Enamine/carbene cascade catalysis in the diastereo- and enantioselective synthesis of functionalized cyclopentanones

Abstract

Herein we report an enantioselective synthesis of complex cyclopentanones using aliphatic aldehydes and activated enones. With the combination of a chiral secondary amine and a chiral triazolium catalyst, high diastereoselectivity and excellent enantioselectivity can be achieved. We present evidence of a clear cooperative effect when these two catalysts are present simultaneously in the system.

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Introduction

The incorporation of multiple catalytic cycles in a single procedure allows for complex compounds to be easily accessed, a concept that has been termed cascade catalysis.^1–3 By eliminating the need for isolation and purification of intermediates, both time and resources are saved. This is especially important if these intermediates prove unstable upon isolation. While attractive, cascade catalysis provides unique challenges. With the possibility of multiple catalysts present simultaneously, the need for reaction selectivity is important. A solution to this problem is to use catalysts of orthogonal reactivity. Our group has previously reported that secondary amine and N-heterocyclic carbene (NHC) catalysts initiate cascade reactions of enals and β-dicarbonyls to form α-hydroxycyclopentanones (Fig. 1a).⁴ This reaction proceeds via iminium activation of the enal to induce a conjugate addition by the dicarbonyl followed by an intramolecular benzoin. Importantly the two catalysts work cooperatively, providing higher yields and enantioselectivities compared to a two-step process. Herein, we report the secondary amine/NHC catalyzed cascade reaction of aliphatic aldehydes and activated Michael acceptors to form complex cyclopentanones with a complementary substitution pattern.

Fig. 1 Secondary amine/NHC cascade reactions⁶

Whereas our previous work employed iminium catalysis, we sought to explore the use of enamine catalysis in combination with NHC's in a cascade reaction. Ma has reported a highly diastereo- and enantioselective Michael addition of aliphatic aldehydes into activated enones with the use of a secondary amine catalyst (3).⁵ We speculated that the aldehyde intermediate formed could undergo an intramolecular benzoin reaction when exposed to an N-heterocyclic carbene catalyst (Fig. 1b). This would provide a cyclopentanone product in what may be considered a formal [3 + 2] cycloaddition. This approach provides complimentary and inaccessible substitution patterns from our previous work.

Results and discussion

Reaction development

The reaction conditions developed by the Ma group were repeated using the Jørgensen–Hayashi catalyst 3⁷ in methanol at room temperature. After observing the consumption of starting material, achiral triazolium salt 5⁸ and sodium acetate were added to catalyze the benzoin cyclization. These conditions provide no desired product (Table 1, entry 1). When methanol is replaced with chloroform, the desired product is formed in 29% yield and 96% ee but with a 3 : 1 : <1 : <1 dr (Table 1, entry 2).⁹ Employing a one-step protocol with all reagents present from the outset results in an increase in yield to 35% (entry 3). Increasing the temperature from 23 °C to 60 °C improves the yield to 89% while maintaining high enantioselectivity (96% ee) and a 5 : 1 : <1 : <1 diastereomeric ratio. The diastereoselectivity is further improved to 290 : 15 : 6 : 1 when the chiral aminoindanol based triazolium 6^10,11 is used (entry 5). The use of the antipode of this catalyst, 6′, results in lower diastereoselectivity (4 : 1 : <1 : <1). This is likely a result of a match/mismatch relationship.

Table 1
^a

	Solvent	Triazolium salt	T (°C)	Yield (%)	ee (%)^b	dr^b
a See supporting information for general procedure.† b Enantioselectivity and diastereoselectivity were determined by GC. c 20 mol % Triazolium salt was added after full consumption of 2a. d 20 mol % Triazolium salt was added at the beginning of the reaction.
1^c	MeOH		23	0	—	—
2^c	CHCl3	5	23	29	96	3 : 1 : <1 : <1
3^d	CHCl3	5	23	35	95	2 : 1 : <1 : <1
4^d	CHCl3	5	60	89	96	5 : 1 : <1 : <1
5^d	CHCl3		60	87	95	19 : 1 : <1 : <1
6^d	CHCl3		60	59	93	4 : 1 : <1 : <1

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Synthetic scope

With suitable conditions established, a variety of substrates were screened to explore the scope of this new cascade. Aliphatic aldehydes provide the desired products in good yield and high enantio- and diastereoselectivity (Chart 1, 4b–c). Isovaleraldehyde competitively forms the Stetter product¹² in a 1 : 1 ratio with cyclopentanone 4d under standard conditions. This side product can be avoided when the introduction of the triazolium is delayed until after complete formation of the intermediate. Larger aldehydes are also viable but routinely require prolonged reaction times (Chart 1, 4f–g).

Chart 1 Aldehyde Scope^a (^aSee Supporting Information†. ^bCatalyst 6 was added after consumption of starting material. ^cDiastereomeric ratio determined by ¹H NMR.)

Variation in the enone component was then explored (Chart 2). Esters and tertiary amides are viable under these conditions (Chart 2, 4h–k).¹³ Substitution at the ketone position is also tolerated. N-Alkyl ketones provide products in excellent yields while maintaining high stereoselectivity. The isopropyl ketone failed to cyclize under standard conditions. By substituting the bulky triazolium 6 with the smaller achiral catalyst 5, the intramolecular benzoin was accomplished albeit with a curiously low enantioselectivity (4o). Phenyl ketone can also be employed, with diminished diastereoselectivity (4n). Diketones may also be used to form products (4p–q) with good selectivity despite diminished yield.

Chart 2 Keto-ester Scope^a (^aSee Supporting Information†. ^bCatalyst 5 was used in place of 6.)

With high complexity already built into the cyclopentanone products, functionalization should allow rapid access to even more elaborate products. The addition of sodium triacetoxyborohydride at the end of the reaction permits a diastereoselective reduction of the ketone to 1,2-diol 7. This action effectively permits the formation of a fourth stereocenter in one pot (eqn (1)).

Mechanistic insights

We then explored if there is an advantage between this one-step protocol versus a two-step reaction. Aldehyde 8 was prepared by exposing butyraldehyde and enone 2a to catalyst 3, catalytic acetic acid, and chloroform at room temperature (Scheme 1). After purification, the aldehyde intermediate was isolated in moderate yield with a 2 : 1 diastereomeric ratio.

Scheme 1 Two-Pot Reactions

Exposure of this intermediate to benzoin conditions provides the cyclized product in comparable yield and enantioselectivity, but with a low diastereomeric ratio (4 : 1 : 1 : <1). This diastereoselectivity can be improved when the benzoin cyclization is performed with the addition of chiral amine catalyst 3 (10 : 1 : <1 : <1 dr).

In our previous work, it was discovered that the amine catalyst is responsible for a retro-Michael reaction, which eroded enantioselectivity in the two-pot reaction. Crossover experiments indicate that this pathway is non-operative in this system.¹⁴ Instead, we propose that the secondary amine catalyst is capable of epimerizing the α-position of the intermediate aldehyde to form an equilibrium between 8 and 8′ (Fig. 2). The chiral triazolium 6 prefers cyclization with only one of these diastereomers, and this adduct continues on to the final product. The amine catalyst thus aids in converting the less reactive diastereomer into its epimer.¹⁵ This hypothesis explains how the amine catalyst can convert aldehyde 8 with low diastereoselectivity to a diastereomerically enriched product.

Fig. 2 Proposed Mechanism

To support this mechanism, the benzoin cyclization was monitored over time by NMR spectroscopy. When intermediate aldehyde 8 is exposed to catalyst 6, we see complete consumption of one diastereomer in preference over the other (Fig. 3). When amine catalyst 3 is included in this reaction, consumption of both diastereomers occurs over the course of the reaction, consistent with the hypothesis that amine catalyst 3 serves to interconvert the two diastereomers of 8.^16,17

Fig. 3 NMR experiments

Conclusion

In summary, a one-pot stereoeselective Michael–Benzoin cascade reaction has been developed for the synthesis of complex cyclopentanones. The presence of both the secondary amine and triazolium catalysts is essential for excellent results, indicating a cooperative relationship between the catalysts. This provides a unique and useful method to form complicated cyclopentanes from simple starting materials.

Acknowledgements

We thank NIGMS for generous support of this research (GM72586). K. E. O. thanks NIH (GM80442-S1 and GM096749) for funding. T.R. thanks Amgen and Roche for unrestricted support. We thank Donald Gauthier and Greg Hughes (Merck) for a generous gift of aminoindanol and Kevin M. Oberg and Derek M. Dalton (CSU) for solving the crystal structure of 9.

Notes and references

1. For recent reviews: (a) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (b) J. Zhou, Chem.–Asian J., 2010, 5, 422; (c) Y. Xinhong and W. Wang, Org. Biomol. Chem., 2008, 6, 2037; (d) D. Enders, C. Grondal and M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (e) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477; (f) J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001.
2. For some recent examples of multicatalytic systems: (a) A. Quintard, A. Alexakis and C. Mazet, Angew. Chem. Int. Ed, 2011, 50, 2354; (b) B. M. Trost and X. Luan, J. Am. Chem. Soc., 2011, 133, 1706; (c) D. E. A. Raup, B. Cardinal-David, D. Holte and K. A. Scheidt, Nat. Chem., 2010, 2, 766; (d) C. Yu, Y. Zhang, S. Zhang, J. He and W. Wang, Tetrahedron Lett., 2010, 51, 1742; (e) B.-C. Hong, N. S. Dange, C.-S. Hsu and J.-H. Liao, Org. Lett., 2010, 12, 4812; (f) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 127, 15051; (g) B. Simmons, A. M. Walji and D. W. C. MacMillan, Angew. Chem., Int. Ed., 2009, 48, 4349; (h) H. Jiang, P. Elsner, K. L. Jensen, A. Falcicchio, V. Marcos and K. A. Jørgensen, Angew. Chem., Int. Ed., 2009, 48, 6844; (i) S. Belot, K. A. Vogt, C. Besnard, N. Krause and A. Alexakis, Angew. Chem., Int. Ed., 2009, 48, 8923; (j) Y. Wang, R.-G. Han, Y.-L. Zhou, S. Yang, P.-F. Xu and D. J. Dixon, Angew. Chem., Int. Ed., 2009, 48, 9834; (k) T. A. Cernak and T. H. Lambert, J. Am. Chem. Soc., 2009, 131, 3124; (l) B. D. Kelly, J. M. Allen, R. E. Tundel and T. H. Lambert, Org. Lett., 2009, 11, 1381; (m) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322, 77; (n) Y. Chi, S. T. Scroggins and J. M. J. Fréchet, J. Am. Chem. Soc., 2008, 130, 6322; (o) L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming and W.-J. Xiao, J. Am. Chem. Soc., 2008, 130, 6946; (p) J. Zhou and B. List, J. Am. Chem. Soc., 2007, 129, 7498; (q) W. Wang, H. Li, J. Wang and L. Zu, J. Am. Chem. Soc., 2006, 128, 10354.
3. For select recent examples of cascade reactions with a single catalyst: (a) C. Liu, X. Zhang, R. Wang and W. Wang, Org. Lett., 2010, 12, 4948; (b) N. T. Jui, E. C. Y. Lee and D. W. C. MacMillan, J. Am. Chem. Soc., 2010, 132, 10015; (c) P. G. McGarraugh and S. E. Brenner, Org. Lett., 2009, 11, 5654; (d) L. Zu, S. Zhang, H. Xie and W. Wang, Org. Lett., 2009, 11, 1627; (e) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaoli, M.-P. Song, G. Bartoli and P. Melciorre, Angew. Chem., Int. Ed., 2009, 48, 7200; (f) J. Wang, H. Li, H. Xie, L. Zu, X. Shen and W. Wang, Angew. Chem., Int. Ed., 2007, 46, 9050; (g) H. Xie, L. Zu, H. Li, J. Wang and W. Wang, J. Am. Chem. Soc., 2007, 129, 10886; (h) J. Zhou and B. List, J. Am. Chem. Soc., 2007, 129, 7498; (i) D. Enders, M. R. M. Hüttl, C. Grondal and G. Raabe, Nature, 2006, 441, 861; (j) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 15051.
4. (a) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc., 2009, 131, 13628. For other contributions to cascade catalysis from our laboratories, see: (b) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129, 13796; (c) C. M. Filloux, S. P. Lathrop and T. Rovis, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 20666.
5. J. Wang, A. Ma and D. Ma, Org. Lett., 2008, 10, 5425.
6. The “IM” and “EN” convention to denote iminium and enamine catalysis was first introduced by MacMillan and coworkers and subsequently adopted by others. See: (a) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 15051; (b) also see ref. 1a..
7. (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794; (b) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212.
8. M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Org. Chem., 2005, 70, 5725.
9. Absolute configuration determined by Single Crystal X-ray diffraction of the chiral salt (see ESI†): .
10. (a) H. U. Vora, S. P. Lathrop, N. T. Reynolds, M. S. Kerr, J. Read de Alaniz and T. Rovis, Org. Synth., 2010, 87, 350; (b) M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298.
11. (a) Y. Hachisu, J. W. Bode and K. Suzuki, J. Am. Chem. Soc., 2003, 125, 8432; (b) H. Takikawa, Y. Hachisu, J. W. Bode and K. Suzuki, Angew. Chem., Int. Ed., 2006, 45, 3492; (c) D. Enders, O. Niemeier and T. Balensiefer, Angew. Chem., Int. Ed., 2006, 45, 1463.
12. Stetter Product formed: .
13. Secondary amides and thioesters do not provide desired products.
14. See Supporting Information for crossover experiment results†.
15. The second step of this reaction could then be considered analogous to a dynamic kinetic resolution, which has been invoked in several other organocatalyzed transformations: (a) A. Lee, A. Michrowska, S. Sulzer-Mosse and B. List, Angew. Chem., Int. Ed., 2011, 50, 1707; (b) S. Hoffman, M. Nicoletti and B. List, J. Am. Chem. Soc., 2006, 128, 13074; (c) D. E. Ward, V. Jheengut and O. T. Akinnusi, Org. Lett., 2005, 7, 1181.
16. See Supporting Information for spectra from NMR experiments†.
17. In addition, when intermediate 8 is exposed to catalyst 3 in deuterated methanol at elevated temperature, complete deuteration is observed at the α-position .

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectra, and crystal structures are provided. See DOI: 10.1039/c1sc00175b

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