Catalytic Enantioselective Carboannulation with Allylsilanes

Abstract

The first catalytic asymmetric carboannulation with allylsilanes is presented. The enantioselective [3+2] annulation is catalyzed using a Sc(III)-indapybox complex with tetrakis-[3,5-bis(trifluoromethyl)phenyl]-borate (BArF) to enhance catalytic activity and control stereoselectivity. Functionalized cyclopentanes containing a quaternary carbon are derived from alkylidene oxindole, coumarin, and malonate substrates with high stereoselectivity. The enantioselective 1,4-conjugate addition and enantioselective lactone formation (via trapping of the β-silyl carbocation) is also described.Keywords asymmetric catalysis; cyclopentane; NaBArF; scandium; conjugate addition Lewis acid-catalyzed conjugate addition and cyclization reactions of unsaturated carbonyl compounds are important routes for the synthesis of complex heterocycles and carbocycles. Despite significant advances in asymmetric catalysis, [1,2] many conjugate addition and cyclization reactions using unsaturated carbonyl compounds still lack catalytic asymmetric variants. First reported by Knölker in 1990, [3] the cyclopentane annulation of air-and moisture-stable allylsilane nucleophiles with unsaturated carbonyl compounds is a transformation where a catalytic asymmetric variant has eluded development. [4][5][6] The challenge associated with controlling additions to unsaturated carbonyl compounds is highlighted by the fact that only one method has been reported for a catalytic enantioselective conjugate addition reaction using allylsilanes ( Figure 1A). [7] Herein, we report the first catalytic asymmetric annulation of allylsilanes with unsaturated carbonyl compounds ( Figure 1B) to access cyclopentanes possessing up to three stereocenters, including a quaternary carbon spirocenter.The reaction of alkylidene oxindole 1 with allylsilane 2a [8] offers a platform to study the reactivity and selectivity for the annulation reaction (Table 1). The selective formation of a cyclic product (e.g. 4) or an allylation (Hosomi-Sakurai) product (e.g. 5) is determined based on control of the β-silyl-stabilized carbocation intermediate (e.g. 3). [9,10] Selective formation of spirocyclopentane 4, resulting from rearrangement of the β-silyl carbocation intermediate, HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript is a critical component of the successful development of this methodology. Our initial studies with chiral tin(IV), [11] copper(II), [7] and scandium(III)[5a,12] complexes afforded only low selectivity and/or low reactivity for the synthesis of spirocyclopentane 4a (e.g. entries 1-4). [13] To identify a more effective catalyst, we investigated Sc(III)-pybox complexes with NaBArF [BArF = B(3,5-C 6 H 3 (CF 3 ) 2 ) 4 ] ( Table 1, entries 5-9). [14] A significant activating effect was observed for both ScCl 3 -and Sc(OTf) 3 -derived complexes, affording spirocyclopentane 4a [15] with high yield and up to 97:3 enantioselectivity (entries 5 and 6).Using other counterions such as NaSbF 6 and KPF 6 , or additives such as...

Ligand-Accelerated Catalysis in Scandium(III)-Catalyzed Asymmetric Spiroannulation Reactions

“…An initial investigation by our group reported the formation of an NaOTf precipitate, characterized by 19 F NMR spectroscopy and FAAS (Figures S1 and S2). It was also noted that conditions using NaBArF disrupt the formation of an inactive catalyst complex (Figures S4 and S5), both supporting our hypothesis, wherein Sc­(OTf) 2 / L1 /BArF acts as the active catalyst complex. Our initial foray into the structure and mechanism of the scandium-catalyzed asymmetric [3 + 2] annulation reaction highlighted several spectroscopic features indicating the complexity of the system.…”

“…Asymmetric metal catalysis has emerged as an important tool for the development of chiral molecules with high molecular complexity with simple operational one-pot procedures, atom efficiency, and mild reaction conditions. − We have reported the asymmetric scandium­(III)-catalyzed [3 + 2] annulation of alkylidene oxindoles and isatins with allylsilane and allenylsilane nucleophiles. − The scandium­(III)–PyBox/BArF (PyBox: pyridine-2,6-bis­(oxazoline); BArF: tetrakis­[3,5-bis­(trifluoromethyl)­phenyl]­borate) complex is a powerful catalyst system, demonstrating robust activity in a variety transformations and with potential application toward further synthetic applications. − However, our previous studies provided an incomplete picture of the active catalyst complex that we were interested in investigating further. We elected to study the Sc­(OTf) 2 -( R , S )-inda-PyBox ( L1 )/BArF complex using the [3 + 2] annulation reaction of allylsilanes 2a with alkylidene oxindole 1a (Scheme ).…”

Further Developments and Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis

“…Franz has extended this carboannulation methodology to include alkylidene oxindoles 1374 as electrophiles, utilizing a ScCl 3 /( R , S )- 1337 /NaBARF catalytic system, to give the corresponding spirooxindoles 1375 in up to 99% yield and 99% ee ( Scheme 407 ). 487 …”

Catalytic Enantioselective Construction of Spiro Quaternary Carbon Stereocenters

“…For instance, in 2014 Franz and co-workers presented a chiral Sc(III) complex-catalyzed asymmetric [3 + 2] annulation of allylsilanes 149 and methyleneindolinones 18 through a Michael/1,2-silyl shift/cyclization process (Scheme 38). 93 They found that a 10 mol % loading of the chiral PyBOXderived Sc(III) complex generated in situ from (R,S)-indaPyBOX 150, Sc(OTf) 3 , and NaBArF smoothly mediated this annulation and provided an array of functionalized spirooxindolic cyclopentanes 151 in good to excellent yields and selectivities. Notably, the additive NaBArF might play two roles in the annulation process: one is to enhance the catalytic activity by forming a cationic (R,S)-indaPyBOX•Sc-(OTf) 2 BArF complex, and the other is to facilitate the generation of a transient β-silyl carbocation.…”