RIay 1967
Cyclopropylogs of Thyronine Derivatives'" ROBERT A. P A G E SAXD ' ~ ALFREDBVRGEI~ D e p u h m t os Clientistry, rniverazty of Viryznia, Chui/otteaz,i//e,
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Received January id, 1967
The syiithesis of 1-amiiio-trans-2-[4-(4-hydrosyphenoxy)-3,.i-diiodopheit?;l] c.yc,lopropaiiecart)~~~yJic acid has been performed, the key step being the addition of CH, (from diazomet,hane) to the exocyclic double build of the axlactoire, 4-[4-(4-acetos2rpherioxy)-3,.i-diiodobeiiz!lide11e] -'L-phenyl-'L-oxazoliit-.i-oiie. The stereochemistry of the amino acid has been established. The 3',3'-dihromo derivative exhibited weak thyromimetic activities it1 basal metabolism and antigoiter tests aud did riot inhibit iucreased metabolism developed by triiodothyronine.
As part of our program to study biologically iiiteresting aniiiies and amino acids with sterically hindering groups adj acent, to t'he amino and/or rarbuxyl f u ~ i c t i o i i s ,we ~ ~ ~are paying particular attention to analogs in which the a-carbon atom is part of a small ~i11g.~--?Such compounds have been shown to inhibit the enzymatic. degradation of some of their natural metabolite prototypes; for the activity of small a-alkyl-substituted analogs of further amino acids, see ref S-10. We iiow describe the synthesis, stereorhemistry, and biological properties of cyclopropylogs of thyronines related t,o the natural thyroid hormones. After exploring several approaches t o t'he synthesis of 1-amino-%-arylcyclopropanecarboxylic we found what appeared to be a very promising pathway j i i the reaction of azlacto~ies'~ with diazomethane; thc resulting l-aryl-5-phenyl-(i-oxa-4-azaspiro [2.4 Ihept4-en-7-ones (e.g., XII)14 appeared to be likely interme-
XII, Ar =4-CH,OC,H,
cli:it es for the prqxirdion of the corresponding cyclopropimeaniirio acidx. Coiiseyuently, 4-[4-(4-acetoxyphenoxy)-3,3-diiodoberizylidene]-2-phenyl2 - oxazolin5-orie (T') wa.* treated with diazometharie and yielded 1- [4-(~-a(.etoxypherioxy)-3,.idiiodophenyl] - 5 - phenyl(i-oxa-4-azaspiro [%.4]hept-4-en-7-one(VI), which on reflus \\-ith hydrochloric. a d gave the 3,;-diiodothyronine analog VII. The azlact.orie V 1va.q obtairied from the 4'-methoxyi)lierioxy-3,3-diiodo azlactorie IT.' which had beeii used I l j (a) Siil,livrterl in 1)art l)y G r a n t GAI-12781 f r o m the I n s t i t u t e of (;rneral l l e d i c i n e , National Institutes of Health, U. 8 . PuI)lic Health Sen.-ice. 11)) Llu Punt Teacliing Fellow, 1963-1964: N.1S.i Trainee, 1965-1966. (2) .\. I3urger, S. E. Zimmerman, a n d E. J. Ariens, J . .\fed. Chem., 9, 469
(1966). ( 3 ) .\. Parulkar.
.I. 13nreer, a n d D. .\iires, i b i d . . 9 , 738 (1966). (-11 R. .I. Pages a n d .I. Hureer, iiiiil., 9, 766 (1966). ( 5 ) (a) .i. Iliirger a n d \\.. E. Coyne, J . Oru. C h e m . , 29, 3079 (1964); (I)) .\. H u r r r r a n d S. E. Zimmerinan. ;Irz,~eimiltel-L'orst.h.. 16, 1571 (1966). (ti) C. L. Zirkle, C'. Kaiser, 1). H. Tedesclii. R. E. Tedesrhi, a n d .\. l j u r g e r , .I. .ll?d. I'hrcrm. Client., 5 , 1265 (19621, a n d references cited tilerein. f i ) C. l(earr1 a n d .\. Ilurger, J . OTQ. Chem., 26, 2385 (1961); 27, 1647
b y Harington arid Barger in their classical synthesis of thyroxine.Ii' We prepared IV b y a more coriveriicii~ route from p-hydroxybenzaldehyde in five steps iii ail over-all yield of 17.5% as shown in Chart' I. At' this point t'he 4'-methoxy group had t,o be removed because it' was expected that ether cleavage with HBr subsequent, to the construction of the cyclopropane ring might' disrupt t,his strained portion of the molecule. This was achieved by treatment' of I V with boron tribromideI6 followed b y acetylation of the reaction mixture.17 Many attempts to iodinate VI1 with 12-1rlrnvr(l l ) i i t sc,mr of titi. nzlacicinr l i n g linil l ) r r n acid. opened with t h e formation of t h e a-l~enzamiducarl)ox~-lic (IS) T h e I~iologicaltests were carried oiit in tlie L)epartinent of PliarinaL. Gemmill culog>-, C n i r e r s i t y of Virginia Sclioul of l l e d i c i n e , I JClialmers ~ and Katlierine Alayu Browning.
\'ill. L O
CHO
(I
CH=C,
/CC)-CH,
I
methodA
I
CSO%,,
I
OH
OH 0
NHCOC,H-
QI
1i:ppuric acid
1
VI
,i A c O
CYCLOPROPYLOGS OF THYIWSISE DERIVATIVES
MAY1967
437
CH \Ill' 11 0
CO,H
g L C b H ,
vi;.:
CO,CH,
&-Coc6H2
OCH,
{HCoc6H7
OCHj
XII"
OCH,
XI11
0
XIV LHhl
PC,. ~
,
\
CH,N
OAc
OAc
OH
XV
,
CHIN
XVI
COLH
0
NHCO C6H5
,
$) I
T
I OAc
I
I I EthH c2 Hot
OH
X IX
XVIII h,rOCH
CH.N
LHOH
f
CHiN.
IM
I
CHJOH-Et,O
I
xx
xXI cis-carbethoxy-trans-carboxylicacid thus obtained w a h converted to IX by Curtius degradation of the free carboxyl.22 Retention of configuration in the benzoylationZ3of IX arid in the ring c l o ~ u r e of ~ ~X~is2 based ~ on
CHjO 1x12
I
CH OH T ~ ~ O H *
I
CHjO
NHCOC H,
OH
XVII
I\'
'
g\l o c b H a
1 haOH, H,O'
X
p e r h e r i t analogies in the literature. Therefore, the oxazolone carbonyl of XI1 is trans to the methoxyphenyl group. The relationship of XI1 to V I was established by the reactions shown in Chart 11. The spirooxazolorie XI1 was hydrolyzed to the benzamido acid XI11 which differed from the isomer X. Esterification of XI11 furnished the ester XIV which was also obtained from the phenolic benzamido acid XVI, separately aynthesized from the p-acetoxy azlactone XV. Iodination of XVI led to the cyclopropylog of 3,3-diiodo-Sbenzoyltyrosirie (XVIII) which in turn was also synthesized from I as shown in Chart 11. The methyl ester (XIX) of XVIII wa coupled with di(p-anisyljiodonium bromide to yield the thyronine analog XX. This compound was also formed from VI with diazomethane in met,hanol-et#her.
I
CH,O
XI ( 2 2 ) For analogous cases see ref 5 a n d 11. ( 2 3 ) R . E. Steiger, .I. Org. Chem., 9, 3% (1944)
(24) R. E. 13uckles, R. Filler, a n d L. Hilfman,
