363

SYNTHESIS OF PREGNENOIC ACID DERIVATIVES POSSESSING STRUCTURAL ELMEhTS OF PROSTAGLANDINS [l]

Jersy Wicha and Karol Bal Institute of Organic Chemistry of the Polish Academy of Sciences 00-961 Warsaw, Poland Rec'd. 5-26-77 Pregnenoic acid derivative V in which the character of functional grouns and distances between them (expressed in terms of C-C bonds) resemble those occurring in prostaglandins has been synthetised. 38-Hydroxyandrost-5-en-17-oneacetate VII was converted to ethyl 3B-acetoxypregn-5-en-21-oateXIIa via a Reformatsky reaction followed by dehydration of adduct EIa and selective hydrogenation of the diene X. Compound XIIa was then transformed into trienone XIII by oxidation of the 3t3-hydroxy-5-ene XIIc with DDQ. The trienone XIII was subsequently epoxidised with alkaline hydrogen peroxide and _*chloroperbenzoic acid tn give diepoxide XV which was reduced with aluminum amalgam to the final uroduct V.

The pronounced physiological activity of prostaglandinshas stimulated the search for their synthetic analogues. The synthesis of several bi- and poly-cyclic comnounds in which the character of functional groups and the distance between them (expressed in the terms of CC bonds) resemble those occurring in the natural nrostaglandinshave been published, for example the indane derivative I [2]. Recently, some attention has been drawn to the synthesis of steroidal analogues of prostaglandins; and, among other compounds, II 131, III [4], IV [5] were obtained. In the hitherto described steroidal modifications the five-membered ring D corresponded to the prostaglandin ring and, as a consequence, the absolute configurations of the analogues were opposite to those of their natural models. The purpose of present work was the synthesis of compound V in which structural elements of steroidal hormones and prostaglandins are combined. Ihis compound contains the 4-en-3-one group which is characteristic of

Volume 30, Nwnber 3

S

TDROXDb

September,

2977

many physiologically

active

steroidal compounds, as well as a carboxy1j.c

acid (esterified), ketonic, and hydroxy groups at distances identical with those occurring in prostaglandins

(cf. PGD2 VI). -

The absolute configura-

tions of these elements of orostaglandin structure in compound V are the same as that in natural prostaglandins. The preparation of the prostaglandin analogue V from 3B-hydroxyandrost5-en-17-one

3-acetate VII comprises two separate problems:

the attachment

of a suitable side chain and the transformation of rings A and 3. The attachment of a two-carbon atom side chain to 1Fketone

VII was

performed by the Reformatsky reaction with ethyl bromoacetate, which was followed by dehydration and hydrogenation. ethyl bromoacetate

The reaction of ketone VII with

and zinc dust in boiling benzene

[8-N]

leads to fonna-

tion of a mixture containing adduct VIIIa (ca. 75% according to PMR), its 3B-hydroxv-derivative

VIIIb

5 X) and unchanged substrate VII (20%). (ca. -

The substrate and main reaction product VIIIa had the same mobility in chromatography on silica gel in several eluting systems and on alumina; therefore, it could not be purified by this method. eventually obtained by oredpitation

Pure compound VIIIa was

of the semicarbazone of VII from sol*

tion of VII and VIIIa or, on small scale, by partial acetylation of diol VIIIb.

Compound VIIIa had the expected spectral properties and its specific

rotation was in agreement with that reoorted in the literature [lo]; however, attempts to obtain it in crystalline form failed. ?iore vigorous conditions of the Reformatsky reaction were tried in order to avoid contamination of the required product with substrate. ketone

VII was reacted with a large excess of ethyl bromoacetate

in a mixture dimethoxyethane

(?YlE)and benzene

[ll].

Thus,

and zinc

In this case, how-

ever, the substrate did not disanpear completely and in addition to compounds VIIa and VIIIb a substantial amount of a new compound was formed.

S

TDP&OIDb

This compound, isolated in ~a. 30% yield, was identified as the "double" reaction product IX on the basis of snectroscopic data.

Its PMR spectrum

contains all the signals observed in the spectrum of compound VIIIa and a wide singlet at 63.5 (2H) which was ascribed to the -LR2-COO-

protons.

A mass spectrum of compound IX contained fragments at m/e 414 (M-C2H50H), 400 (M-CH3COOH), 382 (400-H20), 354 (414-CH3COOH),and an intense 100% peak at m/e 270 corresponding to [M-(CH3COOH)-(CH2COCH2COOC2H5+li) I. Fragmentation with the formation of ion m/e 270 is characteristic for all comoounds containing the Cl7(OH)CH2CC- moiety we investigated. Refluxing monoacetate VIIIb with acetic anhydride for 30 h gave hitherto undescribed diacetate VIIIc.

Pure diacetate VIIIc can also be

prepared by refluxing the crude product of Reformatsky reaction with acetic anhydride.

The PMR spectrum of diacetate VIIIc contains a pair of one

proton doublets at 3.21 and 2.50 ppm (J=14 Hz) which were assigned to those on the C20 methylene group. The large difference (0.7 ppm) between the chemical shift of these geminal protons cannot be due solely to their diastereotonic character since the difference between the chemical shifts of the protons on C20 is smaller than 0.2 ppm 1121 in the corresponding 17-01s VIIIa and VIIIb.

It can result, though, from restricted rotation around

the C-17(20) bond [131 caused by introduction of the acyl group. In accord wfth the report of Plattner and co-workers [9] distillation of diacetate VIIIc under reduced nressure caused elimination of the tertiary acetoxy group and gave the a,B-unsaturated ester X.

The distillate

also contained an almost equal amount of the 17-ketone VII.

Distillation

of diacetate VIIIc at a higher pressure (e.g., 15 nm Hg) gave compounds VII and X accompanied by a by-product to which the triene structure XI was ascribed. Similarly, the acetylated crude product from the Reformatsky

reaction on distillation at 2 mm tig gave a mixture from which unsaturated ester X was isolated in 40% yield and startjng ketone VII was recovered in 45% yield.

The distillation was carried out several times on a 20-60 g

scale: contrary to a previous renort [lo] the yjelds of unsaturated ester i; were satisfactory.

The presence of the 17-ketone VII in the dfstjlla-

tion product of pure diacetate VIIIc indicates that jt is formed as a result of thermal fragmentation of diacetate VIIIc; and, therefore, compound VII is an unavoidable by-product of the pyrolysis. Unsaturated

ester X showed the expected [9] physical properties

116-118°c; Lo];8 = -70").

(m.p.

Careful TLC analysis and a PF*R spectrum indicated

it was isomerically pure: its UV spectrum exhibited Xmax = 222 nn (E = 16500), which is characteristic

for an E jsomer.

Compound X, when heated

with sodium ethoxide, was not isomerised at the C-17(20) double bond, whereas the corresponding compound 2 isomerises under sjmilar conditions [141.

This confirms the suggestion made by Romo and Romo de Vivar [15]

that dehydration of a Reformatsky adduct of the type VIII yields the E isomer of an a,B-unsaturated Selective hydrogenation

ester. of compound X in ethanolic solution in the

presence of platinium catalyst [9] gave a very good yield of compound XIIa, which was hydrolysed methane to ester XIIc.

to hydroxy-acid XIIb and converted with diazo-

Alternatively,

compound XIIc was obtained by

heating diester XIIa in methanol containing sulfuric acid. The rest of the synthesis of prostaglandin analogue V involved transformation of rings A and B. dicyanoquinone

Oxidation of alcohol XIIc with dichloro-

(DDQ) in dioxane [16] gave trienone XIII in about 40% yield.

The trienone XII was oxidised with hydrogen peroxide in methanolic sodium hydroxide

[17] to la, Za-epoxide XIV (Amax=

nm).

A PMR spectrum of

S

367

TDROXDS

OH

HO

COOH 0CH3

f

VI

V

R20

0

R’O

s

CH2COOC2H5

\

& VIII

a R’ =CH$O, b R1= R2=H

R2= H

c R’ = R2= CH3CO

S

TDROXDS

compound XIV exhibited among others a doublet at 63.35 (J-4.5 Hz) corresponding to the lt3-protonand a pair of doublets at 63.43 (3~4.5 Hz and J-2.0 Hz) for the 28 proton. Epoxide XIV was then reacted with an excess of m-chloroperbenzoic acid. The rate of this oxidation was slow but the desired product XV was obtained in 58% yield after 3 days. Diepoxide XV (m.p. 190-192'C: Amax= 244 run) had among others PMR signals for a doublet at 6.1 ppm (J-2 Hz) for a vinylic proton (C4-H), a singlet at 3.65 ppm for an ester methyl group (-COOCE3), and complex signals for epoxide protons in the 3.5-3.25 ppm region. Irradiation of the olefinic proton (6.1 ppm) caused a distinct increase of the intensity of the signal at 3.44 ppm, the average increase being 28%. Alternatively, irradiation of the proton corresponding to the signal at 3.44 ppm effected an increase in intensity of the signal for the olefinic proton at 6.1 ppm.

On the basis of the observed Overhauser effect

the signal at 3.44 ppm was ascribed to the oxirane proton at C6. assignments of signals to definite oxirane protons was made.

No further

The config-

uration of the 6,7-epoxide ring in diepoxide XV was ascribed on the basis of the known preference for a-attack in epoxidation reaction [81. Since the influence of a la, Za-epoxide on the eooxidation of a 6,7olefinic bond is not known, the following experiments were performed. Trienone XIII was treated with m-chloroperbenzoic acid in chloroform for 3 h and gave 6a,7a-epoxide XVI in 90% yield.

Oxidation of monoepoxide

XVI with hydrogen peroxide in acetone (compound XVI is insoluble in methanol) gave the previously obtained diepoxide XV in good yield. These results demonstrate the presence of epoxide functions in positions la, 2a and 6a, 7a does not influence the steric course of the epoxidation of double bonds in positions 6,7 and 1,2, respectively.

S

369

TEIROIDrn

The last stage of the planned synthesis involved the

reduction

of the epoxide rings to la and 7a-hydroxy groups. For the reduction of compound XV two recently described reagents for the transformation of a,&epoxy ketones to B-hydroxy ketones, chromous acetate [19] and aluminum amalgam [20], were tried; but only the latter one was effective. Treatment of the compound XV with freshly prepared chromous acetate 1191 in a combination of acetic

acid,

acetone,

and water leads to a mix-

ture of products from which methyl la-hydroxypregna-4,6-diene-21-oate XVII was isolated in 43% yield.

Reduction of diepoxide XV with aluminum amalgam in

mixture of tetrahydrofuran, ethanol and water in the presence of sodium bicarbonate [20] gave

a mixture

of products in which only one component had

the polarity (TLC) corresponding to a dial. This product (50-60X yield) was assigned the desired structure V for the following reasons: its IR -1 spectrum contained bands for a hydroxy group (3460 cm ) and an a,b-unsaturated ketone (1670 cm-'); its uv spectrum had Amax= (a,&unsaturated ketone); and its m

nm,

6 =

14500

spectrum contained narrow multiplets at

64.06 and 3.86 corresponding to equatorial protons jn a H-C-OH system. The signal at 64.06 was assigned to the 6 proton since its chemical shjft was the same as the 18-H in la-hydroxydienoneXVII. was assigned to the proton at C7.

The other signal at 63.86

The mass spectrum of compound V showed

the presence of a molecular ion at m/e 376. The fragmentation pattern is in agreement with the assigned structure: m/e 358 (?1-K20),340 (358-H20), 332 (U-44), 325 (340-CH3), 314 (332-H20). The signal at m/e 332 probably corresponds to the fragment Y-(CH=CHOH) which arises from cleavage of the C-1(2) bond by a retro-Diels-Alder reaction. Compound V was tested for inhibition of prostaglandin biosynthesis by bovine seminal microsomes according to Gryglewski [21] and for inhibition of contractile action of PGE2 in isolated rat stomach strip. In

S

370

HO

TDROIDEl

.CH$OCH$OOC2H5

H3CCOO

XI

R,o&cooR2 o&xsoo XII

a R’=

CH3C0,

b R’=

R2=H

R2=C2H5

XIII

c R’ = H, R2=CH3

p+, dP ,COOCH3

0

COOCH3

f

”

XIV

0

/e ’

XVI

,,..6

COOCH3

f

e HV

0

//

XVII

COOCH3

f

S

371

T~ROIDE

the systems tested it neither inhibits generation of prostaglandins (at concentrations lo-900 uglml) nor influences their contractile action on a smooth muscle preparation (at concentration 20-50

pg/ml).

EXPERIMENTAL

All melting points were determined with a Kofler hot stage and are uncorrected, Optical rotations were measured with Perkin-Elmer 141 polarimeter on ca. 1% chloroform solutions. The UV spectra were obtained on ethanolic Glutions with Unicam SP 700 and IR spectra with Unicam SP 200 spectrophotometers. The P!m spectra were measured on CDC13 solutions using JEOL 100 MHz or Varian 60 MHz (if stated) instruments, with MS as an internal standard. Mass spectra were recorded with a LKB 9000A spectrometer at 70 ev. Elemental analyses were performed in Analytical Laboratory of our Institute (headed by Mrs. 2. Celler). Extracts were dried over magnesium sulfate or sodium sulfate; SOlVent were removed on a rotary evaporator. The yields reported correspond to chromatographically (TLC) pure compoundsj a pet-ether fraction boiling at 60-80' was used. 1 Reaction

of 3f3-hvdroxyandrost-5-en-17-one acetate VII with -.-ethyl bromo-

acetate and zinc (Reformatsky reaction). ----I_ A. A solution of acetoxyketone VII (60 g) in dry benzene (510 ml) and activated zinc dust (69 g) were placed in a l-reactor fitted with a reflux condenser, an efficient stirrer and a dropping funnel containing ethyl bromoacetate (21 g). About l/10 of the initial amount of ethyl bromoacetate was added dropwise with stirring, and then a crystal of iodine was introduced. The mixture was heated until the reaction started and then the remaining ethyl bromoacetate was carefully added. The mixture was refluxed for 2 h and after cooling in ice water it was acidified with 200 ml of 2N hydrochloric acid. The product was extracted into ether, and the organic layer was washed with water and brine. The solvent was removed and the oily residue (73.5 g) was used in further reactions as "the crude product of the Reformatsky reaction". A part of this product (5.0 g) was chromatographed on a silica gel column. The eluate consisted of fractions I (4.1 g> and II (0.3 g). Fraction I was treated by the known method [22] with semicarbazide acetate and after separation of 3a-hydroxyandrost-5-en-17-one3-acetate semicarbazone, it save ethyl 38, 17S-dihydroxypregn-5-en-21-oate3-acetate VIIIa (3.70 g);[a]E6= - 69'. IR (CHC13) vmax 3500(OH),1720(CO),1260cm-1(CH3CO). PMR 65.37(m,lH,C6-H),4.58(m,lH,C3-H), 4.21(q,J=6Hz,2H,0CH2CH3),2.04 (s,3H,CH3CO), 1.30(t,J-6Hz,3H,0CH2CH3),1.07(s,3H,Clg-H),0.95(s,3H,

C18-H> .

S MS

m/e

400(M+-CH3COOi-l)

,

TDROIDS

382 (400~150)

.

Compound VIIIa could not be obtained in the crystalline form. Lit. [lo] m.p. 112-113'C: [aliZ=-74“. Fraction II was crystallised from dilute acetone and pgr~ efhyl 36, 17B-dihydroxypregn-5-en-21-oate VIIIb; m.p. 112-115'C: [a], = 71 . IR (CHC13)

vmax 3600(OH), 3450(0***H), 1710cm -1(COOC2H5).

F’MR 65.31(m,lH,C6-H), 4.17(q,2H,0CH2CH3), tryst.), 1.30(t,3H,0CH2CH3), MS

1.07(s,3H,Clg-H),

m/e 376(M+), 358(M+-H,O,lOO%),

Anal.

3.48(m,lH,C3-H),

Calcd. for C23H3604*1/2H20:

3.39(s,H20

0.96(s,3H,C18-H).

340(358-H20). C,71.65: H,9.67.

Found: C,72.13: H,9.51. B. Acetoxyketone VII(2.00 S), dry benzene (15 ml) and dry dimethoxyethane (15 ml) were placed in a two necked flask fitted with a reflux condenser, a dropping funnel and a magnetic stirrer. After dissolution of the steroid, activated zinc dust (2.35 ,a)was added. A crystal of I.odine was introduced and then ethyl bromoacetate (6.6 ml) was added dropwise. The mixture was refluxed for 2 h, cooled, acldifled with 2N hydrochloric acid (about 50 ml) and extracted with ether. The extract was concentrated to oily residue which was transferred to a silica eel column. Elution with a mixture of pet. ether-ethylacetate (95:5) gave the following fractions: (1) A mjxture of compounds VII and VIIIa (0.60 g): (2) ethyl 21-nor-36, 178-dihydroxy-22-oxochol-5-en-24-oate 3-acetate IX (0.84 g), and (3) compound VILIb (0.60 g). obtafned in the crystalline form. A sample dried'?gy$ :L:~"~~dn~~]~' -70'. IR (CHC13)

M

vnlax 3500(OH), 1725(C0),1260cm -+CH3CO).

65,38(m,lH,C6-H),

4.58(m,lH,C30 -H), 4.21, (q,J=7Hz,2H,0CH2CH3),

3.52(s,2H,COCH2COOC2H5),

2.05, (s,3H,CH3CO), 1.31(s,3H,0CH2CH3),

1.07(s,3H,Clg -H), 0.93(s,3H,C18-H). *IS m/e 414(M'-C2H50H),

414(M+-CH,COOH),

270(400-CH2COCH2C00C2H5+H,

382(400-H20),

354(414-CH3COOH),

100%)

Acetylation of diol VIIIb 2. _--_~_---.--------Treatment of crystalline diol VIIIb (0.40 g) with acetic anhydride (2 ml) in pyridine (2 ml) at room temperature Save monoacetate VIIIa identical with that obtained earlier. 3 ._.I)reparation of diacetate VITIc _-.--- ---~ -_.--_.-__-._--The crude product of the Reformatsky reaction (24.50 .g)was dissolved in acetic anhydride (200 ml), a few drops of pyridine were added and the mixture was refluxed for 30 h. It was concentrated under reduced pressure to the residue (27 g) which was crystallised from methanol to pive

S

TDROSDS~

373

diacetate VIIIc. A sample recrystallised several times from methanol had m.p. 94.5-95.5"C, [a],16-600. IR (CHC13) vmax 1730(CO), 1260cm-1(CH3CO). PMR

65.37(m,lH,C6-H),4.59(m,lH,C3u-H), 4.11, (q,J=7Hz,2H,0CIi2CH3), -H), 2,01(s,3H,CH3CO), 1.25 3.21(d,J=14Hz,lH), 2.50 (d,J=14Hz,lH,C20 (t,J=7Hz, 3H,0CH2CH3), 1.03(s,3H,Clg-H),0.85(s,3H,C18-H).

MS

m/e 4OO(M+-CH3COOH), 340(400-CH3COOH). Calcd. for C27H4006: C.70.40; H,8.76

Anal.

Found: C.70.30; H.8.72 4.

Preparation 3-acetate -- X. ___-- of ethyl 36-hydroxypregna-5,17(20)-dien-21-oate

Crude diacetate VIIIc(27 g) was distilled slowly at 2 mm Hg in a stream of argon (capillary) and heated with a Bunsen burner. The light yellow distillate (19 g) was dissolved in a small amount of methanol and allowed to crystallise at about -15". The crystals were collected, washed with methanol, and dried to give X (8.00 g, 40% calcd. from VII): m.p. 116-118'C: [a];8=-69'. uv

x_

222nm(~=16500).

IR (RBr) v_

1730(CH3CO), 1700(COOC2H5), 165O(C=C), 1240cmW1(CH3CO)

-H), 5.33(m,lH, C6-H), 4.53(m,lH,C30-H), PMR (60MHz) 65.45(t,J=2.5H~,lH,C~~ ~.~~(~,J=~Hz,~H,OC~~CH~),~.~~(S,~H,CH~CO), 1.24(t,J=7Hz,3H,0CH2CH3), 1.02(s,3H,Clg-H), 0.81(s,3H,Clf-H). MS

m/e 4oo(M+). 385(M+-CH3, 340 M -CH3COOH, 100X), 325 (340-CH3).

Anal.

Calcd. for C25k13604:C,74.96: H.9.06 Found: C.74.64: H,8.91

Lit. [9,lO]m.p. 117'~; [u]i3=-69.8'. Lit. [231 Amax=

nm (~=16600).

Similarly a mixture of unsaturated ester X and ketone VII was obtained from distillation of the analytical sample of diacetate VIIIc at 2 mm Hg. After distillation of crude diacetate VIIIc under the pressure of 15 mm Hg (water pump), preparative layer chromatography of a sample (0.5 g) of mother liquors from isolation of product X gave 50 mg of oily product _1 A -244 nm (a,&unsaturated ester) and 234 nm (diene); urnax1710, 1660 cm tv&ich structure XI was assigned. 5.

Preparation of ethyl 3S-hydroxypregn-5-ene-21-oateacetate XIIa .--

Compound X (13.00 g) in ethanol (250 ml) was shaken in a hydrogen atmosphere with prereduced platinum oxide (1 g). When 1 equiv. of hydrogen was absorbed (ca. 4 hours) the catalyst was filtered off, and the solvent was removed. %e r idue (from methanol) gave ethyl ester XIIa (13.5 g); m.p. 106-108'C; [a]:'--48'. IR (CHC13) vmax 1725(CO), 126Ocm-'(CH3CO). PMR

65.38(m,lH,C6-H),4.60(m,lH,C3a-H), 4.11(q, J=7Hz,2H,0CH2CH3), 2.01 (s,3H,CH3CO), 1.25(t,J=7Hz,3H,-OCH2CH3),1.03(s,3H,Clg-H),0.63(s,3H, C18-H).

S MS

TZEIROXDS

m/e 342(M+-CH3COOH).

Anal.

Cal&.

for C25H3804: C.74.59: H,9.52 Found: C,74.54: H,9.76

6.

Preparation _---_-of metw

36-hydroxypregn-5-en-Zl-oate ____-

XIIc _Y

P. . A solution of KOH(15 g) in water (15 ml) was added to a solution of diester XIIa(13.00 g) in methanol (150 ml) and the mixture was refluxed for 2 h. Then 50 ml of water was added and most of the solvent was removed. The residue was acidified l.vith5% hydrochloric acid and exhaustively extracted with ethyl acetate. The extract was vashed with brine and concentrated. The yield of acid XIIb (amorphous so1j.d) clas 9 g (88%). IR (KBr)

vmax 3300-2500(0H),

171O(COOH), l160cm-1(CO).

Acid XIIb(9 g) was suspended in methanol (150 ml) and an excess of ethereal diazomethane was added. The solvent was evaporated and the residue was crystallised from aqueous acetone to yield hpdroxyester XIIc: m.p. 127-13O“C: [a],=-63.5". IR (CHC13) PYR

vmax 345O(OH), 1730(COOCH3),

65.34(m,lH,C6-H),

3.64(s,3H,0CH3),

105Ccm-1(CO) 3.49(m,lH,C30-H),

1.84$0

tryst.),

o.98(s,311,clg-H), 0.59(s,3H,C18-1~).

?fS m/e 346(Y!+), 328(I+?+-H20),3.13(328-CH3) Lit. [9J m.u. 132-133OC: [a]D=-63.5". B.

Ethyl ester XIIa(0.23 g) was dissolved in methanol

(10 ml), then 95-97%

H SO (0.75 ml) was added. The mixture was refluxed for 3 hours and, after The neutral fraction, isolated in the cZol4ng was poured into ice-water. usual way, gave the ester XIIc(O.15 ~~83%). 7 Preparation of methyl 3-oxopregna-1,4,6-trien-Zl-oate --L___--__-____~-__-~ -

XIV.

A mixture of hydroxyester XIIC(~.OO g, 1.7 mmole), anhydrous dioxane (120 ml) and DDQ(12.7 g, 5.6 mmole) was refluxed for 24 h in an argon atmosphere; then it was filtered and the precipitate was washed with dioxane. The filtrates were combined, diluted with methylene chloride and filtered through a neutral alumina column (120 g). The column was washed with methylene chloride. The combined eluates were concentrated to give trienone X111(2.6 g, 44%) which was crystallised from methanol. An analytical samnle had m.p. 109-llO°C; [a],=-21.0°. 224(~-12000), 258(~=10000), 302nm(E=13000). uv ?nax IR (CHC13) AXmax 1730(COOCH3), 165O(CO), 1605cm-1(C=C). PMR

67.06(d,J=10Hz,lH,C1-H), 0CH3), 1.23(s,3H,Clg-H),

PIS n/e 34O(M+), 325(M?-CH3), Anal ---L

6.50~6.00(m,4H,C2C4,C6 0.75(s,3H,C18-H) 309(Y+-OCH3).

Calcd. C22H2803: C,77.61,H,8.29 Found: C,77.89,H,8.50

and C7-H), 3.65(s.3H,

S

TDROIDB

375

of methyl la,2a-epoxy-3-oxopregna-4,6-dien-21-oate XIV. 8. Preparation ._-.- -----A 10% NaOH solution in methanol (0.75 ml) and 30% hydrogen peroxide (4.8 ml) were added to a solution of trienone X111(2.50 g) in methanol (105 ml); and the mixture was allowed to stand at room temperature for 16h. Then it was diluted with water, a part of the solvent was removed under reduced pressure at room temperature, and the residue was extracted with ether. The extract was washed successively with a potassium iodide solution, a sodium thiosulphate solution, and brine: and after drying the solvent was removed. The residue was crystallised from a mixture of pet. ether and ether to give the la,2a-epoxide XIV 2.10 g (80%); m.p. 97.5-99'C; [aJ,=+205*. 292nm(E=21000). ‘” 'max IR (CHC13) vmax 1730(COOCH3), 166O(CO), 1620cm-l(c=c). P?fR 66.&(s,?G-;C6 and C7-H), 5.65(s,lH,C4-H), 3.65 (s,3H,0CH3), 3.58(d,J =4tiz,11:,Cla-11). 3.42(dd,J=4Hz and J=2Hz,lH,C2S-H), 3.42(dd,J=4Hz and J=~Hz,~H,C~~-Ii),3.42(dd,J=4Hz and J=~Hz,~H,C~~-H), 1.20(s,3H,Clg-H), 0.73(s,3H,C18-H). m/e 356Glf)

.

Calcd. for C22H2804: C,74.13; H,7.92.

Anal.

Found: C,74.35: H,7.88. _.:__Pre_o_a_ao_tion of methyl 6a 7a-epoT-3-oxopregna-l,4-dien_-21-oate XVV 9 --- --.----.----1A solution of trienone X111(2.00 g) in chloroform (2 ml) was added to a cooled solution of m-chloroperbenzoic acid (1.6 g) in chloroform (20 ml) and the mixture was allowed to stand at room temperature for 24 hours. A precipitate which formed was filtered off and washed with chloroform. The filtrates were combined, diluted with ether and treated as in experiment 8. The organic extract was concentrated and the residue was crystallised froyomethanol. The 6a,7a-epoxide XVI(2 g,95%) had m.p. 50-54*C (needles); [al, =-50". UV

Xmax 243nm

IR (CHC13) vmax 1730(COOCt13),1665(U)), 163Ccm-l(M). PMR

66.96(d,J=lOHz,lH,Cl-H),6.41(d,J=2H2,1H,C4-H),6.16(dd,J=lOHz and J=2Hz,1H,C2-H), 3.65(s,3H,0CI13),3.45-3.28(m,2H,eooxideprotons), 1.20(s,3H,Clg-H), 0.72(s,3H,C18-H).

MS

m/e 356(x+).

Anal.

Calcd. for C22H2804: C.74.13; H,7.92. Found: C,74.09; H,7.84.

7a-diepoxy-3-oxopregn-5-en-21-oate XV. 10. Preparation -___~- of methyl la,2a: 6a *-A. A solution of m-chloroperbenzoic acid (2.30 g) in chloroform was added to a solution of lu,2a-epoxide XIV(2.00 g) in the same solvent. The mixture was allowed to stand at room temperature for 3 days, then the precipitate was collected and washed with chloroform. The filtrates were

S

376

TDROXDS

combined, diluted with ether, and treated as in experiment 8. The product (a colorless oil) was transferred to a silica Se1 column. Elution of the column with a mixture of benzene and ether (9:l) gave diepoxide XV(1.2 __. ._ K, 58%). A aample recrystallised from a mixture of acetone and hexane had m.p. 189.5-191.5’; [alD-+1500 244nm(c=13800). 'max IR (CHC13) urnax1730(COOCH3), 1685(CO), 163Ocm-l(C-C).

‘”

PMR 66.10(d,J=2Hs,lH,C4-H),3.65(s,3H,0CH3), 3.60-3.25(m,4H,epoxideprotons), 1.16(s,3H,Clg-HI, 0.72(s,3H,C18-HI; irradlati.onat 6-3.44 pDm Save 28% NOE for C4-H. MS

m/e

&_

412(M+).

Calcd. for C22H2805: C,70.94: H,7.58. Found: C,70.90; H,7.53.

B. A 10% NaOH solution in methanol (0.9 ml) and 30% hydrogen peroxide (0.9 ml) were added to a solution of 6a,7n_epoxydienoneXVI(0.8 g) in acetone (18 ml). The mixture was allowed to stand at room temperature for 13 hours, then worked up as in experiment 8. The oily product was chromatographed on preparative TLC plates (Si02) to yield diepoxide XV(0.41 R, 49%). 11.

Reduction of XV with chromous acetate; preparation of methyl lo-~_ --------__I__----hydr93-oxopregna-4 6-dien-21-oate XVII. _ _ ____ _ __-2-.-___.

Diepoxide XV(0.43 R) was dissolved in a mixture of glacial acetic acid (20 ml) and acetone (10 ml) under argon. Water (5 ml) and freshly prepared [19] chromous acetate (ca. 1.5 g) were added and the mixture was vigorously stirred at room tempeGture for 3 h. It was diluted with water, then extracted with ether. The extract was washed with satd. sodium bicarbonate, dried, and evaporated. The residue was chromatopraphed on prep. The product XVII(O.18 R, TLC plates with pet. ether-ethyl acetate (3:2 &Ie-25". 43.5%) had m.p. 170-173“C(ethyl acetate); [a], 287nm(c=16500). "" 'max -1 IR (CHC13) wmax 3600(OH), 3450(0*.*H), 1730(COOCH3), 166O(CO). 1620~ (C=C>. PI-!R

65.16(s,2H,C6 and C7-H), 5.73(s,lH,C4-H), 4.15(~,W~,~-7Hz,lH,C~~-H), 3.65(s,3H,0CH3), l.ll(s,311,Clg-H>, 0.71(s,3H,C18-H).

MS

m/e

Anal.

358(My+),340(M+-H20,100%).

Calcd. for C22H3004: c,73.71; H,8.44. Found: C,73.04; H,8.30.

12 .

la 7aReduction of XV with aluminium __-- amal&aE; preparation of methyl __.?_--dihydros-3-oxgze&n-4-en-21-oate V. -----~-_._---.A saturated sodium bicarbonate solution (1.5 ml) was added to a sol-

ution of diepoxide XV(0.31 S) in THF(65 ml) and ethanol (96%, 30 ml).

S

TDROXDrn

377

The mixture was cooled in ice water and aluminium amalgam prepared [24] from 2g of aluminium foil was added. The reaction mixture was kept at O-5' until the substrate completely disappeared (TLC; lh); then it was filtered with Celite and the filtrate concentrated under reduced pressure. The oily residue (300 mg) was chromatographed on preparative TLC plates with ethyl acetate-pet. ether (6:l). The methyl ester V(0.12 g,40%) gave an analytical sample (from acetone) with m.p. 176.5-178.5°C;[a]D=+550. UV

xmax 244nm(c=14500).

IR (KBr) v max 3460(0H), 1740(COOCH3), 167O(CO), 1630cm-1(C=C). PMR

65.80(s,1H,C4-H), 4.06(m,Wl,2-7Hz,lH,C18-H),3.86(m,Wl,2=7Hz,lH.C7fi-H), 3.66(~,3H,oCH3),1.18(~,3H,cl9-H),0.66(s,3H,C18-H).

MS

m/e

376(M+>, 358(M+-H,O), 340(358-H20), 332[M+-(CH2=CHOH)],314(332-

H2G). Anal.

Calcd. for C22H3205: C,70.18; H,8.57. Found: C,70.45; H,8.78.

ACKNOWLEDGMENT We express our thanks to Professor R. Gryglewski of the School of Medicine, Krakow, for biological tests and our colleagues from analytical and spectral laboratories of the Institute for determinations and measurements. REFERENCES 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Preliminary communication on this work, Wicha, J. and Bal K., ROCZNIKI CHEM, 49, 1957(1975). Inukai, N., Iwamoto, H., Tamura, T., Yanagisawa, I., Ishii.,Y., Takagi, T., Tomioka, K., and wurakaml, M., CHEM. PHARM. BULL. Japan, 24, 1414(1976). Venton, D. L., Counsell, R. E., Sanner, T. H., and Sierra, K., J. MED. CHEM., 18, 90975). Baumgarth, M. and Innscher, K., TETRAHEDRON, 3l, 3109(1975). Baumgarth, M. and Irmscher, K., TETRAHEDRON, 3l, 3119(1975). Bose, A. K. and Dahill, R. T., TETRAHEDRON LETTERS, 959(1963): Bose, A. K. and Dahill, R. T., J. ORG. CHEF?.,0, 505(1965). Wicha, J., Bal, K., and Piekut, S., SYNTH. COMMIJN.,I_,no. 3 (1977). Reichstein, T., Miiller,H., Meystre, C., and Sutter, M., HELV. CPM. ACTA, 22, 741(1939). Plattner, Pl. A. and Schreck, W., HELV. CHIM. ACTA, 22, 11780939). Magrath, D., Morris, D. S., Petrow, V., and Royer, R., J. CHEM. SOC., 2393(1950). Rathke, W. M., ORG. REACTIONS, 22_,435(1975). Franzen, G. R. and Binsch, G., J. AM. CHEM. SOC., 95, 175(1973). For another example of restricted rotation around the C-17(20) bond see: Osawa, Y., Makino, T., and Weeks, Ch. M., J. CHEM. SOC. CHM. COMMDN., 99o(1976).

378

14.

15. 16. 17. 18. 19. 20.

21. 22. 23. 24.

S

TDROIDS

Hogg, J. A., Beal, P. F., Nathan, A. H., Lincoln, F. H., Schneider, w. P., Magerlein, B. J., Hanze, A. R., and Jackson, R. W., J. AM. CHE?!. sot., 77_, 4436(1955). Romo, J. and Romo de Vivar, A., J. AM. CHM. SOC., 79, 1118(1957). Turner, A. B., J. CHEM. SOC. (C>, 2568(1968). -Glotter, E., Weissenberg, M., and Lavie, D., TETRAHEDRON, --26, 3857 (1970). Kirk, D. N. Hartshorn. PI. P., STEROID REACTION MECHANISMS, Elsevier, Amsterdam, 1968, p. 112. For a review see: Hanson, J. R., SYNTHESIS, l(1974). Corey E. J. and Ensley 11. E., J. ORG. CHEM., 38, 3187(1973); see also Bundy, G. L., Schneider, W. P., Lincoln, F. H., and Pike, J. E., J. AM. Narwid,T. A., Blount J. F., Iacobelli, CHEM. SOC., 96, 2123(1972); J. A., and Uskokovi&, M. R., HELV. CHIM. ACTA, 57, 781(1974): and Hossain,A.M.M., Kirk,D. N., and Mitra.G., STEROIDS, 27. 603(1976). Gryglewski, R., in PROSTAGLANDIN SYNTHETASE INHIBITORS, Robinson H. J., and Vane J. R. (eds), Raven, New York, 1974, pp. 33-52. Vogel, A. I., A TEXT-BOOK OF PRACTICAL ORGANIC CHEMISTRY, 3rd ed., Longmans, Green, London, 1956. Heusser, H., Eichenberg, K., and Piattner, Pl. A., HELV. CHIM. ACTA, 2, 1088(1950). Fieser, L. F. and Fieser M., REAGENTS FOQ ORGANIC SYNTHESIS,J. Wi.ley and Sons, Inc., New York, 1967, p. 20. FOOTNOTE

The simplest way for adding a two-carbon fragment to the 17-ketone is the Wittig-Horner reaction based on trialkoxyphosphonoacetates, but urior to our work negative results of this reaction have been reported [6]. Recently, we have found conditions whereby the Wittig-Homer reaction of 17-oxoandrostane derivatives proceeds in high yield [7].