`
`Journal of Medicinal Chemistry, 1978, Vol. 21, No. 5 443
`
`Zacchei, T. I. Wishousky, Z. E. Dziewanowska, P. J.
`DeSchepper, and G. Hitzenberger, Eur. J. Drug Metab.
`Pharmacokinet., 2, 37 (1977); (c) A. G. Zacchei and T. I.
`Wishousky, Drug Metab. Dispos., 4, 490 (1976).
`(9) H. E. Zaugg and W. B. Martin, Org. React., 14, 63 (1965).
`(10) G. M. Fanelli, D. L. Bohn, A. Scriabine, and K. H. Beyer,
`Jr., J. Pharmacol. Exp. Ther., 200 (2), 402 (1977).
`(11) K. F. Tempero, G. Hitzenberger, Z. E. Dziewanowska, H.
`Halkin, and G. H. Besselaar, Clin. Pharmacol. Ther., 19 (1),
`
`116 (1976).
`(12) K. F. Tempero, J. A. Vedin, C. E. Wilhelmsson, P.
`Lund-Johansen, C. Vorburger, C. Moerlin, H. Aaberg, W.
`Enenkel, J. Bolognese, and Z. E. Dziewanowska, Clin.
`Pharmacol. Ther., 21 (1), 119 (1977).
`(13) Optical purity was determined spectrophotometrically by
`Dr. B. H. Arison on a Varian HA-100 NMR using the chiral
`shift reagent, tris[3-(heptafluorobutyryl)-d-camphorato )(cid:173)
`europium(III) [Eu(hfbc)s).
`
`15,15-Ketals of Natural Prostaglandins and Prostaglandin Analogues. Synthesis
`and Biological Activities 1
`
`W. Skuballa, B. Radi.ichel, 0. Loge, W. Elger, and H. Vorbri.iggen*
`Research Laboratories of Schering AG, Berlin-Bergkamen/Germany, 1000 Berlin 65, Federal Republic of Germany.
`Received August 30, 1977
`
`The synthesis is described of new 15,15-ethylene ketals of natural prostaglandins and prostaglandin analogues.
`Especially the crystalline trisamine salt of the 15,15-ethylene ketal of 15-dehydro-16-phenoxy-17,18,19,20-tetra(cid:173)
`norprostaglandin F 2a is a very active inducer of luteolysis in laboratory animals and cattle.
`
`For the biological activity of natural prostaglandins, the
`presence of a 15a-hydroxy group is essential, whereas the
`corresponding 15/3-hydroxy compounds, e.g., 15/3-
`hydroxyprostaglandin E 1, show drastically diminished
`biological activities. 2
`However, in certain analogues, e.g., 15-methyl- or 16-
`phenoxy-w-tetranorprostaglandins, the 15/3-hydroxy ep(cid:173)
`imers are themselves often biologically active. 3•4
`Since the 15-methyl ether of PFG2a methyl ester shows
`a two to three times stronger abortifacient activity in the
`pregnant hamster than PGF2" methyl ester,5 the presence
`of a free 15-hydroxy group is apparently not essential for
`the biological activity in vivo.
`It seemed therefore logical to us that the combination
`of (a) the sometimes considerable biological activity of
`15/3-hydroxy compounds with (b) the biological activity of
`15-methyl ethers would lead to the conclusion that the
`prostaglandin 15-ketals, e.g., 15,15-ethylenedioxy- or
`15,15-dimethoxyprostaglandins, might also possess in(cid:173)
`teresting biological properties. In all conformations of
`these new analogues, at least one ketal oxygen would
`always be available for the interaction with the receptor
`molecules.
`It should be noted here that the active form of 15-keto
`prostaglandins like 15-keto prostaglandin F2a, which is
`formed during metabolism, might act in the hydrated form
`(15,15-dihydroxyprostaglandins) since they still cause
`pronounced contractions of the smooth muscles of the
`guinea-pig ileum as well as of the gerbil colon. 6
`We have therefore synthesized a series of 15-ketals of
`natural prostaglandins and prostaglandin analogues which
`are readily available by ketalization of the unsaturated keto
`lactones (compare Scheme I). The chiral center at C-15
`in natural PG's is thereby eliminated, resulting in a
`simplification of the Corey synthetic scheme7 (Scheme I).
`Chemistry. Starting from unsaturated ketones 18•9
`(Scheme I) standard ketalization with ethylene glycol in
`benzene in the presence of p-toluenesulfonic acid gave the
`ketals 2 in good yields. Reduction of the lactones and
`simultaneous removal of the benzoate with diisobutyl(cid:173)
`aluminum hydride (DIBAL) afforded the lactols 3 which
`were transformed by Wittig reaction to the 15-deoxy-
`15,15-ethylenedioxyprostaglandins 4. Esterification with
`diazomethane and butyl bromide-silver oxide yielded the
`
`Scheme I
`0
`
`~~
`
`MR, [ OH
`
`OH
`C5 H5, p-TosOH
`
`0
`
`o-1<
`
`DIBAL
`
`~R ,
`OBz
`
`OLJ
`
`la,b
`
`2a,b
`
`OH g-\
`,, 1-(
`
`=
`
`OLJ
`
`Ph3P=CH(cid:173)
`(CH2)3COO"
`~R1
`o'fi
`
`3a,b
`
`Chart I
`
`OH
`f1 , , , , ,~C02R2
`
`~R1
`OLJ
`OH
`4a,b, R 2 = H
`5a,b, R 2 = CH3
`6a,b, R 2 = n-C4 H 9
`7a,b, R 2 = CH 2CO-C6 H4 :C6 H,
`8b, R 2 = H 3 N+C(CH 2OH) 3
`a, R, = n-C,H,,
`b, R, = -CH,oc.H,
`
`OH
`
`1"7,,,,, ~CO2 C H3
`~ OH
`OR
`RO
`9, R,R = -CH 2 CH2CH 2 -
`10, R,R = -CH 2C(CH3 ) 2CH 2 -
`ll, R= -CH3
`
`methyl esters 5 and the butyl esters 6. Treatment of 4 with
`p-phenylphenacyl bromide in the presence of triethylamine
`afforded the esters 7 .10
`The free acid 4b afforded on neutralization with tris(cid:173)
`(hydroxymethyl)aminomethane the crystalline tris salt Sb.
`In an analogous way, starting from known 15-ketones,
`other new 15,15-ethylene ketals in Table II, e.g., substi(cid:173)
`tuted 16-phenoxy- and 15- or 17-arylprostaglandin ana(cid:173)
`logues, were synthesized, and the structure of the inter-
`
`0022-2623/78/1821-0443$01.00/0 © 1978 American Chemical Society
`
`Micro Labs Exhibit 1048
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
`
`444 Journal of Medicinal Chemistry, 1978, Vol. 21, No. 5
`
`Skuballa et al.
`
`Isolated guinea-
`pig ileuma
`
`Table I. Relative Activities of 15-Ketals of Natural
`Prostaglandins
`Isolated rat
`Abortion rat
`uterusa
`Compd
`1 X F 2c/
`5-10 X Fm
`4a
`1XF 2a
`5a 5XF2a
`<0.3 X F,a
`9
`<0.F X Fm
`<0.3 X Fm
`10
`<<0.ld X Fm
`<0.1 X Fm
`11
`0.1 X F 2a
`<0.3 X F,a
`1 X F 2a
`17a
`a Compared with a standard solution of PG F ,a·
`b PGF 2a was active in this standard test at about 0.3-1
`mg/rat/day. c Slightly less active than one-tenth of
`PG F 2a, d Inactive at more than ten times the threshold
`dose of PGF'°'.
`
`0.lXFm
`
`<<0.1 X F 2a
`
`Chart II
`
`Q~
`~
`""
`
`~
`
`OBz
`
`O
`
`0CH3
`12
`OH
`( \ ' ' ' ' '~ co o cH3
`
`-~
`OH
`O
`
`14
`
`mediates and the final PG analogues were characterized
`by physical methods and analysis.
`The 13,14-dihydro-15-ethylene ketal 1-methyl esters 17
`In order to evaluate the influence of different ketal
`were prepared according to Scheme II starting from 15
`moieties in natural prostaglandins on the biological ac(cid:173)
`which are readily available by hydrogenation of l.
`tivity, we prepared the ketals 9 and 10 in an analogous way
`Results and Discussion
`(Chart I).
`a. Variation of the Ketal Moiety. The antifertility
`To synthesize the dimethyl ketal 11 (Chart II) we first
`attempted to prepare the 15,15-dimethyl ketal of la by
`data of Table I show that the 15,15-ethylene ketals of the
`heating la with methanol in the presence of p-toluene(cid:173)
`F2" series (4a and 5a) have the highest biological (lu(cid:173)
`teolytic) activities. Variation of this ketal moiety leads to
`sulfonic acid but obtained only a mixture of the 1,4-ad(cid:173)
`a decrease in luteolytic activity. The lower biological
`dition products 12 and 13. Since dimethyl ketals are
`efficacy of 9 and 10 might be due to steric hindrance by
`usually less stable than the corresponding ethylene or
`the bulky ketal groups. Saturating the 13,14 double bond
`propylene ketals and may not survive the DIBAL re(cid:173)
`as in 17a and 17b leads to a decrease in abortive activity
`duction and Wittig reaction, we converted the corre(cid:173)
`sponding 15-dehydroprostaglandin F 2" methyl ester 14,
`without diminishing the uterotropic activity.
`b. Variation of the Lower Side Chain. From all the
`which is readily available by hydrolysis of 5a, into 11 in
`new prostaglandin analogues described in Table II, the
`24% yield at room temperature by treatment with
`16-phenoxy-w-tetranorprostaglandin 15,15-ethylene ketals
`methanol-trimethyl orthoformate in the presence of traces
`have the highest abortive activity in rats.
`of hydrochloric acid.
`Table II. Relative Activities of 15,15-Ethylene Ketals of PGF Analogues with Modified Lower Side Chain
`
`OH (::=t''~ COOR
`
`-
`
`2
`
`Compd
`
`R,
`
`R2
`
`A
`
`Isolated rat Isolated guinea·
`uterusa
`pig ileuma
`
`Abortion rat Refb
`
`$'
`
`xR1
`OH O
`0
`\_J
`
`4b
`
`-CH 2O-C,H,
`
`5b
`
`-CH 2 O-C,H,
`
`H
`
`CH,
`
`6b
`
`-CH,O-C,H,
`
`n-C 4 H 9
`
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`-CH2CH2-
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`
`H
`-C=C-
`H
`
`10 X F,a
`
`0.1 X F 2a
`
`10-30 X F,a
`
`;;.10 X F,a
`
`<0.1 X F,a
`
`100 X F,a
`
`10 X F 2a
`
`>10 X F,a
`
`;;.10 X F,a
`
`10 X F,a
`
`30 X F,a
`
`10 X F,a
`
`10 X F,a
`
`;;.10 X F,a
`
`<0.1 X F,a
`
`10 X F,a
`
`>10 X F,a
`
`-10 X F,a
`
`30 X F,a
`
`10 X F,a
`
`9
`
`9
`
`9
`
`9
`
`9
`
`9
`
`9
`
`12
`
`13
`
`Sb
`
`-CH 2 O-C 6 H 5
`
`17b
`
`-CH,O·C6 H 5
`
`-CH,O-C 6 H4 -4-F
`
`+
`NH 3 C(CH 2OH) 3
`
`CH 3
`
`CH 3
`
`-CH,o-c,H.-3-CF 3
`
`CH 3
`
`-CH,CH, -C,H,
`
`-C,H4-4-Cl
`
`CH 3
`
`CH 3
`
`18
`
`19
`
`20
`
`21
`
`a See footnote a in Table I.
`
`9.J/,,
`b The references refer to the origin of the starting keto lactone ~('
`
`0
`
`~R1
`OBz
`0
`
`Micro Labs Exhibit 1048-2
`
`
`
`15,15-Ketals of Natural Prostaglandins
`
`Scheme II
`0
`
`DIBAL
`
`1. Wittig
`
`2. CH2N2
`
`~.JZ
`~.
`
`OBz
`
`O
`
`15a,b
`
`OH
`,:.
`:::. ' ' '~ c O R 2 2
`R1
`~
`
`OH Ou
`
`16a,b, R 2 = H
`17a,b, R 2 = CH3
`a, R, = n-C 5H 11
`b, R, = -CH2OC6HS
`
`The esters 5b and 6b showed a higher activity (in vivo)
`in the pregnant rat than the free carboxylic acid 4b. 5b
`exhibited a 100 times stronger abortifacient activity than
`PGF 2a and a diminished activity on other smooth muscles
`like guinea-pig ileum in vitro. However, from a practical
`point of view the water-soluble sodium salt of the free acid
`4b and especially the water-soluble and crystalline tris salt
`Sb seem to be the most interesting compounds. They show
`excellent efficacy to induce luteolysis and have been used
`in aqueous (saline) solution to synchronize estrus in cattle
`and heifers efficiently. 11
`Experimental Section
`Chemistry. The IR spectra were measured in CHC13 with a
`Perkin-Elmer G 157 instrument, if not indicated otherwise, and
`the NMR spectra with a Varian HA-100 instrument. The melting
`points were determined with a Kofler melting point microscope
`and are not corrected. Column chromatography was carried out
`on E. Merck silica gel 60, particle size 0.063-0.2 mm.
`( 3aR ,4R ,SR ,6a S )-S-Benzoyloxy-4-[ (E)-3,3-ethy lenedi(cid:173)
`oxy-1-octenyl]perhydrocyclopenta[ b ]furan-2-one (2a). la8
`(15.38 g, 41.52 mmol), 44.5 mL of ethylene glycol, 237 mg of
`p-toluenesulfonic acid hydrate, and 1080 mL of benzene were
`heated for 7 h in a Dean-Stark apparatus. After cooling and
`extracting with saturated NaHCO3 and finally saturated NaCl
`solution, the benzene solution was dried (MgSO4) and evaporated
`in vacuo to give 15.26 g (97 % ) of crystalline 2a. Recrystallization
`from CH2Cl2-hexane afforded the analytical sample: mp 91-93
`°ᵮC; [a] 220 -80.2° (c 1.0, CHC13); IR 1770, 1715, 1602 cm·1; NMR
`(Me2SO-d6) o 3.71 (4 H, m, -OCH2CH2O-). Anal. Calcd for
`C24H30O6 (414.48): C, 69.55; H, 7.30. Found: C, 69.5; H, 7.46.
`(2RS ,3aR ,4R ,SR ,6aS )-4-[ (E)-3,3-Ethy Ienedioxy-1-octe(cid:173)
`nyl]perhydrocyclopenta[ b ]furan-2,S-diol (3a). To a solution
`of 7.54 g (18.19 mmol) of 2a in 200 mL of absolute toluene, 74
`mL of a 20% solution of diisobutylaluminum hydride (DIBAL)
`in toluene was added dropwise at -70 °C under argon. After
`stirring 30 min at -70 °C, the excess reagent was destroyed by
`addition of a few drops of 2-propanol and the reaction mixture
`warmed up to O °C. Water (37 mL) was added and the mixture
`stirred at room temperature until the gel-like mass had turned
`crystalline (ca. 30 min). The mixture was then filtered and washed
`with CH2Cl2, and the combined organic phase was evaporated
`in vacuo. Chromatography on 100 g of silica gel and elution with
`hexane-ethyl acetate gave 3a (5.20 g, 91 %) as a colorless oil: [a] 0 22
`-6.0° (c 1.0, CHC13); IR 3600, 3410, 2955, 2875, 978, 948, 915 cm-1.
`15-Deoxy-lS,lS-ethylenedioxyprostaglandin F2., (4a). A
`solution of dimsylsodium was prepared from 6.0 g (125 mmol)
`of a 50% dispersion of NaH in paraffin oil and 120 mL of Me2SO
`at 70-75 °C (under argon) and added dropwise to a solution of
`28.37 g (64 mmol) of (4-carboxybutyl)triphenylphosphonium
`bromide in 125 mL of Me2SO. After 30 min of stirring at 24 °C,
`a solution of 5 g (16 mmol) of 3a in 60 mL of Me2SO was added,
`
`Journal of Medicinal Chemistry, 1978, Vol. 21, No. 5 445
`and the reaction mixture was stirred 16 hat 24 cc. After dilution
`with ice-cold NaCl solution and extraction with ether, the aqueous
`phase was acidified with a 10% aqueous solution of citric acid
`to pH 5. After extraction with hexane-ether (1:1), washing with
`saturated NaCl solution, drying (MgSO4), and evaporation in
`vacuo the residue (4.66 g) was chromatographed on a column of
`200 g of SiO2• Elution with mixtures of ether-dioxane gave 1.62
`g (26%) of 4a as a yellowish oil: IR 1710 cm-1; NMR (Me2SO-d6)
`o 0.85 (3 H, t, J = 7 Hz, CH3CH2), 3.65--4.00 (6 H, m, --OCH2CH2O,
`2CHO), 5.2-5.8 (4 H, m, 2(--CH=CH-)]. Anal. Calcd for C22H36O6
`T396.53): C, 66.64; H, 9.15. Found: C, 66.21; H, 9.10.
`15-Deoxy-lS,15-ethylenedioxyprostaglandin F2a Methyl
`Ester (Sa). To a solution of 1.62 g (4.06 mmol) of 4a in 20 mL
`of CH3OH a slight excess of an ethereal diazomethane solution
`was added dropwise at O cc. After evaporation in vacuo the
`residue was filtered with ether-dioxane (9:1) over 25 g of SiO2
`to give 1.52 g (91 % ) of oily Sa: IR 1730 cm·1; NMR o 3.58 (3 H,
`s, CH3O), 3.83 (4 H, m, -OCH2CH2O-).
`lS-Deoxy-lS,lS-ethylenedioxyprostaglandin F2.. 4-
`Phenylphenacyl Ester (7a). To a solution of 200 mg (0.50
`mmol) of 4a and 56 mg (0.55 mmol) of triethylamine in 4 mL of
`acetone, 152 mg (0.55 mmol) of p-phenylphenacyl bromide was
`added and the mixture stirred 18 h at 24 cc. After dilution with
`H 2O, extraction with ether, and drying (MgSO4), evaporation gave
`the crude ester which was chromatographed on 30 g of SiO2 with
`ether-dioxane (1-5%) to give 140 mg (47%) of crude 7a. Re(cid:173)
`crystallization from hexane-CH2Cl2 afforded 105 mg of pure 7a:
`mp 77-79 °C; IR 1730, 1680 cm·1; NMR (Me2SO-d6) fi 3.5-4.1 (6
`H, m, -OCH2CH2O-, 2CHO), 7.35-8.12 (9 H, m, aromatic H); UV
`Amax 284 nm (e 23600). Anal. Calcd for C3sH4sO7 (590.76): C,
`73.19; H, 7.85. Found: C, 73.75; H, 8.22.
`15-Deoxy-lS,lS-(propylene-l,3-dioxy)prostaglandin F2 ..
`Methyl Ester (9). (3aR,4R,5R,6aS)-5-(4-Phenylbenzoyloxy)-
`4-[ (E)-3-oxoocten-1-yl]perhydrocyclopenta[b ]furan-2-one7 (1 g,
`2.24 mmol) was ketalized with 1,3-propylenediol in analogy to the
`preparation of 2a to give 770 mg (68%) of the 15,15-propylene
`ketal lactone: mp 84-85 °C. Anal. Calcd for C31H36O6 (504.63):
`C, 73.78; H, 7.19. Found: C, 73.88; H, 6.97. After DIBAL re(cid:173)
`duction, Wittig reaction, and esterification with CH2N2 (as de(cid:173)
`scribed during the preparation of 4a and Sa), 9 was obtained as
`an oil: IR (neat) 1738, 1625 cm·1; NMR (CDC13) o 3.64 (3 H, s,
`CH3OCO), 3.72-4.30 (6 H, m, -OCH2CH2CH2O-, 2CHO).
`l S-Deoxy- IS, 15-[ (2,2-dimethy l)trimethy lene-1,3-di(cid:173)
`oxy]prostaglandin F 2a Methyl Ester (10).
`(3aR,4R,5R,-
`6aS)-5-( 4-Phenylbenzoyloxy )-4-( (E)-3-oxoocten -1-y l] perhydro(cid:173)
`cyclopenta[ b] furan-2-one 7 (1.6 g, 3.58 mmol) was ketalized with
`1 g of 2,2-dimethylpropane-1,3-diol and 30 mg of p-toluenesulfonic
`acid in 70 mL of C6H6 in a Dean-Stark apparatus to furnish 1.35
`g (71 % ) of crystalline ketal, mp 104-105 °C, which was converted
`by DIBAL reduction, Wittig reaction, and esterification with
`CH2N2 into oily 10: IR (neat) 1735 cm-1; NMR (Me2SO-d6) o 0.62
`(3 H, s, CH3C), 0.82 (3 H, t, J = 7 Hz, CH3CH2), 1.05 (3 H, s,
`CH3C-), 3.54 (3 H, s, CHsOCO), 3.40-4.05 (6 H, m, OCH2CCH20--,
`2CHO-).
`lS-Deoxy-lS,lS-dimethoxyprostaglandin F2a Methyl Ester
`(11). 15-Dehydroprostaglandin F 2a methyl ester (14) (220 mg,
`0.60 mmol) in 4 mL of CHC13 and 4 mL of CH3OH was reacted
`for 18 h with 2 mL of methyl orthoformate and 0.2 µL of con(cid:173)
`centrated HCI. After addition of 0.1 mL of triethylamine and
`evaporation, the residue was chromatographed on a column of
`10 g of SiO2• On elution with hexane-ether mixtures and finally
`with ether-1 % dioxane, 11 (58 mg) followed by a mixture of 11
`and 14 (65 mg) was obtained. 11 gave IR 1730 cm-1.
`15-Dehydroprostaglandin Fz., Methyl Ester (14). A solution
`of 800 mg (1.95 mmol) of 5a in 30 mL of methanol was stirred
`for 1 h with 0.5 mL of 10% H2SO4, poured on ice, and extracted
`with CH2Cl2• After washing with NaHCO3 and NaCl solutions,
`drying (MgSO4), and evaporation, the residue was chromato(cid:173)
`graphed with hexane-ethyl acetate (1:1) on SiO2 to give 560 mg
`(78%) of 14 as yellowish oil: [a] 220 +50.7° (c 0.75, CHC13); UV
`Amax MeOH 233 nm (e 12 600); IR 1730, 1690, 1668, 1625 cm-1; NMR
`(CDC13) o 3.68 (3 H, s, CH3OCO), 6.14 (1 H, d, J = 15.5 Hz, trans
`-CH=CHCO), 6.68 (1 H, dd, J = 15.5, 9 Hz, trans --CH=CHCO).
`(3aR ,4S ,5R ,6aS )-5-Benzoyloxy-4-(3-oxo-1-octyl)per(cid:173)
`hydrocyclopenta[ b ]furan-2-one (15a). A solution of 5 g (13.5
`mmol) of la in 75 mL of ethyl acetate was shaken with H 2 in the
`
`Micro Labs Exhibit 1048-3
`
`
`
`446 Journal of Medicinal Chemistry, 1978, Vol. 21, No. 5
`
`Skuballa et al.
`
`presence of 500 mg of Pd/C (10%). After uptake of 340 mL of
`H2, the catalyst was filtered off and the filtrate evaporated in
`vacuo. The crystals were triturated with hexane and filtered to
`give 4.80 g (95%) of colorless crystals: mp 42-43 °C; [a]220 -79.4°
`(c 1.00, CHC13); IR 1770, 1718 (sh), 1710, 1600 cm-1; NMR (CDC13)
`o 0.88 (3 H, t, J = 7 Hz, -CH3), 4.85-5.28 (2 H, m, CHO).
`13, 14-Dihydro-15-deoxy- l 5, 15-ethy lenedioxyprostaglandin
`F 2a Methyl Ester (17a). 15a (2.80 g, 7.52 mmol) was ketalized
`with ethylene glycol analogous to the preparation of 2a to give
`the oily ketal (2.90 g, 93 % ): IR 1770, 1710 cm-1; NMR (CDC13)
`o 3.94 (4 H, s, -OCH2CH2O-). The ketal (2.88 g, 6.92 mmol) was
`reduced with DIBAL at -70 °C (compare preparation of 3a) to
`give 1.45 g ( 67 % ) of an oily lactol which was transformed by
`standard Wittig reaction (compare preparation of 4a) and
`treatment with diazomethane into 17a (215 mg, 22% of pure
`material, + 163 mg of slightly impure 17a): IR 3600 (sh), 3405,
`2995, 2950, 2875, 1710, 948 cm-1.
`(3aR ,4R ,5R ,6aS )-5-Benzoyloxy-4-[ (E)-3,3-ethylenedi(cid:173)
`oxy-4-phenoxy-1-butenyl]perhydrocyclopenta[ b ]furan-2-one
`(2b). lb9 (9.6 g, 23.6 mmol), 22.5 mL of ethylene glycol, and 140
`mg of p-toluenesulfonic acid hydrate in 225 mL of benzene were
`heated for 14 h in a Dean-Stark apparatus. After cooling and
`dilution with ether, the solution was washed with saturated
`NaHCO3 solution, dried (MgSO4), and evaporated. The residue
`was dissolved in ether and filtered over a column of 220 g of SiO2
`to give 10.4 g (98.5%) of 2b as a homogeneous colorless oil. On
`trituration with 2-propanol-ethyl acetate 2b crystallized to give
`colorless crystals: mp 69-71 °C; IR 1772, 1715, 1600 cm-1; NMR
`ii 3.82-4.06 (6 H, m, -OCH2CH2O-, -CH2O-). Anal. Calcd for
`C26H 26O7 (450.47): C, 69.32; H, 5.82. Found: C, 68.92; H, 6.14.
`(2RS ,3aR ,4R ,5R ,6aS )-4-[ (E)-3,3-Ethylenedioxy-4-
`phenoxy-1-b uteny l]per hydrocyclopenta[ b ]furan-2,5-diol
`(3b). To a solution of 9.5 g (22.1 mmol) of 2b in 450 mL of
`absolute toluene, 95 mL of a 20% solution of DIBAL in toluene
`was added at -70 °C under an atmosphere of argon. After 30 min
`of stirring at -70 °C, the excess reagent was destroyed by addition
`of 2-propanol and finally of 48 mL of H2O. After warming to 24
`°C and stirring for 1.5 hat 24 °C, the precipitate was filtered and
`washed with CH2Cl2, and the filtrate was evaporated in vacuo.
`The residue was dissolved in ether and filtered over a column of
`150 g of SiO 2 to give 6.3 g (86 % ) of crude 3b.
`15-Deoxy-15,15-ethy lenedioxy-16-phenoxy-17 ,18, 19,20-
`tetranorprostaglandin F2a (4b). A mixture of 4.90 g (102 mmol)
`of a 50% dispersion of NaH in paraffin oil and 90 mL of absolute
`Me2SO was stirred for 1 hat 70 °C under argon. This solution
`was added dropwise to a solution of 23.4 g (53 mmol) of 4-
`(carboxybutyl)triphenylphosphonium bromide in 94 mL of Me2SO
`and stirred for 30 min at 24 °C. To the Wittig reagent a solution
`of 5.60 g (16 mmol) of 3b in 56 mL of Me2SO was added dropwise
`with stirring and the reaction mixture heated for 3 h at 50 °C
`under argon. After dilution with an ice-cold saturated aqueous
`solution of NaCl, the reaction mixture was extracted three times
`with ether and finally with ether-ethyl acetate (1:1). After
`acidification of the aqueous phase with citric acid to pH 5 and
`extraction with ethyl acetate, the extracts were washed with
`saturated NaCl solution, dried (MgSO4), and evaporated in vacuo.
`The residue was chromatographed with CH2Cl2-2-propanol on
`a column of 100 g of SiO2 to give 2.50 g (36%) of 4b as a colorless
`oil and a further quantity of 0.96 g of slightly impure 4b: IR 1705,
`1600, 1588 cm-1; NMR o 3.85-4.03 (6 H, m, -OCH 2CH2O-,
`-CH2O-), 5.23-5.40 (2 H, m, cis CH=CH), 5.50 (1 H, d, J = 16
`Hz, structure i), 5.79 (1 H, dd, J = 8, 16 Hz, structure ii), 6.80-7.40
`(5 H, m, aromatic H). Anal. Calcd for C24H32O7 (432.50); C, 66.65;
`H, 7.46. Found: C, 66.78; H, 7.09.
`
`trans CH=CHl-<:J
`
`ii
`
`15-Deoxy-15,15-ethylenedioxy-16-phenoxy-l 7 ,18,19,20-
`tetranorprostaglandin F2a Methyl Ester (5b). To a solution
`of 2.20 g (5.08 mmol) of 4b in 50 mL of CH2Cl2, a slight excess
`of ethereal CH2N2 solution was added dropwise at O °C. After
`evaporation in vacuo the residue was dissolved in ether-dioxane
`(9:1) and filtered over a column of 50 g of SiO2 to give 2.05 g (90%)
`of 5b as a colorless oil: IR 1728 cm-1; NMR o 3.60 (3 H, s, CH30--).
`
`Anal. Calcd for C25H34O7 (446.52): C, 67.27; H, 7.68. Found: C,
`66.63; H, 8.30.
`15-Deoxy-15,15-ethylenedioxy-16-phenoxy-17, 18, 19,20-
`tetranorprostaglandin F 2a n-Butyl Ester (6b). A mixture of
`85 mg (0.197 mmol) of 4b, 23 mg of Ag2O, and 0.15 mL of n-butyl
`bromide was stirred for 56 h in 1.5 mL of N,N-dimethylacetamide
`at 24 °C under argon. After dilution with ether, the organic phase
`was extracted twice with H 2O, dried (MgSO4), and evaporated
`in vacuo. On preparative TLC with ether-dioxane (8:2), 35 mg
`(37%) of 6b was isolated as a colorless oil: IR 1730 cm-1.
`15-Deoxy-15,15-ethylenedioxy-16-phenoxy-17 ,18, 19,20-
`tetranorprostaglandin F 2a Tris(hydroxymethyl)methyl(cid:173)
`amine Salt (Sb). To a boiling solution of 2.14 g (4.95 mmol) of
`4b in 300 mL of acetonitrile, 1.10 mL of an aqueous solution of
`82.25 g of tris(hydroxymethyl)methylamine in 150 mL of H 2O
`was added. On slowly cooling to 55 °C and scratching of the
`reaction flask, the mixture started to crystallize. After stirring
`for 16 hat 24 °C, the crystals of Sb were filtered and dried at 60
`°C (0.1 mm) to give 1.81 g (66%) of 8b as colorless crystals: mp
`105-106 °C; IR (KBr) 1596 cm-1; NMR o 3.31 [6 H, s, H3N+c.
`(CH2OH) 3], 3.55-4.05 (8 H, m, -OCH2CH2O-, CH 2O, 2CHO-),
`5.1-5.45 (2 H, m, cis -HC=CH-), 5.47 (1 H, d, J = 16 Hz, see
`structure i), 5.77 (1 H, dd, J = 8, 16 Hz, see structure ii), 6.8-7.35
`(5 H, m, aromatic H). Anal. Calcd for C28H43NO 10 (555.63): C,
`60.74; H, 7.83; N, 2.53. Found: C, 60.45; H, 8.30; N, 2.52.
`(3aR ,4R ,5R ,6aS )-5-Benzoyloxy-4-(3-oxo-4-phenoxy(cid:173)
`butyl)perhydrocyclopenta[b ]furan-2-one (15b). A solution
`of 1.60 g (3.95 mmol) of lb9 in 25 mL of ethyl acetate was treated
`with 200 mg of Pd/C (10%) and shaken with H2 until 90 mL of
`H2 had been taken up. After filtration of the catalyst and
`evaporation, 1.60 g (99%) of 15b was obtained as a colorless oil:
`IR 1770, 1718, 1598 cm-1.
`l 5-Deoxy-15, 15-ethy lenedioxy-13, 14-dihydro-16-phen(cid:173)
`oxy-17,18,19,20-tetranorprostaglandin F 2a Methyl Ester ( 17b ).
`15b (1.60 g, 3.92 mmol) was ketalized with ethylene glycol as
`described for 2 to give 0.80 g (45%) of 15-ethylene ketal as a
`colorless oil: IR 1770, 1713, 1598 cm-1; NMR o 3.85-4.05 (6 H,
`m, -OCH2CH2O, -CH2O), 5.0-5.25 (2 H, m, >CHO).
`To a solution of 780 mg (1.75 mmol) of this ketal in 40 mL of
`absolute toluene, 8 mL of a 20% solution of DIBAL in toluene
`was added at -70 °C under argon. After 30 min 2-propanol was
`added, followed by 5 mL of H2O, and the reaction mixture was
`warmed and stirred 30 min at 24 °C. CH2Cl2 was added and the
`precipitate filtered. After evaporation of the filtrate the residue
`was dissolved in ether and filtered over a column of 15 g of silica
`gel to give 390 mg (70%) of the corresponding lactol as a colorless
`oil: IR 1598, 1588 cm-1.
`The Wittig reagent was prepared from 576 mg (12 mmol) of
`NaH (50%) and 2.66 g (6.02 mmol) of 4-(carboxybutyl)tri(cid:173)
`phenylphosphonium bromide and reacted with 390 mg (1.21
`mmol) of lactol (as described for 4b). The crude product (400
`mg) was dissolved in 10 mL of CH2Cl2 and treated at O °C with
`an excess ethereal CH2N2 solution. After evaporation the crude
`ester was purified by preparative TLC (ether-dioxane 9:1) to give
`120 mg (22%) of 17b as a colorless oil: IR 1728, 1598, 1586 cm-1;
`NMR o 3.62 (3 H, s, CH3O), 3.81-4.05 (6 H, m, -OCH2CH2O,
`CH2O), 5.17-5.6 (2 H, m, cis CH=CH), 6.82-7.40 (5 H, m, aromatic
`H).
`15-Deoxy-15, 15-ethylenedioxy-17-pheny l-18,19,20-trinor(cid:173)
`prostaglandin F2a Methyl Ester (20).
`(3aR,4R,5R,6aS)-5-
`Benzoyloxy-4-( (E)-3-oxo-5-phenyl-1-pentenyl)perhydrocyclo(cid:173)
`penta[ b )furan-2-one12 (3.45 g, 8.52 mmol) was ketalized with
`ethylene glycol as described for 2 to give, after crystallization from
`isopropyl alcohol, 2.94 g (77 % ) of the 15-ethylene ketal, mp
`134.5-135 °C. This material (2.91 g, 6.52 mmol) was reduced with
`DIBAL as described for 3 to give 2.05 g (92%) of the lactol as
`a colorless oil: IR 3600, 3400, 2954, 1603, 1450, 978, 948 cm-1. This
`lactol (2.0 g, 5.78 mmol) was converted into 20 by Wittig reaction
`and treatment with ethereal CH2N2 solution to give 1.15 g (45%)
`of 20: mp 62-64 °C (from diisopropyl ether-methylene chloride);
`NMR (Me2SO-d6) o 1.50 (2 H, t, J = 7 Hz, -CH2C(=O)O-], 3.56
`(3 H, s, CH3O), 3.78-4.02 (4 H, m, -OCH2CH2O), 5.25-5.75 (4 H,
`m, cis CH=CH and trans CH=CH), 7.10-7.30 (5 H, m, aromatic
`H). Anal. Calcd for C26H36O6 (444.57): C, 70.24; H, 8.16. Found:
`C, 69.70; H, 8.19.
`
`Micro Labs Exhibit 1048-4
`
`
`
`15,15-Ketals of Natural Prostaglandins
`
`Journal of Medicinal Chemistry, 1978, Vol. 21, No. 5 447
`
`15-Deoxy-15, 15-ethy lenedioxy-15-( 4-chlorophenyl)-16,-
`17,18,19,20-pentanorprostaglandin F2a Methyl Ester (21).
`(3aR ,4R ,5R ,6aS)-5-Benzoyloxy-4-[ (E)-3-oxo-3-( 4-chlorophe(cid:173)
`nyl)-1-propenyl]perhydrocyclopenta[ b ]furan-2-one13 (7 g, 15.1
`mmol) was ketalized for 48 h with ethylene glycol as described
`for 2 to give 6.01 g (77%) of the ethylene ketal: mp 83-84 °C
`(from diisopropyl ether-methylene chloride); IR 2955, 2890, 1770,
`1714, 1600, 1270, 970,947,832 cm-1. This ketal (2.0 g, 4.40 mmol)
`was reduced with DIBAL as described for 3 to give 1.20 g (77%)
`of the lactol as a colorless oil: IR 3600, 3400, 2945, 1600, 972,947,
`832 cm-1. This lactol (1.20 g, 3.40 mmol) was converted into 21
`by Wittig reaction and treatment with ethereal CH2N2 solution
`to give 900 mg (59%) 21 as a colorless oil: NMR o 3.60 (3 H, s,
`CH30), 5.25-5.88 (4 H, m, cis CH==CH, trans CH==CH), 7.28--7.52
`(4 H, m, aromatic H); IR 3600, 3520, 2923, 1732, 1600, 976, 947,
`835 cm-1.
`Assay Methods. (a) In Vitro. Isolated Rat Uterus. When
`incubated in salt solutions whose composition corresponds to the
`medium of extracellular fluid and stimulated with prostaglandins,
`isolated horns of the rat uterus respond with contractions. Under
`isotonic conditions these contractions can be recorded and an(cid:173)
`alyzed as changes in length. Uteri of estrous rats (wt 150 g) were
`used for the tests.
`The investigations were carried out using an apparatus for tests
`on isolated organs developed by Braun, Melsungen, West Ger(cid:173)
`many. A modified Tyrode's solution was used as the bath fluid.
`The isotonic contractions of the uterine musculature were
`transferred via a potentiometer to a Servogor S compensatory
`recorder of Metrawatt and could be traced as waves.
`The response obtained with the test preparation was assessed
`in a paired comparison with the reference preparation, four
`replicates (n = 4) being performed in each case. Both uterine
`horns of each animal were used, contraction being stimulated by
`adding the test preparation to the organ bath containing one horn
`and the reference preparation to that containing the other horn.
`The test data (height of contraction in millimeters) were analyzed
`statistically by means of an analysis of variance.
`Isolated Guinea-Pig Ileum. The contractions of isolated
`guinea-pig ileum segments were recorded isotonically as changes
`in length.
`Female guinea pigs weighing about 300 g were used for the
`investigations. The guinea pigs were sacrificed by decapitation,
`after which the ileum was immediately removed. After removal
`of the mesentery, the intestinal portions were bisected and the
`portions, each of which was about 4 cm long, immediately sus(cid:173)
`pended in the bath fluid (modified Tyrode's solution).
`Tests were carried out with the same apparatus as was used
`for the investigations performed on isolated rat uteri.
`Four replicates (n = 4) were carried out to permit paired
`comparisons of the responses obtained with the test and reference
`
`preparations. The test data (height of contraction in millimeters)
`were analyzed statistically by means of an analysis of variance.
`(b) In Vivo. Assay for Luteolytic and Abortifacient
`Effects in Rats. PG's exert their abortifacient activity in rats
`by functional disintegration of the corpora lutea of pregnancy
`(luteolysis). The luteolytic activities of test compounds were
`estimated from their ability to depress serum progesterone levels
`and induce abortion in early pregnant rats.
`Female Wistar rats were mated at proestrus. If sperm were
`found in the vaginal smear the next day, this day was defined
`as day 1 of gestation. The test compounds were administered
`in 0.2 mL of oil sc (benzyl benzoate + castor oil, 1:3) on days 4-7
`of gestation. Four animals per group were used. Blood for serum
`progesterone determinations by RIA was collected from the orbital
`venous plexus on days 3, 5, 7, and 9 of gestation. On day 9 the
`animals were killed and the number in which abortion had been
`induced was determined by inspection of the uteri.
`The lowest dose of a PG inducing abortion in 50% of the
`animals was determined (0.3-1.0 mg per animal per day sc for
`PGF2a) by this assay. Analogues which did not show any activity
`with 10 mg/ animal were considered inactive.
`References and Notes
`(1) Prostaglandin Analogues. 2. For paper 1, see B. Raduchel,
`U. Mende, G. Cleve, G.-A. Hoyer, and H. Vorbruggen,
`Tetrahedron Lett., 633 (1975).
`(2) P. W. Ramwell, J.E. Shaw, E. J. Corey, and N. Andersen,
`Nature (London), 221, 1251 (1969).
`(3) G. L. Bundy, E.W. Yankee, J. R. Weeks, and W. L. Miller,
`Adv. Biosci., 9, 125 (1972).
`(4) Unpublished results.
`(5) G. A. Youngdale and F. H. Lincoln, Prostaglandins, 6, 207
`(1974).
`(6) W. Dawson, R. L. Lewis, R. E. McMahon, and W. J. F.
`Sweatman, Nature (London), 250, 332 (1974).
`(7) E. J. Corey, S. M. Albonico, U. Koelliker, T. K. Schaaf, and
`R. K. Varma, J. Am. Chem. Soc., 93, 1491 (1971).
`(8) E.W. Yankee, U. Axen, and G. L. Bundy, J. Am. Chem.
`Soc., 96, 5865 (1974).
`(9) D. Binder, J. Bowler, E. D. Brown, N. S. Crossley, J. Hutton,
`M. Senior, L Slater, P. Wilkinson, and N. G. A. Wright,
`Prostaglandins, 6, 87 (1974).
`(10) Beside their interesting biological properties, the crystalline
`prostaglandin phenacyl esters are well suited for the
`characterization and purification of prostaglandins and their
`analogues; see German Patent DOS 2 322 655.
`(11) W. Elger, D. Hartmann, and B. Kosub, unpublished results.
`(12) B. J. Magerlein, G. L. Bundy, F. H. Lincoln, and G. A.
`Youngdale, Prostaglandins, 9, 5 (1975).
`(13) German Patent DOS 2 322 142.
`
`Micro Labs Exhibit 1048-5
`
`