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2768 J. Org. Chem. 1993,58, 2168-2773 Intramolecular Addition of a Dioxolanyl Radical to the Indole Nucleus: Preparation of Enantiomerically Pure, Oxygenated Perhydro-3H-pyrrolo[ l,%-alindoles Frederick E. Ziegler' and Patrick G. Harran Sterling Chemistry Laboratory, Yale University, New Haven, Connecticut 0651 1 Received December 14, 1992 The cyclization of dioxolanyl radicals, which were generated by the Barton tartrate-derived thiohydroxamate ester (mixed anhydride) procedure, with an indole nucleus has been explored. The products derived from these reactions have been identified and their chemistry investigated with the goal of uncovering new entries into enantiomerically pure, mitomycin-like structures. Thus, the photolysis of 1-hydroxy-2-thiopyridone ester 8c and l-hydroxy-4-methylthiazole-2(3H)-thione ester 8d has been conducted with UV and visible light. The photochemistry of the producta, namely, dimer 9, dihydroindole 12a, indole 11, and thiazole 13c, derived from the thiohydroxamate esters and putative intermediates 18a and 18b, was also explored. Introduction A previous report from this laboratory described the radical cyclization 1 - 2 as a route to 9,9a-dihydro-3H- pyrrolo[l,2-alindoles, which are substructures related to mitomycins.112 This approach suffered in two respects: the olefin would have required functionalization and the products would have been racemic. To circumvent these difficulties, the sequence 3 - 4 - 5 was considered as a %Br 1 3 2 R R R 4 5 useful study. The dioxolanyl radical 3 could undergo cyclization to form the benzylic radical 4, which would be reduced by an appropriate hydrogen atom source to afford 5. The starred stereogenic, enantiomerically pure center of 3 could serve as a stereocontrol element in the cyclization. Barton has demonstrated that thiohydroxamate esters (mixed carboxylic acid/ thiohydroxamic acid anhydrides) can serve as a convenient source of carbon radicals3 that can engage in intramolecular additions to olefins4 in both chain and nonchain reactions.6 In addition, tartrate- derived thiohydroxamate esters can be used to generate dioxolanyl radicals that participate in intermolecular additions to electron deficient olefins! We chose to explore the tartrate-derived radicals to achieve the transformation described in the reaction 3 - 4 - 5. Results and Discussion Methyl 2,3-0-isopropylidene-~-threonate (7a) was pre- pared from dimethyl L-tartrate as described by Rap~port.~ Neither the derived mesylate 7b7 nor the iodide 7ceserved as effective electrophiles for the alkylation of 3-cyanoindole (6). However, when the triflate 7d, which was prepared in situ, was treated with the potassium salt of 3-cyanoin- dole, the ester 8a was isolated in 86% yield. Acid 8b, which wa~ readily prepared by saponification with aqueous LiOH, was converted to the thiohydroxamate esters 8c and 8d by a variation of the mixed anhydride method? When isobutyl chloroformate and N-methylmorpholine were added to the carboxylic acid to form the mixed anhydride prior to the addition of 1-hydroxy-2-thiopyri- done or l-hydroxy-4-methylthiazole-2(3H)-thione, sub- stantial amounts of the carboxylic acid were eventually reisolated. This order of addition was suspect because it allows excess carboxylic acid to exist in the presence of mixed anhydride, which could lead to symmetrical an- hydride, a source of acid upon acylation of the N-hydroxy species. The yields of the thiohydroxamates were im- proved by adding slowly the amine and carboxylic acid to a solution of the chloroformate. Because the thiohydrox- mates proved somewhat labile, 8c more so than Sd, they were not subjected to chromatographic purification. The (1) Ziegler, F. E.; Jeroncic, L. 0. J. Org. Chem. 1991,56, 3479. (2) For reviews on the synthesis of mitomycins, see: (a) Kametani, T.; Takahashi, K. Heterocycles 1978,9,293. (b) Takahashi, K.; Kametani, T.; Heterocycles 1979,13,411. (c) Franck, R. W. Fortschr. Chem. Org. Naturst. 1979,38,1. (d) Kishi, Y. J. Nat. Prod. 1979,42,649. (e) Kasai, M.; Kono, M. Synth. Lett. 1992, 778. For more recent, notable contributions tothe field, see: (0 Danishefsky, S.;Berman,E. M.; Ciufolini, M.; Etheredge, S. J.; Segmuller, B. E. J. Am. Chem. SOC. 1985,107,3891. (g)Fukuyama,T.;Yang,L. J.Am.Chem.Soc. 1987,109,7880. (h) Benbow, J. W.; Schulte, G. K.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1992, 31, 916. (3) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901. 0022-3263/9311958-2168$04.00/0 (4) a) Barton, D. H. R.; Crich, D.; Kretzachmar, G. J. Chem. Soc., Perkim Tram. I 1986,39. b) Barton, D. H. R.; Guilhem, J.; Herv6, Y.; Potier, P.; Thierry, J. Tetrahedron Lett. 1987,28, 1413. (5) a) Barton, D. H. R.; Crich, D.; Potier, P. Tetrahedron Lett. 1985, 26,5943. b) Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z. Tetrahedron 1987, 43, 2733. (6) Barton, D. H. R.; Gateau-Olesker, A.; Gero, S. D.; Lacher, B.; Tachdjian, C.; Zard, S. Z. J. Chem. SOC., Chem. Commun. 1987, 1790. (7) Munich, J. A.; Rapoport, H. J. Am. Chem. SOC. 1978, 100, 4866. (8) Tanaka, A,; Yamashita, K. Chem. Lett. 1981, 319. (9) a) Barton, D. H. R.; Bridon, D.; Hervb, Y.; Potier, P.; Thierry, J.; Zard, S. Z. Tetrahedron 1986, 42, 4983. b) Barton, D. H. R.; Crich, C.; Hew& Y.; Potier, P.; Thierry, J. Ibid. 1985,41, 4347. 0 1993 American Chemical SocietyOxygenated Perhydro-3H-pyrrolo [ 1,2-a] indoles J. Org. Chem., Vol. 58, No. 10, 1993 2769 displayed an odd number of protons (nine) and the high- resolution mass spectrum indicated a molecular formula of C30H30N404. The unanticipated stereochemistry of the dimer was revealed by a single crystal X-ray analpis.11 The initial expectation was that cyclization would occur through the less-congested transition state with the geometry of 15 to avoid any interaction between the gem- dimethyl group and the aromatic ring. It is clear that the more-congested transition state 16 is involved in the cyclization. Transition state 16 may be governed by an electronic effect, perhaps electron transfer, that leads to the stabilized radical 17, which is compelled to undergo dimerization on the convex face. Alternatively, the odd electron may be transferred to the electron-deficient aromatic system via 15 to give a charge-transfer species that cyclizes through the geometry of 16. H 6 8 a, R = Me XLp2Me b,R=H I\ Ox" 78. x =OH '.";Os I b, X = OMS C,X=I d, X = OTf I


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