Catalytic cross-benzoin/Michael/acetalization cascade for asymmetric synthesis of trifluoromethylated γ-butyrolactones

Abstract

A sequential NHC-amine catalytic cascade reaction has been developed to assemble aromatic aldehydes, trifluoroacetaldehyde ethyl hemiacetal and enals asymmetrically into CF₃-substituted chiral γ-butyrolactone derivatives featuring vicinal quaternary and tertiary stereocenters. This approach incorporates a highly chemoselective intermolecular cross-benzoin reaction and a highly regioselective Michael-acetalization cascade. Various multi-functionalized tetrahydrofuran scaffolds were readily prepared from hemiacetal intermediates through convenient organic transformations.

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Introduction

One of the most fascinating areas of organofluorine chemistry is the asymmetric synthesis of trifluoro-methylated compounds.¹ Stereoselective introduction of trifluoromethyl groups into organic molecules may significantly improve their usefulness as drugs, such as by improving the metabolic stability, binding affinity, membrane permeability and bioavailability.² To this end, several methods have been developed to generate medicinally important chiral γ-butyrolactone derivatives³ with a trifluoromethyl-substituted quaternary stereocenter.^4–6 In 2004, Glorius's group reported the synthesis of racemic trifluoro-methylated γ-butyrolactone via a process involving N-heterocyclic carbine (NHC)-catalyzed conjugate umpolung of α,β-unsaturated aldehydes, with trifluoro-acetophenone as the electrophilic reaction partner.⁴ Subsequently, the Glorius group, as well as the groups of Ishida, Saigo, Fiksdahl and others used chiral NHC catalysts to achieve the asymmetric version of this [3 + 2] annulation, albeit with unsatisfactory stereocontrol (Scheme 1, path a).⁵ Chi and co-workers have since achieved good enantioselectivity and moderate diastereoselectivity when synthesizing CF₃-substituted γ-butyrolactones; their method involves NHC-catalyzed ester β-activation of a mixture of saturated ester and trifluoroketone (Scheme 1, path b).⁶ These advances, though important, are not likely to generate the full diversity of pharmacologically interesting, multi-functionalized CF₃-substituted γ-butyrolactone derivatives,⁷ highlighting the need for more research into asymmetric catalytic syntheses that show good efficiency and high stereoselectivity.

Scheme 1 Catalytic asymmetric synthesis of trifluoromethylated γ-butyrolactones.

Several groups have exploited the inherent basicity and compatibility of chiral amines and NHCs to develop organocatalytic domino or cascade reactions based on sequential amine-NHC catalytic reactions in order to construct stereochemically complex molecules.⁸ However few studies have explored the potential of a reverse relay NHC-amine catalytic pathway to synthesize enantio-enriched architectures.⁹ In 2015, Anand's group described a highly chemoselective, NHC-catalyzed cross-benzoin reaction of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal to afford trifluoromethyl-containing acyloins.¹⁰ This achievement, coupled with our own recent success developing organocatalytic cascade reactions to assemble synthetically important cyclic molecules,¹¹ led us to ask whether trifluoromethylated acyloins could serve as the basis for subsequent aminocatalytic cascade reactions (Scheme 1, path c). If successful, this approach might broaden the applications of sequential NHC-amine catalysis.

We envisioned a two-step organocatalytic cascade as a way to asymmetrically synthesize CF₃-substituted γ-butyrolactone derivatives (Scheme 2). The protocol begins with NHC-catalyzed cross-benzoin condensation of aromatic aldehyde 1 and CF₃CH(OH)OEt 2. The resulting trifluoromethylated α-hydroxyketone intermediate 3 participates directly in the second aminocatalytic cycle by serving as the 1,2-bisnucleophile. Subsequent Michael-acetalization cyclization of α-hydroxyketone with chiral secondary amine-mediated α,β-unsaturated iminium forms the desired chiral hemiacetal 5, which features vicinal quaternary and tertiary stereocenters.

Scheme 2 Synthetic strategy.

Results and discussion

To probe the feasibility of the proposed cascade, we performed preliminary experiments using benzaldehyde 1a, CF₃CH(OH)OEt 2a and cinnamaldehyde 4a as substrates. The first crossed acyloin condensation proceeded smoothly in the presence of 10 mol% of catalyst Ia in THF at room temperature for 4 h. Next we added benzoic acid to neutralize the reaction mixture and induce formation of the enol nucleophile. This acidic additive also serves as co-catalyst in the subsequent iminium catalytic cycle. Finally, we added the Jørgensen–Hayashi catalyst IIa and α,β-unsaturated aldehyde 4a, and the cascade process afforded the hemiacetal 5a, albeit in moderate yield. Direct oxidation of the hemiacetal with PCC gave the more stable corresponding γ-butyrolactone as a 80 : 20 mixture of diastereomers, with 90% ee for the major isomer 6a and 85% ee for the minor isomer 6a′ (Table 1, entry 1).

Table 1 Optimization of reaction conditions^a

Entry	Cat. I	Cat. II	Solvent	Acid	Yield^b (%)	dr^c 6a : 6a′	ee^d (%) 6a/6a′
a Unless indicated otherwise, the reaction was performed with precatalyst I (0.05 mmol), DBU (0.1 mmol), 1a (0.25 mmol) and 2a (0.5 mmol) in solvent (2 mL) at room temperature, after which acidic additive (0.2 mmol), catalyst II (0.1 mmol) and 4a (0.5 mmol) were added.b Yield of isolated 6a and 6a′.c The diastereomeric ratio (dr) was calculated by ^1H NMR analysis of the crude reaction mixture.d Determined by HPLC using a chiral stationary phase.e Reaction performed at 70 °C.f 1 mL THF and 1 mL toluene were used.g 1 mL DMF and 1 mL toluene were used.
1	Ia	IIa	THF	BzOH	40	80 : 20	90/85
2	Ib	IIa	THF	BzOH	26	75 : 25	88/85
3	Ic	IIa	THF	BzOH	<10	—	—
4	Ia	IIb	THF	BzOH	<10	—	—
5^e	Ia	IIa	THF	BzOH	52	80 : 20	90/84
6^e	Ia	IIa	DMF	BzOH	<10	—	—
7^e	Ia	IIa	MeCN	BzOH	32	78 : 22	90/84
8^e	Ia	IIa	Toluene	BzOH	<10	—	—
9^e	Ia	IIa	Mix.^f	BzOH	35	70 : 30	85/80
10^e	Ia	IIa	Mix.^g	BzOH	40	76 : 24	89/86
11^e	Ia	IIa	THF	p-FBA	38	82 : 18	88/84
12^e	Ia	IIa	THF	AcOH	61	78 : 22	93/85

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Next we screened additional parameters in order to optimize the reaction (Table 1). This was challenging because the sequential NHC-amine catalytic systems in the cascade are mixed together in the same pot, meaning that reaction conditions must simultaneously maximize the catalytic efficiency of both systems. Screening a few catalyst combinations (entries 2–4) identified triazolium salt Ia and diphenyl prolinol TMS ether IIa as the most efficient pair for this tandem reaction. Increasing reaction temperature increased reaction yield without compromising dr or ee (entry 5). DMF, acetonitrile, toluene, and some mixed solvents were unsatisfactory because they led to lower yields of final product or to unacceptably slow reactions (entries 6–10). Screening acidic additives in the second catalytic cycle affected reaction efficiency (entries 11 and 12), with acetic acid giving the best results.

Once we had optimized reaction conditions (Table 1, entry 12), we examined substrate scope, beginning with a wide range of aromatic aldehydes 1 (Table 2). The reaction proceeded with good yield and high stereoselectivity with nearly any electron-withdrawing substitution at the ortho-, meta-, or para-position on the aromatic aldehydes (entries 2–7). Reaction was slightly slow when aromatic aldehyde was substituted at the ortho-position (entry 6), which may reflect steric hindrance. Good yield and high stereoselectivity were obtained in the case of aromatic aldehyde bearing an electron-donating group (entry 8). Heteroaryl aldehydes gave better yields of products 6i and 6j than aryl aldehydes did, and with greater diastereoselectivities (entries 9 and 10). Cinnamaldehyde reacted efficiently with CF₃CH(OH)OEt, and the product 6k containing a cinnamoyl group was generated with good stereocontrol (entry 11). Unfortunately aliphatic aldehydes did not work in the first cross-benzoin step,¹² suggesting that the overall cascade reaction is compatible only with aromatic aldehydes and aromatic enals.

Table 2 Investigation of the scope of the cascade reaction using the optimized conditions^a

Entry		R^1	R^2	Product	Yield^b (%)	dr^c 6 : 6′	ee^d (%) 6/6′
a See entry 12 and footnote a in Table 1.b Yield of isolated 6 and 6′.c The diastereomeric ratio (dr) was calculated by ^1H NMR analysis of the crude reaction mixture.d Determined by HPLC using a chiral stationary phase.
1		Ph	Ph	6a/6a′	61	78  :22	93/85
2		3-Cl–C6H4	Ph	6b/6b′	66	88 : 12	97/91
3		4-Cl–C6H4	Ph	6c/6c′	69	83 : 17	92/85
4		3-Br–C6H4	Ph	6d/6d′	65	86 : 14	89/88
5		4-Br–C6H4	Ph	6e/6e′	63	74 : 26	90/88
6		2-F–C6H4	Ph	6f/6f′	48	62 : 38	90/85
7		4-F–C6H4	Ph	6g/6g′	56	85 : 15	85/88
8		4-iPr–C6H4	Ph	6h/6h′	58	79 : 21	85/83
9		2-Furyl	Ph	6i/6i′	75	86 : 14	88/88
10		2-Thienyl	Ph	6j/6j′	78	86 : 14	89/86
11		Cinnamoyl	Ph	6k/6k′	59	89 : 11	89/87
12		Ph	2-Cl–C6H4	6l/6l′	68	78 : 22	94/81
13		Ph	4-Cl–C6H4	6m/6m′	71	77 : 23	86/95
14		Ph	4-Br–C6H4	6n/6n′	67	78 : 22	86/86
15		Ph	2-F–C6H4	6o/6o′	70	69 : 31	86/91
16		Ph	3-F–C6H4	6p/6p′	69	78 : 22	85/88
17		Ph	4-F–C6H4	6q/6q′	65	74 : 26	88/84
18		Ph	4-NO2–C6H4	6r/6r′	62	72 : 28	90/86
19		Ph	4-CH3–C6H4	6s/6s′	55	73 : 27	83/81
20		Ph	2-CH3O–C6H4	6t/6t′	54	75 : 25	85/85
21		Ph	2-Furyl	6u/6u′	75	86 : 14	60/61
22		Ph	CH3	6v/6v′	51	84 : 16	92/80

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After defining the substrate scope for component 1, we turned to the scope for the α,β-unsaturated aldehyde partner. A broad array of β-aryl-substituted enals 4 proved to be competent substrates (entries 12–21). Nevertheless, the electronic properties of the substituent on the aromatic ring of substrate 4 slightly affected the reaction. When the aromatic ring carried an electron-withdrawing substituent, the reactions proceeded smoothly to completion, affording products 6l–6r in good yield with high to excellent stereoselectivity (entries 12–18). In contrast, when the aromatic ring carried an electron-donating substituent, the reactions were relatively slow, and the products 6s and 6t were attained in moderate yields (entries 19 and 20). Heteroaryl enal also led to the target product 6u in high yield with good diastereoselectivity, but the ee value was relatively low (entry 21). Even the less reactive crotonaldehyde participated in the reaction, giving product 6v with high enantioselectivity, albeit in lower yield (entry 22). The absolute configuration of 6c was determined by X-ray crystallographic analysis,¹³ and the absolute configurations of other products were tentatively assigned by analogy.

Remarkably, acid-promoted formation of the asymmetric enediol intermediate assured a steady supply of nucleophile for the second catalytic cycle. Although both the α- and β-position of the CF₃ can, in principle, serve as the nucleophilic site (Scheme 3), giving rise to the respective cyclization products 6 and 7, we detected only α-selective cyclization products (two diastereoisomers) using ¹³C- and ¹⁹F-NMR. We never detected β-selective cyclization products under our reaction conditions.

Scheme 3 High regioselectivity in the Michael-acetalization step.

We propose the transition state model in Scheme 4 to explain the high diastereo- and enantioselectivities observed in our cascade process with a variety of substrates. In this model, which is analogous to the one proposed by the Jørgensen group for amine-catalyzed epoxidation¹⁴ or Michael addition,¹⁵ the asymmetric enediol is able to approach the β-position of the chiral iminium intermediate close enough to allow carbon–carbon bond formation selectively between the Re face of the enediol and the Si face of the iminium. This approach minimizes steric repulsion among the enediol, bulky diphenylsiloxymethyl group on the pyrrolidine ring, and β-substituent on the enal. The resulting hemiacetal is generated in the S,S configuration with high stereoselectivity.

Scheme 4 Proposed mechanism of the asymmetric cascade reaction.

To demonstrate the synthetic utility of our asymmetric cascade process, we smoothly converted the chiral hemiacetal 5a into some versatile building blocks different from γ-butyrolactones (Scheme 5). Treating 5a with Et₃SiH and BF₃–Et₂O in dichloromethane at −10 °C led to simultaneous removal of the hydroxyl group and reduction of the benzoyl carbonyl group, generating the chiral tetrahydrofuran derivative 8. We were also able to acetylate the hydroxyl group of hemiacetal 5a to give stable 9 in high yield. Treating 5a with 1-phenyl-2-(triphenylphosphoranylidene)-ethanone led to an apparent Wittig-oxa-Michael process, affording the multi-functionalized tetrahydrofuran 10 with three chiral centers.

Scheme 5 Chemical transformation of 5a.

Conclusions

In conclusion, we have developed an efficient and practical one-pot cascade process that delivers synthetically useful, multi-functionalized chiral hydrogenated γ-butyrolactone derivatives featuring a CF₃-substituted quaternary stereocenter in good yield with high stereoselectivity. The process comprises a highly chemoselective NHC-catalyzed intermolecular cross-benzoin reaction of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal; followed by a highly regioselective amine-catalyzed Michael-acetalization cascade involving α,β-unsaturated aldehyde. This novel approach broadens the useful scope of sequential dual catalysis.¹⁶ Further study of asymmetric domino reactions involving NHC-amine catalysis are underway in our laboratory.

Acknowledgements

We are grateful for financial support from NSFC (21302016, 81573588 and 81573589), the Science & Technology Department of Sichuan Province (2014JQ0020) and the Foundation for the Author of National Excellent Doctoral Dissertation of PR China (201487).

Notes and references

1. For recent reviews on the asymmetric synthesis of trifluoro-methylated compounds, see: (a) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470–477; (b) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011, 111, 455–529; (c) O. A. Tomashenko and V. V. Grushin, Chem. Rev., 2011, 111, 4475–4521; (d) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950–8958; (e) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214–8264; (f) E. Merino and C. Nevado, Chem. Soc. Rev., 2014, 43, 6598–6608.
2. For recent reviews on the applications of fluorine in medicinal chemistry, see: (a) C. Isanbor and D. O'Hagan, J. Fluorine Chem., 2006, 127, 303–319; (b) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013–1029; (c) K. Müeller, C. Faeh and F. Diederich, Science, 2007, 317, 1881–1886; (d) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359–4369; (e) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320–330; (f) J. Wang, M. Sánchez-Roselló, J. Luis Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 114, 2432–2506; (g) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and N. A. Meanwell, J. Med. Chem., 2015, 58, 8315–8359.
3. For recent reviews on the synthesis of chiral γ-butyrolactone derivatives, see: (a) M. Seitz and O. Reiser, Curr. Opin. Chem. Biol., 2005, 9, 285–292; (b) S. Gil, M. Parra, P. Rodriguez and J. Segura, Mini-Rev. Org. Chem., 2009, 6, 345–358; (c) R. R. A. Kitson, A. Millemaggi and R. J. K. Taylor, Angew. Chem., Int. Ed., 2009, 48, 9426–9451; (d) J. M. J. Nolsøe and T. V. Hansen, Eur. J. Org. Chem., 2014, 3051–3065.
4. (a) C. Burstein and F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 6205–6208; (b) K. Hirano, I. Piel and F. Glorius, Adv. Synth. Catal., 2008, 350, 984–988.
5. (a) C. Burstein, S. Tschan, X. Xie and F. Glorius, Synthesis, 2006, 2418–2439; (b) Y. Matsuoka, Y. Ishida and K. Saigo, Tetrahedron Lett., 2008, 49, 2985–2989; (c) Y. Matsuoka, Y. Ishida, D. Sasaki and K. Saigo, Chem.–Eur. J., 2008, 14, 9215–9222; (d) R. B. Strand, T. Helgerud, T. Solvang, A. Dolva, C. A. Sperger and A. Fiksdahl, Tetrahedron: Asymmetry, 2012, 23, 1350–1359.
6. Z. Fu, J. Xu, T. Zhu, W. W. Y. Leong and Y. R. Chi, Nat. Chem., 2013, 5, 835–839.
7. For some other approaches to CF₃-substituted chiral γ-butyrolactone derivatives, see: (a) P. V. Ramachandran, K. J. Padiya, V. Rauniyar, M. V. R. Reddy and H. C. Brown, Tetrahedron Lett., 2004, 45, 1015–1017; (b) P. Bravo, M. Frigerio, A. Melloni, W. Panzeri, C. Pesenti, F. Viani and M. Zanda, Eur. J. Org. Chem., 2002, 1895–1902; (c) Y. Komatsu, F. Sasaki, S. Takei and T. Kitazume, J. Org. Chem., 1998, 63, 8058–8061.
8. (a) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc., 2009, 131, 13628–13630; (b) L. Deiana, P. Dziedzic, G.-L. Zhao, J. Vesely, I. Ibrahem, R. Rios, J. Sun and A. Cordova, Chem.–Eur. J., 2011, 17, 7904–7917; (c) D. Enders, A. Grossmann, H. Huang and G. Raabe, Eur. J. Org. Chem., 2011, 4298–4301; (d) C. B. Jacobsen, K. L. Jensen, J. Udmark and K. A. Jørgensen, Org. Lett., 2011, 13, 4790–4793; (e) Y.-Z. Liu, J. Zhang, P.-F. Xu and Y.-C. Luo, J. Org. Chem., 2011, 76, 7551–7555; (f) K. E. Ozboya and T. Rovis, Chem. Sci., 2011, 2, 1835–1838; (g) C. B. Jacobsen, Ł. Albrecht, J. Udmark and K. A. Jørgensen, Org. Lett., 2012, 14, 5526–5529; (h) Y. Liu, M. Nappi, E. C. Escudero-Adán and P. Melchiorre, Org. Lett., 2012, 14, 1310–1313; (i) L. Dell'Amico, G. Rassu, V. Zambrano, A. Sartori, C. Curti, L. Battistini, G. Pelosi, G. Casiraghi and F. Zanardi, J. Am. Chem. Soc., 2014, 136, 11107–11114.
9. (a) B.-C. Hong, N. S. Dange, C.-S. Hsu and J.-H. Liao, Org. Lett., 2010, 12, 4812–4815; (b) B.-C. Hong, N. S. Dange, C.-S. Hsu, J.-H. Liao and G.-H. Lee, Org. Lett., 2011, 13, 1338–1341; (c) G. He, F. Wu, W. Huang, R. Zhou, L. Ouyang and B. Han, Adv. Synth. Catal., 2014, 356, 2311–2319.
10. B. T. Ramanjaneyulu, S. Mahesh and R. V. Anand, Org. Lett., 2015, 17, 6–9.
11. (a) X. Xie, C. Peng, G. He, H.-J. Leng, B. Wang, W. Huang and B. Han, Chem. Commun., 2012, 48, 10487–10489; (b) X. Li, L. Yang, C. Peng, X. Xie, H.-J. Leng, B. Wang, Z.-W. Tang, G. He, L. Ouyang, W. Huang and B. Han, Chem. Commun., 2013, 49, 8692–8694; (c) B. Han, X. Xie, W. Huang, X. Li, L. Yang and C. Peng, Adv. Synth. Catal., 2014, 356, 3676–3682; (d) B. Han, W. Huang, W. Ren, G. He, J.-h. Wang and C. Peng, Adv. Synth. Catal., 2015, 357, 561–568; (e) R. Zhou, Q. Wu, M. Guo, W. Huang, X. He, L. Yang, F. Peng, G. He and B. Han, Chem. Commun., 2015, 51, 13113–13116.
12. We screened 2-phenylacetaldehyde and 3-phenylpropanal.
13. CCDC 1440711† (6c) contains the ESI crystallographic data for this article.
14. (a) M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 6964–6965; (b) W. Zhuang, M. Marigo and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 3883–3885.
15. S. Brandau, A. Landa, J. Franzen, M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006, 45, 4305–4309.
16. (a) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167–178; (b) M. Rueping, R. M. Koenigs and I. Atodiresei, Chem.–Eur. J., 2010, 16, 9350–9365; (c) Ł. Albrecht, H. Jiang and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492–8509; (d) C. C. J. Loh and D. Enders, Chem.–Eur. J., 2012, 18, 10212–10225; (e) C. M. Marson, Chem. Soc. Rev., 2012, 41, 7712–7722; (f) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237–294; (g) Z. Du and Z. Shao, Chem. Soc. Rev., 2013, 42, 1337–1378; (h) H. Pellissier, Tetrahedron, 2013, 69, 7171–7210.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for new compounds. CCDC 1440711. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra03571j

‡ These authors contributed equally to this work.

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