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Cite this: Chem. Commun., 2014, 50, 13676 Received 20th August 2014, Accepted 17th September 2014
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Organocatalytic asymmetric strategies to carbocyclic structures by c-alkylation-annulation sequences† Bjarke S. Donslund, Kim Søholm Halskov, Lars A. Leth, Bruno Matos Paz and Karl Anker Jørgensen*
DOI: 10.1039/c4cc06556e www.rsc.org/chemcomm
Attractive carbocyclic structures are accessed via a highly regioand enantioselective aminocatalytic c-addition of cyclic enals to vinyl phosphonates followed by a one-pot intramolecular Horner– Wadsworth–Emmons reaction. It is also demonstrated that nitro olefins can act as electrophiles in a similar reaction concept, providing carbocycles in equally high stereoselectivity.
Chiral carbocyclic structures are widespread in naturally occurring compounds and while numerous tools are available to the synthetic chemist for the asymmetric construction of linear molecules, strategies for the rapid stereoselective formation of (poly)cyclic frameworks represent more challenging tasks.1 Inspired by biosynthesis, a recent approach to total synthesis of structurally complex terpenes has included the division into two phases: a cyclase phase and an oxidation phase.2 Traditional approaches to the so-called cyclase phase often rely on a few widely used reactions, e.g. Diels–Alder reactions3 and Robinson annulations.4 Hence, it is of interest to develop new methodologies for the formation of carbocyclic scaffolds in order to expand the pallet of opportunities for the synthetic community. Since the breakthrough of asymmetric aminocatalysis around the millennium,5 development of new activation modes within the field has occurred at a breathtaking pace. An exciting recent development in this field is vinylogous aminocatalysis, in which unsaturated carbonyl compounds are employed as substrates.6 This strategy allows for stereoselective functionalizations at remote centers.7 By application of the HOMO-raising strategy, which is well-known for enamine catalysis,8 new activation modes such as dienamine,9 trienamine10 and tetraenamine11 catalysis have been developed. However, a challenge in performing vinylogous aminocatalysis, is the ability to carry out transformations with control of the regioselectivity, due to several reactive centers being present in Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, spectroscopic data, crystallographic data, copies of spectra and UPC2 traces. CCDC 971515 and 1009726. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06556e
13676 | Chem. Commun., 2014, 50, 13676--13679
the reactive intermediate. For dienamine-catalyzed reactions, a number of strategies have been applied in order to direct the reaction to the g-center. These include the application of a-branched substrates,12 bifunctional catalysts which deliver the electrophile in the appropriate position13 and application of substrates which undergo [4+2]-additions, in which spontaneous cyclization onto the ipso-position is exploited as a means of favoring the g-position.14 Recently, one report has shown that the application of cyclic 2,4-dienals favor functionalization in the g-position over the a-position via cross-trienamine activation.15 In the present work, we will present the development of an organocatalytic methodology, which allows for one-pot assembly of optically active 6-membered carbocycles, fused with a variety of ring systems. These moieties are found in natural products such as cafestol,16 codeine,17 and tetrahydrocannabinol18 which display a wide range of biological activities (Fig. 1). Inspired by the recent advances in vinylogous aminocatalysis, we envisioned that the targeted carbocyclic structures could be obtained by g-alkylation of enals via 1,4-addition onto an appropriate olefin containing a phosphonate substituent. Initially, the electron-withdrawing effect of the phosphonate group could facilitate the Michael addition and upon addition of a base, the oxophilicity of the phosphorous atom should promote an intramolecular Horner–Wadsworth–Emmons (HWE) reaction (Scheme 1, bottom).19 Previous work by Alexakis et al. and Lu et al. describes the stereoselective a-alkylation of simple aldehydes by Michael addition to vinyl bis-phosphonates and vinyl bis-sulfones (Scheme 1, top).20 When employing similar electrophiles 2, a-alkylation of the dienal could prove a potential pitfall for the envisioned reaction strategy.
Fig. 1 Examples of naturally occurring and biologically active compounds which contain the targeted core structures (marked in red).
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by-product were observed. Upon isolation the carbocyclic products were found to be stable. After optimizing the reaction conditions, the scope of the developed procedure was explored (Scheme 2). The reaction tolerated substituents of different electronic nature in various positions on the aromatic moiety and in most cases, the desired carbocycles were formed in good to excellent yields and excellent enantioselectivities (5a–g). By the employment of an enal containing a 7-membered ring, the product 5h was achieved in a slightly lower yield and enantioselectivity. Enals with heteroatoms in the aliphatic ring performed well in the reaction, yielding their respective products 5i,j in moderate to good yields and excellent enantioselectivities. Carbocyclic products carrying annulated heteroaromatic systems were formed in high yields and
Scheme 1 Previous work on a-alkylation of aldehydes (top) and strategy for formation of chiral carbocycles by g-selective Michael addition followed by an intramolecular HWE reaction (bottom).
Gratifyingly, no a-alkylation was observed during this work, enabling clean conversion to the desired intermediate 4. For the initial tests with enal 1a and olefin 2a, catalyst 3a (20 mol%) and benzoic acid (20 mol%) were employed, which resulted in formation of the g-adduct 4a. Upon one-pot addition of Cs2CO3 (1.5 eq.) the desired product 5a was isolated in 32% yield and 94% ee (Table 1, entry 1). The acid additive proved to be necessary to achieve conversion (entry 2). Satisfyingly, by lowering catalyst and additive loadings to 5 mol% a cleaner conversion to 4a was observed and the annulated product was isolated in 65% yield (entry 3), maintaining the high level of enantioselectivity. Further lowering of acid and/or catalyst loadings resulted in lower conversion after 24 h (entries 4 and 5). It was also found that prolonged reaction time (424 h) for the second step resulted in slightly diminished yields, as small amounts of aromatized Table 1 Optimization of aminocatalytic one-pot annulation of carbocycles 5
Entrya
3a (mol%)
PhCO2H (mol%)
Conv.b (%)
eec (%)
1 2 3 4 5
20 20 5 2 2
20 0 5 5 2
495 (32) o5 495 (65) 67 30
94 — 94 — —
a
Reactions were carried out on a 0.1 mmol scale for 24 h using 1.0 eq. of 1a, 1.2 eq. 2a and 0.3 mL CHCl3. The second step was carried out by further addition of 0.6 mL CHCl3 along with 1.5 eq. Cs2CO3. b Conversion of 1a was determined by 1H NMR of the crude mixture of the adduct intermediate. Isolated yields of 5a are given in parenthesis. c Determined by chiral stationary phase UPC2.
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Scheme 2 Scope of chiral carbocycles 5 formed via dienamine-catalyzed Michael addition-HWE reaction sequence. Reactions performed on a 0.1 mmol scale, see ESI† for further details. The presented yield was attained as the isolated compound 5 upon FC on silica. Enantiomeric excess was determined by chiral stationary phase UPC2. a 5c,h were formed by the employment of 10 mol% of catalyst 3a and 10 mol% PhCO2H. b 5e was formed with a reaction time of 4 h for the second step. c 5j,l were formed with a reaction time of 48 h for the first step. d 5m was formed with 20 mol% of catalyst 3a in the absence of PhCO2H.
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enantioselectivities (5k,l). The reaction could be performed with g-substituted 2,4-dienals through a cross-trienamine catalyzed reaction,15 although slightly altered reaction conditions were necessary in this case (5m). Variations of the electrophile were also performed; products carrying an ester (5n), a phosphonate (5o), or a sulfone (5p) could be synthesized in excellent enantioselectivities and moderate to good yields. The absolute configuration of the products was determined from X-ray analysis of compound 5p and the configuration of the remaining structures 5 were assigned by analogy (Scheme 2). During investigation of the scope, a few limitations were identified. b-Substituted vinyl phosphonates were tested as potential electrophiles, which could allow access to products bearing additional substituents; unfortunately, these electrophiles did not perform well in the reaction. While ketone-, ester-, sulfone-, and phosphonate-carrying electrophiles 2 were easily synthesized by Knoevenagel condensation, it was found that the corresponding Michael acceptor containing a nitro-group was unstable and could not be isolated. In order to address these limitations other electrophiles were tested and nitro olefins 6 were found to be potential candidates as these could afford carbocyclic products, which contain an additional stereocenter and a nitro-group. When nitrostyrene 6a was tested as electrophile under reaction conditions similar to those applied for the scope of the g-alkylation-HWE reaction, no product formation was observed. By switching from catalyst 3a to the bifunctional catalyst 3b, product 7a was formed (Table 2). It is peculiar to note that this bifunctional catalyst, carrying a pyrrolidine ring and a squareamide moiety has previously been applied in reactions with enals and nitrostyrenes but with a significantly different outcome.13 In the case of linear enals, which were utilized in the previous work, a formal [2+2]-cycloaddition was observed, while in the case of cyclic enals 1 [4+2]-reactivity appears to prevail. Initially, enal 1a (2.0 eq.), nitrostyrene 6a (1.0 eq.), catalyst 3b (20 mol%) and additive diethyl acetamide (DEA) were mixed in acetonitrile and heated to 50 1C (Table 2, entry 1). The reaction was quite slow and a 4 : 1 dr was observed. Employing DABCO as an additive
turned out to improve the diastereoselectivity and lower reaction times (entries 2–4). A few organic bases were tested as alternative additives and DIPEA proved to be the best in terms of selectivity as product 7a was obtained in 420 : 1 dr and 93% ee (entry 7). DEA is believed to alleviate aggregation issues of catalyst 3b, which could also be the case for the basic additives. The reaction rate enhancement observed in the presence of base is potentially related to faster catalyst release via an E1cb-pathway. With reaction conditions in hand a series of enals were tested in the reaction setup (Scheme 3). In all entries only a single diastereoisomer was observed. The unsubstituted enal yielded product 7a in modest yield and excellent stereoselectivity. Substrates carrying two substituents afforded their respective products in moderate to good yields and excellent enantioselectivities (7b,f). Products carrying a methoxy substituent in various positions were formed in moderate yields and excellent stereoselectivities (7c–e). A substrate containing a seven-membered ring also proceeded to form the expected product with high enantioselectivity, albeit in lower yield (7g). Enals containing electron-withdrawing substituents in the aromatic ring (1f,g) did not function well in this procedure. A few nitro olefins, other than nitrostyrene, were also shown to give rise to the desired products. An alkyl-substituted nitro olefin gave the product
Table 2 Optimization of aminocatalytic Michael–Henry reaction affording chiral carbocycles 7
Entrya Additive (eq.) 1 2 3 4 5 6 7
T (1C) Time (h) Conv.b (%) drb
DEA (1.0) 50 DABCO (0.2) 50 DABCO (0.2) 40 DABCO (0.5) 40 Quinuclidine (0.5) 40 40 Et3N (0.5) DIPEA (0.5) 40
120 72 96 22 22 22 22
60 495 495 495 495 495 495
(50) (53) (59) (30) (16) (33) (43)
a
4:1 420 : 1 11 : 1 420 : 1 420 : 1 420 : 1 420 : 1
eec (%) 81 84 89 88 87 90 93
Reactions were carried out on a 0.1 mmol scale using 2.0 eq. of 1a and 1.0 eq. of 6a. b Conversion of 6a and diastereomeric ratios were determined by 1H NMR of the crude reaction mixture. Isolated yields of 7a are given in parenthesis. c Determined by chiral stationary phase UPC2.
13678 | Chem. Commun., 2014, 50, 13676--13679
Scheme 3 Scope of chiral carbocycles 7 formed by dienamine catalyzed Michael–Henry reaction from nitro olefins. Reactions were performed on a 0.1 mmol scale, see ESI† for further details. The presented yield was attained as the isolated compound 7 upon FC on silica. The ratio of diastereoisomers was determined from NMR analysis of the crude reaction mixture. Enantiomeric excess was determined by chiral stationary phase UPC2. a 7b was formed employing DABCO (0.5 eq.) as base. b 7j was formed using enal 1a (0.1 mmol) and ortho-chloro nitrostyrene (0.2 mmol).
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Fig. 2 Proposed transition-state structures rationalizing the observed configuration of the isolated carbocyclic compounds (a, b) and a previously proposed transition-state structure for a related reaction (c).
7h in moderate yield and excellent stereoselectivity. Substituted nitrostyrenes afforded their respective products 7i,j in moderate yields and high to excellent stereoselectivities. The absolute configuration of compound 7j was determined by X-ray crystallography and the remaining compounds 7 were assigned by analogy (Scheme 3). A rationale for the observed stereochemistry applying catalysts 3a and 3b are outlined in Fig. 2. The carbocyclic structures obtained by the g-alkylation-HWE sequence have a configuration expected to arise from reaction via an s-cis dienamine with the steric bulk of catalyst 3a shielding one face (Fig. 2a). However, the reaction of nitro olefins 6 with the cyclic enals 1 catalyzed by the dual-activating catalyst 3b showed a surprising stereochemical outcome compared to what was expected from reaction through the s-cis conformation as above. In previous studies employing the bifunctional catalyst 3b and nitrostyrenes with linear enals furnishing cyclobutanes, a reaction via an s-trans dienamine was proposed (Fig. 2c). If a similar transition state should operate in this case, an intermediate which is incapable of undergoing an intramolecular Henry reaction would arise. Hence, to account for the observed products and stereoselectivity, it is proposed that the reaction takes place via an s-cis dienamine as displayed (Fig. 2b). In conclusion, a highly enantioselective annulation of carbocycles has been achieved via an aminocatalytic g-alkylationHWE one-pot procedure. This method grants access to a variety of polycyclic systems containing heteroarenes, different ring sizes and heteroatoms. It was also demonstrated that related products could be obtained in excellent diastereo- and enantioselectivities utilizing a bifunctional catalyst and nitro olefins. We are grateful for X-ray analysis performed by Dr Jacob Overgaard and Magnus E. Jensen. We also thank L. Caruana for assistance during the screening process. This work was made possible by grants from FNU, Carlsberg Foundation, Aarhus University and CAPES Foundation, Ministry of Education of Brazil, for the predoctoral fellowship to B. M. Paz (no. 9525-13-0).
Notes and references 1 For books on asymmetric catalysis, see e.g.: Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, vol. 1–3; R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994. 2 T. J. Maimone and P. S. Baran, Nat. Chem. Biol., 2007, 3, 396; K. Chen and P. S. Baran, Nature, 2009, 459, 824; E. M. Davis and R. Croteau, Top. Curr. Chem., 2000, 209, 53.
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ChemComm 3 For a review on Diels–Alder reactions in total synthesis, see: K. C. Nicolaou, S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1780; for selected recent examples, see: L.-Z. Liu, J.-C. Han, G.-Z. Yue, C.-C. Li and Z. Yang, J. Am. Chem. Soc., 2010, 132, 13608; Y. Nishiyama, Y. Han-ya, S. Yokoshima and T. Fukuyama, J. Am. Chem. Soc., 2014, 136, 6598. 4 For selected examples, see: B. Bradshaw, G. E. Jardı´ and J. Bonjoch, J. Am. Chem. Soc., 2010, 132, 5966; J. Xu, L. Trzoss, W. K. Chang and E. A. Theodorakis, Angew. Chem., Int. Ed., 2011, 50, 3672; L. Trzoss, J. Xu, M. H. Lacoske, W. C. Mobley and E. A. Theodorakis, Chem. – Eur. J., 2013, 19, 6398. 5 Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications, ed. P. I. Dalko, Wiley-VCH, Weinheim, 2013; D. W. C. MacMillan, Nature, 2008, 455, 304; A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703; P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 9748; J.-L. Li, T.-Y. Liu and Y.-C. Chen, Acc. Chem. Res., 2012, 45, 1491; R. C. Wende and P. R. Schreiner, Green Chem., 2012, 14, 1821; U. Scheffler and R. Mahrwald, Chem. – Eur. J., 2013, 19, 14346. 6 I. D. Jurberg, I. Chatterjee, R. Tannert and P. Melchiorre, Chem. Commun., 2013, 49, 4869. 7 H. Jiang, Ł. Albrecht and K. A. Jørgensen, Chem. Sci., 2013, 4, 2287. 8 For a review on enamine catalysis: S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471. 9 For a review on dienamine catalysis, see: D. B. Ramachary and Y. V. Reddy, Eur. J. Org. Chem., 2012, 865; for selected examples, see: ´r and K. A. Jørgensen, S. Bertelsen, M. Marigo, S. Brandes, P. Dine ¨hlich J. Am. Chem. Soc., 2006, 128, 12973; R. M. de Figueiredo, R. Fro and M. Christmann, Angew. Chem., Int. Ed., 2008, 47, 1450; G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli and P. Melchiorre, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20642. 10 For a review on trienamine catalysis, see: I. Kumar, P. Ramaraju and N. A. Mir, Org. Biomol. Chem., 2013, 11, 709; for seminal report, see: Z.-J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen and K. A. Jørgensen, J. Am. Chem. Soc., 2011, 133, 5053. 11 J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L. Davis and K. A. Jørgensen, Chem. Sci., 2014, 5, 2052; Q.-Q. Zhou, Y.-C. Xiao, X. Yuan and Y.-C. Chen, Asian J. Org. Chem., 2014, 3, 545. 12 G. Bergonzini, S. Vera and P. Melchiorre, Angew. Chem., Int. Ed., ´pez, R. P. Herrera, R. Fro ¨hlich, 2010, 49, 9685; J. Stiller, E. M. Lo C. Strohmann and M. Christmann, Org. Lett., 2011, 13, 70. 13 Ł. Albrecht, G. Dickmeiss, F. C. Acosta, C. R. Escrich, R. L. Davis and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134, 2543; D. Bastida, Y. Liu, ´n and P. Melchiorre, Org. Lett., 2013, 15, 220. X. Tian, E. E. Ada 14 B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su and J.-H. Liao, J. Org. Chem., 2007, 72, 8459; A. Orue, E. Reyes, J. L. Vicario, L. Carrillo and U. Uria, Org. Lett., 2012, 14, 3740; T. K. ´mez, J. R. Bak, R. L. Davis and K. A. Jørgensen, Johansen, C. V. Go Chem. – Eur. J., 2013, 19, 16518; K. S. Halskov, B. S. Donslund, ¨sser and K. A. Jørgensen, Angew. Chem., Int. Ed., 2014, S. Barfu 53, 4137. 15 K. S. Halskov, T. K. Johansen, R. L. Davis, M. Steurer, F. Jensen and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134, 12943. 16 See e.g.: C. Cavin, D. Holzhaeuser, G. Scharf, A. Constable, W. W. Huber and B. Schilter, Food Chem. Toxicol., 2002, 40, 1155; M. L. Ricketts, M. V. Boekschoten, A. J. Kreeft, G. J. E. J. Hooiveld, ¨ller, R. R. Frants, S. Kasanmoentalib, S. M. Post, C. J. A. Moen, M. Mu H. M. G. Princen, J. G. Porter, M. B. Katan, M. H. Hofker and D. D. Moore, Mol. Endocrinol., 2007, 21, 1603. 17 See e.g.: H. Krueger, N. B. Eddy and M. Sumwalt, The Pharmacology of the Opium Alkaloids, U. S. Government Printing Office, Washington D.C., 1941; H. Akil, in Opiates: Biological Mechanisms, Mechanisms in Psychopharmacology from Theory to Practice, ed. J. D. Barchas, Y. A. Berger, R. D. Ciaranello and G. R. Elliot, Oxford University Press, New York, Oxford, 1977. 18 See e.g.: Cannabinoids, ed. R. G. Pertwee, Springer, Berlin, 2005; M. Guzman, Nat. Rev. Cancer, 2003, 3, 745. 19 For other aminocatalysis-annulation sequences, see: A. R. Choudhury and A. Mukherjee, Adv. Synth. Catal., 2013, 355, 1989; H. Ishikawa, T. Suzuki and Y. Hayashi, Angew. Chem., Int. Ed., 2009, 48, 1304. ´, M. Tissot and A. Alexakis, Org. Lett., 2007, 9, 3749; 20 S. S. Mosse ´ and A. Alexakis, Org. Lett., 2005, 7, 4361; Q. Zhu and Y. Lu, S. Mosse Org. Lett., 2008, 10, 4803.
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Cite this: Chem. Commun., 2014, 50, 13676 Received 20th August 2014, Accepted 17th September 2014
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Organocatalytic asymmetric strategies to carbocyclic structures by c-alkylation-annulation sequences† Bjarke S. Donslund, Kim Søholm Halskov, Lars A. Leth, Bruno Matos Paz and Karl Anker Jørgensen*
DOI: 10.1039/c4cc06556e www.rsc.org/chemcomm
Attractive carbocyclic structures are accessed via a highly regioand enantioselective aminocatalytic c-addition of cyclic enals to vinyl phosphonates followed by a one-pot intramolecular Horner– Wadsworth–Emmons reaction. It is also demonstrated that nitro olefins can act as electrophiles in a similar reaction concept, providing carbocycles in equally high stereoselectivity.
Chiral carbocyclic structures are widespread in naturally occurring compounds and while numerous tools are available to the synthetic chemist for the asymmetric construction of linear molecules, strategies for the rapid stereoselective formation of (poly)cyclic frameworks represent more challenging tasks.1 Inspired by biosynthesis, a recent approach to total synthesis of structurally complex terpenes has included the division into two phases: a cyclase phase and an oxidation phase.2 Traditional approaches to the so-called cyclase phase often rely on a few widely used reactions, e.g. Diels–Alder reactions3 and Robinson annulations.4 Hence, it is of interest to develop new methodologies for the formation of carbocyclic scaffolds in order to expand the pallet of opportunities for the synthetic community. Since the breakthrough of asymmetric aminocatalysis around the millennium,5 development of new activation modes within the field has occurred at a breathtaking pace. An exciting recent development in this field is vinylogous aminocatalysis, in which unsaturated carbonyl compounds are employed as substrates.6 This strategy allows for stereoselective functionalizations at remote centers.7 By application of the HOMO-raising strategy, which is well-known for enamine catalysis,8 new activation modes such as dienamine,9 trienamine10 and tetraenamine11 catalysis have been developed. However, a challenge in performing vinylogous aminocatalysis, is the ability to carry out transformations with control of the regioselectivity, due to several reactive centers being present in Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, spectroscopic data, crystallographic data, copies of spectra and UPC2 traces. CCDC 971515 and 1009726. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06556e
13676 | Chem. Commun., 2014, 50, 13676--13679
the reactive intermediate. For dienamine-catalyzed reactions, a number of strategies have been applied in order to direct the reaction to the g-center. These include the application of a-branched substrates,12 bifunctional catalysts which deliver the electrophile in the appropriate position13 and application of substrates which undergo [4+2]-additions, in which spontaneous cyclization onto the ipso-position is exploited as a means of favoring the g-position.14 Recently, one report has shown that the application of cyclic 2,4-dienals favor functionalization in the g-position over the a-position via cross-trienamine activation.15 In the present work, we will present the development of an organocatalytic methodology, which allows for one-pot assembly of optically active 6-membered carbocycles, fused with a variety of ring systems. These moieties are found in natural products such as cafestol,16 codeine,17 and tetrahydrocannabinol18 which display a wide range of biological activities (Fig. 1). Inspired by the recent advances in vinylogous aminocatalysis, we envisioned that the targeted carbocyclic structures could be obtained by g-alkylation of enals via 1,4-addition onto an appropriate olefin containing a phosphonate substituent. Initially, the electron-withdrawing effect of the phosphonate group could facilitate the Michael addition and upon addition of a base, the oxophilicity of the phosphorous atom should promote an intramolecular Horner–Wadsworth–Emmons (HWE) reaction (Scheme 1, bottom).19 Previous work by Alexakis et al. and Lu et al. describes the stereoselective a-alkylation of simple aldehydes by Michael addition to vinyl bis-phosphonates and vinyl bis-sulfones (Scheme 1, top).20 When employing similar electrophiles 2, a-alkylation of the dienal could prove a potential pitfall for the envisioned reaction strategy.
Fig. 1 Examples of naturally occurring and biologically active compounds which contain the targeted core structures (marked in red).
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by-product were observed. Upon isolation the carbocyclic products were found to be stable. After optimizing the reaction conditions, the scope of the developed procedure was explored (Scheme 2). The reaction tolerated substituents of different electronic nature in various positions on the aromatic moiety and in most cases, the desired carbocycles were formed in good to excellent yields and excellent enantioselectivities (5a–g). By the employment of an enal containing a 7-membered ring, the product 5h was achieved in a slightly lower yield and enantioselectivity. Enals with heteroatoms in the aliphatic ring performed well in the reaction, yielding their respective products 5i,j in moderate to good yields and excellent enantioselectivities. Carbocyclic products carrying annulated heteroaromatic systems were formed in high yields and
Scheme 1 Previous work on a-alkylation of aldehydes (top) and strategy for formation of chiral carbocycles by g-selective Michael addition followed by an intramolecular HWE reaction (bottom).
Gratifyingly, no a-alkylation was observed during this work, enabling clean conversion to the desired intermediate 4. For the initial tests with enal 1a and olefin 2a, catalyst 3a (20 mol%) and benzoic acid (20 mol%) were employed, which resulted in formation of the g-adduct 4a. Upon one-pot addition of Cs2CO3 (1.5 eq.) the desired product 5a was isolated in 32% yield and 94% ee (Table 1, entry 1). The acid additive proved to be necessary to achieve conversion (entry 2). Satisfyingly, by lowering catalyst and additive loadings to 5 mol% a cleaner conversion to 4a was observed and the annulated product was isolated in 65% yield (entry 3), maintaining the high level of enantioselectivity. Further lowering of acid and/or catalyst loadings resulted in lower conversion after 24 h (entries 4 and 5). It was also found that prolonged reaction time (424 h) for the second step resulted in slightly diminished yields, as small amounts of aromatized Table 1 Optimization of aminocatalytic one-pot annulation of carbocycles 5
Entrya
3a (mol%)
PhCO2H (mol%)
Conv.b (%)
eec (%)
1 2 3 4 5
20 20 5 2 2
20 0 5 5 2
495 (32) o5 495 (65) 67 30
94 — 94 — —
a
Reactions were carried out on a 0.1 mmol scale for 24 h using 1.0 eq. of 1a, 1.2 eq. 2a and 0.3 mL CHCl3. The second step was carried out by further addition of 0.6 mL CHCl3 along with 1.5 eq. Cs2CO3. b Conversion of 1a was determined by 1H NMR of the crude mixture of the adduct intermediate. Isolated yields of 5a are given in parenthesis. c Determined by chiral stationary phase UPC2.
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Scheme 2 Scope of chiral carbocycles 5 formed via dienamine-catalyzed Michael addition-HWE reaction sequence. Reactions performed on a 0.1 mmol scale, see ESI† for further details. The presented yield was attained as the isolated compound 5 upon FC on silica. Enantiomeric excess was determined by chiral stationary phase UPC2. a 5c,h were formed by the employment of 10 mol% of catalyst 3a and 10 mol% PhCO2H. b 5e was formed with a reaction time of 4 h for the second step. c 5j,l were formed with a reaction time of 48 h for the first step. d 5m was formed with 20 mol% of catalyst 3a in the absence of PhCO2H.
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enantioselectivities (5k,l). The reaction could be performed with g-substituted 2,4-dienals through a cross-trienamine catalyzed reaction,15 although slightly altered reaction conditions were necessary in this case (5m). Variations of the electrophile were also performed; products carrying an ester (5n), a phosphonate (5o), or a sulfone (5p) could be synthesized in excellent enantioselectivities and moderate to good yields. The absolute configuration of the products was determined from X-ray analysis of compound 5p and the configuration of the remaining structures 5 were assigned by analogy (Scheme 2). During investigation of the scope, a few limitations were identified. b-Substituted vinyl phosphonates were tested as potential electrophiles, which could allow access to products bearing additional substituents; unfortunately, these electrophiles did not perform well in the reaction. While ketone-, ester-, sulfone-, and phosphonate-carrying electrophiles 2 were easily synthesized by Knoevenagel condensation, it was found that the corresponding Michael acceptor containing a nitro-group was unstable and could not be isolated. In order to address these limitations other electrophiles were tested and nitro olefins 6 were found to be potential candidates as these could afford carbocyclic products, which contain an additional stereocenter and a nitro-group. When nitrostyrene 6a was tested as electrophile under reaction conditions similar to those applied for the scope of the g-alkylation-HWE reaction, no product formation was observed. By switching from catalyst 3a to the bifunctional catalyst 3b, product 7a was formed (Table 2). It is peculiar to note that this bifunctional catalyst, carrying a pyrrolidine ring and a squareamide moiety has previously been applied in reactions with enals and nitrostyrenes but with a significantly different outcome.13 In the case of linear enals, which were utilized in the previous work, a formal [2+2]-cycloaddition was observed, while in the case of cyclic enals 1 [4+2]-reactivity appears to prevail. Initially, enal 1a (2.0 eq.), nitrostyrene 6a (1.0 eq.), catalyst 3b (20 mol%) and additive diethyl acetamide (DEA) were mixed in acetonitrile and heated to 50 1C (Table 2, entry 1). The reaction was quite slow and a 4 : 1 dr was observed. Employing DABCO as an additive
turned out to improve the diastereoselectivity and lower reaction times (entries 2–4). A few organic bases were tested as alternative additives and DIPEA proved to be the best in terms of selectivity as product 7a was obtained in 420 : 1 dr and 93% ee (entry 7). DEA is believed to alleviate aggregation issues of catalyst 3b, which could also be the case for the basic additives. The reaction rate enhancement observed in the presence of base is potentially related to faster catalyst release via an E1cb-pathway. With reaction conditions in hand a series of enals were tested in the reaction setup (Scheme 3). In all entries only a single diastereoisomer was observed. The unsubstituted enal yielded product 7a in modest yield and excellent stereoselectivity. Substrates carrying two substituents afforded their respective products in moderate to good yields and excellent enantioselectivities (7b,f). Products carrying a methoxy substituent in various positions were formed in moderate yields and excellent stereoselectivities (7c–e). A substrate containing a seven-membered ring also proceeded to form the expected product with high enantioselectivity, albeit in lower yield (7g). Enals containing electron-withdrawing substituents in the aromatic ring (1f,g) did not function well in this procedure. A few nitro olefins, other than nitrostyrene, were also shown to give rise to the desired products. An alkyl-substituted nitro olefin gave the product
Table 2 Optimization of aminocatalytic Michael–Henry reaction affording chiral carbocycles 7
Entrya Additive (eq.) 1 2 3 4 5 6 7
T (1C) Time (h) Conv.b (%) drb
DEA (1.0) 50 DABCO (0.2) 50 DABCO (0.2) 40 DABCO (0.5) 40 Quinuclidine (0.5) 40 40 Et3N (0.5) DIPEA (0.5) 40
120 72 96 22 22 22 22
60 495 495 495 495 495 495
(50) (53) (59) (30) (16) (33) (43)
a
4:1 420 : 1 11 : 1 420 : 1 420 : 1 420 : 1 420 : 1
eec (%) 81 84 89 88 87 90 93
Reactions were carried out on a 0.1 mmol scale using 2.0 eq. of 1a and 1.0 eq. of 6a. b Conversion of 6a and diastereomeric ratios were determined by 1H NMR of the crude reaction mixture. Isolated yields of 7a are given in parenthesis. c Determined by chiral stationary phase UPC2.
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Scheme 3 Scope of chiral carbocycles 7 formed by dienamine catalyzed Michael–Henry reaction from nitro olefins. Reactions were performed on a 0.1 mmol scale, see ESI† for further details. The presented yield was attained as the isolated compound 7 upon FC on silica. The ratio of diastereoisomers was determined from NMR analysis of the crude reaction mixture. Enantiomeric excess was determined by chiral stationary phase UPC2. a 7b was formed employing DABCO (0.5 eq.) as base. b 7j was formed using enal 1a (0.1 mmol) and ortho-chloro nitrostyrene (0.2 mmol).
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Fig. 2 Proposed transition-state structures rationalizing the observed configuration of the isolated carbocyclic compounds (a, b) and a previously proposed transition-state structure for a related reaction (c).
7h in moderate yield and excellent stereoselectivity. Substituted nitrostyrenes afforded their respective products 7i,j in moderate yields and high to excellent stereoselectivities. The absolute configuration of compound 7j was determined by X-ray crystallography and the remaining compounds 7 were assigned by analogy (Scheme 3). A rationale for the observed stereochemistry applying catalysts 3a and 3b are outlined in Fig. 2. The carbocyclic structures obtained by the g-alkylation-HWE sequence have a configuration expected to arise from reaction via an s-cis dienamine with the steric bulk of catalyst 3a shielding one face (Fig. 2a). However, the reaction of nitro olefins 6 with the cyclic enals 1 catalyzed by the dual-activating catalyst 3b showed a surprising stereochemical outcome compared to what was expected from reaction through the s-cis conformation as above. In previous studies employing the bifunctional catalyst 3b and nitrostyrenes with linear enals furnishing cyclobutanes, a reaction via an s-trans dienamine was proposed (Fig. 2c). If a similar transition state should operate in this case, an intermediate which is incapable of undergoing an intramolecular Henry reaction would arise. Hence, to account for the observed products and stereoselectivity, it is proposed that the reaction takes place via an s-cis dienamine as displayed (Fig. 2b). In conclusion, a highly enantioselective annulation of carbocycles has been achieved via an aminocatalytic g-alkylationHWE one-pot procedure. This method grants access to a variety of polycyclic systems containing heteroarenes, different ring sizes and heteroatoms. It was also demonstrated that related products could be obtained in excellent diastereo- and enantioselectivities utilizing a bifunctional catalyst and nitro olefins. We are grateful for X-ray analysis performed by Dr Jacob Overgaard and Magnus E. Jensen. We also thank L. Caruana for assistance during the screening process. This work was made possible by grants from FNU, Carlsberg Foundation, Aarhus University and CAPES Foundation, Ministry of Education of Brazil, for the predoctoral fellowship to B. M. Paz (no. 9525-13-0).
Notes and references 1 For books on asymmetric catalysis, see e.g.: Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, vol. 1–3; R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994. 2 T. J. Maimone and P. S. Baran, Nat. Chem. Biol., 2007, 3, 396; K. Chen and P. S. Baran, Nature, 2009, 459, 824; E. M. Davis and R. Croteau, Top. Curr. Chem., 2000, 209, 53.
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ChemComm 3 For a review on Diels–Alder reactions in total synthesis, see: K. C. Nicolaou, S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1780; for selected recent examples, see: L.-Z. Liu, J.-C. Han, G.-Z. Yue, C.-C. Li and Z. Yang, J. Am. Chem. Soc., 2010, 132, 13608; Y. Nishiyama, Y. Han-ya, S. Yokoshima and T. Fukuyama, J. Am. Chem. Soc., 2014, 136, 6598. 4 For selected examples, see: B. Bradshaw, G. E. Jardı´ and J. Bonjoch, J. Am. Chem. Soc., 2010, 132, 5966; J. Xu, L. Trzoss, W. K. Chang and E. A. Theodorakis, Angew. Chem., Int. Ed., 2011, 50, 3672; L. Trzoss, J. Xu, M. H. Lacoske, W. C. Mobley and E. A. Theodorakis, Chem. – Eur. J., 2013, 19, 6398. 5 Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications, ed. P. I. Dalko, Wiley-VCH, Weinheim, 2013; D. W. C. MacMillan, Nature, 2008, 455, 304; A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703; P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 9748; J.-L. Li, T.-Y. Liu and Y.-C. Chen, Acc. Chem. Res., 2012, 45, 1491; R. C. Wende and P. R. Schreiner, Green Chem., 2012, 14, 1821; U. Scheffler and R. Mahrwald, Chem. – Eur. J., 2013, 19, 14346. 6 I. D. Jurberg, I. Chatterjee, R. Tannert and P. Melchiorre, Chem. Commun., 2013, 49, 4869. 7 H. Jiang, Ł. Albrecht and K. A. Jørgensen, Chem. Sci., 2013, 4, 2287. 8 For a review on enamine catalysis: S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471. 9 For a review on dienamine catalysis, see: D. B. Ramachary and Y. V. Reddy, Eur. J. Org. Chem., 2012, 865; for selected examples, see: ´r and K. A. Jørgensen, S. Bertelsen, M. Marigo, S. Brandes, P. Dine ¨hlich J. Am. Chem. Soc., 2006, 128, 12973; R. M. de Figueiredo, R. Fro and M. Christmann, Angew. Chem., Int. Ed., 2008, 47, 1450; G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli and P. Melchiorre, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20642. 10 For a review on trienamine catalysis, see: I. Kumar, P. Ramaraju and N. A. Mir, Org. Biomol. Chem., 2013, 11, 709; for seminal report, see: Z.-J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen and K. A. Jørgensen, J. Am. Chem. Soc., 2011, 133, 5053. 11 J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L. Davis and K. A. Jørgensen, Chem. Sci., 2014, 5, 2052; Q.-Q. Zhou, Y.-C. Xiao, X. Yuan and Y.-C. Chen, Asian J. Org. Chem., 2014, 3, 545. 12 G. Bergonzini, S. Vera and P. Melchiorre, Angew. Chem., Int. Ed., ´pez, R. P. Herrera, R. Fro ¨hlich, 2010, 49, 9685; J. Stiller, E. M. Lo C. Strohmann and M. Christmann, Org. Lett., 2011, 13, 70. 13 Ł. Albrecht, G. Dickmeiss, F. C. Acosta, C. R. Escrich, R. L. Davis and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134, 2543; D. Bastida, Y. Liu, ´n and P. Melchiorre, Org. Lett., 2013, 15, 220. X. Tian, E. E. Ada 14 B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su and J.-H. Liao, J. Org. Chem., 2007, 72, 8459; A. Orue, E. Reyes, J. L. Vicario, L. Carrillo and U. Uria, Org. Lett., 2012, 14, 3740; T. K. ´mez, J. R. Bak, R. L. Davis and K. A. Jørgensen, Johansen, C. V. Go Chem. – Eur. J., 2013, 19, 16518; K. S. Halskov, B. S. Donslund, ¨sser and K. A. Jørgensen, Angew. Chem., Int. Ed., 2014, S. Barfu 53, 4137. 15 K. S. Halskov, T. K. Johansen, R. L. Davis, M. Steurer, F. Jensen and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134, 12943. 16 See e.g.: C. Cavin, D. Holzhaeuser, G. Scharf, A. Constable, W. W. Huber and B. Schilter, Food Chem. Toxicol., 2002, 40, 1155; M. L. Ricketts, M. V. Boekschoten, A. J. Kreeft, G. J. E. J. Hooiveld, ¨ller, R. R. Frants, S. Kasanmoentalib, S. M. Post, C. J. A. Moen, M. Mu H. M. G. Princen, J. G. Porter, M. B. Katan, M. H. Hofker and D. D. Moore, Mol. Endocrinol., 2007, 21, 1603. 17 See e.g.: H. Krueger, N. B. Eddy and M. Sumwalt, The Pharmacology of the Opium Alkaloids, U. S. Government Printing Office, Washington D.C., 1941; H. Akil, in Opiates: Biological Mechanisms, Mechanisms in Psychopharmacology from Theory to Practice, ed. J. D. Barchas, Y. A. Berger, R. D. Ciaranello and G. R. Elliot, Oxford University Press, New York, Oxford, 1977. 18 See e.g.: Cannabinoids, ed. R. G. Pertwee, Springer, Berlin, 2005; M. Guzman, Nat. Rev. Cancer, 2003, 3, 745. 19 For other aminocatalysis-annulation sequences, see: A. R. Choudhury and A. Mukherjee, Adv. Synth. Catal., 2013, 355, 1989; H. Ishikawa, T. Suzuki and Y. Hayashi, Angew. Chem., Int. Ed., 2009, 48, 1304. ´, M. Tissot and A. Alexakis, Org. Lett., 2007, 9, 3749; 20 S. S. Mosse ´ and A. Alexakis, Org. Lett., 2005, 7, 4361; Q. Zhu and Y. Lu, S. Mosse Org. Lett., 2008, 10, 4803.
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