This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2989--2991 2989 Cite this: Chem. Commun., 2013, 49, 2989 Conformationally restricted pyrrolidines by intramolecular [2+2] photocycloaddition reactions† Diego A. Fort, a Thomas J. Woltering, b Matthias Nettekoven, b Henner Knust b and Thorsten Bach* a Intramolecular [2+2] photocycloaddition reactions of diversely substituted N-Boc protected 4-(allylaminomethyl)-2(5H)-furanones resulted in rigid products (53–75%) with three spatially defined positions for further functionalisation. One of the key ideas in the synthesis of new molecular scaffolds for drug discovery is to generate platforms which allow for the presentation of functional groups in a defined spatial fashion. 1 In this respect, there is great interest in the synthesis of new and unusual scaffolds for medicinal chemistry. 2 Although 3-azabicyclo- [3.2.0]heptanes have been previously recognized as conforma- tionally restricted analogues of pyrrolidine 3 there have so far been no analogues, which allow for further functionalisation at posi- tions C5 and C6 as depicted by structure A in Scheme 1. A concise way to achieve this goal was envisioned by generating the respec- tive [2+2] photocycloaddition 4 products B from lactones C. Despite the relative straightforward approach it was surprising to note that reactions of this type have not yet been conducted. 5–7 Herein we disclose our preliminary experiments in this area, which revealed that tert-butyloxycarbonyl (Boc) is a suitable protecting group PG for this type of chemistry allowing the photochemical generation of type B products on the gram scale. The closest analogy found in the literature for a related intramolecular [2+2] photocycloaddition was the reaction of b-allyloxymethyl substituted enones. 8 It was substantiated that related lactone substrates such as 4-(allyloxymethyl)-2(5H)- furanone (1) undergo a photocycloaddition upon short wave- length irradiation (Scheme 2). The desired product 2 was formed smoothly and in an unoptimised yield of 55%. Disappointingly, the corresponding aza-analogues 3 failed to produce the desired photocycloaddition products. There was no reaction with the unprotected amine (PG = H) while the protected amines (PG = Ac, Ts) decomposed upon irradiation at l = 254 nm. After substantial experimentation we were delighted to discover that the N-Boc protected derivatives 7 are much better behaved when photochemically excited. The respective amines 5, which were required as starting materials in the photocycloaddition, were prepared by Gabriel synthesis 9 (see ESI† for further information). Substitution of bromide 4 10 by these amines led to the unprotected 4-(allylaminomethyl)- 2(5H)-furanones 6 which were without further characterisation treated with Boc 2 O to generate the desired precursors 7 for the photochemical reaction (Table 1). In the photocycloaddition reaction the parent compound 7a delivered cleanly the desired product 8a (entry 1) together with minor amounts of the crossed regioisomer 9a. Separation was facile, however, and tricyclic lactone 8a was isolated in a yield of 73%. The relative configuration was confirmed by extensive one- and two- dimensional 1 H-NMR studies. Mechanistically, it is likely that the reaction proceeds via the respective pp* triplet state of the lactone, 11 with rapid five-membered ring closure 12 prevailing over formation of the six-membered ring. The former ring closure occurs via the respective 1,4-diradical to the straight Scheme 1 3-Azabicyclo[3.2.0]heptanes as conformationally restricted pyrrolidines with three exit vectors and their putative precursors B and C. Scheme 2 [2+2] Photocycloaddition of lactone 1 and structure of 4-(allylamino- methyl)-2(5H)-furanones 3. a Lehrstuhl fu ¨r Organische Chemie I, Technische Universita ¨t Mu ¨nchen, 85747 Garching, Germany. E-mail: [email protected]; Fax: +49 89 28913315; Tel: +49 89 28913330 b Discovery Chemistry, PRCB, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel, Switzerland † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cc40757h Received 29th January 2013, Accepted 25th February 2013 DOI: 10.1039/c3cc40757h www.rsc.org/chemcomm ChemComm COMMUNICATION Downloaded by University of Hong Kong Libraries on 16 March 2013 Published on 06 March 2013 on http://pubs.rsc.org | doi:10.1039/C3CC40757H View Article Online View Journal | View Issue
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This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2989--2991 2989
resulted in rigid products (53–75%) with three spatially defined
positions for further functionalisation.
One of the key ideas in the synthesis of new molecular scaffoldsfor drug discovery is to generate platforms which allow for thepresentation of functional groups in a defined spatial fashion.1
In this respect, there is great interest in the synthesis of new andunusual scaffolds for medicinal chemistry.2 Although 3-azabicyclo-[3.2.0]heptanes have been previously recognized as conforma-tionally restricted analogues of pyrrolidine3 there have so far beenno analogues, which allow for further functionalisation at posi-tions C5 and C6 as depicted by structure A in Scheme 1. A conciseway to achieve this goal was envisioned by generating the respec-tive [2+2] photocycloaddition4 products B from lactones C. Despitethe relative straightforward approach it was surprising to note thatreactions of this type have not yet been conducted.5–7 Herein wedisclose our preliminary experiments in this area, which revealedthat tert-butyloxycarbonyl (Boc) is a suitable protecting group PGfor this type of chemistry allowing the photochemical generationof type B products on the gram scale.
The closest analogy found in the literature for a relatedintramolecular [2+2] photocycloaddition was the reaction ofb-allyloxymethyl substituted enones.8 It was substantiated thatrelated lactone substrates such as 4-(allyloxymethyl)-2(5H)-furanone (1) undergo a photocycloaddition upon short wave-length irradiation (Scheme 2). The desired product 2 wasformed smoothly and in an unoptimised yield of 55%.Disappointingly, the corresponding aza-analogues 3 failed toproduce the desired photocycloaddition products. There wasno reaction with the unprotected amine (PG = H) while theprotected amines (PG = Ac, Ts) decomposed upon irradiation atl = 254 nm. After substantial experimentation we weredelighted to discover that the N-Boc protected derivatives 7are much better behaved when photochemically excited. Therespective amines 5, which were required as starting materialsin the photocycloaddition, were prepared by Gabriel synthesis9
(see ESI† for further information). Substitution of bromide 410
by these amines led to the unprotected 4-(allylaminomethyl)-2(5H)-furanones 6 which were without further characterisationtreated with Boc2O to generate the desired precursors 7 for thephotochemical reaction (Table 1). In the photocycloadditionreaction the parent compound 7a delivered cleanly the desiredproduct 8a (entry 1) together with minor amounts of thecrossed regioisomer 9a. Separation was facile, however,and tricyclic lactone 8a was isolated in a yield of 73%. Therelative configuration was confirmed by extensive one- and two-dimensional 1H-NMR studies. Mechanistically, it is likely thatthe reaction proceeds via the respective pp* triplet state of thelactone,11 with rapid five-membered ring closure12 prevailingover formation of the six-membered ring. The former ringclosure occurs via the respective 1,4-diradical to the straight
Scheme 1 3-Azabicyclo[3.2.0]heptanes as conformationally restricted pyrrolidineswith three exit vectors and their putative precursors B and C.
Scheme 2 [2+2] Photocycloaddition of lactone 1 and structure of 4-(allylamino-methyl)-2(5H)-furanones 3.
a Lehrstuhl fur Organische Chemie I, Technische Universitat Munchen,
2990 Chem. Commun., 2013, 49, 2989--2991 This journal is c The Royal Society of Chemistry 2013
regioisomer 8 whereas the latter (disfavored) ring closureaccounts for the formation of the minor product. In order toestablish a lipophilic group at 1-position of the 3-azabicyclo-[3.2.0]heptanes 8, the respective 2-substituted allylamines 7b–fwere prepared (entries 2–6). The reactions proceeded smoothlyand delivered mainly the desired compounds 8 as majorproducts. Only the bromo compound 7f led to significantamounts of the respective regioisomer 9f (19% yield). Appar-ently, in this case the formation of the bond between C1 and C5in the precursor to product 8 is retarded for steric reasons andan attack of the lactone b-carbonyl atom occurs to a significantdegree also at the terminal end of the olefin. The resultingsix-membered 1,4-diradical provides after rapid intersystemcrossing the other regioisomer.
A beneficial aspect of the studied [2+2] photocycloaddition isthe fact that it proved amenable to scale-up in a continuousflow system.13,14 The only modification was a change of solventto the more polar acetonitrile, which avoids precipitation ofphotochemical side products. At flow rates of 0.25 mL min�1
(c = 40–100 mM) gram quantities of photoproducts 8 could besecured. Product 8a was obtained in a yield of 69% (1.8 g) andthe yield of product 8b was improved to 62% (2.7 g).
Functionalisation at the lateral cyclobutane position withinthe 3-azabicyclo[3.2.0]heptane skeleton was possible by employingallylic amines as substrates, which were substituted at theterminal position. The difluoro-substituted substrate 10 (Scheme 3)was prepared from the respective amine, which in turn wasaccessible from 1,1,1-bromodifluoro-2-propene by Gabrielsynthesis. As recorded previously for intramolecular photo-cycloaddition reaction,15 the electron-deficient fluorinated
alkene did not compromise the yield of the reaction. Ratherthe desired product 11 was formed in a good yield of 63%.Similarly, allene 12 reacted smoothly and delivered cleanly thetricyclic product 13, which exhibits an exocyclic double bondfor further functionalisation.
The propargylic amine 14 did not – as we had hoped – reactto a cyclobutene but delivered a major product, to whichstructure 15 was assigned (Scheme 4). Since a cyclobuteneintermediate was not detected we assume that spiro compound15 is not the result of a secondary photoreaction16 but rather isformed directly from the starting material upon excitation.A possible mechanistic explanation for the result could be aninitial hydrogen abstraction of the photoexcited 2(5H)-furanonefrom the solvent.17 Subsequent intramolecular 5-exo-digcyclisation18 of intermediate 16 delivers a vinylic radical, whichabstracts a hydrogen atom from the solvent to form product 15.In agreement with this suggestion the reaction was significantlyretarded when performed in d10-ether and led to the intro-duction of a deuterium atom at the exocyclic vinylic carbonatom (see ESI† for more detailed information).
Product 15 was also obtained (41% yield) when a 2-iodo-propenyl substituted amine, i.e. the iodo analogue of bromocompound 5f, was employed under the conditions of the [2+2]photocycloaddition. In this case monitoring the reaction courseover time indicated that product formation occurred via alkyne14. After an irradiation time of 20 minutes the starting materialhad completely vanished and alkyne 14 was detected as themajor primary product.
Preliminary experiments were performed to evaluate furtherfunctionalisation reactions of compounds 8, 11, and 13. Apartfrom being pyrrolidine derivatives, the tricyclic 3-amino-9-oxatricyclo[5.3.0.01,5]decan-8-ones also represent buildingblocks with a latent g-amino acid functionality, which in turn
Table 1 Preparation of 4-(allylaminomethyl)-2(5H)-furanones 7 from amines 5and results of their intramolecular [2+2] photocycloaddition
1 5a H 87 3 h 80/20 732 5b Me 76 3 h 90/10 533 5c Ph 68 4 h >95/5 694 5d CF3 74 1 h >95/5 755 5e F 54 90 min 90/10 716 5f Br 90 40 min 77/23 65
a Yield of isolated products. b All photochemical reactions wereconducted for the indicated irradiation time using a RPR-100reactor with 16 Rayonet RPR-2540 Å lamps (quartz apparatus) as theirradiation sources in deaerated diethyl ether (c = 5 mM) as the solvent.c Regioisomeric ratio (rr) denotes the ratio of regioisomers 8 and 9 asdetermined by 1H-NMR integration. d Yield of isolated product 8 as asingle regio- and diastereoisomer.
Scheme 3 [2+2] Photocycloaddition of the terminally substituted olefin 10 andallene 12.
Scheme 4 Reductive cyclisation of propargyl amine 14 to spiro compound 15and structure of the putative intermediate 16.
This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2989--2991 2991
is present in several approved drugs and drug candidates.19
Along these lines, it was probed whether the relatively strainedlactone ring in the representative substrates 8a and 8b could beopened by a suitable nucleophile. To our delight, it waspossible to achieve the ring opening with benzyl amine simplyby stirring the substrates with the nucleophile in THF solutionat ambient temperature. Diastereomerically pure products 17aand 17b were obtained in good yields (Scheme 5). Ring openingwith ammonia required a slightly increased reaction temperatureto provide the primary amides 18a and 18b in high yields. Thereaction was performed with ammonia in a methanol solution at60 1C. While the latter reaction is known to occur also with lessstrained lactones under mild conditions,20 the former reaction isnormally performed at high reaction temperatures20c or with therespective aluminum amides.21 The facile ring opening withcompounds 8a and 8b is the testimony of the higher ring strainof lactones in tricyclic compounds of this type.22
In summary, a new approach to diastereomerically pure3-azabicyclo[3.2.0]heptanes has been presented, which relieson the intramolecular [2+2] photocycloaddition reaction ofN-Boc protected 4-(allylaminomethyl)-2(5H)-furanones. A sub-stituent at C1 is introduced via the respective substrates, whilefurther functionalisation at the nitrogen atom (N3) and atpositions C5 and C6 is feasible. The products should allowaccess to conformationally restricted di- and trifunctionalcompounds, the biological and physical data of which will befurther studied.
D.A.F. wishes to acknowledge funding by the Roche PostdocFellowship (RPF) Program.
Notes and references1 (a) P. Maass, T. Schulz-Gasch, M. Stahl and M. Rarey, J. Chem. Inf.
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2 Review: C. M. Marson, Chem. Soc. Rev., 2011, 40, 5514–5533.3 (a) G. Steiner, A. Bach, S. Bialojan, G. Greger, H.-G. Hege, T. Hoger,
K. Jochims, R. Munschauer, B. Neumann, H.-J. Teschendorf,M. Traut, L. Unger and G. Gross, Drugs Future, 1998, 23, 191–204;(b) T. Bach, C. Kruger and K. Harms, Synthesis, 2000, 305–320;(c) P. Casara, A.-M. Chollet, A. Dhainaut, P. Testage and F. Panayi,U.S. Pat. Appl. Publ., US 20110136886 A1 201106092011.
4 Selected reviews: (a) M. T. Crimmins and T. L. Reinhold, Org. React.,1993, 44, 297–588; (b) J.-P. Pete, Adv. Photochem., 1996, 21, 135–216;(c) J. Iriondo-Alberdi and M. F. Greaney, Eur. J. Org. Chem., 2007,4801–4815; (d) N. Hoffmann, Chem. Rev., 2008, 108, 1052–1103;(e) T. Bach and J. P. Hehn, Angew. Chem., Int. Ed., 2011, 50,1000–1045.
5 For intramolecular [2+2] photocycloaddition reactions of 2(5H)-furanones, see: (a) R. M. Coates, J. W. Muskopf and P. A. Senter,J. Org. Chem., 1985, 50, 3541–3557; (b) R. Alibes, J. L. Bourdelande,J. Font, A. Gregori and T. Parella, Tetrahedron, 1996, 52, 1267–1278;
(c) F. Busque, P. de March, M. Figueredo, J. Font, P. Margaretha andJ. Raya, Synthesis, 2001, 1143–1148; (d) B. T. B. Hue, J. Dijkink,S. Kuiper, S. van Schaik, J. H. van Maarseveen and H. Hiemstra, Eur.J. Org. Chem., 2006, 127–137; (e) R. Miao, S. G. Gramani andM. J. Lear, Tetrahedron Lett., 2009, 50, 1731–1733; ( f ) G. Lutteke,R. A. Kleinnijenhuis, I. Jacobs, P. J. Wrigstedt, A. C. A. Correia,R. Nieuwenhuizen, B. T. B. Hue, K. Goubitz, R. Peschar, J. H.van Maarseveen and H. Hiemstra, Eur. J. Org. Chem., 2011,3146–3155; (g) P. Lu and T. Bach, Angew. Chem., Int. Ed., 2012, 51,1261–1264; (h) S. Pares, R. Alibes, M. Figueredo, J. Font andT. Parella, Eur. J. Org. Chem., 2012, 1404–1417; (i) P. Lu andT. Bach, Chem.–Asian J., 2012, 7, 1947–1958.
6 For a review on photochemical reactions of 2(5H)-furanones, see:A. I. Hashem, A. Senning and A.-S. S. Hamad, Org. Prep. Proced. Int.,1998, 30, 401–425.
7 For intramolecular [2+2] photocycloaddition reactions of cyclica,b-unsaturated ketones with N-alkenoylamino and N-alkenyl-aminocarbonyl substitution at the b-carbon atom, see: (a) A. Amougay,J.-P. Pete and O. Piva, Tetrahedron Lett., 1992, 33, 7347–7350;(b) S. Le Blanc, J.-P. Pete and O. Piva, Tetrahedron Lett., 1993, 34,635–638.
8 (a) M. T. Crimmins and E. B. Hauser, Org. Lett., 2000, 2, 281–284;(b) N. T. Tzevtkov, T. Arndt and J. Mattay, Tetrahedron, 2007, 63,10497–10510.
9 (a) S. Gabriel, Ber. Dtsch. Chem. Ges., 1887, 20, 2224–2236;(b) M. S. Gibson and R. W. Bradshaw, Angew. Chem., Int. Ed. Engl.,1968, 7, 919–930.
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11 D. I. Schuster, G. Lem and N. A. Kaprinidis, Chem. Rev., 1993, 93,3–22.
12 (a) R. Srinivasan and K. H. Carlough, J. Am. Chem. Soc., 1967, 89,4932–4936; (b) R. S. H. Liu and G. S. Hammond, J. Am. Chem. Soc.,1967, 89, 4936–4944; (c) D. J. Maradyn and A. C. Weedon, J. Am.Chem. Soc., 1995, 117, 5359–5360; (d) S. A. Bradley, B. J. Bresnan,S. M. Draper, N. W. A. Geraghty, M. Jeffares, T. McCabe,T. B. H. McMurry and J. E. O’Brien, Org. Biomol. Chem., 2011, 9,2959–2968.
13 M. Nettekoven, B. Puellmann, R. E. Martin and D. Wechsler, Tetra-hedron Lett., 2012, 53, 1363–1366.
14 For recent contributions to flow photochemistry, see: (a) B. D. A.Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. Berry and K. I.Booker-Milburn, J. Org. Chem., 2005, 70, 7558–7564; (b) F. Levesqueand P. H. Seeberger, Angew. Chem., Int. Ed., 2012, 51, 1706–1709;(c) A. Yavorskyy, O. Shvydkiv, N. Hoffmann, K. Nolan andM. Oelgemuller, Org. Lett., 2012, 14, 4342–4345; (d) K. G. Maskill,J. P. Knowles, L. D. Elliott, R. W. Alder and K. I. Booker-Milburn,Angew. Chem., Int. Ed., 2013, 52, 1499–1502 and references citedtherein.
15 D. A. Fort, T. J. Woltering, M. Nettekoven, H. Knust and T. Bach,Angew. Chem., Int. Ed., 2012, 51, 10169–10172.
16 Examples: (a) I. Mancini, M. Cavazza, G. Guella and F. Pietra,J. Chem. Soc., Perkin Trans. 1, 1994, 2181–2185; (b) J. D. Winklerand E. C. McLaughlin, Org. Lett., 2005, 7, 227–229.
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20 Recent examples: (a) H. Yang, N. Goyal, J. R. Ella-Menye, K. Williamsand G. Wang, Synthesis, 2012, 561–568; (b) B. Baragana,O. McCarthy, P. Sanchez, C. Bosch-Navarrete, M. Kaiser, R. Brun,J. L. Whittingham, S. M. Roberts, X.-X. Zhou, K. S. Wilson,N. Gunnar Johansson, D. Gonzalez-Pacanowska and I. H. Gilbert,Bioorg. Med. Chem., 2011, 19, 2378–2391; (c) K. Kulig, K. Wickowski,A. Wickowska, J. Gajda, B. Pochwat, G. C. Hofner, K. T. Wanner andB. Malawska, Eur. J. Med. Chem., 2011, 19, 183–190.
21 A. Conejo-Garcia and C. J. Schofield, Bioorg. Med. Chem. Lett., 2005,15, 4004–4009.
22 B. Basler, O. Schuster and T. Bach, J. Org. Chem., 2005, 70,9798–9808.
Scheme 5 Facile ring opening of lactones 8a and 8b upon treatment withN-benzylamine or ammonia.
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