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DOI: 10.1039/C5CC09581F (Communication) Chem. Commun., 2016, 52, 2609-2611

Asymmetric synthesis of cyclopentanes bearing four contiguous stereocenters via an NHC-catalyzed Michael/Michael/esterification domino reaction†

Tao Shu a, Qijian Ni a, Xiaoxiao Song a, Kun Zhao a, Tianyu Wu a, Rakesh Puttreddy b, Kari Rissanen b and Dieter Enders *a
aInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074, Aachen, Germany. E-mail: enders@rwth-aachen.de
bDepartment of Chemistry, University of Jyväskylä, 40014 Jyväskylä, Finland

Received 19th November 2015 , Accepted 5th January 2016

First published on 5th January 2016

Abstract

An NHC-catalyzed Michael/Michael/esterification domino reaction via homoenolate/enolate intermediates for the asymmetric synthesis of tetrasubstituted cyclopentanes bearing four contiguous stereocenters is described. A variety of α,β-unsaturated aldehydes and 2-nitroallylic acetates react well with good domino yields and high stereoselectivities.

Cyclopentane motifs are privileged scaffolds present as characteristic structural features in a large number of bioactive natural products and pharmaceuticals such as for instance aristeromycin,1 travoprost,2 pactamycin3 and peramivir4 (Fig. 1). However, to develop direct and efficient catalytic methods for the stereocontrolled construction of multi-substituted cyclopentanes is still challenging for organic chemists.5
image file: c5cc09581f-f1.tif
Fig. 1 Representative natural products and pharmaceuticals bearing a cyclopentane core.

Nitroalkenes are among the most useful Michael acceptors due to their versatile reactivity and their inherent capacity to undergo further synthetic transformations of the nitro function into other functional groups.6 NHC-catalyzed cascade reactions have emerged as a powerful tool to construct C–C bonds in organic synthesis7 and NHC-catalyzed reactions with nitroalkenes gained quite some interest in recent years.8 The first NHC-catalyzed homoenolate reaction of enals with nitroalkenes to afford anti δ-nitroesters was reported by Nair and co-workers.9a Later the groups of Liu and Rovis reported complementary asymmetric versions of this reaction affording anti and syn δ-nitroesters, respectively.9b–d Very recently, Wang and co-workers have also developed an NHC-catalyzed reaction of enals with nitroalkenes to prepare enantioenriched dihydrocoumarins.8i

Nitroallylic acetates served as versatile dielectrophiles to assemble relatively complex molecules in a domino fashion.10 Seebach and co-workers developed a [3+3] carbocyclization reaction of 2-nitroallylic acetates and enamines to form bicyclic skeletons with multiple stereocenters using the chiral auxiliary concept under stoichiometric conditions.10a An organocatalytic domino reaction of 2-nitroallylic acetates had not been reported until 2009. Tang and Li et al. developed a pyrrolidine-thiourea catalyzed tandem reaction of 2-nitroallylic acetates and cyclic ketones to construct bicyclic [3.3.1] skeletons with four or five stereocenters in a single operation.10b However, to the best of our knowledge, an NHC-catalyzed cascade reaction employing 2-nitroallylic acetates has not been reported yet. Herein, we describe such an NHC organocatalyzed [3+2]-cycloaddition reaction of enals with (E)-2-nitroallylic acetates to afford enantioenriched tetrasubstituted cyclopentanes with four contiguous stereocenters featuring a nitro and an ester group, which can be used for further transformations.

Initially we investigated the reaction of cinnamaldehyde (1a) and (E)-2-nitroallylic acetate 2a as model substrates catalyzed by the NHC catalysts derived from the pre-catalysts A–F in THF/EtOH using one equivalent of NaOAc as a base. The aminoindanol-based triazolium pre-catalyst B provided the desired cyclopentane product 3a in 30% yield and 78[thin space (1/6-em)]:[thin space (1/6-em)]22 e.r., albeit with a low diastereoselectivity (d.r. 3[thin space (1/6-em)]:[thin space (1/6-em)]1) (Table 1).

Table 1 Optimization of the reaction conditionsa

image file: c5cc09581f-u1.tif
Entry Cat. Solvent Base Yield (%)b d.rc e.r.d
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), NHC catalyst (10 mol%), base (1.0 equiv.), 24 h at rt. b Yield of isolated compound 3a. c d.r. determined by 1H NMR. d The e.r. values were determined by HPLC on a chiral stationary phase. e The reaction was carried out at −5 °C, 48 h. f The reaction was carried out at −15 °C, 96 h. g The reaction was carried out at −10 °C, 60 h.
1 A THF NaOAc <5 — —
2 B THF NaOAc 30 3[thin space (1/6-em)]:[thin space (1/6-em)]1 78[thin space (1/6-em)]:[thin space (1/6-em)]22
3 C THF NaOAc n.r — —
4 D THF NaOAc n.r — —
5 E THF NaOAc 18 6.2[thin space (1/6-em)]:[thin space (1/6-em)]1 63[thin space (1/6-em)]:[thin space (1/6-em)]37
6 F THF NaOAc 26 8[thin space (1/6-em)]:[thin space (1/6-em)]1 40[thin space (1/6-em)]:[thin space (1/6-em)]60
7 B CHCl3 NaOAc 45 3.6[thin space (1/6-em)]:[thin space (1/6-em)]1 85[thin space (1/6-em)]:[thin space (1/6-em)]15
8 B DME NaOAc 36 1.7[thin space (1/6-em)]:[thin space (1/6-em)]1 72[thin space (1/6-em)]:[thin space (1/6-em)]28
9 B CCl4 NaOAc 56 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 82[thin space (1/6-em)]:[thin space (1/6-em)]18
10 B CH2Cl2 NaOAc 30 4.3[thin space (1/6-em)]:[thin space (1/6-em)]1 75[thin space (1/6-em)]:[thin space (1/6-em)]25
11 B TBME NaOAc 30 1.6[thin space (1/6-em)]:[thin space (1/6-em)]1 78[thin space (1/6-em)]:[thin space (1/6-em)]22
12 B Toluene NaOAc 42 1.2[thin space (1/6-em)]:[thin space (1/6-em)]1 81[thin space (1/6-em)]:[thin space (1/6-em)]19
13 B CHCl3 NEt3 45 3.3[thin space (1/6-em)]:[thin space (1/6-em)]1 71[thin space (1/6-em)]:[thin space (1/6-em)]29
14 B CHCl3 DIPEA 40 3[thin space (1/6-em)]:[thin space (1/6-em)]1 75[thin space (1/6-em)]:[thin space (1/6-em)]25
15 B CHCl3 DABCO 26 5[thin space (1/6-em)]:[thin space (1/6-em)]1 70[thin space (1/6-em)]:[thin space (1/6-em)]30
16 B CHCl3 TMEDA 32 3.7[thin space (1/6-em)]:[thin space (1/6-em)]1 69[thin space (1/6-em)]:[thin space (1/6-em)]31
17 B CHCl3 CsOAc 30 1.8[thin space (1/6-em)]:[thin space (1/6-em)]1 68[thin space (1/6-em)]:[thin space (1/6-em)]32
18 B CHCl3 LiOAc 36 2.6[thin space (1/6-em)]:[thin space (1/6-em)]1 74[thin space (1/6-em)]:[thin space (1/6-em)]26
19e B CHCl3 Cs2CO3 20 1.3[thin space (1/6-em)]:[thin space (1/6-em)]1 87[thin space (1/6-em)]:[thin space (1/6-em)]13
20e B CHCl3 K3PO4 49 7.8[thin space (1/6-em)]:[thin space (1/6-em)]1 91[thin space (1/6-em)]:[thin space (1/6-em)]9
21f B CHCl3 K3PO4 40 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 93[thin space (1/6-em)]:[thin space (1/6-em)]7
22g B CHCl3 K3PO4 52 16[thin space (1/6-em)]:[thin space (1/6-em)]1 93[thin space (1/6-em)]:[thin space (1/6-em)]7

After the screening of the solvents, CHCl3 turned out to be the best solvent, affording 3a in a good domino yield of 45%, a d.r. of 3.6[thin space (1/6-em)]:[thin space (1/6-em)]1 and an e.r. of 85[thin space (1/6-em)]:[thin space (1/6-em)]15 (entry 7). The reaction proceeded well with different bases (entries 13–20). Using strong organic bases such as DBU or DMAP resulted in complex mixtures without any starting material remained and no desired product could be detected. We also screened some Lewis acid additives such as Mg(OtBu)2, Ti(OiPr)4 and Sc(OTf)3 and also MgSO4 as well as 4 Å molecular sieves, but no better result was obtained. Lowering the reaction temperature improved the d.r. and e.r., but the reaction time was extended. The reaction proceeded well at −5 °C (49% yield, 7.8[thin space (1/6-em)]:[thin space (1/6-em)]1 d.r, 91[thin space (1/6-em)]:[thin space (1/6-em)]9 e.r) in 48 h, −15 °C (40% yield, >20[thin space (1/6-em)]:[thin space (1/6-em)]1 d.r., 93[thin space (1/6-em)]:[thin space (1/6-em)]7 e.r.) in 96 h with starting material left and −10 °C (52% yield, 16[thin space (1/6-em)]:[thin space (1/6-em)]1 d.r., 93[thin space (1/6-em)]:[thin space (1/6-em)]7 e.r.) in 60 h. Lowering the loading of the base gave inferior results. Finally, we chose pre-catalyst B, CHCl3[thin space (1/6-em)]:[thin space (1/6-em)]EtOH (10[thin space (1/6-em)]:[thin space (1/6-em)]1), K3PO4 (100 mol%) at −10 °C as the optimized condition for our reaction (entry 22).

With the optimized conditions in hand, we next evaluated the substrate scope with respect to the enals and 2-nitroallylic acetates. With different substituted cinnamaldehydes, heterocyclic enals or (E)-2-nitroallylic acetates, the reaction proceeded well, affording the desired products in good domino yields (18–55%) and enantiomeric ratios (86[thin space (1/6-em)]:[thin space (1/6-em)]14–98[thin space (1/6-em)]:[thin space (1/6-em)]2) (Scheme 1).


image file: c5cc09581f-s1.tif
Scheme 1 Substrate scope. All reactions were performed on a 0.5 mmol scale. The yields of the isolated products are after column chromatography. The diastereomeric ratios were determined by 1H NMR spectroscopy and the e.r. values by HPLC on a chiral stationary phase.

The absolute configuration was unambiguously determined by X-ray crystal structure analysis of compound 3h and all other cyclopentane products were assigned by analogy (Fig. 2).


image file: c5cc09581f-f2.tif
Fig. 2 Absolute configuration of 3h determined by X-ray structural analysis.11

A plausible mechanism for the NHC-catalyzed [3+2] Michael/Michael/esterification cascade is shown in Scheme 2. The reaction proceeds via an extended Breslow intermediate, which as a homoenolate I undergoes a first Michael addition to the nitroallylic acetates 2, followed by the elimination of the acetyl group from the adduct II to generate the second Michael acceptor intermediate III for the intramolecular Michael addition. The resulting acylazolium intermediate IV undergoes an ethanolysis with external ethanol to afford the cyclopentane esters 3 and returns the NHC catalyst for further cycles.


image file: c5cc09581f-s2.tif
Scheme 2 Proposed catalytic cycle.

In conclusion, we have developed a concise protocol for the NHC-catalyzed direct construction of functionalized cyclopentanes bearing four contiguous stereocenters in one single operation with good domino yields and stereoselectivities. A range of functional groups and substituents are tolerated by variation of the enal and nitroallylic acetate substrates. In the novel one-pot protocol two C–C bonds via Michael addition and one C–O bond through a terminating ethanolysis step are formed.

We thank the European Research Council (ERC Advanced Grant 320493 “DOMINOCAT”) for financial support and the BASF SE for the donation of chemicals.

Notes and references

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  11. CCDC 1437686.

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization date (NMR, IR, MS, HPLC). CCDC 1437686. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc09581f
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