Catalytic Enantioselective Synthesis of anti Vicinal Silylboronates by Conjunctive Cross Coupling

Abstract

Chiral 1,2-bimetallic reagents are useful motifs in synthetic chemistry. Although syn-1,2-bimetallic compounds can be prepared by alkene dimetallation, anti-1,2-bimetallics are still rare. The stereospecific 1,2-metallate shift that occurs during conjunctive cross-coupling is shown to enable a practical and modular approach to the catalytic synthesis of enantioenriched anti-1,2-borosilanes. In addition to reaction development, the synthetic utility of anti-1,2-borosilanes was investigated, including applications to the synthesis of anti-1,2-diols and anti-1,2-amino alcohols.

Graphical Abstract

Vicinal Dimetallics: Enantioselective catalytic conjunctive cross-coupling reactions employing readily available silyl alkenyl boronic esters provide direct access to anti vicinal silyl boronic esters. These compounds provide a versatile tool for the construction of 1,2-difunctional organic building blocks.

Because of their ability to undergo a variety of stereospecific carbon-carbon and carbon-heteroatom bond forming reactions, configurationally stable, chiral organometallic compounds are valuable reagents in modern chemical synthesis.¹ Among this class of compounds, structures bearing two carbon–metal bonds, most often configured as either geminal or vicinal dimetallic reagents, are particularly useful species.² When the two metallic species in these structures can be independently transformed by stereospecific chemical reactions, new opportunities for streamlined synthesis can be engineered. For this reason, many efforts have focused on the development of methods to construct dimetallic reagents in a catalytic enantioselective fashion. Through the use of Rh, Pd, Pt, Cu, and carbohydrate-based catalysts, non-racemic 1,2-diboronate species have been constructed from alkene, alkyne, and allene starting materials.³ Important advances have also enabled catalytic enantioselective synthesis of vicinal disilanes⁴, silylboronic esters⁵, and stannylboronic esters.⁶ Despite extensive efforts in this area of research, significant gaps still exist in our ability to prepare strategically useful vicinal dimetallic reagents. For instance, while enantioselective alkene diboration extends to both terminal^3e–i and internal^3b,h,i alkene substrates, selective reaction of the latter is restricted to E alkenes; reaction of Z alkenes, substrates that lead to useful anti 1,2-diboronates (Scheme 1a, eq. 1), is generally nonselective. While related anti 1,2-silylboronates can be prepared by a diastereoselective alkoxide-promoted silylboration of alkenes⁷ (eq. 2), this process is not stereospecific and an enantioselective variant has not been established. In this report, we describe an alternate catalytic synthesis of anti 1,2-dimetallic reagents (eq. 3) that can be accomplished with excellent diastereo- and enantioselectivity, and that furnishes products with C–M bonds that can be independently transformed.

Scheme 1.

Strategies for the catalytic construction of internal anti 1,2-dimetalloid species.

Recent efforts in our laboratory led to the development of Pd⁸ and Ni-catalyzed⁹ conjunctive cross-coupling reactions.¹⁰ These processes occur by a modified direct cross-coupling reaction in which a stereospecific 1,2-metallate shift¹¹ occurs in lieu of transmetalation (Scheme 1c). This mechanism enables the anti addition of two carbon atoms across an alkenyl boronate and, with appropriate catalysts, enables reactions that occur with excellent levels of enantioselectivity. We reasoned that if the conjunctive coupling reaction could extend to β-metalloalkenylboronates, it might provide a selective route to anti 1,2-dimetalloid compounds in a modular straightforward process.

At the outset of this investigation, a number of β-metalloalkenylboronate substrates were examined for their ability to participate in the conjunctive coupling process. In each case, the requisite “ate” complex was generated from commercially available phenyllithium and the alkenyl boron species, and then subjected to a cross-coupling reaction with phenyl triflate, 3% Pd(OAc)₂, and 3.6% (R,R)-MandyPhos¹² L1. As shown in Table 1, when the M group of the substrate was either a B(pin) or a B(mida) group (1 and 2), only trace amounts of product were detected. For these experiments, ¹¹B NMR analysis of the reaction mixture derived from phenyllithium and 1 indicated a complex mixture, whereas the complex from compound 2 was poorly soluble. We considered that substrates where the M group is a silane might provide better reactivity: with only one electrophilic site, the silane-based compounds were expected to provide a cleaner “ate” complex. Moreover, the electronic properties of the silane group might facilitate the metallate shift by stabilizing bonding electrons in the incipient C-Pd bond (σ_C-Pd → σ*_Si-C).¹³ After optimization of catalyst loading, solvent, temperature and additives (see Supporting Information for details), it was found that reaction of trimethylsilyl-substituted substrate 3 produced the desired product (41% isolated yield) along with a comparable amount direct Suzuki-Miyaura coupling product. In line with a previous report^8e that the boron ligand can influence the chemoselectivity of the reaction, we found that B(mac)-derived substrate 4 provided enhanced yield and also outstanding stereoselectivity. With an eye towards synthetic utility¹⁴, alternate silyl groups were investigated and it was found that benzyl-derived¹⁵ silane 5 and aryl-substituted silanes 6 and 7 also participated in the reaction, providing good yields and stereoselectivity. Of note, the reaction products are chemically stable species, readily handled in the open atmosphere, and they do not decompose during silica gel chromatography.

Table 1.

Conjunctive Couping with β-Metalloalkenylboron Reagents.^[a]

substrate	BL2	M	yield (%)	er	dr
1	B(pin)	B(pin)	<5	na
2	B(pin)	B(mida)	<5	na
3	B(pin)	SiMe3	41	73:27	>20:1
4	B(mac)	SiMe3	89	97:3	>20:1
5	B(mac)	SiMe2Bn	62	96:4	>20:1
6	B(mac)	SiMe2Ph	82	97:3	>20:1
7	B(mac)	SiMe2(PMP)	76	97:3	>20:1

^[a]See the main text and the Supporting Information for details. Yields refer to isolated, purified material and are an average of two experiments. The er values were determined by SFC analysis on a chiral stationary phase. Product isolated as 2-hydroxyl metal species.

As depicted in Table 2, a number of substrates were examined in the conjunctive coupling employing reagent 6. Good reactivity was observed with both organotriflates and organobromides as long as potassium triflate¹⁶ was added to reactions of the latter. Across a variety of electrophiles, the diastereoselectivity was generally >20:1 and the enantioselectivity ranged from 79:21 to 98:2 er. Electron-rich aryl bromides (9–11) and heteroaryl bromides (16–18) reacted efficiently and with high levels of enantioselectivity. Although electrophiles bearing electron-withdrawing chloride (13), ketone (14) and ester (15) groups reacted with good efficiency, diminished levels of enantioselectivity were observed in these reactions. Also of note, ortho substituted electrophiles did not engage in the reaction (data not shown), likely due to steric interactions between the substituent and the large silyl group. In terms of migrating groups, a number of substitutents were found to migrate with good yield and selectivity. Electron-rich (25, 26), electron-poor (19–21), and heteroaromatic (27, 28) migrating groups reacted with relatively good yield and selectivity. It is also worth noting that simple alkyl groups (29–32) could engage in the migration with excellent enantioselectivity. Lastly, reactions of alkenyl bromide electrophiles (32, 33) provide a route to useful enantiomerically-enriched allylsilane reagents as the product.

Table 2.

Examination of Various Substrates in Conjunctive Couplings with 2-Silylalkenylboronates^a

^[a]Compounds 8 and 9 prepared with PhOTf; the oxidation step was omitted for 8. Compounds 10-18 prepared with ArBr. For compounds 19-28, the organolithium is prepared by lithium/halogen exchange and the coupling employs PhOTf. Compounds 29-32 and 34 employ commercial organolithium solutions. Compounds 32 and 33 employ the alkenyl bromide.

In terms of practical utility, it is worth noting that the silyl-substituted alkenyl boron reagent 6 is easily accessible on preparative scale by a two-step, one-pot procedure involving conversion of diol 36 into HB(mac), followed by zirconium-catalyzed hydroboration¹⁷ of commercially available phenyldimethylsilylacetylene (Scheme 2a). Reagent 6, the product of this sequence, was found to be an air-stable, storable solid. The ready availability of compound 6 renders the conjunctive cross-coupling practical on larger scale. Investigating this feature, it was found that couplings could be conducted on gram scale and still operate efficiently even when the catalyst loading was decreased to 0.5 mol% palladium. Under these conditions, the vicinal silylboronate product 8 could be accessed in 70% yield and with very good levels of stereoselectivity (Scheme 2b).

Scheme 2.

Practical features of the conjunctive coupling reaction with β-silylalkenyboronates.

With access to a class of enantiomerically enriched anti-1,2-silylboronates, their synthetic utility was examined. Since both boron and silicon can serve as hydroxyl group equivalents, we examined oxidation of the silylboronates to the derived anti 1,2-diol. As expected, the boronate was found to be more reactive than the silane towards oxidation; however, the boronate oxidation was nontrivial due to the propensity of the intermediate β-hydroxylsilane to undergo Peterson elimination¹⁸ under both acidic and basic conditions. In addition, under neutral oxidation conditions (NaBO₃¹⁹ or H₂O₂ in pH=7 buffer) epimerization of the intermediate β-hydroxysilane occurred. Extensive examination of reaction parameters (see Supporting Information) revealed that with only a modest excess of NaOH (3 equiv) and H₂O₂ (7 equiv), the boronates could be oxidized in 5 minutes without elimination or epimerization. Subsequent to oxidation, the hydroxyl group was protected, and the Fleming–Tamao²⁰ oxidation was examined. It was found that use of molecular bromine required for activation of the PhMe₂Si group led to bromination of other aryl rings in the substrate. However, this problem was avoided by employing the more electron-rich p-methoxyphenyldimethylsilyl (Me₂PMPSi) analogs.²¹ Of note, the Me₂PMPSi-containing substrates underwent conjunctive cross-coupling in yields that are comparable to the Me₂PhSi-derived substrates (products 34 and 35, Table 1) and, as shown in Scheme 3, Fleming-Tamao oxidation of 36 and 37 allowed clean anti-1,2-diol product formation for products of both alkyl and aryl migration (to give 38 and 39). To the best of our knowledge, this is the first demonstration of the utility of the Me₂PMPSi group in Tamao-Fleming oxidation.

Scheme 3.

Conversion of anti-1,2-silylboronates to anti diol and aminoalcohol derivatives. (a) NaOH, H₂O₂, THF, rt; (b) Benzoic anhydride, dimethylaminopyridine, triethylamine, CH₂Cl₂, rt, 15 h; (c) KBr, AcOOH, NaOAc, HOAc, rt, 12 h; (d) n-BuLi, MeONH₂, THF; (e) Boc₂O, rt, 3 h.

Because of the orthogonal reactivity of the organoboron and organosilane functional groups, site-selective amination of the boronate groups in compounds 34 and 35 is also possible. As shown in Scheme 3, stereospecific and chemoselective amination with lithiated methoxyamine²², followed by protection and Tamao-Flemming oxidation provided the anti-1,2-amino alcohols 42 and 43 in reasonable yields further highlighting the utility of the silylboronate products obtained from conjunctive coupling.

In summary, we have described a new strategy to assemble enantiomerically enriched anti-1,2-silylboronates by Pd-catalyzed conjunctive cross-coupling. This reaction is straightforward to conduct on a preparative scale and the products may be converted into useful diols and amino alcohol derivatives. We anticipate that this process should find us in the construction of other enantiomerically enriched difunctional materials.