Abstract: Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from -hydrox... more Abstract: Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from -hydroxy aldehydes and another aldehyde. These two aldehydes form a diastereomeric mixture of 1,3-dioxan-4-ol hemiacetal derivatives which can be further converted to monoesters with suitable catalysts. Limitations in the formation and esterification of this hemiacetal intermediate have been investigated in this work and the formation and stability of 1,3-dioxan-4-ols was found to be aldehyde-, temperature-, and solvent-dependent. A new method was developed for selective preparation of monoesters of 1,3-diols with this mixed Tishchenko reaction via 1,3-dioxan-4-ols without any significant side products. During the development of this method a possibility to scale up the reactions to reach a selective and economical process was one of the main targets in this work. The conventional Tishchenko reaction of aldehydes gives simple esters with moderate-to-excellent yield (Scheme 1; 1f2) 1 typically i...
Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge... more Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx. To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C. Herein, we demonstrate a concise route to access the C1–C12 tetraene fragment of calyculin C using transition-metal-catalyzed coupling reactions (Suzuki–Miyaura, Stille, Negishi and Heck) for the key connections. The synthesis starts from propionaldehyde and proceeds in 10 steps with 7.5% overall yield. We also describe an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile in four steps and 68% yield.
Combinatorial Chemistry & High Throughput Screening, 2015
The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes s... more The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers. We first performed an in-house screen of 20,480 compounds, and later we tested the assay against 342,046 compounds from the NIH Molecular Libraries Small Molecule Repository. Primary screening hit rates were about 1% with the majority of those affecting the primary readout, an enzyme-coupled GDP detection assay. After orthogonal and counter screens, we identified two hits with high selectivity towards MgcRacGAP, compared with other RhoGAPs, and potencies in the low micromolar range. The most promising hit, termed MINC1, was then examined with cell-based testing where it was observed to induce an increased rate of cytokinetic failure and multinucleation in addition to other cell division defects, suggesting that it may act as an MgcRacGAP inhibitor also in cells.
The aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,... more The aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,3-diol monoesters, which are widely used as coalescing agents in the paint industry. The use of monoalcoholates of 1,3-diols as catalysts gives fast and clean reactions compared with the previous use of several inorganic catalysts. The use of the proper 1,3-diol moiety in the catalyst also reduces the amount of side products which are due to ester interchange between product esters and the catalyst. The rapid water-free method developed herein allows fast preparation of monoesters with excellent yield and minimized formation of side products.
Journal of the Chemical Society, Chemical Communications, 1990
A rapid high yielding synthesis of N-t-butoxycarbonyl-I-amino-2-oxo-3-oxabicyclo[3.1 .O]hexane is... more A rapid high yielding synthesis of N-t-butoxycarbonyl-I-amino-2-oxo-3-oxabicyclo[3.1 .O]hexane is described; the synthesis relies on an intramolecular carbenoid reaction of an appropriate malonate derivative followed by Curtius degradation to give the unprotected amino group. Conformationally constrained peptide analogues have for receptor binding studies4 and elucidation of ethylene recently become of importance in the study of bioactive biosynthesis5 have been reported. In connection with our peptides. Cyclopropane analogues of amino acids exhibit investigations into the mode of action of certain neuromodulparticularly favourable characteristics in this respect .2 Some ator peptides, we needed l-amino-2-oxo-3-oxabicyclocongeners are also of natural origin,3 and other applications [3.1 .O]hexane (2,3-methanohomoserine lactone) in a form
In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the tas... more In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the task of preparing the furyl substituted allyl alcohol 5 enantioselectively. Several different methods starting from enantioselective zinc-mediated alkylations were attempted, but none of them proved entirely satisfactory. The solution turned out to be enzymatic kinetic resolution through a highly enantioselective (E > 300) acylation in the presence of Candida antarctica lipase A.
A highly diastereoselective dihydroxylation protocol has been developed for acyclic allylic alcoh... more A highly diastereoselective dihydroxylation protocol has been developed for acyclic allylic alcohol derivatives leading to triol derivatives with diastereoselectivity reversed to the classical osmylation (anti-Kishi). Selectivities ate acceptable for E-allylic derivatives 1, and high for those derived from Z-derivatives 4.
A highly diastereoselective synthesis of the title fragment of calyculin C has been developed bas... more A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asymmetric induction between a chiral aldehyde and Z-crotyl trifluorosilane.
A stereoselective synthesis of the C 13-C 25 of Calyculin C is described. Key steps involve the c... more A stereoselective synthesis of the C 13-C 25 of Calyculin C is described. Key steps involve the coupling of a terminal acetylene with a thiol ester and subsequent spirocyclisation using a double intramolecular hetero-Michael addition.
A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyfe... more A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth-Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituent in the oxolane ring.
A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative... more A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on amino acid and b-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1, 7.3%, compares well with the literature syntheses of similar compounds.
A new, short and highly diastereoselective synthetic route aiming at the C(33)-C(37) fragment of ... more A new, short and highly diastereoselective synthetic route aiming at the C(33)-C(37) fragment of Amphotericin B has been developed. Studies with a model aldehyde (benzaldehyde) have given very promising results: the desired stereochemistry of all four stereocenters of the target molecule has been achieved with high diastereoselection. The stereochemistry of three key intermediates and the target segment has been confirmed by X-ray crystallography.
In this paper we describe the synthesis of a diastereomer of the C(9)-C(20) dipropionate-lactone ... more In this paper we describe the synthesis of a diastereomer of the C(9)-C(20) dipropionate-lactone fragment of Calyculin C. A short and enantioselective synthesis of the key intermediate 2 has been developed. This intermediate will play a critical role also in the synthesis of the correct diastereomer of C(9)-C(20) dipropionatelactone fragment of Calyculin C.
An asymmetric synthesis of the C 9-C 25 spiroketal fragment of calyculin C is described. Key step... more An asymmetric synthesis of the C 9-C 25 spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively Brown's reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.
Abstract: Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from -hydrox... more Abstract: Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from -hydroxy aldehydes and another aldehyde. These two aldehydes form a diastereomeric mixture of 1,3-dioxan-4-ol hemiacetal derivatives which can be further converted to monoesters with suitable catalysts. Limitations in the formation and esterification of this hemiacetal intermediate have been investigated in this work and the formation and stability of 1,3-dioxan-4-ols was found to be aldehyde-, temperature-, and solvent-dependent. A new method was developed for selective preparation of monoesters of 1,3-diols with this mixed Tishchenko reaction via 1,3-dioxan-4-ols without any significant side products. During the development of this method a possibility to scale up the reactions to reach a selective and economical process was one of the main targets in this work. The conventional Tishchenko reaction of aldehydes gives simple esters with moderate-to-excellent yield (Scheme 1; 1f2) 1 typically i...
Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge... more Calyculins are a class of highly cytotoxic metabolites originally isolated from the marine sponge Discodermia calyx. To date, a total of twelve different calyculins (A–J) and calyculinamides (A, B and F) have been described, the most abundant (in D. calyx) being calyculins A and C. Herein, we demonstrate a concise route to access the C1–C12 tetraene fragment of calyculin C using transition-metal-catalyzed coupling reactions (Suzuki–Miyaura, Stille, Negishi and Heck) for the key connections. The synthesis starts from propionaldehyde and proceeds in 10 steps with 7.5% overall yield. We also describe an efficient route for the preparation of (Z)-3-iodobut-2-enenitrile in four steps and 68% yield.
Combinatorial Chemistry & High Throughput Screening, 2015
The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes s... more The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers. We first performed an in-house screen of 20,480 compounds, and later we tested the assay against 342,046 compounds from the NIH Molecular Libraries Small Molecule Repository. Primary screening hit rates were about 1% with the majority of those affecting the primary readout, an enzyme-coupled GDP detection assay. After orthogonal and counter screens, we identified two hits with high selectivity towards MgcRacGAP, compared with other RhoGAPs, and potencies in the low micromolar range. The most promising hit, termed MINC1, was then examined with cell-based testing where it was observed to induce an increased rate of cytokinetic failure and multinucleation in addition to other cell division defects, suggesting that it may act as an MgcRacGAP inhibitor also in cells.
The aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,... more The aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,3-diol monoesters, which are widely used as coalescing agents in the paint industry. The use of monoalcoholates of 1,3-diols as catalysts gives fast and clean reactions compared with the previous use of several inorganic catalysts. The use of the proper 1,3-diol moiety in the catalyst also reduces the amount of side products which are due to ester interchange between product esters and the catalyst. The rapid water-free method developed herein allows fast preparation of monoesters with excellent yield and minimized formation of side products.
Journal of the Chemical Society, Chemical Communications, 1990
A rapid high yielding synthesis of N-t-butoxycarbonyl-I-amino-2-oxo-3-oxabicyclo[3.1 .O]hexane is... more A rapid high yielding synthesis of N-t-butoxycarbonyl-I-amino-2-oxo-3-oxabicyclo[3.1 .O]hexane is described; the synthesis relies on an intramolecular carbenoid reaction of an appropriate malonate derivative followed by Curtius degradation to give the unprotected amino group. Conformationally constrained peptide analogues have for receptor binding studies4 and elucidation of ethylene recently become of importance in the study of bioactive biosynthesis5 have been reported. In connection with our peptides. Cyclopropane analogues of amino acids exhibit investigations into the mode of action of certain neuromodulparticularly favourable characteristics in this respect .2 Some ator peptides, we needed l-amino-2-oxo-3-oxabicyclocongeners are also of natural origin,3 and other applications [3.1 .O]hexane (2,3-methanohomoserine lactone) in a form
In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the tas... more In the course of the synthesis of the DEFG ring system of cneorin C 1, we were faced with the task of preparing the furyl substituted allyl alcohol 5 enantioselectively. Several different methods starting from enantioselective zinc-mediated alkylations were attempted, but none of them proved entirely satisfactory. The solution turned out to be enzymatic kinetic resolution through a highly enantioselective (E > 300) acylation in the presence of Candida antarctica lipase A.
A highly diastereoselective dihydroxylation protocol has been developed for acyclic allylic alcoh... more A highly diastereoselective dihydroxylation protocol has been developed for acyclic allylic alcohol derivatives leading to triol derivatives with diastereoselectivity reversed to the classical osmylation (anti-Kishi). Selectivities ate acceptable for E-allylic derivatives 1, and high for those derived from Z-derivatives 4.
A highly diastereoselective synthesis of the title fragment of calyculin C has been developed bas... more A highly diastereoselective synthesis of the title fragment of calyculin C has been developed based on an internal asymmetric induction between a chiral aldehyde and Z-crotyl trifluorosilane.
A stereoselective synthesis of the C 13-C 25 of Calyculin C is described. Key steps involve the c... more A stereoselective synthesis of the C 13-C 25 of Calyculin C is described. Key steps involve the coupling of a terminal acetylene with a thiol ester and subsequent spirocyclisation using a double intramolecular hetero-Michael addition.
A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyfe... more A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth-Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituent in the oxolane ring.
A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative... more A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on amino acid and b-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1, 7.3%, compares well with the literature syntheses of similar compounds.
A new, short and highly diastereoselective synthetic route aiming at the C(33)-C(37) fragment of ... more A new, short and highly diastereoselective synthetic route aiming at the C(33)-C(37) fragment of Amphotericin B has been developed. Studies with a model aldehyde (benzaldehyde) have given very promising results: the desired stereochemistry of all four stereocenters of the target molecule has been achieved with high diastereoselection. The stereochemistry of three key intermediates and the target segment has been confirmed by X-ray crystallography.
In this paper we describe the synthesis of a diastereomer of the C(9)-C(20) dipropionate-lactone ... more In this paper we describe the synthesis of a diastereomer of the C(9)-C(20) dipropionate-lactone fragment of Calyculin C. A short and enantioselective synthesis of the key intermediate 2 has been developed. This intermediate will play a critical role also in the synthesis of the correct diastereomer of C(9)-C(20) dipropionatelactone fragment of Calyculin C.
An asymmetric synthesis of the C 9-C 25 spiroketal fragment of calyculin C is described. Key step... more An asymmetric synthesis of the C 9-C 25 spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively Brown's reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.
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Papers by Ari Koskinen