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Pyrimidine homonucleoside analogues from 2,5-anhydroaldose derivatives
Carbohyciiate Research, 43 (1975) 265-280 0 EIsevier Scientific PubIishing Company, Amsterdam - Printed in Belgium
PYRIMIDINE HOMONUCLEOSIDE ANALOGUES 2,5-ANHYDROALDOSE DERIVATIVES*t
FROM
JACQUES DEFAYE,DEREKHORTON,SATBHS. KOKFWDY,AND ZDZI.%AW MACHONQ Centre de Recherches sur Ies MacromolPcules V&g&ales, C.N.R.S., B. P. 53,38041 Grenoble (France), and Department of Chemistry, The Ohio State Unioersity, Columbus, Ohio 43210 (U. S. A.) (Received March 27th, 1975; accepted for publication, April 22nd, 1975)
AFsrRAcT
3,4-Di-U-acetyl-2,5-anhydro-D-xylose diisobutyl dithioacetal (1) reacts with bromine to give a monobromo derivative which, on condensation with 2,4-diethoxypyrimidine or its 5-methyl analogue, affords the protected nucleoside derivatives 4 and 11,respectively; ammonolysis of 4 gave the cytosine “homonucleoside” 7, and hydrolysis of 11 gave the thymine “homonucleoside” 12. The same type of “homonucleoside” may be produced by cyclization of the sugar chain in a suitable acyclicsugar nucleoside, as in the conversion of 1-S-ethyI-1-thio-1-(uracil-1-yl)-D-xylitol(P6, obtained from tetra-O-acetyl-D-xylose diethyl dithioacetal, 9), by the action of one molar equivalent of p-toluenesulfonyl chloride, into a homonucleoside isolated as its diacetate 17; acyclic-sugar derivatives not susceptible to such cyclization afford instead the 5-p-toluenesulfonates, as exemplif?ed by the conversion of the D-arabino analogue (13) of 16 into the 5’-ester 14. When cyclohexene is used to remove the excess of bromine in the preparation of nucleoside analogues from dithioacetals, the alkylsulfenyl bromide produced may react, by way of its cyclohexene adduct, with the heterocyclic base +q give cyclohexane-base adducts, for example, compounds 6 and 10. INTRODUCTION
The work described here developed out of an interest, in the Grenoble laboratoriesls6, in the synthesis from anhydro sugar precursors of “homonucleosides” having a carbon atom interposed between a furanosyl group and a residue of a nucleic acid base, together with a program in the Columbus 1ab0ratcXies3~’ for the preparation and evaluation of acyclic-sugar nucleosides in which the heterocyclic base *Part X in the series “Homoanalogues of Aldofurauosyl Nucleosides”, for Part IX, see ref. 1; and PartXVI of the series“2,5-Anhydrides of Sugars”, for PartXV, see ref. 2; see also, ref. 3 for previous, related work. tFor preliminary reports, see refs. 4 and 5. tCNRS Visiting Research Associate; present address: Institute for Chemistry and Technology of Drugs, Medical Academy, 50-140 Wrocfaw, Poland.
266
J.DEFAYE,
D. HORTON,
S. S. KOKRADY,
2.
hfACHON
is attached to a non-cyclized sugar chain. Reactions leading to oxolane rings in the former laboratory’, and studies on acyclic-chain conformations in the latterg, have provided the basis for joint studies” on the influence of conformational and configurational factors on the cyclization of sugar chains. The present investigation describes the synthesis of cytosine and thymine homonucleosides from a 2,5-anhydroaldose precursor, and also illustrates stereochemical control in the formation of a uracil homonucleoside from a pre-formed, acyclic-sugar nucleoside by subsequent cyclization of the sugar chain. DISCUSSION
The synthetic procedure3*l ’ used for base-sugar coupling to give acyclic-sugar nucleosides involves halogenation of an acylated aldose dialkyl dithioacetal to give an unstable, monohalo monothio derivative” which is at once coupled to a suitable derivative of a heterocyclic base1 3. Essentially the same route has been applied” with acylated 2,5-anhydroaldose dialkyl dithioacetals to give homonucleosides. In general, the route gives good yields of coupled product2*3v7, although variable and unexplained low yields have on occasion been encountered in certain preparations for which high yields have been demonstrated. The cause of this difficulty is now shown to arise from the use of cyclohexene2*3 as the scavenging agent for the excess of bromine in the first step of the reaction sequence, as illustrated in the two examples that follow: the difficulty is readily circumvented by use of a slightly modified experimental procedure_ 3,4-Di-U-acetyl-2,5-anhydro-D-xylose diisobutyl dithioacetal’ (1) in carbon tetrachloride was treated with an excess of bromine at room temperature; the resultant, unstable, monobromo derivative 3 was immediately treated, without isolation, with 2,4_diethoxypyrimidine, and then cyclohexene was added to trap the residual bromine. The reaction product was found to be a mixture containing the anticipated, coupled derivative 4 as the major product (whose characterization is described later), together with a minor product migrating more rapidly than 4 on silica gel. The minor product was crystalline, optically inactive, had the empirical formula C1eHz6N20ZS, and gave u.v.- and n.m.r.-spectral data indicative of the presence of an aromatic ring (monoethoxypyrimidinone), an isobutyl group, and methylene groups of a cyclohexane ring. From these data, the mass spectrum (see Scheme I and Experimental section), and the properties of the product of acid hydrolysis, this compound was assigned the structure 5, namely, a disubstituted cyclohexane having adjacent isobutylthio and uracil-l-y1 substituents. Evidently, the cyclohexene used in the procedure reacts with isobutylsuIfeny1 bromide (2, formed in equimolar proportion to the bromide 3), and the resultant adduct, presumably 2-(isobutylthio)cyclohexyl bromide, then reacts with 2&diethoxypyrimidine to give compound S through replacement of the bromine by the base. By analogy with observed reactions’ 3 of 2,4_diethoxypyrimidine with glycosyl halides, and from the
PYRIMIDINE
HOMONUCLEOSIDE ANALOGUES
279
12.30, 13.10, and 13.90 pm. T.1.c. indicated that the product still contained a trace of the slower-moving component present in the originaI reaction-product. Acetylation of the foregoing product (400 mg) by the procedure described for 14 gave 3,4-di-O-acetyl-2,5-anhydro-l-S-ethyl-l-thio-l-(urac~-l-yl)-~-xylitol (17)as a chromatographically homogeneous glass (a small quantity of chIoroform-insoluble material that resulted was discarded); yield 330 mg (62%), [OiJg’ -74” (c 2.0, chloroform); R, 0.32 (ether); A::” 264 nm (E 5,600); Izit! 3.10 (NH), 5.70 (OAc), 5.9, 6.9 (uracil),7.3,8.05-8.2O(ester), 8.5,9.25,9.6,9.8, 10.1, 10.6, 12.25, 13.15, and 13.65pm; n.m.r. (100 MHz, CDCI,): 6 7.73 (doublet, J5,e 8.0 Hz, H-6 of pyrimidine), 5.82 (doublets, H-5 of pyrimidine), 6.06 (doublet, Jr,z 7.0 Hz, H-l), 5.40 (dd, J3,4 - 1 Hz, H-3), 5.25 (multiplet, H-4), 4.38 (quartet, J5=,+ 10.5 Hz, f4,5b 5 Hz, H-5b), 4.18 (doublet of doublets, J2,3 3.5 Hz, H-2), 3.83 (quartet, J_,sa 2.5 Hz, H-5a), 2.55 (quartet, J 7.5 Hz, CH, of Et), 2.14 and 2.08 (singlets, OAc), and 1.26 (triplet, CH, of Et); m/e 372 (1.2, M*), 343 (0.2, M+- *C,H,), 311 (4.1, Mf - -SEt), 283 (1.4), 269 (1.6, Mf - - SEt-CH,=CO), 261 (M* -B), 251 (1.6, M% - *SEt-AcOH), 241 (1.4), 187 (8.8, anhydro ring), 185, (14.5, B-C+HSEt), 167(1.5), 127(1.3, anhydro ring-AcOH), 113 (5.3, BfH,), 112 (4.7, BfH), and 111 (1.8, B’). The overah yield of 17 from 16 was 34%. Anal. Calc. for C,,H,eN,O,S: C, 48.43; H, 5.41; N, 7.52; S, 8.61. Found: C, 48.41; H, 5.68; N, 7.22; S, 8.58. The band containing the minor component (RF 0.09) was extracted, and the product was acetylated to afford the tetraacetate (18) of 16; yield 150 mg (12%), identified by comparison with an authentic specimen3 of 18 by t.1.c. and by-i-r. and n.m.r. spectroscopy. The procedure was repeated with the following changes. The acyclic nucleoside 16 (410 mg, 1.14 mmoles) was dried, and dissolved in anhydrous pyridine (2 ml). The solution was cooled to -lo”, and a solution of p-toluenesulfonyl chloride (253 mg, 1.3 mmoles) in anhydrous pyridine was added. The mixture was kept for 1 h at - 10” and 18 h at 25”, and then processed by the procedure already described, to afford 17 as a chromatographically homogeneous glass; yield 250 mg (51%, based on 16). ACKNOWLEDGMENTS
This work was supported, in part, by a grant from the Ligue National Francaise contre le Cancer, and, in part, by Grant No. CA-15675 (O.S.U.X.F. Project 3980) from the National Cancer Institute, Bethesda, Md. 20014. REFERENCES 1 V. ZECCHI, L. GARUIT, G. GIOVA NNINEITI, L. RODRIGUEZ, M. AMOROSA, AND 3. DEFAAYE,Bull. Sot. Chim. Fr., (1974) 1389-1394. 2 J. DEFAYE AND Z. MACHON, Carbobydr. Res., 24 (1972) 235-245. 3 D. HORTON AND S. S. KOKRADY, Carbohydr. RPS., 24 (1972) 333342. 4 D. HORTON, S. S. KOKRADY, AND J. DEFAYE, Abstr. Papers Amer. Chem. Sot. Meeting, 163 (1972) CARB-11.
280
J. DEFAYE, D. HORTON, S. S. KOKRADY,
2. M.AC!HON
5 J. DEFAYE AND Z. MACHON, Abstr. Papers Sci. Gong. 6 7 8
9 10
11
Polish Pharmaceut. Sac., I&h, Warsaw, Sept. 26-28,1974. J. DEFAME AND M. NAUMBERG, Abstr. Papers Intern. Congr. IUPAC Chem. Nucleic Acid Components, XXIst, Prague, 1967, ~-32. D. HORTON, Pare Appl- Chem., in press; D. HORTON, D. C. BAKER, AND S. S. KOICRADY, Ann. IV_ Y. Acad. Sci., in press. J. DEFAYE, BuCI. Sot. Chim. Fr., (1964) 999-1002, 2686-2689; J. DEFA~ AND J. HILDESHEIM, Tetrahedron Lett., (1968) 313-317; J. DEFAYE AND V. FUTOVELOMANANA, Carbohydr. Res., 17 (1971) 57-65. See D. HORTON AND J. D. WANDER, J. Org. Cizem., 39 (1974)1859-1863,and earlier papersin this series. J. DEFAYE AND D. HORTON, Carbohydr. Res., 14 (1970) 128-132; J. DEFAYE, D. HORTON, AND M. MUESSER,ibid., 20 (1971) 305-318; J. DEFAYE, D. GAGNAIRE, D. HORTON, AND M. MUESSER, ibid., 21 (1972) 407416; J. DEFAYE, D. HORTON, AND M. MUESSER, Abstr. Papers Amer. Chem. Sot. Meeting, 168 (1974) cARI+1. M. L. WOLFROM, A. B. FOSTER, P. MCWAIN, W. VON BEBENBURG, AND A. THOMPSON, J. Org. Chem., 30 (1965) 2732-2735.
12 B. GAUTHIER, Ann. Pharm. Fr., 12 (1954) X51-285; F. WEYGAND, H. Z&mm,
MANN,Chem. Ber., 91 (1958) 2534-2537.
AND H. J. BEST-
13 G. E. HILBERTAND T. B. JOHNSON,J. Amer. Chem. Sot., 52 (1930) 2001-2007; for reviews, see: J. J. Fox AND I. WEMPEN, Adtian. Carbohydr. Chem., 14 (1959) 283-380; J. PLIMLAND M. PRYSTAS, Adcun. Heterocycl. Chem., 8 (1967) 115-142. 14 J. J. Fox, N. C. MILLER, AND R. J. CVSHLEY, Tetrahedron Lett., (1966) 4927-4934; B. A. OI-I-ER AND J. J. Fox, J. Amer. Chem. Sot., 89 (1967) 3663-3664; B. A. OIXR, E. A. FALCO, AND J. J. FOX, J. Org. Chem., 33 (1968) 3593-3600; 34 (1969) 1390-1396. 15 M. L. WOLFROM, M. R. NEWLIN, AND E. E. STAHLY, J. Amer. Chem. Sot., 53 (1931) 4379-4383.
PYRIMIDINE HOMONUCLEOSIDE ANALOGUES 2,5-ANHYDROALDOSE DERIVATIVES*t
FROM
JACQUES DEFAYE,DEREKHORTON,SATBHS. KOKFWDY,AND ZDZI.%AW MACHONQ Centre de Recherches sur Ies MacromolPcules V&g&ales, C.N.R.S., B. P. 53,38041 Grenoble (France), and Department of Chemistry, The Ohio State Unioersity, Columbus, Ohio 43210 (U. S. A.) (Received March 27th, 1975; accepted for publication, April 22nd, 1975)
AFsrRAcT
3,4-Di-U-acetyl-2,5-anhydro-D-xylose diisobutyl dithioacetal (1) reacts with bromine to give a monobromo derivative which, on condensation with 2,4-diethoxypyrimidine or its 5-methyl analogue, affords the protected nucleoside derivatives 4 and 11,respectively; ammonolysis of 4 gave the cytosine “homonucleoside” 7, and hydrolysis of 11 gave the thymine “homonucleoside” 12. The same type of “homonucleoside” may be produced by cyclization of the sugar chain in a suitable acyclicsugar nucleoside, as in the conversion of 1-S-ethyI-1-thio-1-(uracil-1-yl)-D-xylitol(P6, obtained from tetra-O-acetyl-D-xylose diethyl dithioacetal, 9), by the action of one molar equivalent of p-toluenesulfonyl chloride, into a homonucleoside isolated as its diacetate 17; acyclic-sugar derivatives not susceptible to such cyclization afford instead the 5-p-toluenesulfonates, as exemplif?ed by the conversion of the D-arabino analogue (13) of 16 into the 5’-ester 14. When cyclohexene is used to remove the excess of bromine in the preparation of nucleoside analogues from dithioacetals, the alkylsulfenyl bromide produced may react, by way of its cyclohexene adduct, with the heterocyclic base +q give cyclohexane-base adducts, for example, compounds 6 and 10. INTRODUCTION
The work described here developed out of an interest, in the Grenoble laboratoriesls6, in the synthesis from anhydro sugar precursors of “homonucleosides” having a carbon atom interposed between a furanosyl group and a residue of a nucleic acid base, together with a program in the Columbus 1ab0ratcXies3~’ for the preparation and evaluation of acyclic-sugar nucleosides in which the heterocyclic base *Part X in the series “Homoanalogues of Aldofurauosyl Nucleosides”, for Part IX, see ref. 1; and PartXVI of the series“2,5-Anhydrides of Sugars”, for PartXV, see ref. 2; see also, ref. 3 for previous, related work. tFor preliminary reports, see refs. 4 and 5. tCNRS Visiting Research Associate; present address: Institute for Chemistry and Technology of Drugs, Medical Academy, 50-140 Wrocfaw, Poland.
266
J.DEFAYE,
D. HORTON,
S. S. KOKRADY,
2.
hfACHON
is attached to a non-cyclized sugar chain. Reactions leading to oxolane rings in the former laboratory’, and studies on acyclic-chain conformations in the latterg, have provided the basis for joint studies” on the influence of conformational and configurational factors on the cyclization of sugar chains. The present investigation describes the synthesis of cytosine and thymine homonucleosides from a 2,5-anhydroaldose precursor, and also illustrates stereochemical control in the formation of a uracil homonucleoside from a pre-formed, acyclic-sugar nucleoside by subsequent cyclization of the sugar chain. DISCUSSION
The synthetic procedure3*l ’ used for base-sugar coupling to give acyclic-sugar nucleosides involves halogenation of an acylated aldose dialkyl dithioacetal to give an unstable, monohalo monothio derivative” which is at once coupled to a suitable derivative of a heterocyclic base1 3. Essentially the same route has been applied” with acylated 2,5-anhydroaldose dialkyl dithioacetals to give homonucleosides. In general, the route gives good yields of coupled product2*3v7, although variable and unexplained low yields have on occasion been encountered in certain preparations for which high yields have been demonstrated. The cause of this difficulty is now shown to arise from the use of cyclohexene2*3 as the scavenging agent for the excess of bromine in the first step of the reaction sequence, as illustrated in the two examples that follow: the difficulty is readily circumvented by use of a slightly modified experimental procedure_ 3,4-Di-U-acetyl-2,5-anhydro-D-xylose diisobutyl dithioacetal’ (1) in carbon tetrachloride was treated with an excess of bromine at room temperature; the resultant, unstable, monobromo derivative 3 was immediately treated, without isolation, with 2,4_diethoxypyrimidine, and then cyclohexene was added to trap the residual bromine. The reaction product was found to be a mixture containing the anticipated, coupled derivative 4 as the major product (whose characterization is described later), together with a minor product migrating more rapidly than 4 on silica gel. The minor product was crystalline, optically inactive, had the empirical formula C1eHz6N20ZS, and gave u.v.- and n.m.r.-spectral data indicative of the presence of an aromatic ring (monoethoxypyrimidinone), an isobutyl group, and methylene groups of a cyclohexane ring. From these data, the mass spectrum (see Scheme I and Experimental section), and the properties of the product of acid hydrolysis, this compound was assigned the structure 5, namely, a disubstituted cyclohexane having adjacent isobutylthio and uracil-l-y1 substituents. Evidently, the cyclohexene used in the procedure reacts with isobutylsuIfeny1 bromide (2, formed in equimolar proportion to the bromide 3), and the resultant adduct, presumably 2-(isobutylthio)cyclohexyl bromide, then reacts with 2&diethoxypyrimidine to give compound S through replacement of the bromine by the base. By analogy with observed reactions’ 3 of 2,4_diethoxypyrimidine with glycosyl halides, and from the
PYRIMIDINE
HOMONUCLEOSIDE ANALOGUES
279
12.30, 13.10, and 13.90 pm. T.1.c. indicated that the product still contained a trace of the slower-moving component present in the originaI reaction-product. Acetylation of the foregoing product (400 mg) by the procedure described for 14 gave 3,4-di-O-acetyl-2,5-anhydro-l-S-ethyl-l-thio-l-(urac~-l-yl)-~-xylitol (17)as a chromatographically homogeneous glass (a small quantity of chIoroform-insoluble material that resulted was discarded); yield 330 mg (62%), [OiJg’ -74” (c 2.0, chloroform); R, 0.32 (ether); A::” 264 nm (E 5,600); Izit! 3.10 (NH), 5.70 (OAc), 5.9, 6.9 (uracil),7.3,8.05-8.2O(ester), 8.5,9.25,9.6,9.8, 10.1, 10.6, 12.25, 13.15, and 13.65pm; n.m.r. (100 MHz, CDCI,): 6 7.73 (doublet, J5,e 8.0 Hz, H-6 of pyrimidine), 5.82 (doublets, H-5 of pyrimidine), 6.06 (doublet, Jr,z 7.0 Hz, H-l), 5.40 (dd, J3,4 - 1 Hz, H-3), 5.25 (multiplet, H-4), 4.38 (quartet, J5=,+ 10.5 Hz, f4,5b 5 Hz, H-5b), 4.18 (doublet of doublets, J2,3 3.5 Hz, H-2), 3.83 (quartet, J_,sa 2.5 Hz, H-5a), 2.55 (quartet, J 7.5 Hz, CH, of Et), 2.14 and 2.08 (singlets, OAc), and 1.26 (triplet, CH, of Et); m/e 372 (1.2, M*), 343 (0.2, M+- *C,H,), 311 (4.1, Mf - -SEt), 283 (1.4), 269 (1.6, Mf - - SEt-CH,=CO), 261 (M* -B), 251 (1.6, M% - *SEt-AcOH), 241 (1.4), 187 (8.8, anhydro ring), 185, (14.5, B-C+HSEt), 167(1.5), 127(1.3, anhydro ring-AcOH), 113 (5.3, BfH,), 112 (4.7, BfH), and 111 (1.8, B’). The overah yield of 17 from 16 was 34%. Anal. Calc. for C,,H,eN,O,S: C, 48.43; H, 5.41; N, 7.52; S, 8.61. Found: C, 48.41; H, 5.68; N, 7.22; S, 8.58. The band containing the minor component (RF 0.09) was extracted, and the product was acetylated to afford the tetraacetate (18) of 16; yield 150 mg (12%), identified by comparison with an authentic specimen3 of 18 by t.1.c. and by-i-r. and n.m.r. spectroscopy. The procedure was repeated with the following changes. The acyclic nucleoside 16 (410 mg, 1.14 mmoles) was dried, and dissolved in anhydrous pyridine (2 ml). The solution was cooled to -lo”, and a solution of p-toluenesulfonyl chloride (253 mg, 1.3 mmoles) in anhydrous pyridine was added. The mixture was kept for 1 h at - 10” and 18 h at 25”, and then processed by the procedure already described, to afford 17 as a chromatographically homogeneous glass; yield 250 mg (51%, based on 16). ACKNOWLEDGMENTS
This work was supported, in part, by a grant from the Ligue National Francaise contre le Cancer, and, in part, by Grant No. CA-15675 (O.S.U.X.F. Project 3980) from the National Cancer Institute, Bethesda, Md. 20014. REFERENCES 1 V. ZECCHI, L. GARUIT, G. GIOVA NNINEITI, L. RODRIGUEZ, M. AMOROSA, AND 3. DEFAAYE,Bull. Sot. Chim. Fr., (1974) 1389-1394. 2 J. DEFAYE AND Z. MACHON, Carbobydr. Res., 24 (1972) 235-245. 3 D. HORTON AND S. S. KOKRADY, Carbohydr. RPS., 24 (1972) 333342. 4 D. HORTON, S. S. KOKRADY, AND J. DEFAYE, Abstr. Papers Amer. Chem. Sot. Meeting, 163 (1972) CARB-11.
280
J. DEFAYE, D. HORTON, S. S. KOKRADY,
2. M.AC!HON
5 J. DEFAYE AND Z. MACHON, Abstr. Papers Sci. Gong. 6 7 8
9 10
11
Polish Pharmaceut. Sac., I&h, Warsaw, Sept. 26-28,1974. J. DEFAME AND M. NAUMBERG, Abstr. Papers Intern. Congr. IUPAC Chem. Nucleic Acid Components, XXIst, Prague, 1967, ~-32. D. HORTON, Pare Appl- Chem., in press; D. HORTON, D. C. BAKER, AND S. S. KOICRADY, Ann. IV_ Y. Acad. Sci., in press. J. DEFAYE, BuCI. Sot. Chim. Fr., (1964) 999-1002, 2686-2689; J. DEFA~ AND J. HILDESHEIM, Tetrahedron Lett., (1968) 313-317; J. DEFAYE AND V. FUTOVELOMANANA, Carbohydr. Res., 17 (1971) 57-65. See D. HORTON AND J. D. WANDER, J. Org. Cizem., 39 (1974)1859-1863,and earlier papersin this series. J. DEFAYE AND D. HORTON, Carbohydr. Res., 14 (1970) 128-132; J. DEFAYE, D. HORTON, AND M. MUESSER,ibid., 20 (1971) 305-318; J. DEFAYE, D. GAGNAIRE, D. HORTON, AND M. MUESSER, ibid., 21 (1972) 407416; J. DEFAYE, D. HORTON, AND M. MUESSER, Abstr. Papers Amer. Chem. Sot. Meeting, 168 (1974) cARI+1. M. L. WOLFROM, A. B. FOSTER, P. MCWAIN, W. VON BEBENBURG, AND A. THOMPSON, J. Org. Chem., 30 (1965) 2732-2735.
12 B. GAUTHIER, Ann. Pharm. Fr., 12 (1954) X51-285; F. WEYGAND, H. Z&mm,
MANN,Chem. Ber., 91 (1958) 2534-2537.
AND H. J. BEST-
13 G. E. HILBERTAND T. B. JOHNSON,J. Amer. Chem. Sot., 52 (1930) 2001-2007; for reviews, see: J. J. Fox AND I. WEMPEN, Adtian. Carbohydr. Chem., 14 (1959) 283-380; J. PLIMLAND M. PRYSTAS, Adcun. Heterocycl. Chem., 8 (1967) 115-142. 14 J. J. Fox, N. C. MILLER, AND R. J. CVSHLEY, Tetrahedron Lett., (1966) 4927-4934; B. A. OI-I-ER AND J. J. Fox, J. Amer. Chem. Sot., 89 (1967) 3663-3664; B. A. OIXR, E. A. FALCO, AND J. J. FOX, J. Org. Chem., 33 (1968) 3593-3600; 34 (1969) 1390-1396. 15 M. L. WOLFROM, M. R. NEWLIN, AND E. E. STAHLY, J. Amer. Chem. Sot., 53 (1931) 4379-4383.