Catalytic enantioselective Mannich-type reactions of ketoimines.
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Amino Acids↗
Biomedical subjects
Masakatsu Shibasaki
Publications and source records attributed to Masakatsu Shibasaki.
Second generation catalytic asymmetric synthesis of Tamiflu: allylic substitution route.
Catalytic asymmetric synthesis of Tamiflu, an important antiinfluenza drug, was achieved. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the C=C double bond were introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile. This second generation route of Tamiflu is more practical than our previously reported route. [reaction: see text].
Catalysis↗
Bismuth-catalyzed direct substitution of the hydroxy group in alcohols with sulfonamides, carbamates, and carboxamides.
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Alcohols↗
Key role of the Lewis base position in asymmetric bifunctional catalysis: design and evaluation of a new ligand for chiral polymetallic catalysts.
New chiral ligands for asymmetric polymetallic catalysts were designed on the basis of the assumption that the higher-order assembly structure is stabilized by modifying the modular unit. The designed ligands 6 and 7 contained a scaffolding cyclohexane ring with a Lewis base phosphine oxide directly attached to the scaffold. A module in the polymetallic complex contains two metals per ligand, and a stable 6-, 5-, 5-membered fused chelation ring system should be generated. Synthesis of these ligands is simple and high yielding, using a catalytic dynamic kinetic resolution promoted by the Trost catalyst as a key step. Ligand function was assessed in a catalytic asymmetric ring-opening reaction of meso-aziridines with TMSCN, a useful reaction for the synthesis of optically active beta-amino acids. The Gd complex generated from Gd(OiPr)3 and the ligand was a highly active and enantioselective catalyst in this reaction. Enantioselectivity was reversed compared to the previously reported d-glucose-derived catalyst containing the same chirality of the individual module. ESI-MS analysis and X-ray crystallographic studies indicate that the assembly state of the modules in the polymetallic catalysts differs depending on the chiral ligand. The difference in the higher-order structure stems from a subtle change (one carbon) in the position of the Lewis base relative to the Gd metal. The change in the higher-order structure of the polymetallic complex led to a dramatic reversal of the enantioselectivity and increased catalyst activity.
Aziridines↗
Dramatic ligand effect in catalytic asymmetric reductive aldol reaction of allenic esters to ketones.
A general catalytic asymmetric reductive aldol reaction of allenic esters to ketones is described. Two distinct constitutional isomers were selectively produced depending on the reaction conditions. A combination of CuOAc/(R)-DTBM-SEGPHOS/PCy3 as the catalyst predominantly produced gamma-cis-products in high yield with excellent enantioselectivity (up to 99% ee). The reaction was applicable to both aromatic and aliphatic ketones, including unsaturated ketones. On the other hand, CuF-Taniaphos complexes produced alpha-aldol products with high diastereo- and enantioselectivity (up to 84% ee). The new Taniaphos derivative L3, containing di(3,5-xylyl)phosphine and morpholine units, produced optimum results in the alpha-selective reaction. The products are versatile chiral building blocks in organic synthesis. Furthermore, the basic reaction pattern (i.e., conjugate addition-aldol reaction) was extended to a catalytic enantioselective alkylative aldol reaction to ketones using dialkylzinc reagents as the initiator.
Catalysis↗
Mixed La-Li heterobimetallic complexes for tertiary nitroaldol resolution.
A kinetic resolution of tertiary nitroaldols derived from simple ketones is described. Mixed BINOL/biphenol La-Li heterobimetallic complexes gave the best selectivity in retro-nitroaldol reactions of racemic tertiary nitroaldols. By using a mixture of La-Li3-(1a)3 complex (LLB 2a) and La-Li3-(1b)3 (LLB* 2b) complex in a ratio of 2/1, chiral tertiary nitroaldols were obtained in 80-97% ee and 30-47% recovery yield.
Alcohols↗
Short synthesis of (+)-cylindricine C by using a catalytic asymmetric Michael reaction with a two-center organocatalyst.
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Catalysis↗
Catalytic enantioselective allylation of ketoimines.
A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.
Alkanes↗
Catalytic enantioselective aldol reaction to ketones.
An enantioselective aldol reaction between ketones and ketene silyl acetals is described using CuF-chiral phosphine as a catalyst. The key for high enantioselectivity was the development of a novel ligand derived from Taniaphos combined with the unique accelerative effect of PhBF3K. These conditions are applicable to various substrates such as aromatic, aliphatic, and heteroaromatic ketones. In the case of substituted nucleophiles, the reaction proceeds well. The diastereoselectivity is independent of ketene silyl acetal geometry. This is the first example of a catalytic enantio- and diastereoselective aldol reaction to ketones using ketene silyl acetals.
Aldehydes↗
Assembly state of catalytic modules as chiral switches in asymmetric Strecker amino acid synthesis.
Self-assembled chiral polymetallic complexes often demonstrate novel properties as asymmetric catalysts. We report the three-dimensional structures of two such asymmetric catalysts (crystals A and B) for Strecker alpha,alpha-disubstituted amino acid synthesis. These complexes are constructed via assembly of the same chiral modules derived from d-glucose, but their assembly modes differ. The enantioselectivity in the Strecker reaction was dramatically switched, depending on which assembly mode was used: the catalyst generated in situ whose structure is represented by crystal B, or by crystal A. These findings provide insight into the functional importance of higher-order structures of an artificial catalyst.
Amino Acids↗
De novo synthesis of Tamiflu via a catalytic asymmetric ring-opening of meso-aziridines with TMSN3.
An asymmetric ring-opening reaction of meso-aziridines with TMSN3 was developed using a catalyst prepared from Y(OiPr)3 and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality.
Antiviral Agents↗
Trichloromethyl ketones as synthetically versatile donors: application in direct catalytic mannich-type reactions and the stereoselective synthesis of azetidines.
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Azetidines↗
Design and application of linked-BINOL chiral ligands in bifunctional asymmetric catalysis.
The design and application of linked-BINOLs investigated in our group are reviewed. Linked-BINOLs are a kind of semi-crown ether, thus they are flexible and applicable to metals having various ionic radii (Ga3+, Li+, Zn2+, In3+, La3+, and Y3+). The flexible linker segment, containing a coordinative heteroatom, has a crucial role in the construction of a unique and effective chiral environment that is not accessible from BINOL itself. Applications of linked-BINOLs to an epoxide opening reaction, Michael reactions, a direct aldol reaction, direct Michael reactions of a hydroxyketone, and direct Mannich-type reactions of hydroxyketones and N-acylpyrrole are described.
Journal Article↗
Bismuth-catalyzed intermolecular hydroamination of 1,3-dienes with carbamates, sulfonamides, and carboxamides.
A Bi(OTf)(3)/Cu(CH(3)CN)(4)PF(6) system efficiently promoted intermolecular 1:1 hydroamination of 1,3-dienes with various carbamates, sulfonamides, and carboxamides to afford allylic amines in good yield (up to 96%). Reaction proceeded with 0.5-10 mol % catalyst loading at 25-100 degrees C (generally at 50 degrees C) in 1,4-dioxane within 24 h. The Bi(OTf)(3)/Cu(CH(3)CN)(4)PF(6) system constitutes a new entry into series of intermolecular hydroamination catalysis. Mechanistic studies and the postulated reaction mechanism are also discussed.
Alkenes↗
Catalytic asymmetric total synthesis of (+)-lactacystin.
Total synthesis of (+)-lactacystin, a potent and selective proteasome inhibitor, was accomplished using a catalytic enantioselective Strecker reaction of a ketoimine as the initial key step. An enone-derived N-phosphinoyl ketoimine 7 was selected as a stable masked alpha-hydroxy ketoimine analogue. Excellent enantioselectivity (98% ee) and practical catalyst activity were produced under the optimized catalyst preparation method using 2.5 mol % Gd{N(SiMe3)2}3 as a metal source and 3.8 mol % D-glucose-derived ligand 8. This reaction was conducted on a 5 g scale. The chiral tetrasubstituted C-5 carbon efficiently controlled the stereochemistry of the other three chiral centers of lactacystin. Chelation-controlled Meerwein-type reduction of ketone 5 using i-PrMgBr (originally reported by Kang in a related substrate) selectively produced the desired secondary alcohol at the C-9 position. The C-6 hydroxy and C-7 methyl groups were introduced via a silyl conjugate addition followed by the Tamao oxidation and Donohoe methylation, respectively, in a highly stereoselective manner. A practical amount of enantiomerically pure clasto-lactacystin beta-lactone (2), the biologically active form of (+)-lactacystin, can be synthesized using this route. clasto-Lactacystin beta-lactone (2) was converted to (+)-lactacystin following the reported procedure.
Acetylcysteine↗
Catalyst-controlled asymmetric synthesis of fostriecin and 8-epi-fostriecin.
Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.
Alkenes↗
syn-selective direct catalytic asymmetric Mannich-type reactions of hydroxyketones using Y{N(SiMe3)2}3/linked-BINOL complexes.
[reaction, structure: see text] Chiral Y{N(SiMe3)2}3/linked-BINOL catalyst generated Y-enolate in situ from various hydroxyketones (R2 = aryl, heteroaryl). Beta-amino-alpha-hydroxy ketones (R1 = aryl, heteroaryl, alkenyl) were obtained syn-selectively (up to 96/4) in high ee (up to 98%) and good yield (up to 98% yield).
Journal Article↗
Total synthesis of (+/-)-garsubellin A.
The first total synthesis of garsubellin A, a neurotrophic compound with potent choline acetyltransferase-inducing activity, is described. Keys for success were (1) stereoselective intermolecular aldol reaction at the C-4 position with acetaldehyde, (2) stereoelective Claisen rearrangement to introduce an allyl group to the most sterically crowded position at C-6, (3) ring-closing metathesis to construct the B-ring, and (4) Wacker-type oxidative C-ring formation. This synthetic route can be extended to an asymmetric synthesis of garsubellin A using the Koga catalytic enantioselective alkylation, which produced enantioenriched alpha-prenyl cyclohexenone with excellent enantioselectivity (95% ee).
Molecular Conformation↗