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. 2015 Sep 1;6(9):5164-5171.
doi: 10.1039/c5sc01909e. Epub 2015 Jun 17.

Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system

J Pedroni  1 , T Saget  1 , P A Donets  1 , N Cramer  1
Affiliations

Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system

J Pedroni et al. Chem Sci. .

Abstract

Taddol-based phosphoramidite ligands enable enantioselective palladium(0)-catalyzed C-H arylation of cyclopropanes. The cyclized products are obtained in high yields and enantioselectivities. The reported method provides efficient access to a broad range of synthetically attractive cyclopropyl containing dihydroquinolones and dihydroisoquinolones as well as allows for an efficient enantioselective construction of the 7-membered ring of the cyclopropyl indolobenzazepine core of BMS-791325.

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Figures

Fig. 1
Fig. 1. Marketed drugs and development candidates having an annulated cyclopropyl ring system.
Scheme 1
Scheme 1. Rapid enantioselective assembly of dihydroquinolones and dihydroisoquinolones by Pd0-catalyzed C–H functionalization.
Scheme 2
Scheme 2. Enantioselective dihydroquinolone synthesis.
Scheme 3
Scheme 3. Scope of the enantioselective cyclopropanecarboxamide cyclization. Reaction conditions: 1 (0.10 mmol), Cs2CO3 (0.15 mmol), Pd(dba)2 (2.00 μmol), L2 (4.00 μmol), PivOH (30 μmol), 0.30 M in mesitylene at 130 °C for 12 h. Yields of isolated products 2; er's determined by HPLC with a chiral stationary phase. a [(η3-cinnamyl)Pd(Cp)] instead of Pd(dba)2. b With Cs2CO3 (0.20 mmol), Pd(dba)2 (10.0 μmol), L2 (20.0 μmol), PivOH (50 μmol).
Scheme 4
Scheme 4. Cyclopropane C(sp3)–H activation over arene C(sp2)–H activation in 1f. Conditions: 2.0 mol% [(η3-cinnamyl)Pd(Cp)], 4.0 mol% L2, 0.3 equiv. PivOH (30 μmol), 1.5 equiv. Cs2CO3, mesitylene, 130 °C, 12 h.
Scheme 5
Scheme 5. Enantioselective double C–H arylation process.
Scheme 6
Scheme 6. PMB group cleavage and determination of the absolute configuration.
Scheme 7
Scheme 7. Reports on cyclopropane ring-opening under Pd0/PdII catalysis.
Scheme 8
Scheme 8. Scope of the enantioselective aminocyclopropane cyclization. Reaction conditions: 3 (0.10 mmol), Cs2CO3 (0.15 mmol), Pd(dba)2 (2.50 μmol), L2 (5.00 μmol), AdCO2H (20.0 μmol), 0.25 M in toluene at 110 °C for 12 h. Yields of isolated products 4; er's determined by HPLC with a chiral stationary phase. a With Pd(dba)2 (5.00 μmol) and L2 (10.0 μmol) for 12 h. b 24 h reaction. c With Pd(dba)2 (5.00 μmol) and L2 (10.0 μmol) in mesitylene at 130 °C for 12 h. d 1.0 mmol scale.
Scheme 9
Scheme 9. Removal of the PMB group and X-ray crystal structure of product 4q.
Scheme 10
Scheme 10. A consecutive C–H activation strategy for BMS-791325.
Scheme 11
Scheme 11. Enantioselective synthesis of the BMS-791325 ring system.
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