758 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 8
WITIAK,et al.
6-Chlorochroman-2-carboxylic Acids. Synthesis and Biological Evaluation as Antagonists for Cholesterol Biosynthesis and Lipolysis in V i t r o DONALD T. W-ITIAK,* EUGENE 8. ST RAT FORD,'^,^ R A L P H SAZARETH, GWENWAGXER,'~ AND DENNIS R. FELLER Divisions of Medicinal Chemistry and Biochemical Pharmacology, College of Pharmacu, The Ohio State University, Columbus, Ohio 43310 Received November 23, 1970 Studies leading to, and the synthesis of, nrA-chlorochroman-2-carboxylic acid (2) and ~~-2-methyl-6-chlorochroman-2-carboxylic acid (3) are presented. These compounds are cyclic analogs of the hypocholesterolemic and hypolipidemic agent a-(4-chlorophenoxy)-a-methylpropionic acid (1). Preliminary results on their ability to antagonize glycerol release from rat epididymal fat pads and inhibit mevalonate-$?-"C incorporation into nonsaponifiable material of rat liver homogenate are discussed.
As part of a continuing program designed to prepare asymmetric analogs of the hypocholesteroleniic and antilipidemic agent, cr-(4-chlorophenoxy-cu-methylpropionic acid (1),2-4 we set out to synthesize the cyclic chroman analogs 2 and 3. Xhereas 1 contains
1
logical studies relating t o their ability to block glycerol release from rat epididymal fat pads, and their inhibitory action of me~alonate-2-'~Cincorporation into nonsaporiifiable products in L: rat liver homogenate preparation. Synthetic Aspects.-In our initial attempts to synthesize 2 Iie employed 6-chlorochromone-2-carboxylic acid (8) and its Et ester 7. Standard procedures5 for the Fries rearrangement reaction n ere used to convert p-chlorophenyl acetate (4) to 2-hydroxy-5-chloroacetophenone ( 5 ) . Treatment of acetophenone 5 with diethyl oxalate in the presence of XaOEt afforded intermediate 6 which ivas riot purified; the crude intermediate was cyclized to the known chromone deriv-
2,R-H 3,R=Me
no asymmetric center, chromans 2 arid 3 may ultimately be resolved and their respective enantiomorphs employed as stereoselective chemical probes for repClCQH40Ac 4
----t
Jgy-
c1
5
c1
C0,Et 0
0
6
J.
.1 c1
11 0 10
ceptor site studies. I n t,his re,port we discuss the synthesis of the DL compounds, our preliminary bio(1) (a) Abstracted in p a r t from a dissertation presented t o the Graduate School of The Ohio State University (1970); (b) U. S. Public Health Service Predoctoral Fellow (5-F01-GM-37591): ( c ) K S F Undergraduate Research Participant, Summer, 1970. ( 2 ) (a) D. T. Witiak, T. C-L. Ho, R. E. Hackney, and K. E. Connor, J . Med. Chem., 11, 1086 (1968); (b) D. T . Witiak, R . E. Hackney, and hf. W . Whitehouse, ibid., la, 697 (1969). (3) (a) D. T. Witiak and M. W. Whitehouse, Biochem. Pharmacol., 18, 971 (1969); (b) D. T. Witiak, T . D. Sokoloski, If.IT, Whitehouse, and F . Hermann, J . M e d . Chem., 14, 754 (1969). (4) D. T. Witiak, D. R . Feller, E. S. Stratford, R . E. Hackney, R . Kazareth, a n d G. Wagner, J. Med. Chem., 14, 754 (1971).
atives 7 and 8. Ester 7 was obtained by heating 6 in HOAc containing HCL6 Acid 8 was obtained either from intermediate 6 or from ester 7 by heat'ing crude 6 or pure 7 in concd HC1-HOAc (1:4).7 Although the nmr spectra of chromones show that the heterocyclic ring is not aromatic in character,* ( 5 ) A. H. Blatt, Ore. React., 1, 359 (1042). (6) V. A. Zagorevskii, D. A . Zykov, and E. K . Orlova, Zh. O h s k c h . Khim., SO, 3894 (19601, cf. Chem. Abslr., 66, 22301/ (1961). (7) P . Xiviere, P . Tronche, and J. Couquetet, Bull. Soc. Chim. Fr.. 3658 (1965). (8) (a) ?VI. hf. Badawi and ?VI.B . E . Fayez, Indian J . Chem., 6 , 93 (1967); (b) G . Govil and C. L. Khetrapal, Curr. Sci., 36, 564 (1966).
6-CHLOROCHROMAN-2-CARBOXYLIC ACIDS
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 8 759
attempts to reduce the isolated double bond were unsuccessful. Treatment with Zn dust in HOAcg afforded a mixture consisting mainly of starting material and dimer 10. These compounds were separated by repeated column chromatography on silicic acid-CHCh and the structure for dimer 10 was assigned primarily on the basis of its nmr spectrum (see Experimental Section). Reductive dimerizations in the absence of a protic solvent are well known. A possible explanation for
G c1
C
0
2
R
0 ~ 1 2R,= Me, R’ = H 13, R = R’=H 7 1 4 , R = H, R’ = Et
r ’
The use of less polar solvents ( e . g . , EtOAc) in the presence of Pd/C or with PtO, catalyst resulted in the formation of a complex mixture of products analyzing for as many as 10 compds by glpc. A second approach to the synthesis of 2 involves cyclization of a P-(2-hydroxyaroyl) acrylate according to methods reported by Cocker and coworkers.12 Starting P- (2-hydroxy-5-chlorobenzoyl) acrylic acid (13) was prepared from p-chloroanisole and maleic anhydride followed by demethylation of 12.13 In-
-
cl&COJ3t
C02Et
c1 19
0 18
It
Mew c1
COzEt 21
c1
20
0 25
Me *C02Me
+
@C02Me R
Me Me02CCH2
17, R0= Me
Me CH2C02Me 22
15, R = Me
R C02Me 23, R = Me 24, R = H
26
the formation of dimer 10 involves formation of resonance-stabilized anion radical 9 resulting from donation of an electron from the Zn metal surface. The combined influence of the C02Et group and the ring 0 may enhance the stabilization of free radical 9 which ultimately dimerizes and abstracts a proton from the solvent by either a concerted or stepwise process to yield 10. Low pressure hydrogenation of 8 (max 2.1 kg/cm2) over Raney Xi catalystlo or hydrogenation of the Na salt of 8 over copper chromate catalyst a t high pressures and temperatures” only afforded starting material. Hydrogenation of 8 in HOAc in the presence of 5% Pd/C afforded the expected deschlorochroman 11.
creasing the temp of the reaction results in formation of 13 directly. Ester 14 was prepared from 13; the large coupling constant ( J = 15.7 Hz) for the vinyl protons substantiates the trans geometry for 12, 13, and 14.14 However, whereas 15 is reported to cyclize to chromanone 17 in the presence of X(Pr)3 and 5 equiv of diethyl malonate,I2 in our hands monomer 14 only afforded dimer 21. The structural assignment for 21 is based on ir and nmr analysis and differs from structures proposed by other investigators. For example, Cocker and coworkers reported that if diethyl malonate was omitted from the reaction a mixture of dimer 22 and chromanone 17 is obtained.I2 Barr and coworkers15 obtained a mixture of 17 and 22 irrespective of con-
(9) K . Alder and G. Stein, JustusLiebigs Ann. Chem., Sol, 247 (1933). (10) (a) P. Naylor, G. R . Ramage, and F. Schofield, J . Chem. Soc., 1190 (1958); (b) C. J. Jarowski, W. J. Moran, and B. J . Cramer, J. Amer. Chem. Soc., 11, 944 (1949). (11) (a) L. F. Fieser and W. H. Daubt, ibid., 63, 782 (1941); (b) H. 0. House and R . J. McCaulley, J. O r g . Chem., 24, 725 (1959).
(12) W. Cocker, D. H. Hayes, and W.R . N. Williamson, J. Chem. Soc., 824 (1955). (13) G. Baddeley, S. M. Makar, and M. G. Ivinson, ibzd., 3969 (1953). (14) N. Sugiyama, Y. Gasha, H. Kataoka, and C. Kashima, Bull. Chem. SOC.Jap., 41, 971 (1968). (15) K. P. Barr, F. M . Dean, and H. D . Locksley, J. Chem. Soc., 2425 (1959).
760 Jownal of Medicinal Chemistry, 1971, Vol. 14, N o . R
WITIAK,et al.
ditions employed. Based on the uv spectrum for dimer 22 and potentiometric titration of the partial hydrolysis products these investigator^'^ assigned structure 23 to dimer 22. Of particular interest is the observation that 16 afforded only the dimer 24; the structure of this dimer was assigned on the basis of its similarity to 23. The uv spectrum12 and the ir CO absorption frequencies'j for dimer 23 are similar to the data obtained for our &mer 21 (Experimental Section) and suggest that the structural types of the 2 dimers may be the same. Additional evidence, however, does not support either of the structural types previously proposed. The ir absorption of the chromanone CO in 25 occurs :it 1690 cm-l. The higher frequency of the nonchelated CO in the dimer suggests a hmembered ring rather than a 6-membered ring. The CH resonance signal in a number of compounds possessing structural unit 26 has been observed, in our studies, to appear in the region 4.5 to 5.3 ppm downfield from TMS (see Table 11, Experimental Section). ?Jo resonance is observed in this region of the spectrum for the dimer obtained in our laboratories and the nmr spectrum is in agreement with structure 21.16 Further support for the proposed structure was obtained by the use of chromanone 25 prepared under different conditions. Barr and com orkersIb reported that chromanone 17 could be converted to dimer 23 by treatment with NEt3. In our studies, however, 25 was not affected under similar conditions; only the starting material could be isolated. The reasons for the discrepancy between our observations and those of Barr and coworkers is not k1i0u-n.~~ When equal parts of chromanone 25 and acrylate 14 were stirred with ?rTEt,3in EtOH, the chromanone could be quantitatively recovered from the reaction mixture. Thii observation indicated that the chrom:inone 15 as iiot a n intermediate in the formation of the dimer as proposed by the previous investigators." The formation of 21 can be rationalized as follov-s: cyclization of the initially formed anion 18 to give carbanion 19 would be kinetically favored over cyclization to the 6-membered ring. l Y ,2 prototropic shift in carbanion 19 to give the more stable carbanion would afford 20. Reaction of 20 with another molecule of starting material, followed by protonation, mould afford the observed dimer. The insolubility of the dimer in the reaction mixture also serves to drive the reaction toward its formation. Cyclization of 14 to the desired chromanone wab accomplished by the method of Annigeri arid Siddappa.lg Refluxing 14 in EtOH in the presence of orthophosphoric acid afforded chromanone 25 in low yields. The low yields obtained in this reaction made it desirable to find an alternative pathway to the synthesis of the chromanone intermediate. We therefore
employed the method of Julia and BaillargeZ0 in preparing a-(p-ch1orophenoxy)-y-butyrolactone (28) from 26 and 27; this product was oxidized with CrOa affording the succinic acid derivative 29. 2n Acylation reactions on aromatic ringb irivolvirig cyclodehydration have been shon 11 to be accomplished readily by employing polyphosphoric acid (PI'iZ) as the condensing reagent arid solverit.21 Examples of the use of thii synthetic method in the preparation of the 4-chromanone system have ;~1so :tppe:tred in the literature.?? €Io\\ever, when 29 was heated in I'J'A, the expected keto :tcid 31 n:t< not obtained. The major product of the reaction \\as a neutral compound identified by its physical and spectral characteristics as 6-chlorochromonc (30). This compound \\.as also obtained when ZnCla in POCL was employed according to the method of Iyer and Shah.23 A phosphorylated derivative of the desired keto acid is probably ;m intermediate in this conversion which is further dehydrodecarbosy1:Lted to the observed product. Evidence iti support of this assumptioil was obtained by coiiversion of keto acid 31 under similar reaction conditions to chromoiie 30. Keto acid 31 \\:is obtained i n good yield by cyclization of 29 i ~ i \{arm coricd H2SOI Reduction of chromanone 25 3s first attempted b j the method involving dithiolietalizatiori and IZaliey Ki desulfurization according to the procedure of Sondheimer and Roserithal.?4 The dithioketal ester 32 n a> obtained readily in good j ield. However, attempted desulfurization in EtOH I\ ith Raney Xi W-2 catalyst resulted i n dechlorination :ib ell as dcsulfurizatiori affording v t e r 33. This rbter was found to be identicd J\ it h the eiter produced by acid-cattdyzed e5terificatioii of 11. Conversion of 25 and 31 t o 2 on reduction con:IS accomplished under Clrmm ditions :iccording to the mcthod of Bridge a i d conorker2,)of 7, nip 13.5-137". A further recrystn from EtOH, after treatment with charcoal, afforded white needles, mp 137.3-138.3" (lit.Gmp 1:36-136.5'). the so111 wi. ( . o i i ( , i l tiiI!l(>i, 6-Chlorochromone-2-carboxylic Acid (8).-This compd was prepd by the same procedure used for the prepn of the ester except uiStd r r 2 0 : t t ~ ~ i elI) ti i SLJ111 1VRA COOled liJ (I-->". that in the cyclization stage a 4 : 1 ratio of AcOH to concd €IC1 and dried affordiiig 1 .:; g (6: tlinicr 21, mp 104-10i0. liewas employed. The white solid obtained was then recrystd from AcOII affording 8, mp 267-260" dec, mp 262" and 273". crystu from PhII-petr cth Hydrolysis of ester 7 in AcOH-coned HC1 afforded the same acid. nip 112--114..?O. T r i :i niot1ifii~:iticiii oi thct procedure, S . 0 g (3.0 2-(2-Carbethoxy-6-chloro-4-chromanon-2-yl)-2-carbethoxy-6- x 10-2 inc~le)of 14 W:I. diyv,lvetl i i i : i I + IItOII iIO0 1111) :inti chloro-4-chromanone (lo).-A s o h of 5.0 g (0.02 mole) of 7 ?;Et3 (0.4 nil; \v:tq :iddctf The. ,.(h cvith -rirretl :i1 r t ~ o i i iiemp i n AcOH (100 ml) was stirred at 20" and 2.3 g (0.04 g-atom) of while the iiiiti:il rctl ('IJlil1.c~11:ingedt o :I light yellow detl. Tht: pp! \ w i filtered Zn dust added iri small portion^.^ The mixt was allowed to stir till. 21. A I i :1ddnl 0.4 at room temp for 0.5 hr and heated at 30" for 1 hr. The solvent 'ate t o O-.?" :ifi'c,rdiiig ii t( was concd under reduced pressure to near dryness, and the residue i J I e 0 I I I, A,,,,,,, m p (log E ) : of 7.1 g ( % I r ; ) of dimer 21 : was dissolved in CHClt and extd to neutrality with satd NaHC03 (4.66), 2.51 (4.222, 837 1:$,911: ir, I' 40 (OFI), 1740-17It-i soln. The org layer was dried (KasSOa), and the solvent was iC-=O iirid COyEt :r 161:1 (c,hcl:rte removed. The amorphous solid obtained was dissolved in CHCla 1.07 i t , Y, J = 7.2 H z C'II,I, ~ 1.15 ( -= 7.2 I i z , (.'II:
