Asymmetric Syntheses of (Z)- or (E)-β,γ-Unsaturated Ketones via Silane-Controlled Enantiodivergent Catalysis

Abstract

Cu-catalyzed highly stereoselective and enantiodivergent syntheses of (Z)- or (E)-β,γ-unsaturated ketones from 1,3-butadienyl silanes are developed. The nature of the silyl group of the dienes has a significant impact on the stereo- and enantioselectivity of the reactions. Under the developed catalytic systems, the reactions of acyl fluorides with phenyldiemthylsilyl-substituted 1,3-diene gave (Z)-β,γ-unsaturated ketones bearing an α-tertiary stereogenic center with excellent enantioselectivities and high Z-selectivities, where the reactions with triisopropylsilyl-substituted 1,3-butadiene formed (E)-β,γ-unsaturated ketones with high optical purities and excellent E-selectivities. The products generated from the reactions contain three functional groups with orthogonal chemical reactivities, which can undergo a variety of transformations to afford synthetically valuable intermediates.

Graphical Abstract

INTRODUCTION

Enantioenriched small molecules with multiple functional groups are valuable intermediates in synthetic organic chemistry.¹ In this context, chiral nonracemic, acyclic β,γ-unsaturated ketones with an α-tertiary stereocenter (e.g., A in Scheme 1) are of great importance. Such entities are common scaffolds in bioactive natural products,^2,3 and more importantly, the functional groups embedded in these molecules provide useful handles for further derivatization.⁴ However, several challenges exist for asymmetric syntheses of chiral nonracemic acyclic β,γ-unsaturated ketones A.⁵ For classic base-mediated enolate alkylation chemistry, Enders’ SAMP/RAMP chiral auxiliary-assisted ketone α-alkylation for instance, the enolate geometry and the π-facial selectivity of the alkylation will dictate stereochemical outcomes of the C–C bond formation event.⁶ In the cases of ketones B and C, regioselective formation of stereodefined enolates is challenging when R is an alkyl group with hydrogen atom(s) α to the carbonyl group.⁷ Moreover, the α-tertiary stereocenter in A is prone to epimerization via enolization under basic conditions typically required for the enolate generation. Modern Pd-catalyzed cross-coupling chemistry has seen much success in ketone α-vinylation that forms a quaternary stereocenter at the α-position.⁸ However, an analogous process to generate enantioenriched acyclic ketones with an α-tertiary stereocenter has yet to be accomplished, likely owing to the similar epimerization issue. Moreover, in contrast to the carbonyl compounds bearing an α-quaternary stereocenter, the alkene group in ketones A could undergo isomerization to form thermodynamically more stable α,β-unsaturated ketones and abolish the stereogenic center at the α-position in A.

Scheme 1.

Methods for Enantioselective Syntheses of β,γ-Unsaturated Ketones with an α-Tertiary Stereocenter

Not surprisingly, the development of novel methods that can overcome these challenges and permit the access to enantioenriched acyclic β,γ-unsaturated ketones has attracted significant attention from the organic synthesis community. In the past 10 years, several approaches have been disclosed for asymmetric syntheses of such ketones.^9,10 As shown in Scheme 1, Fu and co-workers developed an elegant Ni-catalyzed enantioconvergent cross-coupling of racemic α-bromoketone D with E-alkenylzirconium reagent E to generate β,γ-unsaturated ketone A with high enantioselectivity.^9a,b By taking advantage of the single-electron transfer processes in electrochemistry, the Meggers group showed that enantioenriched ketone A can be synthesized via nucleophilic α-alkenylation of 2-acyl imidazole F with potassium alkenyl trifluoroborate G.^9c More recently, Sawamura and co-workers reported a copper-catalyzed asymmetric acylation of allylic phosphate I with acylsilane H to generate β,γ-unsaturated ketone A under photochemical conditions.^9d In spite of these important achievements, methods that could allow for rapid construction of such enantioenriched ketones with the flexibility of controlling the alkene geometry would be valuable.

As our continuing research interest in asymmetric catalysis, we report herein Cu-catalyzed enantiodivergent syntheses of acyclic (E)- or (Z)-β,γ-unsaturated ketones with an α-tertiary stereocenter from 1,3-butadienyl silanes and acyl fluorides (Scheme 1).¹¹ We discovered that, with an appropriate silyl group in place, either Z- or E-isomers can be synthesized with high stereo- and enantioselectivities via distinct α-silyl-allylic copper intermediates. Intriguingly, the absolute configuration of the α-tertiary stereocenter in the Z-isomers is opposite to the one in the E-isomers using the same (R,R)-Ph-BPE ligand. The products generated from the reactions contain three functional groups, a ketone, a vinyl silane, and an alkyl boronate, which have orthogonal chemical reactivities. Chemoselective transformations of these functional groups provide a variety of valuable intermediates for organic synthesis.

RESULTS AND DISCUSSION

Reaction Development.

We began our studies by identifying a suitable catalytic system to synthesize β,γ-unsaturated ketone using diene 1a and benzoyl fluoride as the model substrates.¹² As shown in Table 1, initial experiments were conducted with Cu(CH₃CN)₄PF₆ as the precatalyst and NaO^tBu as the base. The reaction did not occur without the ligand (entry 1). In the presence of 12 mol % of Cu(CH₃CN)₄PF₆, 10 mol % of Xantphos, and 1.5 equiv of B₂pin₂ and NaO^tBu, the reaction of diene 1a with PhCOF proceeded in Et₂O at ambient temperature to give racemic product 3aa in 76% yield with excellent E-selectivity (entry 2). When Xantphos was replaced by a chiral, nonracemic bidentate phosphine ligand (R)-SegPhos, ketones ent-3aa and 2a were obtained in 74% combined yield and 4:1 E-selectivity with 36% ee for ketone 2a (entry 3). The reaction with (+)-DuanPhos as the ligand gave ent-3aa and 2a in a similar yield and E-selectivity (83% combined, 4:1) with poor enantioselectivity for 2a (14% ee, entry 4). In the presence of ligand (S,S)-QuinoxP, the reaction generated ent-3aa and 2a in 69% combined yield with 2:1 E-selectivity, although in this case, respectable enantiomeric excess (65% ee) was observed for ketone 2a (entry 5). The reaction conducted with (R,R)-Ph-BPE as the ligand, intriguingly, afforded a 7:1 mixture of ketones 2a and ent-3aa, favoring Z-isomer 2a. More importantly, excellent enantiomeric excess was observed for 2a (99% ee, entry 6). Encouraged by the results, we further explored the reaction parameters aiming to improve the Z-selectivity of the reaction. Examining the experiments with several solvents revealed that the Z-selectivity is not sensitive to the reaction media (6–7:1), while there is some degree of variation in enantioselectivities (92–98% ee for 2a, entries 7–11). In the case with THF as the solvent, a significant amount of t-butyl benzoate was obtained from the reaction of PhCOF with NaO^tBu, and 2a was isolated only in 29% yield (entry 7). Varying the copper precatalyst and the base did not improve the Z-selectivity of the reaction either (data not shown). Gratifyingly, when (R,R)-ⁱPr-Duphos was utilized as the ligand, product 2a was obtained in 81% yield with >20:1 Z-selectivity and 99% ee (entry 12). The catalyst loadings can be decreased to 5 or 2.5 mol %, and ketone 2a with an epimerizable α-tertiary stereocenter was isolated in similar levels of yields, Z-selectivities, and enantioselectivities under these conditions.

Table 1.

Evaluation of Reaction Conditions^a

^aReaction conditions: diene 1a (0.1 mmol, 1.0 equiv), Cu(CH₃CN)₄PF₆ (10 mol %), ligand (12 mol %), B₂pin₂ (1.5 equiv), NaO^tBu (1.5 equiv), PhCOF (1.5 equiv), Et₂O (1.5 mL), rt.

^bThe Z/E-selectivities were determined by ¹H NMR analysis of the crude reaction products.

^cYields of isolated products are listed (2a and ent-3aa combined).

^dEnantioselectivities were determined by HPLC analysis using a chiral stationary phase.

To investigate whether the nature of the silyl group has any impact on the E/Z-selectivity and enantioselectivity of the reaction, we synthesized a variety of 1,3-dienes 1b-g with different silyl groups¹³ and conducted the reactions under the standard conditions with (R,R)-Ph-BPE as the ligand. As shown in Table 2, the reaction with Me₃Si-substituted diene 1b formed Z-isomer 2 as the major product (Z:E = 6:1) with 90% ee (entry 2). Poor E/Z-selectivities were observed for MePh₂Si-, Et₃Si-, or ^tBuMe₂Si-substituted diene 1c, 1d, or 1e (entries 3–5). While the optical purities of Z-products 2 are high in these reactions (94–98% ee), the enantiomeric excesses of the E-isomers ent-3 are moderate (68–86% ee). Unexpectedly, when the reactions were conducted with Ph₂^tBuSi- or ⁱPr₃Si-substituted diene, 1f or 1g, excellent E-selectivities (>20:1) were observed, and formation of the Z-isomers was not detected (entries 6–7). In the case of ⁱPr₃Si-substituted diene 1g, the enantioselectivity of the E-product was 96% ee (entry 7). Slightly lower enantioselectivity (90% ee) was observed for the reaction with diene 1f (entry 6). It is worth mentioning that, under an identical catalytic system with (R,R)-Ph-BPE as the ligand, the absolute configuration of the α-tertiary stereocenter in the Z-isomer 2 (entry 6; Table 1) is opposite to that in the E-isomer ent-3 (entries 6 and 7; Table 2), although the Z-selectivity can be further improved by employing (R,R)-ⁱPr-Duphos as the ligand (entry 12; Table 1).

Table 2.

Evaluation of the Impact of the Silyl Group of Diene 1 on the Selectivities of the Reaction^a

entry	[Si]	Z/Eb	yield (%)c	ee (2) (%)d	ee (ent-3) (%)d
1	SiMe2Ph (1a)	7:1	90	99	ND
2	SiMe3 (1b)	6:1	73	90	ND
3	SiMePh2 (1c)	3:1	89	95	68
4	SiEt3 (1d)	1:1	75	94	71
5	SiMe2tBu (1e)	1:2	83	98	86
6	SiPh2tBu (1f)	1:>20	82	ND	90
7	SiiPr3 (1g)	1:>20	93	ND	96

^aReaction conditions: diene 1 (0.1 mmol, 1.0 equiv), Cu(CH₃CN)₄PF₆ (2.5 mol %), (R,R)-Ph-BPE (3 mol %), B₂pin₂ (1.5 equiv), NaO^tBu (1.5 equiv), PhCOF (1.5 equiv), Et₂O (1.5 mL), rt.

^bThe Z/E-selectivities were determined by ¹H NMR analysis of the crude reaction products.

^cYields of isolated products are listed (2 and ent-3 combined).

^dEnantioselectivities were determined by HPLC analysis using a chiral stationary phase.

Substrate Scope.

Scheme 2 summarizes the scope of acyl fluorides that participated in the reactions with dienes 1 under the optimized conditions. For diene 1a, (R,R)-ⁱPr-Duphos was employed as the ligand, and in the case of diene 1g, ligand (S,S)-Ph-BPE was utilized. In general, the reactions worked well with a broad range of acyl fluorides, including aromatic, heteroaromatic, and aliphatic acyl fluorides to generate ketones 2 or 3 in good yields with high enantioselectivities. For instance, reactions of 1a with para-substituted benzoyl fluorides gave products 2b–d in 82–90% yields with 99% ee and excellent Z-selectivities (>20:1). In the case of 2e, the Z-selectivity is moderate, although the enantiomeric excess remains high (99% ee). Reactions of benzoyl fluorides bearing a substituent at either the meta- or ortho-position proceeded smoothly to furnish ketones 2f-h in 81–84% yields with 99% ee and 9–20:1 Z-selectivities. The reaction tolerates alkenes with various substitution patterns, affording ketones 2i-k in 61–90% yields with 98–99% ee and >20:1 Z-selectivities. Benzoyl fluoride with a cyclic acetal is also a suitable substrate for the reaction, and ketone 2l was isolated in 84% yields with 99% ee and >20:1 Z-selectivity. Acyl fluorides containing a heterocycle such as an indole, benzothiophene, furan, or thiophene reacted under the standard conditions to generate products 2m-p in 70–84% yields with 98–99% ee and high Z-selectivities. The reaction with an α,β-unsaturated acyl fluoride gave ketone 2q in 75% yield with 99% ee and >20:1 Z-selectivity. Importantly, a variety of aliphatic acyl fluorides participated in the reactions to deliver products 2r-t with 99% ee and excellent Z-selectivities, albeit in moderate yields (51–68%). The absolute configuration of the tertiary stereocenter was assigned by modified Mosher ester analysis of the diol derivatives and coupling constant analysis of the acetonides derived from the diols (c.f., compounds 13 and 15; Scheme 4).¹⁴ The scope of acyl fluorides that reacted with diene 1g in the presence of ligand (S,S)-Ph-BPE was explored next. As shown in the bottom panel of Scheme 2, a range of acyl fluorides reacted with diene 1g to give ketones 3a-l in 67–94% yields with 84–96% ee. Although, in general, the enantioselectivity in this series is not as high as those from the reactions with diene 1a, the stereoselectivity remains excellent (>20:1 E-selectivities in all cases).

Scheme 2. Scope of Acyl Fluorides in Reactions with Dienes 1^a–d.

^aReaction conditions: dienylsilane 1 (0.1 mmol, 1.0 equiv), Cu(CH₃N)₄PF₆ (5 mol %), ligand (6 mol %), B₂pin₂ (1.5 equiv), NaO^tBu (1.5 equiv), acyl fluoride (1.5 equiv), Et₂O (1.5 mL), rt, 0.5–3 h. Reactions with a 2.5 mol % catalyst and 3 mol % ligand loadings gave products with similar levels of yields, E/Z-selectivities, and enantioselectivities. ^bThe E/Z-selectivities were determined by ¹H NMR analysis of the crude reaction mixture. ^cYields of isolated products are listed. ^d Enantiomeric excesses were determined by HPLC analysis using a chiral stationary phase. ^eB₂pin₂ (1.05 equiv) was used.

Scheme 4.

Transformation of Reaction Products from Diene 1a

Reactions with Complex Molecule-Derived Acyl Fluorides.

To probe whether the reaction can be applied to more complex systems, we prepared several acyl fluorides 4–6 derived from lithocholic acid, (S)-naproxen, and indomethacin.¹⁵ As shown in Scheme 3, the reaction of acyl fluoride 6 with diene 1a utilizing (R,R)-ⁱPr-Duphos as the ligand gave ketone 7 in 53% yield with 98% ee and 7:1 Z-selectivity. The reactions between acyl fluoride 4 and diene 1a with either (R,R)-ⁱPr-Duphos or (S,S)-ⁱPr-Duphos as the ligand gave ketones 8a-b in 62–83% yields and excellent diastereoselectivities. A slightly lower Z-selectivity (18:1) was observed in the case of 8a. Similar results were achieved in reactions with diene 1g, furnishing ketones 8c-d in 83–89% yields with excellent diastereoselectivities and E-selectivities. For (S)-naproxen-derived acyl fluoride 5 with an epimerizable tertiary stereocenter, reactions with diene 1a were conducted with CuOAc as the precatalyst to achieve higher conversions. Ketone products 9a-b were isolated in 72–74% yields with >20:1 Z-selectivities and diastereoselectivities. The reaction with diene 1g employing (S,S)-Ph-BPE as the ligand gave ketone 9c in 76% yield with 10:1 diastereoselectivity and >20:1 E-selectivity. A synthetically useful diastereoselectivity (6:1) and E-selectivity (12:1) were observed when the reaction was conducted with (R,R)-Ph-BPE as the ligand, affording 9d as the major product (84% combined yield). These data indicate that reactions with complex molecule-derived acyl fluorides proceeded under the catalyst control with good to excellent diastereoselectivities. Notably, the mild conditions tolerate racemizable acyl fluorides such as 5, and the results from these diastereoselective reactions bode well for further synthetic applications of this method.

Scheme 3. Reactions with Complex Molecule-Derived Acyl Fluorides^a–d.

^aReaction conditions: dienylsilane 1 (0.10 mmol, 1.0 equiv), [Cu] catalyst (5 mol %), ligand (6 mol %), B₂pin₂ (1.5 equiv), NaO^tBu (1.5 equiv), acyl fluoride (1.5 equiv), Et₂O (1.5 mL), rt. ^bThe E/Z-selectivities and diastereoselectivities were determined by ¹H NMR analysis of the crude reaction mixture. ^cYields of isolated products are listed. ^dEnantiomeric excess of 7 was determined by HPLC analysis using a chiral stationary phase.

Product Derivatization.

Ketone products 2 generated from the reactions with diene 1a contain three functional groups, ketone, alkyl boronate, and Z-alkenyl silane, which can undergo a variety of chemoselective transformations to afford synthetically valuable building blocks. As shown in Scheme 4, oxidation of the alkyl boronate group of 2a with NaBO₃ gave keto-alcohol 10 in 92% yield. Chelation-controlled vinyl Grignard addition to 10 afforded tertiary alcohol 11 in 59% yield with 6:1 diastereoselectivity.¹⁶ The stereochemistry of 11 was assigned by nOe analyses of acetonide derivative 12. Treatment of 10 sequentially with NaH, TiCl₄, and LiBH₄ provided diol 13 in 87% yield with >20:1 diastereoselectivity.¹⁷ Alternatively, direct reduction of 10 with NaBH₄ gave diol 13 in 90% yield with 12:1 diastereoselectivity.¹⁸ The primary hydroxyl group of diol 13 was selectively converted into an azide group, and product 14 was isolated in 74% yield by using a two-step reaction sequence. Diol 13 was transformed into acetonide 15 under the standard conditions. The coupling constant analyses established the anti-relative stereochemistry of 13.¹⁹ Tosylation of diol 13 occurred selectively at the primary hydroxyl group to give 16 in 80% yield. Treatment of tosylate 16 with BuLi formed oxetane 17 in 54% yield.²⁰ Mesylation of both hydroxyl groups of diol 13 gave product 18 in 86% yield. Exposure of bismesylate 18 to BnNH₂ at 100 °C gave azetidine 19 in 63% yield.²¹ The Bpin group in ketones 2 also offers a handle for product derivatization. For instance, reduction of the carbonyl group of 2a followed by protection of the resulting alcohol gave TBS-ether 20a in 59% yield with a 13:1 dr. Amination of the Bpin group using the protocol developed by the Morken group furnished product 21 in 78% yield.²² By adopting the method developed by the Aggarwal group,²³ the Bpin group was converted into a furyl group, and product 22 was isolated in 76% yield. Similarly, ketone 2a was converted into TES-ether 20b in 61% yield. Subsequent vinylation of the Bpin group afforded product 23 in 87% yield.²⁴

Scheme 5 summarizes the transformations of ketone products 3 generated from diene 1g. Ketone 3a was transformed into a TBS-ether using the same reduction–protection reaction sequence, affording 24 in 58% yield and 17:1 dr. Amination, arylation, or vinylation of the Bpin group of 24 delivered products 25–27 in 64–85% yields. The alkyl boronate group of 3a also underwent oxidation with NaBO₃ to give keto-alcohol 28 in 84% yield. Reduction of the carbonyl group of 28 with NaBH₄ formed diol 29 in 94% yield with 20:1 diastereoselectivity. The anti-relative stereochemistry of 29 was confirmed by coupling constant analyses of acetonide derivative 30. Tosylation of the primary alcohol of diol 29 and base-mediated cyclization afforded oxetane 31 in 63% yield. Diol 29 was converted into azetidine 32 in 52% yield using a mesylation–cyclization reaction sequence. Additionally, the vinyl silane group of diol 29 can also participate in reactions to construct a C–C bond. Protection of diol 29 under the standard conditions gave silyl ether 33. Treatment of 33 with NIS and 2,6-lutidine furnished vinyl iodide 34 in 81% yield.²⁵ Pd-catalyzed Stille coupling of 34 with E-vinyl stannane 35 generated E,E-1,3-diene 36 in 87% yield.²⁶ Such a diene is a common structural motif in numerous natural products, for instance, mollipilin D, mycinolide IV, and aldgamycin O (Figure 1).²⁷ Vinyl iodide 34 also reacted with Z-vinylstannane 37 to afford E,Z-diene 38 in 84% yield. Sonogashira coupling of 34 with ethyl propiolate 39 occurred to deliver enyne 40 in 77% yield.²⁸ These derivatization studies (Schemes 4 and 5) highlight the synthetic utilities of ketones 2 and 3 as these reactions provide a variety of highly valuable building blocks for organic synthesis.

Scheme 5.

Product Derivatization

Figure 1.

Selected natural products.

Alkene Isomerization Studies.

As shown in Scheme 2, the enantiopurities of ketone 3 with an E-alkene group are not as high as ketone 2 with a Z-alkene. One factor might contribute to such a discrepancy is the potential racemization of ketone 3 under the reaction conditions owing to the acidity of the allylic hydrogen in 3. As shown in Scheme 6, for ketone 2 with a Z-alkene unit, the allylic hydrogen (highlighted in red in compound 2; Scheme 6) should occupy an eclipse position with the SiMe₂Ph group to minimize the A^1,3 allylic strain.²⁹ Such a spatial arrangement would only permit the C–H bond to be perpendicular to the carbonyl group, which is stereoelectronically required for the deprotonation event as shown by Evans et al. in their pioneering studies.³⁰ Consequently, the pKa of the allylic hydrogen in 2 should be close to the pKa of an hydrogen at the α-position of a simple ketone. Therefore, deprotonation–enolization of 2 is likely prevented under the reaction conditions. By contrast, for ketone 3 with an E-alkene group, the lack of A^1,3 allylic strain would allow the allylic hydrogen (highlighted in blue in compound 3; Scheme 6) to orient orthogonally to both π-systems of the carbonyl and the alkene groups, which enforces the overlap between the σ-orbital of the scissile C–H bond and both π*-orbitals of the carbonyl and E-alkene groups. Such a stereoelectronic alignment will substantially increase the acidity of the allylic hydrogen of 3. Therefore, slow racemization could occur to erode the enantiopurity of 3 under basic reaction conditions (NaO^tBu).

Scheme 6.

Alkene Isomerization Approach to Highly Enantioenriched α-Tertiary (E)-β,γ-Unsaturated Ketones

To obtain ketone 3 with high optical purity, conditions that could prevent deprotonation–enolization would be desirable. While we were not able to perform the reaction under neutral conditions, we were intrigued whether it is possible to isomerize the Z-alkene of ketone 2 to an E-alkene using a transition metal complex. The conditions for alkene isomerization are typically neutral, which should prevent product racemization. To validate this hypothesis, we conducted alkene isomerization with ketone 10 first. Upon exposure of 10 (99% ee) to the Pd-complex, [Pd(μ-Br)^tBu₃P]₂, in 1:1 mixture of DCE and toluene for 2 h, ketone 41 with an E-alkene was isolated in 97% yield and >50:1 E-selectivity and, remarkably, with 96% ee (Scheme 6).³¹ We also performed isomerization studies with ketones 2c (99% ee) and 2i (98% ee), which contain an aryl bromide or an alkene group that may not be compatible with the Pd complex. To our satisfaction, products 42 and 43 were obtained in 84–96% yields and >50:1 E-selectivity with minimum loss of enantiomeric purities (94–95% ee). To test whether racemization could occur under basic conditions to erode the optical purities of ketones 2 and 3, we subjected ketones 2c (Z-alkene, 99% ee) and 43 (E-alkene, 95% ee) separately to the reaction conditions shown in Scheme 2. After 2 h, the recovered ketone 43 suffered a substantial loss of enantiopurity (84% ee), while the ee of ketone 2c remained the same (even after 12 h). This observation provides the support for our analyses of different acidities of allylic hydrogen of ketones 2 and 3. Slow racemization of ketones 3 under basic reaction conditions is likely the origin of lower enantioselectivities of ketones 3. This issue can be solved through alkene isomerization of ketones 2 to access highly enantioenriched ketones with an E-alkene unit.

Mechanistic Analyses.

While the mechanism of Cu-catalyzed alkene addition with boron reagents has been well established, the stereochemical outcomes and enantiodivergence we observed are worthy of commenting.³² One of the elementary steps in the Cu-catalyzed reaction with 1a is the diene addition with the ligand-bound copper complex, L*Cu-Bpin, generated from Cu(CH₃CN)₄PF₆, (R,R)-Ph-BPE, B₂pin₂, and NaO^tBu. It has been shown that a bidentate phosphine-ligated Cu-Bpin complex reacted with 1,3-dienes in a 1,2-addition manner.³³ Therefore, it is anticipated that the initially generated Cu-complex from diene addition should be 44 (Scheme 7) where the (R,R)-Ph-BPE-ligated Cu-Bpin complex adds to the terminal alkene group of diene 1a. Owing to facile and reversible 1,3-metallo shifts of allylcopper species,³⁴ complex 44 should equilibrate with ¹η-allylcopper species 45, 46, and 47 or ³η-allylcopper species (structures not shown).³⁵ Reactions of allylcopper with aldehydes are known to proceed by way of a cyclic, Zimmerman–Traxler transition state.^34,36 It is therefore reasonable to assume that an analogous chair-like transition state is operable for the reactions of allylcopper with acyl fluorides. The structural features of product 2 indicate that α-silyl allylcopper 45 and/or 47 should be the reactive intermediates as a ketone product with a vinyl silane unit will be generated through the allyl addition from these two copper species via a chair-like transition state.³⁷ As shown in Scheme 7, the addition of 45 to the si face of the acyl fluoride via transition state TS-1 forms ketone 2. The competing transition state TS-2 via re face addition gives ketone 48. The reaction of allylcopper 47 with the acyl fluoride should proceed via TS-3 preferentially through minimization of A,^1,3 allylic strain to deliver ketone 48 as well.²⁹ Transition state TS-1 leading to ketone 2 is favored likely owing to the pseudoaxial orientation of the SiMe₂Ph group to minimize the steric interaction. In comparison, the competing transition states TS-2 and TS-3 suffer from the nonbonding steric interactions between the pseudo-equatorially positioned SiMe₂Ph group and the ligand on copper (shown with red arrows in TS-2 and TS-3) and therefore are disfavored. In addition, the exceptional optical purities (98–99% ee) of ketones 2 indicate that the borocupration step that forms the allylic copper 44 intermediate is highly enantioselective because the optical purity of copper species 45 (derived from 44) dictates the enantiomeric excess of ketones 2 as the reactions of 45 with acyl fluorides proceed with a chirality transfer process.

Scheme 7.

Reaction Pathway Analyses of Dienylsilane 1a

In the case of ⁱPr₃Si-substituted diene 1g with the same (R,R)-Ph-BPE as the ligand, products ent-3 with an E-alkene unit are formed. Assuming that the reactions also proceeded through a chair-like transition state,³⁴ the E-alkene group in ent-3 indicates that the ⁱPr₃Si group occupies a pseudoequatorial position in the reaction transition state. For the two potentially reactive intermediates, α-silyl allylcopper 49 and 50, the reaction of 49 with benzoyl fluoride via transition state TS-4 gives E-product ent-3a (Scheme 8). By contrast, the reaction of 49 via transition state TS-5 leads to Z-product 51, which is not a favorable reaction pathway as the formation of any Z-product was not detected. Meanwhile, the reaction of Z-α-silyl-allylcopper 50 with benzoyl fluoride also produces E-isomer ent-3a via transition state TS-6. To discern which allylic copper species, 49 or 50,³⁸ is involved in the reaction, or if both intermediates are involved, we compared the energies of transition states TS-4, TS-5, and TS-6 using computation studies. The density functional theory (DFT) studies were performed at the ωB97xd/6-31G* density functional level of theory for structure optimization and energy calculation. As shown in Scheme 8, the results from computation studies suggest that TS-6, the reaction transition state of Z-allylcopper intermediate 50 with benzoyl fluoride, has the lowest energy. Transition state TS-4, which features allyl addition to benzoyl fluoride with E-allylcopper intermediate 50, is 1.8 kcal/mol higher in energy than TS-6. Although transition state TS-4 also leads to the formation of the same product ent-3a as TS-6, it is deemed to be a minor reaction pathway at most. Meanwhile, the addition to benzoyl fluoride with E-allylcopper 50 via TS-5, which leads to Z-isomer 51, has the highest activation barrier (ΔΔG^≠ = 2.6 kcal/mol). Such an energy difference is in good accord with the observed experimental data where the formation of any Z-isomer was not detected in reactions using diene 1g.

Scheme 8.

Reaction Pathway Analyses of Dienylsilane 1g

Based on these data, we propose that the initial addition of the L*Cu-Bpin complex to diene 1 forms a γ-silyl allylic copper intermediate (e.g., 44; Scheme 7). This step generates a stereogenic center α to the Cu, and it is the enantiodetermining step. However, this initial adduct is not reactive toward the addition to acyl fluorides. Instead, it equilibrates with α-silyl allylcopper species (e.g., 45–47, Scheme 7, or 49–50, Scheme 8) via reversible 1,3-metallo shifts. Depending on the nature of the silyl group of dienes 1 and the ligand on Cu, the reaction of acyl fluorides operates under the Curtin-Hammett principle to give either Z-isomers 2 or E-isomers 3 through either E-allylcopper 45 or Z-allylcopper 50, respectively.³⁹ It is remarkable that the different silyl groups of dienes 1 could drastically impact the nature of reactive intermediate α-silyl allylcopper species and the stereoselectivities of the reactions.

CONCLUSIONS

In summary, we developed diastereoselective and enantiodivergent syntheses of (Z)- or (E)-β,γ-unsaturated ketones from 1,3-butadienyl silanes.⁴⁰ The nature of the silyl group of the dienes not only dictates the reactive allylic copper intermediates (45 or 50) in the reactions with acyl fluorides but also has a significant impact on the face-selective addition to acyl fluorides to control the E/Z-selectivities and enantioselectivities of the products. Under the developed catalytic systems, the reactions of acyl fluorides with PhMe₂Si-substituted 1,3-diene gave (Z)-β,γ-unsaturated ketones bearing an α-tertiary stereocenter with high Z-selectivities and excellent enantioselectivities, while reactions with ⁱPr₃Si-substituted 1,3-diene formed (E)-β,γ-unsaturated ketones with high optical purities and excellent E-selectivities. Computational studies were conducted to provide the support to these fundamentally important discoveries. The products generated from the reactions contain three functional groups with orthogonal chemical reactivities, which can undergo a variety of transformations to afford synthetically valuable intermediates. Synthetic applications of this method are currently ongoing.