Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization

Article abstract of DOI:10.1126/science.aat2299

Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Here we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.

Full text of DOI:10.1126/science.aat2299

REPORTS
Cite as: S. Zhao et al., Science
10.1126/science.aat2299 (2018).
Enantiodivergent Pd-catalyzed C–C bond formation
enabled through ligand parameterization
Shibin Zhao,1,2* Tobias Gensch,3* Benjamin Murray,1,2 Zachary L. Niemeyer,3 Matthew S. Sigman,3†
Mark R. Biscoe1,2
†
1Department of Chemistry, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA. 2Ph.D. Program in Chemistry, The Graduate Center of the City
University of New York, 365 Fifth Avenue, New York, NY 10016, USA. 3Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA.
*These authors contributed equally to this work. †Corresponding author. Email: sigman@chem.utah.edu (M.S.S.); mbiscoe@ccny.cuny.edu (M.R.B.)
Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally
manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of
stereochemistry in these reactions remain poorly understood. Herein we report a mechanistic and
synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-
catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine
ligands, we could apply predictive statistical models to select or design distinct ligands that respectively
promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched
structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and
a general model for the mechanism of alkylboron transmetallation was proposed.
electronically activated via inclusion of a C(sp2) α-carbon, an
α-heteroatom, and/or a strongly coordinating β-carbonyl
Palladium-catalyzed cross-coupling reactions have revolu-
tionized the construction of C(sp2)–C(sp2) bonds. Among
these cross-coupling processes, the Suzuki–Miyaura reaction
has found particularly broad application due to its extensive
reaction scope, as well as the stability, availability, and low
toxicity of organoboron reagents (1). The 2010 Nobel Prize in
chemistry was awarded, in part, to recognize the transforma-
tive impact of the Suzuki cross-coupling reaction on chemical
synthesis. However, although C(sp2)–C(sp2) bond construc-
tion is now considered routine using the Suzuki reaction, ex-
tension of this process to the formation of C(sp3)–C(sp2)
bonds using alkylboron nucleophiles remains a significant
challenge. Of particular interest, a variant using secondary
alkylboron nucleophiles with predictable and controllable
stereospecificity would establish a powerful synthetic strat-
egy to access molecular geometries with precise three-dimen-
sional control, expanding the exceptional capabilities of the
Suzuki reaction (Fig. 1A).
Many efforts have focused on the use of enantioenriched
secondary alkylboron nucleophiles in Suzuki cross-coupling
reactions (2–4). Significant limitations remain due to slow
transmetallation of the highly covalent and sterically con-
gested C(sp3)–B bond in these reagents, as well as the propen-
sity of the resulting Pd-alkyl species to undergo β-hydride
elimination/reinsertion sequences, which can result in isom-
erization of the alkyl group and racemization of the stereo-
center. To circumvent prohibitively slow transmetallation, as
group (5–17). In addition, alkylboron nucleophiles can un-
dergo transmetallation via either stereoretentive or stereoin-
vertive pathways depending on the nature of the substrate,
catalyst, and/or reaction conditions. In many cases, the fac-
tors controlling the dominant mechanism of transmetalla-
tion are not understood (Fig. 1B). Thus, a predictive
stereochemical model for transmetallation of alkylboron rea-
gents remains elusive.
Recently, we reported a stereospecific Pd-catalyzed cross-
coupling reaction using unactivated secondary alkylboron
nucleophiles (18). With PtBu3 as a supporting ligand, enanti-
oenriched arylation products were obtained with transmetal-
lation proceeding primarily via a stereoinvertive mechanism.
Whereas several enlightening mechanistic studies have re-
cently been conducted on the transmetallation of arylboron
nucleophiles (19–23), these studies have not addressed the
transmetallation of alkylboron nucleophiles in C(sp3)–C(sp2)
bond-forming processes (24, 25). Thus, unactivated alkyl-
boron nucleophiles constitute an attractive starting point
from which to investigate the reaction parameters most in-
fluential to the mechanism of alkylboron transmetallation.
This mechanistic work should simultaneously facilitate the
development of new synthetic methods to rationally incorpo-
rate/manipulate stereocenters via cross-coupling strategies.
To this end, we report a study using predictive statistical
well as competing β-hydride elimination/reinsertion path- models (26, 27) to relate phosphine ligand properties to ste-
ways, most stereospecific Suzuki reactions have required the reochemical outcomes obtained from Pd-catalyzed Suzuki re-
use of secondary alkylboron nucleophiles that are actions of unactivated enantioenriched secondary alkylboron
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nucleophiles and aryl electrophiles. With statistical models and stereoinvertive transmetallation mechanisms that deter-
that rely on a next generation set of molecular descriptors, mine the final stereochemistry of the cross-coupling product
we achieved a stereoretentive Pd-catalyzed cross-coupling re-
action of such nucleophiles. Furthermore, we have identified
an improved ligand for the stereoinvertive variant, thus ena-
bling an entirely ligand-controlled enantiodivergent process
from a single-enantiomer organoboron nucleophile (28). Our
statistical models also provide compelling evidence that each
transmetallation pathway is intimately tied to specific elec-
tronic properties of the supporting ligand, which serves as a
predictive guide to the mechanism of alkylboron transmetal-
lation to palladium.
Initial investigations using electronically differentiated
aryl chlorides with enantioenriched sBuBF3K revealed a trend
correlating diminished stereofidelity with the use of more
electron-deficient coupling partners (Fig. 1C, I). This observa-
tion suggested that subtle electronic effects could influence
the mechanism of transmetallation and the resulting stereo-
chemical outcome. Additionally, when the phosphine ligand
was varied in an initial screen with a common aryl chloride
electrophile, a considerable change in the reaction outcome
from stereoinvertion to stereoretention was found (Fig. 1C,
II). No obvious correlation was observed between these re-
sults and the steric properties (solid angle) of the ligand.
Taken together, these outcomes were difficult to interpret
and inspired the use of ligand parameterization tools to pro-
vide a platform for both predictive ligand performance and
mechanistic interrogation.
An expanded inventory of common phosphines with var-
ied properties was evaluated in the Suzuki reaction of enan-
tioenriched sBuBF3K and ethyl 4-chlorobenzoate. This dataset
was then subjected to correlation analysis of phosphine struc-
tural features with the stereochemical outcomes as well as
the ratios of branched:linear products in these reactions. We
devised a workflow and universal parameter set to describe
the catalyst properties from the phosphine itself (29–32). The
workflow was initiated by performing a molecular mechanics
(MM) conformational search to reveal representative low en-
ergy conformers. (Fig. 2A). Next, geometry optimization of
the conformers using DFT was followed by parameter collec-
tion. Subsequently, four descriptor subsets were defined to
capture the conformational dynamics of the ligands by in-
cluding the mathematical extreme descriptor values (mini-
mum and maximum), the lowest energy conformer values,
and the Boltzmann weighted averages. We viewed the unique
treatment of representative conformers as a crucial means of
describing ensemble properties such as chemical shift while
also probing structural flexibility during catalysis.
and ii) the competitive β-hydride elimination/isomerization
sequences that follow transmetallation. A correlation of the
branched:linear ratio with the final enantiopurity of the
product reveals that β-hydride elimination is responsible for
both racemization and isomerization to the linear side prod-
uct. Furthermore, a modest trend is observed relating the
minimum width B1 of the phosphine ligand to the
branched:linear ratio (Fig. 2B). This is consistent with reports
of large ligands facilitating reductive elimination over β-hy-
dride elimination (33), and suggests the use of a parameteri-
zation approach to take into account the conformational
flexibility of ligands.
Since the inherent selectivity of the transmetallation mech-
anism is masked by deleterious racemization as a consequence
of β-hydride elimination, only ligands providing high selectiv-
ity were further investigated (>30% ee, Fig. 2B). The molecular
electrostatic potential minimum in the phosphorus lone pair
region (Vmin) has been shown to correlate with the classical Tol-
man electronic parameter (34). Thus, Vmin serves as an easily
computable measure for the overall ligand electronics. A cor-
relation between enantioselectivity and Vmin was observed
within the abridged dataset indicating that electronic proper-
ties of the ligand determine the mechanism of transmetalla-
tion. Specifically, electron-rich trialkylphosphines promoted
stereoinvertive reactions, whereas the electron-poorer tri-
arylphosphines provided modest selectivity for stereoreten-
tion. Use of the bulky, electron-rich ligand PAd3 (9), which was
recently reported by Carrow (35), resulted in a particularly
large preference for the stereoinvertive outcome. Based on
these data, we hypothesized and virtually evaluated ligands for
improved stereoretentive outcomes with the following fea-
tures: i) large ligand bulk to prevent β-hydride elimination and
racemization, and ii) electron-deficient aryl substituents at
phosphorus to promote the stereoretentive mechanism and to
accelerate reductive elimination (Fig. 2B). Among the pro-
posed ligands was a set of biaryl phosphines (11-15), as pio-
neered by Buchwald (36), featuring various electron-deficient
aryl groups at phosphorus. Gratifyingly, ligands 11 and 14 pro-
mote the alkyl Suzuki cross-coupling reaction with signifi-
cantly enhanced selectivity (up to 90% ee) and minimal alkyl
isomerization. Thus, parameterization-driven optimization fa-
cilitated development of a stereoretentive Suzuki reaction in-
volving unactivated alkylboron nucleophiles. When considered
alongside the introduction of 9 to achieve stereoinvertive cou-
plings, predictable control of the absolute sense of enantiose-
lectivity (retention or inversion) can be engendered by simply
selecting the appropriate ligand.
The final step in the workflow involved the analysis of
both the stereofidelity and the branched:linear product ratio.
These two readouts presumably describe two stages of the re-
action mechanism (Fig. 1B): i) the competing stereoretentive
Our stereochemical investigations of secondary alkyl-
boron transmetallation in the Suzuki reaction suggested that
both enantiomers of a cross-coupling product could be
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selectively accessed through use of a single enantioenriched transmetallation using the parameterization strategy de-
alkylboron reagent with the proper selection of the phos- scribed above (Fig. 4). To accomplish this, phenyl-substituted
phine ligand. The scope of this process is depicted in Fig. 3. substrate 20 was selected due to enhanced performance and
Using enantioenriched, unactivated alkyltrifluoroborate nu- thus a greater output range. A singular aryl chloride electro-
cleophiles, ligand-controlled stereoselectivity was broadly phile was chosen for this analysis to avoid potential attenua-
achieved in cross-coupling reactions with aryl electrophiles. tion of the ligand effects by the influence of different counter-
ions (e.g., bromide or triflate). Additionally, 24 ligands were
tested, excluding smaller ligands to reduce the complexity as-
Strongly π-accepting ligands bis-CF3PhSPhos (11) and bis-
CF3PhXPhos (14), which emerged from our parameteriza-
tion-guided optimization, preferentially promote the stere- sociated with β-hydride elimination. Multivariate linear re-
oretentive pathway, while strongly σ-donating ligand PAd3 gression revealed that most of the outputs can be expressed
(9) preferentially promotes the stereoinvertive pathway. Be- in two readily interpretable terms that discriminate the
cause electron-poor palladium catalysts commonly undergo transmetallation pathways: the average energy of the P−C an-
slow oxidative addition with aryl chlorides, we also evaluated tibonding orbitals Eσ*(P−C), representative of π-back bonding,
aryl bromide and triflate electrophiles in reactions involving and the energy of the lone pair orbital of phosphorus ELP(P), a
11 and 14. A particular highlight of this protocol is the uni-
formity of the conditions used for both the stereoinvertive
and stereoretentive reactions: each operates in a toluene/wa-
ter mixture as solvent, with a carbonate base, and no addi-
tional additives. Both reaction variants tolerated the use of
electron-rich and electron-deficient aryl electrophiles, as well
as an aryl electrophile bearing an ortho-substituent. High ste-
reofidelity was achieved for all of these reactions, including
those involving alkylboron nucleophiles bearing thiophenyl
and phenoxide substituents. Use of an alkylboron nucleophile
containing a larger substituent (replacing methyl with ethyl)
at the stereogenic center was also well tolerated (16i). In the
absence of a methyl substituent, the stereoinvertive variant
shows modestly reduced selectivity that may be improved by
reducing the reaction temperature. This was partially antici-
pated due to the greater sensitivity of the metal fragment to
steric congestion at carbon in the stereoinvertive SE2
transmetallation mechanism. Diastereomeric products 17a
and 17b could be generated from a single alkylboron diastere-
omer (37) using 14 and PAd3, respectively (Fig. 3B). In these
reactions, replacement of ligand 14 with PAd3 resulted in a
change in diastereoselectivity from 30:1 to 1:5, a 3.6 kcal/mol
free energy of activation difference dependent only on the lig-
and identity. No erosion of specificity was observed for elec-
tron-deficient aryl substrates in stereoinvertive Suzuki
reactions using PAd3, in contrast to analogous reactions using
PtBu3. Furyl and thiophenyl electrophiles are also compatible
with our system (Fig. 3C). As an additional mechanistic
probe, trans-2-methylcyclopentyltrifluoroborate was sub-
jected to the stereodivergent reaction conditions. Because
trans-2-methylcyclopentyltrifluoroborate is sterically im-
peded from undergoing stereoinvertive transmetallation,
only the stereoretentive process using 14 should be mecha-
nistically viable. Indeed, we observed that use of ligand 14
smoothly generates 18 with stereoretention, while use of
PAd3 results in low alkylboron conversion.
measure of the ligand’s σ-donation capability (Fig. 4B). This
outcome suggests that the stereoinvertive pathway is depend-
ent on strong σ-donation from the ligand, which may stabi-
lize
a
two-coordinate, cationic palladium complex.
Conversely, the stereoretentive pathway is enhanced by
π-back bonding, which may stabilize the coordination of a
π-donor ligand X (presumably OH−) to Pd. Including two ste-
ric descriptors such as B1 and L improves the model fit by
treating the competitive β-hydride elimination that occurs
using smaller ligands and decreases the observed specificity.
This becomes evident when the four smallest ligands in this
dataset are removed from the analysis, which results in an
excellent correlation using just the two electronic descriptors
with the experimentally observed stereochemical outcomes
(Fig. 4D). Multivariate regression analysis thereby provides
compelling evidence for the electronic factors favoring each
transmetallation mechanism and thus a guideline for future
developments in stereospecific cross-coupling reactions.
REFERENCES AND NOTES
1. J. C. H. Lee, D. G. Hall, “State-of-the-art in metal-catalyzed cross-coupling reactions
of organoboron compounds with organic electrophiles,” in Metal-Catalyzed Cross-
Coupling Reactions and More, A. de Meijere, S. Bräse, M. Oestreich, Eds. (Wiley-
VCH, ed. 3, 2014), vol. 1, pp. 65–132.
2. C.-Y. Wang, J. Derosaa, M. R. Biscoe, Configurationally stable, enantioenriched
organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling
reactions: An alternative approach to asymmetric synthesis. Chem. Sci. 6, 5105–
5113 (2015). doi:10.1039/C5SC01710F Medline
3. C. Sandford, V. K. Aggarwal, Stereospecific functionalizations and transformations
of secondary and tertiary boronic esters. Chem. Commun. (Camb.) 53, 5481–
5494 (2017). doi:10.1039/C7CC01254C Medline
4. J. P. G. Rygus, C. M. Crudden, Enantiospecific and iterative Suzuki-Miyaura cross-
couplings. J. Am. Chem. Soc. 139, 18124–18137 (2017). doi:10.1021/jacs.7b08326
Medline
5. D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, Cross coupling reactions
of chiral secondary organoboronic esters with retention of configuration. J. Am.
Chem. Soc. 131, 5024–5025 (2009). doi:10.1021/ja8094075 Medline
6. D. L. Sandrock, L. Jean-Gérard, C. Y. Chen, S. D. Dreher, G. A. Molander,
Stereospecific cross-coupling of secondary alkyl β-trifluoroboratoamides. J. Am.
Chem. Soc. 132, 17108–17110 (2010). doi:10.1021/ja108949w Medline
7. T. Ohmura, T. Awano, M. Suginome, Stereospecific Suzuki-Miyaura coupling of
chiral α-(acylamino)benzylboronic esters with inversion of configuration. J. Am.
Chem. Soc. 132, 13191–13193 (2010). doi:10.1021/ja106632j Medline
To further probe the origin of the ligand-dependent enan-
tiodivergent process, we interrogated the mechanism of
First release: 20 September 2018
www.sciencemag.org
(Page numbers not final at time of first release)
3

8. T. Awano, T. Ohmura, M. Suginome, Inversion or retention? Effects of acidic
additives on the stereochemical course in enantiospecific Suzuki-Miyaura
coupling of α-(acetylamino)benzylboronic esters. J. Am. Chem. Soc. 133, 20738–
20741 (2011). doi:10.1021/ja210025q Medline
9. J. C. H. Lee, R. McDonald, D. G. Hall, Enantioselective preparation and
chemoselective cross-coupling of 1,1-diboron compounds. Nat. Chem. 3, 894–
899 (2011). doi:10.1038/nchem.1150 Medline
10. B. M. Partridge, L. Chausset-Boissarie, M. Burns, A. P. Pulis, V. K. Aggarwal,
Enantioselective synthesis and cross-coupling of tertiary propargylic boronic
esters using lithiation-borylation of propargylic carbamates. Angew. Chem. Int.
Ed. 51, 11795–11799 (2012). doi:10.1002/anie.201203198 Medline
11. G. A. Molander, S. R. Wisniewski, Stereospecific cross-coupling of secondary
organotrifluoroborates: Potassium 1-(benzyloxy)alkyltrifluoroborates. J. Am.
Chem. Soc. 134, 16856–16868 (2012). doi:10.1021/ja307861n Medline
12. S. C. Matthew, B. W. Glasspoole, P. Eisenberger, C. M. Crudden, Synthesis of
enantiomerically enriched triarylmethanes by enantiospecific Suzuki-Miyaura
cross-coupling reactions. J. Am. Chem. Soc. 136, 5828–5831 (2014).
doi:10.1021/ja412159g Medline
27. M. S. Sigman, K. C. Harper, E. N. Bess, A. Milo, The development of
multidimensional analysis tools for asymmetric catalysis and beyond. Acc. Chem.
Res. 49, 1292–1301 (2016). doi:10.1021/acs.accounts.6b00194 Medline
28. S. Krautwald, E. M. Carreira, Stereodivergence in asymmetric catalysis. J. Am.
Chem. Soc. 139, 5627–5639 (2017). doi:10.1021/jacs.6b13340 Medline
29. C. A. Tolman, Steric effects of phosphorus ligands in organometallic chemistry
and homogeneous catalysis. Chem. Rev. 77, 313–348 (1977).
doi:10.1021/cr60307a002
30. J. Jover, N. Fey, J. N. Harvey, G. C. Lloyd-Jones, A. G. Orpen, G. J. J. Owen-Smith,
P. Murray, D. R. J. Hose, R. Osborne, M. Purdie, Expansion of the ligand knowledge
base for monodentate P-donor ligands (LKB-P). Organometallics 29, 6245–6258
(2010). doi:10.1021/om100648v
31. Z. L. Niemeyer, A. Milo, D. P. Hickey, M. S. Sigman, Parameterization of phosphine
ligands reveals mechanistic pathways and predicts reaction outcomes. Nat.
Chem. 8, 610–617 (2016). doi:10.1038/nchem.2501 Medline
32. K. Wu, A. G. Doyle, Parameterization of phosphine ligands demonstrates
enhancement of nickel catalysis via remote steric effects. Nat. Chem. 9, 779–784
(2017). doi:10.1038/nchem.2741 Medline
13. C. Sun, B. Potter, J. P. Morken, A catalytic enantiotopic-group-selective Suzuki
reaction for the construction of chiral organoboronates. J. Am. Chem. Soc. 136,
6534–6537 (2014). doi:10.1021/ja500029w Medline
14. T. P. Blaisdell, J. P. Morken, Hydroxyl-directed cross-coupling: A scalable synthesis
of debromohamigeran E and other targets of interest. J. Am. Chem. Soc. 137,
8712–8715 (2015). doi:10.1021/jacs.5b05477 Medline
33. R. Jana, T. P. Pathak, M. S. Sigman, Advances in transition metal (Pd, Ni, Fe)-
catalyzed cross-coupling reactions using alkyl-organometallics as reaction
partners. Chem. Rev. 111, 1417–1492 (2011). doi:10.1021/cr100327p Medline
34. C. H. Suresh, N. Koga, Quantifying the electronic effect of substituted phosphine
ligands via molecular electrostatic potential. Inorg. Chem. 41, 1573–1578 (2002).
doi:10.1021/ic0109400 Medline
15. S. Miyamura, M. Araki, T. Suzuki, J. Yamaguchi, K. Itami, Stereodivergent synthesis
of arylcyclopropylamines by sequential C–H borylation and Suzuki-Miyaura
35. L. Chen, P. Ren, B. P. Carrow, Tri(1-adamantyl)phosphine: Expanding the
boundary of electron-releasing character available to organophosphorus
coupling.
Angew.
Chem.
Int.
Ed.
54,
846–851
(2015).
compounds.
J.
Am.
Chem.
Soc.
138,
6392–6395
(2016).
doi:10.1002/anie.201409186 Medline
doi:10.1021/jacs.6b03215 Medline
16. Y. Lou, P. Cao, T. Jia, Y. Zhang, M. Wang, J. Liao, Copper-catalyzed enantioselective
1,6-boration of para-quinone methides and efficient transformation of gem-
diarylmethine boronates to triarylmethanes. Angew. Chem. Int. Ed. 127, 12302–
12306 (2015). doi:10.1002/ange.201505926
17. G. L. Hoang, J. M. Takacs, Enantioselective γ-borylation of unsaturated amides and
stereoretentive Suzuki-Miyaura cross-coupling. Chem. Sci. 8, 4511–4516 (2017).
doi:10.1039/C7SC01093A Medline
18. L. Li, S. Zhao, A. Joshi-Pangu, M. Diane, M. R. Biscoe, Stereospecific Pd-catalyzed
cross-coupling reactions of secondary alkylboron nucleophiles and aryl chlorides.
J. Am. Chem. Soc. 136, 14027–14030 (2014). doi:10.1021/ja508815w Medline
19. C. Amatore, A. Jutand, G. Le Duc, Kinetic data for the transmetalation/reductive
elimination in palladium-catalyzed Suzuki-Miyaura reactions: Unexpected triple
role of hydroxide ions used as base. Chemistry 17, 2492–2503 (2011).
doi:10.1002/chem.201001911 Medline
20. B. P. Carrow, J. F. Hartwig, Distinguishing between pathways for transmetalation
in Suzuki-Miyaura reactions. J. Am. Chem. Soc. 133, 2116–2119 (2011).
doi:10.1021/ja1108326 Medline
21. A. A. Thomas, S. E. Denmark, Pre-transmetalation intermediates in the Suzuki-
Miyaura reaction revealed: The missing link. Science 352, 329–332 (2016).
doi:10.1126/science.aad6981 Medline
22. A. A. Thomas, H. Wang, A. F. Zahrt, S. E. Denmark, Structural, kinetic, and
computational characterization of the elusive arylpalladium(II)boronate
complexes in the Suzuki–Miyaura reaction. J. Am. Chem. Soc. 139, 3805–3821
(2017). doi:10.1021/jacs.6b13384 Medline
23. A. A. Thomas, A. F. Zahrt, C. P. Delaney, S. E. Denmark, Elucidating the role of the
boronic esters in the Suzuki–Miyaura reaction: Structural, kinetic, and
computational investigations. J. Am. Chem. Soc. 140, 4401–4416 (2018).
doi:10.1021/jacs.8b00400 Medline
36. D. S. Surry, S. L. Buchwald, Dialkylbiaryl phosphines in Pd-catalyzed amination: A
user’s guide. Chem. Sci. 2, 27–50 (2011). doi:10.1039/C0SC00331J Medline
37. S. Balieu, G. E. Hallett, M. Burns, T. Bootwicha, J. Studley, V. K. Aggarwal, Toward
ideality: The synthesis of (+)-kalkitoxin and (+)-hydroxyphthioceranic acid by
assembly-line synthesis. J. Am. Chem. Soc. 137, 4398–4403 (2015).
doi:10.1021/ja512875g Medline
38. H. Li, L. Wang, Y. Zhang, J. Wang, Transition-metal-free synthesis of pinacol
alkylboronates from tosylhydrazones. Angew. Chem. Int. Ed. 51, 2943–2946
(2012). doi:10.1002/anie.201108139 Medline
39. V. Bagutski, A. Ros, V. K. Aggarwal, Improved method for the conversion of
pinacolboronic esters into trifluoroborate salts: Facile synthesis of chiral
secondary and tertiary trifluoroborates. Tetrahedron 65, 9956–9960 (2009).
doi:10.1016/j.tet.2009.10.002
40. G. A. Molander, L. N. Cavalcanti, Oxidation of organotrifluoroborates via oxone. J.
Org. Chem. 76, 623–630 (2011). doi:10.1021/jo102208d Medline
41. S. D. Dreher, P. G. Dormer, D. L. Sandrock, G. A. Molander, Efficient cross-coupling
of secondary alkyltrifluoroborates with aryl chlorides—Reaction discovery using
parallel microscale experimentation. J. Am. Chem. Soc. 130, 9257–9259 (2008).
doi:10.1021/ja8031423 Medline
42. W. F. Bailey, X. Jiang, Cyclization of (4-methoxy-5-hexenyl)lithium. J. Org. Chem.
59, 6528–6533 (1994). doi:10.1021/jo00101a010
43. R. Larouche-Gauthier, T. G. Elford, V. K. Aggarwal, Ate complexes of secondary
boronic esters as chiral organometallic-type nucleophiles for asymmetric
synthesis. J. Am. Chem. Soc. 133, 16794–16797 (2011). doi:10.1021/ja2077813
Medline
44. A. Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K. Aggarwal, Enantiospecific sp2-
sp3 coupling of secondary and tertiary boronic esters. Nat. Chem. 6, 584–589
(2014). doi:10.1038/nchem.1971 Medline
24. B. H. Ridgway, K. A. Woerpel, Transmetalation of alkylboranes to palladium in the
Suzuki coupling reaction proceeds with retention of stereochemistry. J. Org.
Chem. 63, 458–460 (1998). doi:10.1021/jo970803d Medline
25. K. Matos, J. A. Soderquist, Alkylboranes in the Suzuki–Miyaura coupling:
Stereochemical and mechanistic studies. J. Org. Chem. 63, 461–470 (1998).
doi:10.1021/jo971681s Medline
26. C. B. Santiago, J.-Y. Guo, M. S. Sigman, Predictive and mechanistic multivariate
linear regression models for reaction development. Chem. Sci. 9, 2398–2412
(2018). doi:10.1039/C7SC04679K Medline
45. M. Burns, S. Essafi, J. R. Bame, S. P. Bull, M. P. Webster, S. Balieu, J. W. Dale, C. P.
Butts, J. N. Harvey, V. K. Aggarwal, Assembly-line synthesis of organic molecules
with tailored shapes. Nature 513, 183–188 (2014). doi:10.1038/nature13711
Medline
46. T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, Catalysts for Suzuki-
Miyaura coupling processes: Scope and studies of the effect of ligand structure.
J. Am. Chem. Soc. 127, 4685–4696 (2005). doi:10.1021/ja042491j Medline
47. N. Hartmann, M. Niemeyer, Easy large-scale synthesis of sterically encumbered 2-
iodobiphenyls and some derivatives thereof. Syn. Comm. 31, 3839–3845 (2001).
First release: 20 September 2018
www.sciencemag.org
(Page numbers not final at time of first release)
4

doi:10.1081/SCC-100108234
methods. XX. A basis set for correlated wave functions. J. Chem. Phys. 72, 650–
654 (1980). doi:10.1063/1.438955
66. J. R. Cheeseman, G. W. Trucks, T. A. Keith, M. J. Frisch, A comparison of models
for calculating nuclear magnetic resonance shielding tensors. J. Chem. Phys. 104,
5497–5509 (1996). doi:10.1063/1.471789
48. J. D. Hicks, A. M. Hyde, A. M. Cuezva, S. L. Buchwald, Pd-catalyzed N-arylation of
secondary acyclic amides: Catalyst development, scope, and computational
study. J. Am. Chem. Soc. 131, 16720–16734 (2009). doi:10.1021/ja9044357
Medline
49. N. C. Bruno, M. T. Tudge, S. L. Buchwald, Design and preparation of new palladium
precatalysts for C–C and C–N cross-coupling reactions. Chem. Sci. 4, 916–920
(2013). doi:10.1039/C2SC20903A Medline
50. N. C. Bruno, N. Niljianskul, S. L. Buchwald, N-substituted 2-
aminobiphenylpalladium methanesulfonate precatalysts and their use in C–C and
C–N cross-couplings. J. Org. Chem. 79, 4161–4166 (2014).
doi:10.1021/jo500355k Medline
51. S. D. Friis, T. Skrydstrup, S. L. Buchwald, Mild Pd-catalyzed aminocarbonylation of
(hetero)aryl bromides with a palladacycle precatalyst. Org. Lett. 16, 4296–4299
(2014). doi:10.1021/ol502014b Medline
52. L. Li, C. Y. Wang, R. Huang, M. R. Biscoe, Stereoretentive Pd-catalysed Stille cross-
coupling reactions of secondary alkyl azastannatranes and aryl halides. Nat.
Chem. 5, 607–612 (2013). doi:10.1038/nchem.1652 Medline
53. S. A. Green, J. L. Matos, A. Yagi, R. A. Shenvi, Branch-selective hydroarylation:
Iodoarene-olefin cross-coupling. J. Am. Chem. Soc. 138, 12779–12782 (2016).
doi:10.1021/jacs.6b08507 Medline
54. W. M. Czaplik, M. Mayer, A. J. V. Wangelin, Direct cobalt-catalyzed cross-coupling
between aryl and alkyl halides. Synlett 18, 2931–2934 (2009).
55. A. Wilsily, Y. Nguyen, E. Fillion, Hydrogenolysis of unstrained carbon-carbon σ
bonds: Stereoselective entry into benzylic tertiary centers. J. Am. Chem. Soc. 131,
15606–15607 (2009). doi:10.1021/ja9076815 Medline
67. Y. Zhao, D. G. Truhlar, The M06 suite of density functionals for main group
thermochemistry, thermochemical kinetics, noncovalent interactions, excited
states, and transition elements: Two new functionals and systematic testing of
four M06-class functionals and 12 other function. Theor. Chem. Acc. 120, 215–241
(2008). doi:10.1007/s00214-007-0310-x
68. F. Weigend, R. Ahlrichs, Balanced basis sets of split valence, triple zeta valence
and quadruple zeta valence quality for H to Rn: Design and assessment of
accuracy. Phys. Chem. Chem. Phys. 7, 3297–3305 (2005).
doi:10.1039/b508541a Medline
69. E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold, NBO Version 3.1
(University of Wisconsin–Madison, 1990).
70. S. K. Latypov, F. M. Polyancev, D. G. Yakhvarov, O. G. Sinyashin, Quantum
chemical calculations of 31P NMR chemical shifts: Scopes and limitations. Phys.
Chem. Chem. Phys. 17, 6976–6987 (2015). doi:10.1039/C5CP00240K Medline
71. H. Clavier, S. P. Nolan, Percent buried volume for phosphine and N-heterocyclic
carbene ligands: Steric properties in organometallic chemistry. Chem. Commun.
(Camb.) 46, 841–861 (2010). doi:10.1039/b922984a Medline
72. L. Falivene, R. Credendino, A. Poater, A. Petta, L. Serra, R. Oliva, V. Scarano, L.
Cavallo, SambVca 2. A web tool for analyzing catalytic pockets with topographic
steric
maps.
Organometallics
35,
2286–2293
(2016).
doi:10.1021/acs.organomet.6b00371
56. J. E. Baldwin, S. Bonacorsi Jr., Stereochemistry of the thermal isomerizations of
73. SambVca 2.0 server; www.molnac.unisa.it/OMtools/sambvca2.0/index.html.
74. A. Verloop, in Drug Design, E. J. Ariens, Ed. (Academic Press, 1976), vol. 3, pp. 133–
187.
75. T. Piou, F. Romanov-Michailidis, M. Romanova-Michaelides, K. E. Jackson, N.
Semakul, T. D. Taggart, B. S. Newell, C. D. Rithner, R. S. Paton, T. Rovis, correlating
reactivity and selectivity to cyclopentadienyl ligand properties in Rh(III)-catalyzed
C–H activation reactions: An experimental and computational study. J. Am. Chem.
Soc. 139, 1296–1310 (2017). doi:10.1021/jacs.6b11670 Medline
(1R,
2R)-1-((E)-styryl)-2-methylcyclopropane
to
3-phenyl-4-
methylcyclopentenes. J. Am. Chem. Soc. 115, 10621–10627 (1993).
doi:10.1021/ja00076a021
57. Schrödinger Release 2018-1: MacroModel (Schrödinger, LLC, New York, 2018).
58. K. Ermanis, K. E. B. Parkes, T. Agback, J. M. Goodman, Expanding DP4: Application
to drug compounds and automation. Org. Biomol. Chem. 14, 3943–3949 (2016).
doi:10.1039/C6OB00015K Medline
59. K. Ermanis, J. M. Goodman, PyDP4 workflow integrating MacroModel/TINKER,
76.
K.
Jackson,
R.
Paton,
Sterimol.py
(2017);
Gaussian/NWChem
and
DP4
analysis,
version
0.7
(2016);
https://github.com/bobbypaton/Sterimol.
https://github.com/KristapsE/PyDP4/.
77. I. A. Guzei, M. Wendt, An improved method for the computation of ligand steric
effects based on solid angles. Dalton Trans. 2006, 3991–3999 (2006).
doi:10.1039/b605102b Medline
78. I. A. Guzei, M. Wendt, Program Solid-G (University of Wisconsin–Madison, 2004).
79. MATLAB R2017a (Mathworks, Inc., Natick, MA, 2017).
60. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M.
Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P.
Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding,
F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe,
V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. J.
Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R.
Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski,
R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J. Fox, Gaussian 16,
Revision A.03 (Gaussian, Inc., Wallingford, CT, 2016).
61. C. Adamo, V. Barone, Toward reliable density functional methods without
adjustable parameters: The PBE0 model. J. Chem. Phys. 110, 6158–6170 (1999).
doi:10.1063/1.478522
62. W. J. Hehre, R. Ditchfield, J. A. Pople, Self-consistent molecular orbital methods.
XII. Further extensions of Gaussian-type basis sets for use in molecular orbital
studies of organic molecules. J. Chem. Phys. 56, 2257–2261 (1972).
doi:10.1063/1.1677527
80. J.-Y. Guo, Y. Minko, C. B. Santiago, M. S. Sigman, Developing comprehensive
computational parameter sets to describe the performance of pyridine-oxazoline
and
related
ligands.
ACS
Catal.
7,
4144–4151
(2017).
doi:10.1021/acscatal.7b00739
ACKNOWLEDGMENTS
We acknowledge R. Kinthada for contributions to the diastereoselectivity studies. We
thank G. Ralph for assistance with chiral HPLC analysis. We thank Prof. Luigi
Cavallo for providing us with the command line tool for computing percent
buried volume. Funding: we are grateful to the National Institutes of Health
(grant SC1GM110010 to M.R.B.), the National Science Foundation (grant CHE-
1665189 to M.R.B. and grants CHE-1361296 and CHE-1763436 to M.S.S), and the
Leopoldina Fellowship Programme of the German National Academy of Sciences
Leopoldina (LPDS 2017-18 to T.G.). The support and resources from the Center
for High Performance Computing (CHPC) at the University of Utah are gratefully
acknowledged. Further computational resources were provided by the Extreme
Science and Engineering Discovery Environment (XSEDE), which is supported by
the NSF (ACI-1548562) and provided through allocation TG-CHE180003. Author
contributions: S.Z. and B.M. performed all synthetic experiments and isolated
all products. T.G. computed all ligand parameters and performed multivariate
analyses. Z.L.N. performed initial multivariate analyses. M.R.B., M.S.S., and T.G.
wrote the manuscript. M.R.B. and M.S.S. directed the project. Competing
interests: The authors declare no competing interests. Data and materials
availability: All additional data are in the supplementary materials.
63. P. C. Hariharan, J. A. Pople, The influence of polarization functions on molecular
orbital hydrogenation energies. Theor. Chim. Acta 28, 213–222 (1973).
doi:10.1007/BF00533485
64. T. Clark, J. Chandrasekhar, G. W. Spitznagel, P. V. R. Schleyer, Efficient diffuse
function-augmented basis sets for anion calculations. III. The 3-21+G basis set for
first-row elements, Li-F. J. Comput. Chem. 4, 294–301 (1983).
doi:10.1002/jcc.540040303
65. R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, Self-consistent molecular orbital
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Supplementary Text
Fig. S1
Tables S1 to S6
NMR Spectra
References (38–80)
18 May 2018; accepted 6 September 2018
Published online 20 September 2018
10.1126/science.aat2299
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Fig. 1. Reaction development. (A) Enantiodivergent Suzuki reactions of secondary
alkylboron nucleophiles. (B) General mechanism. (C) Initial investigation of substrate and
ligand influences on stereoselectivity. +% ee = net retention, –% ee = net inversion.
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Fig. 2. Phosphine parameterization. (A) Workflow of parameter generation and statistical
modeling. (B) Application of phosphine parameterization to ligand optimization of the
reaction shown in Fig. 1C with Z = CO2Et. b:l = branched to linear ratio. +% ee = net retention,
–% ee = net inversion.
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Fig. 3. Stereodivergent Pd-catalyzed cross-coupling reactions using enantioenriched
alkylboron nucleophiles. The general reaction scheme is shown at the top. (A to C) Isolated
yields are shown for stereoretentive and stereoinvertive cross-coupling reactions (A),
diastereoselective cross-coupling reactions (B), and additional individual reactions (C).
% es = % ee (final product) / % ee (starting material). † 44% yield, 84% ee (86% es) when
run at 60°C.
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Fig. 4. Mechanistic investigation by multidimensional regression modeling. (A) Data
from the arylation of 20 was used. [PdL] is the precatalyst as shown in Fig. 3 with varying
Boltz
ligands. (B) Regression model containing all 24 ligands of this data set. Eσ*(P−C)avg
:
Boltzmann-weighted average across the conformers of the average energies of the three
P−C σ* antibonding orbitals in each phosphine. ELP(P)Boltz: Boltzmann-weighted average of the
energy of the phosphorus lone pair orbital. Sterimol B1Boltz is the least width and Sterimol
Lminconf is the length of the lowest-energy conformer as seen from opposite the P
substituents. Red points in the diagram: validation data (EV) not used in the model training.
LOO = leave-one-out cross validation score. K-fold: average threefold cross-validation score.
(C) Illustration and interpretation of the model terms. (D) Regression model after removing
the four smallest ligands in this data set to exclude the influence of competitive β-hydride
elimination on the data.
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Enantiodivergent Pd-catalyzed C−C bond formation enabled through ligand parameterization
Shibin Zhao, Tobias Gensch, Benjamin Murray, Zachary L. Niemeyer, Matthew S. Sigman and Mark R. Biscoe
published online September 20, 2018
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REFERENCES
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