sp3-sp3 Coupling reactions in the synthesis of natural products and biologically active molecules

Geist, Egor; Kirschning, Andreas; Schmidt, Thomas A.

doi:10.1039/c3np70108e

Cited by 138 publications

(112 citation statements)

References 43 publications

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“…3B). In this review, we describe recent progress in addressing these objectives, with a particular focus on initial breakthroughs (new families of coupling partners and new transition-metal catalysts) in alkyl–alkyl cross-couplings of unactivated alkyl electrophiles (7,8,9,10). …”

Section: Introductionmentioning

confidence: 99%

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Choi

2017

Science

762

363

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Because the backbone of most organic molecules is composed primarily of carbon–carbon bonds, the development of efficient methods for their construction is one of the central challenges of organic synthesis. Transition-metal-catalyzed cross-coupling reactions between organic electrophiles and nucleophiles serve as particularly powerful tools for achieving carbon–carbon bond formation. Until recently, the vast majority of cross-coupling processes had employed either aryl or alkenyl electrophiles as one of the coupling partners. In the past 15 years, versatile new methods have been developed that effect cross-couplings of an array of alkyl electrophiles, thereby greatly expanding the diversity of target molecules that are readily accessible. The ability to couple alkyl electrophiles opens the door to a stereochemical dimension that significantly enhances the already remarkable utility of cross-coupling processes, specifically, enantioconvergent couplings of racemic electrophiles.

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Section: Introductionmentioning

confidence: 99%

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Choi

2017

Science

762

363

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“…Indeed, the predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas 1 . However, the construction of sp 3 –sp 3 bonds, a fundamental unit of organic chemistry, remains an important yet elusive objective for cross-coupling reaction engineering 2 . In comparison to related procedures with sp 2 -hybridized species, the development of methods for sp 3 –sp 3 bond formation via transition metal catalysis has been historically hampered by deleterious side-reactions, such as β-hydride elimination with Pd-catalysis, and the reluctance of alkyl halides to undergo oxidative addition 3,4 .…”

mentioning

confidence: 99%

Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Johnston

Smith

Allmendinger

et al. 2016

Nature

398

207

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Over the last half-century, transition metal-mediated cross-coupling reactions have changed the way in which complex organic molecules are synthesized. Indeed, the predictable and chemoselective nature of these transformations has led to their widespread adoption across a vast array of chemical research areas1. However, the construction of sp3–sp3 bonds, a fundamental unit of organic chemistry, remains an important yet elusive objective for cross-coupling reaction engineering2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3–sp3 bond formation via transition metal catalysis has been historically hampered by deleterious side-reactions, such as β-hydride elimination with Pd-catalysis, and the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, a number of research groups have demonstrated the feasibility of nickel-catalyzed cross-coupling processes to form sp3–sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5–7. In particular, the coupling of alkyl halides with pregenerated organozinc8–10, Grignard11,12, and organoborane13 species has been used to furnish diverse molecular structures. However, the poor step and atom economies along with the operational difficulties associated with making, carrying, and using these sensitive coupling partners has hindered their widespread adoption. The prospect of establishing a generically useful sp3–sp3 coupling technology that employs bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be a valuable addition to fields of research that rely on organic molecule construction. Here, we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3–sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. The outlined protocol is suitable for a wide array of primary and secondary carboxylic acids and does not require the presence of radical stabilizing groups. The merit of this coupling strategy is illustrated by the expedient synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

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“…[1] As an increasingly populars trategy,t ransition-metal-catalyzed C(sp 3 )ÀC(sp 3 )c ross-coupling reactions enabledc onvergent synthesis of complex molecules. [2] For al ong time, the use of alkyl organometallic reagents and alkyl halidesd ominated the field of C(sp 3 )ÀC(sp 3 )c ross-coupling ( Figure 1A). [3][4][5][6][7][8] New C(sp 3 )-C(sp 3 )c ross-coupling reactions ben- [a] Dr.…”

mentioning

confidence: 99%

“…As ystematic screening of different bases and silanes was then carriedo ut to optimize the reactionp erformance (Figure3). Under the optimal conditions (base = Mg(OAc) 2 . 4H 2 O, silane = PMHS), the GC yield was found to be 81 %( with an isolated yield of 76 %).…”

mentioning

confidence: 99%

Formation of C(sp³)–C(sp³) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

Lü

Xiao

Liu

et al. 2016

Chemistry A European J

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Olefins and carboxylic acids are among the most important feedstock compounds. They are commonly found in natural products and drug molecules. We report a new reaction of nickel-catalyzed decarboxylative olefin hydroalkylation, which provides a novel practical strategy for the construction of C(sp(3) )-C(sp(3) ) bonds. This reaction can tolerate a variety of synthetically relevant functional groups and shows good chemo- and regioselectivity. It enables cross-coupling of complex organic molecules containing olefin groups and carboxylic acid groups in a convergent fashion.

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sp3-sp3 Coupling reactions in the synthesis of natural products and biologically active molecules

Abstract: This Highlight covers the current status of relatively unexplored sp 3 -sp 3 cross-coupling reactions with particular focus on natural product and related syntheses.

Cited by 138 publications

References 43 publications

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Formation of C(sp³)–C(sp³) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

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sp3-sp3 Coupling reactions in the synthesis of natural products and biologically active molecules

Abstract: This Highlight covers the current status of relatively unexplored sp 3 -sp 3 cross-coupling reactions with particular focus on natural product and related syntheses.

Cited by 138 publications

References 43 publications

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Transition metal–catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Metallaphotoredox-catalysed sp3–sp3 cross-coupling of carboxylic acids with alkyl halides

Formation of C(sp3)–C(sp3) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

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Product

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Formation of C(sp³)–C(sp³) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions