Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates

Open AccessCCS ChemistryRESEARCH ARTICLE1 May 2022Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates Xiaohong Huo, Ling Zhao, Yicong Luo, Yue Wu, Yuwen Sun, Guanlin Li, Tatiana Gridneva, Jiacheng Zhang, Yong Ye and Wanbin Zhang Xiaohong Huo Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Ling Zhao Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Yicong Luo Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Yue Wu Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Yuwen Sun Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Guanlin Li Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Tatiana Gridneva Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Jiacheng Zhang Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 , Yong Ye College of Chemistry, Zhengzhou University, Zhengzhou 450052 and Wanbin Zhang *Corresponding author: E-mail Address: [email protected] Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240 College of Chemistry, Zhengzhou University, Zhengzhou 450052 https://doi.org/10.31635/ccschem.021.202101044 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed, which was successfully applied to the asymmetric synthesis of β-hydroxycarbonyl motifs bearing a versatile carbon–carbon double bond in an enantio- and diastereodivergent manner. A wide scope of substrates including challenging alkyl-substituted, 2-substituted, and 3,3′-disubstituted allylic species are compatible with this catalytic system, delivering the substituted products in high to excellent yields and with excellent diastereo- (up to >20:1 dr) and enantioselectivities (up to >99% ee). Furthermore, the mechanism of this dual Pd/Cu catalytic system including: (1) the desymmetrization process of geminal dicarboxylates; (2) the origin of regioselectivity (branched or linear); (3) the enantio- and diastereoselectivity observed by changing the combinations of two chiral metal catalysts, have been carefully investigated by theoretical calculations. Download figure Download PowerPoint Introduction β-Hydroxycarbonyl motifs bearing vicinal stereogenic centers are privileged structural motifs, which exist in many bioactive molecules including natural products and pharmaceuticals (Erythromycin, Discodermolide, Epothilone C, etc.) (Scheme 1a).1–5 Their stereochemistries have an important influence on their chemical and biological properties.6–9 Therefore, the development of efficient access to all stereoisomers of these motifs is a significant research topic as well as a great challenge in this field. Catalytic asymmetric aldol reactions, as the most efficient method for synthesizing β-hydroxycarbonyls, typically only generate one diastereoisomer (syn or anti). In fact, much effort has been devoted to the synthesis of the complementary diastereomers. However, these methods are mainly limited to chiral auxiliary-based approaches10,11 or careful choices of additives, catalysts, and reaction conditions.12–14 Thus, a general and unified method that achieves enantio- and diastereodivergent synthesis of the β-hydroxycarbonyl motifs is urgently needed but remains underdeveloped. Scheme 1 | Stereodivergent Pd/Cu catalysis for desymmetric alkylation of allylic geminal dicarboxylates. Download figure Download PowerPoint The Pd-catalyzed asymmetric allylic alkylation (AAA) reaction serves as one of the most versatile and powerful tools for asymmetric construction of carbon–carbon bond.15–22 A wide range of functionalized allylic electrophiles have been developed for the rapid construction of complex molecules in an atom- and step-economical manner. Since the pioneering works by Lu and Trost, geminal dicarboxylates as carbonyl surrogates have attracted increasing attention due to their high efficiency in the preparation of chiral allylic alcohol derivatives (Scheme 1b).23–30 Combined with a suitable prochiral enolate nucleophile, Pd-catalyzed AAA with a geminal dicarboxylate provide a direct and convenient route for the enantio- and diastereoselective synthesis of β-hydroxycarbonyl motifs bearing a versatile carbon-carbon double bond. However, currently available methods are mostly limited to the generation of a single stereocenter and only one report has been reported with one favored diastereoisomer being obtained. In addition, the diastereoselectivity ratio (dr) value is sensitive to the steric hindrance of the substrate.26 Enantio- and diastereoselective substitution of the allylic geminal dicarboxylates with common prochiral nucleophiles remain a formidable challenge and no stereodivergent examples have been reported yet (Scheme 1c). In recent years, since the seminal studies carried out by Carreira,31,32 cooperative catalysis including metal/organo catalysis,31–39 bimetallic catalysis,40–50 and organo/organo catalysis51 has become a powerful method for stereodivergent synthesis.52–55 As a result of our continued interest in cooperative bimetallic catalysis and stereodivergent synthesis,40–43,56 we envisioned using this strategy to address the stereodivergent synthesis of β-hydroxycarbonyl motifs using the same starting materials. This strategy involves concurrent activation and independent stereocontrol of the two reactants by two different chiral catalysts. If the configurations of the two stereocenters are adamantly fixed by the chiral ligands, we can easily control the configuration of the products (RR, RS, SR, or SS) by only changing the combinations of two chiral metal catalysts. Considering the highly functionalized building blocks of the target products and the increasing importance of stereochemical diversity, this methodology may influence diversity-oriented synthesis and the design of compound libraries for drug discovery.57–59 Herein, we report a cooperative Pd/Cu catalytic system utilized for the asymmetric synthesis of β-hydroxycarbonyl motifs through the desymmetrization of allylic geminal dicarboxylates in an enantio- and diastereodivergent manner (Scheme 1c). This Pd/Cu dual catalytic system can accommodate a wide range of substrates including challenging alkyl-substituted, 2-substituted, and 3,3′-disubstituted allylic species, delivering the corresponding products in high yields (up to 95% yield) and with excellent enantioselectivities (ee) and diastereoselectivities (up to >99% ee and >20:1 dr). Additionally, the mechanism of this dual Pd/Cu catalytic system including (1) the desymmetrization process of geminal dicarboxylates; (2) the origin of regioselectivity (branched or linear); (3) the enantio-, and diastereodivergence observed by changing the combinations of two chiral metal catalysts, were computationally investigated. The predicted regio-, enantio-, and diastereoselectivity are consistent with the experimental results. Experimental Methods General procedure for the asymmetric desymmetrization of allylic geminal esters The preparation of Pd catalyst: [Pd(η3-allyl)Cl]2 (2.5 mol %), (S)- L4 or (R)- L4 (5.5 mol %) were stirred in tetrahydrofuran (THF; 1.0 mL) in a Schlenk flask under nitrogen atmosphere at room temperature (RT) for 40 min. The preparation of Cu catalyst: [Cu(MeCN)4]PF6 (5.0 mol %), (S,Sp)-L5 or (R,Rp)-L5 (5.5 mol %) were stirred in THF (1.0 mL) in a Schlenk flask under nitrogen atmosphere at RT for 40 min. A flame dried Schlenk tube was cooled to RT and filled with N2. To this flask imino ester (0.20 mmol, 1.0 equiv) and base (0.28 mmol, 1.4 equiv) were added. Next, Cu catalyst (1.0 mL) and Pd catalyst (1.0 mL) were added. Allylic geminal diacetates (0.28 mmol, 1.4 equiv) were then added, and the reaction mixture was stirred at RT or 0 °C for 12 h. After the reaction was complete, the reaction mixture was filtered through a small pad of silica and washed with EtOAc. The dr was determined by 1H NMR analysis of the crude reaction mixture. Purification by silica gel column chromatography [petroleum ether (PE)/ethyl acetate (EA) = 5:1–10:1] afforded the desired β-hydroxycarbonyl product (see Supporting Information for more details on experimentation and characterization data). Results and Discussion Initial trials were carried out using (E)-3-phenylprop-2-ene-1,1-diyldiacetate ( 1a) and cyclic imino ester ( 2a) as model substrates under a cooperative Pd/Cu catalytic system (Table 1).60–81 When the combination of Pd/(R,R)- L1 and Cu/(S,Sp)- L5) was used in THF at RT, only 6% isolated yield of the substituted product 3aa was obtained with 1.3:1 dr (entry 1). The poor activity might be due to the mismatch between the (R,R)- L1 and (S,Sp)- L5. The privileged Trost's ligand bearing a big "chiral pocket" blocks the nucleophilic attack of the chiral metalated imino ester. Then, three classic axially-chiral ligands with different dihedral angles were screened (entries 2–4).82 The desired product (S,S)- 3aa could be smoothly obtained with excellent diastereo- and enantioselectivity (>20:1 dr and >99% ee) but in low yield (38–45% yield). Careful analysis revealed that the imino ester 2a was completely consumed and a considerable amount of disubstituted by-product was generated. To inhibit this process, the reaction temperature was decreased to 0 °C. Positively, the yield was increased to 71% (entry 5). To further increase the yield of (S,S)- 3aa, phosphino-oxazoline (PHOX) ligands bearing a methyl or tert-butyl group were also explored (entries 6 and 7). It was found that (S,Sp)- L5 bearing an iso-propyl group proved to be the best in this reaction. Imino esters modified with methyl or tert-butyl group were also examined (entries 8 and 9). Different results were observed: methyl ester ( 2a′) is also suitable for this catalytic system but the tert-butyl ester ( 2a″) gave its corresponding product in 17% yield and with 8:1 dr and 95% ee. When the absolute configuration of (R)- L4 was reversed, the diastereoisomer (R,S)- 3aa was smoothly obtained in high yield and with satisfactory stereoselectivity (87% yield, >20:1 dr, >99% ee) (entry 10). These results suggested that two chiral palladium and copper catalysts could independently control the stereochemical configuration of both allylic substrate and imino ester. Table 1 | Optimization of the Reaction Conditions for Enantio- and Diastereodivergent Synthesisa Entry 2 L for Pd L for Cu Yield (%)b Drc ee (%)d (Config.) 1 2a (R,R)- L1 (S,Sp)- L5 6 1.3:1 97 (S,S)/66 2 2a (R)- L2 (S,Sp)- L5 38 >20:1 >99 (S,S) 3 2a (R)- L3 (S,Sp)- L5 43 >20:1 >99 (S,S) 4 2a (R)- L4 (S,Sp)- L5 45 >20:1 >99 (S,S) 5e 2a (R)- L4 (S,Sp)- L5 71 >20:1 >99 (S,S) 6e 2a (R)- L4 (S,Sp)- L6 75 12:1 >99 (S,S) 7e 2a (R)- L4 (S,Sp)- L7 71 13:1 >99 (S,S) 8e 2a' (R)- L4 (S,Sp)- L5 70 >20:1 >99 (S,S) 9e 2a″ (R)- L4 (S,Sp)- L5 17 8:1 95 (S,S) 10 2a (S)- L4 (S,Sp)- L5 87 >20:1 >99 (R,S) 11f 2a (S)- L4 (S,Sp)- L5 87 >20:1 >99 (R,S) 12e 2a No Pd (S,Sp)- L5 nr — — 13e 2a (R)- L4 no Cu nr — — 14e,g 2a (R)- L4 (S,Sp)- L5 Trace — — aReaction conditions: 1a (0.28 mmol, 1.4 equiv), 2a-2a″ (0.20 mmol, 1.0 equiv), [Pd(allyl)Cl]2 (2.5 mol %), L1–L4 (5.5 mol %), [Cu(MeCN)4]PF6 (5 mol %), L5–L7 (5.5 mol %), K3PO4 (1.5 equiv), THF (2 mL), 12 h, at RT. bIsolated yield of all diastereoisomers based on the starting material 2. However, 5 mol % of nucleophiles were consumed by the [Pd(allyl)Cl]2. nr = no reaction. cDetermined by 1H NMR integration. dDetermined by HPLC analysis using an IC (CHIRALPAK® IC) column. e0 °C instead of RT. fA large-scale reaction with 2.0 mmol of 2a. gNo K3PO4. Furthermore, a large-scale reaction was also conducted under optimized reaction conditions, providing the desired product in similar results (entry 11). To understand the specific role of this Pd/Cu catalytic system, control experiments were carried out (entries 12–14). The reaction did not occur in the absence of either the Cu-catalyst or Pd-catalyst and only trace amounts of products were detected if no base was present, showing the excellent facilitative nature of our bimetallic catalytic system. Then, all four stereoisomers of 3aa were successfully obtained using the same method and starting materials by choosing the configuration combinations of the chiral ligands L4 and L5 (For all, >20:1 dr and >99% ee). These catalytic products could be easily transformed into the products 4aa through a simple hydrolysis process without changing the stereochemical configuration (Scheme 2). Scheme 2 | Stereodivergent synthesis of 3aa and 4aa. (a) 5N HCl in THF at RT. Download figure Download PowerPoint With the optimized reaction conditions in hand, the substrate scope of allylic geminal dicarboxylates was explored with 2a in a diastereodivergent manner using the combinations of (R)-BINAP (BINAP = 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthalene) or (S)-BINAP with (S,Sp)- L5 (Table 2). All the substituted products, regardless of electronic and steric properties of the substituents, were smoothly prepared in high to excellent yields, and with excellent enantio- and diastereoselectivities. There were no obvious differences in catalytic activity and stereo-induction of the two catalyst combinations for most substrates. Specifically, for (R,S)-products: for the substrates bearing fluoro- and methyl substituents at the 2-position, the desired products ( 3ab and 3ac) were obtained in 87% and 80% yields, 14:1 dr, and 8:1 dr, and both >99% ee. The electronic properties of the functional groups at the 3-position showed a different effect on the diastereoselectivity. Increasing the electron-donation ability of the substituents by changing the fluoro group to a methoxyl group showed great improvements in diastereoselectivity ( 3ad– 3ah). The 3ag and 3ah products were smoothly obtained with excellent diastereoselectivities (both >20:1 dr). The performances of substrates substituted with different groups at the 4-position of the aryl showed that the electronic properties have a negligible influence on the experimental results ( 3ai– 3am, >20:1 dr, >99% ee). Disubstituted substrates were also compatible with these reaction conditions ( 3an, >20:1 dr, >99% ee). Changing the phenyl group of 2a to the naphthyl group afforded the corresponding products with satisfactory results ( 3ao, 8:1 dr, >99% ee). Notably, the alkyl substituted geminal dicarboxylates, which are regarded as challenging substrates for allylic substitution reactions,83,84 showed high reactivity and stereoselectivity in our Pd/Cu dual catalytic system (>20:1 dr, >99% ee for all examples 3ap– 3av). With these encouraging results, less explored substrates, such as 2-substituted allylic substrates and 3,3′-disubstituted allylic substrate were explored, providing the substituted products in moderate yields and with almost perfect stereoselectivities ( 3aw- 3ay). For (S,S)-products, a similar trend was observed for the aryl-substituted dicarboxylates. Most of substrates gave the desired products in high to excellent yields and with excellent diastereo- and enantioselectivities (up to >20:1 dr, >99% ee). For the alkyl-substituted substrates, the corresponding (S,S)-( 3ap- 3av) could also be obtained in 57–69% yields and with 4:1–7:1 dr and 91–>99% ee. The absolute configurations of (R,S)- 3av and (S,S)- 3av were determined by X-ray crystallography. Table 2 | Substrate Scope with Geminal Dicarboxylatesa a 1 (0.28 mmol, 1.4 equiv), 2a (0.20 mmol, 1.0 equiv), [Pd(allyl)Cl]2 (2.5 mol %), (S)- L4 or (R)- L4 (5.5 mol %), [Cu(MeCN)4]PF6 (5 mol %), (S,Sp)- L5 (5.5 mol %), K3PO4 (1.5 equiv), THF (2 mL), 12 h. Then, the scope of imino esters was also investigated by incorporating 1a as the standard substrate under the optimal reaction conditions in a diastereodivergent manner (Table 3). Various imino esters with aryl substituents bearing electron-withdrawing or -donating groups furnished the substituted products in high to excellent yields with excellent stereoselectivities. Overall, the yields of (R,S)-products are slightly higher than that of (S,S)-products, and the products ( 3ba– 3qa) are smoothly synthesized in high yields (56–95%) and with high to excellent stereoselectivities (up to >99% ee and >20:1 dr). Notably, the imino esters substituted with furan, thiophene, and pyridine were also conducted, affording the substituted products 3ma– 3oa in high yields and with satisfactory stereoselectivities (12:1–20:1 dr and 98–>99% ee). 2-Thiazoline-4-carboxylates and acyclic aldimine ester were conducted in our Pd/Cu bimetallic catalyst system, affording the desired products 3pa and 3qa [for (R,S)- 3pa: 87% yield, >20:1 dr, 99% ee; for (S,S)- 3pa: 56% yield, 3:1 dr; 98% ee; for (R,S)- 3qa: 75% yield, 9:1 dr, 98% ee; for (S,S)- 3qa: 63% yield, 16:1 dr; >99% ee). Table 3 | Substrate Scope with Imino Estersa a 1a (0.28 mmol, 1.4 equiv), 2 (0.20 mmol, 1.0 equiv), [Pd(allyl)Cl]2 (2.5 mol %), (S)- L4 or (R)- L4 (5.5 mol %), [Cu(MeCN)4]PF6 (5 mol %), (S,Sp)- L5 (5.5 mol %), K3PO4 (1.5 equiv), THF (2 mL), 12 h. bThe yield, dr, and ee were determined after reduction of 3qa with NaBH4. A proposed catalytic cycle is presented, showing an overview of this bimetallic catalysis mechanism (Scheme 3). The reaction starts with the generation of Pd(0)/ L4 catalyst from [Pd(allyl)Cl]2. The Pd(0)/ L4 catalyst then interacts with the allylic geminal dicarboxylate to produce the π-allyl-Pd intermediate (syn,anti)- 6 or (syn,syn)- 7 with one AcO− group leaving via 5a or 5b. In another cycle, the α-H of the imino methyl ester 2a′ is activated in the presence of the Cu/ L5 catalyst. The base captures this proton, giving the corresponding nucleophile 8 or 17. Next, the π-allyl-Pd intermediate 7 and the nucleophile 8 or 17 undergo nucleophilic substitution, furnishing the final product 3. Scheme 3 | Proposed mechanism of synergistic Pd/Cu catalysis. Download figure Download PowerPoint To explore the origin of the regio-, enantio-, and diastereoselectivity, density functional theory (DFT) calculations were conducted (Figure 1). At first, we investigated the underlying reason for the asymmetric desymmetrization of geminal dicarboxylates with Pd/(R)- L4. Two pathways for the generation of two π-allyl-Pd intermediates (syn,anti)- 6 and (syn,syn)- 7 were proposed. These two intermediates mainly originated from the specific conformations of the complex 5. The calculations revealed that the π-allyl-Pd intermediate with configuration of (syn,anti)- 6 is 5.81 kcal/mol higher in energy compared with (syn,syn)- 7 and the (syn,syn)-configuration to be favored by 7.69 kcal/mol, in consistent with the experimental observations. Figure 1 | Gibbs free energy (y-axis, in kcal/mol) profile for four possible pathways regarding the regio-, enantio-, and diastereoselectivity of the synergistic catalytic reaction with the combinations of Pd/(R)-L4 and Cu/(R,Rp)-L5. Download figure Download PowerPoint After the asymmetric desymmetrization process of the dicarboxylates was established, we explored the origin of regio-, enantio-, and diastereoselectivity of this transformation with combinations of Pd/(R)- L4 and Cu/(R,Rp)- L5) (Figure 1). In general, the π-allyl-Pd intermediate has two reaction sites whereby the benzyl position leads to branched products (teal pathway and gray pathway) and the other position leads to linear products (brown pathway and pale green pathway). Considering there are two π-allyl-Pd intermediates ( 6 and 7), four possible reaction pathways are established. At first, the reactions with nucleophile 8 (Cu catalyst modified with (R,Rp)- L5) were studied (Figure 1).85,86 The calculations suggest that the energy barrier for the formation of the linear product from the intermediate 6 is favored by 10.90 kcal/mol compared with that for the branched product ([ 10-14]‡ vs [ 9-13]‡), and the linear product from intermediate 7 is favored by 10.97 kcal/mol over the branched product ([ 12–16]‡ vs [ 11–15]‡). According to the Gibbs free energy profiles, the pathway for (S,R)-linear product (the brown pathway) is the major one with the lowest energy barrier and the lowest Gibbs free energy among all four pathways. Similar trends were found with combinations of Pd/(R)- L4 and Cu/(S,Sp)- L5), giving the major (S,S)-linear product ( Supporting Information Figure S1).87–89 These theoretical calculations agree well with the experimental results. Conclusion We have successfully developed a cooperative Pd/Cu catalytic system that was applied to the asymmetric synthesis of β-hydroxycarbonyl motifs through the desymmetrization of allylic geminal dicarboxylates in an enantio- and diastereodivergent manner. The present bimetallic catalytic system is compatible with a wide scope of substrates including challenging alkyl-substituted, 2-substituted, and 3,3′-disubstituted allylic substrates, delivering the β-hydroxycarbonyl products in high to excellent yields and with excellent enantio- and diastereoselectivities (up to >99% ee and >20:1 dr). Furthermore, the asymmetric desymmetrization process and the origin of regio-, enantio-, and diastereodivergence is reasonably explained by the computational study. Supporting Information Supporting Information is available and includes general information, experimental procedures, optimization details, X-ray crystallographic data, product characterization data, computational details, and copies of high-performance liquid chromatography (HPLC) and NMR spectra. Conflict of Interest There is no conflict of interest to report. Acknowledgments This work was supported by the National Natural Science Foundation of China (nos. 21620102003, 21831005, 21901158, and 21991112), the Shanghai Sailing Program (no. 19YF1421900), Shanghai Municipal Education Commission (no. 201701070002E00030), National Key R&D Program of China (no. 2018YFE0126800), the Science and Technology Commission of Shanghai Municipality (no. 19JC1430100), and Zhiyuan Scholar Program (no. ZIRC2020-04). References 1. Mahrwald R.; Evans D.Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004. Google Scholar 2. Schetter B.; Mahrwald R.Modern Aldol Methods for the Total Synthesis of Polyketides.Angew. Chem. Int. Ed.2006, 45, 7506–7525. Google Scholar 3. Trost B. M.; Brindle C. S.The Direct Catalytic Asymmetric Aldol Reaction.Chem. Soc. Rev.2010, 39, 1600–1632. Google Scholar 4. Mahrwald R.Modern Methods in Stereoselective Aldol Reactions; Wiley-VCH: Weinheim, 2013. Google Scholar 5. Wu L.; Yang G.; Zhang W.Ni-Catalyzed Enantioconvergent Coupling of Epoxides with Alkenylboronic Acids: Construction of Oxindoles Bearing Quaternary Carbons.CCS Chem.2019, 1, 623–631. Google Scholar 6. Jozwiak K.; Lough W. J.; Wainer I. W.Drug Stereochemistry: Analytical Methods and Pharmacology; CRC Press: Boca Raton, FL, 2012. Google Scholar 7. Harrison B. A.; Gierasch T. M.; Neilan C.; Pasternak G. W.; Verdine G. L.High-Affinity Mu Opioid Receptor Ligands Discovered by the Screening of an Exhaustively Stereodiversified Library of 1,5-Enediols.J. Am. Chem. Soc.2002, 124, 13352–13353. Google Scholar 8. Kim Y.-k.; Arai M. A.; Arai T.; Lamenzo J. O.; Dean E. F.; Patterson N.; Clemons P. A.; Schreiber S. L.Relationship of Stereochemical and Skeletal Diversity of Small Molecules to Cellular Measurement Space.J. Am. Chem. Soc.2004, 126, 14740–14745. Google Scholar 9. Gerard B.; Duvall J. R.; Lowe J. T.; Murillo T.; Wei J.; Akella L. B.; Marcaurelle L. A.Synthesis of a Stereochemically Diverse Library of Medium-Sized Lactams and Sultams via SNAr Cycloetherification.ACS Comb. Sci.2011, 13, 365–374. Google Scholar 10. Van Draanen N. A.; Arseniyadis S.; Crimmins M. T.; Heathcock C. H.Protocols for the Preparation of Each of the Four Possible Stereoisomeric α-Alkyl-β-hydroxy Carboxylic Acids from a Single Chiral Aldol Reagent.J. Org. Chem.1991, 56, 2499–2506. Google Scholar 11. Walker M. A.; Heathcock C. H.Acyclic Stereoselection. 54. Extending the Scope of the Evans Asymmetric Aldol Reaction: Preparation of anti and "Non-Evans" syn Aldols.J. Org. Chem.1991, 56, 5747–5750. Google Scholar 12. Denmark S. E.; Su X.; Nishigaichi Y.The Chemistry of Trichlorosilyl Enolates. 6. Mechanistic Duality in the Lewis Base-Catalyzed Aldol Addition Reaction.J. Am. Chem. Soc.1998, 120, 12990–12991. Google Scholar 13. Gao J.; Bai S.; Gao Q.; Liu Y.; Yang Q.Acid Controlled Diastereoselectivity in Asymmetric Aldol Reaction of Cycloketones with Aldehydes Using Enamine-Based Organocatalysts.Chem. Commun.2011, 47, 6716–6718. Google Scholar 14. Martínez-Castañeda Á.; Rodríguez-Solla H.; Concellón C.; del Amo V.Switching Diastereoselectivity in Proline-Catalyzed Aldol Reactions.J. Org. Chem.2012, 77, 10375–10381. Google Scholar 15. Trost B. M.; Van Vranken D. L.Asymmetric Transition Metal-Catalyzed Allylic Alkylations.Chem. Rev.1996, 96, 395–422. Google Scholar 16. Helmchen G.; Pfaltz A.Phosphinooxazolines-A New Class of Versatile, Modular P,N-Ligands for Asymmetric Catalysis.Acc. Chem. Res.2000, 33, 336–345. Google Scholar 17. Miyabe H.; Takemoto Y.Regio- and Stereocontrolled Palladium- or Iridium-Catalyzed Allylation.Synlett2005, 2005, 1641–1655. Google Scholar 18. Mohr J. T., Stoltz B. M.Enantioselective Tsuji Allylations.Chem. Asian J.2010, 2, 1476–1491. Google Scholar 19. Lu Z.; Ma S.Metal-Catalyzed Enantioselective Allylation in Asymmetric Synthesis.Angew. Chem. Int. Ed.2008, 47, 258–297. Google Scholar 20. Oliver S.; Evans P. A.Transition-Metal-Catalyzed Allylic Substitution Reactions: Stereoselective Construction of α- and β-Substituted Carbonyl Compounds.Synthesis2013, 45, 3179–3198. Google Scholar 21. Butt N. A.; Zhang W.Transition Metal-Catalyzed Allylic Substitution Reactions with Unactivated Allylic Substrates.Chem. Soc. Rev.2015, 44, 7929–7967. Google Scholar 22. Kazmaier U., Ed.; Transition Metal Catalyzed Enantioselective Allylic Substitution in Organic Synthesis; Springer Verlag: Berlin and Heidelberg, Germany, 2012. Google Scholar 23. Lu X.; Huang Y.Palladium-Catalyzed Reaction of Nucleophiles with Diacetates of Allylic 1,1-Diols.J. Organomet. Chem.1984, 268, 185–190. Google Scholar 24. Trost B. M.; Vercauteran J.Allylic Geminal Diacetates. Unusual Carbonyl Substitutes via Metal Catalyzed Reactions.Tetrahedron Lett.1985, 26, 131–134. Google Scholar 25. Trost B. M.; Lee C. B.; Weiss J. M.Asymmetric Alkylation of Allylic gem-Dicarboxylates.J. Am. Chem. Soc.1995, 117, 7247–7248. Google Scholar 26. Trost B. M.; Ariza X.Catalytic Asymmetric Alkylation of Nucleophiles: Asymmetric Synthesis of α-Alkylated Amino Acids.Angew. Chem. Int. Ed. Eng.1997, 36, 2635–2637. Google Scholar 27. Trost B. M.; Lee C. B.Geminal Dicarboxylates as Carbonyl Surrogates for Asymmetric Synthesis. Part I. Asymmetric Addition of Malonate Nucleophiles.J. Am. Chem. Soc.2001, 123, 3671–3686. Google Scholar 28. Trost B. M.; Lee C. B.Geminal Dicarboxylates as Carbonyl Surrogates for Asymmetric Synthesis. Part II. Scope and Applications.J. Am. Chem. Soc.2001, 123, 3687–3696. Google Scholar 29.