahydropyranyl group in ether 3 with 10% aq.

HCI afforded the fluoro alcohol 4 in 82% yield. The iodo derivative 5 was obtained in 85% yield with PPh 3,

12, imidazole in xylene at 80cC 6 and finally transformed into the white crystalline phosphonium salt 67 with

PPh 3 in toluene in 87% yield.

The 19(RS)-F-LTA 4 methyl ester 8 8 (a diastereoisomer mixture) was obtained by coupling the

epoxydienal 7 (1 eq.) with phosphonium iodide 6 (3 eq.) in presence of n-BuLi (3 eq.) in a THF/HMPT (5:1)

mixture at-78~C (68% yield after purification by flash chromatography).

Acknowledgment. We wish to thank the "Minist~re de rEnseignement Sup6rieur et de la Recherche" (MESR)

for financial support of one of us (M.G.).

References and Notes 1. Kunau, W.H.; Dommes, P. Eur. J. Biochem. 1978, 91, 533-544. Kunau, W.H.; Bartnik. Eur. J. Biochem.

1974, 48, 311-318. Hiltunen, J.K.; Kiirki, T.; Hassinen I.E.; Osmundsen, H. J. Biol. Chem. 1986, 261, 16484-16493 and references herein.

2. Jedlitschky, G.; Leier, I.; Huher, M.; Mayer, D.; Keppler, D. Arch. Biochem. Biophys. 1990, 282, 333-339 and references herein.

3. Pastouret, A.; Vidal, J.P.; Durand, T.; Girard, J.P.; Rossi, J.C.BulI. 8oc. Chim. Fr. 1993, 130, 206-213. 4. Durand, T.; Garcia, M.; Rossi, J.C.; Kuldev, D.V.; Bezuglov, V.V.Abstractof9thlnternationalConferenceon

Prostaglandins and Related Compounds (Florence, Italy), 1994, pp. 43. 5. Bezuglov, V.V:; Manevich, E.M.; Bergelson, L.D.; Ovchinnikov, Yu.A. inProstaglandins and Cardiovascular

Diseases: Ozawa, T.; Yamada, K.; Yamamoto, S., Eds.; Japan Scientific Societies Press: Tokyo. 1986, pp. 191- 200 and references herein.

6. Rondot, B.; Durand, T.; Rossi J.C.; Rollin, P. Carbohydr. Res. 1994, 621, 149-156.

7. 6: m.p, 112'U (ether): H-NMR (360 MHz, CDCI 3) 8:7.69-7.84 (m, 15H, At), 5.33-5.6 (m, 2H, H-3, H-4),

4.46-4.63 (din, JH.F = 48.6 Hz, 1H, H-8), 3.68-3.76 (in, 2H, H-l), 2.39-2.47 (in, 2H, H-2), 1.80-1.84 (m,

2H, H-5), 1.28-1.53 (in, 4H, H-6, H-7), 1.24 (dd, J= 6.1, JH.F = 24.1 Hz, 3H, H-9). 13C-NMR (90 MHz,

CDCI 3) 8:135.2 (Ar), 133.8 (At), 133.7 (At), 132.1 (C-4), 130.7 (At), 130.5 (Ar), 126.5 (C-3), 118.6 (At),

117.5 (At), 91.7-89.9 (d, J¢.F = 162 Hz, C-8), 36.4-36.1 (d, JC.F = 27 Hz, C-7), 27 (C-5), 24.8 (C-6), 23.8-

23.2 (d, Jc_p= 54 Hz, C-l), 21.1-20.9 (d, JC.F= 18 Hz, C-9), 20.3 (C-2). 31P-NMR (81 MHz, CDC13)

8: + 24.89.

8. 8: UV (ether) ~hnax: 277 run, shoulders 269 and 290 nm.; 1H.NMR (360 MHz, CDCI 3) 8:6.41-6.55 (m, 2H,

H-8, H-10), 6.17 (dd, J= 10.4, 14.8 Hz, 1H, H-9), 6.00 (t, J= 10.8 Hz, 1H, H-11), 5.32-5.46 (m, 4H, H-7, H-12, H-14, H-15), 4.52-4.73 (din, JH_F = 50 Hz, 1H, H-19), 3.65 (s; 3H, CH30), 3.11 (dd, J= 2.2, 8.3 Hz, 1H, H-6), 2.93 (t, J= 6.5 Hz, 2H, H-13), 2.83 (t, J= 5.6 Hz, 1H. H-5), 2.36 (t, J= 7.6 Hz, 2H, H-2), 2.06- 2.12 (m, 2H, H-16), 1.76-1.81 (m, 2H, H-3), 1.56-1.66 (m, 6H, H-4, H-17, H-18), 1.30 (rid, J= 6.1, JH.F =

23.8 Hz, 3H, H-20). IaC-NMR (90MHz, CDCI3) 8:173.6 (C-I), 134.5 (C-8), 131.5 (C-9, C-12), 130.2 ((2-

15), 130.1 (C-7), 128.8 (C-10), 128.4 (C-11), 127.6 (C-14), 91.7 - 89.9 (d, JC_F= 162 Hz, C-19), 60.5 (C-5), 58.3 (C-6), 51.5 (CH30), 36.6-36.3 (d, JC.F = 27 Hz, C-18), 33.5 (C-2), 31.4 (C-4), 27 (C-16), 26.2 (C-13), 25 (C-17), 21.3 (C-3), 21.1-20.9 (d, JC_F = 18 Hz, C-20).

(Received in France 29 May 1995; accepted 5 July 1995)