DOI: 10.1002/chem.201404468
Communication
& Aminocatalysis
Novel Organocatalytic Activation of Unmodified Morita–Baylis– Hillman Alcohols for the Synthesis of Bicyclic a-AlkylideneKetones Julian Stiller,[b] Dorota Kowalczyk,[a] Hao Jiang,[b] Karl Anker Jørgensen,*[b] and Łukasz Albrecht*[a] Abstract: The organocatalytic activation of Morita–Baylis– Hillman alcohols via H-bonding-iminium-ion formation is demonstrated for the first time. This activation strategy enables the Morita-Baylis–Hillman alcohols to undergo a formal SN2’ reaction. In combination with the well-established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic a-alkylidene-ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature-inspired target products with four contiguous stereogenic centers in a highly stereoselective manner.
Asymmetric transformations of carbonyl compounds aiming at the introduction of specific structural motives to target molecules have gained increasing attention of the chemical community.[1] A key to success of such a target-oriented strategy is the ability of chiral catalysts to ensure high levels of stereoinduction while providing a reactive intermediate with the desired reactivity profile defined by the structure of the target products. In this respect, aminocatalytic strategies, utilizing chiral primary or secondary amines as the catalyst, are highly reliable tools in modern asymmetric synthesis equipping chemists with a broad range of possibilities to access new reaction profiles in order to introduce specific structural motifs in a stereoselective fashion.[1c–e] Morita–Baylis–Hillman (MBH) alcohols and their derivatives constitute highly useful type of building blocks that have been rarely employed in the field of aminocatalysis.[2, 3] However, a direct application of unmodified MBH alcohols in asymmetric synthesis is still challenging and the development of methods enabling their catalytic activation is of high interest in modern organic chemistry. Furthermore,
the introduction of alkylidene moiety through a formal SN2’ reactivity of MBH alcohols seems to be particularly interesting, which has not been explored in aminocatalysis before. We envisioned that a novel activation mode of MBH alcohols might rely on the corresponding iminium-ion formation capable of H-bonding interactions (Scheme 1). Such an iminium-ion should possess enhanced reactivity towards formal SN2’ reaction leading to the introduction of a new stereogenic center in the b-position and a-alkylidene moiety in the a-position to the carbonyl functionality (Scheme 1, top). It was anticipated that merging of such an activation strategy with the well-recognized enamine activation should enable the formation of a unique aminocatalytic intermediate and result in the development of a novel cascade reactivity—addition followed by a formal SN2’ reaction (Scheme 1, middle). An important challenge of such a synthetic strategy relates to the presence of a stereogenic center in the MBH alcohol substrate. For this reason mismatching interactions between the chirality of the molecule and the catalyst might take place resulting in overall enantioselectivity deterioration.
[a] D. Kowalczyk, Dr. Ł. Albrecht Institute of Organic Chemistry, Chemistry Department Lodz University of Technology, Z˙eromskiego 116, 90-924 Łdz´ (Poland) E-mail: [email protected] [b] Dr. J. Stiller, Dr. H. Jiang, Prof. Dr. K. A. Jørgensen Center for Catalysis, Chemistry Department, 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.201404468. Chem. Eur. J. 2014, 20, 13108 – 13112
Scheme 1. A novel aminocatalytic activation mode.
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Communication Importantly, the devised cascade reactivity should enable a facile construction of the a-alkylidene-ketone framework. This is a privileged scaffold that is found in natural products and pharmacologically relevant molecules, such as chiloscyphone, a naturally occurring sesquiterpene[4a] methylenomycin A and sarkomycin belonging to the family of cyclopentanoid antibiotics[4b–d] with sarkomycin possessing interesting anticancer activity (Scheme 2, bottom).[5] The synthetic relevance of a-alkylidene-ketones has been confirmed recently.[6] In particular their ability to act as effective Michael acceptors has been utilized in organic synthesis, including asymmetric organocatalysis.[6a,b]
Table 1. Enantioselective approach to bicyclic a-alkylidene-ketones 4: optimization studies.[a]
Scheme 2. Enantioselective approach to bicyclic a-alkylidene-ketones.
Herein, we report a novel aminocatalytic activation of unmodified MBH alcohols and its application for the synthesis of bicyclic a-alkylidene-ketones. The developed approach utilizes a combination of a simple enamine activation with the unique ability of an aminocatalyst to activate MBH alcohols for a formal SN2’ reaction via iminium-ion activation. As a proof-ofconcept, the reaction between 2-(hydroxyalkyl)cyclopent-2-en1-one 1 and olefinic oxindoles 2 in the presence of a primary amine organocatalyst 3 was studied (Scheme 2). We initiated our studies with the goal of finding appropriate reaction conditions for the devised synthetic strategy. The initial catalyst screening identified a quinine-derived primary amine catalyst in combination with (S)-mandelic acid[7] as the most suitable catalytic system for the transformation and chloroform as the best solvent (see the Supporting Information for details). Further screening revealed that lowering reaction temperature resulted in longer reaction times and led to improved enantio- and diastereoselectivity (Table 1, compare entries 1–3). It was found that the reaction rate at ambient temperatures could easily be improved by employing an excess of alcohol 1 a maintaining the stereoselectivity of the transformation at the comparable level (Table 1, compare entries 3–7). Interestingly, isolated unreacted alcohol 1 a was enantiomerically enriched, indicating that the reaction also occurs in a kinetic resolution manner (Table 1, entries 6 and 7). Hence matching– mismatching interactions between the catalyst-bound enamine part of the substrate and its chiral MBH alcohol moiety have an influence on the stereoselectivity of the reaction. The use of olefinic counterpart in excess resulted in a decrease in reactivity (Table 1, entry 8). Notably, all reactions afforded a-alkylidene-ketone 4 a as single E-isomer. With the optimized reaction conditions in hand, the scope and limitations of the methodology were investigated. GratifyChem. Eur. J. 2014, 20, 13108 – 13112
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Entry
1a [equiv]
2a [equiv]
T [oC]
t [h]
Conv. (yield [%])[b]
d.r.[c]
ee [%][d]
1 2 3 4 5[e] 6[f] 7[g] 8
1.1 1.1 1.1 2 2 2.5 3 1
1 1 1 1 1 1 1 2
50 40 RT RT RT RT RT RT
20 20 8d 67 40 40 40 9d
84 80 > 95 > 95 > 95 > 95 > 95 85
> 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5
72 86 87 91 90 90 90 89
(71) (72) (83) (83) (83) (79) (84)
[a] Reactions performed on 0.1 mmol scale (for details see the Supporting Information). [b] Conversion as determined by 1H NMR spectroscopy of a crude reaction mixture. Isolated yields are given in parenthesis. [c] Determined by 1H NMR spectroscopy of a crude reaction mixture. [d] Determined by a chiral stationary phase UPC2. [e] Concentration 0.5 m. [f] Unreacted alcohol 1 a isolated with 29 % ee. [g] Unreacted alcohol 1 a isolated with 25 % ee.
ingly, various olefinic oxindoles 2 were successfully employed in the developed reaction sequence (Scheme 3). Importantly, both electron-donating and electron-withdrawing substituents could be present on the aromatic moiety of olefinic oxindole framework of 2 affording target products in good yields and in high stereoselectivities. Furthermore, the position of the substituent had no significant influence on the reaction outcome and disubstituted derivatives were well-tolerated. Interestingly, N-unprotected oxindoles could also be employed in the reaction sequence with similar results as demonstrated in the synthesis of 4 h. In all cases the formation of E-configured a-alkylidene-ketone 4 a–h was observed. In the course of further studies various MBH alcohols 1 were utilized in the developed reaction sequence (Scheme 4). It was found that MBH alcohols 1 i and 1 j derived from both electron-poor and electron-rich benzaldehydes, respectively, easily reacted under optimized reaction conditions. Furthermore, a heteroaromatic framework and alkyl side-chain could be introduced on the alkylidene moiety of the target ketones 4 as demonstrated in the synthesis of 4 k and 4 l. Although a slightly lower enantioselectivity was observed in those cases, the diastereoselectivity was still perfect. Notably, products 4 i–l were formed as single E-isomers. Finally, synthesis of terminal methylene-derivative 4 m proved possible employing 2-(hydroxymethyl)cyclopentenone (1 m) as starting alcohol, albeit resulting in lower diastereoselectivity in this single case. Disappointingly,
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Scheme 4. Enantioselective approach to bicyclic a-alkylidene-ketones 4 - reaction scope. Scheme 3. Enantioselective approach to bicyclic a-alkylidene-ketones 4: reaction scope.
MBH alcohol derived from 2-cyclohexen-1-one failed to react under optimized reaction conditions. Interestingly, when compound 7, which was prepared according to a literature procedure,[8] was employed in the developed annulation strategy the efficient and highly stereoselective formation of an unexpected reaction product (4 o) was observed (Scheme 5, bottom). Single crystal X-ray analysis revealed its structure as 4 o in contrast to anticipated 4 n. This finding prompted us to re-elucidate the structure of 7. It was unambiguously assigned as 8 by a single crystal X-ray analysis. This indicates that when benzo[b]thiophene-2,3-dione 5 was treated with stabilized phosphorus ylide 6 the Wittig reaction occurred at the carbonyl group adjacent to the sulfur atom affording 8. This result is in marked contrast with previous literature reports involving 5 as a substrate in a Wittig reaction yielding 7 as a product.[8] Moreover, it demonstrates that 5 shows a completely different and so far unexpected reactivity compared to the isatines and coumarandione which react at the b-carbonyl functionality.[8, 9] The single crystal X-ray analysis of 4 o and 4 h allowed us to unambiguously assign the relative and absolute configuration.[10] The absolute configuration of other products 4 a–g and 4 i–m is assigned by analogy. Based on the configurational assignments of the products 4 a plausible reaction mechanism is Chem. Eur. J. 2014, 20, 13108 – 13112
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Scheme 5. Revised reactivity of benzo[b]thiophene-2,3-dione: application in the synthesis of a-alkylidene-ketone 4 o.
proposed (Scheme 6). The reaction is initiated by condensation of the catalyst 3 a with the starting MBH alcohol 1 to give imi-
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Communication nium ion 9. Subsequent tautomerization affords diene intermediate 10 which can undergo a formal [4+2]-cycloaddition with the olefinic oxindole 2. A stepwise mechanism for this process is postulated,[11] in which the first step is an enaminemediated conjugate addition to the Michael acceptor 2 affording 11, followed by cyclization via SN2’-type reaction proceeding with the elimination of a water molecule. However, a mechanism of the cyclization step involving a simple addition and subsequent E1cb-elimination might also be possible. Notably, in both of the cases elimination step is assisted via the Hbonding-interactions with iminium-ion moiety of the molecule. The stereochemical outcome of the reaction is postulated to be based on p-stacking interactions between the quinoline ring in the catalyst and the diene moiety, facilitating a transition state of the reaction which provide an effective shielding of one of the faces of the diene. Thereby, olefin 2 approaches 10 from the side opposite to the functionalities providing the pstacking interactions giving 4 in a highly enantio- and diastereoselective fashion. Interestingly, when an O-protected MBH alcohol was employed in the developed reaction sequence, no conversion was observed, supporting the importance of postulated activation of MBH alcohol 1 via intramolecular H-bonding interactions present in the developed iminium-ion-mediated activation strategy.
Scheme 6. Enantioselective approach to bicyclic a-alkylidene-ketones 4: reaction mechanism.
In conclusion, we have developed a novel enantioselective approach to bicyclic a-alkylidene-ketones. It combines a wellestablished enamine reactivity of carbonyl compounds with a unique activation of Morita–Baylis–Hillman alcohols via iminiChem. Eur. J. 2014, 20, 13108 – 13112
www.chemeurj.org
um-ion formation making it more prone to undergo formal SN2’ reaction. The developed synthetic strategy benefits from operational simplicity, high efficiency and excellent enantioand diastereoselectivities. Importantly, it enables a direct application of unmodified MBH alcohols. Furthermore, the a-alkylidene moiety was introduced with complete selectivity yielding target products as single E-isomers.
Acknowledgements Thanks are expressed to Aarhus University, FNU and Carlsberg Foundation for support. This project was realized within the Homing Plus Programme (co-financed from European Union, Regional Development Fund) and Kolumb Supporting Grant, both from the Foundation for Polish Science. Thanks are expressed to Jacob Overgaard for performing X-ray analysis. Keywords: activation strategies · alpha-alkylidene-ketones · asymmetric synthesis · Morita–Baylis–Hillman adducts · organocatalysis [1] a) Comprehensive Asymmetric: Catalysis I – III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New York, 1999; b) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; c) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed. 2008, 47, 6138; d) P. Melchiorre, Angew. Chem. 2012, 124, 9886; Angew. Chem. Int. Ed. 2012, 51, 9748; e) H. Jiang, Ł. Albrecht, K. A. Jørgensen, Chem. Sci. 2013, 4, 2287. [2] For a recent review, see: T.-Y. Liu, M. Xiec, Y.-C. Chen, Chem. Soc. Rev. 2012, 41, 4101. [3] For the seminal report involving application of Morita–Baylis–Hillman alcohols in asymmetric aminocatalysis, see: a) Z. Qiao, Z. Shafiq, L. Liu, Z.-B. Yu, Q.-Y. Zheng, D. Wang, Y.-J. Chen, Angew. Chem. 2010, 122, 7452; Angew. Chem. Int. Ed. 2010, 49, 7294. For selected examples involving application of Morita – Baylis – Hillman bromides in asymmetric aminocatalysis, see: b) J. Xu, X. Fu, R. Low, Y.-P. Goh, Z. Jiang, C.-H. Tan, Chem. Commun. 2008, 5526; c) E. Gmez-Bengoa, A. Landa, A. Lizarraga, A. Mielgo, M. Oiarbide, C. Palomo, Chem. Sci. 2011, 2, 353; d) J. Jimnez, A. Landa, A. Lizarraga, M. Maestro, A. Mielgo, M. Oiarbide, I. Velilla, C. Palomo, J. Org. Chem. 2012, 77, 747. [4] a) A. Matsuo, S. Hayashi, Tetrahedron Lett. 1970, 11, 1289; b) T. Haneishi, N. Kitahara, Y. Takiguchi, M. Arai, S. Sugawara, J. Antibiot. 1974, 27, 386; c) T. Haneishi, A. Terabara, M. Arai, T. Hata, C. Tamura, J. Antibiot. 1974, 27, 393; d) H. Umezawa, T. Takeuchi, K. Nitta, Y. Okami, T. Yamamoto, S. Yamaoka, J. Antibiot. Ser. A 1953, 6, 147. [5] a) S.-c. Sung, Antibiotics 1967, 1, 156; b) S.-c. Sung, J. H. Quastel, Cancer Res. 1963, 23, 1549; c) G. B. Magill, R. B. Golbey, D. A. Karnofsky, J. H. Burchenal, C. C. Stock, C. P. Rhodes, C. E. Crandall, S. N. Yorukoglu, A. Gellhorn, Cancer Res. 1956, 16, 960. [6] For selected examples, see: a) E. J. Corey, F.-Y. Zhang, Org. Lett. 1999, 1, 1287; b) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 6844; c) B. M. Trost, J. P. Stambuli, S. M. Silverman, U. Schwoerer, J. Am. Chem. Soc. 2006, 128, 13328; d) S.-M. Lu, C. Bolm, Angew. Chem. 2008, 120, 9052; Angew. Chem. Int. Ed. 2008, 47, 8920. [7] For the influence of the acid on the reaction outcome, see the Supporting Information. [8] For selected examples, see: a) F. M. Soliman, M. M. Said, Sulfur Lett. 1991, 13, 213; b) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang, R. Wang, Angew. Chem. 2011, 123, 9290; Angew. Chem. Int. Ed. 2011, 50, 9124; c) Y.-M. Cao, F.-F. Shen, F.-T. Zhang, R. Wang, Chem. Eur. J. 2013, 19, 1184. [9] For a recent review, see: L. Hong, R. Wang, Adv. Synth. Catal. 2013, 355, 1023. [10] See the Supporting Information for details. CCDC 999371 (8), 999372 (4 o) and 999373 (4 h) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The
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Communication Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [11] a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P. Song, G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121, 7336; Angew. Chem. Int. Ed. 2009, 48, 7200; b) Ł. Albrecht, G. Dickmeiss, F. Cruz Acosta, C. Rodrguez-Escrich, R. L. Davis, K. A. Jørgensen, J. Am. Chem. Soc.
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2012, 134, 2543; c) J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L. Davis, K. A. Jørgensen, Chem. Sci. 2014, 5, 2052.
Received: July 18, 2014 Published online on August 25, 2014
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Communication
& Aminocatalysis
Novel Organocatalytic Activation of Unmodified Morita–Baylis– Hillman Alcohols for the Synthesis of Bicyclic a-AlkylideneKetones Julian Stiller,[b] Dorota Kowalczyk,[a] Hao Jiang,[b] Karl Anker Jørgensen,*[b] and Łukasz Albrecht*[a] Abstract: The organocatalytic activation of Morita–Baylis– Hillman alcohols via H-bonding-iminium-ion formation is demonstrated for the first time. This activation strategy enables the Morita-Baylis–Hillman alcohols to undergo a formal SN2’ reaction. In combination with the well-established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic a-alkylidene-ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature-inspired target products with four contiguous stereogenic centers in a highly stereoselective manner.
Asymmetric transformations of carbonyl compounds aiming at the introduction of specific structural motives to target molecules have gained increasing attention of the chemical community.[1] A key to success of such a target-oriented strategy is the ability of chiral catalysts to ensure high levels of stereoinduction while providing a reactive intermediate with the desired reactivity profile defined by the structure of the target products. In this respect, aminocatalytic strategies, utilizing chiral primary or secondary amines as the catalyst, are highly reliable tools in modern asymmetric synthesis equipping chemists with a broad range of possibilities to access new reaction profiles in order to introduce specific structural motifs in a stereoselective fashion.[1c–e] Morita–Baylis–Hillman (MBH) alcohols and their derivatives constitute highly useful type of building blocks that have been rarely employed in the field of aminocatalysis.[2, 3] However, a direct application of unmodified MBH alcohols in asymmetric synthesis is still challenging and the development of methods enabling their catalytic activation is of high interest in modern organic chemistry. Furthermore,
the introduction of alkylidene moiety through a formal SN2’ reactivity of MBH alcohols seems to be particularly interesting, which has not been explored in aminocatalysis before. We envisioned that a novel activation mode of MBH alcohols might rely on the corresponding iminium-ion formation capable of H-bonding interactions (Scheme 1). Such an iminium-ion should possess enhanced reactivity towards formal SN2’ reaction leading to the introduction of a new stereogenic center in the b-position and a-alkylidene moiety in the a-position to the carbonyl functionality (Scheme 1, top). It was anticipated that merging of such an activation strategy with the well-recognized enamine activation should enable the formation of a unique aminocatalytic intermediate and result in the development of a novel cascade reactivity—addition followed by a formal SN2’ reaction (Scheme 1, middle). An important challenge of such a synthetic strategy relates to the presence of a stereogenic center in the MBH alcohol substrate. For this reason mismatching interactions between the chirality of the molecule and the catalyst might take place resulting in overall enantioselectivity deterioration.
[a] D. Kowalczyk, Dr. Ł. Albrecht Institute of Organic Chemistry, Chemistry Department Lodz University of Technology, Z˙eromskiego 116, 90-924 Łdz´ (Poland) E-mail: [email protected] [b] Dr. J. Stiller, Dr. H. Jiang, Prof. Dr. K. A. Jørgensen Center for Catalysis, Chemistry Department, 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.201404468. Chem. Eur. J. 2014, 20, 13108 – 13112
Scheme 1. A novel aminocatalytic activation mode.
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Communication Importantly, the devised cascade reactivity should enable a facile construction of the a-alkylidene-ketone framework. This is a privileged scaffold that is found in natural products and pharmacologically relevant molecules, such as chiloscyphone, a naturally occurring sesquiterpene[4a] methylenomycin A and sarkomycin belonging to the family of cyclopentanoid antibiotics[4b–d] with sarkomycin possessing interesting anticancer activity (Scheme 2, bottom).[5] The synthetic relevance of a-alkylidene-ketones has been confirmed recently.[6] In particular their ability to act as effective Michael acceptors has been utilized in organic synthesis, including asymmetric organocatalysis.[6a,b]
Table 1. Enantioselective approach to bicyclic a-alkylidene-ketones 4: optimization studies.[a]
Scheme 2. Enantioselective approach to bicyclic a-alkylidene-ketones.
Herein, we report a novel aminocatalytic activation of unmodified MBH alcohols and its application for the synthesis of bicyclic a-alkylidene-ketones. The developed approach utilizes a combination of a simple enamine activation with the unique ability of an aminocatalyst to activate MBH alcohols for a formal SN2’ reaction via iminium-ion activation. As a proof-ofconcept, the reaction between 2-(hydroxyalkyl)cyclopent-2-en1-one 1 and olefinic oxindoles 2 in the presence of a primary amine organocatalyst 3 was studied (Scheme 2). We initiated our studies with the goal of finding appropriate reaction conditions for the devised synthetic strategy. The initial catalyst screening identified a quinine-derived primary amine catalyst in combination with (S)-mandelic acid[7] as the most suitable catalytic system for the transformation and chloroform as the best solvent (see the Supporting Information for details). Further screening revealed that lowering reaction temperature resulted in longer reaction times and led to improved enantio- and diastereoselectivity (Table 1, compare entries 1–3). It was found that the reaction rate at ambient temperatures could easily be improved by employing an excess of alcohol 1 a maintaining the stereoselectivity of the transformation at the comparable level (Table 1, compare entries 3–7). Interestingly, isolated unreacted alcohol 1 a was enantiomerically enriched, indicating that the reaction also occurs in a kinetic resolution manner (Table 1, entries 6 and 7). Hence matching– mismatching interactions between the catalyst-bound enamine part of the substrate and its chiral MBH alcohol moiety have an influence on the stereoselectivity of the reaction. The use of olefinic counterpart in excess resulted in a decrease in reactivity (Table 1, entry 8). Notably, all reactions afforded a-alkylidene-ketone 4 a as single E-isomer. With the optimized reaction conditions in hand, the scope and limitations of the methodology were investigated. GratifyChem. Eur. J. 2014, 20, 13108 – 13112
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Entry
1a [equiv]
2a [equiv]
T [oC]
t [h]
Conv. (yield [%])[b]
d.r.[c]
ee [%][d]
1 2 3 4 5[e] 6[f] 7[g] 8
1.1 1.1 1.1 2 2 2.5 3 1
1 1 1 1 1 1 1 2
50 40 RT RT RT RT RT RT
20 20 8d 67 40 40 40 9d
84 80 > 95 > 95 > 95 > 95 > 95 85
> 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5 > 95:5
72 86 87 91 90 90 90 89
(71) (72) (83) (83) (83) (79) (84)
[a] Reactions performed on 0.1 mmol scale (for details see the Supporting Information). [b] Conversion as determined by 1H NMR spectroscopy of a crude reaction mixture. Isolated yields are given in parenthesis. [c] Determined by 1H NMR spectroscopy of a crude reaction mixture. [d] Determined by a chiral stationary phase UPC2. [e] Concentration 0.5 m. [f] Unreacted alcohol 1 a isolated with 29 % ee. [g] Unreacted alcohol 1 a isolated with 25 % ee.
ingly, various olefinic oxindoles 2 were successfully employed in the developed reaction sequence (Scheme 3). Importantly, both electron-donating and electron-withdrawing substituents could be present on the aromatic moiety of olefinic oxindole framework of 2 affording target products in good yields and in high stereoselectivities. Furthermore, the position of the substituent had no significant influence on the reaction outcome and disubstituted derivatives were well-tolerated. Interestingly, N-unprotected oxindoles could also be employed in the reaction sequence with similar results as demonstrated in the synthesis of 4 h. In all cases the formation of E-configured a-alkylidene-ketone 4 a–h was observed. In the course of further studies various MBH alcohols 1 were utilized in the developed reaction sequence (Scheme 4). It was found that MBH alcohols 1 i and 1 j derived from both electron-poor and electron-rich benzaldehydes, respectively, easily reacted under optimized reaction conditions. Furthermore, a heteroaromatic framework and alkyl side-chain could be introduced on the alkylidene moiety of the target ketones 4 as demonstrated in the synthesis of 4 k and 4 l. Although a slightly lower enantioselectivity was observed in those cases, the diastereoselectivity was still perfect. Notably, products 4 i–l were formed as single E-isomers. Finally, synthesis of terminal methylene-derivative 4 m proved possible employing 2-(hydroxymethyl)cyclopentenone (1 m) as starting alcohol, albeit resulting in lower diastereoselectivity in this single case. Disappointingly,
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Scheme 4. Enantioselective approach to bicyclic a-alkylidene-ketones 4 - reaction scope. Scheme 3. Enantioselective approach to bicyclic a-alkylidene-ketones 4: reaction scope.
MBH alcohol derived from 2-cyclohexen-1-one failed to react under optimized reaction conditions. Interestingly, when compound 7, which was prepared according to a literature procedure,[8] was employed in the developed annulation strategy the efficient and highly stereoselective formation of an unexpected reaction product (4 o) was observed (Scheme 5, bottom). Single crystal X-ray analysis revealed its structure as 4 o in contrast to anticipated 4 n. This finding prompted us to re-elucidate the structure of 7. It was unambiguously assigned as 8 by a single crystal X-ray analysis. This indicates that when benzo[b]thiophene-2,3-dione 5 was treated with stabilized phosphorus ylide 6 the Wittig reaction occurred at the carbonyl group adjacent to the sulfur atom affording 8. This result is in marked contrast with previous literature reports involving 5 as a substrate in a Wittig reaction yielding 7 as a product.[8] Moreover, it demonstrates that 5 shows a completely different and so far unexpected reactivity compared to the isatines and coumarandione which react at the b-carbonyl functionality.[8, 9] The single crystal X-ray analysis of 4 o and 4 h allowed us to unambiguously assign the relative and absolute configuration.[10] The absolute configuration of other products 4 a–g and 4 i–m is assigned by analogy. Based on the configurational assignments of the products 4 a plausible reaction mechanism is Chem. Eur. J. 2014, 20, 13108 – 13112
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Scheme 5. Revised reactivity of benzo[b]thiophene-2,3-dione: application in the synthesis of a-alkylidene-ketone 4 o.
proposed (Scheme 6). The reaction is initiated by condensation of the catalyst 3 a with the starting MBH alcohol 1 to give imi-
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Communication nium ion 9. Subsequent tautomerization affords diene intermediate 10 which can undergo a formal [4+2]-cycloaddition with the olefinic oxindole 2. A stepwise mechanism for this process is postulated,[11] in which the first step is an enaminemediated conjugate addition to the Michael acceptor 2 affording 11, followed by cyclization via SN2’-type reaction proceeding with the elimination of a water molecule. However, a mechanism of the cyclization step involving a simple addition and subsequent E1cb-elimination might also be possible. Notably, in both of the cases elimination step is assisted via the Hbonding-interactions with iminium-ion moiety of the molecule. The stereochemical outcome of the reaction is postulated to be based on p-stacking interactions between the quinoline ring in the catalyst and the diene moiety, facilitating a transition state of the reaction which provide an effective shielding of one of the faces of the diene. Thereby, olefin 2 approaches 10 from the side opposite to the functionalities providing the pstacking interactions giving 4 in a highly enantio- and diastereoselective fashion. Interestingly, when an O-protected MBH alcohol was employed in the developed reaction sequence, no conversion was observed, supporting the importance of postulated activation of MBH alcohol 1 via intramolecular H-bonding interactions present in the developed iminium-ion-mediated activation strategy.
Scheme 6. Enantioselective approach to bicyclic a-alkylidene-ketones 4: reaction mechanism.
In conclusion, we have developed a novel enantioselective approach to bicyclic a-alkylidene-ketones. It combines a wellestablished enamine reactivity of carbonyl compounds with a unique activation of Morita–Baylis–Hillman alcohols via iminiChem. Eur. J. 2014, 20, 13108 – 13112
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um-ion formation making it more prone to undergo formal SN2’ reaction. The developed synthetic strategy benefits from operational simplicity, high efficiency and excellent enantioand diastereoselectivities. Importantly, it enables a direct application of unmodified MBH alcohols. Furthermore, the a-alkylidene moiety was introduced with complete selectivity yielding target products as single E-isomers.
Acknowledgements Thanks are expressed to Aarhus University, FNU and Carlsberg Foundation for support. This project was realized within the Homing Plus Programme (co-financed from European Union, Regional Development Fund) and Kolumb Supporting Grant, both from the Foundation for Polish Science. Thanks are expressed to Jacob Overgaard for performing X-ray analysis. Keywords: activation strategies · alpha-alkylidene-ketones · asymmetric synthesis · Morita–Baylis–Hillman adducts · organocatalysis [1] a) Comprehensive Asymmetric: Catalysis I – III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, New York, 1999; b) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; c) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed. 2008, 47, 6138; d) P. Melchiorre, Angew. Chem. 2012, 124, 9886; Angew. Chem. Int. Ed. 2012, 51, 9748; e) H. Jiang, Ł. Albrecht, K. A. Jørgensen, Chem. Sci. 2013, 4, 2287. [2] For a recent review, see: T.-Y. Liu, M. Xiec, Y.-C. Chen, Chem. Soc. Rev. 2012, 41, 4101. [3] For the seminal report involving application of Morita–Baylis–Hillman alcohols in asymmetric aminocatalysis, see: a) Z. Qiao, Z. Shafiq, L. Liu, Z.-B. Yu, Q.-Y. Zheng, D. Wang, Y.-J. Chen, Angew. Chem. 2010, 122, 7452; Angew. Chem. Int. Ed. 2010, 49, 7294. For selected examples involving application of Morita – Baylis – Hillman bromides in asymmetric aminocatalysis, see: b) J. Xu, X. Fu, R. Low, Y.-P. Goh, Z. Jiang, C.-H. Tan, Chem. Commun. 2008, 5526; c) E. Gmez-Bengoa, A. Landa, A. Lizarraga, A. Mielgo, M. Oiarbide, C. Palomo, Chem. Sci. 2011, 2, 353; d) J. Jimnez, A. Landa, A. Lizarraga, M. Maestro, A. Mielgo, M. Oiarbide, I. Velilla, C. Palomo, J. Org. Chem. 2012, 77, 747. [4] a) A. Matsuo, S. Hayashi, Tetrahedron Lett. 1970, 11, 1289; b) T. Haneishi, N. Kitahara, Y. Takiguchi, M. Arai, S. Sugawara, J. Antibiot. 1974, 27, 386; c) T. Haneishi, A. Terabara, M. Arai, T. Hata, C. Tamura, J. Antibiot. 1974, 27, 393; d) H. Umezawa, T. Takeuchi, K. Nitta, Y. Okami, T. Yamamoto, S. Yamaoka, J. Antibiot. Ser. A 1953, 6, 147. [5] a) S.-c. Sung, Antibiotics 1967, 1, 156; b) S.-c. Sung, J. H. Quastel, Cancer Res. 1963, 23, 1549; c) G. B. Magill, R. B. Golbey, D. A. Karnofsky, J. H. Burchenal, C. C. Stock, C. P. Rhodes, C. E. Crandall, S. N. Yorukoglu, A. Gellhorn, Cancer Res. 1956, 16, 960. [6] For selected examples, see: a) E. J. Corey, F.-Y. Zhang, Org. Lett. 1999, 1, 1287; b) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004, 126, 6844; c) B. M. Trost, J. P. Stambuli, S. M. Silverman, U. Schwoerer, J. Am. Chem. Soc. 2006, 128, 13328; d) S.-M. Lu, C. Bolm, Angew. Chem. 2008, 120, 9052; Angew. Chem. Int. Ed. 2008, 47, 8920. [7] For the influence of the acid on the reaction outcome, see the Supporting Information. [8] For selected examples, see: a) F. M. Soliman, M. M. Said, Sulfur Lett. 1991, 13, 213; b) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang, R. Wang, Angew. Chem. 2011, 123, 9290; Angew. Chem. Int. Ed. 2011, 50, 9124; c) Y.-M. Cao, F.-F. Shen, F.-T. Zhang, R. Wang, Chem. Eur. J. 2013, 19, 1184. [9] For a recent review, see: L. Hong, R. Wang, Adv. Synth. Catal. 2013, 355, 1023. [10] See the Supporting Information for details. CCDC 999371 (8), 999372 (4 o) and 999373 (4 h) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The
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Communication Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [11] a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P. Song, G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121, 7336; Angew. Chem. Int. Ed. 2009, 48, 7200; b) Ł. Albrecht, G. Dickmeiss, F. Cruz Acosta, C. Rodrguez-Escrich, R. L. Davis, K. A. Jørgensen, J. Am. Chem. Soc.
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2012, 134, 2543; c) J. Stiller, P. H. Poulsen, D. C. Cruz, J. Dourado, R. L. Davis, K. A. Jørgensen, Chem. Sci. 2014, 5, 2052.
Received: July 18, 2014 Published online on August 25, 2014
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