Tetrahedron Letters, Vol. 37, No. 50, pp. 8967-8970, 1996 Pergamon Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0040-4039196 $15.00 + 0.130 PII: S0040-4039(96)02103-X The Stereocontrolled Synthesis of Enantiopure ~-Methano Heterocycles and Constrained Amino Acid Analogs Stephen Hanessian,* Ulrich Reinhold and Sacha Ninkovic Department of Chemistry, Universit~ de Montr6al, P.O.Box 6128, Station Centre-ville, Montr6al, Quebec H3C 3J7, CANADA Abstract: Addition of trimethylstannyl radicals to acrylate and acrylamide derivatives that contain olefmic groups leads to the corresponding lactones and lactams with good to excellent stereochemical control. ¢t-Methano heterocycles can be easily elaborated from the ct-trimethylstannylmethyl intermediates via putative oxonium and iminium ions generated under acids conditions. Copyright © 1996 Elsevier Science Ltd The synthesis of conformationally constrained amino acids and related molecules has gained enormous popularity in the context of peptidomimetic research and the quest for novel mechanism-based drug design, l In 1992, we reported on an expedient and unprecedented free-radical addition-carbocyclization of terminal dienes induced by trimethylstannyl radicals leading to tetrahydrofurans, pyrrolidines and related heterocycles, as well as to carbocyclic compounds.2, 3 A novel oxidative cleavage of the C-Sn bond with ceric ammonium nitrate was also discovered in the course of the study. We now report on the application of this methodology to the stereocontrolled synthesis of lactones and lactams. We also disclose a new and general route to enantiomerically pure ¢t-methano bicyclic and tricyclic heterocycles by solvolytic cleavage of ot-trimethylstannylmethyl oxonium and iminium ions generated under acidic conditions (Scheme 1). Scheme 1
`
`RI:~I R3
`
`Me3SnCl, NaCNBH3 Me3Sr] R2~R3
`1::12./R3
`M S
`e3 i~
`DIBAH, toluene
`t.....y....K,.iy~...
`-78°C (X = O) -
`AIBN, t-BuOH, reflux
`t.....~,~...
`.[
`1
`"
`32-81%
`,~
`~
`: I °rLiEt3BH'THI~
`O"
`-X"
`-R~ °
`-78°C (X= NBoc) RdOH'~-X'/"R;"
`
`O"
`
`"")
`-R;" n = 0, 1
`-X "~
`O, NR (R = H, Boc, Bn, allyl)
`R 1 = H, alkyl, cycloalkyl, etc.
`R 2 , R 3 = H, CO2Me, alkyl, aryl, etc.
`
`TFA, CH2CI2, 0*C (n = 0) m,
`or PTSA, CH2CI;yMeOH
`r.t. (n = 1)
`
`MezSn
`
`L
`
`(.~
`
`""
`-R; J
`
`~ n<~. "l'n''";X/M"
`R;"
`NH
`
`The method involves the addition of trimethylstannyl radicals to acrylates and acrylamide derivatives that contain a suitably situated acceptor olefinic extremity. In general, the cyclizations were reasonably effective in spite of the intermediacy of resonance stabilized trimethylstannyl propionyl ix-radicals.4, 5 Table 1 lists a number of di- and trisubstituted lactones and lactams prepared in yields ranging from 32-81%. 6 The newly formed bond included vicinal substituents at C2/C3 in all of the five-membered ring heterocycles with 8967
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`X =
`X = O, NBoc; X =
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`8968 an anti (trans) disposition in the major isomers (Table 1, entries 1-9, I1). It is of interest that the amide nitrogen atom can be unsubstituted, or protected as an N-Boc, N-benzyl or even an N-allyl group (Table 1, entries 3-5). The N-allylamide led to the product arising from the initial attack of the trimethylstannyl radical onto the acryloyl group exclusively (Table 1, entry 5). 7 The effect of resident chirality that is vicinal to the acceptor end of the dienic system was also studied. Thus, the product elaborated upon from L-phenylalanine gave the anti~anti isomer as the major product (Table 1, entry 9). The homologated analog shown in entry 10, led to the synlsyn isomer in preponderance. Stereochemical assignments were ascertained from n.O.e. studies and single crystal X-ray diffraction analysis. Carbocyclizations to bicyclic lactams led to surprisingly good selectivities while maintaining efficiency (Table 1, entries 11, 12). The C2/C3 anti stereochemical outcome of the carbocyclization reactions leading to the butyrolactone and pyrrolidinone analogs shown in Table 1 is different from analogous tetrahydrofurans and pyrrolidines, where the syn isomer was invariably favored. 2 Although the reasons for the reversal are not entirely clear, the anti stereochemistry may be the consequence of the geometry of the "radical-enolate", 4 the relative orientation of the other olefinic appendage, and the fact that the transition state of such stabilized radicals may be more product-like. The possibility of equilibration of an initially formed syn isomer under the reaction conditions cannot be excluded. With an efficient access to stereochemically and functionally diverse c¢-trimethylstannylmethyl lactones and lactams in hand, we explored methodology that would lead to (x-heteroatom substituted bicyclic and tricyclic cyclopropanes (Scheme 2). 6 We envisaged that the acid-catalyzed formation of oxonium or iminium ion intermediates would trigger spontaneous cyclization to the corresponding c~-methano products by loss of the trimethylstannyl group as shown in Scheme 2. 8,9 Scheme 2 Meal
`
`%
`
`"
`
`DBU, toluene
`
`'1'~:~'~ ~'°'°/'Ph O ~....../Ph I reflux (70°/*) == o~L'~N~""~'Ph I Boe Boc Boe
`.
`[ a) 1. TFA, CH2CI2
`Ib~ 1. LiEt3BH, THF,-78°C
`/
`
`78 '/. ~ 3.2" 3N HCI, refluXDowex®50WX8
`63o/* ~ -,/"CO2R22" PTSA, CH2CI2 / MeOH
`84'/* ~/CO~R2b)
`
`.j/'-CO2H
`
`;'~
`
`H
`
`h
`[aiD -30.0°
`(c 0.61, H20)
`
`~
`,..,,Kh
`.... '....,/",0, /Ph
`'~,
`"
`R'
`
`r--R 1 = Boc; R2= Me
`
`[~D +20.3°
`(c 0.35, HL:,O)
`
`~
`
`.I--'R 1 =Boc; R 2 = Me
`a
`1
`"~t"N/'l""/Ph
`{MO-22.3°
`(c 0.69, H20)
`
`Reduction 10 of the lactone and the lactam derivatives followed by acid treatment of the corresponding hemiacetals and hemiaminals respectively led to the expected ~-methano heterocycles in excellent yields (Table 1, entries 1-5, 8-11). The all-syn isomer (Table 1, entry 10) could be smoothly epimerized with DBU in refluxing toluene to afford the syn-anti diastereomer in 70% yield with recovery of starting material (16%) (Scheme 2). Treatment with PTSA in methanol/dichloromethane afforded the corresponding ~-methano derivative. The N-Boc and ester groups were cleaved under standard conditions to afford the corresponding cc-methano bicyclic amino acids as pure diastereomers. The novel ct-methano heterocycles reported in this paper can be considered to be rigid mimics of o)- amino acids such as GABA and its congeners, with potentially interesting CNS-related agonist or antagonist activity. I 1 On the other hand, when deployed with an appropriate DNA-binding motif or an intercalating
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`8969 Table 1. Diastereoselective Synthesis of Lactones, Lactams and (x-Methano Heterocycles Entry Diene Major Lactone, Lactam Method c (x-Methano derivative Yielda, b Yielda,b,d
`
` R2 ,,~.~-R2 85% f % Me3Sr~ ,o, I' R2
`
`
`
`I=HR2 ~
`0~
`~
`"~0
`53%
`"
`Xray (4:1)" A 1 2
`A
`66% (14:1)
`RI= R2 = Ph
`R=Bn
`
`Me3Sno-~.Me .-
`58% (4.3:1)g B
`,~,
`.. Me
`
`32% (7:1) B 82%f 5 -= Boc
`R = allyl
`R
`R
`64% (5:1)
`A
`Boc
`R
`
`94% (14:1)
`
`R = Ph
`
`Ph
`
`0
`
`N
`Bn
`
`..~¢
`0
`N
`H
`
`81% (4:1)
`
`B
`
`-
`
`,
`Bn
`
`Me3Sno~, ~--Ph
`
`57% (4.5:1) g B
`
`(~02Me
`
`H
`Me3Sn~,,).~'--CO2Me
`
`I~
`H
`10 Me02C~
`
`[O.]D -23.1 o
`(c 0.60, CHCI3)
`
`H
`
`.~'C02Me
`
`7
`
`8
`
`l 1
`
`12
`
`~...--- Ph
`81%f
`
`Boc
`~--C02Me
`
`Boc
`
`(c 0.75, CHCI3)
`
`.-"~02Me
`
`"
`
`63%f
`,,,,,/Ph
`I
`[Ot]D +27.1 o
`Boc
`(c 0.59, CHCI3)
`
`• , jPh
`"
`[¢t]D -26.1°
`(c 1.05, CHCl3}
`
`Me3 Sn/''~'~
`0-.,-~N~ ,,,,,jPh
`H
`
`60% (4.5:1)g.i B
`
`~13
`0
`N
`H
`
`~
`
`0
`
`N
`Bn
`Me02C"~ H
`~
`~[(Z]D
`0
`
`-82.1°
`(c 0.9, CHCI3)
`
`Me3Sn
`
`O~'~N' ~"
`Bn
`'C02Me
`
`Me3Sn\
`-.....,~
`0
`
`(>10:1) g A
`
`Boc
`
`63*/. (5.5:1) A
`
`-
`
`a. Isolated product, b. Diastereomer ratio b IH, 13C NMR. c. Method A, B, see ref. 6. d. Cycle xopanation method, see ref. 6. e. Major isomer isolated by fractional crystallization from MeOH. f. Single diastereomer, g. For transformation into the N-Boc protected iactams see ref. 6; N-Boc products of entry 3, 8 and 10 are separable by column chromatography, h. Diastereomers separable by flash column chromatography, i. X-ray structure of corresponding racemic 6-phenyl lactam analog.
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`-
`3 ~N ~
`4 0 R
`6 '~ ¢ R=CO2Me Me3Sno~--R 80%(4:1) A
`9
`0 • /Ph %'N, "2 ..... laid +58.6 °
`g"O
`74*/*
`86% f
`/~N~
`

`
`8970 agent on the heterocycle, these tx-methano analogs could act as potential DNA bioalkylation agents by virtue of the generation of onium species and their reaction with specific purine or pyrimidine bases. 12 Further studies aimed at the synthesis of tx-methano heterocycles as rigid analogs of amino acids with demonstrated CNS functions, and base-specific DNA modifiers are in progress. Acknowledgments We thank NSERCC for generous financial assistance through the Medicinal Chemistry Chair program, and the Deutsche Forschungsgemeinschaft for a DFG research fellowship to U. R. We thank Dr. Michel Simard of our crystallography laboratory for the X-ray analyses. References and Notes 1. For recent reviews on peptidomimetics see, Peptide Secondary Structure Mimetics. Tetrahedron Symposia-in print No. 50, Kahn, M., Ed., 1993, 49, 2433-3689; Giannis, A.; Kolter, T.;Angew, Chem. Int. Ed. Engl. 1993, 32, 1244; Kahn, M. Synlett 1993, 821. 2. Hanessian, S.; L6ger, R. J. Am. Chem. Soc. ,1992,114, 3115; Synlett, 1992, 402. 3. For recent reviews on free radicals, see: Jasperse, C. P.; Cutran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron 1990, 46, 1385. Curran, D. P. Synthesis 1988, 417, 489. C-Radicale. In Methoden der Organischen Chemie; Regitz, M.; Giese, B., Eds.; Houben-Weyl: Stuttgart, Germany, 1989; Voi. E19A. 4. Lung-rain, W.; Fischer, H. Helv. Chim. Acta 1983, 66, 138; Barnabas, M. V.; Venkateswaran, K.; Walter, D. C. J. Am. Chem. Soc. 1990, 112, 7163. 5. Hanessian, S.; Di Fabio, R.; Marcoux, J.-F.; Prud'homme, M. J. Org. Chem. 1990, 55, 3436, and references cited therein. 6. Methods of radical cyclization. Method A: Diene, Me3SnCI, NaCNBH3 and AIBN (cat.) are heated in refluxing t-BuOH (see ref. 2). Method B: A solution of 1.5-4.0 eq. NaCNBH3 and AIBN (cat.) in MeOH is added slowly (1 to 13 h) to a solution of diene and 1.1 - 1.3 eq. Me3SnCI in refluxing t-BuOH using a syringe pump. Method ofcyclop'ropanation: Lactones are reduced to the corresponding lactols with Dibal in toluene at -78°C; the N-Boc protected lactams are reduced with LiEt3BH in THF at -78°C (see ref. 10). The lactols and the N,O-hemiaminals are then treated with 12 eq. TFA in CH2CI 2 (0.05M) at 0°C to give the cyclopropane derivatives. For entry 10, 3 eq. of PTSA in a 1:1 mixture of CH2CI2/MeOH (0.02M) at r.t was used. In entry 1, the lactol was treated first with i-PrOH under acid catalysis (PPTS) to form the corresponding acetal in 82% yield. N-Boc protection of lactam: The deprotection of N-Bn protected lactams was performed by reductive cleavage with Li/NH 3. The N-Boc protection was carried out with Boc20, DMAP and Et3N in CH202 (78%, 96%, 96%, 97%, 71% and 28 % starting material for entry 3, 7-9 and 11) or in CH3CN (90% for entry 10). The diastereomers of the Boc-protected lactams (entry 3, 8 and 10) are separable by column chromatography. 7. See for example, Stork, G.; Mah, R. Heterocycles, 1989, 28, 723; Keusenkothen, P. F.; Smith, M. B. Tetrahedron Lett. 1989, 30, 3369; Jolly, R. S.; Livinghouse, T. J. Am. Chem. Soc. 1988, 110, 7536. 8. For carbocyclizations mediated by alkyltin (IV) intermediates, see Macdonald, T. L.; Delahunty, C. M.; Mead, K.; O'Dell. D. E. Tetrahedron Lett. 1989, 30, 1573; Macdonald, T. L.; Mahalingam, S.; O'Dell, D. E. J. Am. Chem. Soc. 1981, 103, 6767; for cyclopropane formation from ~,-stannyl alcohols, see Davis, D. D.; Johnson, H. T. J. Am. Chem. Soc. 1974, 96, 7576; Kuivila, H. G.; Scarpa, N. M. J. Am. Chem. Soc. 1970, 92, 6990; for cyclopropane formation from [~-stannyl ketones, see Sato, T.; Watanabe, M.; Watanabe, T.; Onoda, Y.; Murayama, E. J. Org. Chem. 1988, 535, 1894; Johnson, C. R., Kadow, J. F. J. Org. Chem. 1987, 52, 1493. 9. For Simmons-Smith type cyclopropanations of enol ethers and related compounds, see Hoberg, J. O.; Claffey, D. J. Tetrahedron Lett. 1996, 37, 2533; Timmers, C. M.; Leeuwenburgh, M. A.; Verheijen, J. C.; van tier Marel, G. A.; Van Boom, J. H. Tetrahedron: Asymmetry 1996, 7, 49; Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. J. Ant Chem. Soc. 1991, 113, 5227; see also Beddoes, R. L.; Lewis, M. L.; Quayle, P.; Johal, S.; Attwood, M.; Hurst, D. Tetrahedron Lett. 1995, 36, 471. 10. For lactam reduction see Pedregai, C.; Ezquerra, J. Tetrahedron Lett. 1994, 35, 2053. Reduction of lactones was performed by a modified procedure of Bitch, R.; Gilbert, L. J. Org. Chem. 1987, 52, 4605. 11. See for example, KnOpfel, T.; Kuhn, R. Allgeier, H. J. Med. Chem. 1995, 38, 1417; for tz-methano benzopyran analogs, see Annoora, H.; Fukanaga, A.; Llesugi, M.; Tatsuoka, T.; Horikawa, Y. Bioorg. Med. Chem. Lett. 1996, 6, 763. 12. See for example, Chen, X.-Y.; Link, T. M.; Schramm V. L. J. Am. Chem. Soc. 1996,118, 3067. (Received in USA 19 August 1996; revised 21 October 1996; accepted 22 October 1996)
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