Periodic Reporting for period 1 - HISUBMET (New Catalysts for Synthesis of Stereodefined and Modifiable Tetrasubstituted Alkenes)
Periodo di rendicontazione: 2023-01-01 al 2025-06-30
Catalytic olefin metathesis (OM) remains one of the most pivotal transformations in modern chemistry. Since the 1990s, a plethora of Mo/W and Ru catalysts have been developed for ring-closing (RCM), ring-opening (ROM), cross-metathesis (CM), and polymerization reactions. These processes, in some cases carried out on metric ton scale, are used to generate materials for applications in the pharmaceutical, fragrance, agricultural, and polymer industries.
A key question then is: What truly compelling problems remain unaddressed? Our goal is to address three key shortcomings in the state of the art:
a) Ring-opening of relatively stable small and medium-sized cyclic alkenes,
b) cross-metathesis between two electronically deficient alkenes, and
c) synthesis of stereodefined tetrasubstituted alkenes.
OM is an attractive strategy for accessing the above classes of compounds. However, effective solutions to these challenges will require innovation in catalyst design and development. For instance, the available complexes, regardless of their core metal, are ineffective in promoting the formation of many tetrasubstituted alkenes, particularly in high stereoisomeric purity (i.e. >95%). As a result, we have set out to develop a class of new Mo/W complexes, bearing a structural motif distinct from the state of the art, with the hope that these entities would be able to address the abovementioned challenges. The development of such catalysts, along with new strategic approaches, will offer access to a range of compounds that are either unknown or difficult to access, pave the way to uncharted chemical space, and impact discoveries in pharmaceuticals, agrochemicals, fragrances, and polymer chemistry.
A key question then is: What truly compelling problems remain unaddressed? Our goal is to address three key shortcomings in the state of the art:
a) Ring-opening of relatively stable small and medium-sized cyclic alkenes,
b) cross-metathesis between two electronically deficient alkenes, and
c) synthesis of stereodefined tetrasubstituted alkenes.
OM is an attractive strategy for accessing the above classes of compounds. However, effective solutions to these challenges will require innovation in catalyst design and development. For instance, the available complexes, regardless of their core metal, are ineffective in promoting the formation of many tetrasubstituted alkenes, particularly in high stereoisomeric purity (i.e. >95%). As a result, we have set out to develop a class of new Mo/W complexes, bearing a structural motif distinct from the state of the art, with the hope that these entities would be able to address the abovementioned challenges. The development of such catalysts, along with new strategic approaches, will offer access to a range of compounds that are either unknown or difficult to access, pave the way to uncharted chemical space, and impact discoveries in pharmaceuticals, agrochemicals, fragrances, and polymer chemistry.
A. We have developed protocols for nearly 30 new Mo and W alkylidene complexes, all fully characterized, including six X-ray structures. These high oxidation-state complexes differ in imido ligands (adamantyl, 2,6-dialkyl-phenyl, pentafluorophenyl), aryloxide substitution (mono-/disubstituted), aryl substituents (3,5-di-t-butyl, mesityl), and anionic ligands (pyrrolyl, chloro). Additionally, they were prepared in stabilized form with bipyridyl or pyridyl ligands.
We have been able to demonstrate that the active complex can be generated in situ when catalytic amounts of Zn(II) salts are present. Two additional points merit brief note: (i) None of the foregoing complexes have been reported previously. (ii) We have developed various new methods to be able to obtain a number of these novel entities.
We have evaluated the ability of the aforementioned new Mo and W complexes to promote various olefin metathesis reactions:
(i) Ring-opening/cross-metathesis (ROCM) of small and medium rings. For instance, it was discovered that reaction involving cyclohexene with Z-dichloroethylene generates the desired product in high yield and stereoselectivity. This is the first case where cyclohexene, used as the limiting reagent, is transformed to a modifiable Z,Z-diene in high efficiency.
(ii) Polymerization processes that deliver unique structural motifs. The new catalysts can be used for synthesis of stereodefined polymers (0.01–0.1 mol % loading) that are not accessible with previously reported complexes. Relevant mechanistic studies are ongoing.
(iii) Cross-metathesis (CM) between two electronically deficient alkenes. Preliminary data have shown that the new class of catalysts can efficiently promote CM between vinyl B(pin) and a dihalogenated alkene—both electron-poor substrates. Such a transformation is not achievable with any of the currently available catalyst systems.
Finally, we have begun exploring the feasibility of obtaining silica-supported complexes. Such entities might be able to mitigate bimolecular decomposition pathways, a major cause of reduced metathesis activity. The insights garnered from these preliminary studies will be central to our ongoing investigations aimed at the development of stereocontrolled synthesis of tetrasubstituted alkenes through catalytic olefin metathesis.
B. We have developed two Cu-catalyzed methods that can be used to prepare stereochemically defined tetrasubstituted alkenyl boronates. These compounds can be modified by stereoretentive catalytic cross-coupling, providing access to a myriad of other stereoisomerically pure tetrasubstituted olefins. We have achieved considerable progress on two distinct fronts:
(i) Synthesis of enantiomerically enriched allylic alcohols and amines that contain a stereodefined tetrasubstituted alkene. By utilizing a Cu-catalyzed multicomponent reactions that enantio- and diastereoselectively merges a nitrile, an allene and a diboron reagent and a mild alkene isomerization process, we have been able to develop a broadly applicable and modular approach for synthesis of different analogs of anti-cancer agent tamoxifen in high enantiomeric purity.
(ii) We have developed a highly enantioselective method for intramolecular reaction of allenyl-nitrile substrates. The products are cyclic ketones that contain an α-alkenylboronate substituent. The method may be used to access small, medium as well as macrocyclic rings in exceptional enantiomeric purity. What is more, alkene isomerization proceeds with complete stereocontrol, delivering enones that contain an easily modifiable exocyclic tetrasubstituted alkenyl boronate. The applicability of the approach has been demonstrated through the first diastereo- and enantioselective total syntheses of naturally occurring and bioactive (anti-cancer, antibiotic, anti-inflammatory) sesquiterpenes curcumenol and neocurcumenol and selected analogs. This advance constitutes the first generally applicable method for enantioselective synthesis of cyclic ketones that contain an α -stereogenic center. The fact that the substituent is an otherwise difficult-to-access alkenyl moiety and the resident C–B bond allows conversion to a considerable variety of derivatives, renders this advance of enormous utility.
We have been able to demonstrate that the active complex can be generated in situ when catalytic amounts of Zn(II) salts are present. Two additional points merit brief note: (i) None of the foregoing complexes have been reported previously. (ii) We have developed various new methods to be able to obtain a number of these novel entities.
We have evaluated the ability of the aforementioned new Mo and W complexes to promote various olefin metathesis reactions:
(i) Ring-opening/cross-metathesis (ROCM) of small and medium rings. For instance, it was discovered that reaction involving cyclohexene with Z-dichloroethylene generates the desired product in high yield and stereoselectivity. This is the first case where cyclohexene, used as the limiting reagent, is transformed to a modifiable Z,Z-diene in high efficiency.
(ii) Polymerization processes that deliver unique structural motifs. The new catalysts can be used for synthesis of stereodefined polymers (0.01–0.1 mol % loading) that are not accessible with previously reported complexes. Relevant mechanistic studies are ongoing.
(iii) Cross-metathesis (CM) between two electronically deficient alkenes. Preliminary data have shown that the new class of catalysts can efficiently promote CM between vinyl B(pin) and a dihalogenated alkene—both electron-poor substrates. Such a transformation is not achievable with any of the currently available catalyst systems.
Finally, we have begun exploring the feasibility of obtaining silica-supported complexes. Such entities might be able to mitigate bimolecular decomposition pathways, a major cause of reduced metathesis activity. The insights garnered from these preliminary studies will be central to our ongoing investigations aimed at the development of stereocontrolled synthesis of tetrasubstituted alkenes through catalytic olefin metathesis.
B. We have developed two Cu-catalyzed methods that can be used to prepare stereochemically defined tetrasubstituted alkenyl boronates. These compounds can be modified by stereoretentive catalytic cross-coupling, providing access to a myriad of other stereoisomerically pure tetrasubstituted olefins. We have achieved considerable progress on two distinct fronts:
(i) Synthesis of enantiomerically enriched allylic alcohols and amines that contain a stereodefined tetrasubstituted alkene. By utilizing a Cu-catalyzed multicomponent reactions that enantio- and diastereoselectively merges a nitrile, an allene and a diboron reagent and a mild alkene isomerization process, we have been able to develop a broadly applicable and modular approach for synthesis of different analogs of anti-cancer agent tamoxifen in high enantiomeric purity.
(ii) We have developed a highly enantioselective method for intramolecular reaction of allenyl-nitrile substrates. The products are cyclic ketones that contain an α-alkenylboronate substituent. The method may be used to access small, medium as well as macrocyclic rings in exceptional enantiomeric purity. What is more, alkene isomerization proceeds with complete stereocontrol, delivering enones that contain an easily modifiable exocyclic tetrasubstituted alkenyl boronate. The applicability of the approach has been demonstrated through the first diastereo- and enantioselective total syntheses of naturally occurring and bioactive (anti-cancer, antibiotic, anti-inflammatory) sesquiterpenes curcumenol and neocurcumenol and selected analogs. This advance constitutes the first generally applicable method for enantioselective synthesis of cyclic ketones that contain an α -stereogenic center. The fact that the substituent is an otherwise difficult-to-access alkenyl moiety and the resident C–B bond allows conversion to a considerable variety of derivatives, renders this advance of enormous utility.
As noted, the cyclic Mo and W complexes and the strategies used to prepare them are entirely new. Equally novel is the reactivity and selectivity profiles that is made possible through the use of these complexes. The strategies for stereocontrolled synthesis of tetrasubstituted allylic alcohols and amines are similarly unprecedented. All these chemistries offer pathways for preparation of high-value organic molecules that are otherwise far more difficult to synthesize.
The research involve new olefin metathesis catalysts brings together the disciplines of catalysis, organometallic chemistry, chemical synthesis, polymer chemistry and materials research. The investigations that are focus on diastereo- and enantioselective synthesis of tetrasubstituted allylic alcohols and amines bring together catalytic synthesis method development, total synthesis of bioactive compounds, and drug discovery and development.
We are in the process of filing a patent that covers the new olefin metathesis catalysts. We collaborate with the group of Michael Buchmeiser (University of Stuttgart) in understanding the properties of the polymers that are generated by the new Mo and W alkylidenes. We collaborate with the group of Christophe Copéret (ETH, Zurich) towards the developed of silica supported Mo and W complexes. We collaborate with the University of Texas cancer centre to evaluate to anti-cancer activity of our synthetic materials against nearly 20 different cancer cell lines.
The research involve new olefin metathesis catalysts brings together the disciplines of catalysis, organometallic chemistry, chemical synthesis, polymer chemistry and materials research. The investigations that are focus on diastereo- and enantioselective synthesis of tetrasubstituted allylic alcohols and amines bring together catalytic synthesis method development, total synthesis of bioactive compounds, and drug discovery and development.
We are in the process of filing a patent that covers the new olefin metathesis catalysts. We collaborate with the group of Michael Buchmeiser (University of Stuttgart) in understanding the properties of the polymers that are generated by the new Mo and W alkylidenes. We collaborate with the group of Christophe Copéret (ETH, Zurich) towards the developed of silica supported Mo and W complexes. We collaborate with the University of Texas cancer centre to evaluate to anti-cancer activity of our synthetic materials against nearly 20 different cancer cell lines.