J. Org. Chem. 1982,47, 222-226
222
Biologically Oriented Organic Sulfur Chemistry. 22. 2-(3-Chloropropyl)-5-chloropentanolas a Prototype for Synthesis of Functionalized Polysulfides and Prodrugs’ Gary T. Bowman and Lamar Field* Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235 Received August 18, 1981
A synthetic approach based on 2-(3-chloropropyl)-5-chloropentanol(5) is reported that permits synthesis of trisulfides containing either C1 or four other groups. The carbinol 5 was prepared by converting diethyl bis(3-chloropropy1)malonate(2) with Me&I to the malonic acid, which was decarboxylated (with some remediable lactonization to 6), followed by reduction. The carbinol 5 was converted via the triflate (11) to a thiosulfonate, which thioalkylated NalS to give a trisulfide containing four C1 atoms (7). Replacement of the four C1 atoms of the carbinol 6 with PhCH2Sgroups, followed by formation of the tosylate (14; the triflate polymerized) and then of the thiosulfonate (13), permitted synthesis of a tetrakis(benzy1thio) trisulfide (12) that illustrates tetrafunctionalization. Several intermediates are potential progenitors of prodrugs, although an effort to use bis(quaternary ammonium salts) prepared from 5 in this way was unpromising owing (chiefly)to very sparing solubilities.
Di- and trisulfide sulfinates typified by structure 1 are Na02SRS,RS02Na 1 promising antiradiation agents that are significantly atypical in lacking nitrogen.2 In order to delineate the structural requirements for radioprotective activity with such compounds, we have thus far increased n of S, beyond 33 and have used ArS,ArS(O),4and S(0)OMe5in lieu of S02Na. This paper reports a flexible synthetic approach that permits doubling the number of functional groups associated with the S, linkage and should also permit introduction of a considerable variety of functional groups. Scheme I shows an application of this approach to synthesis of a tetrafunctionalized trisulfide (12), where (CH& and P h C H a respectively are prototypes for the chain and functional groups. Reference compounds exemplified by 7 will permit assessment of the radioprotective effect of the S, linkage by itself, and compounds exemplified by 12 will permit assessment of the effect of introducing four other functions. Lending another element of interest to Scheme I is the likelihood that several of the intermediates may be useful progenitors of prodrugs.6 Examples of functional groups of drugs that might be modified by using various intermediates are OH (with 4), COzH (with 5,10,11, 15), SH (with 4, 8, 13), and NH (with 4). Nucleophilic displacement of C1 before or after the prodrug linkage is established should permit introducing a wide variety of functional groups into the prodrug. Furthermore, in view of the “high frequency of chemically symmetrical drugs”,’ advantages may accrue from the symmetry of such prodrugs. (1) (a) Paper 21: Heimer, N. E.;Field, L.; Neal, R. A. J . Org. Chem.
Initially, entry into the approach of Scheme I was attempted with use of the butylene homologue of 2, i.e., with sought by alkylating diethyl bis(4-~hlorobutyl)malonate, malonic ester with 4-chlorobutyl tosylate.8 These efforts were thwarted by cyclization of the (chlorobuty1)malonate to diethyl cyclopentane-1,l-dicarboxylate(characterized by spectra, refractive index, and conversion to the known diacid). We therefore turned instead to the propyl homologue 2 as a prototype; 2 is conveniently available from alkylation of diethyl malonate with l-bromo-3-chloropropane? In a procedure based on one of Jung and Lyster,lo Me3SiI smoothly converted the malonate 2 to the malonic acid 3 (83%yield); NMR monitoring of Et0 to Et1 showed the reaction of the malonate to be much slower than is typical of monocarboxylates. Saponification, acid-catalyzed hydrolysis, or transeaterificationllwere unsatisfactory for converting 2 to 3 or 4, the less expensive reagent Me3SiC1-NaI led chiefly to the bis(iodopropyl)malonate,l2 and attempted conversion of 2 to the monocarboxylate, for reduction to 5, by using Me2SO-NaCl was unpromising (probably because of reaction of a chloroalkyl group with the intermediary carbanion presumably involved).13 Decarboxylation of the malonic acid 3 gave the monoacid 4 (52% yield). However, a considerable amount of product was insoluble when the 4 was extracted into aqueous bicarbonate for purification. NMR indicated this material to be the lactone and/or polymeric linear ester formed by loss of HCl (collectively termed 6); indeed, when 4 itself was heated at 150-170 “C for 9 h, NMR indicated about 29% conversion to 6. Extracting a solution of 6 with 5% aqueous KOH removed nearly all of the 6 (presumably saponifying it to the hydroxy acid salt, since acid regenerated 6); KOH therefore is not an alternative to NaHC03 for extracting 4. Fortunately, reaction of the bicarbonate-insoluble product with SOC12-ZnC12 and then H 2 0 converted it into 4 (63% yield). Borane-methyl
1981,46, 1374. (b) The Ph.D. Dissertation of G.T.B., from which this
paper is abstracted, can be consulted for further details (Vanderbilt University, Aug 1981). (2) (a) Srivastava, P. K.; Field, L.; Grenan, M. M. J. Med. Chem. 1975, 18, 798. (b) Field, L.; Khim, Y. H. Ibid. 1972, 15, 312. (3) Field, L.; Ehwarakrishnan, V. J. Org. Chem. 1981, 46, 2025. (4) Field, L.; Bowman, G. T. J. Org. Chem. 1981, 46, 2771. (5) Eswarakrishnan, V.; Field, L. J. Org. Chem. 1981, 46, 4182. (6) Higuchi, T.; Stella, V., Ed. ‘Pro-drugs as Novel Drug Delivery Systems”; American Chemical Society: Washington, DC, 1975. (7) Ari6ns, E. J. In “Drug Design”;Ari&ns,E. J., Ed.; Academic Press: New York, 1971 Vol. 1, pp 107-119.
(8) Field, L.; Holsten, J. R. J. Am. Chem. SOC.1955, 77, 1286.
(9) Fischer, E.; Bergmann, M. Justus Liebigs Ann. Chem. 1913,398, 122-124. (10) Jung, M. E.; Lyster, M. A. J. Am. Chem. SOC.1977, 99,968. (11) Loev, B. Chem. Ind. (London) 1964, 193. (12) (a) Morita, T.; Okamoto, Y.; Sakurai, H. J. Chem. SOC.,Chem. Commun. 1978,874. (b) Olah,G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J. Org. Chem. 1979,44, 1247. (13) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E., Jr.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978,43, 138.
0022-3263/82/1947-0222$01.25/0 0 1982 American Chemical Society
J. Org. Chem., Vol. 47, No. 2, 1982 223
Biologically Oriented Organic Sulfur Chemistry. 22 Scheme Ia C W 1.Me Si1 C14Ac(C02H)2 C ~ C ( C 0 2 E t ) 2,Hpi 'C 1 W
?
a
~e -3
Me 3
l
CHCHpOH 2x- Me3N(2S°C,10 days,NaI catalysis) !
4
- _.
16 (X=Cl,I,PFG,picrate)
Ai- = p-CH,C,H,; Py = pyridine.
sulfide reduced the acid 4 to the carbinol 5. For the synthesis of the trisulfide 7, the carbinol 5 first was converted to the tosylate 10 ( h y l chloride-pyridine). Efforts to obtain the thiosulfonate 8 by using the thiosulfonate 9 to replace the tosylate moiety of 10 evidently succeeded in large part, since reaction of 9 and 10 at 60 "C for 24 h in DMF gave a product estimated to contain 86% of thiosulfonate linkages by the method of Barnard and C01e.l~ However, NMR spectra indicated partial replacement of C1, as well as of tosylate, and a variety of conditions failed to obviate this problem. The triflate 11 therefore was prepared. When the reaction of 11 was attempted with the thiosulfonate 9 in DMF,the 11 reacted exothermically with the DMF, and none of the thiosulfonate 8 could be isolated. In sulfolane on the other hand, the triflate 11 reacted rapidly with 9 at 25 "C, although the yield of 8 was only 26-30% (after chromatography), perhaps partly because of loss of elemental sulfur from 9 and formation of the sulfone counterpart of 8. Sodium sulfide converted the thiosulfonate 8 to the nearly pure trisulfide 7 in 87-99% yield. The preparation of a tetrafunctionalized trisulfide is illustrated by conversion of the dichlorocarbinol5 to 12. In the first step, alkylation of phenylmethanethiolate ion by 5 replaced both of the chlorine atoms of 5 with PhCH.$ to give 15 (80% yield). In related preliminary work, C1 also was replaced by SH in good yield and practicable purity by alkylating sodium trithiocarbonate with 5 and acidifying the resulting trithiocarbonate, i.e., [NaSCS&H&&S!HCH20H, by a method based on one of Martii and Greco;16this supplement to Scheme I should permit synthesis of polysulfides (or other carbinol-derived products) containing a variety of functional groups of sulfur derived from the thiol moieties. ~
~~~
(14) Barnard, D.; Cole, EXAnal. Chim. Acto. 1969,20, 540. (15) Martin, D. J.; Greco, C. C. J. Org. Chem. 1968, 33,1276.
In the next step toward 12, efforta to prepare the triflate of 15 analogously to 11led to polymerization, presumably because of displacement of triflate by benzylthio moieties (the product had a molecular weight of ca. 1059 by vapor-pressure osmometry). Fortunately, the enhanced reactivity of the triflate necessitated by the competition of chlorine as a leaving group in the preparation of 8 was unnecessary. The tosylate 14 could be prepared in good yield and then converted to the thiosulfonate 13 (62% yield). The thiosulfonate 13 thioalkylated NazS to give 12 (87% yield). Potentialities of intermediates in Scheme I as progenitors of prodrugs was mentioned above. Interest in penicillamine (17) in relation to diseases of collagen, especially +
Me,C(SH)CH( NH,)CO,H 17
+
Me,N( CH,),NMe, 2X18
rheumatoid arthritis,16prompted us to explore the use of the dichloro carbinol 5 for this purpose. Since anticholinergic blocking agents of structure 18 accumulate preferentially in cartilage," linkage of 18-related structures with 17 was attempted in seeking a prodrug of 17 that might localize in connective tissue and show fewer adverse effects than 17.lS Reaction of 5 with trimethylamine gave 16 (X= C1) as a hygroscopic solid (100% yield). This chloride was convertible to iodide or hexafluorophosphate salts (16, X = I or PFB)but was best characterized as the picrate [ 16, X = (NO&PhO]. Since anticholinergic activities would preclude use of 16 for prodrugs, it was determined that 16 (18) For leading citations, see ref 5. (17) Asghar, K.; Roth, L. J. Biochem. Pharmocol. 1971,20, 3151. (18)For discuseion of adverse effects of 17, see: Lyle, W. H. 'Distamine D(-) Penicillamine-a Review": Dista Products Ltd.: Liverpool, 1973; pp 22-28.
224
J. Org. Chem., Vol. 47,No. 2, 1982
(X = C1) does not possess significant anticholinergic or neuromuscular activitie~.'~ Unfortunately, quaternary salts of structure 16 proved to be unpromising choices as prodrug progenitors, chiefly because of such sparing solubility in suitable solvents that conversions and purifications were unsatisfactory (for details, see ref lb). For example, preparation of an unsymmetrical disulfide of 17 was frustrated by inability to convert 16 (X = C1 or PF6)to the requisite tosylate or triflate. Preparation of a thiazolidine of 17 showed promise by spectra when 16 (X = PF6)was oxidized to the aldehyde (MezSO-dicyclohexylcarbodiimide),followed by reaction with 17; however, this product seemed too sparingly soluble (and potentially too toxic) for biological use, and use of this model route failed because of the sparing solubility of 16 (X = C1) and formation of Iz with 16 (X = I). Conversion of the carbinol 5 through the aldehyde to the bis(3-chloropropyl)methylthiazolidineof 17, followed by quaternization with Me3N, was defeated by reaction of a chloropropyl group with the NH of the thiazolidine ring. Acid-catalyzed interchange of 16 (X = C1) with the methyl ester hydrochloride of 17 gave no indication of an ester of 17 when an ethylene dichloride medium was distilled during 23 h to remove MeOH. Experimental Section Melting points were determined by using a Thomas-Hoover stirred-liquid apparatus and are corrected. N M R spectra, reported in parta per million (6), were obtained with a JEOLCO Model JNM-MH-100 spectrometer using MelSi as an intemal standard (or in DzO with Me3Si(CHz)3S03Na).IR spectra were obtained by using Nujol mulls, neat liquids, or KBr pellets with a Perkin-Elmer 727 spectrometer. Elemental analyses were performed by Galbraith Laboratories. Moist extracts were dried by using NazS04 or MgSO,, and the solvent then was removed under reduced pressure by using a rotary-flask evaporator. TLC was performed on Eastman Chromagram Catalog No. 13181 by using the solvents as stated, with visualization by UV or development by Iz vapor. Brinkmann 7729 silica gel (
