Cycloaddition-oxidative cleavage pathways to 14β-formyl-19-norsteroids

Cycloaddition-oxidative cleavage pathways to 14β-formyl-19-norsteroids

Tewahedron Letters. Vol. 35. No. 33, pp. 6171-6174, 1994 Else&r Science Ltd Printed in Great Britain ao40-4039/94 57.m+o.00 0040-4039(94)0 1224-S C...

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Tewahedron Letters. Vol. 35. No. 33, pp. 6171-6174, 1994 Else&r Science Ltd Printed in Great Britain ao40-4039/94 57.m+o.00



Cycloaddition-Oxidative Cleavage Pathways to [email protected]@-19-norsteroids James R Bull’ and Clarissa Hoadley Deputment of Chemistry, University of Cap Town RolKiebosch 7m0, south ma.

Abrtrrt: Cychddition of 3-Mtboxycstn-lfJ(10),14,1Cpe~cn-17-yl ra8atc 1 with methyl pmpiokte, followed by cbemoackcUw modification of the cychddu~ h1misbc14 intcrmcdi*s for rcduaio~~~xidativc cleavage ruction scqucaccs, kding to the l+rOrmyl amiogue of c&one lxl nhtcd [email protected]

An efficient synthetic route to the 14a-fonnyl

analogue of estroner relies upon cycloaddition

cleavage of the residual14a,l7a-etheno bridge in the modified cycloadduct. 14p-Eormyl analogue of e&one investigations

and related 14p-fotmyl-19-norsteroids

of structure-activity


access to the

was of interest, in order to extend our

relationships in ring D modified analogues of steroidal hormones.

purpose, an alternative cycloaddition appropriate cycloadduct

of an

acetate 1, followed by oxidative

ethylene equivalent to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl

For this

mediated pathway was envisaged, in which the 14fi,17~-bridge of an

derived from

1 could be chemoselectively cleaved whilst retaining the 14cz,17a-

bridge. With appropriate choices of functionality on the 14&17fi-bridge

it would thus be possible to generate

14p-formyl products variously functionalised at C(17).


3 CO,Me

LO hr





4 Reagptk (i) HC-CC$Me. a (iv) NATO,, EtoH, H20, 20 lC

5 100 % (ii) PdX,

Hz (iii) 0~04,


6 CsHsN or at. oSO*



scope for a one-pot procedure. However, attempts to achieve the desired chemoselectivity

of reduction at

qZ0) were unsuccessful: treatment of 6 with sodium borohydride or LSelectride

led to mixtums which were not simpIifkd by subsequent reaction with sodium periodate or lead tetraseetate. Exhaustive reduction of 6 with lithium aluminium hydride in refluxing tetrahydu~fmar~gave a highly polar pmduct, which precluded adequate charscterisation, but subsequent treatment with sodium periodate furnished the &lactone 15 (55% from 6). It was concluded that an intermediate arising from initial reduction at C(14t) must be intercepted as a 141,20-hemiacetaI, thus preventing further reduction at C(20) but allowing reduction at c/21), to give a presumed intermediate 14 which undergoes selective period&e cleavage of the C(2Oj-C(21) bond. Repetition of the reduction-oxidative cleavage sequenceon the &la&one 15 yielded the 14fIfotmyloxymetbyI17-ketone 16, via the evident intermediacyof a Wactol, and alkaline hydrolysis of 16

furnished 14-hydroxymethyl-3-methoxy-14+%ra-1,3,5(1O)-trien-17-one





J t 20

v *



xu 0





Reqgeats: (i) LAH, TEE’, A (ii) NJIO+ EitOH,&O, ‘26 ‘C (iii) pb(OAc),, THF, 20°C (iv) KOH, MeOII, 20‘C

(v) AqO, C&HsN,20lC {vi) NaB&, EtOH

Although the overall conversion of 6 into this immediate precursor of the target compound 19 was thus achieved, the number of steps detracted from its utility, and attention was turned to exploring more direct procedures, mediated by formal cleavage of both C(lS)-C(l6)

and C(16)-C(17)

in suitably modified here for the

derivativesof the bridged dials 4 or 5. The outcome of these invesdgations is exempiified

[email protected]

5, but both isomers behaved similarly. Exhaustivereductionof5 gsve the highly polar tetraol

18, which could not be directly character&d, but underwentoxidative cleavage with lead tetraacetateto give


the 17-0~0 14#Itarbaldehydc 19 (57% from 5). Interestingly, trestment of 18 with sodium periodate resulted in formation of uneharacterisable, polar material which, upon subsequent treatment with lead tetrsacctate, furnished the desired product 19 in greatly improved yield (80% fkom 5). It was concluded that preFemntial

oxidative cleavage of t8 must oocur at C(l6)-C(l61},

accompanied perhaps by competitive C(15)-C(16)

cleavage, and that the rcs&.ant (mlxtures of) a-hydroxy ketone(s) resists further reaction in the presence of periodate. The resson for the diminished efficiency of direct lead tetraacetate oxidation of 18 isobswn, but may arise from less discriminate

initial oxidative cleavage, leading to oxidatively less vulnerable

intermediates. In an attempt to clarify the course of events, and perhaps to develop complementary routes to Zlfunctionalised [email protected], selective protection of the primary hydroxy group in 18 was attempted as a preamble to oxidatlve Cleavage. Attempts to achieve selective silylation at C(16t) were inconclusive, experiment in which 18 was first treated with acetic anhydrlde-pyridine

but an

at 20 “C, then subjected to periodate

oxidation, furnished the 21-acetate 29 (80%), clearly arising from selective 16i-acetylation

followed by

C(15)-C(16) cleavage. Reduction of 29 with lithium aluminium hydride gave a complex, polar mixture, which could not be characterised or selectively derivatised. However, reduction of 20 with sodium ~rohydride proceeded cleanly, to give a product (70%) formulated as the hemiacetal21, on the basis of distinctive spectroscopic properties. This result implies an unexpected reversal of the reduction chemoselectivity observed for the u-0x0 ester 6, and invites speculation upon possible protection of the 148formyl group as a hydrate under these reaction coaditionqthereby subsequent intramolecular hemiacetal formation. In urns,

the original objectives of this ~vesti~tion

range of 14&carbaldehydes


promoting reduction at C(20) and

were achieved with efficient syntheses of a

and 20, the further chemistry of which is under investigation.

unexpected course of certain reduction-oxidatlve


cleavage procedures highlights the need for careful control

of reaction conditions in order to avoid interfering intramolecular reactions and to optimise product yields. We acknowledge, with appreciation, the financial support of the Foundation for Research Development, the University of Cape Town, and Schering AG.


References and Notes

Bull, J.R.; Thomson, R.I. J. C&m. Sue.,P&in Trans 1, 1990,241~251. Atwal, KS.: Sshcq S.P.; Tssi, T.Y.R.;Wiesncr,K. H~fuocycles,1982,19.641-646. Wiaterfeidt,E. CJtem. Rev., 1993,93,827-843 and nfs citedtherein. AU new compoundswan fully ckacteriscd by ekmenmlsaalyscsandspccttuscopic data. SelectedNMR data(CJXX, 200MHZ; unqualifiedassignments referto methy1 singbzts): cpd4,1),0&Z (13&Mc), 2.14(17&0.4c), 3.73(laS_CO$k), 4.42(lH, d,J 1.5Hz, 15&H); cpd5. S, 1.23(l?I&Me), 2.07(17&OAc) 3.76(16a-CO$Ke), 4.11(lH, s, lSa-H); cpd6, i$t 1.31(13&Mc), 2.11(17a-OAc), [email protected]), 9.67(lH, s, 14a-CHO); cpd l3,8” 1.18(13pMc), 2.04(17uOAc). 2.15(17fNZOMe), 9.67(lH, s, [email protected]); cpd IS,&, 1.0(13&Me). 4.15(lH, dd,J 10.7and 1.9Hz. i4kT*-Ii), 4.37(lH, d.J 10.7Hz, 14tR’-H); cpd 16,i+.,1.04(13e-Me), 4.05and4.38 (esch lH, d,J 11.4Hz, 141-I&), 8.01(lH, s, 14t-OCHO); qd t9.6” 1.12(13&h&), 9.62(lH, s, lSg-CHO); cpd20, a, 1.17(U&Me), 2.14(21-OAC), 4.86and5.41 (each lH, d,J 17.9Hz, 21-m 9.54(lH, s, 14&CHO); cpd21.&t.t 1.25(13&Me), 2.05(21-OAc), 4.09 (IH, dd,f Ii 6, and 7.0 Hz, 21-H), 429 (1% dd,f 7.0 sod 2.6 Hz, 20-H), 4.5 (1% d&J llfiaad 2.6Hz, 21-H) 5.01(lH, d,J 3.5 Hz * s 01) D.20cxch.,14t-IQ.

Sot., Per&r Tranr. J, 1991,285~2865.


Bull, J.R.; Bischotberger,K J. Ch


Aa intramolecular aIdolcondensation of 17~-~~xy-3-mcthoqy-2~xo-l9-oor-17a-p~a-1,3~(lO>trknc-l~ cntirldehydeprovidesa syntheticmuteto 14a, 17a.p~pano-19-norsteroids; Bull, J.R.;Steer,L.&f.; Jaworski,K. Uqmblisbcd results.

(Received in UK 6 .Tune 1994,


24 Druze 1994)