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Zr-catalyzed methylalumination of alkynes (ZMA) shows high regioselectivity and nearly perfect stereoselectivity. Its mechanistic studies have reveale...
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Zirconium-Catalyzed Asymmetric Carboalumination of Unactivated Terminal Alkenes Shiqing Xu* and Ei-ichi Negishi* Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States

CONSPECTUS: Carbometalation of alkenes with stereocontrol offers an important opportunity for asymmetric C−C bond formation. However, the scope of catalytic stereoselective carbometalation of alkenes had until recently been limited to electronically biased alkenes or those with the presence of directing groups or other auxiliary functionalities to overcome the challenge associated with regio- and stereoselectivity. Catalytic asymmetric carbometalation of unactivated alkenes on the other hand remained as a formidable challenge. To address this long-standing problem, we sought to develop Zr-catalyzed asymmetric carboalumination of alkenes (namely, ZACA reaction) encouraged by our discovery of Zr-catalyzed alkyne carboalumination in 1978. Zr-catalyzed methylalumination of alkynes (ZMA) shows high regioselectivity and nearly perfect stereoselectivity. Its mechanistic studies have revealed that the ZMA reaction involves acyclic carbometalation with “superacidic” bimetallic reagents generated by interaction between two Lewis acids, i.e., alkylalanes and 16-electron zirconocene derivatives through dynamic polarization and ate complexation, affectionately termed as the “two-is-better-than-one” principle. With the encouraging results of Zr-catalyzed carboalumination of alkynes in hand, we sought to develop its alkene version for discovering a catalytic asymmetric C−C bond-forming reaction by using alkylalanes and suitable chiral zirconocene derivatives, which would generate “superacidic” bimetallic species to promote the desired carbometalation of alkenes. However, this proved to be quite challenging. Three major competing side reactions occur, i.e., (i) β-H transfer hydrometalation, (ii) bimetallic cyclic carbometalation, and (iii) Ziegler−Natta polymerization. The ZACA reaction was finally discovered by employing Erker’s (−)-(NMI)2ZrCl2 as the catalyst and chlorinated hydrocarbon as solvent to suppress the undesired side reactions mentioned above. The ZACA reaction has evolved as a powerful tool for the efficient preparation of a wide range of chiral natural products through the following methodological developments: (1) three mutually complementary protocols for methyl-branched chiral alkanols; (2) water, MAO, and IBAO as promoters to accelerate otherwise sluggish carboaluminations; (3) one-step homologation synthesis of deoxypropionates based on one-pot ZACA−Pd-catalyzed vinylation tandem process; (4) ZACA−lipase-catalyzed acetylation−transition-metal-catalyzed cross-coupling processes for preparing various virtually enantiopure chiral alcohols; (5) the chemoselective ZMA and ZACA reactions as well as alkyne elementometalation−Pd-catalyzed cross-coupling for constructing a variety of chiral compounds containing regio- and stereodefined substituted alkenes; (6) the ZACA reaction of dienes to generate chiral organocyclic compounds including those with all-carbon quaternary stereocenters.

1. INTRODUCTION Carbometalation is an organometallic transformation involving the addition to alkenes and alkynes of a diverse range of organometallic reagents such as organolithium, organocopper, organozinc, organoaluminum, and Grignard reagents, with the simultaneous formation of a carbon−carbon bond and a carbon−metal bond (Scheme 1).1 Controlled carbometalation reactions, with high regio- and/or stereoselectivity, can produce synthetically useful organometallic compounds which can be further used for various subsequent transformations. Therefore, carbometalation serves as a powerful tool for organic synthesis. Catalytic asymmetric carbometalation of alkenes offers an important opportunity for enantioselective transformations (Scheme 1, eq 1). However, the current scope of catalytic © 2016 American Chemical Society

stereoselective carbometalation of alkenes is mostly limited to electronically biased alkenes or those with the presence of chelating groups, directing groups, or auxiliaries.2 As substrates, unactivated alkenes, especially terminal alkenes, are among the most attractive synthons for chemical synthesis since a wide array of them are stable, low-cost and readily available from raw materials and/or products in petrochemical industry. In addition to their ready availability, unactivated olefin moieties are relatively inert and thus resistant to a good number of synthetic transformations. Despite these favorable features of unactivated alkenes, their enantioselective carbometalation Received: July 1, 2016 Published: September 29, 2016 2158

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Accounts of Chemical Research Scheme 1. Carbometalation of Alkynes and Alkenes

Scheme 2. Zr-Catalyzed Methylalumination of Alkynes (ZMA)

reactions are rare due to the difficulty of enantiofacial differentiation.2 In addition, from an industrial and synthetic viewpoint, the organoaluminum compounds are one of the most important organometallic reagents for the following reasons: (1) aluminum is the most abundant metal and the third most abundant element in the Earth’s crust (after oxygen and silicon); (2) the low price of aluminum (98% ee) compounds containing two stereogenic centers. The presence of three or more chiral centers will further lower the threshold of average stereoselectivity level. These favorable features provide a foundation for developing ZACA-based protocols for enantiopure deoxypolypropionates. Our initial strategy is two three-step processes for the synthesis of 2,4-dimethyl-1-alkanols (Scheme 14).21 The first three-step process for chain elongation involves (i) oxidation of alcohols to aldehydes, (ii) Wittig olefination, and (iii) ZACA−oxidation. The other protocol also involves a three-step process: (i) iodination, (ii) zincation followed by Pd-catalyzed vinylation, and (iii) ZACA− oxidation. The second protocol is iterative, and can be applied to the synthesis of deoxypropionates containing higher number of branching methyl groups. It should be noted that the diastereomeric mixtures of various 2,4-dimethyl-1-hydroxybutyl

3.2. One-Step Homologation for Deoxypropionates

Deoxypropionate subunits are common structural motifs found in a broad range of naturally occurring compounds. Substantial efforts have been made for their stereoselective construction.22 2162

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Accounts of Chemical Research Scheme 14. Three-Step Homologation Protocols for Deoxypropionates

Scheme 16. One-Step Homologation Synthesis of Deoxypropionates

Iteration of one-pot ZACA−Pd-catalyzed vinylation tandem process achieved the efficient synthesis of 23 in just three steps from styrene. After acetylation, oxidative cleavage of the phenyl group, and reduction, diheterofunctional deoxypropionate 24 was formed, which was further converted to 25, a key intermediate for the total synthesis of ionomycin (Scheme 17).23

derivatives can be readily separated by ordinary chromatographic separation. The initial three-step iterative chain elongation for constructing one deoxypropionate unit consisted of (i) ZACA−oxidation, (ii) iodination, and (iii) zincation−Pdcatalyzed vinylation.21 If the initial ZACA product alkylalane can be directly used for the Pd-catalyzed vinylation to skip oxidation and iodination steps, the newly formed terminal double bond can undergo a second ZACA reaction to achieve a one-step iterative homologation for deoxypropionates (Scheme 15), which is contrastive to most other methods that require three to six steps per unit.22

Scheme 17. One-Step Homologation Synthesis of a Key Intermediate for Ionomycin

Scheme 15. One-Step Homologation Strategy for Deoxypropionates

To this end, one-pot ZACA−Pd-catalyzed vinylation tandem process was developed.23 The β-methyl-substituted alkylalane, generated by ZACA reaction of 1-octene, can undergo Pdcatalyzed Negishi coupling with vinyl bromide in the presence of Zn(OTf)2 and catalytic Pd(DPEphos)Cl2/i-Bu2AlH with DMF as the solvent, producing 19 in 71% yield and 75% ee (Scheme 16, eq 1). This one-pot ZACA−Pd-catalyzed vinylation tandem process has been applied for constructing various deoxypropionate natural products. For example, alkene 20 was synthesized by carbozirconation of 2-butyne with ZrCp2Cl2 and EtMgBr, and subsequent in situ treatment with allyl ether. After ZACA−Pd-catalyzed vinylation tandem process, 21 was subjected to a second ZACA reaction followed by in situ oxidation with O2 to produce 22 in just three steps from 2-butyne (Scheme 16, eq 2).24 Alcohol 22 was previously synthesized as a key intermediate for the total synthesis of apoptosis inducer (−)-rasfonin in 12 steps.25

Recently, we developed a new convergent strategy for highly concise and enantioselective access to polydeoxypropionates.26 Smaller deoxypropionate building blocks were efficiently synthesized by ZACA-based one-step homologation protocol. Then two sequential Cu-catalyzed stereocontrolled sp3−sp3 cross-couplings of secondary tosylates with alkyl Grignard reagents linked the smaller fragments together with full inversion of configuration to assemble long-chian polydeoxypropionates. Through the combination of the ZACA reaction and Cu-catalyzed stereospecific (>99% inversion) crosscoupling, this strategy provides a facile and efficient method for the straightforward construction of diastereo- and enantiomerically pure polydeoxypropionates without resorting to very difficult late-stage purification of the diastereomeric mixtures, as exemplified by the synthesis of phthioceranic acid, a key constituent of the cell-wall lipid of Mycobacterium 2163

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Accounts of Chemical Research tuberculosis, via a longest linear sequence of eight steps from styrene (Scheme 18).26

Scheme 19. ZACA/Iodinolysis−Lipase-Catalyzed Acetylation−Transition-Catalyzed Cross-Coupling Protocol

Scheme 18. Highly Convergent Synthesis of Phthioceranic Acid

virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-26 of ≥99% ee can be obtained by lipasecatalyzed acetylation. A broad range of chiral 2-alkyl-1-alcohols including isotopomers, that have been otherwise very difficult to synthesize, can now be produced in high enantiomeric purities by Pd- or Cu-catalyzed cross-coupling reactions of 26 to introduce various primary, secondary, and tertiary alkyl, aryl, and alkenyl groups with retention of all carbon skeletal features. The synthetic scope of the protocol in Scheme 19 is limited to 2-substituted-1-alcohols. An alternative ZACA/oxidation− lipase-catalyzed acetylation−transition-catalyzed cross-coupling protocol was developed for the synthesis of various γ- and more-remotely chiral alcohols. A sequential (−)- or (+)-ZACA reaction of TBS-protected ω-alkene-1-ols, oxidation, and lipasecatalyzed acetylation produced key intermediate 28 of ≥99% ee. These α,ω-dioxyfunctional intermediates 28 serve as versatile synthons for the construction of various remotely chiral alcohols by using Cu- or Pd-catalyzed cross-coupling reactions with essentially perfect fidelity of stereochemical configuration (Scheme 20).30,31

3.3. ZACA−Lipase-Catalyzed Acetylation−Transition-Metal-Catalyzed Cross-Coupling Processes

Lipase-catalyzed selective acetylation has been applied to further improve the enantiomeric purity of the chiral 2methyl-1-alkanols generated by the ZACA reaction.27 This ZACA−lipase-catalyzed acetylation sequential process provides an efficient route to various 2-methyl-1-alkanols with high enantiopurity (≥98% ee) (Table 1). This process is particularly applicable when the initial purity of alcohols is greater than 70% ee to achieve a high recovery yield. Table 1. ZACA−Lipase-Catalyzed Acetylation Synergy for the Synthesis of 2-Methyl-1-Alkanols

3.4. Chemoselective ZMA and ZACA Reactions of Enynes

A large number of natural products and related compounds contain 2,4-dimethyl-1-penten-1,5-ylidene moieties with a broad range of biological activities, such as nafuredin,32 milbemycin β3,33 and (−)-bafilomycin A134 (Figure 3) . With the notion of the significant synthetic value, two protocols by employing chemoselective ZMA and ZACA reactions of 1,4-pentenyne 32 and its silyl derivatives 33 as five-carbon synthons have been developed for constructing 2,4dimethyl-1-penten-1,5-ylidene derivatives as shown in Scheme 21.35 1,4-Pentenyne underwent the ZMA reaction selectively, without affecting the doube bond, to generate (E)-trisubstituted alkenylalane 34, followed by in situ zincation, and Pd-catalyzed Negishi coupling, producing 35 with ≥98% isomeric purity in 78% yield. The ZACA reaction of 35 with AlMe3 and subsequent lipase-catalyzed acetylation provided 36 (≥98% ee), a key intermediate for nafuredin. Similarly, selective ZMA

In more demanding cases of R1R2CHCH2OH where two carbon groups R1 and R2 are structurally similar, the selectivity factors (E)28 would be not sufficiently high to achieve an efficient enantiomeric purification to the level of ≥98% ee even from enantiomerically enriched mixtures by lipase-catalyzed acetylation. To overcome this challenge, the ZACA/iodinolysis−lipase-catalyzed acetylation−transition-metal-catalyzed cross-coupling sequential process was developed (Scheme 19).29,30 ZACA−in situ iodinolysis of allyl alcohol yielded both (S)- and (R)-ICH2CH(R)CH2OH 26 in 80−90% ee. By 2164

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Accounts of Chemical Research Scheme 20. ZACA/Oxidation−Lipase-Catalyzed Acetylation−Transition-Catalyzed Cross-Coupling Protocol

Scheme 22. Chemoselective ZMA and ZACA Reactions of 1,4-Pentenyne

Scheme 23. Chemoselective ZMA and ZACA Reactions of 1,4-Pentenyne Silyl Derivative

ylidene moieties have been developed in both head-to-tail (Hto-T)36 and tail-to-head (T-to-H)37 construction directions by taking advantage of alkyne elementometalation, Pd-catalyzed Negishi coupling and Suzuki coupling (Scheme 24). Through the combination of the ZACA reaction, these protocols have been applied to the efficient synthesis of various chiral natural products containing trisubstituted alkene moieties.36,37

Figure 3. Some natural products containing 2,4-dimethyl-1-penten1,5-ylidene moieties.

Scheme 21. Two Protocols to 2,4-Dimethyl-1-penten-1,5ylidene Derivatives

Scheme 24. H-to-T and T-to-H Routes to Stereodefined Trisubstituted Alkenes

reaction of 32 and in situ epoxide opening generated 37 of ≥98% E. Alkene 37 underwent ZACA reaction to give 38 in 78% yield and 75% ee, which was further purified by lipasecatalyzed acetylation to 98% ee, a key intermediate for milbemycin β3 (Scheme 22).35 1,4-Pentenyne silyl derivative 33 can selectively undergo ZACA reaction to give 39 in 85% yield and 73% ee. Crude 39 was readily purified to 97% ee by lipase-catalyzed acetylation. After oxidation, asymmetric allylboration, and TBAF deprotection, terminal alkyne 41 was subjected to the ZMA reaction to produce 42, which was further transformed to 43, a key intermediate for (−)-bafilomycin A1 (Scheme 23).35 Several other highly satisfactory procedures for the synthesis of trisubstituted alkenes including 2,4-dimethyl-1-penten-1,52165

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Accounts of Chemical Research 3.5. ZACA Reaction of α,ω-Dienes

unattractive. The undesired cyclobutanation can be completely suppressed by introducing substituents at either of the double bonds of 1,4-pentadiene. The ZACA reactions of 1,4-diene derivatives can proceed normally in good yields with enantioselectivity of 70−92% ee, providing an efficient route to alkene-containing chiral compounds.38 Most recently, the ZACA reaction of various 2-substituted1,5-dienes was found to undergo a cascade intermolecular− intramolecular carbometalation process to generate a tertiary chiral center and an all-carbon quaternary stereogenic center.39 The first carbometalation selectively proceeded at the less hindered monosubstituted double bond, followed by a subsequent intramolecular carbozirconation of disubstituted double bond to generate a quaternary stereogenic center. The ZACA reactions of different types of dienes and trienes are in progress in our laboratory.

Carboalumination of dienes can potentially proceed through a cascade intermolecular−intramolecular carbometalation process to generate carbocyclic scaffolds, which would have significant synthetic value for the synthesis of chiral organic cyclic compounds. Indeed, the ZACA reactions of 1,6-diene 44 with AlMe3 and AlEt3 produced cyclization products 45 (Scheme 25).4a,b The reaction is believed to proceed through Scheme 25. ZACA Reactions of 1,6-Dienes

4. APPLICATIONS IN NATURAL PRODUCT SYNTHESIS Since the discovery of the ZACA reaction, it has been developed into a powerful tool for efficiently preparing a wide range of chiral natural products including those with methyl-branched hydrocarbon skeleton, which is a common structural motif found in a broad range of naturally occurring compounds. Without the detailed discussion on the applications of the ZACA reaction, several representative natural products of biological and medicinal interest synthesized by ZACA reaction are listed in Figure 4.

a carbozirconation of one double bond by cationic zirconocene species, followed by a subsequent intramolecular carbozirconation of the second double bond to generate >95% cis 48 through a chair conformation of cyclohexane-like transition state 47. After the transmetalation and oxidation, cyclization products 45 were generated. The ZACA reaction of 1,4-pentadiene with 5 mol % of (−)-(NMI)2ZrCl2, after oxidation, produced 2-methyl-4penten-1-ol in 80% yield but as a racemate. The deuterium labeling experiment suggested that the loss of enantioselectivity should arise from the facile racemerization through an intramolecular carboalumination to generate an unstable and achiral cyclobutylcarbinylmetal derivative 53 (Scheme 26).38 Although very interesting, this reaction is synthetically Scheme 26. ZACA Reaction of 1,4-Dienes

Figure 4. Representative natural products synthesized via ZACA reaction.

5. SUMMARY In summary, carbometalation serves as a versatile tool for carbon−carbon bond formation. Following the discovery of Zrcatalyzed carboalumination of alkynes in 1978, systematic explorations of organozirconium and organoaluminum chemistry with structural and mechanistic clarifications finally led to the discovery of the ZACA reaction, a very rare catalytic asymmetric C−C bond formation reaction of terminal alkenes of one-point-binding without requiring any directing groups. 2166

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Accounts of Chemical Research

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The ZACA reaction has evolved as a powerful tool for general and efficient construction of various chiral compounds through the extensive investigations as follows. (1) Three alternative and mutually complementary protocols for methyl-branched chiral alkanols have been developed, allowing the flexible design for the asymmetric synthesis. (2) Water, MAO, and IBAO have been found to accelerate otherwise sluggish carboaluminations. (3) One-step homologation synthesis of deoxypropionates has been achieved based on the development of one-pot ZACA−Pd-catalyzed vinylation tandem process. For the synthesis of long-chain polydeoxypolypropionates, a novel convergent strategy has been developed by the combination of ZACA reaction and Cu-catalyzed cross coupling of secondary tosylates with excellent stereocontrol (>99% inversion). (4) The ZACA−lipase-catalyzed acetylation−transitionmetal-catalyzed cross-coupling processes provide an efficient route to a variety of virtually enantiopure chiral alkanols that are not readily accessible by using other methods. (5) The chemoselective ZMA and ZACA reactions of enynes as well as alkyne elementometalation−Pd-catalyzed cross coupling have proven to be very useful for constructing a variety of chiral compounds containing regio- and stereodefined substituted alkenes. (6) The ZACA reaction of dienes proceeded though a cascade intermolecular−intramolecular carbometalation process to generate carbocyclic skeletons in regio- and stereoselective manner, providing a new entry to chiral organocyclic compounds including those with all-carbon quaternary stereocenters. It is gratifying to note that, through these methodological developments, the ZACA reaction does provide, in most cases, substantial improvements in efficiency and selectivity over previous syntheses of various natural products. Despite the significant advances, there remains room for further improvements with regard to the scope of substrates, enantioselectivity of methylalumination, and reaction mechanisms.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Shiqing Xu received his BS degree in 2004 and Ph.D. degree in 2009 from Fudan University (China). He is currently working as an Assistant Research Scientist at Purdue University. Ei-ichi Negishi received his Bachelor degree from the University of Tokyo (Japan), and his Ph.D. degree from University of Pennsylvania. He became Assistant Professor at Syracuse University in 1972 and Associate Professor in 1976. He moved to Purdue Universityas Full Professor in 1979. He is currently the Herbert C. Brown Distinguished Professor of Chemistry at Purdue University.

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ACKNOWLEDGMENTS We thank the Negishi-Brown Institute, Purdue University and Teijin Limited for the support of this research. EN thanks his former co-workers whose names and contributions are referenced. 2167

DOI: 10.1021/acs.accounts.6b00338 Acc. Chem. Res. 2016, 49, 2158−2168

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(28) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. QuantitativeAnalyses of Biochemical Kinetic Resolutions of Enantiomers. J. Am. Chem. Soc. 1982, 104, 7294−7299. (29) Xu, S.; Lee, C.-T.; Wang, G.; Negishi, E. Widely Applicable Synthesis of Enantiomerically Pure Tertiary Alkyl-Containing 1Alkanols by Zirconium-Catalyzed Asymmetric Carboalumination of Alkenes and Palladium- or Copper-Catalyzed Cross-Coupling. Chem. Asian J. 2013, 8, 1829−1835. (30) Xu, S.; Oda, A.; Negishi, E. Enantioselective Synthesis of Chiral Isotopomers of 1-Alkanols by a ZACA-Cu-Catalyzed Cross-Coupling Protocol. Chem. - Eur. J. 2014, 20, 16060−16064. (31) Xu, S.; Oda, A.; Kamada, H.; Negishi, E. Highly Enantioselective Synthesis of γ-, δ-, and ε-Chiral 1-Alkanols via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)-Cu- or PdCatalyzed Cross-Coupling. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 8368−8373. (32) Omura, S.; Miyadera, H.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.; Nagamitsu, T.; Takano, D.; Sunazuka, T.; Harder, A.; Kolbl, H.; Namikoshi, M.; Miyoshi, H.; Sakamoto, K.; Kita, K. An Anthelmintic Compound, Nafuredin, Shows Selective Inhibition of Complex I in Helminth Mitochondria. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 60−62. (33) Mishima, H.; Kurabayashi, M.; Tamura, C.; Sato, S.; Kuwano, H.; Saito, A.; Aoki, A. Structures of Milbemycin β1, β2, and β3. Tetrahedron Lett. 1975, 16, 711−714. (34) Evans, D. A.; Calter, M. A. Diastereoselective Aldol Reactions of Beta-Silyloxy Ethyl Ketones - Application to the Total Synthesis of Bafilomycin A1. Tetrahedron Lett. 1993, 34, 6871−6874. (35) Zhu, G.; Negishi, E. 1,4-Pentenynes as a Five-Carbon Synthon for Efficient and Selective Syntheses of Natural Products Containing 2,4-Dimethyl-1-penten-1,5-ylidene and Related Moieties via ZrCatalyzed Carboalumination of Alkynes and Alkenes. Chem. - Eur. J. 2008, 14, 311−318. (36) Negishi, E.; Tobrman, T.; Rao, H.; Xu, S.; Lee, C.-T. Highly (≥98%) Selective Trisubstituted Alkene Synthesis of Wide Applicability via Fluoride-Promoted Pd-Catalyzed Cross-Coupling of Alkenylboranes. Isr. J. Chem. 2010, 50, 696−701. (37) (a) Huang, Z.; Negishi, E. Highly Stereo- and Regioselective Synthesis of (Z)-Trisubstituted Alkenes via 1-Bromo-1-Alkyne Hydroboration-Migratory Insertion-Zn-Promoted Iodinolysis and Pd-Catalyzed Organozinc Cross-Coupling. J. Am. Chem. Soc. 2007, 129, 14788−14792. (b) Xu, S.; Lee, C.-T.; Rao, H.; Negishi, E. Highly (≥98%) Stereo- and Regioselective Trisubstituted Alkene Synthesis of Wide Applicability via 1-Halo-1-alkyne Hydroboration-Tandem Negishi-Suzuki Coupling or Organoborate Migratory Insertion. Adv. Synth. Catal. 2011, 353, 2981−2987. (38) Tan, Z.; Liang, B.; Huo, S.; Shi, J.; Negishi, E. ZirconiumCatalyzed Asymmetric Carboalumination (ZACA Reaction) of 1,4Dienes. Tetrahedron: Asymmetry 2006, 17, 512−515. (39) From unpublished results (40) Pitsinos, E.; Athinaios, N.; Xu, Z.; Wang, G.; Negishi, E. Total Synthesis of (+)-Scyphostatin Featuring an Enantioselective and Highly Efficient Route to the Side-Chain via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA). Chem. Commun. 2010, 46, 2200−2202. (41) Zeng, X.; Zeng, F.; Negishi, E. Efficient and Selective Synthesis of 6,7-Dehydrostipiamide via Zr-Catalyzed Asymmetric Carboalumination and Pd-Catalyzed Cross-Coupling of Organozincs. Org. Lett. 2004, 6, 3245−3248.

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DOI: 10.1021/acs.accounts.6b00338 Acc. Chem. Res. 2016, 49, 2158−2168