E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing

Mu, Yucheng; Hartrampf, Felix; Yu, Elsie C.; Lounsbury, Katherine E; Schrock, Richard R.; Romiti, Filippo; Hoveyda, Amir H.

doi:10.1038/s41557-022-00935-y

Cited by 10 publications

(8 citation statements)

References 60 publications

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“…While classic reactions for alkene synthesis, such as the Wittig and Julia-Kocienski methods, are reliably used to prepare disubstituted alkenes, challenges associated with forming highly substituted (i.e., tri- and tetrasubstituted) alkenes using these methods limit their broad applicability. Efforts to enable the synthesis of highly substituted alkenes have resulted in the development of catalytic strategies based on olefin metathesis and cross-coupling . As an alternative approach, transition-metal catalysis has been applied to the synthesis of alkenes via the hydroalkylation of alkynes (Figure A).…”

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confidence: 99%

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

et al. 2023

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Alkenes are ubiquitous in organic chemistry, yet many classes of alkenes remain challenging to access by current synthetic methodology. Herein, we report a copper hydride-catalyzed approach for the synthesis of Z-configured trisubstituted alkenes with high stereo- and regioselectivity via alkyne hydroalkylation. A DTBM-dppf-supported Cu catalyst was found to be optimal, providing a substantial increase in product yield compared to reactions conducted with dppf as the ligand. DFT calculations show that the DTBM substitution leads to the acceleration of alkyne hydrocupration through combined ground and transition state effects related to preventing catalyst dimerization and enhancing catalyst–substrate dispersion interactions, respectively. Alkyne hydroalkylation was successfully demonstrated with methyl and larger alkyl tosylate electrophiles to produce a variety of (hetero)aryl-substituted alkenes in moderate to high yields with complete selectivity for the Z stereochemically configured products. In the formation of the key C–C bond, computational studies revealed a direct SN2 pathway for alkylation of the vinylcopper intermediate with in situ-formed alkyl iodides.

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Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

et al. 2023

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“…In contrast, there was 77% conversion to the trisubstituted enoate 3a (71% yield, 93:7 Z / E ) with Mo(MAP)-2 (entry 2), which has a sterically less demanding aryloxide. When Mo(MAP)-3 (entry 3), bearing a 2,3,5,6-tetraphenyl aryloxide, , was employed, formation of 3a was more efficient and more stereoretentive (81% yield and 97:3 Z / E ). A more striking trend involved the monoaryloxide chloride (MAC) complexes [entries 4–6, Table ; B(C 6 F 5 ) 3 is to help dissociate the stabilizing pyridine ligand].…”

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confidence: 99%

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

et al. 2023

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Catalytic cross-metathesis (CM) reactions that can generate trisubstituted alkenes in high stereoisomeric purity are important but remain limited in scope. Here, CM reactions are introduced that generate Z-trisubstituted α-methyl, α,β-unsaturated, alkyl and aryl esters, thiol esters, and acid fluorides. Transformations are promoted by a Mo bis-aryloxide, a monoaryloxide pyrrolide, or a monoaryloxide chloride complex; air-stable and commercially available paraffin tablets containing a Mo complex may also be used. Alkyl, aryl, and silyl carboxylic esters as well as thiol esters and acid fluoride reagents are either purchasable or can be prepared in one step. Products were obtained in 55–95% yield and in 88:12–>98:2 Z/E ratio (typically >95:5). The applicability of the approach is highlighted by a two-step conversion of citronellol to an isomintlactone precursor (1.7 g, 73% yield, and 97:3 Z/E) and a single-step transformation of lanosterol acetate to 3-epi-anwuweizic acid (72% yield and 94:6 Z/E). Included are the outcomes of DFT studies, regarding several initially puzzling catalyst activity trends, providing the following information: (1) it is key that a disubstituted Mo alkylidene, generated by a competing homo-metathesis (HM) pathway, can re-enter the productive CM cycle. (2) Whereas in a CM cycle the formation of a molybdacyclobutane is likely turnover-limiting, the collapse of related metallacycles in a HM cycle is probably rate-determining. It is therefore the relative energy barrier required for these steps that determines whether CM or HM is dominant with a particular complex.

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“…However, when Mo-1a was used, CM afforded only ∼15% E , E -10 (20% disappearance of E -12 ). A brief screening study indicated that with a bromine substituent at C4 of the aryloxide ligand, specifically, with Mo-3 , CM, which occurs only at the more electron rich trisubstituted olefin, is considerably more efficient. We were therefore able to isolate E , E -10 in 77% yield and 95:5 E : Z ratio and Z , E -10 in 68% yield and 97:3 E : Z .…”

Section: Resultsmentioning

confidence: 99%

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights

et al. 2023

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Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or β-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

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E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing

Cited by 10 publications

References 60 publications

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights

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