Synthesis of Quaternary Carbon Stereogenic Centers by Diastereoselective Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones

Abstract

A method for the site-selective and diastereoselective conjugate addition of boron-stabilized allylic nucleophiles to α,β-unsaturated ketones is disclosed. Transformations involve easily prepared γ,γ-disubstituted allyldiboron reagents and proceed in the presence of a fluoride activator at 80°C. Reactions proceed with a wide variety of enones and allyldiboron reagents efficiently to deliver ketone products that contain otherwise difficult-to-access vicinal β-tertiary and γ-quaternary carbon stereogenic centers and an alkenylboron moiety. The utility of the method is highlighted by several transformations, including cross-coupling and carbocyclizations.

Stereoselective methods for the synthesis of compounds that contain quaternary carbon centers are critical to the preparation and discovery of bioactive molecules.¹ 1,4-Addition of allylic nucleophiles to electron-deficient alkenes provides an effective strategy for the generation of complex molecular structures. Pioneering studies by Hosomi-akurai with allylsilanes² have led to the development of methods with other allylmetals (Si,³ Sn,⁴ Cu,⁵ Ta,⁶ Ba,⁷ In⁸) that provide access to β-allyl-substituted carbonyls (Scheme 1A). Related catalytic enantioselective variants have also been reported that employ copper and ytterbium chiral Lewis acid catalysts in the presence of an allylsilane⁹ or stannane.¹⁰ Pinacolato allylboronates have also been successfully employed in catalytic enantioselective 1,4-addition reactions with dialkylidene ketones with a chiral nickel catalyst.¹¹ Furthermore, enantioselective Cu-catalyzed 1,4- and 1,6-conjugate additions of in situ generated boron-substituted allylcopper species to dienoates proceed with high selectivity.^12,13 Indirect synthesis of enantioenriched 1,4-allyl conjugate addition products can also be achieved by an enantioselective 1,2-allylboration/oxy-Cope rearrangement sequence with β,γ-unsaturated α-ketoesters.¹⁴

Scheme 1.

Allylic Nucleophile 1,4-Addition and Boron-Stabilized Carbanion Reactivity

In the examples noted above, reactions involve the intermolecular addition of either the parent allyl fragment, or in a few cases, the stereoselective addition of γ-monosubstituted allylic nucleophiles.^12b,c In contrast, protocols for the diastereoselective synthesis of γ-quaternary carbon stereocenters through intermolecular 1,4-allyl additions are nonexistent.¹⁵ Transformations are limited to a small number of reports on intramolecular Lewis acid promoted Hosomi-Sakurai annulations.¹⁶

At the center of the present studies is the generation and reactivity of α-boryl carbanions (e.g., 8) that begin with the deborylation of geminal bis(boronates) (Scheme 1C).¹⁷ Recently, efforts in our laboratory and others have focused on the formation of boron-stabilized carbanions generated by deborylation of 1,1-bis(boronates) and their utility in C-C bond forming methods.¹⁸ In this context, reactions generally utilized alkyl or benzyl 1,1-bis(boronates) reagents with a variety of carbon electrophiles. Of particular significance is a recent study by Chirik on the deborylative 1,4-addition of 1,1,1-tris-boronates (4) (Scheme 1B).¹⁹ Recently, we have introduced Cu-catalyzed allylic nucleophile additions to ketones and imines with γ,γ-disubstituted allyldiborons (e.g., 7b).^20,21 In this study, we report the first general method for the diastereoselective synthesis of γ-quaternary carbon stereogenic centers via site-selective intermolecular allylic nucleophile 1,4-addition to α,β-unsaturated ketones. Reactions employ γ,γ-disubstituted allyldiboron reagents (e.g., 7b) in the presence of CsF as an activator, and furnish products in up to 96% yield and >98:2 dr. The proposed reaction proceeds via a boron-stabilized allyl carbanion (10), and C-C bond formation occurs with high γ-selectivity at the more congested carbon. Of note, in a recent report of alkoxide promoted deborylative alkylation of 1,1-allyldiborons (e.g., via 10), C-C bond formation was found to proceed with high α-selectivity.²²

To investigate the reactivity of boron-stabilized allylic carbanions, we began by evaluating the reaction of cyclohexenone 1 with the 1,1-diborylallylic reagent 12 to afford 13a (Table 1). From the outset, a key objective of our studies was to develop a robust process that is not only efficient but also highly diastereoselective and site-selective. Initial control reactions, either in the absence of a Lewis base activator or in the presence of typical Hosomi-Sakurai Lewis acids (e.g., TiCl₄), established that there is no background reaction to either 1,4- or 1,2-addition products (see Supporting Information (SI) for details). In contrast, treatment of 1 and 12 with 100 mol % of KOtBu, NaOtBu, or NaOMe (entries 1–3) in THF at 22°C for 18 h affords 13a in up to 31% yield and 96:4 dr. Switching to CsF as a less basic activator to avoid competitive deprotonation resulted in a slight improvement, delivering 13a in 33% yield, 96:4 dr, and 96:4 γ:α (entry 4). Further increasing the amount of CsF to 500 mol % delivers 13a in 65% yield (95:5 dr); however, significant decomposition of 12 (35%) is observed.²³ Increasing the reaction temperature to 60°C led to a marked improvement in reaction efficiency, affording 13a in 54% yield, >98:2 dr (entry 5); however, increasing CsF to 200 mol % proved deleterious (entry 6). At this juncture, a brief survey of solvents (entries 7–9) and further temperature optimization identified 50 mol % CsF in DME at 80°C as optimal reaction conditions for the formation of 13a (90% yield, 96:4 dr, and 90:10 rr, entry 10). Notably, 20 mol % CsF at 80°C delivers 13a in 56% yield and >98:2 dr (entry 11), while use of 50 mol % KF instead of CsF results in <2% conversion to 13a (entry 12).

Table 1.

Reaction Optimization^a

entry	activator (mol %)	solvent	temp (°C)	yield (%);b drc	rr(γ:α)c,d
1	KOtBu; 100	THF	22	8; 92:8	>98:2
2	NaOtBu; 100	THF	22	20; 96:4	79:21
3	NaOMe; 100	THF	22	31; 92:8	>98:2
4	CsF; 100	THF	22	33; 96:4	96:4
5	CsF; 100	THF	60	54; >98:2	93:7
6	CsF; 200	THF	60	29; 98:2	94:6
7	CsF; 100	DME	60	59; 96:4	90:10
8	CsF; 100	Diaxane	60	34; >98.2	93:7
9	CsF; 100	C6H6	60	33; >98.2	88:12
10	CsF; 50	DME	80	90; 96:4	90:10
11	CsF; 20	DME	80	56; >98:2	89:11
12	KF; 50	DME	80	<2	n.d.

^aReactions performed under a N₂ atmosphere.

^bYield determined by analysis of ¹H NMR spectra of unpurified reactions with DMF as internal standard.

^cDiastereomeric ratios (dr’s) determined by analysis of ¹H NMR spectra of purified products (diastereoisomers cannot be separated by SiO₂ chromatography).

^d>98:2 1,4:1,2 addition all cases. Experiments were run in duplicate. See the SI for details.

With an effective protocol developed, an analysis of the α,β-unsaturated ketone component in the site-selective and stereoselective allylic nucleophile 1,4-addition was undertaken. As illustrated in Scheme 2, the reaction is tolerant of a broad range of enones generally exhibiting high levels of efficiency and selectivity. For example, reactions with cyclic enones of various ring sizes (5 → 8; 13a-d), as well as enones bearing gem-dimethyl functionality on the ring (13e-f), proceed efficiently. Enones bearing 2-methyl substitution enable the formation of three contiguous stereocenters; for example, 13g is generated in 92% yield, and >98:2 dr 2:3 but 74:26 dr 1:2 due to moderate selectivity of enolate protonation. Reaction of racemic enones bearing monomethyl substitution at the 4- and 6-positions also permits the generation of three stereogenic centers in high stereoselectivity; the formation of 13h and 13i in 94% and 96% yield in 95:5 dr and 96:4 dr, respectively, are illustrative. Equally efficient C-C bond formation proceeds with apoverbenone (13j) a naturally occurring terpene with a [3.1.1] scaffold. Unfortunately, it was found 3-substituted and acyclic enones do not react under the current reaction conditions (e.g., 13k-l).

Scheme 2.

α,β-Unsaturated Ketone Scope^a-c

^aReactions performed under a N₂ atmosphere. ^bYields of purified products after SiO₂ chromatography. ^cDiastereomeric ratios (dr’s) determined by analysis of ¹H NMR spectra of purified products. Experiments were run in duplicate. See the SI for details. ^dTreatment of 13g with 1 equiv of DBU in THF at 22°C increases dr from 74:26 to 93:7. ^eDr with respect to all stereocenters.

Next, we set out to determine the ability of the reaction to tolerate structural variations relating to the allyldiboron component (Scheme 3). A series of trisubstituted allyldiborons bearing pendant functionality were prepared and subjected to the reaction conditions with enone 1. Reaction of both E and Z geometrical isomers of allyldiboron containing Et/Me substituents proceed stereospecifically to afford 16a (82% yield, 98:2 dr) and 16b (87% yield, >98:2 dr). These results demonstrate that, at 80°C, the stereochemical integrity of the B-stabilized carbanion is maintained, enabling selective access to both stereoisomers. Allyldiborons bearing various substituents, for example, pendant aryl, silylether, isopropyl, and cyclopropyl groups, undergo stereoselective C-C bond formation to afford 16c-f in high yield. Furthermore, cyclic allyldiboron reagents can be employed to incorporate cyclobutane (16g) and cyclohexene (16h) ring systems, albeit with diminution in dr. Notably, 16h is formed exclusively as the B-substituted quaternary center in >98:2 α:γ site selectivity. Relatedly, it was found increasing sterics in acyclic allylic nucleophiles results in lower γ:α site selectivity; for example, reaction of an isopropyl-substituted reagent with 1 under standard reaction conditions furnishes 16i in 76% yield and 93:7 dr (γ isomer) but 76:24 γ:α. Symmetrical substituted allyl nucleophiles also react equally effectively under standard conditions to afford alkenyl borons 16j-k in high yield. Lastly, aryl substituted quaternary carbon stereocenters (e.g., 16l) could not be formed through the current protocol.

Scheme 3.

γ,γ-Disubstituted Allyldiboron Scope^a-c

^aReactions performed under a N₂ atmosphere. ^bYields of purified products after SiO₂ chromatography. ^cDiastereomeric ratios (dr) determined by analysis of ¹H NMR spectra of purified products. Experiments were run in duplicate. See the SI for details.

Having established a protocol for the site-selective and diastereoselective 1,4-addition of γ,γ-disubstituted allylboron carbanions, mono-γ-substituted allyldiborons²¹ were investigated to allow for the stereoselective preparation of vicinal tertiary carbon stereogenic centers (Scheme 4). Under the optimal reaction conditions (50 mol % CsF, 80°C), both Z-17 and E-17 crotyl isomers react with cyclohexenone to deliver 18a and 18b in 83% and 97% yield (>98:2 γ:α), albeit with diminished diastereoselectivity (18a: 81:19 dr; 18b: 85:15 dr). A rationale for the lower dr is likely the result of a smaller substituted allyl nucleophile or minor E/Z isomerization prior to C-C bond formation. An additional noteworthy point is that in both cases the sterically less hindered crotyl nucleophiles react with high 1,4:1,2 (>98:2) selectivity. In comparison, synthetically versatile diboronate 19, formed by the reaction of trisboronate Z-23²⁴ and 1, is afforded in 82% yield as a single diastereoisomer (>98:2 dr) and site isomer (>98:2 rr). Three additional examples, 20–22, serve to illustrate that mono-γ-substituted allylic nucleophiles display increased reactivity but slightly lower stereospecificity compared with trisubstituted variants. Moreover, the reduced steric congestion renders mono-γ-substituted nucleophiles more broadly reactive; for example, the formation of 20–22 arise from reactions with enones that do not currently engage with the γ,γ-disubstituted variants (e.g., see 13l Scheme 2).²⁵

Scheme 4.

Stereoselective 1,4-Addition with γ-Monosubstituted Allylic Nucleophiles^a-c

^aReactions performed under a N₂ atmosphere. ^bYields of purified products after SiO₂ chromatography. Experiments were run in duplicate. ^cDiastereomeric ratios (dr) determined by analysis of ¹H NMR spectra of purified products. See the SI for details. ^dWith 2.0 equiv of 1. ^eFrom rac 4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-one.

To highlight the synthetic utility of the 1,6-keto-alkenylboronate products prepared by this method, the experiments in Scheme 5 were conducted. In Scheme 5A, it was shown that hydrogenation of the alkenylboron proceeds without issue and affords the boronate ester 24 in excellent yield. Next, it was shown that C-C and C-O cross-coupling of the alkenylboron can be achieved under Pd and Cu catalysis to afford the derived alkenylarene 25, diene 26, and enol ether 27 with complete preservation of diastereomeric purity.²⁶ Lastly, sodium perborate oxidation furnishes aldehyde 28 (Scheme 5B), which can be cyclized (1) with HCl_(aq) to bicyclic enone 29 and (2) by a two-step Horner-Wadsworth-Emmons olefination/NaOH cyclization to hydrindane 30 containing four contiguous stereocenters (>98:2 dr).

Scheme 5.

Synthetic Utility of the 1,6-Ketoalkenylboronates^a

^aSee SI for details.

To gain a mechanistic understanding of the 1,4-allyl addition reaction, a deuterium quench was used to probe whether an enolate was formed at the end of the reaction (Scheme 6A). It was found that 32 is generated in 66% yield with 83% D incorporation at the α-position corresponding to a boronenolate protonation.^27,28 Next, a comparison to the reactivity of monoboronallyl reagents was probed. Under standard conditions, treatment of 33 with 50 mol % CsF at 80°C results in <2% conversion to either 1,2- or 1,4-allyl addition products, clearly highlighting that the second boron group is critical for reactivity. The relative stereochemistry of the major diastereomer was determined by NOE experiments with 29 (Scheme 6C), establishing the E-substituent of the nucleophile as anti to the methine of the cyclohexane ring. This was further confirmed since the stereochemistry of 18b, formed by reaction of Z-17, was established by protodeboration to known compound 35.²⁹ A proposed stereochemical model for the reaction is shown by structure A. Allyl carbanion addition to an enone, activated by either (pin)B-F or cesium bridge between a pinacol oxygen,³⁰ allows for stereoselective C-C bond formation where the nucleophile stereochemistry (R^E and R^Z) is relayed to the product with high fidelity. Addition via the opposite face of the nucleophile (B) appears disfavored due to sterics. Based on the data above, a proposed mechanism is depicted in Scheme 6D. Cesium fluoride initiates the reaction to generate 37, which can then be reformed by reaction of the resulting enolate with another equivalent of 36. The need for 50 mol % CsF versus 10 mol % likely arises due to reaction of the enolate (39) with (pin)B-F, which inhibits the process. The lack of E/Z isomerization of the allylic carbanion can also be rationalized by an unfavorable σ-bond rotation that localizes the carbanion on carbon (e.g., B).

Scheme 6.

Mechanism Experiments and Stereochemical Analysis^a,b

^aSee SI for details. ^bAttempted reaction of 30 with PhCHO or MeI afforded <5% conv.

In summary, the investigations described above detail a practical and efficient method for the first diastereoselective synthesis of γ-quaternary carbon stereogenic centers through intermolecular 1,4-allyl additions. Boron-stabilized allylic nucleophiles, formed by Lewis base boron activation, react site selectively and stereospecifically to deliver versatile 1,6-ketoalkenylboronate products. Development of other stereoselective C-C bond forming reactions of B-stabilized allylic nucleophiles are in progress.