Alpha,beta-unsaturated beta-silyl imide substrates for catalytic, enantioselective conjugate additions: a total synthesis of (+)-lactacystin and the discovery of a new proteasome inhibitor

Chiral (salen)Al mu-oxo dimer 1 catalyzes the highly enantioselective conjugate addition of carbon-centered nucleophiles to alpha,beta-unsaturated silyl imides. Allyldimethylsilane-substituted imide 4 was identified as an optimal substrate, undergoing addition reactions with a variety of nitrile nucleophiles in high yield and enantiomeric excess. The silicon-containing products are synthetically useful chiral building blocks, as demonstrated by their application to an enantioselective total synthesis of the potent proteasome inhibitor (+)-lactacystin (2). Elaboration of lactam 5a to the natural product was effected in 12 steps and in 11% overall yield and proceeded through an unusual spiro beta-lactone intermediate (11). This compound was found to inhibit the chymotrypsin-like site of the 26S proteasome at similar levels to known inhibitor clasto-lactacystin beta-lactone (omuralide).     

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.     

Chiral Lewis acid-catalyzed asymmetric Baylis-Hillman reactions

An effective chiral Lewis acid-catalyzed asymmetric Baylis-Hillman reaction is described. Good to high enantioselectivities were obtained using 3 mol % chiral catalyst. Novel camphor-derived dimerized ligands were prepared from the condensation of (+)-ketopinic acid with the corresponding diamines and hydrazine under acidic conditions. When alpha-naphthyl acrylate was used as a Michael acceptor, the reaction is complete within 20 min with high stereoselectivity and in reasonable chemical yields.     

(R)-TTCA·K催化下环己酮与丙烯腈的加成反应

手性催化剂催化下的不对称合成反应是近年来不对称合成研究中受到重视的领域，如在手性催化剂如，在手性冠醚，手性镧配合物、手性硒、手性铑及手性脯氨酸铷盐等催化下，醛、酮与二烃基锌形成手性醇和不对称羟醛缩合反应等，催化下通过Michael加成反应合成手性化合物的方法近年来也有报道，     

Olefin cross-metathesis as a tool in natural product degradation. The stereochemistry of (+)-falcarindiol

[reaction: see text] There are conflicting reports in the literature concerning the absolute sterochemistry at C-3 of the common plant polyacetylene oxylipin (+)-falcarindiol. We have employed olefin cross-metathesis using Grubbs' second generation catalyst and ethylene gas to degrade falcarindiol to the symmetrical 1,9-decadiene-4,6-diyne-3,8-diol. The reaction is completely selective for net removal of the aliphatic side chain. Degradation of (+)-falcarindiol from Tetraplasandra hawaiiensis yields a meso product as shown by chiral HPLC. Hence, (+)-falcarindiol from this source has a (3R,8S)-configuration.     

Stereocontrolled synthesis of substituted chiral piperidines via one-pot asymmetric 6π-azaelectrocyclization: asymmetric syntheses of (-)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine

The asymmetric one-pot 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (-)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminoacetal compounds, resulting from the four-bond formation accompanying by controlling the stereochemistry at the two asymmetric centers. The produced cyclic aminoacetals can be regarded as synthetic precursors of substituted chiral piperidines, and the syntheses of 2,4- and 2,4,6-substituted piperidines were realized from the obtained aminoacetals by the stereoselective hydrogenation of the double bond conjugated with the C-4 ester group and alkylation at the aminoacetal moiety. In addition, the stereoselective synthesis of an indolizidine alkaloid, (-)-dendroprimine, and its three stereoisomers, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine, were achieved.     

Enantioselective total synthesis of (+)-tricycloclavulone

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.     

Rhodium-catalyzed ring-opening reactions of N-boc-azabenzonorbornadienes with amine nucleophiles

In the presence of a rhodium catalyst (5 mol %) generated in situ from [Rh(cod)Cl](2) and (S,S')-(R,R')-C(2)-ferriphos (4a), the asymmetric ring-opening reaction of azabenzonorbornadienes (1a-m) with various aliphatic and aromatic amines (2a-l) proceeded with high enantioselectivity (up to >99% ee) to give the corresponding 1,2-diamine derivatives 3 in high yields. In the specific case of pyrrolidine as nucleophile, Et(3)NHCl was necessary as an additive for good reactivity and enantioselectivity. Additionally, a practical protocol was developed for the ring-opening of 1a with volatile amines at elevated temperatures and standard pressure, using R(2)NH(2)I and i-Pr(2)NEt. The experimental results showed that the nature of the chiral ligand has the significant impact on the reactivity of the catalyst and the use of excess amount (2.2 eq to Rh) of the chiral ligand plays an important role to improve the enantioselectivity in the present asymmetric reaction.     

Enantioselective Catalysis of the Intermolecular [2+2] Photocycloaddition between 2‐Pyridones and Acetylenedicarboxylates

Intermolecular [2+2] photocycloadditions represent the most versatile and widely applicable of photochemical reactions. For the first time, such intermolecular reactions have been carried out in a catalytic fashion using a chiral triplet sensitizer, with high enantioselectivity (up to 92 % ee). The low catalyst loading (2.5–5 mol %) underlines the high efficiency of the process both in terms of reaction acceleration and differentiation of the enantiotopic faces of the substrate. The substrate is anchored to the chiral catalyst through noncovalent interactions (hydrogen bonds), thus providing a chiral environment in which the enantioselective photocycloaddition proceeds. The densely functionalized products present numerous possibilities for further synthetic transformations.     

Highly Enantioselective Intermolecular Cross Rauhut–Currier Reaction Catalyzed by a Multifunctional Lewis Base Catalyst

The highly enantioselective intermolecular cross Rauhut–Currier reaction of different active olefins catalyzed by a multifunctional chiral Lewis base was reported. The RC products were obtained in excellent yields (up to 98 %), high chemo‐ and enantioselectivity (up to 96 % ee). The reaction could be performed on a gram scale using 1 mol % of the multifunctional phosphine catalyst.     

Asymmetric Mannich reaction of dicarbonyl compounds with alpha-amido sulfones catalyzed by cinchona alkaloids and synthesis of chiral dihydropyrimidones

The highly enantioselective cinchona alkaloid-catalyzed Mannich reaction of dicarbonyl compounds with alpha-amido sulfones as acyl imine precursors is described. The reaction requires 10 mol % of the cinchona alkaloid catalyst, which serves as a general base to generate acyl imines in situ, and aqueous Na2CO3 to maintain the concentration of free alkaloid catalyst. The reaction products are obtained in good yields and high enantioselectivities, and in diastereoselectivities that range from 1:1 to >95:5. The cinchonine-catalyzed reactions provide practical access to highly functionalized building blocks which have been employed in the synthesis of chiral dihydropyrimidones, a class of compounds rich in diverse biological activity. Dihydropyrimidone modifications include a highly diastereoselective hydrogenation of the enamide moiety, using an H-Cube flow hydrogenator and a Rh(II)-mediated 1,3-dipolar cycloaddition to afford highly functionalized complex heterocycles.     

Highly exo-selective and enantioselective cycloaddition reactions of nitrones catalyzed by a chiral binaphthyldiimine-Ni(II) complex

[reaction: see text] Significant levels of exo-selectivity (exo:endo = >99:1 to 86:14) and enantioselectivity (95-82% ee) were obtained in the 1,3-dipolar cycloadditions of a number of nitrones with 3-(2-alkenoyl)-2-thiazolidinethiones, using the chiral binaphthyldiimine-Ni(II) complex (5-20 mol %), which was easily prepared form N,N'-bis(3,5-dichrolo-2-hydroxybenzylidene)-1,1'-binaphthyl-2,2'-diamine and Ni(ClO4)2 x 6H2O in CHCl3 in the presence of 4 A molecular sieves, as a chiral Lewis acid catalyst.     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.     

A chiral pool approach for asymmetric syntheses of both antipodes of equol and sativan

For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (?)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans' enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(?)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(?)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

Enantioselective intramolecular [2 + 2]-photocycloaddition reactions of 4-substituted quinolones catalyzed by a chiral sensitizer with a hydrogen-bonding motif

Six 2-quinolones, which bear a terminal alkene linked by a three- or four-membered tether to carbon atom C4 of the quinolone, were synthesized and subjected to an intramolecular [2 + 2]-photocycloaddition. The reaction delivered the respective products in high yields (78-99%) and with good regioselectivity in favor of the straight isomer. If conducted in the presence of a chiral hydrogen-bonding template (2.5 equiv) at low temperature in toluene as the solvent, the reaction proceeded enantioselectively (83-94% ee). An organocatalytic reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane, was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at -25 °C in trifluorotoluene as the solvent, three of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72-87% ee). In all catalyzed reactions, the yields based on conversion were moderate to good (40-93%).     

Enantioselective synthesis of cyclic secondary amines through Mo-catalyzed asymmetric ring-closing metathesis (ARCM)

Carbocyclic amines are synthesized efficiently in up to 93% ee by asymmetric ring-closing metathesis (ARCM) with 2-5 mol % chiral Mo complexes. An example is provided where the catalyst is prepared in situ (catalyst isolation not needed) to afford secondary amines that cannot be prepared by alternative methods. [reaction: see text]     

Practical asymmetric Henry reaction catalyzed by a chiral diamine-Cu(OAc)2 complex

The chiral diamine ligand 3 was designed and synthesized from (R,R)-1,2-diphenylethylenediamine, (S)-2,2'-dibromomethyl-1,1'-binaphthalene, and o-xylylene dibromide. The resulting 3-Cu(OAc)2 complex was a highly efficient catalyst for the Henry reaction, giving the various nitroaldols with over 90% ee (up to >99%). The reaction was performed in n-propyl alcohol at room temperature, and the Henry adducts were produced in high yield with excellent enantiomeric excess; these attributes are desirable in a catalyst for practical use.     

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.     

Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols

The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.