The straightforward protonation of lactams by treatment with acid and the full structural characterization of three resulting N-protonated lactams are disclosed. This work provides experimental evidence that N-protonation of amide bonds results in a dramatic increase in nonplanarity about the C-N amide bond. The resulting compounds are discussed in structural, spectroscopic, and reactivity terms. The data suggest that distortion of these amide bonds by -50° is sufficient for their effective N-activation

Aubé, J.

Day, V.W.

Powell, D.R.

Szostak, M.

Yao, L.

Carolina Digital Repository

Structural Characterization of N-Protonated Amides.Regioselective N-Activation of Medium-Bridged TwistedLactamsMichal Szostak, Lei Yao, Victor W. Day, Douglas R. Powell, and Jeffrey Aubé*Department of Medicinal Chemistry, University of Kansas, Structural Biology Center, 2121Simons Drive, West Campus, Lawrence, KS 66047AbstractThe straightforward protonation of lactams by treatment with acid and the full structuralcharacterization of three resulting N-protonated lactams are disclosed. This work providesexperimental evidence that N-protonation of amide bonds results in a dramatic increase of non-planarity about the C-N amide bond. The resulting compounds are discussed in structural,spectroscopic, and reactivity terms. The data suggests that ca. 50° distortion of these amide bondssuffices for their efficient N-activation.Although most amides usually protonate on oxygen, amide N-protonation has beennonetheless proposed in a number of biologically relevant mechanisms,1 including cis–transpeptide bond isomerization,2 amide bond hydrolysis,3 and protein splicing.4 Althoughfundamentally different reactivity patterns are expected – and observed – to result fromamide subsitution,5 the study of N-protonated amides has been hampered by theunavailability of molecules that contain them.The characterization of N-protonated amides is challenging because such species arethermodynamically disfavored relative to their O-protonated isomers by ca. 40 kcal/mol.1 Todate, examples of isolated and otherwise unadorned N-protonated amides are severelylimited to perpendicularly twisted 2-quinuclidone derivatives (Figure 1a).6a–f In addition,Lectka reported an elegantly designed N-protonated amide that was stabilized by theproximity of an additional tertiary amine (Figure 1b).6g To date, only two N-protonatedamides have been characterized by X-ray crystallography.7 Herein, we demonstrate that aseries of medium-bridged N-protonated lactams can be readily prepared by acid treatment.This streamlined access to multiple lactam conjugate acids has permitted the full structuralcharacterization of three N-protonated amides and provided the first experimental evidenceshowing that the N-protonation of amide bonds results in a dramatic increase ofpyramidalization around the C-N amide bond.8 Our data also suggest that ca. 50° distortionjaube@ku.edu.Supporting Information Available: Experimental details, characterization data for new compounds and .cif files of 1d, 3a–c. Thismaterial is available free of charge via the Internet at http://pubs.acs.org.NIH Public AccessAuthor ManuscriptJ Am Chem Soc. Author manuscript; available in PMC 2011 July 7.Published in final edited form as:J Am Chem Soc. 2010 July 7; 132(26): 8836–8837. doi:10.1021/ja101690u.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptof amide bonds (where 0° would correspond to planar amide, 90° to a fully orthogonalamide bond) suffices for efficient N-protonation or alkylation of lactams.Recent efforts in this laboratory have provided ready access to a family of bridged lactamsthat are characterized by moderate amide bond distortion (twist values ca. 40–50°).9 Suchcompounds display decidedly non-traditional amide bond reactivity patterns that includeunusual cleavage reactions of a C-N σ bond adjacent to the amide bond.9d–f Wehypothesized that these reactions take place via initial N-alkylation made possible by theincreased basicity of the non-planar amide bond nitrogen. The facility of these reactionssuggested it might be possible to isolate the responsible species by straightforwardprotonation or alkylation. Indeed, when tricyclic amides 1a–c were exposed to mild acids,protonation took place at nitrogen to afford the corresponding stable salts in excellent yields(Scheme 1). The tosylates 3a–c were crystalline, and their structures could be confirmed byX-ray crystallography (Figure 2). Table 1 summarizes Winkler-Dunitz distortion parametersτ, χC, and χN (describing magnitude of rotation around the N-C(O) bond, pyramidalization atcarbon and pyramidalization at nitrogen, respectively)10 and bond lengths of the N-protonated lactams.Notably, the availability of crystal structures of both 1c and 3c allowed the neutral amideand its conjugate acid to be easily compared. As expected, N-protonation of amide bondsenhances the pyramidal character at nitrogen (χN). The resulting change is substantial: froma moderately pyramidal to practically sp3 hybridized nitrogen (in series c χN increases from36.1° to 52.1°). This is accompanied by the flattening of the C=O carbon (in series c χCdrops from 12.8° to 1.4°) and a dramatic decrease in C-N bond planarity (in 2c τ is 81.9°, cf.51.5° for 1c). The bond lengths were also influenced by N-protonation. The N-C(O) bondexperiences significant lengthening (in 1c by 0.115 Å), while the C=O bond was moderatelyshortened (in 1c by 0.026 Å). Overall, these structural changes indicate substantialrehybridization upon N-protonation and C-N bond rotation, even in the fairly rigid tricyclicring system of 1.8a, bFurthermore, the X-ray structures reveal that the N-protons are stabilized by hydrogenbonding to tosylate oxygens (Figure 2). The O1A-H1 (O3A-H1) distances of 1.79–1.82 Åand the N1-H1-O1A (N1-H1-O3A) angles of 163–177° are consistent with the presence ofmoderately strong hydrogen bonds. The bond distances between the amide bond nitrogensand tosylate oxygens in salts 3a–3c (2.68–2.72 Å) also support the formation of medium-strength hydrogen bonds engaging the amide nitrogen atoms.11We earlier reported that tricyclic lactams react with MeI to form the correspondingamidinium salts followed by regioselective SN2 displacement with iodide.9e As expected,similar chemistry was observed upon exposure of tricyclic amides to related electrophilesunder mild conditions (Scheme 2a, see SI for details). In contrast, treatment withMeerwein’s reagent, lacking a nucleophilic counterion, permitted isolation of two rareexamples of N-alkylated amides (Scheme 2b).12 Unfortunately, we were not able to obtainhigh-resolution crystal structures of these compounds.Our attempts to similarly protonate or alkylate [4.3.1] bicyclic lactams like 1d revealeddifferences in reactivity between these species and their tricyclic cousins 3a–c (Scheme 2c).For example, 1d did not readily form a salt upon room-temperature treatment with acid orMeI However, under forcing conditions 1d did afford products resulting from N-methylationfollowed by I− displacement (Scheme 2c, R = Ph, see SI for details). Control reactionsconfirmed that both the bridged structure and the alkylating agent were necessary for thisreaction. Comparison of twist parameters for the bicyclic and tricyclic lactams suggests thata twist angle of ≥50° is required for efficient N-protonation and N-alkylation of amideSzostak et al. Page 2J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptbonds8a, b although a twist angle of ca. 40° may be sufficient to result in N-alkylation undersuitably vigorous conditions.In summary, this work demonstrates that the N-protonation of amide bonds results in adramatic increase of distortion around the N-C(O) bond. Furthermore, even moderatelydistorted amide bonds participate in electrophilic N-activation of amides. Studies on generalactivation of amide bonds are underway.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgmentsThis work was supported by the National Institute of General Medical Sciences (GM-49093). We thank Dr. KevinFrankowski for helpful suggestions.References1. Greenberg, A.; Breneman, CM.; Liebman, JF. Amide Linkage: Selected Structural Aspects inChemistry, Biochemistry, and Materials Science. Wiley; New York: 2000.2. (a) Harrison RK, Stein RL. Biochemistry. 1990; 29:1684–1689. [PubMed: 2184885] (b) Liu J,Albers MW, Chen CM, Schreiber SL, Walsh CT. Proc Natl Acad Sci U S A. 1990; 87:2304–2308.[PubMed: 2179953] (c) Fischer G. Chem Soc Rev. 2000; 29:119–127. (d) Cox C, Lectka T. AccChem Res. 2000; 33:849–858. [PubMed: 11123884] (e) Eakin CM, Berman AJ, Miranker AD. NaStruct Mol Biol. 2006; 13:202–208.3. (a) Williams A. J Am Chem Soc. 1976; 98:5645–5651. (b) Somayaji V, Brown RS. J Org Chem.1986; 51:2676–2686. (c) Perrin CL. Acc Chem Res. 1989; 22:268–275. (d) Brown RS, Bennet AJ,Slebocka-Tilk H. Acc Chem Res. 1992; 25:481–488. (e) Mujika JI, Mercero JM, Lopez X. J AmChem Soc. 2005; 127:4445–4453. [PubMed: 15783227] (f) Mujika JI, Formoso E, Mercero JM,Lopez X. J Phys Chem B. 2006; 110:15000–15011. [PubMed: 16869615]4. (a) Poland BW, Xu MQ, Quiocho FA. J Biol Chem. 2000; 275:16408–16413. [PubMed: 10828056](b) Romanelli A, Shekhtman A, Cowburn D, Muir TW. Proc Natl Acad Sci U S A. 2004;101:6397–6402. [PubMed: 15087498] (c) Shemella P, Pereira B, Zhang YM, Van Roey P, BelfortG, Garde S, Nayak SK. Biophys J. 2007; 92:847–853. [PubMed: 17085503] (d) Johansson DGA,Wallin G, Sandberg A, Macao B, Aqvist J, Hard T. J Am Chem Soc. 2009; 131:9475–9477.[PubMed: 19534521]5. (a) Shimada T, Nakamura I, Yamamoto Y. J Am Chem Soc. 2004; 126:10546–10547. [PubMed:15327305] (b) Ito M, Sakaguchi A, Kobayashi C, Ikariya T. J Am Chem Soc. 2007; 129:290–291.[PubMed: 17212405] (c) Ueno S, Chatani N, Kakiuchi F. J Am Chem Soc. 2007; 129:6098–6099.[PubMed: 17444647] (d) Kajita Y, Matsubara S, Kurahashi T. J Am Chem Soc. 2008; 130:6058–6059. [PubMed: 18412348] (e) Yoshino Y, Kurahashi T, Matsubara S. J Am Chem Soc. 2009;131:7494–7495. [PubMed: 19435347]6. (a) Levkoeva EI, Nikitskaya ES, Yakhontov LN. Dokl Akad Nauk. 1970; 192:342–345. (b)Levkoeva EI, Nikitskaya ES, Yakhontov LN. Khim Geterotsikl Soedin. 1971:378–384. (c) PracejusH. Ber. 1959; 92:988–998. (d) Pracejus H. Ber. 1965; 98:2897–2905. (e) Pracejus H, Kehlen M,Kehlen H, Matschin H. Tetrahedron. 1965; 21:2257–2270. (f) Tani K, Stoltz BM. Nature. 2006;441:731–734. [PubMed: 16760973] (g) Cox C, Wack H, Lectka T. Angew Chem, Int Ed. 1999;38:798–800.7. (a) See, references 6f and 6g. (b) Note that Kirby et al. described protonated 2-azaadamantanone inits hydrated form. Kirby AJ, Komarov IV, Feeder N. J Chem Soc, Perkin Trans. 2001; 2:522–529.8. (a) Greenberg A, Venanzi CA. J Am Chem Soc. 1993; 115:6951–6957. (b) Greenberg A, MooreDT, DuBois TD. J Am Chem Soc. 1996; 118:8658–8668. (c) Laidig KE, Cameron LM. Can JChem. 1993; 71:872–879. (d) Mo YR, Schleyer PV, Wu W, Lin MH, Zhang Q, Gao JL. J PhysSzostak et al. Page 3J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptChem A. 2003; 107:10011–10018. (e) Kemnitz CR, Loewen MJ. J Am Chem Soc. 2007; 129:2521–2528. [PubMed: 17295481]9. (a) Yao L, Aubé J. J Am Chem Soc. 2007; 129:2766–2767. [PubMed: 17302421] (b) Szostak M,Yao L, Aubé J. Org Lett. 2009; 11:4386–4389. [PubMed: 19722508] (c) Szostak M, Yao L, Aubé J.J Org Chem. 2009; 74:1869–1875. [PubMed: 19178141] (d) Szostak M, Aubé J. Org Lett. 2009;11:3878–3881. [PubMed: 19708701] (e) Lei Y, Wrobleski AD, Golden JE, Powell DR, Aubé J. JAm Chem Soc. 2005; 127:4552–4553. [PubMed: 15796502] (f) Szostak M, Aubé J. ChemCommun. 2009:7122–7124. (g) Szostak M, Yao L, Aubé J. J Am Chem Soc. 2010; 132:2078–2084.[PubMed: 20095610] For reviews on bridged amides, see: (h) Hall HK, Elshekeil A. Chem Rev.1983; 83:549–555. (i) Clayden J, Moran WJ. Angew Chem, Int Ed. 2006; 45:7118–7120.10. Winkler FK, Dunitz JD. J Mol Biol. 1971; 59:169–182. [PubMed: 5283751]11. Formation of the N-protonated amides is also evident from changes in the 13C NMR and IRspectra. See Table B in the SI for details.12. To the best of our knowledge only three examples of isolated N-alkylated amides have beenreported to date (Ref. 6a, 6e and 7b). In contrast to the current study, all of these lactams containedperfectly perpendicular amide bonds. For an elegant study on the methylation of quinuclidonederivatives, see: Werstiuk NH, Brown RS, Wang Q. Can J Chem. 1996; 74:524–532.Szostak et al. Page 4J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.Previously reported examples of isolated N-protonated amides.Szostak et al. Page 5J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 2.Crystal structures of (a) 3a, (b) 3b, and (c) 3c. Selected bond lengths [Å] and angles [°]: (a)N1-C1, 1.492(3), C1-O1, 1.202(4), C1-C2, 1.489(4), N1-H1, 0.93, C7-N1-C1-O1,−121.5(5)°; C6-N1-C1-O1, 111.1(5)°; C7-N1-C1-C2, 59.3(3)°; C6-N1-C1-C2, −68.2(3)°.(b) N1-C1, 1.491(3), C1-O1, 1.197(3), C1-C2, 1.487(4), N1-H1, 0.86(4), C7-N1-C1-O1,−126.3(3)°; C6-N1-C1-O1, 106.2(3)°; C7-N1-C1-C2, 56.1(3)°; C6-N1-C1-C2, −71.5(3)°.(c) N1-C1, 1.502(2), C1-O1, 1.192(2), C1-C2, 1.488(3), N1-H1, 0.89(3), C7-N1-C1-O1,−124.84(18)°; C6-N1-C1-O1, 107.21(19)°; C7-N1-C1-C2, 56.58(19)°; C6-N1-C1-C2,−71.38(19)°.Szostak et al. Page 6J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Szostak et al. Page 7J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 2.Szostak et al. Page 8J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak et al. Page 9Table 1Summary of structural parameters of amides and N-protonated amides.entryamide (notes)N-C(O) [Å]C=O [Å]χ N [deg]χ C [deg]τ [deg]1a1c (tricyclic)1.3871.21836.112.851.52b1d (bicyclic)1.3671.22734.116.542.833a (N-protonated)1.4921.20252.60.785.243b (N-protonated)1.4911.19752.52.481.253c (N-protonated)1.5021.19252.11.481.96c3d (N-protonated)1.5261.19259.50.290.97d,e1e (formamide)1.3491.1930.00.00.0a Reference 9c ;b Scheme 2c, R = 4-(MeO)C6H4;c 3d = 2-quinuclidonium tetrafluoroborate, Reference 6f ;d Reference 8a ;e Calculated.J Am Chem Soc. Author manuscript; available in PMC 2011 July 7.

Structural characterization of N-protonated amides: Regioselective N-activation of medium-bridged twisted lactams

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Structural characterization of N-protonated amides: Regioselective N-activation of medium-bridged twisted lactams

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