SOTES
May 1969 Synthesis of Fatty Acids with Smooth Muscle Stimulant Activity. 11. Alyristoylbutyrolactones and Analogs' E. CRCNDWELL AND P. FARMER
547 TABLE I No. of
Chemical shift,
T
5.30 7.2-7.9 8.78 and 9.10
protons
Assignment
1 6 25
d c, e, f b and a
School of Pharwiacy, Portsmoufh College of Technology, Portsmouth, Hampshire, England
guinea pig intestine it showed no effects which were different from those of the solvent mixture. It was soluble in DMF but rapidly precipitated on dilution Recehed J u l y 29, 1968 Revised Manuscript Received October 14, 1968 in an organ bath. No spasmogenic effects were observed. From Feronia limonia a compound termed feronolide, We were unable to obtain a sample of feronolide for mp 115", has been obtained2 and the structure 1 was direct comparison. assigned on the basis of chemical evidence and on the Because of the differences between 1 and feronolide, presence of a band at 1754 cm-I in the ir spectrum. we began synthesis of isomers. 5,G-DihydroxyoctaThe location of other bands and the phase or solvent decanoic acidlo was converted to the hydroxy d-lactone. were not reported. The chemical evidence does not Oxidation gave a small yield of the ketolactone 3. exclude the d-lactone 2, but this has been de~cribed;~ This showed some enhancement of C=O stretching mp 69". Feronolide was reported4 to have spasmogenic frequencies.
1
2
activity though it does not have the structural features suggested' to be common to fatty acids with smooth muscle stimulant action. We therefore undertook synthesis of 1. 4,5-Dihydroxyoctadecanoic acid ylactone5 was oxidized to give a solid, mp 67-68'. The same ketolactone (1) was also obtained in small yield from the react'ion of butyrolactone-4-carbonyl chloride6 with bistridecylcadmium. Our compound (1) shows (in CClJ two well-resolved peaks at 1805 and 1730 cm-'. Electron-attracting subst'ituents in the y position of butyrolact'one are known7 to enhance the lactone carbonyl stretching frequency. A mutual enhancement of bot'h C=O stretching frequencies has been observed in compounds containing acetoxyacetyl groupings.* The C=O absorption of our compound (1) differs considerably in ot'her conditions, being at 1760 and 1715 cm-' in a mull (Sujol) or disk (KC1). This shift on change of phase is greater than the 10-15 cm-l normally encountered. The nmr spectrum (Table I) of our compound is consistent with the formulat'ion as 1. Reduction of this compound (with SaBH4) gave back t'he hydroxylactone which also shows an enhanced lactone C=O &retching frequency (1790 cm-' in CCI,) remarkably sensit'ive t,o change in state. A colloidal suspension of feronolide (10 mg) in CHClz (1 ml) and H2O (9 ml) has been reported4 t,o have spasmogenic act'ivity. Compound 1 did not form a stable suspension. Tested in a similar way on isolated
Methyl 3-0xohexadecanoate~~ was converted to the myristoyl ester (4). The corresponding acetyl ester, similarly prepared,'2 was reported to decarboxylate in the course of the reaction. However the myristoyl ester (4) proved difficult to decarboxylate, remaining unchanged or cleaving to myristic acid under a variety of conditions. P-1Iyristoylbutyrolactonewas not obtained. Treatment of methyl 3-0xohexadecanoate~I with ethylene oxide gave a-myristoylbutyrolactone. This showed no enhancement of the lactone C=O stretching frequency and little alteration on change of state. Tested in the same way as the y isomer (1) it showed no spasmogenic a ~ t i v i t y . ~
(1) P a r t I: E. Crundxell, RI. A . Pinnegar, a n d \I-.Templeton, J . Med. Chem., 8 , 41 (1965). (2) R. D. Tiwari and J. P. Tewari, Arch. Pharm., 297, 236 (1964). (3) B. W.Boughton, R. E. Bowman, and D. E. Ames, J . Chem. Soc., 671 (1952). (4) S . S.Jlishra, R . D. Tiwari, J. P. Tewari. a n d K. C. D u t t a , Indian J . M e d . Res., 51, l ( 1 9 6 3 ) . (5) D. E. Ames, A. N. Covell, and T. G . Goodburn, J . Chem. Sac., 5889 (1963). (6) H. Plieninger. G. Ege, R . Fischer, and W, Hoffman, Chen. Ber., 94, 2106 (1961). (7) R. S. Rasmussen a n d R. R. Brattain, J . Amer. Chem. Soc., T i , 1073
(9) * !]e t h a n k D r . D. Roberts for these determinations. (10) D. E. Ames, A. N. Covell, and T. G. Goodburn, J . Chem. Sac., 894 (1965). (11) 9. Stallberger-Stenhagen, Arliiu Kemi, Mineral. Geol., A20 (191, 1 (1945). (12) Y. Nishizawa and S. Kitamura, Japanese Patent 2965-6 (1959); Chem. Abstr., 54, 13000 (1960). (13) T h e compounds described below were all synthesized from either myristic acid (British Drug Houses, 99% by glpc) or 1-bromododecane (Fluka 99.5TC by glpc); uv spectra mere measured on Unicam S.P. 800: ir spectra on a Perkin-Elmer Model 257; and nmr spectra on a Perkin-Elmer XIodeI R10 (60 &IC). Where analyses are indicated only by symbols of t h e elements, analytical results obtained for those elements were within i O . 4 7 ? of t h e theoretical values. Melting points are uncorrected.
(1949). (8) E . G. R .
Ei. Jones and J. B. Di Gorgio, Can. J . Chem., 43, 182 (1965).
Experimental Section13
4-Hydroxy-5-oxooctadecanoicAcid ?-Lactone (1 ).--4 solution of the hydr~xylactone~ (1.70 g) in MezCO (40 ml) was cooled (ice bath) and treated dropwise with 2 M HPCr04(12 ml). The two-phase mixture was stirred for 6 hr while the bath came to room temperature. The acid layer l+-as extracted (EtnO) and this extract was combined with the residue from evaporation of the MePCO, washed (H20, 10% SaHCOs), dried (1\rgso4), and evaporated to give the crude product (1.56 g ) which was treated with charcoal in CHC13 and recrystallized (petroleum ether, bp 60-80'); yield 1.26 g ( 7 5 % ) , mp 66.5-68.5". Anal. Calcd for CI8H3203: C, 72.92; H, 10.88. Found: C, 72.87; H, 10.69. The absorption spectra are discussed above. The 2,4-dinitrophenylhydrazone had mp 61-63 '. Anal.
N. 5,6-Dihydroxyoctadecanoic Acid 6-Lactone.-The
(C14H3&40e.)
dihydroxy
acid'" ( 2 . 7 3 g ) was heated in vacuo at 130" (bath temperature) for 2..i hr. The product was dissolved in CKCl,, washed ( 1 O C ; KaIlC03), dried (JIgSOi), concentrated, and re (petrolerim ether, bp 4 0 - 6 0 O ) : yield 1.18 g ( 7 0 : ; ) . mp 68-69", ir ICCl..) 1750 cni-'. Anal. (CJ-1340,) C, €1. 5-Hydroxy-6-oxooctadecanoicAcid &Lactone (3).--A solution i ) f t-biityl alcohol (1186 mg) and Cr03 (493 m g ) in petroleum ether it)p 40-60') was dried (Ka?S04)and treated with :I solrition ( i f t lie h!-~li,oxylac~toiie(397 nig) in petroleiim ether (150 1111). The iiiirtrire \viis allowed t~ ,qtand in a btoppered f l a k for 70 hr. It was [hen kept at refliix for 4 hr, cooled, and t x a t e d with H20 (:3,> nil) and oxalic wid ( c n . O..? g), then with H~SO.,(1 inl) and Ac0l-I ( 2 nil). Thr mixtlire was shaken for 43 min, and the aqueoris 1:tyer was separated and extracted with petiulemi ether. The combined oiy~anic.solutions were washed (lO(;;, SaHCOI, J f i O j, di,ieti (Na,SO,), xnd conceiitrated t o give a slo~vlysolidifyiiig br[iwn oil(36~rn::j,\yhich~vanre llized (petroleum ether, bp 40-60"); yield 2 3 mg (4 '; ir ICCl,) 1760, l i 2 . i Dm-'. Alnal. (Cl8H,,OI) C, Dimethyl Myristoy1succinale.-A s o l u h i i of methyl .'j~ ~ s ~ ~ h e s n t l r c ~ a(2.13 n o a t ge)~ in ~ JteOH (13 nil) was added to a h(iliiiion of Xa ( I Z 3 rng) in h1eOI-l (13 d j , stirred at worn teniprratirre for .5 hi,, and then methyl hmnioacetate (1.13 g j 15-a.q :ititled. Stirring TV:W continiied for 30 hr. The mistrire w c~oirce~iti~ated, diluted with EhO, mid washed (HCl, JLO, 10 XaHCOa). The dried (Ka2SOr) ,solution was concenirated give a solid (1.S2 g ) which was treated with charcoal in CCL a1111 recrystallized (petroleum ether, bp 40-60"); yield 800 iiig ( 3 0 ' ; ): inp 40-47.5', ati,sorptioii peaks (ir, rinir) as expected. .Inn/. ICr,J1360jjC', II. 3-HydroxymethyI-3-methoxycarbon~~-4-oxoheptadecanoic Acid -/-Lactone (4).--->% siispension of the InS'ricotoyljiicciiiate (1.07 g j in JleOll (20 nil) was stirred at room eratiire foi, 1 h r with olution was adjusted I .V S a O f l (:;.O nil). The resulting cl to p l l 0 with FI,SO4, treated with l o r ; NaFICCh ( 3 nil) and :iqireoris 40('; HCI-IO (5.0 ml), antl stirred at, room temperature f o i , 4s hi.. The soliitioii was diluted with EhO, wnfihed (I-I,SOa, ]I&), dried (Ka?SO4), and concent,rated t,o give an oil (1.00 K). This was stirred with 2 5 5 , I1C1 (3.5 ml) at room temperature for 4.5 h r :ind extracted with I
