Asymmetric induction in steroid synthesis: Synthesis of D-homoestrone methyl ether using a novel annulation reaction

361

2348

ASXUWI'BIC WDU:TION IN STEROID SYNTHESIS:SXNJ'IFIESIS OF

Bio-OrganieDirieion Cents-e mm

Atoricr Rwmroh TrOrn~~, &rbq 400086, Bhrbh Iieceived

'7-24-76 AJHTR&CT

Aeymmetrielyntherie of D-homoeatrone methyl ether rae achieved by a new anaulation reaction. The reoent total

ryntheaie

deweloping hormone

(1) in exoiting

newer mthodn

eetrone

ior

and hold8

great

their syntheaie.

potential

for

‘&henatural

sex

ia of partioular iatereat and hea been the

enbjeot of eeveral aaymetria during reoeat

iaduotionin atereid

oonoept of ssymetrio

(2) and raoemio ryntheeer (3)

year@.

The biayolia aompeunda (1,B'= H or alkyle) fsoa important C/D intermediateain the ltereoeeleativetotal lteroide,particularlyof ertrone. the oorrwponding

triketome

ef

Tbeae

the general

lyntheeia of

aan be prepared from struatura

(II) by

raid or base aatalyredaycliration. Becently, it haa been observed (4) that aompoumde (II) rhioh could

be atilixod

primary or reaondary

33, Nwnber 4

a proahiral

oentre

ip an laonoaia prooeee ior the preparationoi

ahiral biayalia enedionea

Vohne

aontain

(I), Henae the ode of opticrally active

amines

S

in prcaenoe

W131EOXDIll

of acids

was evident

.qlY~iZ,

to

1979

S aqmmtrie

effeot

enedionee

degree

The natural

In the

syntheeis

(Robineon-Mannich (III),

has

ospable

neoeeeitatee

eearoh

general methyl

and ita

to a remarkable

by Michael

1,3-dionee

of vinyl there

method6

for

paper

in the arymmetria

to vinyl

of triketonea

ketones

in situ --

The preeent

addition

(IV)

and the purity

alternative

uae

even more effective

(III,

R’= alkyls)

ie

oumbereome.

the

eyntheeie

deearfbee

aynthesie

(II)

This of

one such of D-homoeetrone

ether. We have

ootal-l-one

f-batoxide

(5)

a novel

eyntheeia

(V, II I 2; B I CE3) ueiag in A-bntanol

on the

flow-rheet).

eimilar

produatr

enbatitnted

beea

reported

of S-methyl-A NW_

(VI, n - 2) from 2-(4-carbomethoxybutyroyl)-2-methgl-

cyolohexauone

nor

of generating

B*= alkyle).

method

(II)

of oyclia

the yield8

for

proved

to bicyclic

of steroide.

syntheafe

the preparation

or products

(II)

exploited

of compounds

although

(II,

acida

bar been

annnlation)

been optirired,

triketones

emino

Thie

oyolisatione.

in the asymmetric

ketone6

of triketonee

ayalisation

(I).

in these

TRROlcDb

(The meohaniem The reaotion

were

obtained

extended

to the

4,5,6,7-tetrahydroinden-Gene

eyntheeia

of this

appoared

of

reaotion

is

to be a general

other

oarboayolia

ohloridee

(6).

with

4oarbomethoxybutyroyl

one equivalent

potaeeium outlined one aa

ketone8 Thfe

reaction

of 1-~-(3~etho~~~hen=l~pre~I~-

(XIII).

end hae

2-(4~arbom8tho~butyroyl)~yalop8n~none (6a)

was prepared

pentene

by the condensation of l-Bl-merpholino-1-oyelo-

n = 1) with

(VII,

according

to the

alkylated

with

(V, II I 1; 2 I H)

4-carbonethoxybufyroyl

prooedure

of Stork

chloride

oo-worker8

and

(VIII)

(7).

It was

1-ahloro-3-(taethoxypbenyl)-2-propene

(X,X I Cl)

to

2-(4-oarbonethoxybutyroyl)-2-~-(3laetboxyphenyl)prep-2-enyl~ oyc lopentanono 264

(G9,650)

conjugated

aromatio

dieappeared

rryetsa

showed in the

hydrogenated

(XIII).

the

prsrence

hydrogenated

compound

(XII)

product

W apeotrum

preoenoe

oentered

(XII).

potassium

of a

at & 6.12

proton0

in the

which

Cyoliaation

A-batoxide

at

of the

in A-butsnol

i-~-(8-inethoxyphelyrl)propyl~4,6,6,7-t8trahydroind~4-one

It

had W maximum at 252 nm ( e 13,500)

by a bathoahromio

&fit

1670 om-’

of -18

(C - 0),

characteri8tio

CryOliC ketone, nm for

ite

of

which

was aonfirmed

lemiaarbasone.

The p8ake

1640 om-1 (C II C) in the

IB epeutrum

eonfinred

atmature.

Hawing obtained introduce

an augnlar

hydroindan_C-one steroidal iodide dry

the

of two vinylio

with

o$pun%aturated

it8

indicated

and a multipled

a tstraanbetituted

at

maxima in the

and 291 nm (62,900)

NWi rpeotrum

yielded

The absorption

(XI).

methyl

moiety, Thie

mo18od8~

Sn presence

the

indanone group

1,2_dimrthoxyethane,

next

whiab might was achieved

of potassium

(XIII),

it

to the

later

aarbonyl

in

(free

yield

using

fror

when 1-&(&methoryphenyl)propyq-3a-

to

the fetra-

be the C13-methyl

in high

A-batoxide

was necessary

of

the

methyl

A-butanol)

in

S

TElROXDb

methyl-3,3a,4,5,6,7-hexahydro-2H-inden4-one The ehift of

of

a C = C peak

appearance

of

three

protons,

figure

(XN).

required

C I 0 peak

the

at

the

function

achieved

by oxonolyeis

due

was

amounts

the

furnished

with

to

spectral

As in

it

polypbosphoric

trione

the

methyl

the

ether

eetra-1,3,5(10),8,14-pentaen-17a-one etruoture the in

of

angular its

trione

methylation

transformation With

a stage

the

was

the set

of

the

indan-4-one

the

trione

metboxyphenyl)ethy~-Q-methyl-b

and

in

1 ,?\-dicarbonyl This

was trione

the

structure

(XV) oonld

not

be ahara-

to

its

structure

confirm

compounds.

With

of

the

beating, and

(8).

figure

(XIII)

varying trione

(XV)

D-homo-3-methoxy-

This

(XV).

(XV)

confinsed It

is

evident

the that

served

a dual

purpose

of

trione

(XV),

(XV).

cycliaation 500)

a masked

whom the

characterisation

asymmetric

forms

will

with

(8)

(XVII) depicted

into

its

(XVI)

ar

preparation for

time

(XIV).

(XIV)

the

agreement

known

atoms

compound

present

for in

carbon

inden4-one

preparations

the

the

depicted

transformations.

in

and

the

absence

the

with

ae

furnish

purification,

acid

D-bomoequilenin

the

would

was

into

and

integrating

twenty

in

bond

scale

data

(XV).

convert

of

further

cm

obtained.

-1

together

the

present

demasked

small

1720

structure

all

structure

for

to

was

NM2 spectrum,

the

double

for

trione

the

are

the

to diffionlty

decided of

at

in

alkylation

required

The

cterired it

(8)

obtained. to

this

and when

(XV)

assigned

d 1.26.

em

IB epectrum

the

tefrasubstituted

oompound

was

in

objective

look

the

1570

conformity

final

A closer

dicarbonyl

in

iron

-1

at

Through

that

cm

a singlet was

for

reveal

1640

(XIV) -1

to

-ootali.n-l,B-dione

the

S-&Z-(3(XVIII,

x-

0).

Of

the

rarionr

combiAatio8

amino said8 in varying

of

proportion8of perahloricacid under different roaetion aondition8, the

employed

one

by Dani8hef8ky

and oo-worksr8

(2c)wa8fmnd to be

mO8t 8aitable. Thu8 with L-pheAylalauinoin aoetenitrile perohlorio

aoid,

(XVIII,x

. 0).

the

triono (XV) yielded tho ootalin-l,&dione

The 8poatral data

agreed

very

well

with

tho

The W maximunAt 251.6 AA (GlO, 300) wa8 indicative

8trAotAro.

the tetrarub8titatod~,fi-un8aturatod

of

and

ayolio ketone which wa8

-1 in t&e IB rpeotrlrr.The po8k aonfirmod by the peak at 1670 om at

-1 1726 om ooold be attributed to a [I-membered cyolio ketone at

Cl

aAd the ringlet in the M

three

(XVIII,

homoertrono methyl Tho well type

be attributed to th8 angular methyl group.

protoA8, oould

The ootalindione

rpeatrum at 61.30, integratilrg for

ether

X - 0) ~a8 than

tran8formed into

(XXI).

knewn preaeduro

(20,8)

for

the comerrion

of oatalindioner with a balky rPb8tituent at C5 to

pending

D-

of thi8

the oorre8-

*ran8 fu8ed dooaliae-1,6_dioner COlPmOACedin our work with

the 8oleative 8edi~m borohydrideroduotion of the onedione (~111,

X = 0) rhiah led to the enone aloohol (XVIII,X I<)

havi.Ag

probably th8p-rtorooahemi8tryfor the hydroxy group. Catalytia hydrogenationof nently

to

the

the

tram

eAOA8

frued

anslogy (2a,8). Furthor

ahah

(XVIII,X -4:)

led predomi-

hydroxydeoalone(XIX, X I -
oonverrion

X - 0) to D-hOmOe8trOA8methyl other

of the (XXI)

by

oatalindione(XVIII,

(8ee blow)

through

S

TPEOLDlb

the sequence of reaotious given supported the stereochomiatry Chromic acid oxidation

ar8igned to the intermediate products.

furnished the tram

of the hydroxydecalone (XIX, X =-
fu8ed

deoalindione (XIX, X - 0), xhioh ~88 evident from the ID and N&B speotra.

The rtereoohemistry of the alkyl chain at Cg as

depioted was confirmed when the compound (XIX, X - 0) ra8 reoovered unchanged on equilibration with mothanolic 8odium methoxide (vide experimental).

Henae, the oxidised product could be repre-

sented as 5-~-(3-methoxyphenyl)efhy~-9-m8thyl-trana-decalinl,tI-dione (XIX, X - 0).

The compound (XIX, X = 0) was then

eyclieed to Q~ll)~ehydro-D-hoaoe8trone methyl ether (XX) by alcoholic hydrochloric acid.

The eignifioant feature of the

speotral data of this compound was the UV maximum at 261.5 nm (c-17, 660) which is very characteristia of the 9(U)

doable bond

oonjngated with the phenyl ring in these fgpesof compoundr.

A

hump centred at 6 6.16 in the NMQ spectrum rignified the presenoe of a vinylic proton.

On catalytic hydrogenation it gave D-homo-

eetrone methyl ether (XXI) m.p. MOO, which dieplayed identioal W,

de

+ 25O prepared from

The 1?-keto analogue (XXII) of the

oompound (XXI) was also isolated in the same roaotion. m.p. 192O, m/e 298 (M+), ,@J"

+ 130,

ID and NMB 8peotra as an authentio

sample mop. 140°, m/e 298 (II+),&$" natural estrone (9).

298 (M*), />J2"

+ 15O.

title It

had

Though the optioal purity

of the synthetic praduot ia 80$, the synthetic approach io new and general with relatively simple reactions u8ing readily available starting

materials.

367

S

TZUROXDIS

Mechanism 01 the formation of B-methyl&(iO’-octi\ll-one (VI) Prom 2-(4-carbometlioxybutyroyl)-Z-methylcyclohexenone &,I.

Y=O 0CH3

(VI

CH3 I ca 4

( VI 1 /

sodium iodide, iodide.

(1) Potaeelum ;i-butoxide, i-butanof hydroohloric aaid (3) Dimathyl carbonate, methoride (free from methanol) (43 Methyl potaeeiau A-butoxide, A-butanol (5) Methyl

C=O 0

bCH3

S

TRROLDS

369

( XVII 1

(XVI 1

oJc$)-oJi$j!p R (XVIII

1

5H2

)2

R (XIX

1

H3C0 (XX) \1

1 XXIII)

(XXII)

(XXI

1

370

S

TIIR.OXDCI

Ultraviolet spectra Recorded temperaanres are uuoorrected. were obtained for a eolution in methanol on a Carl Zeier 8pectrophotometer RIQ 20. Infrared epeotra were taken 81 filme for liquids and potassium bromide pellets for solida with Perkin Elmer Infratord spactrophotometer 137B. %I NM? epeatra were obtained in oarbon tetraohloride am eolvent (esaept stated otherwise) and TIE6 optiea1 ae internal atandard on a Varian A40A epeatrometer. rotations were recorded on the Perkin Elmer model 141 apeatropolarimeter for a solution in cblorofotm, concentrationr 1 mg/l al. Optioal purity and yields are reproduaeable. Silioa gel 4 0.08 lllp (~140 g per 0.S g of the compound; i.d. of columu -8 urns) was ared for ookmn chromatography. Methvl ~3-(3-~thorvuheqpl]-2-~ro~enaate

(IX.

R = c83).

Ethyl 3-(30methoryphenyl)-2-propenoate (IX, B - C2iiS) war prepared follawing the known procedure (to) for the preparation of ethyl 3-phenyl-2-propenoste. It wae then hydrolyeed with aqueour alcoholic sodium hydroxide solution to 3-(3-methoxyphe~l)-20 propenoic aaid (XX, R - 8), m.p, 116’. The acid (IX, B * II) (89 g, 0.5 mol) wae diaeolved in dry acetone (1.8 1) and potaeeium carbonate (freshly fueed, 348.5 g, 2.6 mol) war added to the oolution. The mixture was stirred at room temperature when methyl iodide (312 ml, S mol) wae added to it. After refluxing gently for 8 hro the eolvenf wa8 reaored aompletely and water was added to the residue. It was extraoted with ether-benzene, the organic layer washed free of base and dried over sodium sulphate. Bemoval of the solvent and dietillafion of the residue obtained, gave methyl 3-(3-methoxyphenyl)2- ropenoate (IX, B = CE13), b.p. 13ab/2 mDHg (92 g es%); n.jj8 1.5738; )cmax 231 (f 12, MO), 276,s ( dlS, SOO), 318 nm ( f. 3, 4SO); \f tp~x 2860, 1740, 1360 om-1; 43.88 (6, 3E, -COOCl&), d3.63 (e, 3H, Arm&), & 6.21 (d, 2H, J = USBe, vinylio protone). us Calcd. for Found: c, 68.73; 3-(3-MethoxrBhenyl

CllH120 ; H, 5.80 B .

C, 68.73;

I-2-propen-l-01

H, 6.29.

(X, X a OH2.

Powdered lithium aluminium hydride (1.44 g, 0.038 mol) in anhydroua ether (200 ml) wae stirred at Ob. To thie a solution of methyl 3-(3-methoxyphenyl)-2-pro noate (IX, B - CH3) (9.0 g, 0.0s mol) in anhydroua ether (26 ml !ie was added during 16 minutes. ft war gently refluxed for 1 hr and ethyl acetate (IO ml) war then added to destroy exeeas of the hydride. Aqueour tartario aoid solution was then added to the reaotion mixture aad was

S

371

TmIIEOXDI

The product obtained was purified with ether-benzene. chromatography over silica gal using 2OP ethyl amtat in benaene ae eluent when the alaohal (X, X = OX), b.p* 130”22’/ 0.2 IW@; (7.8 g, 95%); ~59 1.5706 was obtained; h max 262.6 (~.;12,300), 292.0 nm (~3,40O);-\mrax 3420, 3055, 2970, 288% 1681, 1630, 1600 CB’1; 33.0 (OII disappears on D20 exchange), c;i, J I 4.5Xx, -Oa&-),46.2-7.3 63.75 (8, 3ll, -OC@,~4.28 (5, !!%I, vinylic and aromatia protons). extracted by 001~

m. Calad. for Found: C, 73.43;

Cl0Q20 ; C, 73.14; II, 7.53 B.

l-C&loro-3-(3_methoxynhenvl)-2-prooene

8,

7.31* (X. X - Cl).

A stirred mixture of allylic alcohol (X, X - Oli) (8.2 g, 0.06 mol) and s-COllidin8 (6.66 g, 0.055 mol) under nitrogen wan treated with 1Tthitua chloride (2.12 g, 6.05 sol) dissolved in dry IMP (30 ml). On cooling to O”, a suspension was formed which was treated dropwise with mefhylsulfonyl dhloride (6.3 g, After stirring for 1.5 hrs at O”, the reaation 0.056 mol). mixture was poured on ice and salt, extracted thoroughly with ether-benzene and washed suoaeeeively with cuprio nitrate eolution until no further intensification of the colour of the blue copper solution ocaurred, indicating the complete removaf of g-collidias (iiaj. The organic layer was dried, aolvent removed and the product obtained was distilled, b.p. IOS-loo,/ 0.2

m&ig

(7.35

g,

80$)

@lb).

-(3-methoxvphenvl)pron2-(4-Carbomethoxybutyroyl)cyclopentanone (V, n = 1; H-B), b.p. 102-1030/0.6 mmlig (6a) waa prepared from I-N-morphoIino-lcyclopentene (VII, n-l), b.p. 84-86’ 4 mu@ and 4-carbomethorybutyroyl chloride (VIII), b.p. 66058. / 0.6 mmllg according to the procedure of Stork and coworkers (7). A solution of the diketo eater (V, n - 1; R II H) (10.6 g, 6.6 mol) in f-butanol (50 ml) was added to a cold oolution of potassium t-butoxide (from 1.96 g of potassium, 0.05 g atom) in f-butaaol 7100 ml) under dry nitrogea with stirring. After 30 miuut8s, it was cooled to Oe and a solution of I-caoro-3-(3=mefhoWphenyl)-2-propene (X, X = Cl) (10 g, 0.65 1~01) in (25 ml) was added. Ths solution was stirred st room temperature overnight a Next day, it was warmed at 50-5S” for 1 hr, Cool8d to O’, acidified and solvent removed completely. Th8 residue obtained was extraoted with ether-benzene,, washed with N aodium hydroxide solution (4 x 50 ml) followed by water

f-butanol

372

S

TEIEOIDSB

After removing the solvent, the product obtained and was dried. was distilled, b.p. 280-86O/O.2 m&g (14.7 g, 82%). The analytical sample waa prepared by column chromatography over silica gel (5% ethyl acetate in benzene) followed by distillation, b.p. 291 MI 280-820/0.2 u&g; ns0 1.5389;hmax 254 (C 9 550), (E2, 900 ;Vmax 1760, 1730, 1820, 1595 cm- I; cj 3.60 (s, 3H, (5, 3H, -ArOC&),d6.12 (III, 2H, vinylic protons). -COOC_l&),d 3.73 u. Calcd. for Pound : C, 70.53;

C2182605; H, 7.50%.

C,

70.37;

II, 7.31.

.‘-(4-Carbolaethoxybutvroyl)-2-/~-(3-methoxyphen?yl)pro~y,yl~cyclopentanone (XII). The diketo ester g, 0.025 mol) wda hydrogenated XI) (8.95 (Parr) over 10% Pd/CaCO3 t 1.25 g) in ethanol (50 ml) at room temperature for 6 hours. ‘The catalyst was filtered off and the solvent removed completely under reduced pressure. The product obtained was distilled. The compound (XII) had b.p. 185-87”/ A sample was chromatographed on silica gel 0.3 mmHg (8.0 g, 95%). in benzene) and distilled for analysis, b.p. (109 eth lacetate 272 (G 2,300 , 278 (C 2,100), 180-81° /’ 0.2 mmHg; ni5 1.518O;~max 1620, 1600 cm- l ; 63.60 (s, 3H, 300 nm (G 390);vmax 1755, 1720 -coocH&, 3.73 (9, 3H, -ArOC&). a. Calcd, for Pound: C, 60,90;

C2lH2805; H, 7.68s.

C,

69.97;

H,

7.83,

~~-(3-hIethoxyplleuyl)propyl7-~1;,5,6,7-tetrahydroindan-i~-one

(XIII).

A solution of potassium A-butoxide (from potassium 1 g, 0.025 g atom) in t-butanol (125 ml) was stirred and cooled to O”. To this a solution of diketo eater (XII) (9 g, 0.025 mol) in t-butanol (25 ml) waa added under nitrogen. Stirring was continued for 1 hr under nitrogen and the coutents were then brought to room s toppered and shaken mechanically for 24 hrs. temperature, After cooling to O*, the product waa acidified with cold dilute hydrochloric acid with stirring and the solvent removed completely under reduced pressure. The residue was thoroughly extracted with etherbenzene and washed free of acid. The product obtained after removal of the solvent was hydrolysed with barium hydroxide octahydrate (18 g) in water (30 ml) and ethanol (75 al) for 8 hrs under nitrogen. The solvent was distilled off, the product acidified and extracted with ether-benzene. The organic layer was washed with 10s sodium hydroxide solution (4 x 25 ml) followed by water and dried. The indan-4-one (XIII) thus obtained was purified by column chromatography (silica gel, followed 55 ethyl acetate in benzene by distillation, b.p. 179-810/0.3 mmHg (4.45 g, 62s); n li 1.5571; a

S

373

TXIROXDS~

>mIu 262 (6 13,soo), 279 nm (6 2,900);Gax d3071 (6, 3H, Ar-OCHH). &Q. Cal8d. for Found: C, 80.10;

Cl9E240 ; C, 80.24; H, 8.475.

C2@2702N ; C, 70.36; H, 7.61; 4, 12.34%.

-1 1640 cm ;

H, 3.51.

Semioarbansone, mop* 194O (deo) (methanol). >m8x 261.6 sh (E24,900), 269.6 (E30,3SO), 319 nm (c 660). &&,. Calod. for Found: C, 70.16;

1670,

279 sh

H, 7.97;

(G.24,900),

N, 12.31.

l- /5-(3-MethoxyPhenyl)Propyl7-38-metJlyl-3.38.4.s.6,7hexahvdro-2H-iadenn-4.one (xX71. Potassium (1 g, 0.026 g atom) wae dissolved in t-butanol (SO ml) and mart of the solvent TM then distilled off.The reeidue was heated at 900/1 m!Ig for 1 hr to remove lad tracer 1,2-Dimethoxyethane (25 ml, freshly distilled Of A-bntanol. wer NaH) was added to the solid, stirred and oooled to O”. A solution of the indan-4-one (XIII), (7.1 g, 0.026 mol) in 1,2dimethoxyethaae (20 ml) was added to the suspension under nitrogen. The mixture war stirred at O” for 1 hr, when all the alkotide dissolved. The light red rolution was brought to room temperatnr e, stoppered and shaken mechanically for 92 hrs. It wa8 oooled to O*, methyl iodide (10 ml) added with stirring when a white precipitate 8ep8rated immediately. It was left overnight at room temperature and then gently ref luxed for 4 hrr. The rolvent was removed completely, water added and the product wa8 extracted with ether-benzene. It ~88 warhed with 8odium hydroxide and water, dried and rolrent removed aompletely. The product thus obtained war ahromatographed over silica gel acetate in benaene 88 elnent when the indcn_Q-one 185-570/0.3 mmEg (6.6 g, 93% bared en recovered 1.6492 and the rtarting indan4one (XIII Am8x 272.6 (t 2,000), 278.5 (E 1,850 1600 amol;d 1.21 (a, 3E, C38- CEE), &&. Calcd. fer c2&@ ; C, 80.49; Found: C, 80.54; H, 8.72 3 . Semicarbarone, m.p. 137* (methanol). A=&. Calad. for Found: C, 70.90;

C2lII2 0 N ; C, 7O.a; H, 8.867 i, 11.36$.

H, 8.78.

H, 8.22;

N, 11.82.

374

S

TDEOXDI

~~-(3-Methoxynhenyl)-3-oxo-hexy17-2-methylcyclohexane-1.3-dione (XVZ. The indenone (XIV) (0.9 g, 3 mmol) was dissolved in anhydrous ethyl aoetate (25 ml) and ozonised at -78'. After 4 hrs, the solution was brought to room temperature, 10% palladium-on-calcium carbonate catalyst (0.4 g) added and hydrogenated till no more hydrogen was absorbed. The product obtained was purified by column chromatography over silica gel ueing 10% ethyl auetate in benzene as the eluent. The trione (XV), b.p. 240-256*/0.05 mmHg bath) (0.62 g 63s) had gmax 1730, 1720, 1690 cm"; 6 1.26 8, 3H, C2-Cli3j1&3.60 (a, 3H, Ar-oc~3). D-Homoeauilenin methyl ether (XVI). The solution of trione (XV) (330 mg) in benzene (25 ml) was treated with orthophosphoric acid (5 ml, d.l.19) and phosphorus pentoxide (3.5 g) with stirring at O*. The reaction mixture was then refluxed for 4 hrs, cooled and poured on ioe and water. It was extraated with ether-benzene, washed free of acid dried and solvent removed. D%omoeqailenin methyl ether (XVI), m.p. 215-16* (ethanol)(lit. (8) m.p. 209-12O) (110 mg, 37%) was separated by column chromatography on silica gel uaiag 10% ethyl acetate in benzene as eluent. The spectral data was found to be identical with that reported by Smith and co-workers 277 t&5,400), 321 (r3,800), 324 MI 1610 cm-1;61.05 (e, 38, Cl3-cSd),

D-Homo-3-metho~-estra-1.3.5(10).8.14-~entaen-17a-one

(XVII).

The solution of the trione (XV) (330 sag) in benzene (25 ml) was cooled and stirred in ice bath. To this orthophosphoric acid (I.5 ml) and phosphorus pentoxide (2.3 g) were added in one lot. After stirring for 1 hr, it was refluxed for 3 hrs, cooled and poured on ice and water. It was extracted with ether-benzene, washed free of acid and dried over sodium sulphate. The product obtained was recryetallieed from ethanol, (lit. (8) mop6 13941*) (160 1pg, Sl$);&max 230.0 294.0 (Gl9,350), 307.0 (C24,200), 320.0 nm 1720, 1620 cm'1;dl.21 (s, 3H, C13-CHH),A3.79 8, 3H, Ar-0(&),56.04 (m, lH,vinyl proton). This compound was found to be identical in all respects with the one reported (8).

S

T3aEOXDI

375

d nirture containfag the triono (XV) (1.1 g, 3.3 nrmol), ) 3.96 avlol),perohlorioacid (1.7 ml, IN), L-pbenylal%aiAe was reflexed far 42 bra AAder AftrOge5, in metonitrila The solveAt w88 rent5wd at room tamparatura dar radaaad pressure and oodiAm biosrbonatasolnfion added to the residae. It wee thorarghlyextraatedwith ether-benaeue. The orgaAic layer was washed with wutex and dried. The required enedione (XVIII,X I 0) was separated from the reaction mixture by colnm, ohroavrtography on silica gel Asing 10s ethyl %oet%te in beneene 86 elnent. The fractions showing tingle spot on tla were mixed end the oompouAd ebtaiaedwas dietilledwhen the eA8dfeAe @VIII, X = 5), b.p, 240-BO"/O.lmedIg(bath) (0.61 g, 60s) 18s obteined 8% high1 viseour liquid3 &m%x 251.6 (hl~i300), 280.0 PIP (E 3,75O';V-nmx 1725, 1670, 1610 1890 om ;&1,30 s (5, 3H, Cg-C&),63.75 (e, 3H, Ar-OC&); &27 * W&O. &&. Calad+ for C2oH24O ; C, 76.89; 8, 7.74: Pod: C, 77.02; H, 7,38B .

To a aofntion of ootalindiong(XVIII,X - 0) (626 mgI 2 nrslol) %A absolute ethsnol (20 ml) asiataiaed %t #* w%s %dded aodium berohydride (33 W, 1 mmol) in oAe lot. 'Ph8~.eOlTitieA VgS stirred at 0' for 0.6 hr %Ad then at room tempera‘0tlro for lo6 hre. The solvent was removed oomplatelysnder reduosd preaeare at room temperature. The product obtainedrat oooled to O* and treatedwith phosphate buffer (pH 6.6). It ves that eXtr%Uttd

&&e Caled. for C20lI2393; C, 76*4@; H, 8.Qi4, Fowdr C, 76.00; 8, 8.22$.

5-~-(3-Yerthoxypheq~il)athy1~-9-311ethyl-transdeaalin-l.5dione (XIX. X-Ot. The actalin-l-o1 (XVIII, X =-(g*) (630 w) in ethanol (8 ml) containing 5% palladium-on-crarboacatalyst (300 mg) wa# hydrogenated and the prodnat obtained was purified by column chromatography on eilica gel using 5% ethyl a8 eluent. The deoalin-I-ol-5-one (XIX, X --<

e;:Calod. for C20H2503; C, 70.40; H, 8.34. C, 76.70; H, 8.74%. When equilibrated with equinolar amount of methanolic sodinm met&oxide, the decalindione (XIX X 8 0) wan reoovered unchanged, m+p. Bl-92O, mm.p. 01-92O; /$J2 -50. D-Bomo-3~methoxy-estra-1.3.5(10~.9(11~-tetraen-17a-one (XXi. The decalindione (XIX, X - 0) (0.2 g) was disaolwed in methanol (I.5ml) and stirred at room temperature. Cone. hydrochloric acid (0.5 ml) was then added to thir solution (about 5 ml more of methanol was added to dissolve the turbidity if formed). Stirring waa aontinued and after 2 hrs a white solid started separating out. The mixture was stirred for an additional hour and cooled with ofirriug in ice water for 46 lUiId88. The eolid obtained wa filtered and waehed twice with an ice cold methanol followed by water. Two crystallieations from methanol furnished the anal tical sample of B(ll)dehydro-D-homoestrone methyl ether (XX3 , m*p. MO0 (40 pig, 21%); Alllax261.5 (&17,660), 292.0 nm (~3,00O);&.oax 1720, 1625 em-l; d(CDCl3) 1.29 (s, 3*, ),&a.77 (e, 3H, Ar-Of%&),& 6.18 5 + 340, 61, lH, vinylic proton); Anal. Calcd. for C20%240 ; C, 81.04; K, 8.15. Fonnd: C, 80.87; H, 8.30%,

S D-Hemoeetrone

methyl

ether

377

TDEOID= (=I).

The eolation of the Q(ll)-dehydro-D-homoeetrone methyl ether (XX) (9.290 g, 1 mmol) in tetrahydrofuran (8 ml) was etirred with lO$ palladium-on-carbon oatalyst (30 ~8) in an atmosphere of hydrogen until 1 mol of hydrogen was absorbed. The catalyst was filtered and the product obtained after removal of the eolvent rae repeatedly chromatographed on Beoryetalliaation from benzene alumina (bensene-hexane, 1: 1). hexane furniehed D-homoeetrone methyl ether (XXI), m.p. 150’ 5 + 15O (lit. (2b) ioxan); )- max 278.5 1526 or-l;61.08

The UV, ID and NMR of thin compound was found rnperimpoeable with that prepared from natural estrone (following experiment). D-Homo-3-methoxy-eetra-1.3.5 D-homo-3-methoxy-eetra-1.3.5

10 -trien-17a-one 10 -trien-IT-one

to

XXI

XXII

-

be

and

.

Starting from 3-metboxy-l’ld-aminomethyl estra-1,3,5(10)trien-17-01 (XXIII), m.p. 160-620 and following the known prooedure (Q), compounds (XXI) and (XXII) were obtained from the reaction product by columu chromatography on silioa gel with 5% ethyl acetate in benzene aa eluent. The compound (XXI) m.p. 140° (recryetallised from benzene pet. ether) had c&$5 + 25O; m/e 298 (U+). 192O (recryetallieed from + 15O; m/e 298 (&); h max 278 1720, 1630, 1590 cm-l; 3H, Cl3-methyl), da.76 (a, 3H, Ar-OCd). m. Calcd. for Found : C, 80.48;

C2@260 ; 8, 8.&$.

C,

80.54;

H, 8.73.

ACKNOWLEDCEUENTS

optical

The author rotations

thanhe Mr. S.B. Udapa and Mr. S. Mithran for

for reoording hie help.

the

378

S

TEIEOXDII

NOTES ANDRRFEBENCR8

1.

2.

3.

4.

5.

6. 7. 8.

9. 10. 11.

12.

Cohen. N.. ACCOUNTS CEEM. BES.. 9, 412 (1976). T., Matsumoto, H;,?Iemoto~ Ii. &d FuLuoto, 64 &et&i, TETRAEEDBON LEWEfiS, 2426 (1978); K Meier W. and Fib&, A., HELV. CIiIY. J (b) G&riller 60 '2256 (19771 and references oited therein; ACTA., _, (4 Daniehefrky, 9. and Cain, P., J. AMER. CBEy. SOC., 98, 4976 (1976) and reference8 oited therein. (a) Oppolzer, K., Biittig,K. and Petrzilka, M., HELV. CHIY. ACTA., 6l, 1945 (1978); (b) Kametani, T., Nemoto, H., Irhikawa, II., Shiroyama, K., Matrumoto, H. and Fukumoto, K., J. AMER. CHRM. SOC., 2, 3401 (1977) and references cited therein. (a) Buchrchacher,P., Cassal, J-M., Ftlrot, Aa.and Meier, W., HELV. CEIL ACTA., 60, 2747 (1977); 39, 1615 (b) Hajos Z.G. and Parrish, D.R., J. ORG. m., (1974). Bhandari, R.G. and Bhide, G.V., CHEM. and IND. (London), 868 (1970). A complete discussion of the mechanism of this reaction will be published elsewhere. Bhaldari, R.G., M.Sc. Thesis, Bombay University, 1968; Datrani, G., Y.Sc. Thesis, Bombay University, 1974. Stork, G., Brizzolara, A., Landesmzn, It., Szmuszkoricz, J. and Terrell, R., J. AMER. CHEY. SOC., 85, 207 (1963). Douglas, G.H-, Graves, J.Y.H., Hartley, D., liughes, Gd., M&au hlin B-J., Siddall, J. and Smith, H., J. CHRM. SOC., 5072 4 1963). Th eee rorkere have not recorded the b.p. of the trione (XV). Birch A.J. and Karriseon, B-J., AUST. J. CHEM., 2, 519 (1955). Organic Synthesis Collective Volume, &, 252 (1956). _(a) Collington E.W. and Meyers, A.I., J. ORG. CREM. 38, 3044 (1971); Snyder, E.1 ., u., 3& 1466 (1972). (b) White, W.N. and Fife, W.K., J. AMER. CHEU. SOC., g, 3846 (1961) have reported that the ohloride (X, X = Cl) decomposes when distilled at 1 mmHg or when allowed to stand for more than an hour. Brown, H.C., Garg, C.P. and Liu, K.T,, J. ORG. CHEM., 36, 387 (1971).