Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2024 Mar 11.
Published in final edited form as: J Am Chem Soc. 2023 Jul 24;145(30):16344–16349. doi: 10.1021/jacs.3c05815

Enantioselective Construction of Carbocyclic and Heterocyclic Tertiary Boronic Esters by Conjunctive Cross-Coupling Reaction

Xuntong Zhang 1, Chenpeng Gao 1, James P Morken 1
PMCID: PMC10925917  NIHMSID: NIHMS1972318  PMID: 37487220

Abstract

Synthesis of stereodefined carbocyclic and heterocyclic tertiary boronic esters is accomplished by performing conjunctive cross-coupling reaction on preformed cyclic boron ate complexes. Boronates bearing spirocyclic and aryl bicyclic skeletons can be synthesized enantioselectively using a chiral PHOX-ligated Pd catalyst with achiral starting material; while substrates bearing continuous stereogenic centers can be generated diastereoselectively. A variety of aryl and alkenyl electrophiles are incorporated.

Graphical Abstract

graphic file with name nihms-1972318-f0001.jpg

Tertiary functional groups attached to carbocycles are ubiquitous in natural products and therapeutic agents (Scheme 1a)1 and the development of strategies to construct such stereogenic centers has been a focus in synthetic chemistry.2 Among methods for accomplishing this objective, the stereospecific transformation of tertiary alkyl boronic esters has been established as a versatile tool for the construction of tertiary alcohols and amines as well as quaternary carbon centers.3 To construct tertiary boronates, a number of stoichiometric and catalytic processes have been introduced4, with metallate shift-based reactions of α-substituted alkenyl boronate complexes being notable for their ability to effect new C–C and C–electrophile bond formation.5 In this connection, Aggarwal and Studer group have demonstrated that a variety of electrophiles can induce such rearrangement through radical or radical-polar crossover pathways.6 Recently, Aggarwal reported that electrophile-induced 1,2-migration can apply to cyclic boron ate complexes (Scheme 1b), resulting in ring contraction and construction of cyclobutanes and cyclopentanes bearing a tertiary boronic esters.7 Analysis of the stereochemical outcome of these reactions (stereospecific at the migrating carbon, stereoselective at the emerging stereocenter) suggests the reactions may occur through the intermediacy of an α-boryl carbocation (A, inset).

Scheme 1.

Scheme 1.

Open in a new tab

Conjunctive Coupling with Cyclic Boron Ate Complexes and its Applications.

As a catalytic enantioselective method to construct chiral secondary and tertiary organoboronic esters, our group has employed chiral palladium- and nickel-based complexes to effect conjunctive coupling of alkenyl boron ate complexes (Scheme 1c).8,9The stereochemical outcome of these reactions indicates that they occur by a concerted anti addition of the migrating carbon atom (RM) and the metal complex to the alkene (B→C, inset). In contrast, Ready has demonstrated that Ir(allyl)-induced metallate shift may occur by syn addition across alkene.10 To extend the metal-catalyzed conjunctive coupling reaction to the construction of intricate cyclic motifs, we considered reactions of cyclic boron ate complexes (Scheme 1d). In addition to enantiodiscrimination, a critical concern that arises is whether the cyclic constraint of substrates precludes necessary alignment of the participating B–CM bond and the alkene π system (D, inset). If these two features are too far out of alignment, the activation barrier for the metalate shift may be raised sufficiently that direct Suzuki-Miyaura reaction becomes the pre-dominant reaction pathway.11 In this Communication, we demonstrate that Pd-catalyzed conjunctive coupling can indeed operate efficiently on cyclic boron ate complexes (Scheme 1d) and provides access to a range of enantiomerically-enriched spirocycles and benzo-fused carbocycles and heterocycles in an efficient fashion.

To examine the prospects for ring-contracting conjunctive coupling of cyclic ate complexes, tertiary alkylboronate 1 (Table 1) was treated with t-butyllithium at −78 °C, warmed to room temperature, and then employed in couplings with PhOTf, palladium complexes and a series of ligands (note: NaOTf was employed as bromide scavenger12). As shown in Table 1, when the reaction was conducted with Pd(OAc)2 and Mandyphos13 (L1), a ligand that has consistently proven effective across a broad range of acyclic substrates, ring contraction product 3 was generated in 75% isolated yield, but minimal enantioselectivity (72:28 er, entry 1). Examination of tunable phosphinooxazoline ligands that have proven effective in recent conjunctive couplings14 was undertaken and it was found that analogs bearing large oxazoline substituents and electron-rich phosphines provided notably improved results (cf. entries 2–9). When dibenzylideneneacetone, a presumed inhibitor of the reaction was avoided by the use of Pd(PPh3)4 as palladium source, consistently high yields and high selectivity were observed with ligands L9 (91:9 er, entry 11) and L10 (entry 12, 95:5 er).

Table 1.

Survey of Catalysts for Enantioselective Conjunctive Coupling of Cyclic Carbonates.

graphic file with name nihms-1972318-t0002.jpg
entry Pd source ligand yield 3 (%)a erb
1 Pd(OAc)2 L1 75 72:28
2 Pd2(dba)3 L2 83 65:35
3 Pd2(dba)3 L3 79 55:45
4 Pd2(dba)3 L4 86 65:35
5 Pd2(dba)3 L5 69 72:28
6 Pd2(dba)3 L6 77 52:48
7 Pd2(dba)3 L7 80 72:28
8 Pd2(dba)3 L8 55 80:20
9 Pd2(dba)3 L9 30 90:10
10 Pd(ACN)2Cl2 L9 72 86:14
11 Pd(PPh3)4 L9 77 91:9
12 Pd(PPh3)4 L10 72 95:5
graphic file with name nihms-1972318-t0003.jpg
Open in a new tab
(a)

Yield determined by 1H NMR versus and internal standard.

(b)

Enantiomer ratios determined by chiral SFC analysis and have an error of ±1%.

With effective conditions identified for reactions of cyclic tertiary boron ate complexes, a variety of substrates were examined in the coupling reaction. Carbocyclic boronic esters bearing a number of spirocyclic skeletons were successfully prepared by conjunctive cross-coupling reaction. Migrating groups bearing different ring sizes are readily accommodated, allowing access to enantiomerically enriched spirocycles with 4- to 7-membered rings in good yield and selectivity (Figure 1, products 4–7). Heteroatoms are also tolerated thereby providing access to spirocyclic piperidine and tetrahydropyran motifs (8 and 9) as well as products with ketal units (10). With a longer tether connecting the bromoalkene to the boronate in the substrate, the reaction furnishes 6,6-spirocyclic boronic ester 12, however, 7-membered ring closure could not be realized with this method and only delivered Suzuki-Miyaura coupling product (data not shown). Heteroarenes were also found to be suitable electrophiles for the reaction, allowing introduction of pyridine (13), pyrazine (14), pyrimidine (15), thiophene (16), and benzothiophene (17) products. Of note, preparation of compound 20 and 21 represent the first successful use of alkynyl and benzyl electrophiles in metal-catalyzed enantioselective conjunctive couplings. Lastly, configuration assignment of product 9 was accomplished by x-ray crystallographic analysis of the product.

Figure 1.

Figure 1.

Open in a new tab

Substrate survey in enantioselective conjunctive coupling of cyclic boron ate complexes. PMP = p–methoxyphenyl.

Considering the efficiency observed in coupling of heteroatom-containing aliphatic boronic ester substrates in Figure 1, it was of interest to learn whether reactions of aryl boron ate complexes might provide a useful route to substituted tetrahydroquinoline and chromane reaction products. For effective preparation of ate complexes, substrate selection proved to be critical: while treatment of 22 with t-butyllithium provides ate complex 23 cleanly, when the positions of the Br and B(pin) groups are reversed, the addition of t-BuLi to the B(pin) group is competitive with Li–halogen exchange. Therefore, a series of alkenyl boronic esters were examined as conjunctive cross-coupling candidates. As depicted in Figure 2, an ether-tethered substrate participates in ring-contracting coupling with substituted arenes, heteroarenes and an alkenyl electrophile (24–28). Though reactions with aryl migrating group tend to be slower than with alkyl migrating groups and require longer reaction times, the coupling products were often delivered in good yield and high enantioselectivity. Methoxy groups (29, 31) and halogen atoms (30, 32) could be installed on the migrating arene. Moreover, the structure of the tether that connects the alkenyl boron and the bromoarene can include a Boc-protected amine and, in this case, furnishes a tetrahydroquinoline skeleton (33). Similarly, if the heteroatom linker is removed from the substrate, boronate-containing indane skeletons can be constructed efficiently (34–37). Arylbromides bearing a protected catechol (38) or B(pin) functional group (39) can be used as electrophiles to access more complex structures.

Figure 2.

Figure 2.

Open in a new tab

Enantioselective conjunctive coupling of cyclic aromatic boron ate complexes. (a) Reaction was conducted at 40 °C for 24 h

With efficient and selective strategies for conjunctive couplings with cyclic boron ate complexes established, aspects of synthesis utility were examined. In one experiment, we conducted a preparative scale reaction. As depicted in Figure 3a, substrate 42 was prepared by copper-catalyzed coupling between benzyl bromide 40 and allylboron reagent 41.15 Subsequent conjunctive coupling with bromobenzene in the presence of Pd/L9 provided 34 in good and with slightly improved selectivity compared to smaller scale reactions. Given that transformations of hindered tertiary benzylic boronates can be challenging, reactions of 34 were probed. As shown in Figure 3b, subjection of 34 to conditions for Matteson homologation16, oxidation, and Evans-Zweifel olefination17 furnished the corresponding products (43–45) efficiently. Moreover, modified Zweifel olefination18 to an enol ether followed by hydrolysis was found to deliver 46 in good yield. Intermediate 46 was easily brominated to generate 47, which is a known intermediate in the synthesis of β-secretase inhibitor 48.1a In a last set of experiments, we examined the prospect for reactions of secondary boronates to provide trisubstituted ring systems that might be relevant for the construction of tramadol (Figure 1), the promising triple reuptake inhibitor 5119, or other motifs. Since the requisite substrates to address these compounds are chiral, the issue of double asymmetric induction arises. In the event, enantiomerically enriched 49 was prepared and subjected to conjunctive coupling. When the reaction was conducted in the presence of the (S) enantiomer of L9 the reaction occurred in low selectivity; however, when (R)-L9 was employed cyclic boronic ester 50 was generated in good yield and in excellent diastereoselectivity. Thus, with appropriate matching of catalyst chirality and substrate chirality, trisubstituted cyclopentanes should be readily available and this process was examined with aryl, acyl, and alkynyl electrophiles to deliver corresponding compounds 52–54.

Figure 3.

Figure 3.

Open in a new tab

Practical aspects of conjunctive coupling of cyclic aromatic boron ate complexes. (a) NaOH, H2O2, THF, rt, 1 h. (b) vinyl magnesium bromide, then I2, LiOCH3, CH3OH/THF, −78 °C to rt (c) CH2Br2, n-BuLi, −78 °C to rt, 2 h; then NaOH, H2O2 (d) ethyl vinyl ether, t-BuLi, then I2, LiOCH3, CH3OH/THF, then 3M HCl (e) Br2, MeOH, 0 °C to rt, 3 h.

As the examples above indicate, ring-contracting conjunctive couplings to provide five- and six-membered rings proceed with good efficiency thereby suggesting that the cyclic nature of the substrate doesn’t prohibit alignment of the migrating carbon atom with the reacting alkene. However, when the analogous process was applied to a substrate that would deliver a four-membered carbocycle (55, Figure 4a), the reaction did not furnish any of the conjunctive coupling product 56 and instead generated Suzuki-Miyaura coupling product 57. To determine whether this alternate outcome arises from strain that develops during the 1,2-boronate shift (i.e. energetically disfavored metallate shift) or is due to misaligned reaction components (increased barrier to metallate shift) computational analysis of the rearrangement was undertaken for model systems of both ring sizes. As the data in Figure 4b indicates, the 1,2-boronate rearrangement to form both four- and five-membered rings are exergonic reactions, however, the activation barrier to form the four-membered ring is 2.2 kcal/mol higher than the barrier for cyclopentane ring formation. Presumably this increased barrier provides an opportunity for direct transmetalation to be competitive and hence the Suzuki-Miyaura pathway becomes favored for smaller cyclic boronates. Of note, the overall exergonic nature of the reaction suggests that boron or palladium ligand designs that inherently preclude direct transmetalation might prove effective for contraction to form smaller cyclic boronic esters. Studies in this connection are in progress.

Figure 4.

Figure 4.

Open in a new tab

Analysis of coupling reactions with smaller ring sizes. (a) Reaction of a cyclic five-membered ring boronate. (b) DFT analysis of barriers for metallate shift involving six-membered and five-membered cyclic boronates.

In summary, the synthesis of stereodefined carbocyclic tertiary boronic esters is accomplished by performing conjunctive cross-coupling reaction on preformed cyclic boron ate complexes. Boronates bearing spirocyclic and benzo-fused bicyclic skeletons can be synthesized selectively using a phosphino-oxazoline-ligated Pd catalyst with achiral starting material; while substrates bearing continuous stereogenic centers can be generated diastereoselectively.

Supplementary Material

Supp Info

Acknowledgements

This research was supported by instrumentation grants from NSF MRI award CHE2117246, and NIH HEI-S10 award 1S10OD026910. The authors thank Dr. Bo Li and Dr. Thusitha Jayasundera of Boston College for assistance with x-ray structure analysis and NMR spectroscopy, respectively.

Funding Sources

This work was supported by a grant from the NIH (NIGMS R35GM127140 to J.P.M.)

Footnotes

Supporting Information

Procedures, characterization, and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no financial conflicts of interest.

REFERENCES

  • (1).For β-secretase inhibitor:; (a) Merck & Co Inc. WO2009/108550, 2009, A1.; For total synthesis of histrionicotoxin:; (b) Sinclair A; Stockman RA Thirty-five Years of Synthetic Studies Directed Towards the Histrionicotoxin Family of Alkaloids. Nat. Prod. Rep 2007, 24, 298–326. [DOI] [PubMed] [Google Scholar]; For recent total synthesis of Tramadol:; (c) Monos TM; Jaworski JN; Stephens JC; Jamison TF Continuous-Flow Synthesis of Tramadol from Cyclohexanone. Synlett. 2020, 31, 1888–1893. [Google Scholar]
  • (2).For recent advances in catalytic asymmetric synthesis of carbocyclic tertiary alcohols, α-tertiary amines and quaternary carbon centers, see:; (a) Liu YL; Lin XT Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones. Adv. Synth. Catal 2019, 361, 876–918. [Google Scholar]; (b) Liu HC; Lau VH; Xu MP; Chan TH; Huang ZX Diverse Synthesis of α-Tertiary Amines and Tertiary Alcohols via Desymmetric Reduction of Malonic Esters. Nat. Commun 2022, 13, 4759. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Qiao Y; Bai SM; Wu XF; Yang YY; Meng H;Ming JL Rhodium-Catalyzed Desymmetric Arylation of γ,γ-Disubsituted Cyclohexadienones: Asymmetric Synthesis of Chiral All-Carbon Quaternary Centers. Org. Lett 2022, 24, 1556–1560. [DOI] [PubMed] [Google Scholar]
  • (3).For stereospecific amination of tertiary alkylboronates:; (a) Edelstein EK; Grote AC; Palkowitz MD; Morken JP A Protocol for Direct Stereospecific Amination of Primary, Secondary, and Tertiary Alkylboronic Esters. Synlett. 2018, 29, 1749–1752. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Liu XX; Zhu Q; Chen D; Wang L; Jin LQ; Liu C Aminoazanium of DABCO: An Amination Reagent for Alkyl and Aryl Pinacol Boronates. Angew. Chem. Int. Ed 2020, 59, 2745–2749. [DOI] [PubMed] [Google Scholar]; For stereospecific construction of quaternary carbon centers from tertiary boronic esters:; (a) Mykura RC; Songara P; Luc E; Rogers J; Stammers E; Aggarwal VK Studies on the Lithiation, Borylation, and 1,2-Metalate Rearrangement of O-Cycloalkyl 2,4,6-Triisopropylbenzoates. Angew. Chem. Int. Ed 2021, 50, 11436–11441. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Odachowski M; Bonet A; Essafi S; Ramsden P; Harvey JN; Leonori D; Aggarwal VK Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds. J. Am. Chem. Soc 2016, 138, 9521–9532. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Sanford C; Aggarwal VK Stereospecific Functionalizations and Transformations of Secondary and Tertiary Boronic Esters. Chem. Commun 2017, 53, 5481–5494. [DOI] [PubMed] [Google Scholar]
  • (4).(a) Stymiest JL; Bagutski V; French RM; Aggarwal VK Enantiodivergent Conversion of Chiral Secondary Alcohols into Tertiary Alcohols. Nature 2008, 456, 778–782. [DOI] [PubMed] [Google Scholar]; (b) O’Brien JM; Lee K; Hoveyda AH Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by NHC-Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic Esters, Ketones, or Thioesters. J. Am. Chem. Soc 2010, 132, 10630–10633. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Kubota K; Yamamoto E; Ito H Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of Aldehydes: An Efficient Route to Enantiomerically Enriched α-Alkoxyorganoboronate Esters. J. Am. Chem. Soc 2015, 137, 420–424. [DOI] [PubMed] [Google Scholar]
  • (5).Namirembe S; Morken JP Reactions of Organoboron Compounds Enabled by Catalyst-Promoted Metalate Shifts. Chem. Soc. Rev 2019, 48, 3464–3474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (6).For 1,2-migration of α-substituted alkenyl boronate complex using radical-polar crossover strategies:; (a) You C; Studer A Synthesis of 1,3-Bis-(boryl)alkanes Through Boronic Ester Induced Consecutive Double 1,2-Migration. Angew. Chem. Int. Ed 2020, 59, 17245–17249. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Armstrong RJ; Niwetmarin W; Aggarwal VK Synthesis of Functionalized Alkenes by a Transition-Metal-Free Zweifel Coupling. Org. Lett, 2017, 19, 2762–2765. [DOI] [PubMed] [Google Scholar]; (c) Silvi M; Sandford C; Aggarwal VK Merging Photoredox with 1,2-Metallate Rearrangements: The Photochemical Alkylation of Vinyl Boronate Complexes. J. Am. Chem. Soc 2017, 139, 5736–5739. [DOI] [PubMed] [Google Scholar]; (d) You C; Studer A Three-Component 1,2-Carboamination of Vinyl Boronic Esters via Amidyl Radical Induced 1,2-Migration. Chem. Sci 2021, 12, 15765–15769. [DOI] [PMC free article] [PubMed] [Google Scholar]; For a review, see:; (e) Wang H; Jing CC; Noble A; Aggarwal VK Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles. Angew. Chem. Int. Ed 2020, 59, 16859–16872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (7).(a) Davenport R; Silvi M; Noble A; Hosni Z; Fey N; Aggarwal VK Visible-Light-Driven Strain-Increase Ring Contraction Allows the Synthesis of Cyclobutyl Boronic Esters. Angew. Chem. Int. Ed 2020, 59, 6525–6528. [DOI] [PubMed] [Google Scholar]; (b) Fairchild ME; Noble A; Aggarwal VK Diastereodivergent Synthesis of Cyclopentyl Boronic Esters Bearing Contiguous Fully Substituted Stereocenters. Angew. Chem. Int. Ed 2022, e202205816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (8).(a) Zhang L; Lovinger GJ; Edelstein EK; Szymaniak AA; Chierchia MP; Morken JP Catalytic Conjunctive Cross-Coupling Enabled by Metal-induced Metallate Rearrangement. Science 2016, 351, 70–74. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Myhill JA; Zhang L; Lovinger GJ; Morken JP Enantioselective Construction of Tertiary Boronic Esters by Conjunctive Cross-Coupling. Angew. Chem. Int. Ed 2018, 57, 12799–12803. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Wilhelmsen CA; Zhang XT; Myhill JA; Morken JP Enantioselective Synthesis of Tertiary β-Boryl Amides by Conjunctive Cross-Coupling of Alkenyl Boronates and Carbamoyl Chlorides. Angew. Chem. Int. Ed 2022, 61, e2021167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (9).(a) Lovinger GJ; Morken JP Ni-Catalyzed Enantioselective Conjunctive Coupling with C(sp3) Electrophiles: A Radical-Ionic Mechanistic Dichotomy. J. Am. Chem. Soc 2017, 139, 17293–17296. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Koo SM; Vendola AJ; Momm SN; Morken JP Alkyl Group Migration in Ni-Catalyzed Conjunctive Coupling with C(sp3) Electrophiles: Reaction Development and Application to Targets of Interest. Org. Lett 2020, 22, 666–669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (10).Davis CR; Luvaga IK; Ready JM Enantioselective Allylation of Alkenyl Boronates Promotes a 1,2-Metalate Rearrangement with 1,3-Diastereocontrol. J. Am. Chem. Soc 2021, 143, 4921–4927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (11).Zou G; Falck JR Suzuki-Miyaura Coss-Coupling of Lithium n-Alkylborates. Tetrahedron Lett. 2001, 42, 5817–5819. [Google Scholar]
  • (12).Lovinger GJ; Aparece MD; Morken JP Pd-Catalyzed Conjunctive Cross-Coupling between Grignard-Derived Boron “Ate” Complexes and C(sp2) Halides or Triflates: NaOTf as a Grignard Activator and Halide Scavenger. J. Am. Chem. Soc 2017, 139, 3153–3160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (13).Schwink L; Knochel P Enantioselective Preparation of C2-Symmetrical Ferrocenyl Ligands for Asymmetric Catalysis. Chem. Eur. J 1998, 4, 950–968. [Google Scholar]
  • (14).Gao CP; Wilhelmsen CA; Morken JP Palladium-Catalyzed Conjunctive Cross-Coupling with Electronically Asymmetric Ligands. J. Org. Chem 2023, 88, 1828–1835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (15).Wang GZ; Jiang J; Bu XS; Dai JJ; Xu J; Fu Y; Xu HJ Copper-Catalyzed Cross-Coupling Reaction of Allyl Boron Ester with 1°/2°/3°-Halogenated Alkanes. Org. Lett 2015, 17, 3682–3685. [DOI] [PubMed] [Google Scholar]
  • (16).(a) Matteson DS α-Halo Boronic Esters: Intermediates for Stereodirected Synthesis. Chem. Rev 1989, 89, 1535–1551. [Google Scholar]; (b) Matteson DS; Collins BSL; Aggarwal VK; Ciganek E The Matteson Reaction. Organic Reactions 2021, 105, 427–860. [Google Scholar]
  • (17).(a) Zweifel G; Arzoumanian H; Whitney CC A Convenient Stereoselective Synthesis of Substituted Alkenes via Hydroboration-iodination of Alkynes. J. Am. Chem. Soc 1967, 89, 3652–3653. [Google Scholar]; (b) Armstrong RJ; Garcia-Ruiz C; Myers EL; Aggarwal VK Stereodivergent Olefination of Enantioenriched Boronic Esters. Angew. Chem. Int. Ed 2017, 56, 786–790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (18).Sonawane RP; Jheengut V; Rabalakos C; Larouche-Gauthier R; Scott HK; Aggarwal VK Enantioselective Construction of Quaternary Stereogenic Centers from Tertiary Boronic Esters: Methodology and Applications. Angew. Chem. Int. Ed 2011, 50, 3760–3763. [DOI] [PubMed] [Google Scholar]
  • (19).Shao LM; Hewitt MC; Malcolm SC; Wang FJ; Ma JG; Campbell UC; Spicer NA; Engel SR; Hardy LW; Jiang ZD; Schreiber R; Spear KL; Varney MA Synthesis and Pharmacological Characterization of Bicyclic Triple Reuptake Inhibitor 3-Aryl Octahydrocyclopenta[c]pyrrole Analogues. J. Med. Chem 2011, 54, 5283–5295. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supp Info
NIHMS1972318-supplement-Supp_Info.pdf (19.8MB, pdf)

RESOURCES