Intramolecular amidocyclopropanation reactions of diethoxymethyl-lactams containing a pendant alkene were examined using zinc/TMSCI. With a range of 4-6-membered lactams, bicyclic amidocyclopropanes were obtained with very high diastereoselectivity with a preference for the formation of the More hindered endo-cyclopropane. (C) 2009 Elsevier Ltd. All rights reserved

Aliev, AE

Jerome, L

Motherwell, WB

Sheppard, TD

UCL Discovery

The final published version of this article can be found athttp://dx.doi.org/10.1016/j.tetlet.2009.03.224.Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursorsLaure Jerome, Tom D. Sheppard, Abil E. Aliev, William B. Motherwell*Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, UK WC1H 0AJFax: +44 (20)76797524.E-mail: w.b.motherwell@ucl.ac.uk.m = 1, 2, 3n = 1, 2NOHHNONHO OEtEtO(EtO)3CHAlCl3ZnMe3SiClZnCl2 nmmnnmIntramolecular amidocyclopropanation reactions of diethoxymethyllactams containing a pendant alkene were examined usingzinc/TMSCl. With a range of 4-6 membered lactams, bicyclic amidocyclopropanes were obtained with very high diastereoselectivitywith a preference for the formation of the more hindered endo-cyclopropane.Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursorsLaure Jerome, Tom D. Sheppard, Abil E. Aliev, William B. Motherwell*Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, UK WC1H 0AJFax: +44 (20)76797524.E-mail: w.b.motherwell@ucl.ac.uk.Received: The date will be inserted once the manuscript is accepted..Keywords: lactams, carbenoids, cyclopropanes, zinc, alkenes.The aminocyclopropyl unit is present in a considerable number of biologically active natural productsand pharmaceuticals.1 In structural terms, the rigidity of this small ring provides an excellent molecularscaffold for precise location of functional groups within a more complex system. In contrast totraditional carbene or carbenoid methods for aminocyclopropane synthesis such as Simmons-Smithaddition to an enamine or enamide derivative2 or those which require subsequent functional groupmanipulation, as in the Curtius rearrangement of cyclopropyl carboxylic acids,3 our current strategyinvolves direct cyclopropanation of simple alkenes using heteroatom-functionalised organozinccarbenoids.4-6 Thus, as encapsulated in Scheme 1, an organozinc carbenoid 4 can be generated directlyand efficiently from a diethoxymethylamide 1 in the presence of metallic zinc, chlorotrimethylsilane anda Lewis acid. A plausible mechanism involves activation of an ethoxy group of the orthoamide by theLewis Acid and chlorotrimethylsilane, thus generating an intermediate 2, which, on subsequent deliveryof two electrons from zinc leads to the organozinc carbenoid 4 which can then cyclopropanate an alkene(Scheme 1).R1ONR2EtO OEtR1ONR2EtOClZnR1ONR2EtO ZnClR1ONR2Cl ZnClClSiMe3-Me3SiOEt-Me3SiOEt1432Me3SiClR4R6R5R3cyclopropanationN R2R6R5R3R4Horganozinc carbenoidZnCl2R1O56Scheme 1We have recently reported on the use of this protocol for the synthesis of a variety of structurallyinteresting functionalised amidocyclopropanes6 and, in view of the significant number of antiviral,7antibacterial8 and antitumor compounds9 which contain an aminocyclopropyl ring within a polycyclicframework, it was of particular interest to investigate the potential of the intramolecular variant of ourorganozinc carbenoid reaction on suitably substituted lactams 7-12 (Scheme 2).a NOHHmNO OEtEtO7 m=1, n=1, R =H8 m=2, n=1, R =H9 m=2, n=2, R =H10 m=3, n=1, R =H11 m=3, n=2, R =H12 m=2, n=1, R =MeRR13 m=1, n=114 m=2, n=115 m=2, n=216 m=3, n=117 m=3, n=2nnmScheme 2 Reagents and conditions a) Zn source, Me3SiCl, ZnCl2, Et2O, 44 °C.In recent times, a variety of approaches for the preparation of polycyclic aminocyclopropranes viaintramolecular reactions have been reported, including elegant variants of the Kulinkovich10 reactiondeveloped by de Meijere11 using Ti(II)-mediated coupling of tethered N,N-dialkylamides,12 andtransition metal-mediated cyclopropanation of enamides with diazoesters.13 It should be notedhowever, as highlighted in Scheme 2, that the tricyclic products produced in the present method alsocontain a lactam functionality useful for further elaboration, and that, in contrast to the titanium-mediated intramolecular cyclopropanation of -vinylimides,12a a linearly-fused tricyclic system isobtained.The lactams 22-26 were prepared simply from cyclic imides 19 and 20 by a one-pot sequenceinvolving reaction with an excess of the appropriate unsaturated Grignard reagent, followed byreduction,14 whilst lactam 21 was prepared by [2+2] cycloaddition of 1,5-hexadiene 18 andchlorosulfonyl isocyanate (Scheme 3).15 The lactams were then heated in triethyl orthoformate at 160°C in the presence of a catalytic amount of aluminium chloride to give the diethoxymethyllactams 7-12.16 The yields for these steps are given in Table 1.mNHOONHOnm19 m=120 m=2a, b c22-26 7-12Rm = 1, 2; n = 1, 2; R = H or MeRHNOd c2118pnNO OEtEtORRp = 1, 2, 3; n = 1,2; R = H or MeScheme 3 Reagents and conditions: a) R2C=CH(CH2)nCH2MgBr, THF; b) NaBH3CN, AcOH, THF,then 5% aq. NaOH; c) AlCl3, CH(OEt)3, 160 °C; d) ClSO2NCO, CH2Cl2 r.t., 7 days, then Na2SO3,KOH, H2O.With the carbenoid precursors 7-12 in hand, the intramolecular cyclopropanation was readilyperformed using a zinc source in the presence of trimethylsilyl chloride and zinc chloride in refluxingdiethyl ether, to give the corresponding cyclopropanes in moderate yields (Scheme 2, Table 1). Traceamounts of the starting lactam derived from hydrolysis of the orthoamide were also noted.Entry Amide(yield)Orthoamide(yield)Cyclopropane(yield)1NHONO OEtEtONOHHH21 (37%) 7 (32%) 13 (21%)c2NHONOOEtOEt NOHHH22 (64%) 8 (46%) 14 (41%)a3NHONOOEtOEtNOHHH23 (73%) 9 (59%) 15 (41%)b4 NHONOOEtOEtNOHHH24 (66%) 10 (42%) 16 (21%)c5 NHONOOEtOEtNOHHH25 (68%) 11 (55%) 17 (26%)c6NHONOOEtOEtNOHHNOHH272826 (47%) 12 (66%) not isolatedTable 1 a Zn(Hg); b Zn; c Zn/CuClExamination of these results reveals that selection of a tethered γ-lactam derivative provided the highest yields (entries 2 and 3) irrespective of whether the organozinc carbenoid was participatingin formation of a bicyclo [4.1.0] (six-membered ring) or a [5.1.0] (seven-membered ring) subunit.By way of contrast, the use of either the more conformationally mobile tethered δ-lactams (entries 4 and 5) or of the relatively rigid β-lactam (entry 1) led to a significant reduction in yield. Moreover, the selection of a trisubstituted alkene tether as in substrate 12 (entry 6) furnished a mixture of thecyclic alkenes 27 and 28, as evidenced by NMR analysis of the crude reaction mixture, and nocyclopropane was detected. A possible mechanism for the formation of 27 and 28 is outlined inScheme 4.NOHOEtHNOHNOHZnZnClNOHHONO-H+-EtOSiMe3NOHH292728303132H+Scheme 4Clearly, in this instance, cyclisation of the trisubstituted alkene onto the low energy N-acyl iminiumcation 29 must be faster than two-electron reduction by zinc. Proton loss followed by Lewis acid-mediated departure of the second ethoxy group then gives the conjugated acyl iminium ion 31,which can be reduced to give the allylzinc species 32. Protonation of 32 then gives a mixture of thetwo alkenes 27 and 28.From a stereochemical standpoint, it was important to determine whether the cyclopropane unit wasthe more hindered endo isomer 14, as opposed to the sterically less congested exo diastereoisomer33 (Table 2). Since these two isomers were not likely to be distinguishable using simple NMRtechniques, a combined NMR calculation and molecular modelling approach was used to determinewhich structural isomer provided the best fit with the NMR data.endo-C1,C3 exo-C1,C3NOH3aH1' H1H2'H3'H3H4'H414 33NOH3aH1'H1H2'H3'H3H4'H4nOe ratio Dihedral angles/° Couplingconstants/Hzη1’3/η1’2’ H3CCH3a H3aCCH4 J3,3a J3a,4Predicted for 14 4.1 177 154 11.8 (9.6) 10.3 (8.2)Predicted for 33 0.1 177 153 11.8 (9.6) 10.2 (7.9)Observed 3.4 11.5 8.8Table 2 Vicinal 3JHH couplings were predicted using a Karplus-type equation,17 accounting for thedependence of 3JHH on both the dihedral angle and the substituent electronegativities. The valuesshown in brackets are from the B3LYP/6-311+G(2d,p) calculations of the J couplingsThus, the geometry of the predominant configuration and conformation for each polycyliccompound was confirmed by a detailed comparison of the observed 1H-1H coupling constants andnuclear Overhauser enhancements (nOe) with values obtained from molecular mechanicscalculations using the MMX force field18 followed by DFT calculations using the B3LYP/6-31G(d)level of theory.19 As an illustration, in the case of compounds 14 and 33 computational studiesallowed prediction of the nOe ratios, dihedral angles, chemical shifts and coupling constants forboth isomers as depicted in Table 2, showing two large 3JHH couplings on proton 3a-H. Comparisonwith the experimental results clearly indicated the endo-orientation of the 3-CH2 and thecyclopropane ring (denoted as endo-C1,C3). In particular, on selective excitation of proton 1’-H thecorresponding enhancement ratio for protons 3-H and 2’-H (1’→3/1’→2’) was found to be 3.4. Fromthe B3LYP/6-31G(d) optimised geometry, the internuclear distances, r, between protons 1’-3 and1’-2’ in the endo-C1,C3 conformation are 2.44 Å and 3.09 Å, respectively. Thus, using the initialrate approximation,20 which is based on the r–6 dependence of nOe’s, the expected enhancementratio is 4.1. This compares well with the measured value of 3.4. For comparison, the expected nOeratio is only 0.1 in the alternative exo-C1,C3 conformation (Table 2). A detailed discussion of thisapproach and further examples are provided in the supplementary informationThe preference for formation of the more hindered product may possibly be rationalised byconsideration of the two possible transition states shown in Figure 1, both of which feature an“amidoorganozinc carbenoid” in which the oxygen atom of the lactam is coordinated to the zincatom. The observed stereochemical outcome would result from the less strained and less stericallycongested approach of the alkene to the carbenoid A, rather than the somewhat more hinderedapproach B which would lead to the exo isomer.NOHNOH14 33ZnClHA Bendo exoZn ClHFigure 1In summary, the results of this preliminary study clearly demonstrate that amidoorganozinccarbenoids derived from suitably constituted N-diethoxymethyl-lactams can successfully participatein intramolecular reactions with tethered monosubstituted alkenes. In all cases studied, only onediastereoisomer was isolated and the stereochemical preference is for formation of the cyclopropaneon the more hindered concave face of the molecule. From an experimental standpoint, the overallsequence is inexpensive and the zinc/chlorotrimethylsilane-mediated cyclopropanation reactionoccurs under mild conditions, thus paving the way for the construction of a range of usefullyfunctionalised polycyclic amidocyclopropane systems.AcknowledgmentsWe would like to thank the EPSRC for providing both a studentship (to LJ) and a postdoctoralfellowship (to TDS).References1. a) Saläun, J. Top. Curr. Chem. 2000, 207, 1; b) Saläun, J.; Baird, M. S. Curr. Med. Chem. 1995,2, 511; c) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603; d) Stammer, C. H. Tetrahedron1990, 46, 2231; e) Burgess, K.; Ho, K. –K.; Moye-Sherman, D. Synlett 1994, 575.2. a) King, S. W.; Riordan, J. M.; Holt, E. M.; Stammer, C. H. J. Org. Chem. 1982, 47, 3270; b)Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3, 2785; c) Tsai, C. –C.; Hsieh,I. –L.; Cheng, T. –T.; Tsai, P. –K.; Lin, K. –W.; Yan, T. –H. Org. Lett. 2006, 8, 2261.3. a) Vilsmaier, E. The Chemistry of the Cyclopropyl Group; Rappoport Z., Ed, John Wiley &Sons: Chichester, 1987, 1341; b) Davies, H. M. L.; Cantrell Jr, W. R. Tetrahedron Lett. 1991,32, 6509; c) Charette, A. B.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721; d) Davies, H. M. L;Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897.4. Begis, G.; Cladingboel, D. E.; Motherwell, W. B. Chem. Commun. 2003, 2656.5. Begis, G.; Sheppard, T. D.; Cladingboel, D. E.; Motherwell, W. B.; Tocher, D. A. Synthesis2005, 3186.6. a) Motherwell, W. B.; Bégis, G.; Cladingboel, D. E.; Jerome, L.; Sheppard, T. D. Tetrahedron2007, 63, 6462; b) Bégis, G.; Cladingboel, D. E.; Jerome, L.; Motherwell, W. B.l Sheppard, T.D. Eur. J. Org. Chem. 2009, 1532.7. Zhao, C.; Zaho, Y.; Gong, P. Bioorg. Med. Chem. 2006, 14, 2552.8. Brighty, K.E.; Castaldi, M. J. Synlett 1996, 1097.9. Li, Q.; Wodds, K. W.; Clairbone, A.; Gwaltney, S. L., II; Barr, K. J.; Liu, G.; Gehrke, L.;Credo, R. B.; Hui, Y. H.; Lee, J.; Warner, R. B.; Kovar, P.; Nukkala, M. A.; Zielinski, N. A.;Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.; Ng, S. C.; Rosenberg, S.; Sham,H. Bioorg. Med. Chem. Lett. 2002, 12, 465.10. a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.; Prityckaja, T. S. J. Org. Chem.(USSR) 1983, 25, 2027; b) Kulinkovich, O. G.; Sviridov, S. V., Vasilevski, D. A. Synthesis1991, 234; c) Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem. 2007, 2121.11. a) Chaplinski, V.; De Meijere, A. Angew. Chem. Int. Ed. Engl. 1996, 35, 413; b) de Meijere, A.;Kozhushkov, S. I.; Savchenko, A. I. J. Organomet. Chem. 2004, 689, 2033; c) de Meijere, A.;Williams, C. M.; Koudioukov, A.; Sviridov, S. V.; Chaplinski, V.; Kordes, M.; Savchenko, A.I.; Stratmann, C.; Noltemeyer, M. Chem. Eur. J. 2002, 8, 3789; d) Kulinkovich, O. G.; deMeijere, A. Chem. Rev. 2000, 100, 2789; e) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere,A. Synlett 1997, 111.12. For examples of intramolecular Ti-mediated aminocyclopropantion reactions see: a) Bertus, P.;Szymoniak J. Org. Lett. 2007, 9, 659; b) Gensini, M.; Kozhushkov, S. I; Yufit, D. S.; Howard,J. A. K.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2002, 2499; c) Gensini, M.; deMeijere A. Chem. Eur. J. 2004, 10, 785; d) Larquetoux, L.; Ouhamou, N.; Chiaroni, A.; Six, Y.Eur. J. Org. Chem. 2005, 4654; e) Cao, B.; Xiao, D.; Jouillé, M. M. Org. Lett. 1999, 1799; f)Tebben, G.-D.; Rauch, K.; Stratmann, C.; Williams, C. M.; de Meijere, A. Org Lett. 2003, 5,483; g) Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1, 3007; h) Lee, H. B.; Sung, M. J.;Blackstock, S. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 11322; i) Laroche, C.; Bertus, P.;Szymoniak, J. Tetrahedron Lett. 2003, 44, 2485; j) Madelaine, C.; Ouhamou, N.; Chiaroni, A.;Vedrenne, E.; Grimaud, L.; Six, Y. Tetrahedron 2008, 64, 8878.13. Jain, S. L.; Sain, B. J. Mol. Catal. A 2004, 212, 91.14. Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.; Kooijman, H.; Spek, A. L.; Hiemstra, H. J.Organomet. Chem., 2001, 624, 244.15. Bateson, J. H.; Baxter, A. J. G.; Roberts, P. M.; Smale, T. C.; Southgate, R. J. Chem. Soc.,Perkin Trans. 1 1981, 3242.16. Gmeimer, P.; Bollinger, B. Synthesis 1995, 168.17. Haasnoot, C. A. G.; Deleeuw, F. A. A. M.; Altona, C. Tetrahedron, 1980, 36, 2783.18. Schlecht, M. F. Molecular Modelling on the PC, Wiley-VCH, New York, 1998. Software used:PCMODEL (version 8.5, Serena Software).19. Gaussian 03 Revision D.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B., Scuseria, G. E.;Robb, M. A.; Cheeseman, J. R.; Montgomery Jr, J. A.; Vreven, T; Kudin, K. N.; Burant, J. C.;Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.;Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P.Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;. Zakrzewski, V. G.; Dapprich,S.; Daniels, A. D.; Strain, M. C.; Farkas, O; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R.L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;Chen, W; Wong, M. W.; Gonzalez, C;. Pople, J. A. Gaussian, Inc., Wallingford, CT, 2004.20. Neuhaus, D.; Williamson, M. P; The Nuclear Overhauser Effect in Structural andConformational Analysis, Wiley-VCH, 2nd ed., 2000.

Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursors

http://discovery.ucl.ac.uk/170134/1/170134_WBMIntraCyclopropanes.pdf

Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursors

Abstract

Similar works

Full text

Available Versions

UCL Discovery