Formation of Vinyl-, Vinylhalide- or Acyl-Substituted Quaternary Carbon Stereogenic Centers through NHC–Cu-Catalyzed Enantioselective Conjugate Additions of Si-Containing Vinylaluminums to β -Substituted Cyclic Enones

Abstract

A catalytic method for enantioselective conjugate addition (ECA) of Si-containing vinylaluminum reagents to β-substituted cyclopentenones and cyclohexenones is described. Reactions are promoted by 1.0–5.0 mol % of a bidentate NHC–Cu complex, which is prepared from air stable CuCl₂•2H₂O and used in situ, and typically proceed to completion within 15–20 minutes. The requisite vinylmetals are generated efficiently by a site-selective hydroalumination of an alkyne with dibal–H. The desired products, containing a quaternary carbon stereogenic center, are obtained in 48–95% yield after purification and in 89:11 to >98:2 enantiomer ratio (er). The vinylsilane moiety within the products can be functionalized to afford acyl, vinyliodide or desilylated alkenes in 67% to >98% yield and with >90% retention of the alkene's stereochemical identity. The utility of the catalytic process is illustrated in the context of a concise enantioselective synthesis of riccardiphenol B.

Catalytic enantioselective conjugate additions of easily accessible C-based nucleophiles to unsaturated carbonyls faciliates the synthesis of a range of enantiomerically enriched biologically active molecules and are therefore of significant value.¹ Nevertheless, in spite of recent advances,² notable shortcomings persist in this area, particularly in the context of reactions furnishing quaternary carbon stereogenic centers.³ One deficiency relates to the paucity of protocols for catalytic conjugate additions of vinyl units.⁴ A report regarding Cu–phosphine-catalyzed enantioselective conjugate addition (ECA) reactions of vinylaluminums with β-substituted cyclic enones has appeared; however, substrate and reagent scope is narrow and the preparation of the requisite vinylmetals via vinylhalides can be limiting (details below).⁵ We set out to examine whether Cu complexes of N-heterocyclic carbenes (NHCs) can effect ECA of vinylmetals to generate quaternary carbon stereogenic centers.⁶ In this context, use of Si-substituted vinylmetals would be attractive (Scheme 1) for several reasons. First, efficient and stereoselective hydroaluminations of silylacetylenes with inexpensive diisobutyaluminum hydride (dibal–H) afford the requisite vinylaluminums.⁶ Thus, the need for stereoselective synthesis of vinylhalides, only a few of which can be purchased and whose preparation often requires strongly acidic conditions,⁷ would not be necessary. Second, in instances where the vinylmetal is a small molecule, the impracticality of isolation or purification of volatile alkynes or vinylhalides can be avoided. Third, and perhaps most importantly, as illustrated in Scheme 1, efficient synthesis of a variety of enantiomerically enriched products that cannot be directly prepared or, at least, easily synthesized by a catalytic process would become feasible due to the presence of the vinylsilane.

Scheme 1.

Versatility of Catalytic Conjuagte Additions with Si-Substituted Vinylaluminum Reagents

Herein, we report a method for enantioselective conjugate addition of 1-Si-substituted vinylaluminum reagents to five- and six-membered β-substituted cyclic ketones. Reactions are catalyzed by a chiral bidentate NHC–Cu complex derived from air stable and commercially available CuCl₂•2H₂O and afford the desired products in up to 95% yield and >98:2 enantiomeric ratio (er). The resulting enantiomerically enriched vinylsilanes can be protodesilylated, converted to the corresponding vinyl halides, or oxidized to β-acyl-substituted enones in >66% yield. The utility of the NHC–Cu-catalyzed reaction is illustrated through a concise total synthesis⁸ of natural product riccardiphenol B.⁹

From the outset, we appreciated that efficiency of the aforementioned processes would hinge on identification of a chiral catalyst that accomplishes the demanding task of forming the highly congested C–C bond. We were aware that the attendant steric congestion, as well as stabilization of electron density at the Si-bearing carbon might result in diminution of vinylaluminum nucleophilicity to decelerate the vinyl addition process, allowing alternative pathways to become competitive. In the context of Cu-catalyzed allylic substitutions, we had observed that Si-substituted vinylaluminums, although effective in reactions that furnish tertiary C–C bonds, give rise to inefficient and non-selective processes when quaternary carbon stereogenic centers are to be generated.¹⁰ Such concerns were validated in the present studies by the observation that with the NHC–Cu derived from dimeric Ag complex 1 (easily accessed from the imidazolinium salt and Ag₂O)¹¹ and CuCl₂•2H₂O, ECA with β-methylcyclopentenone and vinylsilane 6 delivers 20% of the desired 7a (10:90 er)¹² along with 15% of allylic alcohol 9 (entry 1, Table 1). Reaction efficiency (>98% vs 35% conv) and the preference for transfer of the vinyl unit (85% vs 20%) improve significantly with the sulfonate-bridged complex derived from 2¹³ to afford the β-vinyl ketone in 80:20 er (entry 2, Table 1). Similar efficiency is furnished by the Cu-complex accessed through 3a (entry 3), but enantioselectivity is increased to 90:10 er. Further improvement in efficiency (<2% unidentified products) and selectivity (95% 7a in 93:7 er; 5% 8¹⁴) are attained with 3b, which contains a larger NAr group (entry 4, Table 1). Somewhat surprisingly, NHC–Cu complex derived from 3c, where the size of the NAr is increased further, proves to be substantially less effective (entry 5). As the data in entries 6–7 of Table 1 indicate, ECA with monodentate NHC–Cu complexes, are inefficient, although in one case reasonably selective (17:83 er in entry 6).¹⁵ The relative ineffectiveness of complexes derived from 4 and 5 is in contrast to ECA processes that generate C–B¹⁶ or C–Si¹⁷ bonds, where monodentate NHC–Cu catalysts emerge as optimal. The above findings thus illustrate that, in contrast to allylic substitutions with trisubstituted alkenes,¹⁰ ECA to cyclic enones with Si-substituted vinylaluminums proceed efficiently and with high enantioselectivity in the presence of sulfonate-based NHC–Cu complexes. The precise reason for such reactivity and selectivity difference is unclear, but might be partly due to higher electrophilicity of unsaturated carbonyls (vs allylic phosphates).

Table 1.

Initial Examination of Various Chiral NHC Complexes^a

entry	NHC-Ag; mol %	conv (%)b	7a:8:9b	er (7a)c
1	1; 2.5	35	20:<2:15	10:90
2	2; 2.5	>98	85:<2:15	80:20
3	3a; 2.5	>98	86:05:09	90:10
4	3b; 2.5	>98	95:05:<2	93:7
5	3c; 2.5	70	46:21:03	52:48
6	4; 5.0	31	28:<2:03	17:83
7	5; 5.0	15	04:<2:11	nd

^aReactions performed under N₂ atm.

^bDetermined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures and refers to consumption of the substrate.

^cDetermined by GLC analysis; see the Supporting Information for details.

β-Alkyl-substituted cyclopentenones and a range of alkyl- as well as aryl-substituted 1-trimethylsilyl-vinylaluminums (entries 1–6, Table 2) undergo ECA efficiently (>98% conv in 20 min) and with high enantioselectivity (92.5:7.5–95.5:4.5 er). Reactions with β-substituted cyclohexenones proceed to afford the desired products in up to 98.5:1.5 er (entries 7–12, Table 2). Although there is 4–33% i-Bu addition in transformations shown in Table 2, <2% adventitious 1,2-reduction (cf. 9, Table 1) is detected and pure β-vinyl cycloalkanones are isolated in 50–95% yield. Two additional points regarding the reactions in Table 2 are noteworthy: (1) Cyclopentenones, a particularly challenging substrate class for ECA reactions,¹⁸ generally react more efficiently than cyclohexenones (90:10–95:5 vs 67:33–96:4 vinyl:i-Bu addition). (2) Cu-catalyzed ECA can be performed with lower catalyst loading than used in the studies summarized in Table 2. As an example, with 0.5 mol % 3b and 1.0 mol % CuCl₂•2H₂O, the processes in entries 1 and 8 of Table 2 proceed to >98% conv in 1.5 h (22 °C) to afford products with the same level of enantioselectivity and in 68% and 85% yield, respectively.

Table 2.

Cu–NHC-Catalyzed Enantioselective Conjugate Additions of Si-Substituted Vinylaluminums to β-Substituted Cyclic Enones^a

entry	substrate (R; n)		reagent (R1)	temp (°C); time (min)	vinyl:i-Buaddnb	vinyl prod yield (%)c	erd
1	Me; 1	7a	n-Pr	22; 15	95:5	76	93:7
2	Me; 1	7b	n-Hex	22; 15	91:9	91	94:6
3	Me; 1	7c	(CH2)4Ot-Bu	0; 15	95:5	80	92.5:7.5
4	Me; 1	7d	Ph	22; 15	90:10	75	95:5
5	Me; 1	7e	p-MeOC6H4	22; 20	92:8	67	94:6
6	(CH2)2Ph; 1	7f	n-Hex	22; 15	95:5	95	95.5:4.5
7	Me; 2	10a	n-Hex	0; 20	71:29	64	96:4
8	Me; 2	10b	n-Pr	0; 20	85:15	85	97:3
9	Me; 2	10c	(CH2)4Ot-Bu	0; 20	96:4	85	96:4
10	Me; 2	10d	Ph	0; 20	67:33	50	98.5:1.5
11	Me; 2	10e	p-MeOC6H4	0; 20	78:22	66	98.5:1.5
12	4-hexenyl; 2	10f	n-Pr	0; 20	80:20	63	96:4

^aReactions performed under N₂ atm.

^bDetermined by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures and refers to consumption of the substrate.

^cYields of isolated and purified vinyl addition products.

^dDetermined by GLC analysis; see the Supporting Information for details.

Catalytic additions to cycloheptenones are inefficient (20–40% conv to the vinyl addition product). Relatively large β substituent lead to diminished reaction rates, as demonstrated by the transformation of enone 11 (Scheme 2), affording 12 in 48% yield after purification and 89:11 er. Efficient and highly enantioselective synthesis of 13 (Scheme 2), bearing a gem-dimethyl group at its C2' position, demonstrates that improved selectivity can be achieved with sterically demanding ketones (>98:2 er vs 93:7 er in entry 1, Table 2). As the preparation of 14–15 illustrates, vinylaluminum reagents bearing a more hindered silyl unit (t-BuMe₂Si vs SiMe₃) can be used to access β-vinyl carbonyls efficiently and in high er. Protodesilylation of 14 or 15 (see below for procedure) will generate β-vinyl products that cannot be as easily accessed through the use of the volatile vinyl halide(metal- halogen exchange/reaction with aluminum-halide) or hydroalumination of acetylene.

Scheme 2.

More Variations in Vinylaluminum Reagent and Substrate^a

^aReactions performed under conditions used in Table 1–2, with the noted specifications; conv. (>98% in all cases), yields and selectivity values determined as in Table 1–2. Percent vinyl addition is relative to the i-Bu byproduct and not an absolute value.

The transformations depicted in Scheme 3 highlight the utility of the Si-containing ECA products. Through a two-step procedure that includes site-selective epoxidation of the vinylsilane followed by a rearrangement induced by a mild acid,¹⁹ enone 16 – the product of a hitherto unknown enantioselective acyl anion conjugate addition²⁰ – is obtained in 67% yield. Subjection of 7b to N-iodosuccinimide²¹ delivers enantiomerically enriched vinyl iodide 17, which can be used in catalytic cross-coupling,²² in 91% yield as a 91:9 Z:E mixture. Similar conversion to 18 proceeds in quantitative yield and without detectable loss of alkene stereochemistry (>98% E). Protodesilylation with trifluoroacetic acid is highly effective as well: synthesis of 19–20 in 76% and >98% yield, respectively, are representative.²³

Scheme 3.

Utility of the Enantiomerically Enriched Vinylsilanes

Conditions: (a) 1. 1.5 equiv m-chloroperbenzoic acid, CH₂Cl₂, 0 °C, 3 h; 96%. 2. HCO₂H, 100 °C, 1 h; 70%. (b) 2.6 equiv N-iodosuccinimide, MeCN, 0–22 °C, 12 h. (c) F₃CCO₂H, CHCl₃, 22 °C, 6 h.

The utility of the method is demonstrated through enantioselective synthesis of riccardiphenol B (Scheme 4).²⁴ NHC–Cu-catalyzed reaction of commercially available β-methylcyclohexenone with complex 3b and vinylaluminum 21, conveniently and selectively prepared by hydroalumination of the corresponding enyne, followed by treatment with Ac₂O furnishes enol acetate 22 in 67% overall yield and 98.5:1.5 er. Generation of the corresponding Li-enolate by subjection of 22 to n-BuLi and addition of excess o-quinone methide 23, prepared and used in situ,²⁵ leads to the formation of the derived α-benzyl adduct (>98:2 dr).²⁶ Subsequent ketone alkylation with MeLi affords tertiary carbinol 24 in 70% overall yield. Formation of the tetrasubstituted olefin with SOCl₂ and protodesilylation delivers the target molecule.

Scheme 4.

Application to Enantioselective Synthesis of Riccardiphenol B

Conditions: (a) 1. 2.5 equiv n-BuLi, thf, 0–22 °C, 1.5 h; 10 equiv 23, −78–22 °C, 12 h. 2. 10 equiv MeLi, thf, 0–22 °C, 3 h; 70% overall (2 steps). (b) 1. 10 equiv SOCl₂, pyr, 0–22 °C; 61%. 2. 10 equiv (n-Bu)₄NF, 110 °C, 6 h; 62%.

Development of additional catalytic enantioselective C–C bond forming processes that are promoted by NHC-based chiral catalysts and involve vinylic organometallic reagents as nucleophiles are in progress.