The first example of a Corey-Chaykovsky epoxidation employing amides as substrates is described. Medium-bridged twisted amides serve as precursors to a family of isolable aminoepoxides. The reactivity of bridged spiro-epoxyamines is also investigated

Aubé, J.

Szostak, M.

PubMed

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Corey-Chaykovsky Epoxidation of Twisted Amides: Synthesisand Reactivity of Bridged Spiro-epoxyaminesMichal Szostak and Jeffrey Aubé*Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall,Room 4070, Lawrence, Kansas 66045-7852The epoxide is one of the most useful functional groups in all of organic chemistry due to itseasy formation and ready ring opening, often with a high level of stereo- and regiochemicalcontrol.1 Numerous investigators have sought to leverage the utility of epoxides in synthesisby preparing α-heteroatom substituted versions. Alkoxy-substituted epoxides2 are especiallyuseful as intermediates in carbohydrate synthesis; they can be made from enol ethers usingoxidants, like Oxone®, which lack an interfering nucleophilic component. However, theanalogous aminoepoxides have received much less attention in this regard as their existenceis compromised by nitrogen-assisted ring opening and polymerization. Very few examples ofstable epoxyamines are known, and those that are tend to be highly substituted (Figure 1).3 Inthis communication, we report a new strategy for the synthesis and stabilization ofaminoepoxides and some preliminary studies of the chemistry of this class of compounds.Since the decomposition pathways of aminoepoxides entail ring opening of the epoxide, itshould be possible to stabilize the functional group by limiting the ability of the amino groupto stabilize cations resulting from such pathways. One strategy to accomplish this would be tolimit overlap between nN and σ*C-O through some sort of structural modification. Thisphenomenon is likely responsible for the stability of aziridine-containing aminoepoxides, dueto the effect of ring strain on the nN orbital (Figure 1a, first two examples). A different approachwould utilize geometrical constraints that limit overlap between the nitrogen lone pair and theσ*C-O of the epoxide. Herein, we report the realization of this strategy, demonstrating thatbridged amides4 can provide direct access to stable aminoepoxides. We also show that, aspredicted and demonstrated by Stevens in the study with aziridine-derived epoxyamines,3a-cepoxyamines so obtained have a rich chemistry leading to a variety of useful and unusualstructures.Our investigations began with amide 1a, readily available from an intramolecular Schmidtreaction (eq 1).5a We found that when 1a was exposed to dimethylsulfonium methylide underCorey-Chaykovsky conditions,6 the spiro-epoxyamine 2a was formed in excellent yield,following chromatography. Importantly, the resulting aminoepoxide was stable to the reactionand isolation conditions, and could be stored over long periods of time without detectabledecomposition. To the best of our knowledge, such a direct amide epoxidation reaction iswithout precedent. This transformation is evidence for the increased reactivity of the twistedamide carbonyl group, which arises from limited overlap of the lone pair of electrons of theamide nitrogen and the carbonyl systems.4 In a similar vein, the decreased nN-σ*C–Odelocalization is responsible for the stability of the aminoepoxide 2a.*jaube@ku.edu.Supporting Information Available: Experimental details and characterization data for new compounds. This material is available freeof charge via the Internet at http://pubs.acs.org.NIH Public AccessAuthor ManuscriptJ Am Chem Soc. Author manuscript; available in PMC 2010 September 23.Published in final edited form as:J Am Chem Soc. 2009 September 23; 131(37): 13246–13247. doi:10.1021/ja906471q.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript(1)The epoxidation proved to be very dependent on reaction concentration (see SupportingInformation (SI) for details). Even slight increases in the concentration led to the completedecomposition of the reaction components. In addition, monitoring of the reaction by NMRrevealed a t1/2 of ~ 5 h (cf. a t1/2 of minutes for the ylide at rt6a). This is consistent with initialfast addition of the methylide to the amide carbonyl. We think that the resulting zwitterionexists in equilibrium with the ring-opened 9-membered heterocycle, which is destabilized dueto a transannular interaction between the amine and ketone groups (Scheme 1).5b Notably, nomonocyclic compounds or a reasonable alternative product from the ring-opened intermediatehaving a [4.3.2] ring system were observed.We next examined the scope of this Corey-Chaykovsky reaction by varying the substituentsand the ring systems of bridged amides (Table 1). Substitution with a heteroatom in the αposition, and removal of the bulky tert-butyl group also permits isolation of the desired spiro-epoxyamine in very good yield (entry 2). Remarkably, even the sensitive α-unsubstitutedbridged amide 1c5b could be used to deliver isolable aminoepoxide (entry 3). Although thethiomethyl analogue was incompatible with the polar solvent system, resulting in thepolymerization of the aminoepoxide product, we found that the use of modified conditionsallowed for isolation of the sensitive epoxide 1d (entry 4, SI). However, a 1-carbon-higherhomologue of 1d ([5.3.1] ring system) did not undergo the epoxidation reaction under theseconditions (SI). Tricyclic amides could also be employed to access spiro-epoxyamines (entries5-8). Importantly, increased steric hindrance close to the reactive amide bond did not diminishthe facility of aminoepoxide formation (entry 8).7Having established a general route to bridged spiro-epoxyamines, we probed the reactivity ofthis new class of compounds using epoxide 2a as a test substrate (Scheme 2). In particular, wewere curious how the reactivity of these bridged aminoepoxides would compare to that oftraditional epoxides. Among the most synthetically useful reactions of epoxides are ringopening under acidic and reductive conditions.1 Thus, exposure of 2a to hydrochloric acidSzostak and Aubé Page 2J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptresulted in the selective epoxide opening at the less substituted carbon, however in the case ofaminoepoxide the ensuing collapse of the bicyclic ring system affords a chloromethyl ketone(3a). The reduction of 2a resembled the opening under acidic conditions, involving the finalcollapse of the bicyclic aminal to the ketoamine 3b. In this case, it is likely that the initiallyformed reduction product persists in the reaction mixture prior to workup, since no alcoholcorresponding to 3b was observed. We have determined that aminoepoxides also undergoreactions at nitrogen with preservation of the epoxide structure as exemplified by N-protonationwith p-TsOH (3c).We established that bridged spiro-epoxyamines participate in a number of Lewis acid catalyzedreactions not typical to traditional epoxides. For example, upon exposure of 2a to Et2AlClconversion to aldehyde and subsequent alkyl transfer is observed (3d, see SI for moreexamples). This contrasts with traditional epoxides, which typically undergo direct alkyltransfer when exposed to alkylaluminum compounds.8 Interestingly, although BF3 is the mostcommon Lewis acid used for the transformation of epoxides into carbonyl groups9 (it has evenbeen suggested9a that that “no epoxide is insensitive” to this reagent), 2a was found to be inertto BF3.A number of thermal manipulations were briefly examined as well (Scheme 3, only productsshown). When 2a was subjected to KCN the bridged amide 1a was obtained. Interestingly, theuse of NaI under similar conditions afforded the bicyclic 3e (see SI for proposed intermediates).In addition, when heated to higher temperatures 2a undergoes 1,2-hydride shift to providealdehyde 3f, while exposure to NaN3 resulted in the rearrangement to the primary amide 3g.This reaction proceeds most likely via rearrangement to aldehyde, azide addition, and Schmidtreaction.In conclusion, the Corey-Chaykovsky reaction permits the direct epoxidation of twistedamides. This method allows for preparation and isolation of bridged aminoepoxides,compounds which, as correctly suggested by Stevens 40 years ago, display reactivity divergentfrom traditional epoxides. The generality of this approach was demonstrated by the applicationto a range of bicyclic and tricyclic bridged amide substrates. Further investigation of the scopeof this reaction and the application of the products in a target oriented synthesis is currently inprogress.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgementsThis work was supported by the National Institute of General Medical Sciences (GM-49093).References(1)(a). Yudin, AK. Aziridines and Epoxides in Organic Synthesis. Wiley-VCH; 2006. (b) Smith JG.Synthesis 1984:629–656. (c) Xia QH, Ge HQ, Ye CP, Liu ZM, Su KX. Chem. Rev 2005;105:1603–1662. [PubMed: 15884785]Jacobsen, EN.; Yamamoto, H.; Pfaltz, A. Comprehensive AsymmetricCatalysis. Vol. Vol. 2. Springer; 1999. p. 621-696.(2)(a). Halcomb RL, Danishefsky SJ. J. Am. Chem. Soc 1989;111:6661–6666. (b) Danishefsky SJ,McClure KF, Randolph JT, Ruggeri RB. Science 1993;260:1307–1309. [PubMed: 8493573](3)(a). Stevens CL, Pillai PM. J. Am. Chem. Soc 1967;89:3084–3085.3085(b)Stevens CL, Pillai MP. J.Org. Chem 1972;37:173–178.178(c)Stevens CL, Cahoon JM, Pillai PM, Potts TR. J. Org. Chem1972;37:3130–3133.3133(d)Coffen DL, Korzan DG. J. Org. Chem 1971;36:390–395.395(e)Mithani S, Drew DM, Rydberg EH, Taylor NJ, Mooibroek S, Dmitrienko GI. J. Am. Chem. SocSzostak and Aubé Page 3J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript1997;119:1159–1160.1160 and references cited therein.See also: (f)Bernier D, Blake AJ,Woodward S. J. Org. Chem 2008;73:4229–4232.4232 [PubMed: 18459809](4)(a). For reviews, see: Greenberg A, Breneman CM, Liebman JF. Amide Linkage: Selected StructuralAspects in Chemistry, Biochemistry, and Materials Science. 2000WileyNew York (b)Clayden J,Moran WJ. Angew. Chem., Int. Ed 2006;45:7118–7120.7120For selected examples, see: (c)KirbyAJ, Komarov IV, Feeder N. J. Chem. Soc., Perkin Trans 2001;2:522–529.529(d)Tani K, Stoltz BM.Nature 2006;441:731–734.734 [PubMed: 16760973](e)Lei Y, Wrobleski AD, Golden JE, PowellDR, Aubé J. J. Am. Chem. Soc 2005;127:4552–4553.4553 [PubMed: 15796502](5)(a). Yao L, Aubé J. J. Am. Chem. Soc 2007;129:2766–2767. [PubMed: 17302421] (b) Szostak M,Yao L, Aubé J. J. Org. Chem 2009;74:1869–1875.(6)(a). Corey EJ, Chaykovski M. J. Am. Chem. Soc 1965;87:1353–1364. (b) Aggarwal VK, Winn CL.Acc. Chem. Res 2004;37:611–620. [PubMed: 15311960](7). We have attempted the epoxidation using a number of other sulfur ylides, however we did not observethe formation of the corresponding epoxyamines so far. See SI for details(8)(a). Lundeen AJ, Oehlschlager AC. J. Organomet. Chem 1970;25:337–344.344(b)Schneider C,Brauner J. Eur. J. Org. Chem 2001;23:4445–4450.4450 and references cited therein.(9)(a). Sudha R, Narasimhan KM, Saraswathy VG, Sankararaman S. J. Org. Chem 1996;61:1877–1879.[PubMed: 11667069] (b) Robinson MWC, Pillinger KS, Graham AE. Tetrahedron Lett2006;47:5919–5921.Szostak and Aubé Page 4J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.(a) Examples of isolable aminoepoxides. (b) Common decomposition pathway of unmodifiedaminoepoxides.Szostak and Aubé Page 5J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Szostak and Aubé Page 6J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 2.Transformations of 2a under acidic and reductive conditions.Szostak and Aubé Page 7J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 3.Transformations of 2a under thermal conditions (only products shown).Szostak and Aubé Page 8J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak and Aubé Page 9Table 1Scope of the Corey-Chaykovsky reaction.entry amide epoxide yield (%)1 (1a) R1 = Ph, R2 = t-Bu (2a) 882 (1b) R1 = SPh, R2 = H (2b) 813 (1c) R1 = H, R2 = t-Bu (2c) 414 (1d) R1 = SMe, R2 = H (2d) 895 (1e) R1 = H, R2 = 4-BrC6H4 (2e) 706 (1f) R1 = H, R2 = (CH2)2OBn (2f) 737 (1g) R1 = H, R2 = Ha (2g)a 778 (1h) R1 = i-Pr, R2 = H (2h) 70acompounds 1g and 2g lack the olefin.J Am Chem Soc. Author manuscript; available in PMC 2010 September 23.

Corey-Chaykovsky epoxidation of twisted amides: Synthesis and reactivity of bridged spiro-epoxyamines

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Corey-Chaykovsky epoxidation of twisted amides: Synthesis and reactivity of bridged spiro-epoxyamines

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