Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides

Abstract

Although Csp2–Csp2 Suzuki–Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium–ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (−)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45–50 min, and the reaction is complete within 4–5 h.

Introduction

Carbon–carbon bond–forming reactions are essential in organic synthesis. They enable the assembly of molecules with useful properties, including pharmaceuticals, fragrances and agrochemicals. SMC is a widely used strategy for preparing complex molecules in industry and academia1,2,3 and is one of the most important synthetic tools in drug discovery4. SMC uses stable and readily available sp2-hybridized boronic acid derivatives as coupling partners5, and a wide variety of aryl, heteroaryl and vinyl analogs are commercially available or can be easily prepared. This availability affords great practical advantages to these procedures and avoid the use of highly reactive, moisture-sensitive, pyrophoric organometallic reagents. In addition, SMC displays remarkable functional group tolerance, so it is well suited to the incorporation of important heterocycles into complex molecules (Fig. 1a).

Fig. 1: SMC: from flat to 3D molecules.
figure1

a, Classic Csp2–Csp2 coupling is a powerful synthetic tool that uses widely available boronic acids. b, The development of methods that use Csp3-hybridized coupling partners is an active topic of research. c, This protocol: enantioselective Rh-catalyzed SMC to form Csp3–Csp2 bonds. See Table 1 for conditions. Ar, aryl, heteroaryl, or vinyl; Boc, tert-butoxycarbonyl; Hal, halide or pseudo-halide; R, R′, R″, alkyl, aryl, H, heteroaryl, heteroatom, or vinyl; X, Y, or Z, ≠ CH.

Ease of synthetic access to biaryl compounds, largely due to SMC, is widely understood to have led to overrepresentation of flat molecules in drug development. Consequently, the development of new, broadly useful methods for the synthesis of non-planar molecules, preferably in an asymmetric manner, is highly desirable (Fig. 1b; refs. 6,7,8,9). The incorporation of stereogenic elements is also a current major focus in drug discovery. Enantioselective Csp2–Csp2 coupling methods for the formation of axially chiral biaryls10,11,12,13,14 have been developed, and related desymmetrizations of meso-compounds are known15. Csp3-hybridized coupling partners are scarce in catalytic asymmetric SMCs16, but stereospecific approaches using enantiomerically enriched coupling partners17,18 and enantioselective couplings of sp2-hybridized boron reagents and secondary halides have been reported19,20. However, these approaches use specific electrophiles, and their scope is generally limited to simple aromatic or aliphatic partners, which lack the structural characteristics typically seen in drugs21,22. Catalytic asymmetric SMCs that enable incorporation of heterocyclic motifs have not been well developed, despite how heavily these feature in biologically active molecules.

Catalytic asymmetric reactions featuring boronic acids include 1,2- (refs. 23,24,25) and 1,4-additions26,27,28,29 and allylic substitutions30,31,32,33,34,35. Within our research group, we have reported rhodium-catalyzed cross-couplings between boronic acids and cyclic allyl halides, which effectively serve as an enantioselective variant of the SMC that allows coupling of heterocyclic species (Fig. 1c; refs. 36,37). A key feature of this protocol is that a racemic allyl halide is converted to a highly enantioenriched product with up to quantitative yield, thus avoiding the need for enantiopure substrates or strategies involving prochiral substrates38. These dynamic kinetic asymmetric transformations may proceed via the formation of a (pseudo)prochiral intermediate or rapid interconversion of chiral intermediates39.

Development of the protocol and applications of the method

This protocol is compatible with a range of sp2-hybridized boronic acids in combination with (hetero)cyclic racemic allyl halides. It has been demonstrated that racemic, all-carbon 5-, 6- and 7-membered cyclic allyl chlorides are suitable substrates for this transformation. A dihydropyran-derived electrophile provides access to O-heterocyclic scaffolds, and a nitrogen-containing heterocyclic allyl chloride can be used for the enantioselective synthesis of piperidine derivatives40,41. As for the boronic acid species, aryl and vinyl derivatives have proven to be suitable coupling partners. Moreover, heteroaryl boronic acids are compatible with these methods. For instance, furan, pyrrole, thiophene and their corresponding benzofused derivatives can be used, and the coupling products are obtained with high ee values37. Pyridylboronic acid derivatives are more challenging substrates, because they can inhibit the catalytic cycle and suffer from rapid protodeborylation37,42. However, 2-chloro or 2-fluoropyridylboronic acid derivatives perform well in our protocol, which can then be further functionalized37. Depending on the coupling partners used, conditions can be tuned to achieve the best performance. Optimization of reaction conditions for different target molecules will be discussed in the ‘Experimental design’ section. In Table 1, we give an overview of often-superior conditions for each combination of substrates. Combining these parameters differently would probably result in decreased yield or ee value but would probably not completely suppress the reactivity. This summary is illustrative and is aimed at providing a good starting point when investigating new substrates. However, some specific coupling partners will undoubtedly require further screening to achieve the best results (for instance, some specific substrates may require reactions at room temperature, and some protodeboronations are so rapid that boronic esters should be used)37.

Table 1 Overview of reaction conditions according to the combination of substrates

The utility of the method has been demonstrated in the synthesis of target molecules such as the antipsychotic drug (−)-preclamol43,44 through two related synthetic routes. In addition, (+)-isoanabasine can be easily accessed in a few steps without classic resolution of racemic material, as previously reported45. This method was also used to synthesize the poly(ADP-ribose) polymerase (PARP) inhibitor, niraparib (Zejula), through three different routes. All three of these approaches to niraparib synthesis are shorter, more efficient and more straightforward than those previously described (Fig. 2; refs. 46,47,48).

Fig. 2: Application of the Rh-catalyzed asymmetric SMC in drug synthesis.
figure2

Pin, pinacolato.

Comparison with other methods

This protocol describes the preparation of enantioenriched compounds through the cross-coupling of sp2-hybridized boronic acid derivatives and a racemic cyclic allyl halide. In comparison to other methods for the asymmetric formation of C–C bonds using sp2-hybridized boronic acid derivatives, our protocol presents some advantages (Table 2). Enantioselective variants of classic Pd-catalyzed SMC are mostly limited to the construction of axially chiral biaryls10,11,12,13,14. Fu19 and Shen20 reported asymmetric Ni-catalyzed couplings between organoboron and racemic secondary alkyl halides; however, the scope of these methods is currently narrow and relies on the use of specific electrophiles and simple aromatic organoboron moieties. In addition, desymmetrizations of meso-compounds have been explored by Lautens and colleagues33,34,35 and Willis et al.15.

Table 2 Comparison of representative existing methods for asymmetric C–C bond formation using sp2-hybridized boronic acids with current protocol

The most widely established processes that use sp2-hybridized boronic acid derivatives in asymmetric reactions are 1,4-additions26,27,28,29. These are powerful transformations for benzene-derived nucleophiles. However, many heteroaromatic- and vinyl-boronic acids cannot be used in such additions because they undergo competitive protodeboronation or polymerization.

This current protocol is limited to pseudo-symmetric cyclic allyl halides (structures that—after cleavage of the carbon–halogen bond—are achiral about the allyl unit). It tolerates heterocyclic nucleophiles and electrophiles, which makes it potentially useful for the synthesis of complex natural products, as well as drug discovery and medicinal chemistry. These reactions are often complete within 1 h at 60 °C without any special precautions, although some less reactive coupling partners require additional time or higher temperatures. These conditions are highly unusual for asymmetric reactions with non-stabilized nucleophiles, which typically require cryogenic temperatures and are also of practical significance, particularly when adopting processes for industry use. Many of the products are easily prepared in >99% ee (>200:1 ratio of enantiomers). The observed selectivity is quite remarkable because these reactions start from a 1:1 mixture of enantiomers.

Experimental design

Here, we describe in detail the synthesis of (−)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Fig. 3), which is an intermediate in one of the preparations of niraparib previously described by our group37. In that study, this compound was prepared using 4-bromophenylboronic acid. In addition to producing an important intermediate in Merck’s process route to this drug46, we felt that this particular coupling reaction was especially suitable for detailed examination here because it involves non-trivial coupling partners, which are likely to be more challenging than simpler partners. The boronic acid features para-bromide, which is both electronically non-innocent and useful for subsequent functionalization. Furthermore, our procedures for using the tert-butoxycarbonyl (Boc)-protected dihydropyridine-derived allyl chloride were slightly unusual, in that they require heating the solvent above its boiling point (to 80 °C) a sealed flask (containing tetrahydrofuran (THF) solvent) for several hours to obtain optimal results, although microwave conditions have also been shown to be effective and involve shorter reaction times.

Fig. 3
figure3

Example of an Rh-catalyzed asymmetric SMC, which is detailed in this protocol. aq., aqueous; Boc, tert-butoxycarbonyl; cod, cycloocta-1,5-diene; THF, tetrahydrofuran.

During the course of preparing this protocol, we found that the yields of this particular reaction were somewhat variable, with the first three authors of this protocol obtaining inconsistent results at 80 oC (yields generally ranging from 60 to 74%). Accordingly, we developed a more reliable variation of the reported conditions for this particular nucleophile–electrophile combination, which allows for the reaction to be consistently run with high yield and ee and to be performed on a gram scale. Although the conditions previously reported for the boronic acid involved heating THF in a sealed flask at 80 oC, we found that by simply using the corresponding pinacol boronic ester as the coupling partner and CsOH (50% (wt/wt) in H2O) as the base, optimal results are obtained at 60 °C and there are no issues associated with scaling up this procedure.

We have observed that several reaction parameters have an influence on the reaction outcome in terms of ee and yield. Especially when investigating new substrates, variation of the reaction parameters—Rh(I) complex, ligand, base, solvent, temperature, boronic acid derivatives—may be required to obtain optimal results (Table 3).

Table 3 General tips for the investigation of different or new substrates

The protocol described below uses 2 equiv. of arylboronic ester, 2.5 mol% of [Rh(cod)OH]2, 6 mol% of (S)-Cl-BIPHEP ligand, and 1 equiv. of CsOH (50% (wt/wt) in H2O) in THF (0.1 M) at 60 °C. At a 0.4 mmol scale, these conditions provided the coupling product in an 85–90% yield and a 96% ee. Monitoring the reaction by NMR spectroscopy showed that the allyl chloride is completely consumed within 4 h. In addition, the coupling product is stable under the reaction conditions, and leaving the reaction overnight does not affect the outcome. This procedure proved robust in that similar results were obtained when some reaction parameters were varied, for instance, heating the reaction mixture to 80 °C in a sealed flask did not alter the outcome; neither did doubling the concentration to 0.2 M. Running the reaction using a nitrogen (instead of argon) atmosphere gave the same results. However, conducting the experiment in air was unsuccessful. Importantly, lowering the catalyst loading to 1.25 mol% of [Rh(cod)OH]2 and 3 mol% of (S)-Cl-BIPHEP afforded the product in only slightly lower yield (84 and 96% ee).

When the detailed procedure was performed at a 4.0-mmol scale, we obtained 1.17 g (86% yield) of product in a 96% ee. The first three authors of this protocol reproduced this result on a 0.4-mmol scale, and tests at the 1.0- and 2.0-mmol scale were also carried out; in all cases, comparable yields were obtained (in the range of 85–90%).

Limitations

The enantioselective Rh-catalyzed SMC is limited to pseudo-symmetric cyclic racemic allyl halides (in which, ignoring the chloride, there is a plane of symmetry through the allyl unit). Ortho-substituted arylboronic acids are usually challenging substrates, although the use of allyl bromide or harsher reaction conditions can provide good results. In addition, the procedure was unsuccessful when some heteroaryl boronic acids were used; for example, in the case of pyridylboronic acid derivatives, only their 2-chloro or 2-fluoro analogs are compatible with this procedure.

Materials

Reagents

Caution

All chemicals used in this protocol must be handled with care. Standard lab safety measures are relevant (lab coat, gloves and eyes protection), and all manipulations must be performed in a ventilated laboratory fume hood. All chemicals are stored at room temperature (23 °C) and are flushed with argon. [Rh(cod)OH]2 and (S)-(−)-5,5′-dichloro-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl are air and moisture sensitive.

  • [Rh(cod)OH]2 (Sigma-Aldrich, cat. no. 661023; alternatively, it can be synthesized from [Rh(cod)Cl]2, see ‘Reagent setup’ section)

  • (S)-(−)-5,5′-dichloro-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl (Sigma-Aldrich, cat. no. 76854)

  • Cesium hydroxide (CsOH, 50% (wt/wt) aq. solution; Alfa Aesar, cat. no. 10020)

  • tert-Butyl 3-chloro-3,6-dihydropyridine-1(2H)-carboxylate (see ‘Reagent setup’ section)

  • Tetrahydrofuran (THF; unstabilized; collected fresh from an mBraun SPS-800 solvent purification system)

  • Hexane

  • EtOAc

  • 2-Propanol

  • Argon

  • Silica gel for column chromatography (Merck, cat. no. 111567)

  • Alkaline KMnO4 stain

  • 4-Bromophenylboronic acid (Fluorochem, cat. no. 010981)

  • Pinacol (Sigma-Aldrich, cat. no. 221171)

  • Racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Sigma-Aldrich, cat. no. 481084)

Equipment

  • Argon-vacuum dual manifold equipped with Tygon tubing

  • Vacuum pump

  • Bunsen burner or heat gun

  • Round-bottom single-necked flasks (three)

  • Teflon-coated magnetic stir bar

  • Rubber septa (Sigma-Aldrich, Suba-seal, cat. no. Z124591)

  • Disposable syringes and needles

  • Magnetic stir plates

  • Analytical weighing balance

  • Plastic weighing boats

  • Spatula

  • Silica thin-layer chromatography (TLC) plates (silica gel 60 F254; Merck, model no. 105553)

  • TLC developing chamber

  • Glass column for preparative flash chromatography

  • Test tubes

  • Rotary evaporator with water bath

  • Solvent purifier (mBraun, model no. SPS-800)

  • Chiralpak IC analytical column (Chiral Technologies Europe, cat. no. 83225)

  • Pasteur pipette

  • UV detector

Reagent setup

[Rh(cod)OH]2

[Rh(cod)OH]2, if desired, can be synthesized from [Rh(cod)Cl]2 through a modified procedure reported by Uson et al.49 using 10 equiv. of KOH (reagent grade)

Critical

When synthesizing this catalyst, it is recommended to recrystallize it in dichloromethane/hexane to ensure optimal activity (Supplementary Methods).

4-Bromophenylboronic acid pinacol ester

4-Bromophenylboronic acid pinacol ester is prepared from the corresponding boronic acid and pinacol by stirring both reagents in MeCN at room temperature for 4 h (Supplementary Methods).

tert-butyl 3-chloro-3,6-dihydropyridine-1(2H)-carboxylate

tert-butyl 3-chloro-3,6-dihydropyridine-1(2H)-carboxylate is prepared according to the procedure described in the supplementary information of Schäfer et al.37.

Authentic racemic sample

An authentic racemic sample can be prepared by carrying out the reaction and using racemic BINAP as ligand. We typically prepare the racemic samples at a 0.2-mmol scale. For a detailed procedure, see the supplementary information of Schäfer et al.37.

Equipment setup

Reaction flask

Reaction flask should be equipped with a Teflon-coated magnetic stir bar, flame-dried under reduced pressure on an argon-vacuum manifold and cooled to room temperature while it is under vacuum.

Syringes and needles

Syringes and needles must be clean and purged with argon before use.

Enantiomeric excess

In our lab, we use an authentic racemic sample and compare this with the product by HPLC with a chiral nonracemic stationary phase: Chiralpak IC column, flow: 1 mL min−1; hexane/2-propanol: 99:1; λ = 210 nm, minor enantiomer retention time (tR) = 11.0 min; major enantiomer tR = 12.2 min.

Procedure

Preparation of the catalyst

Timing 45 min

  1. 1

    Flame-dry a 100-mL round-bottom flask containing a Teflon-coated magnetic stir bar under reduced pressure, cool to room temperature and back-fill with argon. Fit the flask with a rubber septum. This is the reaction flask.

  2. 2

    Weigh out 45.6 mg of [Rh(cod)(OH)]2 (0.10 mmol, 0.025 equiv.) and 156.4 mg of (S)-(+)-5,5′- dichloro-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl ligand (0.24 mmol, 0.06 equiv.). Open the flask, place the pre-weighed solids inside and re-fit the rubber septum.

  3. 3

    Connect the flask to an argon-vacuum manifold. Put the flask under reduced pressure for 10 min and then carefully back-fill the flask with argon. Repeat this three times. The reaction flask will remain connected to the argon line with a flow of inert gas until Step 19.

  4. 4

    Add 20 mL of THF to the reaction flask with a syringe (see ‘Reagents’ section). Start stirring the mixture and turn on the heat of the stirring plate (60–63 °C). Add 0.7 mL of aq. CsOH solution (50% (wt/wt) aq. solution) (4.0 mmol, 1.0 equiv.) with an argon-purged syringe through the rubber septum of the reaction flask.

    Critical step

    All syringes used in this procedure should be purged with argon before use.

  5. 5

    Stir the contents of the flask at 60 °C for 30 min. A clear red solution should form (Fig. 4). While the reaction is stirring, proceed to Step 6.

    Fig. 4: Rh complex.
    figure4

    (Left) [Rh(cod)OH]2 and ligand are placed in the flask under vacuum (Step 3) and (right) a red solution is obtained during Step 5.

    troubleshooting

Preparation of the arylboronic ester and allyl halide solutions

Timing 10 min

Critical

Steps 6–14 can be performed while Step 5 is ongoing.

  1. 6

    Flame-dry a 25-mL round-bottom flask containing a Teflon-coated magnetic stir bar under reduced pressure, cool to room temperature and back-fill with argon. Fit the flask with a rubber septum.

  2. 7

    Weigh out 2.26 g (8.0 mmol, 2.0 equiv.) of 4-bromophenylboronic acid pinacol ester. Open the flask, place the pre-weighed solid inside and re-fit the rubber septum.

  3. 8

    Connect the flask to an argon-vacuum manifold. Put the flask under reduced pressure and then carefully back-fill the flask with argon. This flask will remain connected to the argon line with a flow of inert gas for the remainder of its use in the experiment.

  4. 9

    Add 8 mL of dry THF (see ‘Reagents’ section) to this flask containing the boronic ester.

  5. 10

    Stir this flask at room temperature for 3 min. A colorless solution should form.

    Critical step

    Some boronic acids dissolve in THF more readily than others, and some will not fully dissolve (if the mixture is stirred for ±2 mins, that will not affect the results of the experiment).

  6. 11

    Flame-dry another 25-mL round-bottom flask under reduced pressure, cool to room temperature and back-fill with argon. Fit the flask with a rubber septum. Connect the flask to an argon-vacuum manifold. This flask will remain connected to the argon line with a flow of inert gas for the remainder of its use in the experiment.

  7. 12

    Add 870.8 mg of N-tert-butoxycarbonyl-5-chloro-3-piperidene (4.0 mmol, 1.0 equiv.) to this flask with a Pasteur pipette (Fig. 5, left).

    Fig. 5: Preparation of the boronic ester and allyl halide solutions.
    figure5

    (Left) Allyl chloride is weighed (Step 12). (Right) Arylboronic ester and allyl chloride are added to their corresponding flasks under reduced pressure.

  8. 13

    Connect the flask to an argon-vacuum manifold. Evacuate the flask under reduced pressure and then carefully back-fill the flask with argon. This flask will remain connected to the argon line with a flow of inert gas for the remainder of its use in the experiment (Fig. 5, right).

  9. 14

    Add 8 mL of dry THF (see ‘Reagents’ section) to this reaction flask containing the allyl halide

    Critical step

    We prepare a solution of this particular allyl chloride because it is quite viscous. Other, more liquid-like, allyl chlorides can be added neat to the reaction flask via syringe immediately after adding the boronic acid solution (see below).

Reaction setup

Timing 5 h and 10 min

  1. 15

    Pierce the septum of the reaction flask with two 10-mL syringes, one containing the arylboronic ester solution and one containing the allyl chloride solution. Save both needles and syringes for Steps 17 and 18 (Fig. 6, left).

    Fig. 6: Reaction setup.
    figure6

    (Left) Sequential addition of arylboronic ester and allyl chloride solutions to the reaction flask (Steps 15–17). (Right) A dark red mixture is obtained a few minutes after adding the two coupling partners (Steps 19 and 20).

  2. 16

    Add the arylboronic ester solution to the reaction flask. Then add the allyl chloride solution to the reaction flask. To our knowledge, the order of addition and addition speed are not important.

  3. 17

    Rinse the flask that previously contained the allyl chloride with 2 mL of dry THF. Add this rinsing to the reaction flask with the corresponding syringe previously used in Step 16.

  4. 18

    Rinse the flask that previously contained the arylboronic acid with 2 mL of dry THF. Add this rinsing to the reaction flask with the corresponding syringe previously used in Step 16.

  5. 19

    Remove the reaction flask from the argon line while keeping the rubber seal on the flask. The red color of the mixture should turn darker after a few minutes (Fig. 6, right).

    Critical step

    When using CsOH as base, a precipitate can be observed to form within the first 10 s after adding the substrates to the reaction flask.

  6. 20

    Continue to heat the flask to 60–63 °C while stirring for 5 h.

    Critical step

    If the reaction is left stirring for up to 16 h, this will not affect the outcome of the experiment. Some substrates may require increased reaction times, whereas, for others, the reaction is complete in much less than 1 h.

Reaction workup and purification

Timing 1–2 h

  1. 21

    Remove the flask from the hot plate and allow it to cool to room temperature.

  2. 22

    When the flask is at room temperature, remove the rubber septum and add 5.4 g of silica gel (1.35 g mmol−1 of tert-butyl 3-chloro-3,6-dihydropyridine-1(2H)-carboxylate) to the flask.

  3. 23

    Carefully remove the solvent from the reaction flask under reduced pressure using a rotary evaporator.

  4. 24

    Load the resulting solid directly onto a flash chromatographic column made up of silica gel (150 g) and a 9:1 hexane/EtOAc mixture as eluent. Purify the product by flash column chromatography, using positive pressure and 9:1 hexane/EtOAc as eluent. Use KMnO4 stain to analyze developed TLC plates from the column fractions (TLCs run in a 3:1 mixture of hexane/EtOAc; see Fig. 7). The first set of compound-containing fractions consist of mostly unreacted arylboronic ester and minor amounts of tert-butyl pyridine-1(2H)-carboxylate (which is often detected as a minor by-product when using this particular allyl chloride).

    Fig. 7: View of the KMNO4-stained TLC plate used to examine fractions obtained by silica gel flash column chromatography.
    figure7

    Fractions circled in red correspond to unreacted arylboronic ester plus minor by-products. Fractions circled in blue correspond to the desired coupling product.

    troubleshooting

  5. 25

    Fractions containing the desired product are combined and then concentrated under reduced pressure using a rotary evaporator and dried under high vacuum.

Determination of the enantiomeric excess

Timing 40 min

  1. 26

    Prepare a sample of the product (1.5 mg mL−1) in hexane in an appropriately sized vial for the HPLC.

  2. 27

    Inject an aliquot of the prepared sample of the product (10 μL) into an HPLC system equipped with a Chiralpak IC column. Elute with 99:1 hexane/2-propanol at a flow rate of 1.0 mL min−1 while monitoring with a UV detector at 210 nm. Approximate retention times for this product are as follows; minor enantiomer tR = 11.0 min; major enantiomer tR = 12.2 min. However, these should be calibrated with a racemic sample of the product.

    troubleshooting

Troubleshooting

Troubleshooting advice can be found in Table 4.

Table 4 Troubleshooting table

Timing

  • Steps 1–5, preparation of the catalyst: 45 min

  • Steps 6–14, preparation of the arylboronic ester and allyl halide solutions: 10 min

  • Steps 15–20, reaction setup: 5 h and 10 min

  • Steps 21—25, reaction workup and purification: 1–2 h

  • Steps 26 and 27, determination of enantiomeric excess: 40 min

Anticipated results

The reported sequence affords an 86% yield (1.17 g, 3.46 mmol) of the desired cross-coupling product (96% ee).

Analytical data for (−)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

This compound was prepared according to the general procedure. The product was obtained as a pale-yellow amorphous solid (86% yield, 96% ee). The ee was determined by comparison with an authentic racemic sample by using HPLC with a chiral nonracemic stationary phase: Chiralpak IC column, flow: 1 mL min−1; hexane/2-propanol: 99:1; L = 210 nm, minor enantiomer tR = 11.0 min; major enantiomer tR = 12.2 min.

Analytical data: 1H NMR (500 MHz, CDCl3) δ 7.42 (m, 2H), 7.08 (m, 2H), 6.00–5.80 (m, 2H), 4.20–3.60 (m, 3H), 3.46–3.00 (m, 2H), 1.48–1.19 (m, 9H).

13C NMR (126 MHz, CDCl3) δ 154.8, 141.3, 131.6 and 131.2 (rotameric, 2C), 129.7 (2C), 128.7 and 128.6 (rotameric, 1C), 127.6 and 127.5 (rotameric, 1C), 126.5 and 125.6 (rotameric, 1C), 120.7, 79.7, 53.6, 48.4 and 47.1 (rotameric, 1C), 43.7 and 43.0 (rotameric, 1C), 41.1, 28.5–28.0 (rotameric, 3C).

IR (νmax (cm−1)): 2,976, 2,929, 1,696, 1,420.

HRMS (CI) m/z calc. for C16H20BrO2 [M+H]+: 338.0705, found: 338.0706.

Melting point (solid obtained from Et2O): 67–68 °C

[α]25589 = −143.3 (c 1.7, CHCl3)

Reporting Summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

All data supporting this protocol are available within the article and in the Supplementary Information file.

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Acknowledgements

Financial support from the UK Engineering and Physical Sciences Research Council (EP/N022246/1) is gratefully acknowledged. J.G. thanks the European Union’s Horizon 2020 research and innovation program for a Marie Skłodowska-Curie Fellowship (GA 700108). L.v.D. is grateful to the Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. F.W.G. is grateful to the National Research Fund, Luxembourg, for an AFR PhD grant (11588566), the EPSRC Doctoral Training Partnership (DTP) for a studentship (EP/N509711/1) and Vertex Pharmaceuticals for financial support.

Author information

J.G., L.v.D. and F.W.G. conducted the experiments. All authors designed the experiments, analyzed the data and edited the manuscript. S.P.F. guided the research. J.G. wrote the manuscript. All authors contributed to discussions.

Correspondence to Stephen P. Fletcher.

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Oxford University Innovation has filed a patent application (PCT/GB2016/051612) with S.P.F. named as an inventor. The remaining authors declare no competing interests.

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Key references using this protocol

Sidera, M. & Fletcher, S. P. Nat. Chem. 7, 935–939 (2015): https://www.nature.com/articles/nchem.2360

Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Nat. Commun. 8, 15762 (2017): https://www.nature.com/articles/ncomms15762

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González, J., van Dijk, L., Goetzke, F.W. et al. Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides. Nat Protoc 14, 2972–2985 (2019). https://doi.org/10.1038/s41596-019-0209-8

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