Morken Makes Consecutive C(sp3)-C(sp3) Connections Combining Copper and Chiral Boronates
Citation:
Zhang, X.; Palka, K. T.; Zhang, M.; Morken, J. P. Nature 2026, 652, 359-364.
https://www.nature.com/articles/s41586-026-10261-9
The construction of alkyl-alkyl (or C(sp3)-C(sp3) bonds) is one of the key challenges that organic chemists are tackling in the 2020s. Transition metal catalysis, particularly the Suzuki reaction, has enabled the formation of biaryl compounds so easily and so efficiently that it has begun to warp the type of molecules we are making to favor flat, arene-rich compounds. It is not a bad thing that these reactions are so powerful - we are accessing more chemical space than ever before - it just sets a high standard for any future methods. Molecules with a higher fraction of saturated carbons (high Fsp3) are potentially advantageous because there are more possible isomers (regio-isomers, diastereomers, and enantiomers), and therefore may have more specific binding to biological targets.
When it comes to making different enantiomers via cross-coupling reactions (asymmetric cross-coupling), there are 3 main strategies:
1. Stereoconvergent cross-coupling. Using a chiral ligand, you engage with one of the coupling partners in a way that ablates (erases) existing stereochemistry, and then the chiral ligand sets new stereochemistry at that site. In the below example from the Fu group, the chiral diamine ligand is the source of chiral information.
S. L. Zultanski, G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362– 15364.
2. Stereospecific cross-coupling (using chiral electrophiles). Using an enantioenriched starting material, the transition metal engages with the coupling partner in a way that preserves existing stereochemical information. In the below example from the Jarvo group, the nickel catalyst engages in stereospecific oxidative addition with the benzylic carbamate, which can result in either retention or inversion at that stereocenter (in this case, dependent on the ligand used).
Jarvo et al., J. Am. Chem. Soc. 2013, 135, 3303–3306
3. Stereospecific cross-coupling (using chiral nucleophiles/organometallic reagents). The third option is the rarest, and uses an enantioenriched organometallic reagent as a coupling partner. Similarly to the second type, the transition metal catalyst must engage with the coupling partner in a way that preserves the stereochemical information, usually via stereospecific transmetalation. In the below example from the Crudden lab, the chiral boronic ester transmetalates stereospecifically.
Crudden et al. J. Am. Chem. Soc. 2009, 131, 5024–5025
One of the major issues with this third route is that many organometallic reagents cannot be made enantioselectively, at least not without major dificulties. More reactive partners rapidly exchange with one another, racemizing faster than they can be used.
Morken et al., Sci. Adv. 2025, 11, eadz3901.
For example, Reinhard Hoffmann spent a long time developing methods to make a chiral Grignard reagent, eventually succeeding by using chiral sulfoxides:
Hoffmann et al., Angew. Che. Int. Ed. 2000, 39, 3072–3074.
The most straight forward method to make these currently is to first make a chiral alkyllithium reagent by adding a chiral iodide into a pool of tBuLi at -100 C. Then, transmetalation to other metals can be accomplished, followed by different transformations that use these chiral organometallic reagents
Knochel et al., Chem. Eur. J. 2013, 19, 4614–4622.
Knochel et al., Angew. Chem. Int. Ed. 2020, 59, 320
However, chiral organometallic reagents using boron or other more electronegative metals are actually quite stable, and there is a long history of preparing chiral boron reagents. For example, metal-catalyzed asymmetric hydroboration is well established:
Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1988, 53, 5178.
Hayashi and Ito, Tetrahedron Assym. 1991, 2, 601–612.
This sets up the idea that if you want to do alkyl-alkyl coupling reactions with chiral organometallic reagents, then alkyl boron reagents are probably one of the better ways to accomplish this.
In order to engage in alkyl-alkyl couping, then you also need an alkyl electrophile to couple with. There has been a lot of research on cross-coupling reactions using alkyl electrophiles in the past several decades, often using base metal catalysts. Interestingly, copper catalysis has some promising results for Suzuki reactions with alkyl electrophiles:
Liu et al., Angew .. Chem. Int. Ed. 2011, 50, 3904–3907.
Fu et al., Chem. Commun. 2014, 50, 11060–11062.
Xie et al., J. Am. Chem. Soc. 2023, 145, 28146–28155.
Copper has been known to engage with alkyl electrophiles, going back to the Corey-House reaction way back in the 1960s (see my other blog post on the history of cross-coupling reactions for more details: https://alwaysbecoupling.blogspot.com/2025/05/looking-back-how-was-cross-coupling.html). Assuming you are able to transmetalate from the organometallic reagent onto the copper catalyst, it makes sense that you can then engage with the alkyl electrophile. Then the hard part is getting the copper to transmetalate with the organometallic reagent.
This is where the Morken lab comes in. Recently, they published a paper with a bunch of reactions using premade boronate reagents (anionic tetracoordinate boron species), coupling them with different activated electrophiles (allylic halides, benzylic halides, etc.)
Morken et al, J. Am. Chem. Soc. 2022, 144, 11546–11552.
These boronates were easily made by taking boronic esters (the Bpin) and reacting them with tBuLi, which irreversibly binds to the boron center. These reagents are stable enough to be isolated and kept in the glovebox, and then they nicely transmetalate with copper. The tBu group is critical, as of the four bonds to boron, two are oxygen (and won't transmetalate), and the tBu group won't transmetalate due to steric hindrance, leaving only the desired B-C available to transmetalate. This is a selective activation of the B-C bond, in a stereospecific fashion.
How it works:
The core idea of this paper is to couple these activated chiral boronic esters with an alkyl electrophile, forming a C(sp3)-C(sp3) bond asymmetrically. The alkyl electrophile of choice here is this odd trifluoromethylated sulfonate, which actually becomes an alkyl iodide in situ. The kinetics of this are likely delicate, as there is competition with off-cycle pathways such as SN2 with other nucleophiles or elimination.
The ligand here is also this TIPS-protected acetylide, which makes the copper significantly more nucleophilic but doesn't result in the off-cycle pathways that are seen with alkoxide ligands and co.
So after forming the active Cu-acetylide complex A (see below), stereospecific transmetalation generated the copper alkyl-alknyl complex B. This can engage with the alkyl electrophile, presumed to be the alkyl iodide, in a concerted fashion that does not go through a oxidative addition/reductive elimination pathway. Based on their computational data, there is no Cu(III) species, and copper never leaves the +1 oxidation state.
First, all of the examples are with primary electrophiles. The inability to engage with secondary electrophiles precludes the possibility of coupling two stereocenters together, which is one of the eventual targets for alkyl-alkyl coupling reactions. They do show an example with a stereocenter at the electrophile, made using a monodeuterated substrate, which racemizes apparently due to SN2 reactions between the alkyl iodide and additional equivalents of I-.
Some functionalities that are sensitive to bases (esters, nitriles, epoxides) were tolerated, which shows the utility of generating the activated boronate first. Obviously, tBuLi is not compatible with these groups, but the boronate is fine. The copper acetylide complex also forms quickly enough and is stable enough to not lead to decomposition, even though the lithium acetylide is very basic.
Finally, the most important functional group in the entire paper is the presence of a different boronic ester, and the authors know it. By activating one boronic ester, then coupling an electrophile with a tethered different unactivated boronic ester, you can engage in sequential, iterative synthesis.
Now, this idea is behind the company Excelsior Sciences, which has raised $95 million to use this as a platform for "robot and AI"-powered synthesis
Gillis and Burke, J. Am. Chem. Soc. 2007, 129, 6716–6717.
Burke et al, J. Am. Chem. Soc. 2022, 604, 92–98.
Derek Lowe also discussed this idea in a recent blog post about this paper: https://www.science.org/content/blog-post/new-bond-formations-just-keep-coming
While I don't think that this is the end of synthesis- see the takeaways below- I think that the understanding of this general strategy is immensely valuable.
Initial Questions and Key Findings:
1. How do you engage a chiral coupling partner in an asymmetric alkyl-alkyl bond forming reaction?
A. Chiral boronates are stable reagents that undergo stereospecific transmetalation with metals, generating metal alkyl species with a chiral center. Copper is particularly good at then engaging with alkyl electrophiles to form carbon-carbon bonds while preserving this stereocenter.
2. Can you get selectivity for one type of boron reagent over another?
A. Yes, transmetalation is specific for the boronate, not the boronic ester. This means that only the activated coupling partner engaged, leaving a different boronic ester available for later activation and coupling.
3. Can this be used for sequential, iterative synthesis by repeating the same process over and over to make complicated molecules?
A. Sort of. This is the premise of the paper- that you could use this reaction to make complicated molecules by just building up with different building blocks. However, if you look at the two given examples of complicated molecules built up, one involves two of these cross-coupling reactions, and the other just a single one. This means that the iterative nature of the reaction doesn't really come into play. Also, the length of the linker has a significant effect on the efficacy of the reaction. If the other coupling partner is within a few carbons, the reaction doesn't work. Their example of multiple sequential couplings has a significant "spacer" between each building block. The yields are also not great, and requires purification in between steps. One of the major advantages of the Burke group's MIDA strategy is that the purification is extremely easy; the MIDA boronates are retained on silica gel under some solvents and can be released upon solvent change. Needing to do standard organic purification techniques moves this from the realm of "new solid phase peptide synthesis" into "good strategy for organic reactions".
Takeaways:
There are a lot of really powerful strategies in this paper. I really like the use of copper to activate the chiral boronate, and recognizing that these boronates can be generated, kept stable, and then used as precursors is beneficial. I think the requirement of a specific electrophile + ligand + copper salt combination is going to limit the generality of this reaction, as only specific types of substrates can be successfully activated by the copper-alkyl complex without competing degradative side pathways. This hopefully will be a solvable issue, and I look forward to seeing how the authors develop the chemistry further.
Comments
Post a Comment