Catalytic asymmetric Michael reactions of dibenzyl malonate to α,β-unsaturated N-acylpyrroles using a La(O-iPr)3/Ph-linked-BINOL complex

Catalytic asymmetric Michael reactions of a malonate to acyclic α,β-unsaturated N-acylpyrroles as ester equivalent acceptors are described. A La(O-iPr)₃/(S,S)-linked-BINOL complex, which is suitable for Michael addition to cyclic enones, is not suitable for acyclic α,β-unsaturated N-acylpyrroles. A new (S,S)-Ph-linked-BINOL chiral ligand was developed to improve enantioselectivity, and a La(O-iPr)₃/(S,S)-Ph-linked-BINOL complex with the addition of HFIP afforded Michael adducts in good yield and enantioselectivity (up to 96% ee).     

Asymmetric synthesis of naturally occurring (−)-seimatopolides A and B

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

Synthesis of (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratrane. Amplification of enantiomeric purity in the reacti

The synthesis is described of the two enantiomerically pure isomers (+)-(3S,7S,10S)- and (+)-(3S,7S,10R)-3,7,10-trimethylboratr The structures were determined by ¹H- and ¹³C-NMR spectroscopy. A method for increasing the enantiomeric purity by trimerization reactions of partially-resolved (S) propylene oxide is proposed. The reaction was studied from the kinetic viewpoint and interpreted according to a binomial probability scheme. The experimental findings point to a rapid growth in enantiomeric purity for the (SSS) trimer compared with the starting material, whilst no increase was found for the (SSR) trimer.     

Asymmetric synthesis of passifloricin A: a correction in structure

The structure reported in the literature for the pharmacologically active, natural lactone passifloricin A (δ-lactone of 2Z,5R*S*,7R*,9S*,11S*-tetrahydroxyhexacos-2-enoic acid) is incorrect not only as regards stereochemical issues, but also in the placement of one of the hydroxyl groups of the side chain. By means of an unambiguous synthesis, passifloricin A is shown to be the δ-lactone of 2Z,5R,7S,9S,12S-tetrahydroxyhexacos-2-enoic acid. All of the stereogenic centres were created with the aid of Brown's asymmetric allylation methodology. The lactone ring was made via ring-closing metathesis.     

A concise synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid

A concise, multi-gram scale method for producing the bioactive and enantiomerically pure epimers, (2S,4R)- and (2S,4S)-glutamic acids, in a single synthetic scheme is described.     

Stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-glutamine and the absolute stereochemistry of the natural product from papuamides and callipeltin

(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate of callipeltin A.     

Stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine

A convenient and efficient route is described for the highly stereoselective synthesis of δ-amino protected and conformationally restricted (2S,3S)-3-hydroxyornithine through the N-benzylnitrone adduct to the α,β-unsaturated bicyclic lactam 2 derived from (S)-pyroglutaminol.     

Synthesis of enantiomeric pure lithium and potassium benzamidinate complexes

A new synthesis leading to the chiral amidines (S,S)- and (R,R)-N,N-bis-(1-phenylethyl)benzamidine ((S)- and (R)-HPEBA) in good yields is presented. Further reaction of (S)-HPEBA with n-BuLi gave the chiral lithium salt (S)-LiPEBA. Treatment of KH with (S)-HPEBA in boiling THF afforded the corresponding potassium salt (S)-KPEBA. In contrast by performing the reaction in boiling toluene a fast racemization was observed. In the solid state racemic KPEBA formed a dimer, in which all four nitrogen atoms are in a plane. To each potassium atom a toluene molecule is η⁶-coordinated.     

Stereoselective synthesis of 3-deoxy-piperidine iminosugars from l-lysine

A new method using electrochemical oxidation and/or OsO₄ oxidation has been used for the stereoselective synthesis of 2,3,6-trihydroxylated (5S)-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for the conversion of 2,3-didehydro-1-methoxypiperidine derivatives to 2,3-trans-1,2,3-triacetoxypiperidine derivatives. These triacetates were easily transformed into (2S,3S)-6-triacetoxy-(5S)-methylpiperidine and (2R,3R)-6-triacetoxy-(5S)-methylpiperidine. In addition, the 2,3-cis-dihydroxylation of 2,3-didehydro-1-methoxypiperidine derivatives with OsO₄ afforded (2R,3S)-6-triacetoxy-(5S)-methylpiperidine and (2S,3R)-6-triacetoxy-(5S)-methylpiperidine.     

Interaction in the Yb2S3-In2S3 system

A T-x diagram is designed for the Yb₂S₃-In₂S₃ system using physicochemical methods. A complex chemical reaction occurs in the system to yield ternary compounds Yb₃InS₆ (S₁), YbInS₃ (S₂), Yb₃In₅S₁₂ (S₃), and YbIn₃S₆ (S₄). In₂S₃-based limited solid solutions are found. Phases S₁, S₃, and S₄ are formed by peritectic reactions at 1260, 1200, and 1100 K, respectively. Compound S₂ melts congruently at 1390 K. Compound S₃ crystallizes in monoclinic system (a = 10.90 Å, b = 21.01 Å, c = 3.846 Å, β = 96.2°). Compounds S₁ and S₄ crystallize in orthorhombic system (for S₁, a = 16.76 Å, b = 13.70 Å, c = 3.88 Å; for S₄, a = 3.86 Å, b = 11.64 Å, c = 20.98 Å, d _exp = 4.62 g/cm³). Compound S₂ crystallizes in cubic system (a = 10.68 Å).     

Efficient synthesis of an optically pure β-bromo-β,β-difluoroalanine derivative,a general precursor for β,β-difluoroamino acids

A highly efficient enantioselective preparation of a β-bromo-β,β-difluoroalanine derivative, a promising general precursor for optically active β,β-difluoroamino acids, is described. Alkylation of the hydroxypinanone glycinate Schiff base 2a with CF₂Br₂ resulted in the production of undesired dehydrobrominated product 4a promoted by the lithium alkoxide moiety on the hydroxypinanone chiral auxiliary. Dehydrobromination was prevented by protection of the hydroxyl group on the chiral auxiliary. Utilization of TMSOTf resulted in production of (S,S,S,S)-3b as the sole diastereomer without dehydrobromination. Further transformations of (S,S,S,S)-3b to other optically active β,β-difluoroamino acids were demonstrated.     

Stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes—a novel preparation of N-acetyl-l-daunosamine

A general route for the stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes, with almost any desired configuration at the three stereogenic centers, is described by applying a combination of enzymatic and chemical steps. l-Daunosamine 1, for example, the glycosidic fragment of many important anthracycline antibiotics has been prepared by this route starting from O-allyl-l-lactaldehyde (S)-6a. (R)-Hydroxynitrile lyase (HNL) catalyzed addition of HCN to (S)-6a yields the 2,3-dihydroxynitrile (2S,3S)-7a with high stereoselectivity (91% de) in 75% yield. The addition of allyl Grignard to the O-protected 2,3-dihydroxynitrile (2S,3S)-9a and subsequent hydrogenation of the imino intermediate leads to 4-amino-2,3-dihydroxy-1-heptene (4S,5S,6S)-12a, which after ozonization and deprotection gives N-acetylated l-daunosamine 14a in a total yield of 15% referring to (S)-6a. The general applicability of this chemoenzymatic multistep procedure is demonstrated in the stereoselective synthesis of the unnatural aminodeoxy sugar (2S,3S,4S)-14b, starting from isovaleraldehyde 3.     

Asymmetric synthesis of l-proline regio- and stereoselectively labelled with deuterium

A synthesis of l-proline where all of the ring methylenes are stereoselectively labelled with deuterium is described. A catalytic deuteration of protected 3,4-dehydro-l-proline using transition metal catalyst followed by RuO₄-oxidation gave a [3,4-D₂]pyroglutamic acid derivative. A syn-selective deuteration of the aminal derived from the pyroglutamate with Et₃SiD–BF₃·OEt₂ furnished (2S,3S,4R,5S)-[3,4,5-D₃]proline. The present procedure is also applied to the synthesis of the corresponding (2S,3S,4R,5R)-isomer.     

A practical synthesis of the PPARα agonist, (R)-K-13675, starting from (S)-2-hydroxybutyrolactone

A practical synthesis of optically pure PPARα agonist, (R)-K-13675, is described. This process is based on the use of (S)-2-hydroxybutyrolactone, which can be transformed into the requisite n-butyl (S)-2-hydroxybutanoate in an efficient manner. A key reaction is the etherification between the phenol and n-butyl (S)-2-trifluoromethanesulfonyloxybutanoate to give the phenyl ether in excellent yield without loss of optical purity.     

Straightforward access to new vinca-alkaloids via selective reduction of a nitrile containing anhydrovinblastine derivative

A procedure to exclusively obtain 3′S-cyanoanhydrovinblastine 12 from two naturally occurring vinca-alkaloids (catharanthine and vindoline) in one step with good yield is described. Stereoselective reductions of 12, providing straightforward access to three new vinca-alkaloids, including two diastereomers 3′S-cyano-(4′R,5′-dihydro)-anhydrovinblastine and 3′S-cyano-(4′S,5′-dihydro)-anhydrovinblastine as well as (3′S-aminomethyl)-(4′S,5′-dihydro)-anhydrovinblastine in good yields is also reported.     

Preliminary studies on a novel synthesis of β-amino acids: stereocontrolled transformation of d- and l-glyceraldehyde into 3-amino-2-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acids

A stereocontrolled synthesis of the methyl ester of (2S)-3-amino-2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acid from d-glyceraldehyde is described for the first time. This method involves the stereoselective Michael addition of the lithium salt of tris(phenylthio)methane to (S)-2,2-dimethyl-4-((E)-2-nitrovinyl)-1,3-dioxolane followed by hydrolysis of the resulting (4S)-2,2-dimethyl-4-((2′S)-3′-nitro-1′,1′,1′-tris(phenylthio)propan-2′-yl)-1,3-dioxolane to (2S)-methyl 2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-3-nitropropanoate, which was finally reduced to the target compound. A similarly stereocontrolled transformation of l-glyceraldehyde into (2R)-methyl 3-amino-2-((4′R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoate is also described.     

A master equation for S(q,ω) leading to the hydrodynamic regime for simple fluids

A master equation relating the coherent and incoherent dynamical structure factors S(q, ω) and S_S(q, ω) is introduced on the basis of physical arguments suggested by previous theories. It is shown that, once S_S(q, ω) and the first six moments of S(q, ω) are known, the resulting expression for S(q, ω) contains the correct hydrodynamic regime as well as the free particle behaviour. The relationships thus introduced between the transport coefficients and the molecular quantities are compared to the experimental data for liquid argon. Molecular dynamics data are also well reproduced.     

Synthesis and properties of S,R-alternating octinaphthalenes

(S,R,S,R,S,R,S)- and (S,R,S,S,S,R,S)-octinaphthalenes were synthesized by oxidative coupling of (S,R,S)-quaternaphthalene, and differences due to axis chirality of (S,R,S,R,S,R,S)-, (S,R,S,S,S,R,S)-, (S,S,S,R,S,S,S)-, and (S,S,S,S,S,S,S)-octinaphthalenes were compared using the R_f values on TLC, specific optical rotations, ¹H NMR chemical shifts of the hydroxy groups, and CD spectra. A clear CD additivity was found in the Δ? values of the ¹L_a transition around 290 nm, which are proportional to the difference between the numbers of S and R binaphthalene units.     

First chiral synthesis of the N-terminal amino acid congener of nikkomycin Z based on lipase-catalyzed enantioselective acetylation of a primary alcohol possessing two stereogenic centers

A stereoselective synthesis of a versatile chiral synthon possessing two stereogenic centers, (2S,3S)-3-[2-(5-benzyloxypyridyl)]-2-methyl-1,3-propane diol 12 (>99% ee), was achieved by using a chemo-enzymatic method. The conversion of (2S,3S)-12 to the homochiral intermediate (2S,3S,4S)-2-benzyloxycarbonylamino-4-[2-(5-benzyloxypyridyl)]-4-tert-butyldimethylsilyloxy-3-methylbutanoic acid 2 corresponding to the N-terminal amino acid congener of nikkomycin Z 1 is described.