Novel rearrangements of the 2-chloroacrylonitrile cycloadducts of steroidal 14,16-dien-17-yl acetates

Article abstract of DOI:10.1135/cccc20011777

Cycloaddition of 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate (1) with 2-chloroacrylonitrile furnishes 17β-acetoxy-16α-chloro-3-methoxy-14,17α-ethenoestra-1,3,5(10)- triene-16β-carbonitrile (2) as the major product, which undergoes alkali-mediated rearrangement to (16 ¹R)-3-methoxy-17-oxo-16β,15β,14-(ethane[1,1,2]triyl)- 14β-estra-1,3,5(10)-triene-16¹-carbonitrile (7). A similar reaction course is followed by the related 16-methyl derivative 4, and it is shown that minor 15-chloro-15-cyano cycloadducts 3 and 6 undergo Grob fragmentation. Functional group manipulations and regioselective bond-scission processes are described, for conversion of rearrangement product 7 into 16β,15β,14-(ethane[1,1,2]triyl) and cyclobuta[14β,15β] analogues of estradiol.

Full text of DOI:10.1135/cccc20011777

[4 + 2]Cycloadditions
1777
NOVEL REARRANGEMENTS OF THE 2-CHLOROACRYLONITRILE
CYCLOADDUCTS OF STEROIDAL 14,16-DIEN-17-YL ACETATES
1,
James R. BULL *, Richard S. GORDON and Claudia GRUNDLER
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa;
1
e-mail: bull@science.uct.ac.za
Received October 31, 2001
Accepted Novem ber 27, 2001
Dedicated to the memory of Professor Václav Černý.
Cycloaddition of 3-m eth oxyestra-1,3,5(10),14,16-pen taen -17-yl acetate (1) with 2-ch loro-
acrylon itrile furn ish es 17β-acetoxy-16α-ch loro-3-m eth oxy-14,17α-eth en oestra-1,3,5(10)-trien e-
16β-carbon itrile (2) as th e m ajor product, wh ich un dergoes alkali-m ediated rearran gem en t to
(161R)-3-m eth oxy-17-oxo-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-1,3,5(10)-trien e-161-carbo-
n itrile (7). A sim ilar reaction course is followed by th e related 16-m eth yl derivative 4, an d it
is sh own th at m in or 15-ch loro-15-cyan o cycloadducts 3 an d 6 un dergo Grob fragm en tation .
Fun ction al group m an ipulation s an d regioselective bon d-scission processes are described, for
conversion of rearrangement product 7 into 16β,15β,14-(ethane[1,1,2]triyl) and cyclobuta[14β,15β]
an alogues of estradiol.
Keyw ord s: [4 + 2]Cycloaddition s; 2-Ch loroacrylon itrile; Rearran gem en ts; 19-Norsteroids;
Estradiols; Steroids.
Structure–activity in vestigation s in to th e m olecular basis for estrogen icity
an d estrogen an tagon ism h ave gen erated a pleth ora of steroidal an d n on -
steroidal probes for th ese properties1–4, an d recen tly gain ed addition al im -
petus from th e n ew in sigh ts afforded by th e first crystal structure study of
th e ligan d-bin din g dom ain (LBD) of th e h um an estradiol receptor com plex
with estradiol an d with th e n on -steroidal estrogen an tagon ist, raloxifen e5.
As part of an on goin g in vestigation in to skeletally m odified an alogues of
steroidal h orm on es, we h ave recen tly reported on som e aspects of th e de-
sign an d syn th esis of structural varian ts of estradiol, based upon rin g D
bridgin g elem en ts an d alkyl residues6–10. Th is in vestigation h as its origin s
in an early fin din g of poten t oral estrogen icity associated with in corpora-
tion of 14,17-alkan o bridges in to th e estradiol tem plate11, an d h as gen er-
ated n um erous estradiol an alogues th at display h igh ly com petitive in vitro
affin ity toward th e estrogen receptor12,13
.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi:10.1135/cccc20011777

1778
Bull, Gordon, Grundler:
Durin g an in vestigation in to th e scope for carryin g out cycloaddition of
form al keten e equivalen ts to rin g D dien yl acetates, it was discovered th at
2-ch loroacrylon itrile readily un dergoes efficien t cycloaddition with
3-m eth oxyestra-1,3,5(10),14,16-pen taen -17-yl acetate (1), but attem pted
alkali-m ediated con version of th e m ajor 16-ch loro-16-cyan o cycloadduct 2
in to th e targeted 16-keton e resulted in stead in an un preceden ted rearran ge-
m en t. In th is accoun t, we report m ore fully on th e prelim in ary fin din gs14
of th is cycloaddition –rearran gem en t sequen ce in steroidal 14,16-dien -17-yl
acetates, an d discuss aspects of th e furth er ch em istry of derived products.
Th e reaction of dien yl acetate 1 (Sch em e 1) with 2-ch loroacrylon itrile
was th e subject of exten sive experim en tation , owin g to th e ten den cy of th e
dien oph ile to decom pose an d polym erise at th e elevated tem perature
n eeded to prom ote reaction . Furth erm ore, attem pts to catalyse th e reaction
were accom pan ied by exten sive destruction of th e labile dien e 1. Th e m ost
con sisten t results were ach ieved by con ductin g th e reaction in con cen -
trated ben zen e solution at 90 °C (sealed tube) for periods up to 120 h , with
in term itten t addition s of fresh reagen t. In m ost cases, reaction m ixtures
darken ed progressively durin g th e course of reaction , but at a rate th at
m in im ised com plication s durin g work-up an d isolation . Th e m ajor cyclo-
adduct (isolated yield 79%) was form ulated as th e 16α-ch loro-16β-cyan o
com poun d 2, on th e basis of well-establish ed preceden t for regioselectivity
OAc
OAc
R
OAc
(i)
R
CN
Cl
+
R
Cl
MeO
CN
2, R = H
1, R = H
3, R = H
5, R = Me
4, R = Me
6, R = Me
(iv)
O
(ii)
O
O
(iii)
(v)
H
R
R
CONH2
CN
CN
7, R = H
9, R = Me
10, R = H
11, R = Me
8
SCHEME 1
(i) CH2=C(Cl)CN, C6H6, 90 °C; (ii) KOH, THF–DMSO, 0 °C; (iii) KOH, THF–DMSO, 25 °C; (iv)
KOH, EtOH, ∆; (v) P2O5, C6H5CH3, ∆
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1779
an d β-face stereoselectivity6,11. An X-ray crystal structure determ in ation h as
sin ce con firm ed th e structure of 2 (ref.15), an d verified th e assign m en t of
16-con figuration . Ch rom atograph y of m ixed fraction s led to isolation of a
m in or by-product form ulated as th e 15α-ch loro-15β-cyan o com poun d 3,
th e structure of wh ich was verified by en suin g ch em istry.
Previous studies h ave sh own th at th e cycloaddition reactivity an d
h ead-to-h ead, β-face selectivity of steroidal 14,16-dien -17-yl acetates are sig-
n ifican tly perturbed by th e presen ce of a 16-m eth yl group16, an d th is was
born e out by exten din g th is in vestigation to treatm en t of th e 16-m eth yl-
14,16-dien -17-yl acetate 4 with 2-ch loroacrylon itrile. After 120 h at 90 °C,
th e reaction was in com plete but th e m ixture was severely discoloured, n e-
cessitatin g repeated ch rom atograph y of overlappin g fraction s to give start-
in g m aterial 4 (30%), accom pan ied by th e cycloadducts 5 (28%) an d
im pure 6 (≈12%). Th e spectroscopic properties, alth ough in con clusive for
isom er differen tiation , were con sisten t with th e assign ed structures, wh ich
were con firm ed by subsequen t tran sform ation s.
A reported m eth od17 for revealin g th e m asked 16-oxo group in 2 by treat-
m en t with sodium sulfide in refluxin g m eth an ol failed, givin g on ly in trac-
table m ixtures, but treatm en t with aqueous alkali in a m ixed-solven t
m edium at 0 °C gave a sin gle product in h igh yield (90%), wh ich displayed
an alytical an d spectroscopic ch aracteristics com patible with structure 7.
1
Th us, a 500 MHz H NMR spectrum of 7 displayed m ultiplets for a closed
four-proton spin system , wh ich was un iquely assign ed to a rin g D tri-
cyclo[3.2.0.02,7]h eptan oid substructure, sin ce it was possible to assign all
th e rem ain in g 1H sign als by com parison with th ose of estron e 3-m eth yl
eth er. Furth erm ore, th e rin g D in terproton couplin gs displayed good over-
all correspon den ce with th ose reported for a structurally sim ilar tricyclic
rin g system s18, in cludin g a distin ctively large four-bon d couplin g of 2.4 Hz
between 15α-H an d 162-Hendo. Th e apparen t lack of preceden t for th e rear-
ran gem en t of 2 prom pted an X-ray crystal structure determ in ation of th e
product 7 (ref.14), wh ich con firm ed th e structural assign m en t. More pro-
lon ged alkalin e treatm en t of 2 at 25 °C resulted in form ation of th e
161-carboxam ide 8, wh ich displayed closely an alogous spectroscopic prop-
erties to th ose of 7. It is eviden t th at th e rearran ged carbon itrile 7 is th e
obligatory in term ediate wh ich un dergoes partial h ydrolysis to th e corre-
spon din g carboxam ide 8, sin ce con ven tion al deh ydration of 8 resulted in
ready regen eration of 7.
Th e 171-m eth yl cycloadduct 5 un derwen t sim ilarly facile rearran gem en t in
th e presen ce of aqueous alkali at 0 °C to give th e correspon din g 16α-m eth yl
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1780
Bull, Gordon, Grundler:
1
product 9, verified by th e sim plified th ree-proton array of H NMR sign als
associated with th e rin g D substructure.
Rearran gem en ts in itiated by bridgeh ead oxygen fun ction ality are quite
fam iliar, an d in clude n um erous exam ples in volvin g participation by
gem-ch lorocyan o fun ction ality α-located to th e bridgeh ead19, but n on e
wh ich follow th e extraordin ary course observed in th ese exam ples. A first
in terpretation of th e reaction course (Sch em e 2) suggests th at bridgeh ead
sapon ification triggers alkoxide-m ediated α-bon d cleavage (a), followed by
in tram olecular Mich ael addition (b) to th e resultan t rin g D en on e fun ction
an d in tram olecular capture of th e derived en olate an ion with expulsion of
th e ch loro group (c). Th e apparen t ease with wh ich th is sequen tial reaction
occurs m ay be attributable to th e form ation of a bis-fun ction alised
cyclopropyl m oiety, but is n everth eless rem arkable in gen eratin g a h igh ly
strain ed bridge structure with out observable eviden ce of discrete in term edi-
ates or com petin g processes. In deed it is tem ptin g to argue th at th e strain ed
bridge structure in th e startin g m aterials m ay accom m odate a ch arge-
delocalised species en gagin g all six reaction cen tres in a con certed process,
followin g 17-alkoxide form ation , or th at an in itial, rate-lim itin g α-bon d
cleavage is accom pan ied by expulsion of th e ch loro group (d ) to gen erate a
h igh ly reactive carben oid in term ediate wh ich prom ptly adds across th e
proxim ate ∆15-bon d (e). In th e absen ce of furth er eviden ce in support of
O
OAc
R
O
O
CN
Cl
R
CN
OH
R
Cl
R
CN
CN
Cl
2, R = H
5, R = Me
Cl
a
b
c
O
O
O
R
CN
Cl
R
CN
R
CN
7, R = H
d
e
9, R = Me
SCHEME 2
Alkali m ediated rearran gem en t of 16α-ch loro 16β-cyan o cycloadducts: altern ative dom in o-
reaction path ways via 2/5 → a → b → c → 7/9 or 2/5 → d → e → 7/9
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1781
th ese argum en ts th e m ech an istic detail is con jectural, an d offers scope for
m ore detailed study.
It was of in terest to exam in e th e alkali-m ediated reaction s of th e regio-
isom ers 3 an d 6, in th e expectation th at th e 1,3-disposition of fun ction ality
m igh t allow for h ydrolytic cleavage to th e correspon din g 15-keton es. In th e
even t, both com poun ds un derwen t slow tran sform ation in refluxin g
eth an olic potassium h ydroxide, to give th e respective products of Grob
fragm en tation 10 an d 11, th e structures of wh ich were supported by dis-
tin ctive spectroscopic properties. Again , th ere is n o direct an alogy for th is
m ode of fragm en tation in volvin g bridgeh ead-fun ction alised system s, but
th e result is m ech an istically reason able, an d is also un surprisin g given th at
th e altern ative, h ydrolytic process m ay be im peded by steric con gestion .
Th e 161-cyan o 17-keton e 7 (Sch em e 3) provided un expected access to a
skeletally-n ovel 16β,15β,14-(eth an e[1,1,2]triyl) rin g system an d th e atten -
dan t opportun ity to explore syn th esis of n ew an alogues of estradiol. In th e
first in stan ce, th e scope for direct reductive decyan ation to th e paren t
estron e an alogue was exam in ed, but with out success. However, treatm en t
of th e derived 17-ketal 12 with diisobutylalum in ium h ydride (DIBAL-H) in
toluen e at –78 °C gave th e 161-carbaldeh yde 13 (83%), wh ich un derwen t
sm ooth decarbon ylation (92%) in th e presen ce of Wilkin son ’s catalyst in
O
O
O
O
H
(i)
(iv) (14)
H
H
R
CN
7
12, R = CN
13, R = CHO
14, R = H
15
(ii)
(ii)
(vi)
R1
(iii)
(iv) (13 → 18)
R1
R2
R2
H
H
(iii) (16/17)
O
19, R1 = OH, R2 = H
20, R1 = H, R2 = OH
16, R1 = H, R2 = OH
17, R1 = OH, R2 = H
18, R1/R2 = O
(v)
SCHEME 3
(i) (CH2OH)2, TsOH, C6H5CH3, ∆; (ii) DIBAL-H, C6H5CH3, –78 °C; (iii) Rh Cl(PPh 3)3,
C6H5CH3, ∆; (iv) HCl, MeOH, 0 °C; (v) PDC, CH2Cl2, 0 °C; (vi) LAH, THF, ∆
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1782
Bull, Gordon, Grundler:
refluxin g toluen e, an d 17-deprotection of th e product 14 furn ish ed th e par-
en t 16β,15β,14-(eth an e[1,1,2]triyl) 17-keton e 15. Again , it proved possible
to an alyse th e closed five-proton spin system of rin g D fully, with th e aid of
h igh -field 1H NMR spectroscopy an d appropriate correlation tech n iques,
an d th e couplin gs con firm th e structure an d provide in sigh t in to th e con -
strain ts in h eren t in th is rigid rin g system .
In an altern ative approach , targeted at m ore direct syn th esis of estradiol
an alogues, th e cyan o keton e 7 was subjected to DIBAL-H reduction , to give
a separable m ixture of 17α- an d 17β-h ydroxy 161-carbaldeh ydes 16 (43%)
an d 17 (38%). Alth ough th ese in term ediates were separated an d ch aracter-
ised for th e purpose of isom er differen tiation , th e subsequen t ch em istry
was expeditiously perform ed on th e total DIBAL-H reaction product. Th us,
pyridin ium dich rom ate oxidation of th e m ixture furn ish ed th e 161-form yl
17-keton e 18, wh ereas decarbon ylation gave a separable m ixture (≈45 : 55)
of th e respective estradiol 3-m eth yl eth ers 19 an d 20. Th e latter com poun ds
were also available m ore circuitously by h ydride reduction of th e corre-
spon din g 17-keton e 15. Th e respective 17-epim ers were readily differen ti-
ated by 1H NMR con firm ation of th e n ear-eclipsin g vicin al relation sh ip
between 17α-H an d 16α-H (J = 4.8 Hz) in th e 17β-alcoh ol 19, in con trast to
orth ogon ality between 17β-H an d 16α-H (J ≈ 0 Hz) in th e 17α-alcoh ol 20.
Am on g th e furth er, in vitin g objectives in th is ph ase of th e in vestigation
was exploration of th e scope for ch em oselective bon d cleavage in th e
bridged tricyclic system , leadin g to n ew skeletal varian ts of th e estratrien e
core structure (Sch em e 4). In th e first in stan ce, dissolvin g m etal reduction s
of th e cyan o keton e 7 were exam in ed, in expectation th at th e doubly po-
ten tiated 16,161-bon d would be susceptible to reductive cleavage. In itial ex-
perim en ts usin g zin c in acetic acid were based on an alogy with reduction of
sm all-rin g lin ked 1,4-dicarbon yl com poun ds20, but failed to react clean ly,
as did lith ium –liquid am m on ia or sam arium (II) iodide in th e presen ce of
com patible co-solven ts. Th ese outcom es suggested th e n eed for a m ilder
X
X
X
X
?
H
H
Y
Y
Y
H
Y
a
c
b
SCHEME 4
Path ways to skeletal sim plification of th e 16β,15β,14-(eth an e[1,1,2]triyl) rin g system , based
upon bon d cleavage at: a C(16)–C(161); b C(15)–C(161); c C(15)–C(16)
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1783
an d possibly m ore selective reducin g agen t, for wh ich calcium –liquid am -
m on ia seem ed a likely can didate21. In deed, brief treatm en t of 7 with th is re-
agen t in THF at –78 °C furn ish ed a sin gle dih ydro com poun d (71%),
form ulated as th e 14β,15β-cyclobuta 17-keton e 21 (Sch em e 5). 1H NMR
spectroscopy revealed sign als for 16-H2, diagn ostic for a 16,161-seco struc-
ture, an d an appropriate pattern of sign als for th e 3′-H an d 4′-H2, but failed
to furn ish un am biguous eviden ce for th e 3′-con figuration . However, subse-
quen t experim en ts (see later) con firm ed th e provision al assign m en t of
3′β-con figuration to th e CN group in 21, based upon an assum ption of
m ore ready 3′-exo-directed proton ation of th e reaction in term ediate.
An alogous reduction of th e 161-form yl 17-keton e 18 was less successful,
an d th e m ajor product 22 (≈42%) was accom pan ied by a sm all am oun t
(≈7%) of isom eric m aterial wh ich was assum ed to be th e 3′α-epim er 23.
However, th is reaction h as n ot yet been optim ised, an d th e poor yield is
partly attributable to lability of th e products. Neverth eless, it is eviden t th at
R1
O
OH
(vi) (21)
H
R2
H
H
R2
O
R1
7, R1 = O, R2 = CN
12, R1 = O(CH2)2O, R2 = CN
15, R1 = O, R2 = H
(i)
29
( 7 →) 21, R1 = CN, R2 = H
(i)
(18 →) 22, R1 = CHO, R2 = H
18, R1 = O, R2 = CHO
(i)
(18 →) 23, R1 = H, R2 = CHO
(ii)
(vii)
(15 →) 26, R1 = R2 = H
(iv)
(15 →) 27, R1 = H, R2 = OTs
(ii) (12)
(v)
(15 →) 28, R1 = H, R2 = Br
R
H
R1
R2
(viii) (27)
H
24, R = O(CH2)2O
30, R1 = OH, R2 = H
31, R1 = H, R2 = OH
(iii)
25, R = O
SCHEME 5
(i) Ca–NH3, THF, –78 °C; (ii) Li–NH3, THF, –78 °C; (iii) HCl, MeOH, 0 °C; (iv) TsOH,
C6H5CH3, ∆; (v) HBr, C6H5CH3, ∆; (vi) DIBAL-H, C6H5CH3, –78 °C; (vii) Rh Cl(PPh 3)3,
C6H5CH3, ∆; (viii) LAH, THF, ∆
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1784
Bull, Gordon, Grundler:
th e bis-fun ction alised tricyclic com poun ds 7 an d 18 are susceptible to
regiodefin ed reductive cleavage of th e 16,161-bon d as expected, an d atten -
tion was turn ed to exam in in g th e course of reduction in m on o-fun ction -
alised system s.
Th e 17-protected 161-carbon itrile 12 proved resistan t to attem pted
h ydrogen olysis of th e cyclopropyl rin g, an d startin g m aterial was recovered
un ch an ged un der various catalysed reaction con dition s, probably owin g to
steric h in dran ce. Dissolvin g m etal m eth odology gave rise to com plex an d
usually in tractable m ixtures of polar products, but an experim en t in wh ich
12 was subjected to very brief treatm en t with lith ium –liquid am m on ia/THF
at –78 °C furn ish ed a m odest yield (25%) of th e 14β,16β-eth an o 17-ketal
24, as proven by con version in to th e kn own 22 17-keton e 25. Alth ough th is
eviden ce of selective (perh aps preferred?) cleavage of th e 15,161-bon d is
stereoelectron ically un derstan dable in term s of orbital align m en t an d prob-
ably also, strain relief, it is less eviden t h ow reductive decyan ation can take
place in th e absen ce of a proton don or, an d furth er work is n ecessary to op-
tim ise an d in terpret th is process. By con trast, th e 16β,15β,14-(eth an e-
[1,1,2]triyl) 17-keton e 15 un derwen t rapid an d efficien t reduction in
lith ium –liquid am m on ia/THF at –78 °C to give th e 16,161-seco 17-keton e
1
26 (84%), as eviden ced by th e appearan ce of th e diagn ostic H NMR sign als
for 16-H2, an d in accordan ce with stereoelectron ic expectation s based upon
colin earity of th at bon d with th e 17-CO group. A com plem en tary experi-
m en t en tailed attem pted h ydrogen olysis of 15. Alth ough th e 15,16-bon d of
th e cyclopropyl m oiety in 15 is sterically em bedded, it was n ot obvious
wh ich of th e rem ain in g bon ds is sterically m ore am en able to h ydro-
gen olytic cleavage, an d th is was dem on strated wh en catalytic h ydrogen a-
tion , wh ich proceeded slowly an d un selectively, gave a separable m ixture of
25 (39%) an d 26 (25%).
Durin g experim en ts to explore th e scope for acid-m ediated rearran ge-
m en t of th e 16β,15β,14-(eth an e[1,1,2]triyl) rin g system , it was n oted th at
th e 17-keton e 15 un derwen t a slow n on -catalytic tran sform ation in th e
presen ce of 4-m eth ylben zen esulfon ic acid in refluxin g ben zen e, to give a
product (69%) displayin g an alytical an d spectroscopic properties con sisten t
with addition of th e elem en ts of th e reagen t, an d assign ed as th e
3′α-tosyloxy 17-keton e 27. Th e 1H NMR spectrum displayed 16-H2 sign als
com parable to th ose of th e foregoin g cyclobuta[14β,15β] com poun ds, an d a
3′-H sign al differin g diagn ostically from th ose of th e 3′-cyan o an d 3′-form yl
com poun ds 21 an d 22. Sin ce th e obligatory reaction trajectory for Mich ael
addition at C-161 in 15 is anti to th e 16,161-bon d, th ese differen ces con sti-
tute com pellin g eviden ce for th e assign ed con figuration s in th is series of
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1785
com poun ds. A furth er exam ple of con jugate reactivity of th e 17-keton e 15
was furn ish ed by treatm en t with h ydrogen brom ide in ben zen e at 70 °C, to
give th e correspon din g 3′α-brom o 17-keton e 28 (66%). Th ese reaction s of-
fer addition al m eth ods of en try to th e cyclobuta[14β,15β] system , but th e
reductive cleavage product 21 was clearly th e m ost accessible can didate for
furth er elaboration to h orm on e an alogues. Th is was dem on strated th rough
DIBAL-H reduction of 21, followed by treatm en t of th e crude product with
Wilkin son ’s catalyst in refluxin g toluen e, to give a separable m ixture of th e
17β- an d 17α-alcoh ols 30 (8%) an d 31 (52%). Th e com poun ds were differ-
en tiated on th e basis of distin ctive 1H NMR sign als for th eir respective
17-proton s, com parable to th ose of related cycloalka[14β,15β] an alogues of
estradiol8. Th e isom er distribution was also in accordan ce with tren ds ob-
served in h ydride reduction in structurally related 17-keton es6,8. An altern a-
tive path way, based on h ydride reduction of th e 3′α-tosyloxy 17-keton e 27
also furn ish ed th e 17-alcoh ols 30 an d 31.
Th e form ation an d ch em istry of th e rearran gem en t products 7 an d 9 h as
open ed opportun ities for th e study of un usual n ew steroidal substructures, as
well as en tries in to n ew classes of skeletally m odified h orm on e an alogues.
Th e syn th esis an d h orm on al properties of som e of th e estradiol an alogues
based upon th e 16β,15β,14-(eth an e[1,1,2]triyl) an d cyclobuta[14β,15β] rin g
system s form part of a system atic structure–activity study in th is series, as-
pects of wh ich h ave been reported elsewh ere6–12, or are th e subject of on go-
in g in vestigation s13.
EXPERIMENTAL
Meltin g poin ts were determ in ed usin g a Reich ert–Jun g Th erm ovar h ot-stage m icroscope an d
are un corrected. In frared spectra (waven um bers in cm –1) were recorded as ch loroform solu-
tion s on a Perkin –Elm er Paragon 1000 FT-IR spectrom eter. 1H an d 13C NMR were recorded
on a Varian VXR-200 in strum en t at 200 MHz or a Varian Un ity spectrom eter at 400 MHz. All
spectra were recorded in deuterioch loroform , un less oth erwise stated, usin g CHCl3, δ 7.26 as
in tern al stan dard. All ch em ical sh ifts are reported in ppm , couplin g con stan ts (J) an d
h alf-width of m ultiplets (w1/2) in Hz. Elem en tal an alyses were perform ed usin g a Fison ’s In -
strum en ts Elem en tal An alyser EA1108. Mass spectra were recorded on a VG m icrom ass 16F
spectrom eter an d accurate m ass determ in ation s were perform ed on a Kratos Lim ited MS9/50
spectrom eter. All m ass spectra data were perform ed usin g electron im pact tech n iques un less
oth erwise stated. Reagen ts an d solven ts were purified accordin g to stan dard procedures.
Cycloaddition of 14,16-Dien -17-yl Acetates 1 an d 4 with 2-Ch loroacrylon itrile
A) A solution of 3-m eth oxyestra-1,3,5(10),14,16-pen taen -17-yl acetate (1) (10 g, 30.9 m m ol)
an d 2-ch loroacrylon itrile (7.5 m l, 93.9 m m ol) in an h ydrous ben zen e (40 m l) was m ain tain ed
at 90 °C in a sealed tube. Furth er aliquots of 2-ch loroacrylon itrile (each 0.5 m l, 6.3 m m ol)
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1786
Bull, Gordon, Grundler:
were added after 68 an d 92 h . After 114 h , th e reaction m ixture was filtered th rough Celite
an d evaporated un der reduced pressure. Crystallisation of th e solid residue (12 g) from
ch loroform –m eth an ol, gave 17β-acetoxy-16α-chloro-3-methoxy-14,17α-ethenoestra-1,3,5(10)-triene-
16β-carbonitrile (2) (8.17 g, 64%), m .p. 182–185 °C, [α]D +130 (c 0.6). For C24H26ClNO3 (411)
calcu lated: 70.0% C, 6.4% H, 3.4% N; fou n d: 70.1% C, 6.6% H, 3.4% N. IR: 2 242 (CN),
1 749 (CO), 716 (CCl). 1H NMR: 1.21 s, 3 H (13β-Me); 2.02 d, 1 H, J = 13.7 (15α-H); 2.24 s,
3 H (17β-OAc); 2.55 m , 1 H (9α-H); 2.75 d, 1 H, J = 13.7 (15β-H); 2.88 m , 2 H (6α- an d
6β-H); 3.77 s, 3 H (3-OMe); 6.27 an d 6.44 each d, 1 H, J = 6.2 (171- an d 172-H); 6.63 d, 1 H,
J = 2.7 (4-H); 6.73 dd, 1 H, J = 8.6 an d 2.7 (2-H); 7.19 d, 1 H, J = 8.6 (1-H). 13C NMR: 169.2
(17-OCOCH3), 157.6 (C-3), 137.3 (C-5), 133.6 an d 132.8 (C-171 an d C-172), 131.3 (C-10),
127.0 (C-1), 118.4 (16-CN), 113.7 (C-4), 112.0 (C-2), 98.2 (C-17), 62.3, 62.0 an d 56.7 (C-13,
C-14 an d C-16), 55.2 (3-OMe), 46.5 (C-15), 39.4 (C-9), 38.6 (C-8), 31.0, 26.7 an d 23.8 (C-7,
C-11 an d C-12), 29.8 (C-6), 21.3 (17-OCOCH3), 15.7 (C-18). MS (EI, m/z): 411 [M+].
Ch rom atograph y of th e m oth er-liquor residue (3.8 g) on silica gel (200 g), with toluen e as
eluen t, gave th e dien yl acetate 1 (250 m g, 2.5%), a m ixed fraction of th e cycloadducts 2 an d
3 (2.45 g, 19%), an d decom position products (880 m g). Recrystallisation of th e m ixed frac-
tion gave furth er cycloadduct 2 (1.9 g, 15%), an d ch rom atograph y of th e derived m oth er-
liquor residue (0.5 g) on silica gel (100 g), with toluen e as eluen t, gave 17β-acetoxy-
15α-chloro-3-methoxy-14,17α-ethenoestra-1,3,5(10)-triene-15β-carbonitrile (3) (270 m g, 2%),
m .p. 162–164 °C (chloroform –m ethanol), [α]D +73 (c 1.0). For C24H26ClNO3 (411) calculated:
70.0% C, 6.4% H, 3.4% N; found: 69.6% C, 6.2% H, 3.3% N. IR: 2 220 (CN), 1 742 (CO). 1H NMR:
1.26 s, 3 H (13β-Me); 1.72 m , 1 H (7α-H); 2.12 s, 3 H (17β-OAc); 2.60 m , 1 H (9α-H); 2.81 d, 1 H,
J = 13.7 (16α-H); 2.92 m , 2 H (6α- an d 6β-H); 3.04 d, 1 H, J = 13.7 (16β-H); 3.78 s, 3 H
(3-OMe); 6.19 and 6.55 each d, 1 H, J = 6.1 (171- and 172-H); 6.65 d, 1 H, J = 2.8 (4-H); 6.73 dd,
1 H, J = 8.5 an d 2.8 (2-H); 7.20 d, 1 H, J = 8.5 (1-H). 13C NMR: 170.5 (17-OCOCH3), 157.8
(C-3), 137.6 (C-5), 136.1 an d 132.5 (C-171 an d C-172), 131.0 (C-10), 127.5 (C-1), 118.3
(15-CN), 113.8 (C-4), 112.0 (C-2), 91.3 (C-17), 63.5, 62.0 an d 60.2 (C-13, C-14 an d C-15),
55.3 (3-OMe), 49.2 (C-16), 40.0 (C-9), 38.0 (C-8), 31.1, 27.1 an d 24.0 (C-7, C-11 an d C-12),
30.0 (C-6), 21.2 (17-OCOCH3), 16.3 (C-18). MS (EI, m/z): 411 [M+].
B) Sim ilar reaction of 3-m eth oxy-16-m eth ylestra-1,3,5(10),14,16-pen taen -17-yl acetate (4)
(1.25 g, 3.55 m m ol) with 2-ch loroacrylon itrile in ben zen e at 90 °C (sealed tube) for 120 h
gave an oily product wh ich was ch rom atograph ed on silica gel (150 g), with eth yl
aceatate–h exan e (1 : 9) as eluen t, to give startin g m aterial (378 m g, 30%) followed by
17β-acetoxy-16α-chloro-3-methoxy-171-methyl-14,17α-ethenoestra-1,3,5(10)-triene-16β-carbonitrile
(5) (432 m g, 28%), m .p. 189–192 °C (dich lorom eth an e–m eth an ol), [α]D +131 (c 1.7). For
C
25H28ClNO3 (425) calculated: 70.5% C, 6.6% H, 3.3% N; foun d: 70.6% C, 6.7% H, 3.3% N.
IR: 2 236 (CN), 1 726 (CO), 688 (CCl). 1H NMR: 1.21 d, 3 H, J = 0.8 (13β-Me); 1.88 d, 3 H, J =
1.7 (171-Me); 2.08 d, 1 H, J = 13.7 (15α-H); 2.25 s, 3 H (17β-OAc); 2.5 m , 1 H (9α-H); 2.7 d,
1 H, J = 13.7 (15β-H); 2.83 m , 2 H (6α- an d 6β-H); 3.76 s, 3 H (3-OMe); 5.95 br m , 1 H, W ≈ 5
(172-H); 6.64 d, 1 H, J = 2.8 (4-H); 6.72 dd, 1 H, J = 8.6 an d 2.8 (2-H); 7.2 d, 1 H, J = 8.6
(1-H). MS (EI, m/z): 425. Furth er elution gave im pure m aterial wh ich was ch rom atograph ed
repeatedly to give an oily fraction (186 m g, 12%), largely com prisin g 17β-acetoxy-
15α-chloro-3-methoxy-171-methyl-14,17α-ethenoestra-1,3,5(10)-triene-15β-carbonitrile (6). IR: 2 236
(CN), 1 726 (CO), 688 (CCl). 1H NMR: 1.13 d, 3 H, J = 0.8 (13β-Me); 1.82 d, 3 H, J = 1.8
(171-Me); 2.12 s, 3 H (17β-OAc); 2.6 m , 1 H (9α-H); 2.85 d, 1 H, J = 14.1 (16α-H); 2.95 m , 2 H
(6-H2); 3.15 d, 1 H, J = 14.1 (16β-H); 3.76 s, 3 H (3-OMe); 5.78 m , 1 H (172-H); 6.64 d, 1 H, J =
2.7 (4-H); 6.7 dd, 1 H, J = 8.6 an d 2.7 (2-H); 7.18 d, 1 H, J = 8.6 (1-H). MS (EI, m/z): 425 [M+].
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[4 + 2]Cycloadditions
1787
Alkalin e Treatm en t of 16-Ch loro-16-cyan o 17-Acetates 2 an d 5
A) A solution of th e cycloadduct 2 (1.7 g, 4.1 m m ol) in tetrah ydrofuran (25 m l) an d
dim eth yl sulfoxide (25 m l) at 0 °C un der n itrogen was treated with aqueous 2 M potassium
h ydroxide (5.2 m l, 10.4 m m ol). After 5 h at 0 °C, saturated aqueous am m on ium ch loride
was added an d th e m ixture was con cen trated un der reduced pressure. Water was added an d
th e residue was extracted with ch loroform . Th e extract was wash ed with brin e an d water,
dried (MgSO4), an d evaporated un der reduced pressure. Ch rom atograph y of th e residue (1.8 g)
on silica gel (130 g), with eth yl acetate–toluen e (1 : 9) as eluen t, gave (161R)-3-methoxy-
17-oxo–16β,15β,14-(ethane[1,1,2]triyl)-14β-estra-1,3,5(10)-triene-161-carbonitrile (7) (1.24 g,
90%), m .p. 158–161 °C (ch loroform –m eth an ol), [α]D +164 (c 1.0). For C22H23NO2 (333) cal-
culated: 79.3% C, 7.0% H, 4.2% N; foun d: 79.2% C, 7.0% H, 4.1% N. IR: 2 232 (CN), 1 733
(CO). 1H NMR: 0.89 s, 3 H (13β-Me); 1.36 qd, 1 H, J = 2 × 13.1, 12.0 an d 3.4 (11β-H); 1.43 dt,
1 H, J = 13.1 an d 2 × 3.4 (12β-H); 1.49 td, 1 H, J = 2 × 12.0 an d 2.6 (8β-H); 1.55 dd, 1 H, J =
10.6 an d 2.4 (162S-H); 1.59 td, 1 H, J = 2 × 13.1 an d 3.4 (12α-H); 1.73 qd, 1 H, J = 3 × 12.0
an d 6.2 (7α-H); 2.22 ddt, 1 H, J = 12.0, 5.7 an d 2 × 2.6 (7β-H); 2.30 ddt, 1 H, J = 13.1 an d 3 ×
3.4 (11α-H); 2.44 td, 1 H, J = 2 × 12.0 an d 3.4 (9α-H); 2.60 d, 1 H, J = 4.5 (16α-H); 2.71 d, 1 H,
J = 10.6 (162R-H); 2.87–2.98 m , 2 H (6α- an d 6β-H); 3.35 dd, 1 H, J = 4.5 an d 2.4 (15α-H);
3.77 s, 3 H (3-OMe); 6.65 d, 1 H, J = 2.6 (4-H); 6.72 dd, 1 H, J = 8.6 an d 2.6 (2-H); 7.17 d,
1 H, J = 8.6 (1-H). 13C NMR: 212.5 (C-17), 157.9 (C-3), 137.3 (C-5), 130.6 (C-10), 126.4
(C-1), 117.6 (161-CN), 113.6 (C-4), 112.0 (C-2), 55.2 (3-OMe), 53.2 an d 52.9 (C-13 an d
C-14), 39.0 (C-9), 37.5 (C-16), 37.2 (C-8), 36.5 (C-15), 30.0 (C-12), 29.7 (C-6), 27.7 (C-162),
25.0 (C-11), 24.5 (C-7), 12.4 (C-161), 11.8 (C-18). MS (EI, m/z): 333.
B) A solution of th e cycloadduct 2 (1 g, 2.4 m m ol) in tetrah ydrofuran (13 m l) an d
dim eth yl sulfoxide (30 m l) was treated with aqueous 1.5 M potassium h ydroxide (10 m l,
15.0 m m ol) at 25 °C un der n itrogen . After 23 h at 25 °C, saturated aqueous am m on ium
ch loride was added, an d th e m ixture was extracted with ch loroform . Th e extract was wash ed
with brin e, dried (MgSO4), an d evaporated un der reduced pressure to give a solid residue
(0.8 g), wh ich was crystallised from eth an ol to give (161R)-3-methoxy-17-oxo-16β,15β,14-(ethane-
[1,1,2]triyl)-14β-estra-1,3,5(10)-triene-161-carboxamide (8) (684 m g, 80%), m .p. 252–255 °C,
[α]D +96 (c 0.8). For C22H25NO3 (351) calculated: 75.2% C, 7.2% H, 4.0% N; foun d: 75.3% C,
6.9% H, 3.8% N. IR: 3 407 (NH), 1 725 (17-CO), 1 675 (CONH2). 1H NMR: 0.96 s, 3 H
(13β-Me); 1.37 obsc. qd, 1 H, J = 2 × 13.2, 12.4 an d 3.2 (11β-H); 1.44 obsc. dt, 1 H, J = 13.4
an d 2 × 3.2 (12β-H); 1.45–1.51 obsc. m , 1 H (8β-H); 1.47 obsc. dd, 1 H, J = 10.0 an d 2.3
(162S-H); 1.63–1.76 m , 2 H (7α- an d 12α-H); 2.16 ddt, 1 H, J = 12.8, 5.5 an d 2 × 2.6 (7β-H);
2.30 ddt, 1 H, J = 13.2 an d 3 × 3.2 (11α-H); 2.46 td, 1 H, J = 2 × 12.4 an d 3.2 (9α-H); 2.57 d,
1 H, J = 10.0 (162R-H); 2.73 d, 1 H, J = 4.3 (16α-H); 2.85–2.93 m , 2 H (6α- an d 6β-H); 3.23 dd,
1 H, J = 4.3 an d 2.3 (15α-H); 3.76 s, 3 H (3-OMe); 5.88 br d, exch . by D2O, 2 H (161-CONH2);
6.63 d, 1 H, J = 2.6 (4-H); 6.72 dd, 1 H, J = 8.6 an d 2.6 (2-H); 7.18 d, 1 H, J = 8.6 (1-H).
MS (EI, m/z): 351 [M+].
C) Alkaline treatm ent of the cycloadduct 5 (270 m g, 0.63 m m ol) as described in experim ent A,
an d crystallisation of th e product from dich lorom eth an e–m eth an ol gave (161-R)-3-methoxy-
16α-methyl-17-oxo-16β,15β,14-(ethane[1,1,2]triyl)-14β-estra-1,3,5(10)-triene-161-carbonitrile (9)
(150 m g, 68%), m .p. 175–177 °C, [α]D +193 (c 1.1). For C23H25NO2 (347) calculated: 79.5% C,
7.2% H, 4.0% N; foun d: 79.2% C, 7.3% H, 4.1% N. IR: 2 230 (CN), 1 731 (CO). 1H NMR:
0.92 s, 3 H (13β-Me); 1.36 qd, 1 H, J = 2 × 13.2, 11.6 an d 3.3 (11β-H); 1.48 td, 1 H, J = 2 ×
11.6 an d 2.6 (8β-H); 1.49 s, 1 H (16α-Me); 1.55 dd, 1 H, J = 10.6 an d 2.2 (162S-H); 1.59 obsc. m ,
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1788
Bull, Gordon, Grundler:
1 H (12α-H); 1.71 qd, 1 H, J = 3 × 11.6 an d 6.4 (7α-H); 2.22 ddt, 1 H, J = 11.6, 5.7 an d 2 ×
2.6 (7β-H); 2.30 ddt, 1 H, J = 13.2 an d 3 × 3.4 (11α-H); 2.43 td, 1 H, J = 2 × 11.2 an d 2.9
(9α-H); 2.71 d, 1 H, J = 10.6 (162R-H); 2.86 br m , 2 H (6α- an d 6β-H); 3.18 d, 1 H, J = 2.2
(15α-H); 3.78 s, 3 H (3-OMe); 6.64 d, 1 H, J = 2.6 (4-H); 6.74 dd, 1 H, J = 8.6 an d 2.6 (2-H);
7.20 d, 1 H, J = 8.6 (1-H). 13C NMR: 214.8 (C-17), 157.8 (C-3), 137.3 (C-5), 130.7 (C-10),
126.5 (C-1), 117.1 (161-CN), 113.6 (C-4), 112.0 (C-2), 55.2 (3-OMe), 53.2 (C-13), 51.2 (C-14),
42.8 (C-15), 41.6 (C-16), 38.9 (C-9), 37.1 (C-8), 30.2 (C-12), 29.8 (C-6), 28.0 (C-162), 25.1
(C-11), 24.5 (C-7), 18.1 (C-161), 12.1 (C-18), 10.9 (16α-Me). MS (EI, m/z): 347 [M+].
Alkalin e Treatm en t of 15-Ch loro-15-cyan o 17-Acetates 3 an d 6
A) A solution of com poun d 3 (50 m g, 0.12 m m ol) in eth an olic 0.1 M potassium h ydroxide
(25 m l) was refluxed for 7.5 h , th en aqueous am m on ium ch loride was added an d th e solu-
tion was con cen trated un der reduced pressure an d extracted with eth yl acetate. Th e extract
was wash ed with brin e, dried (MgSO4), an d evaporated un der reduced pressure. Ch rom atog-
raph y of th e residue (55 m g) on silica gel (5 g), with eth yl acetate–toluen e (1 : 9) as eluen t,
gave 2-[3-methoxy-17-oxo-14β-estra-1,3,5(10),15-tetraen-14-yl]acrylonitrile (10) (31 m g, 69%),
m .p. 125–128 °C (ch loroform –m eth an ol), [α]D +337 (c 0.5). For C22H23NO2 (333) calculated:
79.3% C, 7.0% H, 4.2% N; foun d: 79.1% C, 7.3% H, 4.0% N. IR: 2 222 (CN), 1 710 (CO).
1H NMR: 1.03 s, 3 H (13′β-Me); 2.78–2.89 br m , 2 H (6′α- an d 6′β-H); 3.75 s, 3 H (3′-OMe);
5.75 an d 6.22 each br s, 2 H (3-H2); 6.45 d, 1 H, J = 5.9 (16′-H); 6.56 d, 1 H, J = 2.6 (4′-H);
6.70 dd, 1 H, J = 8.6 an d 2.6 (2′-H); 7.01 d, 1 H, J = 8.6 (1′-H); 7.38 d, 1 H, J = 5.9 (15′-H).
MS (EI, m/z): 333 [M+].
B) Th e cycloadduct 6 (190 m g, 0.44 m m ol) was subjected to alkalin e treatm en t as de-
scribed in th e foregoin g experim en t, an d th e product was ch rom atograph ed on silica gel, with
eth yl acetate–toluen e (1 : 19) as eluen t, to give 2-[3-methoxy-16-methyl-17-oxo-14β-estra-
1,3,5(10),15-tetraen-14-yl]acrylonitrile (11) (106 m g, 69%), m .p. 135–140 °C (dich loro-
m eth an e–m eth an ol), [α]D +317 (c 0.9). For C23H25NO2 (347) calculated: 79.5% C, 7.2% H,
4.0% N; foun d: 79.3% C, 7.3% H, 4.0% N. IR: 2 225 (CN), 1 708 (CO). 1H NMR: 1.0 s, 3 H
(13′β-Me); 1.89 d, 3 H, J = 1.4 (16′-Me); 2.45 br m , 1 H (9′α-H); 2.78–2.89 br m , 2 H (6′α-
an d 6′β-H); 3.74 s, 3 H (3′-OMe); 5.78 an d 6.2 each br s, 2 H (3-H2); 6.45 d, 1 H, J = 5.9
(16′-H); 6.55 d, 1 H, J = 2.9 (4′-H); 6.70 dd, 1 H, J = 8.5 an d 2.9 (2′-H); 6.95 br s, 1 H (15′-H);
7.01 d, 1 H, J = 8.5 (1′-H). MS (EI, m/z): 347 [M+].
(161R)-17,17-(Eth ylen edioxy)-3-m eth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-
1,3,5(10)-trien e-161-carbon itrile (12)
A m ixture of th e 17-keton e 7 (540 m g, 1.6 m m ol) an d TsOH·H2O (50 m g, 0.29 m m ol) in
eth ylen e glycol (2.0 m l) an d toluen e (54 m l) was refluxed un der a Dean –Stark h ead with
slow rem oval of solven t. After 7.5 h , reflux of th e residual m ixture (≈30 m l) was con tin ued
for a furth er 17 h with return of th e con den sate th rough m olecular sieves (4 Å). Aqueous so-
dium h ydrogen carbon ate was added to th e cooled reaction m ixture an d th e product was ex-
tracted with toluen e. Th e extract was wash ed with water an d aqueous sodium
h ydrogen carbon ate, dried (MgSO4), an d evaporated un der reduced pressure. Crystallisation
of th e solid residue (632 m g) from ch loroform –m eth an ol gave th e 17-ketal 12 (565 m g,
92%), m .p. 232–237 °C, [α]D +133 (c 1.1). For C24H27NO3 (377) calculated: 76.4% C, 7.2% H,
3.7% N; foun d: 76.1% C, 7.3% H, 3.7% N. IR: 2 226 (CN). 1H NMR: 0.72 s, 3 H (13β-Me);
1.84 dd, 1 H, J = 9.7 an d 2.2 (162S-H); 2.17 d, 1 H, J = 5.2 (16α-H); 2.41 d, 1 H, J = 9.7
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[4 + 2]Cycloadditions
1789
(162R-H); 2.89 br m , 2 H (6α- an d 6β-H); 2.99 dd, 1 H, J = 5.2 an d 2.2 (15α-H); 3.75 s, 3 H
(3-OMe); 3.84–4.11 m , 4 H (17-OCH2CH2O); 6.62 d, 1 H, J = 2.7 (4-H); 6.7 dd, 1 H, J = 8.5
an d 2.7 (2-H); 7.18 d, 1 H, J = 8.5 (1-H). MS (EI, m/z): 377 [M+].
(161R)-17,17-(Eth ylen edioxy)-3-m eth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-
1,3,5(10)-trien e-161-carbaldeh yde (13)
A solution of th e ketal 12 (400 m g, 1.06 m m ol) in an h ydrous toluen e (80 m l) at –78 °C
un der n itrogen was treated with diisobutylalum in ium h ydride (20% solution in h exan e; 3.6 m l,
3.6 m m ol). After 160 m in , aqueous am m on ium ch loride was added at –78 °C. Th e reaction
m ixture was acidified with dilute sulfuric acid an d extracted with eth yl acetate, an d th e ex-
tract was wash ed with sodium h ydrogen carbon ate an d water, dried (MgSO4), an d evaporated
to dryn ess un der reduced pressure. Flash ch rom atograph y of th e residue (378 m g) on silica
gel (40 g), with eth yl acetate–toluen e (1 : 9) as eluen t, gave th e 161-carbaldeh yde 13 (335 m g,
83%), m .p. 190–194 °C (ch loroform –h exan e), [α]D +165 (c 0.8). For C24H28O4 (380) calcu-
lated: 75.8% C, 7.4% H; foun d: 75.7% C, 7.2% H. IR: 1 685 (CO). 1H NMR: 0.77 s, 3 H
(13β-Me); 1.62 dd, 1 H, J = 10.3 an d 1.9 (162S-H); 2.45 obsc. d, 1 H, J ≈ 5 (16α-H); 2.49 obsc. d,
1 H, J ≈ 10 (162R-H); 2.84 m , 2 H (6α- an d 6β-H); 3.05 dd, 1 H, J = 5.3 an d 1.9 (15α-H); 3.74 s,
3 H (3-OMe); 3.83–4.05 m , 4 H (-OCH2CH2O-); 6.61 d, 1 H, J = 2.8 (4-H); 6.69 dd, 1 H, J =
8.7 an d 2.8 (2-H); 7.19 d, 1 H, J = 8.7 (1-H); 8.86 s, 1 H (CHO). MS (EI, m/z): 380 [M+].
(161S)-17,17-(Eth ylen edioxy)-3-m eth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-
1,3,5(10)-trien e (14)
Th e 161-carbaldeh yde 13 (340 m g, 0.89 m m ol) an d Rh Cl(PPh 3)3 (912 m g, 0.99 m m ol) in
deoxygen ated toluen e (25 m l) were refluxed un der n itrogen . After 20 h eth an ol was added
to th e cooled reaction m ixture an d m ost of th e Rh Cl(CO)(PPh 3)2 was rem oved by filtration .
Th e filtrate was evaporated to dryn ess un der reduced pressure. Ch rom atograph y of th e resi-
due (805 m g) on silica gel (34 g), with eth yl acetate–toluen e (1 : 99) as eluen t, gave com -
poun d 14 (291 m g, 92%), m .p. 159–163 °C (ch loroform –m eth an ol), [α]D +117 (c 1.0). For
C
23H28O3 (352) calculated: 78.4% C, 8.0% H; foun d: 78.4% C, 8.2% H. 1H NMR: 0.73 s, 3 H
(13β-Me); 2.40 dt, 1 H, J = 2 × 11.6 an d 3.8 (9α-H); 2.85 m , 2 H (6α- an d 6β-H); 3.75 s, 3 H
(3-OMe); 3.84–4.09 m , 4 H (-OCH2CH2O-); 6.61 dd, 1 H, J = 2.7 (4-H); 6.69 dd, 1 H, J = 8.5
an d 2.7 (2-H); 7.20 d, 1 H, J = 8.5 (1-H). MS (EI, m/z): 352 [M+].
(161S)-3-Meth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-1,3,5(10)-trien -17-on e (15)
A solution of th e 17-ketal 14 (150 m g, 0.43 m m ol) in tetrah ydrofuran (6 m l) an d m eth an ol
(18 m l) at 0 °C was treated with 6 M h ydroch loric acid (1.2 m l, 7.2 m m ol). After 6 m in at
0 °C, solid sodium h ydrogen carbon ate was added an d th e m ixture was diluted with water
an d extracted with ch loroform . Th e extract was wash ed with aqueous sodium h ydrogen -
carbon ate an d water, dried (MgSO4), an d evaporated un der reduced pressure. Crystallisation
of th e residue (154 m g) from ch loroform –m eth an ol gave th e 17-keton e 15 (110 m g, 84%),
m .p. 179–184 °C, [α]D +171 (c 1.0). For C21H24O2 (308) calculated: 81.8% C, 7.8% H; foun d:
81.7% C, 7.7% H. IR: 1 711 (CO). 1H NMR: 0.87 s, 3 H (13β-Me); 1.26 dd, 1 H, J = 10.5 an d
2.9 (162R-H); 1.37 qd, 1 H, J = 2 × 13.4, 12.0 an d 3.2 (11β-H); 1.41–1.49 m , 2 H (12α- an d
8β-H); 1.67–1.76 m , 2 H (7α- an d 12β-H); 2.04 dd, 1 H, J = 6.5 an d 4.1 (16α-H); 2.10 ddd,
1 H, J = 6.5, 3.9 an d 3.7 (161α-H); 2.22–2.26 m , 1 H (7β-H); 2.29 ddt, 1 H, J = 13.2 an d 3 ×
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1790
Bull, Gordon, Grundler:
3.7 (11α-H); 2.45 dd, 1 H, J = 10.5 an d 3.9 (162S-H); 2.48 td, 1 H, J = 2 × 11.5 an d 3.2
(9α-H); 2.76 ddd, 1 H, J = 4.1, 3.7 an d 2.9 (15α-H); 2.92 m , 2 H (6α- an d 6β-H); 3.78 s, 3 H
(3-OMe); 6.66 d, 1 H, J = 2.8 (4-H); 6.73 dd, 1 H, J = 8.5 and 2.8 (2-H); 7.21 d, 1 H, J = 8.5 (1-H).
13C NMR: 218.8 (C-17), 157.6 (C-3), 137.7 (C-5), 131.7 (C-10), 126.5 (C-1), 113.6 (C-4),
111.8 (C-2), 55.2 (3-OMe), 53.9 an d 52.9 (C-13 an d C-14), 39.2 (C-9), 37.9 (C-8), 32.9 an d
20.4 (C-16 an d C-161), 30.8 (C-15), 30.6 (C-12), 30.0 (C-6), 26.0 (C-162), 25.4 an d 24.7 (C-7
an d C-11), 12.1 (C-18). MS (EI, m/z): 308 [M+]. Ch rom atograph y of th e m oth er liquor on silica
gel (1.6 g), with eth yl acetate–toluen e (1 : 19) as eluen t, gave furth er 17-keton e 15 (10 m g,
8%).
(161S)-17-Hydroxy-3-m eth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-1,3,5(10)-trien e-
161-carbaldeh ydes (16 an d 17)
A solution of th e carbon itrile 7 (0.8 g, 2.4 m m ol) in an h ydrous toluen e (32 m l) at –78 °C
un der n itrogen was treated with diisobutylalum in ium h ydride (1.5 M solution in toluen e;
5.0 m l, 7.5 m m ol). After 60 m in at –78 °C th e reaction was quen ch ed with water, an d th e
m ixture was extracted with eth yl acetate. Th e organ ic ph ase was wash ed with aqueous am -
m on ium ch loride an d water, dried (MgSO4), an d evaporated un der reduced pressure. Th e
crystallin e residue (1.13 g) was ch rom atograph ed on silica gel (80 g), with eth yl acetate–
ch loroform (1 : 4) as eluen t, to give (161R)-17α-hydroxy-3-methoxy-16β,15β,14-(ethane-
[1,1,2]triyl)-14β-estra-1,3,5(10)-triene-161-carbaldehyde (16) (346 m g, 43%), m .p. 134–137 °C
(eth yl acetate–h exan e), [α]D +115 (c 1.0). For C22H26O3 (338) calculated: 78.1% C, 7.7% H;
foun d: 77.7% C, 7.7% H. IR: 3 608 an d 3 436 (OH), 1 684 (CO). 1H NMR: 0.96 s, 3 H
(13β-Me); 1.75 d, 1 H, J = 6.4, exch . by D2O (17α-OH); 2.32 obsc. d, 1 H, J = 5. 1 (16α-H);
2.48 d, 1 H, J = 11.0 (162R-H); 2.87 m , 2 H (6α- an d 6β-H); 3.12 br dd, 1 H, J ≈ 5 an d 2
(15α-H); 3.78 s, 3 H (3-OMe); 4.28 d, 1 H, J = 6.4 → s on D2O exch . (17β-H); 6.64 d, 1 H, J =
2.5 (4-H); 6.73 dd, 1 H, J = 8.5 an d 2.5 (2-H); 7.22 d, 1 H, J = 8.5 (1-H); 8.81 s, 1 H (CHO).
MS (EI, m/z): 338 [M+], followed by (161R)-17β-hydroxy-3-methoxy-16β,15β,14-(ethane-
[1,1,2]triyl)-14β-estra-1,3,5(10)-triene-161-carbaldehyde (17) (310 m g, 38%), m .p. 178–183 °C
(eth yl acetate–h exan e), [α]D +134 (c 1.0). For C22H26O3 (338) calculated: 78.1% C, 7.7% H;
foun d: 78.1% C, 7.8% H. IR: 3 608 an d 3 440 (OH), 1 688 (CO). 1H NMR: 0.91 s, 3 H
(13β-Me); 1.60 dd, 1 H, J = 10.5 an d 1.9 (162S-H); 1.73 d, 1 H, J = 4.7, exch . by D2O (17β-OH);
2.58 d, 1 H, J = 10.5 (162R-H); 2.76 t, 1 H, J = 2 × 4.7 (16α-H); 2.88 m , 2 H (6α- and 6β-H);
3.09 dd, 1 H, J = 4.7 and 1.9 (15α-H); 3.78 s, 3 H (3-OMe); 4.12 t, 1 H, J = 2 × 4.7 → d, J = 4.7 on
D2O exch . (17α-H); 6.64 d, 1 H, J = 2.8 (4-H); 6.72 dd, 1 H, J = 8.8 an d 2.8 (2-H); 7.20 d, 1 H,
J = 8.8 (1-H); 8.91 s, 1 H (CHO). MS (EI, m/z): 338 [M+].
(161R)-3-Meth oxy-17-oxo-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-1,3,5(10)-trien e-
161-carbaldeh yde (18)
A) A m ixture (pre-ch rom atograph y reaction product of foregoin g experim en t) of th e
17ξ-h ydroxy-161-carbaldeh ydes 16 an d 17 (50 m g, 0.15 m m ol) in dich lorom eth an e (3 m l) at
0 °C was treated with pyridin ium dich rom ate (84 m g, 0.22 m m ol). After 2 h at 0 °C, th e re-
action m ixture was m ain tain ed at 20 °C for 22 h , th en water was added an d th e product was
extracted with ch loroform . Th e extract was wash ed with brin e, dried (MgSO4), an d con cen -
trated un der reduced pressure. Ch rom atograph y of th e product (52 m g) on silica gel (5 g),
with eth yl acetate–toluen e (1 : 9) as eluen t, gave th e 17-oxo-161-carbaldeh yde 18 (30 m g,
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1791
60%), m .p. 182–187 °C (eth yl acetate), [α]D +200 (c 0.8). For C22H24O3 (336) calculated:
78.5% C, 7.2% H; foun d: 78.7% C, 7.1% H. IR: 1 731 (CO), 1 697 (CO). 1H NMR: 0.94 d,
3 H, J = 0.6 (13β-Me); 1.37 dd, 1 H, J = 11.0 an d 2.4 (162S-H); 2.19 m , 1 H (7ξ-H); 2.33 ddt,
1 H, J = 13.4 an d 3 × 3.7 (11α-H); 2.48 td, 1 H, J = 2 × 11.8 an d 3.7 (9α-H); 2.79 d, 1 H, J =
11.0 (162R-H); 2.89 d, 1 H, J = 4.5 (16α-H); 2.92 m , 2 H (6α- an d 6β-H); 3.39 dd, 1 H, J = 4.5
an d 2.4 (15α-H); 3.78 s, 3 H (3-OMe); 6.66 d, 1 H, J = 2.8 (4-H); 6.74 dd, 1 H, J = 8.4 an d 2.8
(2-H); 7.21 d, 1 H, J = 8.4 (1-H); 8.97 s, 1 H (161-CHO). 13C NMR: 214.0 (C-17), 194.0
(161-CHO), 157.8 (C-3), 137.5 (C-5), 130.9 (C-10), 126.5 (C-1), 113.6 (C-4), 112.0 (C-2), 55.2
(3-OMe), 53.7 an d 51.8 (C-13 an d C-14), 39.1 (C-9), 38.8 (C-16), 38.5 (C-15), 37.5 (C-8),
37.4 (C-161), 30.6, 25.3, 24.5 an d 23.6 (C-7, C-11, C-12 an d C-162), 29.8 (C-6), 12.2 (C-18).
MS (EI, m/z): 336 [M+].
B) A solution of th e 17,17-(eth ylen edioxy)-161-carbaldeh yde 13 (300 m g, 0.79 m m ol) in
tetrah ydrofuran (8 m l) at 0 °C was treated with 6 M h ydroch loric acid (0.3 m l, 1.8 m m ol).
After 90 m in at 0 °C, th e reaction was in com plete (TLC), an d th e tem perature was raised to
25 °C for a furth er 140 m in . Aqueous sodium h ydrogen carbon ate was added an d th e reac-
tion m ixture was extracted with ch loroform . Th e product was isolated an d ch rom atograph ed
as described in A, to give th e 17-keton e 18 (230 m g, 87%).
3-Meth oxy-16β,15β,14-(eth an e[1,1,2]triyl)-14β-estra-1,3,5(10)-trien -17ξ-ols (19 an d 20)
A) Th e 17-keton e 15 (398 m g, 1.3 m m ol) in tetrah ydrofuran (24 m l) un der n itrogen was
treated with excess lith ium alum in ium h ydride at reflux. After 8 h , th e reaction m ixture was
cooled an d th e excess reagen t was destroyed by th e addition of aqueous am m on ium ch lo-
ride. Th e m ixture was extracted with eth yl acetate, an d th e extract was wash ed with aque-
ous am m on ium ch loride an d water, dried (MgSO4), an d evaporated un der reduced pressure.
Ch rom atograph y of th e residue (411 m g) on silica gel (40 g), with eth yl acetate–ch loroform
(1 : 99) as eluen t, gave th e 17β-alcoh ol 19 (159 m g, 40%), m .p. 141–145 °C (aqueous m eth a-
n ol), [α]D +133 (c 0.55). For C21H26O2 (336) calculated: 81.3% C, 8.4% H; foun d: 81.0% C,
8.5% H. IR: 3 606 (OH). 1H NMR: 0.82 s, 3 H (13β-Me); 1.39 obsc. dd, 1 H, J = 9.6 an d 2.5
(162R-H); 2.2l obsc. dd, 1 H, J = 9.6 an d 4.1 (162S-H); 2.85 m , 2 H (6α- an d 6β-H); 3.75 s,
3 H (3-OMe); 3.94 d, 1 H, J = 4.8 (17α-H); 6.61 d, 1 H, J = 2.7 (4-H); 6.69 dd, 1 H, J = 8.5
an d 2.7 (2-H); 7.19 d, 1 H, J = 8.5 (1-H), followed by th e 17α-alcoh ol 20 (232 m g, 58%),
m .p. 129–132 °C (eth yl acetate–h exan e), [α]D +750 (c 0.52). For C21H26O2 (336) calculated:
81.3% C, 8.4% H; foun d: 81.3% C, 8.3% H. IR: 3 606 (OH). 1H NMR: 0.90 s, 3 H (13β-Me);
1.27 dd, 1 H, J = 10.2 an d 2.5 (162R-H); 2.13 dd, 1 H, J = 10.2 an d 4.1 (162S-H); 2.43 m , 1 H
(9α-H); 2.89 m , 2 H (6α- an d 6β-H); 3.78 s, 3 H (3-OMe); 4.18 s, 1 H (17β-H); 6.65 d, 1 H, J =
2.7 (4-H); 6.73 dd, 1 H, J = 8.5 an d 2.7 (2-H); 7.24 d, 1 H, J = 8.5 (1-H).
B) A m ixture of th e 17ξ-h ydroxy-161-carbaldeh ydes 16 + 17 (306 m g, 0.9 m m ol) in
deoxygen ated toluen e (42 m l) un der n itrogen was refluxed with Rh Cl(PPh 3)3 (700 m g,
0.76 m m ol) for 19 h . Eth an ol was added to th e cooled reaction m ixture, wh ich was filtered
th rough Celite an d th e filtrate was evaporated un der reduced pressure. Th e residue (400 m g)
was ch rom atograph ed on silica gel (62 g), with eth yl acetate–ch loroform (1 : 99) as eluen t,
to give th e 17β-alcoh ol 19 (97 m g, 36%) an d th e 17α-alcoh ol 20 (116 m g, 43%), followed by
startin g m aterial 7 (20 m g, 7%).
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1792
Bull, Gordon, Grundler:
Reductive Cleavage of 16β,15β,14-(Eth an e[1,1,2]triyl) Derivatives 7, 12, 15 an d 18
A) A solution of th e 161-cyan o 17-keton e 7 (250 m g, 0.75 m m ol) in tetrah ydrofuran (15 m l)
was added dropwise over 15 m in to a stirred m ixture of calcium m etal (300 m g, 7.5 g atom )
in an h ydrous liquid am m on ia (25 m l) (fresh ly distilled from sodium ) an d an h ydrous
tetrah ydrofuran (10 m l) at –78 °C un der n itrogen . After a furth er 3 m in , brom oben zen e
(1 m l, 9.5 m m ol) was added to disperse th e colour, followed by solid am m on ium ch loride.
Water was th en added an d th e am m on ia was allowed to evaporate. Th e residue was ex-
tracted with eth yl acetate, an d th e extract was wash ed with aqueous am m on ium ch loride
an d water, dried (MgSO4), an d evaporated un der reduced pressure. Th e residue (348 m g) was
ch rom atograph ed on silica gel (25 g), with eth yl acetate–toluen e (1 : 19) as eluen t, to give
3-methoxy-17-oxo-3′,4′-dihydro-15αH-cyclobuta[14,15]-14β-estra-1,3,5(10)-triene-3′β-carbonitrile
(21) (178 m g, 71%), m .p. 158–161 °C (ch loroform –m eth an ol), [α]D +170 (c 1.0). For
C
22H25NO2 (335) calculated: 78.8% C, 7.5% H, 4.2% N; foun d: 78.7% C, 7.5% H, 4.3% N.
IR: 2 237 (CN), 1 735 (CO). 1H NMR: 0.93 s, 3 H (13β-Me); 1.33 qd, 1 H, J = 3 × 12.8 an d 3.5
(11β-H); 1.45 td, 1 H, J = 2 × 12.8 an d 3.5 (12α-H); 1.51–1.60 m , 2 H (8β- an d 12β-H); 1.71 qd,
1 H, J = 3 × 12.1 an d 6.8 (7α-H); 1.98 dd, 1 H, J = 12.9 an d 9.5 (4′α-H); 2.17 m , 1 H, W1/2
=
10.1 (7β-H); 2.30 ddt, 1 H, J = 12.8, 3 × 3.5 (11α-H); 2.38 ddd, 1 H, J = 12.9, 9.5 an d 3.9
(4′β-H); 2.46 br t, 1 H, J ≈ 2 × 11, W1/2 ≈ 3.7 (9α-H); 2.72 dd, 1 H, J = 19.3 an d 1.5 (16β-H);
2.93–3.02 m , 3 H (6α-, 6β- an d 15α-H); 3.13 dd, 1 H, J = 19.3 an d 10.4 (16α-H); 3.31 ddd, 1 H,
J = 2 × 9.5 an d 7.9 (3′α-H); 3.75 s, 3 H (3-OMe); 6.62 d, 1 H, J = 2.8 (4-H); 6.72 dd, 1 H, J =
8.6 an d 2.8 (2-H); 7.18 d, 1 H, J = 8.6 (1-H).
B) A solution of th e 161-form yl 17-keton e 18 (100 m g, 0.30 m m ol) in tetrah ydrofuran
(4 m l) was added dropwise over 6 m in to a stirred m ixture of calcium m etal (130 m g, 3.2 g
atom ) in an h ydrous liquid am m on ia (55 m l) (fresh ly distilled from sodium ) an d
tetrah ydrofuran (4 m l) at –78 °C un der n itrogen . After a furth er 10 m in , brom oben zen e (0.5 m l,
4.8 m m ol) was added to disperse th e colour, an d th e reaction m ixture was worked up as in
th e foregoin g experim en t. Th e crude product (136 m g) was filtered th rough silica gel (10 g)
with eth yl acetate–toluen e (1 : 9), an d th e solid residue (90 m g) was crystallised from ethyl
acetate to give 3-methoxy-17-oxo-3′,4′-dihydro-15αH-cyclobuta[14,15]-14β-estra-1,3,5(10)-triene-
3′β-carbaldehyde (22) (19 m g, 19%), m .p. 162–168 °C, [α]D +185 (c 1.0). IR: 1 731 (17-CO), 1 704
(CHO). 1H NMR: 0.97 s, 3 H (13β-Me); 1.33 qd, 1 H, J = 3 × 13.3 an d 3.0 (11β-H); 1.40 td,
1 H, J = 2 × 13.3 an d 3.1 (12α-H); 1.51 dt, 1 H, J = 13.3 an d 2 × 3.0 (12β-H); 1.59 td, 1 H, J =
2 × 12.5 an d 1.8 (8β-H); 1.70–1.80 m , 1 H (7α-H); 1.97 ddd, 1 H, J = 13.0, 8.6 an d 3.8
(4′β-H); 2.09 dd, 1 H, J = 13.0 an d 10.0 (4′α-H); 2.20 dd, 1 H, J = 19.4 an d 1.7 (16β-H);
2.24–2.31 m , 2 H (7β- an d 11α-H); 2.50 br t, 1 H, J ≈ 2 × 11.2, W1/2 ≈ 7.1 (9α-H); 2.91 dd, 1 H,
J = 19.4 an d 10.3 (16α-H); 2.96 m , 2 H (6α- an d 6β-H); 3.15 br t, 1 H, J ≈ 2 × 10.3 an d W1/2
≈
7.4 (15α-H); 3.21 ddd, 1 H, J = 10.0 an d 2 × 8.6 (3′α-H); 3.78 s, 3 H (3-OMe); 6.65 d, 1 H, J =
2.8 (4-H); 6.74 dd, 1 H, J = 8.6 an d 2.8 (2-H); 7.22 d, 1 H, J = 8.6 (1-H); 9.67 d, 1 H, J = 0.8
(3′α-CHO). MS (EI, m/z): 338.187 [M+]. Flash ch rom atograph y of th e m oth er liquor residue
(48 m g) on silica gel (10 g), with eth yl acetate–toluen e (1 : 9) as eluen t, gave 3-methoxy-
17-oxo-3′,4′-dihydro-15α H-cyclobuta[14,15]-14β-estra-1,3,5(10)-triene-3′α -carbaldehyde (23)
(7 m g) as an oil. IR: 1 725 (CO). 1H NMR: 1.01 s, 3 H (13β-Me); 2.85 m , 2 H (6α- an d 6β-H);
3.24 dd, 1 H, J = 17.4 an d 9.9 (16α-H); 3.76 s, 3 H (3-OMe); 6.60 d, 1 H, J = 2.8 (4-H); 6.72 dd,
1 H, J = 8.6 an d 2.8 (2-H); 7.19 d, 1 H, J = 8.6 (1-H); 9.80 s, 1 H (3′β-CHO). MS (EI, m/z): 338
[M+], followed by m ixed fraction s (5 m g) an d furth er 22 (23 m g, 23%).
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[4 + 2]Cycloadditions
1793
C) A solution of th e 17,17-eth ylen edioxy-161-carbon itrile 12 (275 m g, 0.73 m m ol) in
tetrah ydrofuran (70 m l) was added to a stirred m ixture of lith ium m etal (63 m g, 9.1 g
atom ), an h ydrous liquid am m on ia (30 m l) (fresh ly distilled from sodium ) an d an h ydrous
tetrah ydrofuran (22 m l) at –78 °C. After 4 m in , solid am m on ium ch loride was added in
sm all portion s, an d th e reaction m ixture was stirred at –78 °C un til it becam e colourless.
Water was added, and the m ixture was worked up as previously described. The product (277 m g)
was ch rom atograph ed on silica gel (28 g), with eth yl acetate–h exan e (1 : 4) as eluen t, to give
17,17-(ethylenedioxy)-3-methoxy-14,16β-ethano-14β-estra-1,3,5(10)-triene (24) (65 m g, 25%),
m .p. 133–137 °C (ch loroform –m eth an ol), [α]D +52 (c 1.0). For C23H30O3 (354) calculated:
77.9% C, 8.5% H; foun d: 77.8% C, 8.5% H. 1H NMR: 0.95 s, 3 H (13β-Me); 2.24 m , 1 H
(11α-H); 2.42 m , 1 H (9α-H); 2.82 m , 2 H (6α- and 6β-H); 3.75 s, 3 H (3-OMe); 3.80–3.84 m , 4 H
(-OCH2CH2O-); 6.60 d, 1 H, J = 2.8 (4-H); 6.68 dd, 1 H, J = 8.5 an d 2.8 (2-H); 7.21 d, 1 H, J =
8.5 (1-H). MS (EI, m/z): 354 [M+].
A portion of th e ketal 24 (15 m g, 0.04 m m ol) in tetrah ydrofuran (3 m l) an d m eth an ol
(4 m l) at 0 °C was treated with 6 M h ydroch loric acid (0.2 m l, 1.2 m m ol). After 4 h at 0 °C,
aqueous sodium h ydrogen carbon ate was added an d th e product was isolated by extraction
with ch loroform an d flash -ch rom atograph ed on silica gel (3 g), with eth yl acetate–toluen e
(1 : 49) as eluen t, to give th e 14β,16β-eth an o 17-keton e 25 (13 m g, 99%), m .p. 167–172 °C
(ch loroform –m eth an ol), [α]D +174 (c 0.5) (ref.22 gives 168–170 °C, [α]D +174).
D) A solution of th e 17-keton e 15 (50 m g, 0.16 m m ol) in tetrah ydrofuran (2 m l) was
added dropwise over 5 m in to a stirred m ixture of lith ium m etal (12 m g, 1.7 g atom ) in an -
h ydrous liquid am m on ia (10 m l) (fresh ly distilled from sodium ) an d tetrah ydrofuran (1 m l)
at –78 °C un der n itrogen . After a furth er 5 m in , solid am m on ium ch loride was added an d
th e reaction m ixture was worked up as described previously. Flash ch rom atograph y of th e
product (47 m g) on silica gel (5 g), with eth yl acetate–toluen e (1 : 19) as eluen t, gave
3-methoxy-3′,4′-dihydro-15αH-cyclobuta[14,15]-14β-estra-1,3,5(10)-trien-17-one (26) (42 m g,
84%), m .p. 115–116 °C (eth yl acetate–h exan e), [α]D +213 (c 0.4). For C21H26O2 (310) calcu-
lated: 81.3% C, 8.4% H; foun d: 81.3% C, 8.4% H. IR: 1 725 (CO). 1H NMR: 0.93 s, 3 H
(13β-Me); 2.13 dd, 1 H, J = 19.0 an d 1.8 (16β-H); 2.46 td, 1 H, J = 2 × 11.3 an d 2.4 (9α-H);
2.65 br, 1 H (15α-H); 2.93 m , 2 H (6α- an d 6β-H); 3.10 dd, 1 H, J = 19.0 an d 10.2 (16α-H);
3.78 s, 3 H (3-OMe); 6.65 d, 1 H, J = 2.8 (4-H); 6.73 dd, 1 H, J = 8.6 an d 2.8 (2-H); 7.21 d,
1 H, J = 8.6 (1-H). 13C NMR: 221.9 (C-17), 157.5 (C-3), 137.8 (C-5), 131.6 (C-10), 127.3
(C-1), 113.5 (C-4), 112.0 (C-2), 55.2 (3-OMe), 53.5 an d 52.4 (C-13 an d C-14), 43.1 (C-16),
41.2 (C-9), 38.7 (C-8), 33.0, 26.9, 26.3, 25.7 an d 23.9 (C-7, C-11, C-12, C-3′ an d C-4′), 30.9
(C-6), 30.3 (C-15), 12.5 (C-18). MS (EI, m/z): 310 [M+].
E) A solution of th e 17-keton e 15 (100 m g, 0.32 m m ol) in eth yl acetate (5 m l) at 25 °C
was h ydrogen ated in th e presen ce of Pd–C (10%; 100 m g). After 7.5 h , th e m ixture was fil-
tered an d th e filtrate was evaporated un der reduced pressure. Ch rom atograph y of th e resi-
due on silica gel, with eth yl acetate–h exan e as eluen t, gave com poun d 26 (25 m g, 25%),
iden tical with m aterial obtain ed in th e foregoin g experim en t, followed by 14,16β-ethano-
3-methoxy-14β-estra-1,3,5(10)-trien-17-one (25) (39 m g, 39%).
Nucleoph ilic Addition s to th e 15β,161-Cyclo-14β,16β-eth an o 17-Keton e 15
A) A solution of th e 17-keton e 15 (50 m g, 0.16 m m ol) an d TsOH·H2O (93 m g, 0.49
m m ol) in ben zen e (5 m l) was refluxed un der n itrogen for 6 h , th en cooled an d n eutralised
by addition of aqueous sodium h ydrogen carbon ate. Th e m ixture was extracted with ch loro-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1794
Bull, Gordon, Grundler:
form , th e extract was wash ed with water, dried (MgSO4), an d evaporated un der reduced
pressure. The residue (84 m g) was chrom atographed on silica gel (5 g), with ethyl acetate–hexane
(1 : 4) as eluen t, to give 3-methoxy-3′α-(tosyloxy)-3′,4′-dihydro-15αH-cyclobuta[14,15]-14β-estra-
1,3,5(10)-trien-17-one (27) (54 m g, 69%), m .p. 104–109 °C (chloroform –hexane), [α]D +122 (c 0.7).
IR: 1 731 (CO), 1 174 (SO). 1H NMR: 0.94 s, 3 H (13β-Me); 1.67 ddd, 1 H, J = 3 × 12.0 an d
6.6 (7α-H); 2.03 d, 1 H, J = 18.1 (16β-H); 2.45 s, 3 H (3′-OSO2C6H4Me); 2.83–2.92 m , 2 H (6α-
an d 6β-H); 3.07 dd, 1 H, J = 18.1 an d 10.9 (16α-H); 3.79 s, 3 H (3-OMe); 4.22 br ddd, 1 H,
J ≈ 7.5, 2.6 an d 1.3 (3′β-H); 6.65 d, 1 H, J = 2.6 (4-H); 6.73 dd, 1 H, J = 8.6 an d 2.6 (2-H);
7.18 d, 1 H, J = 8.6 (1-H); 7.35 an d 7.76 d, each 2 H, J = 8.0, 3′-OSO2C6H4Me). 13C NMR: 218.7
(C-17), 157.6 (C-3), 145.0 (C-1 of 3′-OSO2C6H4Me), 137.9 (C-5), 133.5 (C-4 of 3′-SO2C6H4Me),
131.1 (C-10), 129.9 (m-C’s of 3′-OSO2C6H4Me), 127.8 (o-C’s of 3′-OSO2C6H4Me), 127.3 (C-1),
113.4 (C-4), 112.2 (C-2), 79.1 (C-151), 55.2 (3-OMe), 37.8 (C-6), 13.8 (C-18). MS (EI, m/z):
480.200 [M+].
B) A solution of th e 17-keton e 15 (140 m g, 0.45 m m ol) an d h ydrogen brom ide (48% in
acetic acid; 0.14 m l, 1.24 m m ol) in an h ydrous ben zen e (2.8 m l) was h eated at 70 °C in a
sealed tube for 22 h . Aqueous sodium h ydrogen carbon ate was added to th e cooled reaction
m ixture, an d th e m ixture was extracted with ch loroform . Th e extract was wash ed with brin e,
dried (MgSO4), evaporated un der reduced pressure, an d th e residue (180 m g) was
ch rom atograph ed on silica gel (14 g), with eth yl acetate–toluen e (1 : 49) as eluen t, to give
3′α-bromo-3-methoxy-3′,4′-dihydro-15αH-cyclobuta[14,15]-14β-estra-1,3,5(10)-trien-17-one (28)
(116 m g, 66%), m .p. 148–151 °C (ch loroform –m eth an ol), [α]D +164 (c 0.7). For C21H25BrO2
(388) calculated: 64.8% C, 6.9% H; foun d: 64.8% C, 6.9% H. IR: 1 731 (CO), 697 (CBr). 1H
NMR: 1.00 s, 3 H (13β-Me); 1.32 dq, 1 H, J = 3 × 12.8 an d 3.9 (11β-H); 1.51 td, 1 H, J = 2 ×
12.8 an d 3.7 (12α-H); 1.83 ddd, 1 H, J = 3 × 12.4 an d 5.1 (7α-H); 2.28 ddt, 1 H, J = 12.8 an d
3 × 3.7 (11α-H); 2.40 br t, 1 H, J ≈ 2 × 11.2 an d W 1/2 ≈ 6.8 (9α-H); 3.79 s, 3 H (3-OMe);
3.93 ddd, 1 H, J = 9.0, 4.5 an d 2.4 (3′β-H); 6.67 d, 1 H, J = 2.8 (4-H); 6.74 dd, 1 H, J = 8.5
an d 2.8 (2-H); 7.20 d, 1 H, J = 8.5 (1-H). 13C NMR: 218.8 (C-17), 157.6 (C-3), 137.9 (C-5),
131.2 (C-10), 127.3 (C-1), 113.4 (C-4), 112.1 (C-2), 55.2 (3-OMe), 51.9 an d 50.3 (C-13 an d
C-14), 45.3 (C-3′), 42.3, 41.5 an d 39.1 (C-8, C-9 an d C-15), 42.1 (C-16), 36.3, 35.2, 27.0 an d
25.9 (C-7, C-11, C-12 an d C-4′), 30.9 (C-6), 14.2 (C-18), followed by startin g m aterial 15
(45 m g, 32%).
3-Meth oxy-3′,4′-dih ydro-15αH-cyclobuta[14,15]-14β-estra-1,3,5(10)-trien -17-ols
(30 an d 31)
A) A solution of com poun d 21 (358 m g, 1.1 m m ol) in toluen e (52 m l) at –78 °C un der
n itrogen was treated with diisobutylalum in ium h ydride (20% solution in h exan e; 3.2 m l,
3.2 m m ol). After 3 h at –78 °C, aqueous am m on ium ch loride was added. Th e m ixture was
extracted with eth yl acetate, an d th e extract was wash ed with aqueous am m on ium ch loride
an d water, dried (MgSO4), an d evaporated un der reduced pressure to give a m ixture of
17ξ-h ydroxy-3′-carbaldeh ydes 29 (350 m g), wh ich was refluxed in deoxygen ated toluen e
(30 m l) un der n itrogen in th e presen ce of Rh Cl(PPh 3)3 (1.31 g, 1.4 m m ol). After 7.5 h , eth a-
n ol was added to th e cooled reaction m ixture an d m ost of th e catalyst was rem oved by fil-
tration . Th e filtrate was evaporated, an d th e residue (1.3 g) was ch rom atograph ed on silica
gel (43 g), with eth yl acetate–toluen e (1 : 49) as eluen t, to give th e 17β-alcoh ol 30 (32 m g,
8%), m .p. 68–69 °C (ch loroform –m eth an ol), [α]D +85 (c 1.0). For C21H28O2 (312) calculated:
80.4% C, 9.0% H; foun d: 80.3% C, 9.0% H. IR: 3 612 (OH). 1H NMR: 0.91 s, 3 H (13β-Me);
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

[4 + 2]Cycloadditions
1795
2.82 m , 2 H (6α- an d 6β-H); 3.71 s, 3 H (3-OMe); 3.81 d, 1 H, J = 5.8 (17α-H); 6.57 d, 1 H,
J = 2.7 (4-H); 6.65 dd, 1 H, J = 8.5 an d 2.7 (2-H); 7.15 d, 1 H, J = 8.5 (1-H). MS (EI, m/z): 312
[M+], followed by th e 17α-alcoh o1 31 (203 m g, 51%), m .p. 49–51 °C (dich loro-
m eth an e–m eth an ol), [α]D +80 (c 0.96). For C21H28O2 (312) calculated: 80.4% C, 9.0% H;
foun d: 80.6% C, 8.9% H. IR: 3 608 (OH). 1H NMR: 0.90 s, 3 H (13β-Me); 2.89 m , 2 H (6α-
an d 6β-H); 3.77 s, 3 H (3-OMe); 4.38 t, 1 H, J = 2 × 8.8 (17β-H); 6.63 d, 1 H, J = 2.5 (4-H);
6.72 dd, 1 H, J = 8.5 an d 2.5 (2-H); 7.24 d, 1 H, J = 8.5 (1-H). MS (EI, m/z): 312 [M+].
B) Th e 3′-tosyloxy 17-keton e 27 (50 m g, 0.1 m m ol) an d lith ium alum in ium h ydride
(50 m g, 1.3 m m ol) in ben zen e (6 m l) was refluxed un der n itrogen for 4 h . Aqueous am m o-
n ium ch loride was added, th e organ ic ph ase was diluted with eth yl acetate an d wash ed with
water, dried (MgSO4), an d evaporated un der reduced pressure. Th e residue was ch rom ato-
graph ed on silica gel (5 g) to give th e 17β-alcoh ol 30 (4 m g, 12%) followed by th e
17α-alcoh o1 31 (18 m g, 55%).
We thank the Foundation for Research Development, AECI Research and Development Department
and Schering AG for financial support.
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Soc., Perkin Trans. 1 1992, 2545.
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