DOI: 10.1002/chem.201303526

Organocatalytic Enantioselective Cycloaddition Reactions of Dienamines with Quinones Tore Kiilerich Johansen, Clarisa Villegas Gmez, Jesper R. Bak, Rebecca L. Davis, and Karl Anker Jørgensen*[a]

Dienamines, which can be generated from the condensation of a,b-unsaturated aldehydes with an organocatalyst, have been applied in organic synthesis for enantioselective g-functionalization[1] and cycloaddition[2] reactions. However, there are challenges to using dienamines in cycloadditions, as the organocatalyst used to generate the dienamine intermediate might be trapped leading to a “dead-end reaction”. Only a few systems that apply the dienamine concept for cycloaddition reactions have shown the ability to liberate the catalyst, as demonstrated by the groups of Christmann,[3] Vicario,[4] and Hong.[5] Enantioselectivity in aminocatalysis is normally governed by facial selectivity by which the catalyst shields one face of the substrate (steric shielding), such as the approach outlined in Scheme 1 a.[6] However, there are examples in which

Scheme 1. Control of enantioselectivity based on: a) steric shielding, and b) hydrogen-bond-directing concepts.

the selectivity has to be controlled in a bifacial manner to obtain enantioselectivity.[7] Strategies for such selectivity often employ a bifunctional catalyst based on hydrogen bonding, which can activate and direct both substrate and reactant (Scheme 1 b).[7a,b] For [4+2]-cycloaddition reactions, a dienophile can approach the diene in both an endo and exo fashion as outlined in Scheme 1 a. An important challenge for these funda-

[a] T. K. Johansen, Dr. C. V. Gmez, J. R. Bak, Dr. R. L. Davis, Prof. Dr. K. A. Jørgensen Center for Catalysis, Department of Chemistry Aarhus University, Langelandsgade 140 8000 Aarhus C (Denmark) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303526.

16518

mental reactions is to control the endo and exo approach of the dienophiles. Control of the endo/exo selectivity can be a challenge to achieve with a steric shielding catalyst. A steric shielding catalyst only provides limited selectivity, and a reaction concept ensuring favorable interactions between the dienamine and the dienophile is necessary. For dienamine-mediated [4+2]-cycloaddition reactions, in which no stereocenters are generated in the aldehyde moiety, the approach of the dienophile is crucial since stereocenters will be generated only in the dienophile. The enantioselectivity generated by such an approach will exclusively be determined by the endo/exo selectivity; that is, what normally leads to the formation of diastereoisomers, will in this case provide enantiomers. To successfully develop a strategy that can both exert bifacial selectivity and allow liberation of the catalyst, we envisioned that 1,4-benzo- and 1,4-naphthoquinones could be appropriate substrates.[8] In the following, we present the highly selective organocatalytic [4+2]-cycloaddition reaction of dienamines with 1,4benzo- and 1,4-naphthoquinones leading to optically active bicyclic and tricyclic products. The reaction design developed ensures high enantioselectivity, which is determined by interactions between the dienamine intermediate and the 1,4-benzo- or 1,4-naphthoquinones. Furthermore, computational studies providing mechanistic insight to the reaction course will also be presented. Another important aspect of this new reaction is that the optically active products obtained contain a quinone moiety, which is present in many biologically active compounds.[9] Initial experiments with 3-methyl-2-butenal (1 a), 2methyl-1,4-naphthoquinone (2 a), 20 mol % of the TMS-prolinol catalyst 3, and 20 mol % o-fluorobenzoic acid (o-FBA) afforded full conversion in 1 h and the cycloaddition product 4 a was isolated in 87 % yield and 99 % ee (ee = enantiomeric excess; Table 1, entry 1). Lowering the catalyst loading to 5 mol % afforded 4 a in 90 % yield and 99 % ee (entry 2). Lowering the acid concentration (entry 3) resulted in a slightly slower reaction, implying a rate-enhancing effect by the acid additive. Reducing the catalyst loading to 2.5 mol % (entry 4) afforded 4 a in 92 % yield and 97 % ee in 24 h. However, attempts to lower the amount of catalyst to 0.5 mol % resulted in only partial conversion (entry 5). To demonstrate the scope of the reaction, different substituted 1,4-benzo- and 1,4-naphthoquinones 2 were employed

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2013, 19, 16518 – 16522

COMMUNICATION Table 1. Screening of catalyst loading.[a]

Table 3. Scope of a,b-unsaturated aldehydes in the [4+2]-cycloaddition reaction.[a]

Entry 3 [mol %]

o-FBA [mol %]

t [h]

Conv. [%][b]

Yield [%]

ee [%][c]

1 2 3 4 5

20 20 0 20 20

1 18 18 24 24

> 95 > 95 94 > 95 35

87 90 n.d.[d] 92 n.d.[d]

99 99 n.d.[d] 97 n.d.[d]

20 5 5 2.5 0.5

[a] All reactions were carried out on 0.1 mmol scale in 0.5 mL CDCl3. [b] Determined by 1H NMR spectroscopy. [c] Determined by chiral ultraperformance convergence chromatography (UPC2). [d] Not determined.

Table 2. Scope of quinones in the [4+2]-cycloaddition reaction.[a]

[a] All reactions were carried out on 0.1 mmol scale in 0.5 mL CDCl3. Yields given are of the isolated product and the ee was determined by UPC2 ; [b] 3 equiv aldehyde and 20 mol % catalyst.

[a] All reactions were carried out on 0.1 mmol scale in 0.5 mL CDCl3. ee was determined by UPC2. [b] 20 mol % catalyst and 50 mol % o-FBA for 48 h at RT.

(Table 2). They all reacted smoothly in the cycloaddition reaction with 3-methyl-2-butenal 1 a. The products obtained from 1,4-benzoquinones provided the optically active products 4 b–d in 74–82 % yield and 98 % ee. It should be noted that 4 d was formed exclusively by addition to the least sterically demanding double bond in the quinone. When exchanging the methyl group with a benzyl group in the 1,4naphthoquinones, the reaction was retarded and 20 mol % of catalyst was applied to give the products 4 e,f in 74–76 % yield and 96 % ee. To further expand the scope of this reaction, 2,6-dimethylbenzoquinone (2 b) was reacted with different a,b-unsaturated aldehydes (Table 3). In all cases, the reaction proceeded to completion at room temperature and, to our delight, it was only slightly affected by the electronic properties when substituted aryl a,b-unsaturated aldehydes were employed. Optically active quinone products containing electron-neu-

Chem. Eur. J. 2013, 19, 16518 – 16522

tral (4 g), electron-poor (4 j,k), and electron-rich (4 l) aryl substituents were obtained in 75–99 % yield and 97–99 % ee. Changing the substituent pattern of the aryl a,b-unsaturated aldehyde to the meta-position did not affect the outcome of the reaction significantly, and 4 i was isolated in 92 % yield and 99 % ee. However, the introduction of a substituent in the ortho-position (4 h) resulted in 55 % yield and 97 % ee. The reaction was also tolerant to different heterocyclic substituents in the a,b-unsaturated aldehyde without loss of activity and 4 m,n were isolated in 73 and 83 % yield and 98 % ee. Employment of an alkyne-substituted a,b-unsaturated aldehyde gave a 99 % yield and 99 % ee of 4 o, thereby demonstrating the tolerance of the system towards nonaryl substituents. The use of alkyl-substituted a,b-unsaturated aldehydes also resulted in successful reactions. The propyl-substituted reagent afforded 4 p in 64 % yield and 97 % ee and the reaction of the dienamine intermediate proceeded exclusively through the methyl group. The reaction also proceeded well when the tert-butyl-substituted a,b-unsaturated aldehyde was applied; however, a higher catalyst loading was necessary and 4 q was isolated in 62 % yield and 98 % ee. The presence of an acetal group in the a,b-unsaturated aldehyde afforded an 84 % yield and 99 % ee of 4 r.

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

16519

K. A. Jørgensen et al.

The absolute configuration of 4 k was unambiguously determined by X-ray crystallographic analysis as shown in Table 3[10] and the remaining products were assumed to have the same configuration. The absolute configuration of the products obtained shows that the reaction proceeds by an endo approach of the dienophile to the dienamine intermediate. In addition to having high endo selectivity, the reaction was also shown to proceed exclusively by addition to the carbon atom in the quinone containing the most sterically demanding alkyl substituent. The high selectivity observed in the reaction prompted us to explore the four possible approaches of an unsubstituted dienamine with 2,6-dimethylbenzoquinone in this cycloaddition and the influences responsible for the high selectivity (Scheme 2). In an attempt

Scheme 2. Calculated transition-state structures and intermediates for the cycloaddition of a model dienamine with 2,6-dimethylbenzoquinone. Activation energies are Gibbs free energies from IEFPCM-M06-2x/6-311 + GACHTUNGRE(2df,2p)//IEFPCM-B97d/6-31 + GACHTUNGRE(d,p) in CHCl3.

to understand this selectivity, a series of DFT calculations were performed.[11] Examination of the two endo pathways shows that both reactions proceed in a stepwise manner (Scheme 2). The first step of these reactions involves addition of the quinone to the g-carbon atom of the dienamine. This addition results in the formation of a zwitterionic intermediate, A1 or B1, respectively, in which the positive charge is localized on the

16520

www.chemeurj.org

nitrogen atom of the iminium ion and the negative charge is localized on the oxygen atom of the carbonyl. The zwitterionic character, can be seen in the increased length of the C O bond (1.28 ) of the carbonyl and in the decrease in the C C distance (1.42 ), supporting the formation of an enolate in the intermediate. The zwitterionic intermediate then undergoes a second bond-forming event, generating the cyclized intermediate, A2 and B2, respectively. Examination of the two exo-pathways shows that the initial attack at the methyl-substituted carbon atom is found to proceed in a concerted, asynchronous manner leading to C1,[12] whereas attack at the unsubstituted carbon atom proceeds through a stepwise pathway via intermediate D1, similar to those described for the two endo reactions. In all of the stepwise pathways, addition to the g-carbon atom of the dienACHTUNGREamine is found to be the highest-energy transition state for the cyclization. In examining the energetics of all four pathways, it was calculated that the first addition step for the endo approaches are 4.0–4.5 kcal mol 1 lower than those of the exo approaches. This is likely due to favorable electrostatic interactions between the quinone and the dienamine. Of the two endo pathways, attack at the methyl-substituted carbon atom of the quinone is favored over attack at the unsubstituted quinone carbon atom by 0.5 kcal mol 1. This appears to be a result of unfavorable steric interactions between the methyl groups of the quinone and the hydrogen atoms of the pyrrolidine ring of the catalyst. Based on these results, we have determined that the high selectivity observed experimentally can be explained by favorable electrostatic interactions that dictate the endo/exo selectivity of the reaction. The slight favorability of the attack at the methyl-substituted carbon atom does not fully explain the full site-selectivity observed experimentally. However, this selectivity may be explained by the thermodynamic preference for product A2 over B2, as the formation of both products is likely reversible under the given reaction conditions, or it may be the result of the choice of model system, which does not account in full for the steric bulk of the catalyst. To demonstrate the utility of the chiral quinone products, we performed several transformations that allowed for the introduction of additional stereocenters. Stereoselective allylic bromination took place by reaction of 4 b with N-bromosuccinimide (NBS) and product 5 was formed in 55 % yield as a single diastereoisomer, which was characterized by X-ray analysis.[10] The X-ray structure showed a trans configuration of the bromine and methyl substituent in 5 (Scheme 3). Reduction of 4 b with one equivalent of NaBH4 at 0 8C afforded complete consumption of the reactant (Table 4, entry 1). The product, 6 a was obtained in 91 % yield as a single diastereoisomer. Increasing the amount of NaBH4 and prolonging the reaction time promoted the reduction of both functionalities of the remaining enone leading to formation of also 6 b under these reaction conditions. (entries 2,3). Finally, by employing 10 equivalents of NaBH4, 6 b was obtained exclusively in 68 % yield as a single diastereo-

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2013, 19, 16518 – 16522

Organocatalytic Enantioselective Cycloaddition Reactions

COMMUNICATION Keywords: asymmetric synthesis · computational studies · cycloaddition · organocatalysis

Scheme 3. Stereoselective bromination.

Table 4. Selective reduction of the carbonyl and alkene functionalities in 4 b.[a]

Entry

6 a/6 b[a]

NaBH4 [equiv]

t [h]

Yield [%]

1 2 3 4

95:5 40:60 14:86 5:95

1 3 6 10

0.16 2 2 2

91 n.d.[b] n.d.[b] 68

All reactions were carried out with 4 b (0.1 mmol) in CH2Cl2 (0.5 mL) and MeOH (0.5 mL). [a] Determined by 1H NMR spectroscopy after workup. [b] Not determined.

isomer (entry 4). The relative configuration of 6 b was determined by 2D NMR spectroscopic studies (see the Supporting Information). The configuration of the alcohol of 6 a was assumed to be the same as in 6 b. In summary, we have developed a new [4+2]-cycloaddition reaction based on the dienamine concept by reaction of a,b-unsaturated aldehydes with 1,4-benzo- and 1,4-naphthoquinones applying a TMS-protected prolinol catalyst. This reaction leads to chiral cycloaddition products in which the stereocenter formed does not originate from the a,b-unsaturated aldehyde, but from the 1,4-benzo- or 1,4-naphthoquinone. The enantioselectivity of the reaction arises from interactions between the dienamine intermediate and the 1,4benzo- or 1,4-naphthoquinone. The scope of the reaction is demonstrated for different a,b-unsaturated aldehydes reacting with 1,4-benzo- and 1,4-naphthoquinones in the presence of only 2.5 mol % organocatalyst. The quinone products are obtained in moderate to high yields ranging from 55–99 % and in all examples excellent enantioselectivity was observed. Computational studies suggest an endo-selective reaction course, calculated to be approximately 4 kcal mol 1 lower in energy than the exo-selective pathway. Finally, three different diastereoselective transformations have been developed to demonstrate the utility of the products, which are important motifs in natural product chemistry and lifescience.

Acknowledgements This work was made possible by grants from the Aarhus University and Carlsberg Foundation. We thank E. Eikeland and Dr. J. Overgaard for performing the X-ray analysis.

Chem. Eur. J. 2013, 19, 16518 – 16522

[1] For selected examples, see: a) C. Cassani, P. Melchiorre, Org. Lett. 2012, 14, 5590; b) G. Bergonzini, S. Vera, P. Melchiorre, Angew. Chem. 2010, 122, 9879; Angew. Chem. Int. Ed. 2010, 49, 9685; c) G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P. Melchiorre, Proc. Natl. Acad. Sci. USA 2010, 107, 20642; d) B. Han, Z.-Q. He, J.-L. Li, K. Jiang, T.-Y. Liu, Y.-C. Chen, Angew. Chem. 2009, 121, 5582; Angew. Chem. Int. Ed. 2009, 48, 5474; e) K. Liu, A. Chougnet, W.-D. Woggon, Angew. Chem. 2008, 120, 5911; f) S. Bertelsen, M. Marigo, S. Brandes, P. Dinr, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 12973; for a review on dienamine chemistry, see: a) D. B. Ramachary, Y. V. Reddy, Eur. J. Org. Chem. 2012, 865. [2] For reviews on organocatalytic cycloadditions, see: a) H. Pellissier, Tetrahedron 2012, 68, 2197; b) A. Moyano, R. Rios, Chem. Rev. 2011, 111, 4703. For selected examples see: c) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243; d) W. S. Jen, J. J. M. Wierner, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 9874; e) H. Sundn, R. Rios, Y. Xu, L. Eriksson, A. Cordova, Adv. Synth. Catal. 2007, 349, 2549; f) Z.-J. Jia, H. Jiang, J.L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen, K. A. Jørgensen, J. Am. Chem. Soc. 2011, 133, 5053; g) Z.-J. Jia, Q. Zhou, Q.-Q. Zhou, P.-Q. Chen, Y.-C. Chen, Angew. Chem. 2011, 123, 8797; Angew. Chem. Int. Ed. 2011, 50, 8638; h) Y. Hayashi, H. Gotoh, M. Honma, K. Sankar, I. Kumar, H. Ishikawa, K. Konno, H. Yui, S. Tsuzuki, T. Uchimaru, J. Am. Chem. Soc. 2011, 133, 20175. [3] R. Marcia de Figueiredo, R. Frçlich, M. Christmann, Angew. Chem. 2008, 120, 1472; Angew. Chem. Int. Ed. 2008, 47, 1450. [4] A. Orue, E. Reyes, J. L. Vicario, L. Carrillo, U. Uria, Org. Lett. 2012, 14, 3740. [5] B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su, J.-H. Liao, J. Org. Chem. 2007, 72, 8459. [6] For selected articles on the topic of mechanisms in amino-catalyzed reactions, see: a) A. Dieckmann, M. Breugst, K. N. Houk, J. Am. Chem. Soc. 2013, 135, 3237; b) J. Burs, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2012, 134, 6741; c) M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend, S. Bertelsen, K. A. Jørgensen, Chem. Commun. 2011, 47, 632; d) U. Groselj, D. Seebach, M. Badine, W. B. Schweizer, A. K. Beck, Helv. Chim. Acta 2009, 92, 1225; e) A. Fu, B. List, W. Thiel, J. Org. Chem. 2006, 71, 320. [7] For some recent articles on organocatalytic bifacial selectivity, see a) D. Bastida, Y. Lui, X. Tian, E. Escudero-Adn, P. Melchiorre, Org. Lett. 2013, 15, 220; b) H. Jiang, C. Rodrguez-Escrich, T. K. Johansen, R. L. Davis, K. A. Jørgensen, Angew. Chem. Int. Ed. 2012, 51, 10271; c) C. Rodrguez-Escrich, R. L. Davis, H. Jiang, J. Stiller, T. K. Johansen, K. A. Jørgensen, Chem. Eur. J. 2013, 19, 2932; d) J.L. Zhu, Y. Zhang, C. Liu, A.-M. Zheng, W. Wang, J. Org. Chem. 2012, 77, 9813; e) D. Monge, A. M. Crespo-PeÇa, E. MartnZamora, E. lvarez, R. Fernndez, J. M. Lassaletta, Chem. Eur. J. 2013, 19, 8421; f) Ł. Albrecht, G. Dickmeiss, F. Cruz Acosta, C. Rodrguez-Escrich, R. L. Davis, K. A. Jørgensen, J. Am. Chem. Soc. 2012, 134, 2543; for reviews on dual-activation in organocatalysis, see: g) L.-Q. Lu, X.-L. An, J.-R. Chen, W.-J. Xiao, Synlett 2012, 23, 490; h) A. Lattanzi, Chem. Commun. 2009, 1452. [8] For examples of organocatalytic strategies using 1,4-benzo- or 1,4napthoquinones, see: a) W.-Y. Siau, W. Li, F. Xue, Q. Ren, M. Wu, S. Sun, H. Guo, X. Jiang, J. Wang, Chem. Eur. J. 2012, 18, 9491; b) J. Alemn, S. Cabrera, E. Maerten, J. Overgaard, K. A. Jørgensen, Angew. Chem. 2007, 119, 5616; Angew. Chem. Int. Ed. 2007, 46, 5520; c) W.-M. Zhou, H. Liu, D.-M. Du, Org. Lett. 2008, 10, 2817. [9] For a review on natural products containing quinone moieties, see: S. N. Sunassee, M. T. Davies-Coleman, Nat. Prod. Rep. 2012, 29, 513; for selected examples of the synthesis of different natural products, see: a) J.-P. Lumb, D. Trauner, Org. Lett. 2005, 7, 5865; b) F. Lçbermann, P. Mayer, D. Trauner, Angew. Chem. 2010, 122, 6335;

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

16521

K. A. Jørgensen et al.

Angew. Chem. Int. Ed. 2010, 49, 6199; c) D. A. Kummer, D. Li, A. Dion, A. G. Myers, Chem. Sci. 2011, 2, 1710. [10] CCDC-939254 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. [11] Calculations were performed with GAUSSIAN09. All structures were optimized at the B97x/6-31 + GACHTUNGRE(d,p) level. Reported free energies were calculated with IEFPCM-M06–2x/6–311 + GACHTUNGRE(2df,2p)// IEFPCM-B97d/6-31 + GACHTUNGRE(d,p). Solvent effects were estimated with IEFPCM, by using chloroform as the solvent. Frequency calculations were performed for all stationary points to identify them as

16522

www.chemeurj.org

local minima or first-order saddle points and to obtain the ZPEs and thermochemical corrections for the free energies. All of the reported values are free energies at 298 K. See the Supporting Information for complete references, methods, and coordinates of reactants, intermediates, and transition-state structures. [12] Attempts to locate the zwitterionic intermediate and second transition-state structure for this exo-pathway with IRC calculations and relaxed potential-energy scans were unsuccessful.

 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Received: September 6, 2013 Published online: November 4, 2013

Chem. Eur. J. 2013, 19, 16518 – 16522

Organocatalytic enantioselective cycloaddition reactions of dienamines with quinones.

Organocatalytic enantioselective cycloaddition reactions of dienamines with quinones. - PDF Download Free
408KB Sizes 0 Downloads 0 Views