14β-hxdroxy steroids - III. Synthesis of digoxigenin from deoxycholic acid

TetrahedronLetters,Vo1.22,No.35, pp 3385 - 5388, 1981 Printedin Great Britain

GG4G-4039/81/353385-G4~02.00/0 01981 PergamonPress Ltd.

14p-HYDF0xYSrERXDS - III.') SEVTHSSISOF DICOXIGENINFFCMDJZXXXHOLICACID Peter Welzel' , and HermannStein

Abteilungfiirchemieder Huhr-Universitit Postfach10 21 48, D-4630Hochun,Germany is discussedwhich employs Abstract: A new syntheticapproachto cardenolides singletoxygenadditionto dienolethers and an intramolecular Prins reaction. The cardiacglycosidesare widely used drugs becauseof their positive inotropiceffecton the failingheart.2) Their aglycones(cardenolides, c. f. digtigenin (j_J) are steroidscharacterized by an CY,/? -unsaturated&-lactcme substituentat the 17p -positionas well as 14p -hydroxygroup.Much efforthas been expendedon the synthesisof naturallycccuringcardenolides. In most cases construction of the butenolideside chain has reliedon C2, steroidsas 3) Recently,directtransformations of 17-oxo-androstane deristartingmaterials. 4,5) Introduction vativesto cardenolides were reported. of the 14p -hydroxygroup 14 3) in all recordedsyntheseswas achievedvia a il -olefinicprecursor. We wish to disclosenew solutionsto both syntheticproblems.0u.r approachis exemplifiedby a short and efficientsynthesisof digoxigenin(z) startingfrun readilyavailabledeoxycholicacid (1,. Treatmentof 2 with a slightexcessof N,Nkarbonyldiimidazole in tetrahydrofuran (0.25M concentration of 1, 3 h at 20°C) led to imidazolide 2 6) which was in situ irradiatedin 0.02 M tetrahydrofuran solutionwith a high pressuremercury lamp (HPK 125) througha water ccc&d qua.rtz inmersionwell Uwasaki method7))to give after chranatography on silicagel a 58% overall yield of 2. Inversionof configuration at C-3 applyingMitsunobu'smethod8) to 2 (1.1equivalentsof acetic acid) gave 3p-acetate 2 in 73% yield. Photosensitized oxygenationof 4 in acetone (8 h at 25OC, 'loo0 W halogenlanp, tetraphenylporphine as sensitizer)folkwed by hydroperoxide reductionwith sodiumiodideafforded,

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after silicagel chranatography, 18% of unsaturatedaldehyde2 and 61% of allylicalcohol2, tiich uponmanganesedioxideaxidationinmethylenechloride generatedP in 88% yield. 5 was transfomed by reactionwith 1.2 equivalents of rsathoxymethylenetriphenylphosphorane ') (preparedfmn the phcsphonim chloridewith potassiunt-butoxide) in ether into theimric dial ethers ~.Since these dienolethersproved.tobevery sensitivecxqounds 10) they ware (aftercentrifugationto rsaovesolidmaterialand evaporation) inmediatelyallowedto react in rrrathylene chloridesolutionwith singletoxygen (20 min at 25'C, loo0W halcgenlamp, rose bengal as sensitizer). The isarericcycloaddition inn&&yproducts~ 11) were not isolated.Ontreatmentwith triethylamine lene chloride(IO min at 2O'C)they were smoothlyconvertedinto cardenolide $, The reactionin assumadto prcceedby protonabstractionat C-23andheterolyticopeningof the peroxidegroup to the anion of a hydroxyester,followed by lactoneformation.I') The overallyield of 9 from 5 was, after chnmmtographicseparation,51%. The next task, stereospecific introduction of the 14p -hydroxy group,was accanplished by a very efficientremoteoxidationprocess.1,12) PhotolysisofketonelO, obtainedfrmn~by Wridini~chlorochrcmateoxi13) dation, in methylenechloride(30min at 15OC,HPK 125, pyrex filter) furnishedamixtureofE

and~.Secoaldehyde~is

fornradbywell-knm

@-cleavageand hydrogenmigrationfran C-14 to C-12, 2 by Patemo-Biichi reactionof 2. Mild acid (tetrahydrofuran / aceticacid / trifluoroacetic acid/water = 1 : 1.2 : 0.4 : 0.4, 24 h at 15OC)effectedrearrangementof gtos

andan intraaolec.&arPrins reaction') ofgtogiveuand&

which were isolatedin 28% and 44% yield.a and g were identifiedby canparisonwith authenticsamples.14) Finally,ester hydrolysis(1.5%mathanolic HCl 16 h at 20°C)transformed2 cleanlyinto l3, identical with an authenticsample.

A&o.&dgsments.

We thank Dr. M. Tauscher (JohannA. Wiilfing, Gmnau) for

agenerous gift of digoxigenin, theDeutscheForschungsgea-einschaftandthe Fends deerChenischen Industriefor financialsupport.

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2 = -q-k

3 =

4 =

-3 1

*co:.i:i’;o~o~ 8 9

=

=

R’ 0

R’ AC AC H R2 OH H R3H -T-

OH

OHH

10 =

References audNotes: 1.

P. Welzel, B. Janssen, and H. Duddeck, Liebigs Ann. Chen., 546 (1981).

2.

For reviews, see R. Thanas, J. Boutagy, and A. GeIbart, J. Pharm. Sci., 52, 1649

(1974); Th. W. Giintert,md

H.H.A. Linde, Experientia, 2,

697 (1977). 3.

For leading references, see St. F. bmvan,

M. A. Avery, and J. E.

3287 (1979); K. Nickisch, W. KIose, and F.Bohlmann, Chen.Ber., 113, 2038 (19801, and ref.4)

Md%iry,TetrahedmnL&t., 4.

A. Kurek, M. GunuIka, and J. Wicha, Chem. Camnun., 25 (1981),

5.

Th. Y. R. Tsai, A. Minta, and K. WieSner, Hetemcycks,

z,

6.

H. A. Staab, M. Liiking,and F. H. D&r, Chm. Ber., 2,

1275 (1962).

I.

S. Iwasaki, Helv. Chim. Acta, 2,

8.

A. K. Bose, B. Lal, W. A. Hofkmnn, and M. S. Manhas, Tetrahedmn Lett.,

1397 (1979).

2753 (1976).

1619 (1973). 9. IO.

G. Wittig, W. Biill,and K. H. Krikk, Chem. Ber., g,

2514 (1962).

An analcqous series of experimentswas carriedoutwithaqxmdshaving a 3P-OH group. In this series the dim01 ethers were characterized: M?= 374, XH3-signals in (D5)pyridineata=

II.

3.48 and 3.42

D. S. Steichen, and C. S. Foote, Tetrahedron I&t., M. Matsmoto, and K. Kuxda, Tetrahedron I&t., C. S. Foote, S. Mazur, P. A. Bums,

$& 12.

4363 (1979);

1607 (1979);

and D. Lerdal, J. Am. Chen. Sot.,

586 (1973)q

see P. Bladon, W. Mcbkekin, and J. A. Williams, J. Chm. Sot., 5727 (1963) L. J. Chinn, J. Org. Chem., g,

687 (19671,

13.

E. J. Corey, and J. W. Suggs, Tetrahedron I.&t., 1649 (1975),

14.

Prepared fmn

3p -acetoxy-14-hydroxy-12ao-5pI

14/3-card-20(22)-en*

lide15) using the procedure of L. Sawlewicz, and K. Meyer, Pharm. Acta HeIv., 42, 261 (1970). 15.

A. Yamada, Chen. Phana. Bull., ;,

(Received in Germany 11 May 1981)

18 (1960).