Multiple approaches to enantiopure spirocyclic benzofuranones using organocatalytic cascade reactions

Abstract

Three distinct aminocatalytic cascade reactions leading to enantiomerically pure spirocyclic benzofuranones have been devised, highlighting the ability of organocascade to generate high degrees of stereochemical and architectural complexity in a single chemical transformation.

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Finding cost-effective and sustainable synthetic ways to reproduce the rich structural diversity and complexity of natural molecules has always captured the attention of chemists,¹ especially in relation to biologically active compounds.² The emerging field of aminocatalytic cascade reactions³ has recently provided a way of achieving stereochemical and molecular complexity while addressing the requests for atom and step economy or protecting-group-free synthesis.⁴ The synthetic potential of this bio-inspired approach has been validated by recent applications of asymmetric aminocascade reactions to the total synthesis of natural products.⁵ Here, we report on complementary approaches to accessing enantiomerically pure spiro-benzofuranone cyclohexane derivatives with multiple stereocenters. Thus, we further illustrate the potential and versatility of aminocascade catalysis for facing challenging synthetic problems using disparate tactics. The three cascade reactions are based on distinct catalytic machineries and provide straightforward access to natural-product-inspired compound collections^2b that would be difficult to synthesise by other catalytic methods.⁶

Our ongoing efforts⁷ to design novel aminocatalytic cascade reactions to access valuable complex compounds prompted us to investigate the preparation of spirocyclic benzofuranones. This scaffold is featured in a number of natural products⁸ that exhibit biological activities ranging from antioxidant properties to potential application in anticancer and Alzheimer's therapy (Fig. 1).

Fig. 1 Naturally occurring and biologically active benzofuranones.

We decided to attack the synthetic problem by exploiting the established ability of chiral secondary amine A⁹ to integrate orthogonal activation modes of aldehydes (enamine and iminium ion catalysis) into more elaborate cascade sequences.¹⁰ Based on the relatively low pK_a of benzofuranone 1,¹¹ we thought we might exploit its ambident nucleophilic profiles¹² to design a cascade reaction with α,β-unsaturated aldehydes 2. As planned in Table 1, we anticipated that benzofuranone 1 should first intercept the iminium ion generated by catalyst A's condensation with enal 2. The resulting prochiral carbon nucleophile I should be reactive enough to initiate a second, intermolecular, iminium catalyzed conjugate addition with another molecule of 2 to afford intermediate II. The last intramolecular aldolization–dehydration sequence, driven by enamine catalysis, should afford the desired spiro-derivative 3.

Table 1 Accessing spirocyclic benzofuranones by aminocatalytic cascade with enals: iminium–iminium–enamine activation sequence^a

Entry	R	3	Yield^b (%)	dr^c	ee^d
a The organocascade proceeds under the catalysis of A by way of an iminium-catalysed Michael addition of 1 to 2, followed by a second iminium-mediated Michael addition of the chiral nucleophilic intermediate I to another molecule of enal 2 and an enamine-driven intramolecular aldol reaction of II followed by a dehydration step, leading to the spiro compounds 3. Reactions were carried out at room temperature using 5 mol% of catalyst A and 3 equiv. of enals 2 on a 0.2 mmol scale. b Yield of isolated product. c A single diastereoisomer was always detected by ^1H NMR analysis of the crude mixture. d ee of 3 determined by HPLC analysis. e Carried out with 1 mol% of catalyst A at 40 °C.
1	Ph	a	75	>19 ∶ 1	>99
2^e	Ph	a	68	>19 ∶ 1	>99
3	p-NO2–C6H4	b	59	>19 ∶ 1	>99
4	p-MeO–C6H4	c	54	>19 ∶ 1	>99
5	p-Cl–C6H4	d	80	>19 ∶ 1	99
6	2-Furyl	e	49	>19 ∶ 1	99
7	Me	f	51	19 ∶ 1	>99
8	CO2Et	g	38	>19 ∶ 1	99

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Our organocascade strategy was evaluated conducting the reactions in toluene at room temperature for 16 hours, under an aerobic atmosphere. Optimization experiments revealed that 5 mol% of catalyst A in combination with an acidic co-catalyst, such as benzoic acid (5 mol%), fully converted benzofuranone 2 into the spiro-adducts 3 with perfect control over the stereochemistry (a single stereoisomer out of the possible 8 being detected, de and ee >99%). Even a catalyst loading as low as 1 mol% afforded the enantiopure spirobenzofuranone 3a with good chemical yield and a practical reaction time of 16 hours (entry 2). As highlighted in Table 1, there appears to be significant tolerance toward structural and electronic variations of enals enabling access to a variety of complex spiro-compounds 3a–g with three stereocenters. Different substituents at the aromatic moiety, regardless of their electronic properties, and a hetero-aromatic substituent were well-tolerated (entries 1–6). Crotonaldehyde and ethyltrans-4-oxo-2-butenoate were also suitable substrates of the cascade (entries 7 and 8).

The ability to address a particular synthetic problem through disparate approaches is a general validation for the versatility and reliability of a chemical strategy. A central goal of our organocascade catalysis studies has been to demonstrate the potential of accessing enantiomerically pure spiro-benzofuranone cyclohexane derivatives using complementary organocascade reactions, based on distinct catalytic machineries. Inspired by previous studies from our laboratory^7a–b and others,^10a we recognized that identifying a suitable compound 4, bearing the benzofuranone moiety, was key to designing novel organocascade reactions. Compound 4 seemed well-tailored to first act as a Michael acceptor and then to originate, after the conjugate addition, a nucleophilic intermediate able to continue the cascade. Given this reactivity profile, we included compound 4 as the third component of a three-component domino strategy that exploited the catalytic ability of secondary amine A to realize an enamine–iminium–enamine sequential activation of aldehydes 5 and α,β-unsaturated aldehydes 2.^10a As portrayed in Table 2, the triple organocascade provides fast and easy access to spiro-benzofuranone cyclohexene carbaldehydes 6 with almost perfect control over stereochemistry. This reaction proceeds at 40 °C in the presence of the catalytic salt A·o-F–C₆H₄CO₂H (20 mol%) in toluene by way of a catalysed Michael/Michael/aldol condensation sequence. A variety of substituents at the β-position of the benzofuranone-based compounds 4 are well tolerated, as are different aldehydic substrate combinations.

Table 2 Accessing spirocyclic benzofuranones by way of an enamine–iminium–enamine activation of aldehydes^a

Entry	R^1	R^2	R^3	6	Yield^b (%)	dr^c	ee^d
a The triple organocascade proceeds by way of an enamine-catalysed Michael addition of 5 to 4, followed by an iminium-mediated Michael addition of the chiral nucleophilic intermediate III to 2 and an enamine-catalysed intramolecular aldol reaction to afford IV. The last dehydration step leads to the spirocyclic compounds 6. Reactions were carried out using 2 equiv. of aldehyde 5 and 1.5 equiv. of 4 on a 0.2 mmol scale. b Yield of isolated product. c A single diastereoisomer was always detected by ^1H NMR analysis of the crude mixture. d ee of 6 determined by HPLC analysis. e Reaction carried out using isomerically pure 4 having an (E) geometry. f Reaction carried out using a 3 ∶ 1 mixture of (E) and (Z) isomers of 4.
1	Ph^e	Me	Ph	a	56	>19 ∶ 1	>99
2	Ph^f	Me	Ph	a	58	>19 ∶ 1	>99
3	p-Cl–C6H4	Me	Ph	b	57	>19 ∶ 1	99
4	p-NO2–C6H4	Me	Ph	c	52	>19 ∶ 1	>99
5	Propyl	Me	Ph	d	56	>19 ∶ 1	>99
6	CO2Et	Me	Ph	e	54	>19 ∶ 1	>99
7	CO2Et	Me	Me	f	70	>19 ∶ 1	95
8	CO2Et	Allyl	Ph	g	57	>19 ∶ 1	>99

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Notably, using a 3 ∶ 1 mixture of E/Z isomers of compound 4 leads to the same stereochemical outcome as employing geometrically pure E isomer (compare entries 1 and 2, Table 2, a single stereoisomer, de and ee >99%).¹³ This stereo-convergent catalytic path provokes interesting mechanistic considerations,¹⁴ as well as delineating a more practical synthetic protocol (a mixture of 4 can be used). Detailed studies along this line are ongoing in our laboratories and will be reported in due course.¹⁵

Next, we wished to develop a complementary organocascade strategy based on the activation of ketone compounds, in which the spiro-benzofuranone cyclohexane architecture was constructed with the simultaneous creation of two bonds and three stereogenic centres in one single chemical step (Table 3). Central to the implementation of this strategy was the unique ability of the primary amine 9-amino(9-deoxy)epi-hydroquinine B¹⁶ to facilitate the formation of the nucleophilic dienamine intermediate V (influencing the equilibrium with the iminium ion generated in situ by condensation with enones 7) while selectively directing the reaction manifold toward a stepwise double-Michael addition sequence.^7a,b The best results in terms of both yield and stereoselectivity were achieved using 20 mol% of amine A in combination with an acidic co-catalyst, such as o-fluoro benzoic acid (30 mol%). Results shown in Table 3 illustrate how this cascade enabled access to a variety of complex spiro-compounds 8 with a good diastereomeric and enantiomeric ratio.

Table 3 Tandem double Michael additions (enamine–iminium activation sequence) toward spirocyclic benzofuranone cyclohexanones^a

Entry	R^1	R^2	8	Yield^b (%)	dr^c	ee^d
a 4 first acts as a Michael acceptor, intercepting the nucleophilic dienamine intermediate V generated by catalyst B condensation with enones 7. The resulting prochiral carbon nucleophile II then selectively engages in an intramolecular, iminium catalyzed conjugate addition to afford spiro-derivatives 8. Reactions were carried out using 2 equiv. of enones 7 on a 0.2 mmol scale. b Yield of isolated product, referred to as the sum of diastereoisomers. c Determined by ^1H NMR analysis of the crude mixture. d ee of 8 determined by HPLC analysis. e Reaction carried out using isomerically pure 4 having an (E) geometry. f Reaction carried out using a 3 ∶ 1 mixture of (E) and (Z) isomers of 4.^15 g Isolated yield of the single, major diastereoisomer.
1	Ph^e	Ph	a	70^g	5.5 ∶ 1	>99
2	Ph^f	Ph	a	71^g	6.3 ∶ 1	>99
3	p-Cl–C6H4	Ph	b	75	3.5 ∶ 1	97
4	p-NO2–C6H4	Ph	c	82	2 ∶ 1	98
5	Propyl	Ph	d	40	>19 ∶ 1	91
6	CO2Et	Ph	e	77	2.2 ∶ 1	85
7	Ph	p-Cl–C6H4	f	85	3.5 ∶ 1	97
8	Ph	3-Thienyl	g	91	4 ∶ 1	96

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The stereochemical outcomes for all three distinct cascade approaches were unambiguously determined by anomalous dispersion X-ray crystallographic analysis of the chlorine derivatives 3d, 6b, and 8b (CCDC 780474, 781708, and 781524, respectively).

In summary, we have presented three direct and easy approaches to accessing densely functionalized spirocyclic molecules in essentially enantiomerically pure form. In view of the abundance of important benzofuranone-derived natural products bearing a spiro-center in the 3-position of the heterocycle, we believe these methods could be useful in asymmetric synthesis.

This research was supported by the Institute of Chemical Research of Catalonia (ICIQ) Foundation, and Ministerio de Educación y Ciencia (grant Consolider Ingenio 2010-CSD2006-0003). We thank Dr J. Benet-Buchholz (X-ray Diffraction Unit, ICIQ) for the structures of 3d, 6b, and 8b.

Notes and references

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8. (a) A. A. Hussein, J. J. M. Meyer, M. L. Jimeno and B. Rodríguez, J. Nat. Prod., 2007, 70, 293–295; for the isolation of hopeahainol A, see: (b) H. M. Ge, C. H. Zhu, D. H. Shi, L. D. Zhang, D. Q. Xie, J. Yang, S. W. Ng and R. X. Tan, Chem.–Eur. J., 2008, 14, 376–381; (c) L. Pérez-Fons, M. T. Garzón and V. Micol, J. Agric. Food Chem., 2010, 58, 161–171; (d) M. W. Pertino, C. Theoduloz, J. A. Rodríguez and V. Lazo, J. Nat. Prod., 2010, 73, 639–643. For the synthesis and biological evaluation of hopeahainol A, see: (e) K. C. Nicolaou, T. R. Wu, Q. Kang and D. Y.-K. Chen, Angew. Chem., Int. Ed., 2009, 48, 3440–3443; (f) K. C. Nicolaou, Q. Kang, T. R. Wu, C. S. Lim and D. Y.-K. Chen, J. Am. Chem. Soc., 2010, 132, 7540–7548.
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12. O. A. Reutov, I. P. Beletskaya and A. L. Kurts, Ambident Anions, Plenum, NY, 1983. For the use of ambident anions in aminocatalytic cascade reactions with enals, see ref. 10b.
13. Partial equilibration of the double-bond geometry of compound 4 bearing a β-phenyl group has been observed under the employed reaction conditions.
14. The stereo-convergence of the triple cascade depicted in Table 2 might be rationalized on the basis of a reversible first enamine-catalysed Michael addition step between aldehydes 5 and 4, leading to intermediate III: a rapid equilibrium may account for a dynamic kinetic resolution process driven by the perfectly suited matched-pair combination of the chiral iminium ion (generated by condensation of catalyst B and enals 2) and only one out of the possible eight stereoisomers of intermediate III. Unfortunately, to date we were not able to isolate the key intermediate III. We are actively pursuing this target. See ref. 15 for another possible stereo-convergent path.
15. At present, we cannot rule out a stereo-convergence path driven by a different reactivity of the E and Z isomers of 4, where the double-bond geometry scrambling continuously regenerates the fast reacting isomer.
16. For recent reviews, see: (a) G. Bartoli and P. Melchiorre, Synlett, 2008, 1759–1771; (b) Y.-C. Chen, Synlett, 2008, 1919–1930 and references therein.

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Footnotes

† This article is part of the ‘Emerging Investigators’ themed issue for ChemComm.

‡ Electronic supplementary information (ESI) available: Experimental, NMR and HPLC data. CCDC 780474 (3d), 781708 (6b), and 781524 (8b). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0cc01957g

§ C.C. and X.T. contributed equally to this research.

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