Crystallization-induced asymmetric transformation of a tertiary phosphine

An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio) undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process can also be carried out at room temperature by using iodine to catalyze the interconversion of 5 and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with retention of phosphorus configuration.     

Design and synthesis of antagonists of substance P

Synthesis and bioassay of about 65 analogs of substance P (SP) over five years yielded the antagonist [D-Arg1,D-Trp7,9,Leu11]-SP, which was named Spantide, and which was used by many investigators as a "tool". Spantide served as a reference antagonist for the design of 47 new peptides toward the goal of more potent inhibitors. Designs emphasized analogs with D-Trp7, D-Trp9, D-Trp10, D-pClPhe10, Nle11, Leu11, Ile11 and Met11, etc. Twenty-one/47 antagonists were superior in potency to that of Spantide, the best was [D-Arg1,D-Na1(5), D-Trp7,9,Nle11]-SP which required a 255-fold increase in SP concentration to give 50% of the maximum response at a concentration of 10(-5)M of the antagonist; this potency is ca. 5 times that of Spantide. For certain, but not all pairs of undecapeptides and truncated analogs, the undecapeptides may be significantly more potent than the truncated counterparts.     

Crystallization-induced asymmetric transformation (CIAT) with simultaneous epimerization at two stereocenters. A short synthesis of conformationally constrained homophenylalanines

CIAT of aza-Michael adducts allows simultaneous build up of two stereocenters. A consequent short and efficient synthesis affords simple access to the both antipodes of various conformationally restricted homophenylalanines.     

Crystallization-induced asymmetric transformation of chiral-at-metal ruthenium(II) complexes bearing achiral ligands

Recently, we observed that the enantiopure Lambda form of the tributylammonium salt of the chiral anion tris[tetrachlorobenzene-1,2-bis(olato)]phosphate, also named Trisphat, was able to induce an efficient resolution of a Delta,Lambda racemic mixture of cis-[Ru(dmp)2(NCCH3)2](PF6)2 (dmp=2,9-dimethyl-1,10-phenanthroline) due to the spontaneous and selective precipitation of the heterochiral pair [Delta-Ru(dmp)2(CH3CN)2][Lambda-Trisphat]2. We report here that the combination of such a stereoselective precipitation process and irradiation results in the quantitative conversion of the initial [Ru(dmp)2(NCCH3)2]2+ racemate into only one of the two enantiomers. This is the first example in inorganic chemistry of an asymmetric transformation that leads to a chiral complex with no chiral ligand. Finally, three new racemic ruthenium bis(diimine) complexes, namely [Ru(dmp)2(NCCH3)Py](PF6)2 (Py=pyridine), [Ru(dmp)2(1,3-diaminopropane)](PF6)2, and [Ru(dmp)2(ethylenediamine)](PF6)2 were synthesized. For all of them, crystallization-induced asymmetric transformation proved to be an efficient way of obtaining the corresponding optically active chiral-at-metal complexes in high yields and with excellent stereoselectivities.     

Design and synthesis of effective antagonists of substance P

The agonist/antagonist activities of four background analogs of substance P (SP) facilitated design and synthesis of 12 new analogs to achieve effective antagonists. (D-Pro2, D-Phe7, D-Trp9)-SP, (D-Pro2, D-Trp7,9)-SP and (D-Arg1, D-Phe7, D-Trp9)-SP showed no agonist activity; 9 analogs showed weak agonist activity of SP. (D-Pro2, D-Trp7,9)-SP was the most potent antagonist which at a concentration of 10(-5) required a 3-fold increase in SP to allow a 50% response by SP. (D-Pro2, Lys6, D-Phe7)-SP and (D-Pro2, D-pClPhe7, D-Trp9)-SP were also potent, and the antagonism was competitive. For specific pairs of peptides, Lys6 is a promising substituent. D-Trp7,9 was as effective as Lys6, D-Phe7. D-pClPhe7 was three times as effective as D-Phe7. D-Dln6 was 1.33-fold better than D-Gln5. D-Pro2 and D-Pro4 were equally effective. D-Pro2 was 1.5 times as effective as D-Lys3. D-Pro2 may not be important. D-pClPhe9 and D-Trp9 were equally effective.     

Crystallization-induced asymmetric transformation. Application to conjugate addition of benzylamine to amides of benzoylacrylic acid

Adducts of the conjugate addition of benzylamine to enantiopure amides of aroylacrylic acid possess high enantiomeric and diastereomeric purity. A high degree of stereoselectivity has been achieved by means of crystallization-induced asymmetric transformation. A practical synthesis leading to dipeptides containing homophenylalanine is depicted.     

Inorganic asymmetric synthesis: asymmetric synthesis of a two-bladed propeller, octahedral metal complex

A C2 hexadentate, in which two pyridine-2-aldehyde 2'-pyridylhydrazone (PAPHY) groups are linked to a chiral auxiliary derived from (R,R)-tartaric acid, (R,R)-1, reacts with iron(II) benzenesulfonate to give the two-bladed propeller, octahedral complex (P(Fe))-[Fe{(R,R)-1}](PhSO3)2 with complete diastereoselectivity, as determined by 1H NMR spectroscopy and X-ray crystallography. Saponification of the ester linkages and deprotonation of the hydrazone-NH groups in the configurationally pure diastereomer affords the complex (P(Fe))-[Fe(5-HOCH2PAPY)2] with 85% retention of configuration at the iron stereocenter, as determined by reprotonation of the neutral complex with enantiomerically pure (aR)-binaphthyl phosphoric acid and analysis of the 1H NMR spectrum of the mixture of diastereomeric salts produced. This is the first asymmetric synthesis of a two-bladed propeller, octahedral metal complex by the classical organic methodology of chiral auxiliary-directed, asymmetric synthesis.     

Dinuclear asymmetric Zn aldol additions: formal asymmetric synthesis of fostriecin

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Enantioselective synthesis of epi-(+)-Sch 642305: observation of an interesting diastereoselection during RCM

In an approach towards the enantioselective total synthesis of the novel bioactive natural product Sch 642305, an unusual diastereoselection during the key RCM reaction, resulted in the synthesis of the 11-epi-isomer of Sch 642305.     

A new approach to the synthesis of peptidomimetic renin inhibitors: palladium-catalyzed asymmetric allylation of acyclic alkyl aryl ketones

A new approach to the synthesis of Tekturna, a recently marketed drug for hypertension, takes advantage of a modified protocol of the Stoltz palladium-catalyzed asymmetric allylation with a t-BuPHOX ligand for the synthesis of allylated acyclic alkyl aryl ketones. The method led to an α-isopropyl α-allyl aryl ketone in 90% yield and 88 to 91% ee, which was used in the synthesis of an advanced intermediate toward Tekturna. A beneficial effect of protic additives, such as BHT (2,6-di-tert-butyl-p-cresol), on the time and enantioselectivity of the reaction was discovered.     

Vanadium-catalyzed asymmetric cyanohydrin synthesis

Based on a mechanistic understanding of asymmetric cyanohydrin synthesis catalyzed by chiral titanium-salen complexes, a new catalyst based on vanadium(IV) has been developed. The chiral (salen)VO catalyst is more enantioselective than the titanium-based systems, 0.1 mol % of the catalyst being sufficient to convert aromatic and aliphatic aldehydes into the corresponding trimethylsilyl ethers of cyanohydrins with 68-95% enantiomeric excess at room temperature.     

Stochastic aspects of asymmetric autocatalysis and absolute asymmetric synthesis

The main goal of the present review is to collect in a unified framework the deterministic and stochastic models of emergence and amplification of chirality by mechanisms such as asymmetric autocatalysis and absolute asymmetric synthesis. Empirical approach and modeling have recently provided a good insight into these phenomena. Our groups in Italy and Hungary have a wide variety of expertise both in fields of experiments and modeling. In the last decade important results have been achieved, however, more experiments and more detailed deterministic and stochastic models are needed for a better understanding of details and significance of asymmetric autocatalysis and absolute asymmetric synthesis.     

Versatile asymmetric synthesis of the kavalactones: first synthesis of (+)-kavain

[reaction: see text] Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.     

First asymmetric synthesis of achaetolide

The first asymmetric synthesis of the 10-membered macrolide achaetolide is reported in this article. The main highlight of the synthetic strategy is the ring-closing metathesis (RCM) of intermediate 19, which in turn can be accessed from coupling between alcohol 11 and acid 18. The synthesis of 11 involves enzymatic kinetic resolution (EKR) coupled with a Mitsunobu inversion strategy, while 18 can be prepared by adopting a metal-enzyme combined dynamic kinetic resolution (DKR) reaction followed by functional group manipulation.     

An asymmetric synthesis of L-pyrrolysine

An efficient asymmetric synthesis of the 22nd amino acid L-pyrrolysine has been accomplished. The key stereogenic centers were installed by an asymmetric conjugate addition reaction. A Staudinger/aza-Wittig cyclization was used to form the acid-sensitive pyrroline ring. Pyrrolysine was synthesized in 13 steps in 20% overall yield.     

Practical asymmetric synthesis of aklavinone

A practical synthesis of( + )-aklavinone, the aglycone of antitumor antibiotic aclacinomycin A, is achieved by using the asymmetric aldol reaction of 6a to 10a as the key step.     

A highly efficient, asymmetric synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase

[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase.