J. Org. Chem. 1992,57,6088-6089
6088
the formation of Sb rather than Sa is not caused by kinetic experiments to prove the existence of l b as intermediate reaaons but rather by the higher stability of the former might also be successful. isomer.15 This agrees with our calculated result that l b is lower in energy than la. Since the olefinic strain energy Acknowledgment. This work was supported by the in should not be signifimtly u h e r in dogous Deutache Forschungsgemeinschaft,the Fonds der Chemischen Industrie. and the comDuter comDanies Silicon Graphics and Convex. Additiod computer-time was given (15) Szeimies, G. Personal communication to G.F. by the HLRZ Julich and the HHLR Darmstadt.
A Polymer-Supported Chiral Auxiliary Applied to the Iodolactonization Reaction: Preparation of r-Butyrolactones Hong-sik Moon, Neil E. Schore,* and Mark J. Kurth*J Department of Chemistry, University of California, Davis, California 95616 Received August 4, 1992
Summary: A reactive polymer strategy for the preparation of nonracemic 3,5-disubstituted y-butyrolactones from a novel (S)-2-pyrrolidine-fctionalizedpolystyrene resin is presented.
Resident stereochemistrycan profoundly influence the course of electrophilic cyclization reactions aa demonstrated by the iodo cyclizations of hepta-1,6-diene-4carboxylic acids (olefin and face selectivity)? 3-hydroxy2-(2’-methylenecyclohex-l’-yl)butyric acids (nucleophile [i.e., -OH vs -C02R] and face selectivity),3 and of abranched y,S-unsaturated N,N-dialkylamides (enantioselective olefin and face ~electivity).~This, coupled with the fact that polymer-supported synthesis is emerging as an important tool in the development of new synthetic strategies in organic chemistry+6 led us to explore the exciting potential of polymer-bound chiral auxiliaries’ in enantioselective electrophilic cyclization protocols. Presumably, the advantages of polymer-supported synthetic strategy would include ease of workup, ease of product isolation, ready recovery of the polymer-supported chiral auxiliary by a simple filtration technique, and minimization of side-product formation.s Intrigued by these potential advantages, we set out to explore the application of polymer-supported chiral aux(1) Sloan Foundation Fellow (1987-1991) and NIH RCDA recipient (1989-1994; EC00182). (2) Kurth, M. J.; Brown, E. G. J. Am. Chem. SOC.1987, 109, 6844. (3) Kurth, M. J.; Beard, R. L.; Macmillan, J. G.; Olmstead, M. J. Am. Chem. Soc. 1989,111, 3712. (4) Najdi, S. D.; Reichlin, D.; Kurth, M. J. J. Org. Chem. 1990, 55, 6241. (5) Reviews: (a) Hodge, P. Polymer-supported Reagents. In Poly-
mer-supported Reactions in Organic Synthesis; Hodge, p., Sherrington, D. C., E~E.; Wiley-Interscience: Chicheater, 1980; Chapter 2. (b) Pittman, C. U., Jr. Catalysis by Polymer-supported Transition Metal Complexes. In Zbid.; Chapter 5. (c) Bergbreiter, D. E. Soluble Polymer-Bound Reagents and Catalysts. In Polymer Reagents and Catalysts; Ford, W. T., Ed.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986, Vol. 308, 17. (d) Hodge, P. Organic Reactions Using Polymer-supported Catalysts, Reagents or Substrata. In Synthesis and Separations wing Functional Polymers; Sherrington, D. D., Hodge, P., Eds.; Wiley: Chichester, 1988; Chapter 2. (e) Hodge, P. Polymer-supported Asymmetric Organic Synthesis. In Znnouation and Perspectiues in Solid Phcrse Synthesis, 1990; Epton, R., Ed. Collected Papers, First International Symposium, 1989; Oxford, Eng. SPCC (UK)Ltd.; Birmingham, 1990. (6) (a) Schore, N. E.; Najdi, S . D. J.Am. Chem. SOC.,1990,112,441. (b) Gerlach, M., Jerdens, F.; Kuhn, H.; Neumann, W. P.; Peterseim, M. J. Org. Chem. 1991, 56, 5971. (c) Blanton, J. R.; Salley, J. M. J. Org. Chem. 1991,56,490. (7) Itsuno, S.; Sakurai, Y.;Ito, K.; Maruyama, T.; Nakahama, S.; Frechet, J. M. J. J. Org. Chem. 1990,55, 304. (8) (a) Hodge, P. Rapra Rev. Rep. 1992,5, 1. (b) Guyot, A.; Hodge, P.; Sherrington, D. C.; Widdecke, H. React. Polym. 1992,16, 233.
Scheme I
1$ - n r W I I R - Y
,
4
iliary reactions in enantioselective synthesis and describe herein a polymer-supported strategy for a three-step process consisting of N-acylation of a chiral amine, amide Ca-alkylation? and iodo cyclization,l0which leads to the enantioselective preparation of a-substituted y-butyrolactones. Having already reported the solution-phase version of this process,4 we decided to extend this chemistry to a polymer-supported version by preparing a polymer-bound secondary amine. Our plan was to Nacylate the secondary amine, Ca-alkylate the resulting amide, and finally iodolactonize to a 3,bsubstituted ybutyrolactone. It is noteworthy that the final step of this process would not only produce the targeted iodo lactone but would also simultaneously regenerate the reactive polymer replete with ita secondary amine chiral auxiliary. A prolinol-functionalized reactive polymer was required to launch this project, and a C-O linkage of the chloromethylated polystyrene resin” and (@-(+)-2-pyrrolidinemethanol (L-prolinol) was targeted. While Evans’ pioneering chiral amide Ca-alkylation work established that solution-phase selectivity is highest when the prolinol hydroxyl is unblocked,12 we chose to pursue this 0-alkylated strategy for two reasons: (i) it would allow us to compare directly our anticipated polymer-supported results to previously reported solution-phaseresulta4J2and (ii) 0-alkylative coupling of L-prolinol to Merrifield’s polymer appeared to offer quickest access to a reactive polymer. As illustrated in Scheme I, we decided to introduce L-prolinol in ita amide form since the resulting 5-pentenamide functionalized polymer would be immediately poised for the key iodo cyclization reaction (2 4).
-
(9) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; M e r , R. J. Am. Chem. SOC.1990,112,5290. (10) BartJett, Paul A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: Orlando, 1983; Vol. 3, pp 411-54. (11) Merrifield’s peptide resin (i.e., chloromethylated form of 2% cross-linked polystyrene/divinylbenzenecopolymer): Merrifield, R. B. J. Am. Chem. SOC.1963,85,2149. (12) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233.
0022-3263/92/1957-6088%03.00/0 , Q 1992 American Chemical Society I
1
J. Org. Chem., Vol. 57, No.23, 1992 6089
Communications Scheme I1
insights were gained from the overall transformation 2 -.+ 6-9. Firstly, no evidence for the nonmethylated lactone 4 was detected in the crude reaction mixture; apparently, Ca-methylation of the polymer-bound amide moiety proceeds nicely. Secondly, diastereoselectivity in this polymer-bound alkylation reaction closely matches that obtained in solution-phase alkylations of prolinol derived amides (i.e., la gives the Ca-methylated amide l b in a 73:27 ratio: ICis obtained as a 62:38 mixture of diastereomers when the corresponding propionamide is alkylated with allyl bromide,12 and 2 5 must proceed with 67:33 selectivity as reflected by the ratio of 6 + 7 vs 8 9). Finally, the W6 kana versus cis (6+ 8 VB 7 + 9)selectivity of the iodo lactonization reaction 5 6-9 nearly equals that of the solution-phase reaction ( l b 6-9;928 trans vs cis). All that remained to complete this polymer-supported reaction cycle was to demonstrate that (S)-2-pyrrolidinefunctionalized resin 3 could be reused in a repetitive process to generate y-butyrolactones with recovery of reactive 3. As the first step, resin 3, previously recovered from the conversion of resin 5 to iodo lactones 6-9, was swollen in THF and treated with propionyl chloride and triethylamine at room temperature for 2 days giving propionamide 10 as evidenced by FTIR analysis (FTIft [KBr] 1642 cm-', c-0). Subsequent Ca-allylation (LDA, THF; allyl iodide) delivers polymer-bound pentenamide 5' with 0.96 mequiv of C=C/g of resin as judged by quantitative bromine titration of the newly introduced olefin; whereas Ca-methylation of resin 2 gave a preponderance of the Ca-(R) diastereomer (i.e., 5), presumably Ca-allylation of 10 causes the Ca-(8-diastereomer to predominate &e., 59. Indeed, this presupposition is supported by the ensuing iodocyclization reaction which generates y-butyrolactones 6-9, but this time in a 33:1:62:4 ratio, respectively. These results demonstrate that polymer-bound chiral auxiliaries have substantive synthetic potential in the preparation of nonracemic, 3,5-disubstituted y-butyrolactones and that all of the reactions employed in this sequence proceed in chemical yields comparable to those obtained in the corresponding solution-phase reactions. Moreover, the diversity of reactions, solvents, and conditions presented in this sequence demonstrates the versatility of polymer-supported methodology in multistep enantioselective sequences. In addition, the polymersupported chiral auxiliary is sufficiently robust to be recovered and recycled through the reaction sequence. Work is underway to develop second-generation polymer-bound chiral auxiliaries which will improve the enantioselectivity of this process.
-
A THF solution of the potassium alkoxide of pentenamide la,13prepared in 83% yield from L-prolinol and 4-pentenoyl chloride, was added to DMF-swollen Merrifield's resin (2% cross-linked;1mequiv of Cl/g) containing l€?-c.rown-6. Incubation of thismixture at 80 OC for 3 days followed by filtration and thorough washing of the resulting resin delivered 2 as evidenced by the appearance of an FTIR (Kl3r) band for the amide at 1646 cm-'. The degree of functionalization of 2 was found to be 0.97 mequiv of C==C/gof resin as determined by bromine titration of the CCl, swollen polymer.14 Iodomethylated poly~tyrene'~ was also used for this auxiliaryresin coupling reaction but appeared to offer no advantage over the commercially available chloromethylated resin. We were pleased to find the iodo lactonization of the polymer-bound pentenamide moeity could be effected by stirring a THF/water (1.41) mixture of resin 2 with iodine for 3 days at room temperature. Filtration and ether washing of the resin delivered y-butyrolactone 416 essentially pure as a 6535 mixture of enantiomers4 in 40% overall yield from pentenamide la. Moreover, (S)-pyrrolidine-functionalid resin 3 was liberated (disappearance of the FTIR amide band at 1646 cm-') by this heterocyclization. Having demonstrated the key iodo cyclization reaction, we next set out to perform the polymer-bound Ca-amide alkylation step. In the event, treatment of a THF suspension of resin 2 with lithium diiipropylamide (1.2 equiy 0 "C, 30 min) followed by methyl iodide (1.0 equiv) delivered Ca-methylated pentenamide 5. Direct evidence for this conversion was not accessible, so we were delighted to fiid that subsequent iodo cyclization of this resin furnished 5-(iodomethyl)-3-methyl-y-butyrolactones 6917in 33% overall yield from pentenamide la as a 63431:2 mixture of isomers, respectively.l8 Several important -(13) (a)Moeller, K.D.; Rothfus, S.L.;Wong, P.L. Tetrahedron 1991, 47, 583. (b) See ref 4.
(14)Yamamoto,Y.;Okubo, M.; Iwasaki, Y. Colloid Polym.Sci. 1991, 269,1126. (15)Lecavalier, P.;Bald, E.; Jiang, Y.; FrCcht, J. M.; Hodge, P. Reactive Polym. 1986,3, 315. (16)(a) Guenther, H. J.; Guntrum, E.; Jaeger, V. Liebigs Ann. Chem. 1984,16. (b) See ref 4. (17)(a) Tamaru, Y.;Mizutani, M.; Furukawa, Y.; Kawamura, S.; Yoshida, Z.;Yanagi, K.; Minobe, M. J. Am. Chem.SOC.1984,106,1079.(b) See ref 4. (18) (a) In our hands, the overall yield in the corresponding solutionphase chemistry (i.e., N-acylation/Ca-alkylation/iodo lactonization) is 45%. (b) For iodo lactones 6-9, enantiomeric excesses were determined by HPLC (SiOP/hexane:EtOAc = 191) separation of the cis and trans mixture and then enantiomer resolution by capillary GC (8-cyclodextrin on OV-1701(30m) column, 100 O C isothermal, Hz at 6 psi: Rf(R,S)-6 = 157.8min, R, (S,R)-8 = 160.2 min].
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+
Acknowledgment. We are grateful to the National Science Foundation (Grant CHE-9108231) and the donors of the Petroleum Research Fund, administered by the American Chemical Society, for the financial support of this research. Supplementary Material Available: Experimental details for the preparation of and spectral data for 1-10 (4 pages). This material is contained in many libraries on microfiche, immediately follows this article in the microfilm version of the journal, and can b ordered from the ACS see any current masthead page for ordering information.
