Letter pubs.acs.org/OrgLett
Asymmetric Synthesis of Functionalized Tricyclic Chromanes via an Organocatalytic Triple Domino Reaction Mukesh Kumar,† Pankaj Chauhan,† Arto Valkonen,‡ Kari Rissanen,‡ and Dieter Enders*,† †
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany Department of Chemistry, Nanoscience Center University of Jyvaskyla, 40014 Jyvaskyla, Finland
‡
S Supporting Information *
ABSTRACT: A highly stereoselective triple domino reaction for the synthesis of functionalized tricyclic chromane scaffolds has been developed. A secondary amine-catalyzed domino Michael/Michael/aldol condensation reaction between aliphatic aldehydes, nitro-chromenes, and α,β-unsaturated aldehydes leads to the formation of synthetically important tricyclic chromanes bearing four contiguous stereogenic centers including a tetrasubstituted carbon in good yields (20−66%) and excellent stereoselectivities (>20:1 dr and >99% ee).
T
chromanes via an organocatalyzed quadruple cascade reaction using 2-((E)-2-nitrovinyl)phenol and α,β-unsaturated aldehydes.6 Later, this strategy was extended for the total synthesis of (+)-conicol by the same research group.7 Recently, the groups of Li8 and Wang9 followed Hong’s protocol and reported the synthesis of tricyclic chromanes via asymmetric domino reactions using 2-hydroxy α,β-unsaturated ketones or 2hydroxyaryl-2-oxobut-3-enoate with α,β-unsaturated aldehydes. Hong’s research group developed an enantioselective organocatalytic domino reaction “on water” for the synthesis of tricyclic chromane scaffolds using 2-hydroxynitrostyrenes and aldehydes.10 Although the previously reported protocols have provided valuable contributions to the medicinal community for the synthesis of highly valuable tricyclic chromane frameworks, some improvements are still required in terms of substrate scope as well as selectivities, and hence, the development of alternate methods is still highly desirable. Recently, 3-nitro-2H-chromenes have attracted much attention due to their frequent application in medicinal chemistry and as valuable building blocks for oxygen-containing natural products.11 In addition, 3-nitro-2H-chromenes are highly reactive substrates and have been widely used as Michael acceptors and dienophiles.12 However, these substrates have been much less explored in asymmetric transformations, especially in the development of domino reactions.13−15 Very recently, Du and co-workers reported a quinine-derived primary amine-catalyzed asymmetric cascade double Michael addition for the synthesis of chromane derivatives (Scheme 1).16 In the past decade, asymmetric domino reactions became a hot research area in modern organic synthesis due to many benefits, such as time and cost effectiveness, avoiding protection/
he chromane skeleton is a privileged structural unit occurring in a variety of important classes of natural products exhibiting a wide range of biological and pharmaceutical properties.1 In particular, the naturally occurring and the synthetic functionalized tricyclic chromanes bearing multiple stereogenic centers have received much interest due to their significant biological activities and structural complexity (Figure 1). For instance, (+)-epiconicol, a marine metabolite isolated
Figure 1. Natural products and synthetic bioactive tricyclic chromane derivatives.
from Aplidium af f. Densum, exhibited anticancer and antibacterial activities,2 whereas (+)-bisabosqual A, a Stachybotrys metabolite, displays antifungal properties.3 (+)-Machaeriol A, isolated from the bark of Machaerium multif lorum, shows antimicrobial and antimalarial activity.1d,e Nabilone, a synthetic molecule, is used as an antiemetic as well as an analgesic for neuropathic pain.4 Over the years, several elegant strategies have been reported for the construction of this privileged skeleton.5 In 2009, Hong et al. reported a well-designed asymmetric synthesis of tricyclic © 2017 American Chemical Society
Received: May 2, 2017 Published: May 23, 2017 3025
DOI: 10.1021/acs.orglett.7b01322 Org. Lett. 2017, 19, 3025−3028
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Organic Letters Table 1. Optimization of the Reaction Conditions.a
Scheme 1. (a) Reported Methods for the Synthesis of Tricyclic Chromane Scaffolds. (b) Asymmetric Synthesis of Functionalized Tricyclic Chromane Scaffolds via a Triple Domino Reaction
deprotection steps as well as the isolation of intermediates.17 Our group has been involved in the development of new asymmetric organocatalytic domino reactions to provide valuable virtually enantiopure molecules.18 To the best of our knowledge, organocatalyzed triple domino reactions using 3-nitro-2Hchromenes have not been explored. Hence, we developed an organocatalyzed triple domino reaction based on a Michael/ Michael/aldol condensation sequence for the asymmetric synthesis of tricyclic chromanes bearing four contiguous stereogenic centers including a tetrasubstituted stereocenter. In order to develop a triple domino sequence, we started our investigation by screening secondary amine organocatalysts 4A− D for the domino Michael/Michael/aldol condensation reaction between nitrochromene 1a, propanal (2a), and cinnamaldehyde (3a) in toluene to provide the chromane product 5a (Table 1). It turned out that (S)-proline (4A) did not provide the desired product (entry 1), whereas an diphenylprolinol (4B) led to the formation of chromane 5a with 8% yield, 10:1 dr, and 85% ee (entry 2). The (S)-TMS-diarylprolinol catalysts 4C and 4D gave 37% and 50% yields of chromane 5a, respectively, with excellent stereoselectivities (>99% ee and >20:1 dr, entries 2 and 4). After we found the best catalyst 4D, we screened different solvents to increase the yield of the product 5a; however, no improvement was observed, whereas the stereoselectivities remained excellent (entries 5−8). When the catalyst loading was decreased to 15 and 10 mol %, the yield of the desired product decreased dramatically, whereas no significant improvement of the yield was observed at a higher catalyst loading of 25 mol % (entries 9− 11). We also examined some additives to further increase the yield of 5a; however, no improvements were observed (entries 12−14). Thus, the best reaction conditions for this domino sequence include 20 mol % of catalyst 4D in toluene at 0 °C to rt. With the optimized reaction conditions in hand, we started to explore the substrate scope of this one-pot triple organocascade sequence. First, we investigated the scope of nitrochromene 1 with aldehyde 2a and enal 3 (Scheme 2). The nitrochromene 1 bearing electron-neutral (H), electron-donating (Me, OMe), or electron-withdrawing groups (F, Cl, Br, NO2) at the C6 or C7
entry
cat. (x mol %)
solvent
yieldb (%)
drc
eed (%)
1 2 3 4 5 6 7 8 9 10 11 12e 13f 14g
4A (20) 4B (20) 4C (20) 4D (20) 4D (20) 4D (20) 4D (20) 4D (20) 4D (10) 4D (15) 4D (25) 4D (20) 4D (20) 4D (20)
toluene toluene toluene toluene CHCl3 CH2Cl2 THF MTBE toluene toluene toluene toluene toluene toluene
trace 8 37 50 36 45 15 22 27 46 48 49 48 47
10:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
85 99 99 99 99 99 99 99 99 99 99 99 99
a
All reactions were carried out with 0.2 mmol of 1a (1 equiv), 0.24 mmol of 2a (1.2 equiv), 0.21 mmol of 3a (1.05 equiv), and 10−25 mol % of the catalyst in the indicated solvent (1.0 mL) at 0 °C to room temperature for 48 h. bYield of isolated product 5a. cDetermined by 1 H NMR analysis of the crude reaction mixture. dThe ee values were determined by HPLC analysis on a chiral stationary phase. eBenzoic acid was used as additive. f2-Fluorobenzoic acid was used as additive. g 4 Å M.S. were used as additive.
position of the 3-nitro-2H-chromene smoothly reacted to form the corresponding tricyclic chromane products 5a−h in good yields with excellent asymmetric inductions. Similar results were obtained with dihalogenated 3-nitro-2H-chromenes at the C6 and C8 positions (5i-k). The nitrochromene-bearing tertiary butyl groups at the C6 and C8 position furnished the desired 5l in good yield with excellent diastereo- and enantioselectivity (>20:1 dr and >99% ee). In contrast, 2-nitro-3H-benzo[f ]chromene afforded the product 5m in only 20% yield with good stereoselectivities (9:1 dr, and 99% ee), whereas 3-nitro-2Hchromene bearing a diethylamino group at the C7 position gave only a trace amount of 5n. To increase the scope of this triple cascade reaction, we replaced the 3-nitro-2H-chromene by 1nitrocyclohex-1-ene, and 2H-chromene-3-carbonitrile showed no reactivity for this protocol.19 Further screening of aldehydes with different groups were investigated. Aliphatic aldehydes 2 bearing ethyl, propyl, and benzyl groups at the R2 position provided the corresponding products in slightly lower yields in comparison to methyl and with excellent stereoselectivities 5o− r. It is noteworthy that isovaleraldehyde and tert-butyl acetaldehyde did not provide the target products even after 5 days. Next, we also screened different α,β-unsaturated aldehydes for this triple domino reaction. An aliphatic α,β-unsaturated aldehyde like acrylaldehyde worked well to provide the desired product 5s in excellent yield (66%) along with >20:1 dr and 3026
DOI: 10.1021/acs.orglett.7b01322 Org. Lett. 2017, 19, 3025−3028
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Organic Letters
and electron-donating groups (OMe) at the ortho and para position of the aryl ring reacted smoothly to furnish the corresponding chromane products 5u−w in moderate to good yields with excellent stereoselectivities. The aromatic enals bearing electron-withdrawing groups (F, Cl, Br) at the para position of the aryl ring provided the desired products 5x−z in slightly lower yield with excellent enantioselectivity (up to >99% ee). To demonstrate the robustness and applicability of asymmetric organocatalytic triple domino reaction, a gram-scale reaction between 1a, 2a, and 3a was conducted under the standard reaction conditions (Scheme 3). The desired tricyclic
Scheme 2. Substrate Scope of the Asymmetric Synthesis of Tricyclic Chromenes 5.a−d
Scheme 3. Gram-Scale Synthesis of Compound 5a
chromane 5a was obtained with 42% yield (0.87 g) and excellent stereoselectivity (>20:1 dr, > 99% ee). Moreover, functionalization of 5a by the reduction with NaBH4 and a Wittig reaction provided the products 6 and 7 with excellent yields and without a change in the stereoselectivities, respectively (Scheme 4). Scheme 4. Transformation of the Triple Cascade Product 5a by Reduction to 6 and Wittig Olefination to 7
The relative and absolute configuration of the triple domino products 5 was determined by X-ray crystal structure analysis of 5a (Figure 2).20
Figure 2. X-ray crystal structure of 5a.
a All reactions were performed with 0.3 mmol of 1 (1.0 equiv), 0.36 mmol of 2 (1.2 equiv), 0.32 mmol of 3 (1.05 equiv), and 20 mol % of catalyst 4D in toluene (2.0 mL) at 0 °C to rt for 24−48 h. bYields of isolated products 5 after column chromatography. cThe diastereomeric ratios were determined by 1H NMR spectroscopy. dThe enantiomeric ratios were determined by HPLC analysis on a chiral stationary phase. e Traces of product after 6 days.
In conclusion, we have developed an asymmetric synthesis of functionalized tricyclic chromane frameworks through an organocatalyzed triple cascade Michael/Michael/aldol condensation sequence. In this protocol, three new bonds and four consecutive stereogenic centers, including a tetrasubstituted one, are generated in good yields with excellent diastereo- and enantioselectivities. We are currently working on the extension of this methodology for the synthesis of heteroterpene natural products.
≤99% ee. Replacing acrylaldehyde by crotonaldehyde delivered a poor yield of 35% of 5t with excellent stereoselectivities. The aromatic α,β-unsaturated aldehydes bearing electron-neutral (H) 3027
DOI: 10.1021/acs.orglett.7b01322 Org. Lett. 2017, 19, 3025−3028
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01322. X-ray data for compound 5a (CIF) Experimental procedures, optimization details, data for all new compounds, and NMR and HPLC spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kari Rissanen: 0000-0002-7282-8419 Dieter Enders: 0000-0001-6956-7222 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the European Research Council (ERC Advanced Grant 320493 “DOMINOCAT”) is gratefully acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01322 Org. Lett. 2017, 19, 3025−3028
