Asymmetric organocatalytic double 1,6-addition: rapid access to chiral chromans with molecular complexity

Sourav Roy, Suman Pradhan, Krishan Kumar and Indranil Chatterjee*
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab-140001, India. E-mail: indranil.chatterjee@iitrpr.ac.in; Web: http://indranilchatterjee9.wixsite.com/icresearchgroup

Received 20th March 2020 , Accepted 28th April 2020

First published on 28th April 2020


An organocatalytic cascade vinylogous double 1,6-addition strategy for the synthesis of chiral chroman derivatives is reported. The cascade reaction follows oxa-Michael/1,6-addition reactions between ortho-hydroxyphenyl-substituted para-quinone methides and 2,4-dienal derivatives to deliver chroman derivatives with excellent yields (up to 96%) and stereoselectivities (up to >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr, >99% ee). The chiral secondary amine-based Jørgensen–Hayashi organocatalysts are shown to catalyze the transformation of unbiased 2,4-dienals under mild reaction conditions with exclusive δ-site selectivity and high control over enantioselectivity at a remote position. The synthetic transformations of the products ensure molecular complexity with a great level of enantiocontrol.


Introduction

Asymmetric organocatalytic cascade reactions in recent years have drawn immense attention due to their ability to generate molecular complexity in a rapid and atom-economical fashion. The utilization of this strategy for the generation of chiral molecules is an essential goal in modern synthetic chemistry.1 Chromans are such imperative target molecules present in various natural products and biologically active molecules.2 Targeting such a privileged scaffold, we envisioned to design the possibility of an organocatalytic cascade reaction between unbiased α,β,γ,δ-unsaturated enals and ortho-hydroxyphenyl-substituted para-quinone methides (p-QMs).

p-QMs in recent years have emerged as potential Michael acceptors for developing various 1,6-addition protocols using different nucleophiles (Scheme 1a). In 2013, the group of Fan developed the first asymmetric 1,6-addition of malonates to p-QMs.3 Following this, the group of Jørgensen elegantly described a secondary amine-catalyzed α-alkylation of aldehydes.4 From then onwards, various metal and metal-free strategies have been developed based on 1,6-addition to p-QMs.5 Comparatively, ortho-hydroxyphenyl-substituted p-QMs have been less explored for developing catalytic cascade approaches (Scheme 1b). In 2016, Enders and co-workers developed an asymmetric cascade oxa-Michael/1,6-addition protocol using ortho-hydroxyphenyl-substituted p-QMs and isatin derivatives to synthesize chroman derivatives.6 Later, several groups applied this strategy to develop numerous cascade reactions.7 Despite the progress in this area, there is still room to design molecular complexity.


image file: d0qo00354a-s1.tif
Scheme 1 Asymmetric 1,6-additions.

The ability of chiral secondary amines to integrate orthogonal activation of carbonyls has been successfully used to functionalize the α- and β-position of carbonyls.8 The translation of this reactivity towards a vinylogous direction has always been a challenging task.9 Our designed process includes 1,6-addition involving a hydroxyl group with exclusive δ-site selectivity towards vinylogous iminium ions generated by the condensation of chiral secondary amines and 2,4-dienals, followed by a cascade intramolecular vinylogous dienamine-based 1,6-addition to p-QMs for constructing chroman scaffolds.10 The envisaged double 1,6-addition process has specific challenges that need to be overcome: (1) site selectivity: β- vs. δ-, as organocatalytic 1,4-addition is generally favored over 1,6-addition. Except for a couple of examples from the group of Jørgensen where linear unbiased 2,4-dienals were used (Scheme 1c),11 in most of the cases, 1,6-addition is strategically directed by suppressing 1,4-addition using β-substituted 2,4-dienals;12 (2) control over enantioselectivity at a remote δ-position, far from the catalyst binding site; (3) control over the geometry of a second vinylogous dienamine-based 1,6-addition; and (4) overcoming the low nucleophilicity of ortho-hydroxyphenyl-substituted p-QMs. Herein, we reveal a highly enantioselective and diastereoselective double 1,6-addition strategy following a cascade process for the synthesis of chiral chroman derivatives (Scheme 1d, this work).

Results and discussion

We commenced our study by reacting (2E,4E)-hepta-2,4-dienal (1a, 2.0 equiv.) as the model substrate with ortho-hydroxyphenyl-substituted p-QM (2a, 1.0 equiv.) in toluene (0.5 M) in the presence of 3a as the catalyst13 at 45 °C for 40 h (Table 1). In the presence of various additives (20 mol%), irrespective of the nature of the base, we observed the product formation in moderate to good yields but with poor diastereoselectivity and enantioselectivity (Table 1, entries 1–3). Increasing the additive loading (40 mol% Et3N) did not improve much the reaction yield (Table 1, entry 4). However, the reaction in the presence of catalyst 3c having bulkier –SiPh3 as the protecting group resulted in a drastic improvement of the reactivity and selectivity and delivered 4a in 69% yield with 3[thin space (1/6-em)]:[thin space (1/6-em)]1 dr and 85% ee (Table 1, entry 5). To our delight, the variation of different solvents revealed that o-xylene performed as the best solvent to deliver the desired product 4a with a good yield and excellent diastereoselectivity and enantioselectivity (Table 1, entry 10, 4.5[thin space (1/6-em)]:[thin space (1/6-em)]1 dr and 94% ee). Lowering the reaction temperature to 10 °C and prolonging the reaction time further improved the reaction yield (Table 1, entries 11–13). The catalyst loading and altering of different other secondary amines as catalysts did not significantly improve the reaction yield (Table 1, entries 14–19). We chose the conditions of Table 1, entry 13, as our optimized reaction conditions for further screening of substrates.
Table 1 Optimization study and reaction setupa

image file: d0qo00354a-u1.tif

Entry Additive (mol%) Solvent (M) Catalyst (mol%) Yieldb% drc eed (%)
a Unless otherwise mentioned, all reactions were carried out on a 0.1 mmol scale at 45 °C for 40 h.b Measured by 1H NMR analysis of the crude reaction mixture using CH2Br2 as an internal standard. Isolated yield is given in brackets.c dr = diastereomeric ratio, determined by 1H NMR analysis of the crude reaction mixture.d Enantiomeric excess was determined by HPLC analysis on a chiral stationary phase.e Reaction was carried out at room temperature.f Reaction was carried out at 10 °C.g Reaction was carried out at 10 °C for 48 h.h Mixture of several diastereomers was observed from 1H NMR analysis of the crude reaction mixture.i 1 mmol scale reaction produced 4a with 60% yield, 5[thin space (1/6-em)]:[thin space (1/6-em)]1 dr and 98% ee.
1 DIPEA (20) Toluene (0.5) 3a (20) 58 1.2[thin space (1/6-em)]:[thin space (1/6-em)]1 71
2 DABCO (20) Toluene (0.5) 3a (20) 23 1.2[thin space (1/6-em)]:[thin space (1/6-em)]1 65
3 Et3N (20) Toluene (0.5) 3a (20) 44 1.4[thin space (1/6-em)]:[thin space (1/6-em)]1 60
4 Et3N (40) Toluene (0.5) 3a (20) 52 1.4[thin space (1/6-em)]:[thin space (1/6-em)]1 81
5 Et3N (40) Toluene (0.5) 3c (20) 69 3[thin space (1/6-em)]:[thin space (1/6-em)]1 85
6 Et3N (40) CH2Cl2 (0.5) 3c (20) 54 3.5[thin space (1/6-em)]:[thin space (1/6-em)]1 94
7 Et3N (40) CHCl3 (0.5) 3c (20) 60 2.5[thin space (1/6-em)]:[thin space (1/6-em)]1 85
8 Et3N (40) Benzene (0.5) 3c (20) 68 3[thin space (1/6-em)]:[thin space (1/6-em)]1 94
9 Et3N (40) p-Xylene (0.5) 3c (20) 74 2.5[thin space (1/6-em)]:[thin space (1/6-em)]1 92
10 Et3N (40) o-Xylene (0.5) 3c (20) 63 4.5[thin space (1/6-em)]:[thin space (1/6-em)]1 94
11e Et3N (40) o-Xylene (0.5) 3c (20) 67 2.5[thin space (1/6-em)]:[thin space (1/6-em)]1 88
12f Et3N (40) o-Xylene (0.5) 3c (20) 72 5[thin space (1/6-em)]:[thin space (1/6-em)]1 94
13g Et3N (40) o-Xylene (0.5) 3c (20) 92 (84)i 8[thin space (1/6-em)]:[thin space (1/6-em)]1 98
14g Et3N (40) o-Xylene (0.5) 3c (10) 68 2[thin space (1/6-em)]:[thin space (1/6-em)]1 93
15g Et3N (40) o-Xylene (0.5) 3a (20) 90 1.1[thin space (1/6-em)]:[thin space (1/6-em)]1 67
16g,h Et3N (40) o-Xylene (0.5) 3b (20) 36
17g Et3N (40) o-Xylene (0.5) 3d (20) 73 1.3[thin space (1/6-em)]:[thin space (1/6-em)]1 75
18g Et3N (40) o-Xylene (0.5) 3f (20) n.r
19g Et3N (40) o-Xylene (0.5) 3c + 3e (20 + 30) 14 1[thin space (1/6-em)]:[thin space (1/6-em)]1


The reactivity of various 2,4-dienals (1a–f) with ortho-hydroxyphenyl-substituted p-QMs 2 was assessed under the optimized reaction conditions, as summarized in Table 2. p-QMs and their derivatives having alkyl, halogen and methoxy groups as substituents at the ortho- or para-position of the hydroxy group worked well in the presence of 3c to furnish chromans 4b–4g in high yields with good to excellent diastereoselectivity and excellent enantioselectivity. In the case of 4-Cl-substituted p-QM, a low yield and moderate diastereoselectivity of 4d were observed. Various 2,4-dienals having aliphatic substituents like methyl, n-pentyl, –CH2CH2Ph and cyclohexyl groups at the δ-position reacted smoothly to provide products 4h–4k in good yields with excellent enantioselectivity and moderate to good diastereoselectivity. Unfortunately, phenyl substituents at the δ-position of 2,4-dienals remained less reactive. Inserting an electron-withdrawing –NO2 group at the aromatic ring moderately increased the reactivity to provide 4l with a low yield and moderate selectivity. A naphthyl-substituted p-QM also furnished the desired chroman product 4m with a moderate yield and selectivity. The absolute configuration of the chroman derivatives was unambiguously determined by X-ray analysis of the 4d derivative. Based on the X-ray structure analysis and literature evidence,11a we proposed a plausible mechanistic pathway for the formation of chroman derivatives. This cascade reaction is triggered by the intermolecular vinylogous iminium ion-based 1,6-addition (oxa-Michael) of the deprotonated nucleophile to the linear unbiased 2,4-dienal to produce intermediate 4I. Intermediate 4I then undergoes another intramolecular vinylogous dienamine-based 1,6-addition to p-QM (Scheme 2, plausible mechanism) to construct the chroman derivative. The vinylogous deprotonated nucleophile prefers selectively an oxa-Michael reaction at the δ-position rather than at the β-position, which is opposite to the observation by Jørgensen et al.11a,f


image file: d0qo00354a-s2.tif
Scheme 2 Plausible mechanism and transition state for double 1,6-addition.
Table 2 Substrate evaluation for chroman derivativesa

image file: d0qo00354a-u2.tif

Entry R1 R2 Yield % drb eec (%)
a Unless otherwise mentioned, all reactions were carried out on a 0.1 mmol scale by taking 1 (2.0 equiv.) and 2 (1.0 equiv.). Yields refer to isolated yield unless otherwise specified.b Diastereomeric mixture was measured by 1H NMR analysis of the crude reaction mixture.c Enantiomeric excess was measured by HPLC on a chiral stationary phase.d Reactions were performed at 45 °C for 40 h.e 20 mol% Et3N was used as an additive.f Reaction was performed at 10 °C for 48 h and gave better ee (96%) but a lower yield (40%).g Reactions were carried out on a 0.1 mmol scale by taking 1 (1.0 equiv.) and 2 (4.0 equiv.) at 45 °C for 7 days using CHCl3 (0.1 M) as a solvent.h ee was measured by converting the aldehyde into alcohol.
1, 4a Et H 84 8[thin space (1/6-em)]:[thin space (1/6-em)]1 98
2, 4b Et 4-Me 80 7[thin space (1/6-em)]:[thin space (1/6-em)]1 >99
3, 4c Et 4-Br 66 5[thin space (1/6-em)]:[thin space (1/6-em)]1 96
4, 4d Et 4-Cl 40 3[thin space (1/6-em)]:[thin space (1/6-em)]1 98
5, 4e Et 4-OMe 72 12[thin space (1/6-em)]:[thin space (1/6-em)]1 >99
6, 4f Et 6-OMe 71 3.5[thin space (1/6-em)]:[thin space (1/6-em)]1 92
7, 4g Et 6-Me 64 6[thin space (1/6-em)]:[thin space (1/6-em)]1 >99
8, 4hd Me H 68 3[thin space (1/6-em)]:[thin space (1/6-em)]1 82
9, 4id n-Pentyl H 66 3[thin space (1/6-em)]:[thin space (1/6-em)]1 92h
10, 4jd,e (CH2)2Ph H 71 4.5[thin space (1/6-em)]:[thin space (1/6-em)]1 >99
11, 4kd,f Cyclohexyl H 60 3[thin space (1/6-em)]:[thin space (1/6-em)]1 92
12, 4lg o-NO2C6H4 H 36 3[thin space (1/6-em)]:[thin space (1/6-em)]1 76
image file: d0qo00354a-u3.tif


The sluggish reactivity of the δ-aryl-substituted 2,4-dienals prompted us to test the reactivity of β,δ-aryl-substituted 2,4-dienals. To our surprise, this dramatically increased the reactivity and selectivity to furnish aryl-substituted chromans 4n–4p (Scheme 3) in excellent yields with excellent diastereoselectivity and good enantioselectivity using catalyst 3a under modified reaction conditions. The absolute configuration of the diaryl-substituted chromans was unambiguously determined by X-ray analysis of the 4p derivative. Based on the X-ray analysis and literature evidence, we proposed a plausible transition state for the formation of products 4n–p (Scheme 4, plausible mechanism).12b,c This organocascade reaction proceeds via a vinylogous iminium ion/dienamine activation sequence of linear 2,4-dienals.


image file: d0qo00354a-s3.tif
Scheme 3 Asymmetric double 1,6-addition of β,δ-aryl-substituted 2,4-dienals. Unless otherwise mentioned, all reactions were carried out on a 0.1 mmol scale by taking 1 (2.0 equiv.) and 2 (1.0 equiv.); yields refer to isolated yield unless otherwise specified; diastereomeric mixture was measured by 1H NMR analysis of the crude reaction mixture and enantiomeric excess was measured by HPLC on a chiral stationary phase.

image file: d0qo00354a-s4.tif
Scheme 4 Plausible mechanism and transition state for double 1,6-addition of β,δ-aryl-substituted 2,4-dienals.

The presence of an α,β-unsaturated system provides an opportunity to modify these chroman derivatives into more complex molecular scaffolds. Compound 4a can be cyclopropanated using 3a as a catalyst to obtain 5 with excellent dr and enantioselectivity (Scheme 5a).14 The Corey–Chaykovsky reaction quickly converted 4a into allylic epoxide 6 (Scheme 5b).15 Simple epoxidation of allylic alcohol also readily furnished epoxide 7 having five continuous chiral centers with a high yield and diastereoselectivity and enantioselectivity (Scheme 5c).


image file: d0qo00354a-s5.tif
Scheme 5 Synthetic transformations of the cascade product.

Conclusions

We disclose here an organocatalytic asymmetric synthesis of chroman derivatives with high selectivity (up to >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr, >99% ee) and high yield (up to 96%). The reaction is initiated by an oxa-Michael reaction (1,6-addition) with exclusive δ-site selectivity to a vinylogous unbiased iminium ion and concluded with another vinylogous dienamine-based 1,6-addition to p-QMs. This work provides a rare example of asymmetric double 1,6-addition. The low reactivity of δ-aryl-substituted unbiased 2,4-dienals can be dramatically influenced using β,δ-aryl-substituted 2,4-dienals. The remaining α,β-unsaturated enal functionality is employed to introduce molecular complexity to the chiral chroman derivatives with high reactivity and stereoselectivity.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors wish to acknowledge the financial assistance from the SERB, DST, India (ECR/2018/000098). S. R., S. P. and K. K. thank IIT va for their research fellowships.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. CCDC 1982963 and 1982953. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0qo00354a

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