COMMUNICATION Directed, Palladium(II)-Catalyzed Enantioselective anti-Carboboration of Alkenyl Carbonyl Compounds

Zhen , Xiaohan , Tian , Keary M. Engle*

Abstract: A substrate-directed enantioselective and electron-deficient olefins (L11–L13) also failed to exert anti-carboboration reaction of alkenes has been developed, any chiral induction. To our delight, screening of monodentate wherein a carbon-based nucleophile and a boron moiety are imidazoline (MIM)(L15–L17) and MOX ligands (L18–L39) installed across the C=C bond through a 5- or 6-membered gave us reasonable levels of enantioselectivity, showing that palladacycle intermediate. The reaction is promoted by a these ligand scaffolds are privileged in this reaction. We palladium(II) catalyst and a mondentate oxzazoline ligand. A decided to choose the MOX scaffold for further optimization range of enantioenriched secondary alkylboronate products were based on synthetic accessibility considerations. The effect of obtained with moderate to high enantioselectivity that could be different MOX ligands on the alkene carboboration reaction is further upgraded by recrystallization. This work represents a new similar to the trends in , , and ’s report.[2c] method to synthesize versatile and valuable alkylboronate building blocks. Building on an earlier mechanistic proposal by Tryptophan-derived ligands showed higher levels of chiral Peng, He, and Chen, a revised model is proposed to account for induction than other amino acid derivatives in terms of chiral the stereoconvergent nature of this transformation. induction. Systematically varying the N-aryl group revealed that the steric and electronic nature of the substituents Substrate-directed nucleopalladation offers a powerful impacts both yield and er (albeit to a minor extent), with platform for generating multiple consecutive stereocenters electron-withdrawing groups proved to be advantageous. (Scheme 1A). The key feature of these transformations is the Ultimately, our optimization efforts converged with earlier [2c] formation of a stabilized 5- or 6-membered metallacycle findings from the aforementioned study in identifying L34, intermediate, which enables trapping with an additional which bears a 3,5-bis-CF3-phenyl substituent on the indole reaction partner, such as a proton, an electrophile, or a nitrogen, as the optimal ligand, providing up to 94:6 er and nucleophile, under various redox manifolds. Recently, our 71% yield. Interestingly, 3,5-bis-nitro-phenyl substituted group[1] and others[2] have developed numerous alkene ligand L36 also offered the same enantioselectivity, albeit hydrofunctionalization and 1,2-difunctionalization reactions by with slightly lower yield. Additionally, several oxazolines exploiting this approach. A frontier in this area of research is bearing a phenyl or methyl group at C-5 (L37–L39) were controlling the absolute stereochemistry of the products by prepared based on the idea that increased steric hindrance developing enantioselective variants of these could further improve the enantioselectivity. Unfortunately, transformations. In 2016, we reported a non-stereoselective none of these ligands performed better than L34. γ-selective hydrocarbofunctionalization, which was subsequently rendered enantioselective in 2018 by He, Peng, A. Versatile substrate-directed PdII-catalyzed alkene difunctionalization and Chen through the elegant design and development of a [2c] O X O monodentate oxazoline (MOX) ligand. In a complementary II cat. Pd Y N AQ line of inquiry using prochiral carbon nucleophiles, our H [X], [Y] R1 N R1 laboratory[1f] and the group of and [2e] have (AQ) achieved enantioselective transformations with a chiral B. Overview of enantioselective variants: precedents and this work phosphoric acid (CPA) ligand and a chiral amine catalyst H O O II [C] ∗ cat. PdII cat. Pd H O respectively. Although these strategies have been successful AQ ∗ 1 ∗ AQ in enantioselective hydrocarbofunctionalization, R MOX Amine n [He, Peng, O R3 n = 1–3 enantioselective alkene 1,2-difunctionalization within this Chen, 2018] [Zhang, Gong, 2019] AQ family of reactions has not been reported to date. Herein, we 1 MeO O H O R Bpin O II cat. PdII ∗ cat. Pd [C] ∗ describe the first asymmetric alkene anti-carboboration R2 ∗ AQ [3] AQ n reaction via directed nucleopalladation. As in our previously NHCOAr1 CPA MOX R1 n = 1, 2 [4] [Engle, 2019] reported racemic version, the reaction proceeds smoothly this work via either 5- or 6-membered palladacycle intermediates. Ar3 Ar2 Furthermore, the resulting enantioenriched organoboron O [5] N Ph Me O O compounds are highly valuable in organic synthesis. P N N Ph O OH To begin our study, we selected N-methylindole (2a) as H OH Ar3 the nucleophile, B2pin2 (3a) as boron coupling partner, and 2 3 [6] Ar = 3,5-(CF3)2C6H3 Ar = 2,4,6-(Cy)3C6H2 8-aminoquinoline (AQ)-masked (Z)-3-hexenoic acid (1d) as MOX Ligand CPA Ligand Chiral Amine our pilot alkene substrate. In order to render this reaction Scheme 1. Background and Project Synopsis enantioselective, we carried out extensive screening of base, solvent, and reaction temperature, while at the same time examining a variety of chiral ligands (Table 1). Commonly used bi- and tridentate oxazoline-based ligands as well as ’s APAO[7] and MPAAM[8] ligands (L2–L10) only induced low to moderate enantioselectivity with attenuated reactivity. Initial screening of monodentate ligands such as CPA (L1)

Z. Liu, X. Li, T. Zeng, Prof. K. M. Engle, Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, BCC-169, La Jolla, CA 92037 USA. E-mail: [email protected]

Supporting information for this article is given via a link at the end of the document. Table 1. Screening of Chiral Ligands[a] Pd(OAc) (10 mol%) O Me 2 MeN Bpin O N L* (20 mol%), NaF (2 equiv) + + B pin ∗ AQ 2 2 AQ BQ (20 mol%), O2 (1 atm) ∗ Et HFIP/THF/DMF (2:2:1), 45 ºC Et 1d (0.05 mmol) 2a (3 equiv) 3a (4 equiv) 4f

Ar Me Me Me Me O O O O O Me O N O O O O Me O P Ph Ph N OH N N N N N AcHN N Me O N N Bn Bn AcHN N Bn Me Ph Ph Ph Ph Me Ar Me Ar = 3,5-(CF3)2C6H3 L1, 50% L2, 7% L3, trace L4, 22% L5, 19% L6, 20% L7, 29% 52:48 er 32:68 er 55:45 er 31:69 er 53:47 er 53:47 er Me Me Bn Me Me OMe O Me Ph Ph Ph O O O2 O Me N O N N S S O N N O Me NMe2 N N O O2 AcHN AcHN AcHN O O O O Bn Me Me Me Me Me Me L8, 14% L9, 21% L10, 13% L11, 18% L12, 31% L13, 20% L14, 24% 50:50 er 50:50 er 50:50 er 50:50 er 50:50 er 50:50 er 51:49 er

O Me Me H Ph Me Ph Ac Ph O O O N N N Me Me Me Me Me Me N N N N N N N Ph Ph Ph Me Ph Bn

L15, 22% L16, 16% L17, 21% L18, 37% L19, 42% L20, 35% L21, 41% 79:21 er 73:27 er 80:20 er 80:20 er 42:58 er 28:72 er 86:14 er

Ts Boc Me O O O O O O NH NH NH N N N Ph Me Et Me Me Me N N N N N N

L22, 34% L23, 47% L24, 39% L25, 63% L26, 61% L27, 59% 86:14 er 88:12 er 86:14 er 90:10 er 92:8 er 92:8 er

t-Bu Me MeO OMe Me Bn Me O t-Bu Me OMe O N N Me O Me N O O O N Me N N N N N Me Me Me N N N

L28, 62% L29, 37% L30, 58% L31, 57% L32, 62% L33, 57% 89:11 er 91:9 er 92:8 er 90:10 er 92:8 er 93:7 er

F3C F CF3 O2N F3C F3C F3C

CF3 F F NO2 CF3 CF3 CF3 O O O O Ph O Me O Ph N N F N N N N Me Me Me Me Me Me N N N N N N

L34, 71% L35, 70% L36, 63% L37, 62% L38, 62% L39, 61% 94:6 er 91:9 er 94:6 er 92:8 er 91:9 er 94:6 er [a] Reaction conditions: 1d (0.05 mmol), 2a (3 equiv), 3a (4 equiv), Pd(OAc)2 (10 mol%), chiral ligand (20 mol%), BQ (20 mol%), NaF (2 equiv), HFIP/THF/DMF 1 (2:2:1, 0.1 mL), 45 °C, O2 (1 atm), 5 d. Percentages refer to H NMR yields with CH2Br2 as internal standard. The enantioselectivity was determined by SFC analysis.

After identifying the optimal ligand and reaction substrates (1b and 1c) resulted in the same major conditions, we next investigated the scope of this diastereomer after carboboration (4d and 4e), which is palladium(II)-catalyzed asymmetric alkene inconsistent with the stereoinduction and -convergence model anti-1,2-carboboration reaction (Table 2). A variety of proposed by He, Peng, and Chen.[2c] We instead believe the AQ-masked alkenyl carbonyl compounds (1a–1h) were E-alkene is first isomerized to Z-configuration upon Pd(II) competent substrates in this transformation, providing the coordination, followed by anti-nucleopalladation to give a desired products in moderate to good yields with satisfactory common alkylpalladium intermediate in both cases (vide infra). er. The absolute configurations of products 4f and 4g were Gratifyingly, AQ-masked 4-pentenoic acid substrate 1i assigned as (R, R) by X-ray crystallography analysis, and underwent this transformation smoothly through a putative other products were assigned by analogy. Increasing the size 6-membered palladacycle delivering 4p in high yield and of R group on the alkene substrate improved the er while moderate er. However, internal alkene 1k was incompatible slightly lowering the yield. For example, terminal alkene 1a (R with this difunctionalization reaction. = H) showed only a moderate er of 86:14, while switching the We have also studied the scope of carbon nucleophiles R group to methyl (4d and 4e) and ethyl (4f), led to higher under the standard reaction conditions. Various indole enantiomeric ratios of 91:9 and 94:6, respectively. More derivatives bearing substituents at different positions on the sterically bulky groups on the alkene, however, shut down the indole ring were well tolerated in this transformation (4m–4o). reaction. For instance, in the case of 4q, only trace amount of Indoles with electron-withdrawing substituents were product was formed under the standard reaction conditions. incompatible coupling partners (2i–2k), potentially due to Generally, Z-alkene substrates are more reactive than diminished nucleophilicity (4r–4t). Different groups on indole E-alkenes. Under the standard conditions, E-alkene 1b was nitrogen also have a significant effect on reaction outcomes. carboborylated in less than 50% conversion. Nevertheless, With larger substituents (4k and 4l), the enantioselectivity of with more forcing conditions, 4d could be generated from 1b the reaction was improved, albeit with diminished yields. To in high yield and good enantioselectivity. In all the cases our delight, 1,3-dicarbonyl compound 2c was found to be a where internal alkene substrates were used, >20:1 dr was suitable nucleophile as well, which could provide the observed, demonstrating the excellent stereocontrol of this corresponding product (4c) in moderate er. carboboration reaction. To our surprise, both E- and Z-alkene

Table 2. Enantioselective Alkene Carboboration Scope[a]

Pd(OAc)2 (10 mol%) O L34 (20 mol%), NaF (2 equiv) Bpin O BQ (20 mol%), O2 (1 atm) Nu ∗ AQ + Nu H + B2pin2 ∗ AQ n n R HFIP/THF/DMF (2:2:1), 45 °C R n = 1, 2 n = 1, 2 1a–k 2a–k 3a 4a–u

O Ph MeN MeN MeN Bpin O HN Bpin O Bpin O Bpin O Bpin O O AQ AQ AQ AQ AQ Ph Me Et

4a, 79% 4b, 71% 4c, 30% (from E) 4d, 79%, 91:9 er[b] 4f, 76% [X-ray] 86:14 er 83:17 er 75:25 er (from Z) 4e, 77%, 91:9 er 94:6 er

MeN MeN Bpin O Bpin O MeN Bpin O MeN Bpin O i-PrN Bpin O AQ AQ 5-OMeAQ AQ AQ Et n-Bu Et Ph BzO 4g, 60% [X-ray] 4h, 57% 4i, 51% 4j, 42% 4k, 63% 94:6 er 94:6 er 94:6 er 94:6 er 95:5 er MeN Bpin O

MeN Bpin O AQ BnN Bpin O Me MeN Bpin O MeN Bpin Et AQ AQ AQ AQ Et Me Et O MeO

4l, 60% 4m, 85% 4n, 85% t-Bu 4o, 55% 4p, 76% 92:8 er 93:7 er 93:7 er 92:8 er 76:24 er

unsuccessful examples

MeN MeN Bpin O MeN Bpin O MeN Bpin O Bpin O MeN Bpin AQ AQ AQ AQ AQ Et Et Et Ph Me O MeO2C Br Bpin 4q 4r 4s 4t 4u

[a] Reaction conditions: 1a–k (0.1 mmol), 2a–k (3 equiv), 3a (4 equiv), Pd(OAc)2 (10 mol%), L34 (20 mol%), BQ (20 mol%), NaF (2 equiv), HFIP/THF/DMF (2:2:1, 0.2 mL), 45 °C, O2, 5 d. Percentages refer to isolated yields. Diastereomeric ratios (dr) are >20:1 in all cases. The enantioselectivity was determined by SFC analysis. [b]KF (2 equiv), HFIP/THF (1:1, 0.2 mL), 60 °C, 2 d.

Me MeN Bpin O aqueous KHF generated trifluoroborate salt 5 in high N Pd(OAc)2 (10 mol%) 2 O L34 (20 mol%), BQ (20 mol%) AQ conversion. Initial attempts of boronate oxidation with strong NaF (2 equiv), O (1 atm) 2 Et AQ + 2a (3 equiv) oxidants, such as H2O2 solution, proved to be unsuccessful, HFIP/THF/DMF, 45 °C 4f, 65%, 95:5 er Et + presumably because of undesired oxidation of the B2pin2 [gram-scale] after recrystallization 1d (2.5 mmol) 3a (4 equiv) 98.7% ee (63.7 mg/100 mg from Et O) electron-rich indole ring. Finally, using a mild oxidant 2 [9] >99.9% ee (67.1 mg/100 mg from EtOH) NaBO3•4H2O, boronate 4f was efficiently converted into

chiral alcohol 6 with almost complete stereoretention. Scheme 2. Large-Scale Synthesis and Recrystallization Ni(tmhd)2-mediated methanolysis of the AQ protecting MeN BF3KO [10] KHF2 (4.5 M) group was also performed to deliver the corresponding AQ MeCN, 25 °C methyl ester 7 with retention of the C–B bond, which could Et potentially be carried forward into further transformations. 5, 95% Both in He, Peng, and Chen’s asymmetric MeN [2c] MeN Bpin O OH O hydrocarbonation reaction and this work, NaBO3•4H2O AQ AQ stereoconvergence was observed, with Z- and E-alkene THF/H2O = 1:1 Et Et substrates giving the same absolute and relative 4f, 95:5 er 6, 88%, 94:6 er stereochemistry (Scheme 4A). In the previously proposed stereoinduction model (Scheme 4B),[2c] with an E-alkene, MeN Bpin O Ni(tmhd)2 Int-E-I-down was computed to be more stable than OMe MeOH, 100 Int-E-II-up, and with a Z-alkene, Int-Z-II-up was computed to °C Et be more stable than Int-Z-I-down. These trends also hold in 7, 55%, 96:4 er the corresponding transition state energies, where Scheme 3. Product Diversification nucleopalladation from Int-E-I-down (to give Int-E-III) and from Int-Z-II-up (to give Int-Z-III) is favored for E and Z 3 Subsequently, this Pd(II)-catalyzed asymmetric alkene alkenes, respectively. This model predicts that the C(sp )–Pd stereocenter at C2 would have opposite configuration with E carboboration method was performed on large scale to [11] demonstrate its operational simplicity and practicality and Z alkenes, which is not in agreement with our results. (Scheme 2). Compound 4f was prepared from Z-alkene 1d, This discrepancy prompted us to consider an alternative explanation (Scheme 4C). Specifically, we envisioned a N-methylindole (2a), and B2pin2 (3a) on gram scale, with the yield and er consistent with the smaller scale experiment. different scenario in which alkene isomerization to interconvert Int-E-III and Int-Z-III takes place under the Furthermore, recrystallization of the final product from Et2O or EtOH could provide nearly enantiopure secondary boronate reaction conditions, followed by nucleopalladation, which 4f in satisfying overall yield. occurs preferentially through the lower-energy pathway involving Int-Z-III. Although the precise mechanism of alkene A series of derivatizations were next conducted to isomerization remains unclear at this stage,[12] evidence further illustrate the synthetic utility of the carboborylated suggests that it occurs in the present system only after alkene products (Scheme 3). Treatment of compound 4f with complexation with palladium(II). To test the viability of this alternative mechanism, several mechanistic experiments substrated-directed palladium(II)-catalyzed were performed (Scheme 4D). At room temperature, 1,2-difunctionalization to other types of reactions and treatment of Z-alkene 1d with stoichiometric Pd(OAc)2 both substrates. These results will be reported in due course. with and without L34 led to formation of the corresponding palladium(II) complex Pd-I with the retention of alkene Acknowledgements geometry. In contrast, E-alkene 1l underwent E/Z This work was financially supported by TSRI, Pfizer, Inc., isomerization in the presence and absence of MOX ligand. Bristol-Myers Squibb (Unrestricted Grant), and the National Interestingly, L34 seems to promote E-to-Z isomerization, Institutes of Health (5R35GM125052-02). We gratefully possibly by creating a more sterically hindered environment acknowledge the Nankai University College of Chemistry for around the palladium(II) center (See Supporting Information [13] an International Research Scholarship (X. L.). We thank Dr. (SI) for additional mechanistic experiments). These results De-Wei , Van T. Tran, Mingyu Liu, and Wei (TSRI) are consistent with the model depicted in Scheme 4C, where for donation of chiral ligands. Dr. Jason Chen (TSRI) is isomerization of Int-E-I-down to Int-Z-II-up takes place acknowledged for SFC and HRMS analysis. John A. Gurak, before the nucleopalladation step for the E-alkene substrates. Jr. (TSRI) is also acknowledged for growing a single crystal of which accounts for the observed stereoconvergence in the Pd-I. We thank Andrew Romine (TSRI) for his assistance of described 1,2-difunctionalization. proofreading the manuscript. We further thank Prof. Arnold L. A. stereoconvergence in enantioselective directed nucleopalladation H O Rheingold and Dr. Milan Gembicky (UCSD) for X-ray cat. PdII, L34 Nu [C]–H, H+ AQ crystallographic analysis. R (R) [He, Peng, O O Chen, 2018] Keywords: palladium • directing group • carboboration • AQ or R AQ II R cat. Pd , L34 Bpin O enantioselective catalysis • MOX ligand [C]–H, B2pin2, [O] Nu (stereoconvergence) AQ this work R (R, R) [1] a) J. A., Gurak Jr., K. S. , Z. Liu, K. M. Engle, J. Am. Chem. Soc. B. originally proposed model for stereoinduction and -convergence (Ref. 2c) 2016, 138, 5805; b) K. S. Yang, J. A., Gurak Jr., Z. Liu, K. M. Engle, J. Am. Chem. Soc. 2016, 138, 14705; c) Z. Liu, T. Zeng, K. S. Yang, K. M. Engle, O Me O Me O Me N N N N N N Pd Pd Nu–H H Pd J. Am. Chem. Soc. 2016, 138, 15122; d) Z. Liu, Y. , Z. Wang, T. Zeng, with N N 2 O R 1 N R vs. O 2 R O P. Liu, K. M. Engle, J. Am. Chem. Soc. 2017, 139, 11261; e) T. Zeng, Z. E-alkene Ar 1 Ar Ar N N N H Nu Liu, M. A. Schmidt, M. D. Eastgate, K. M. Engle, Org. Lett. 2018, 20, 3853; Int-E-I-down Int-E-II-up Int-E-III f) S. K. Nimmagadda, M. Liu, M. K. Karunananda, D.-W. Gao, O. Apolinar, favored disfavored J. S. Chen, P. Liu, K. M. Engle, ChemRxiv 2018, DOI: 10.26434/chemrxiv.7313615. O Me Me [2] a) S. R. Neufeldt, M. S. Sanford, Org. Lett. 2013, 15, 46; b) E. P. A. N N O N O Me Pd N N N R Pd Nu–H Pd Talbot, T. d. A. Fernandes, J. M. McKenna, F. D. Toste, J. Am. Chem. Soc. with N O N N vs. 1 O 2 1 R O Ar Ar 2014, 136, 4101; c) H. Wang, Z. , T. Jiao, Z. , H. Tong, G. He, Q. Z-alkene N 2 Ar H R N N H Nu Peng, G. Chen, J. Am. Chem. Soc. 2018, 140, 3542; d) C. Wang, G. , Int-Z-I-down Int-Z-II-up Int-Z-III T. , Y. , X. , T.-P. Loh, J. Am. Chem. Soc. 2018, 140, 9332; e) disfavored favored H.-C. Shen, L. Zhang, S.-S. Chen, J. Feng, B.-W. Zhang, Y. Zhang, X. Zhang, Y.-D. Wu, L.-Z. Gong, ACS Catal. 2019, 9, 791. C. revised model for stereoinduction and -convergence [3] For selected examples of other approaches to catalytic 1,2-carboboration of alkenes, see: a) K. Semba, Y. Nakao, J. Am. Chem. O Me O Me N N N N Pd Pd Soc. 2014, 136, 7567; b) F. , F. Haeffner, A. H. Hoveyda, J. Am. N R Nu–H R O N O Ar (as above) Chem. Soc. 2014, 136, 11304; c) K. M. Logan, K. B. Smith, M. K. Brown, N Ar fast N Angew. Chem. Int. Ed. 2015, 54, 5228; d) W. , T.-J. Gong, X. , M.-Y. Int-E-I-down Int-Z-II-up , C.-G. Yu, Z.-Y. Xu, H.-Z. Yu, B. Xiao, Y. , Angew. Chem. Int. Ed. 2015, 54, 12957; e) K. Semba, Y. Ohtagaki, Y. Nakao, Org. Lett. 2016, 18, 3956. f) K. Yang, Q. , Org. Lett. 2016, 18, 5460; g) K. M. Logan, S. R. D. evidence for facile E/Z-isomerization upon complexation O Sardini, S. D. White, M. K. Brown, J. Am. Chem. Soc. 2018, 140, 159. For O O 1 equiv Pd(OAc) an example of transition metal-free 1,2-carboboration of alkenes, see: h) Y. 2 N AQ or Et , C. Mück-Lichtenfeld, A. Studer, J. Am. Chem. Soc. 2018, 140, AQ PdII N Et MeCN, rt, 12 h 6221. For an example of 1,1-arylborylation of alkenes, see: i) H. M. Nelson, Et OAc B. D. Williams, J. Miró, F. D. Toste, J. Am. Chem. Soc. 2015, 137, 3213. 1d 1l Pd-I (Z) [4] Z. Liu, H.-Q. Ni, T. Zeng, K. M. Engle, J. Am. Chem. Soc. 2018, 140, Substrate L34 Pd complex Z/E [X-ray] 3223. [5] For a representative review: D. Leonori, V. K. Aggarwal, Angew. Chem. 1d w/o >20:1 Int. Ed. 2015, 54, 1082. 1d w/ >20:1 [6] For a representative review, see: O. Daugulis, H.-Q. Do, D. Shabashov, 1l w/o 1.6:1 Acc. Chem. Res. 2009, 42, 1074. 1l w/ >20:1 [7] Q.-F. Wu, P.-X. Shen, J. He, X.-B. Wang, F. Zhang, Q. , R.-Y. , C. Mapelli, J. X. , M. A. Poss, J.-Q. Yu, Science 2017, 355, 499. Scheme 4. Investigation of Stereoconvergent Nucleopalladation [8] P.-X. Shen, L. , Q. Shao, K. Hong, J.-Q. Yu, J. Am. Chem. Soc. 2018, In conclusion, we have developed an enantioselective 140, 6545. carboboration reaction of unactivated alkenyl carbonyl [9] A. Bonet, H. Gulyás, E. Fernández, Angew. Chem. Int. Ed. 2010, 49, compounds using a chiral monodentate oxazoline (MOX) 5130. [10] T. Deguchi, H.-L. Xin, H. Morimoto, T. Ohshima, ACS Catal. 2017, 7, ligand. This reaction proceeded smoothly through 5- and 3157. 6-membered palladacycle intermediates to install a [11] In hydrocarbofunctionalization (Ref. 2c) this C(sp3)–Pd stereocenter is secondary boron group to the β or γ positions relative to the ablated in the next elementary step (protodepalladation), but in the present 3 3 carbonyl group. A variety of carbon nucleophiles and alkene transformation with B2Pin2, the C(sp )–Pd is transferred to the C(sp )–B stereocenter in the product. substrates were demonstrated to be compatible, with [12] For related references, see: a) P. M. Henry, J. Am. Chem. Soc. 1972, moderate to good yields and enantioselectivity. 94, 7316; b) A. Sen, T.-W. , Inorg. Chem. 1981, 20, 4036; c) N. Solin, K. Recrystallization of the final product was shown to greatly J. Szabó, Organometallics 2001, 20, 5464; d) J.-Q. Yu, M. J. Gaunt, J. B. improve the product er. The reaction was scalable, and Spencer, J. Org. Chem. 2002, 67, 4627; e) A. M. Zawisza, S. Bouquillon, J. cleavage of the 8-aminoquinoline (AQ) directing group with Muzat, Eur. J. Org. Chem. 2007, 3901; f) E. H. P. , G. C. Lloyd-Jones, J. N. Harvey, A. J. J. Lennox, B. M. Mills, Angew. Chem. Int. Ed. 2011, 50, Ni(tmhd)2 in methanol was demonstrated. To explain the 9602. stereoconvergence of Z- and E-alkenes, a revised [13] In Ref. 2c the authors note that isomerized alkene was not observed in mechanism based on Chen’s original stereoinduction model solution during the course of the reaction, but the authors did not examine was proposed. Future work will focus on the development of the E/Z-configuration of the corresponding complex. Stoichiometric new chiral ligands and expanding the scope of experiments in MeOH (the solvent used in Ref. 2c) suggest that E-to-Z isomerization of the complex takes place at room temperature (see SI).