Synthesis and PKC binding of a new class of a-ring diversifiable bryostatin analogues utilizing a double asymmetric hydrogenation and cross-coupling strategy

The design, asymmetric synthesis, and biological evaluation of a new class of bryostatin analogues based on a pseudosymmetric spacer domain are described. An aryl bromide diversification site is incorporated allowing access to systematically varied analogues. The new analogues all exhibit potent, nanomolar affinity to PKC.     

Asymmetric total synthesis of rollicosin

[structure: see text] The first total synthesis of rollicosin, a member of a rare subgroup of Annonaceous acetogenins containing two terminal gamma-lactones, is reported. The approach features a highly regio- and stereoselective tandem ring-closing/cross-metathesis reaction for construction of the east-wing lactone and incorporation of the alkyl spacer. Establishment of the C4 stereocenter and addition of the west-wing lactone were achieved by Sharpless asymmetric dihydroxylation and enolate alkylation.     

Catalytic Asymmetric Total Synthesis of Exiguolide

The catalytic asymmetric total synthesis of (−)-exiguolide, a complex 20-membered macrolide embedded with a bis(tetrahydropyran) motif, is reported. The convergent synthesis involves the construction of the C1–C11 tetrahydropyran segment via catalytic asymmetric allylation and Prins cyclization, and the formation of the C12–C21 phosphonate segment via catalytic asymmetric cyclocondensation reaction and Johnson–Claisen rearrangement. The synthesis of 15-epi-exiguolide is also described.     

Total synthesis and initial biological evaluation of new B-ring-modified bryostatin analogs

[Structure: see text] The total synthesis and preliminary biological evaluation of the first bryostatin analogs (bryologs) to incorporate B-ring substitution are reported. Asymmetric syntheses of two new polyketide "spacer" domains are described, one exploiting the pseudosymmetry of the C1-C13 region. These fragments are convergently joined to the "recognition" domain through a remarkably versatile macrotransacetalization process. The resulting new analogs exhibit potent nanomolar or picomolar affinity to protein kinase C (PKC), comparable to or better than that found for bryostatin.     

Membrane-mimetic films of asymmetric phosphatidylcholine lipid bolaamphiphiles

Membrane-spanning phospholipid bolaamphiphiles either alone or as a constituent of a multicomponent lipid membrane may prove to be facile building blocks for generating robust bioactive membrane-mimetic assemblies. We have previously reported the synthesis of asymmetric dialkyl phospholipid bolaamphiphiles that contain ester linked phosphatidylcholine and amine functionalities at opposite chain ends. In this report, we describe the synthesis of phospholipid bolaamphiphiles that are conjugated to biotin via the terminal amine with or without a poly(ethylene oxide) spacer arm of varying chain length. The behavior of biotinylated bolaamphiphiles as a self-assembled monolayer at an air-water interface was characterized by epi-fluorescence microscopy and revealed that domain structure and pi-A isotherms were substantially influenced by linker type and size. Substrate bound assemblies were produced by Langmuir-Blodgett deposition onto planar substrates coated with an avidin derivatized polyelectrolyte multilayer. Significantly, external reflectance infrared spectroscopy confirmed the fabrication of bolaamphiphile thin films that display extended stability in vitro.     

Stereoselective synthesis of C1–C12 fragment of amphotericin B

An efficient synthesis of C1–C12 fragment of amphotericin B is described. The synthesis is based on asymmetric dihydroxylation and cross-metathesis reactions.     

Total synthesis and structural revision of (+)-amphidinolide W

An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis.     

Synthesis and characterization of halogen-containing ferroelectric liquid crystals and side chain liquid crystalline polymers

A new series of ferroelectric liquid crystals and side chain liquid crystalline polymers based on halogen-containing chiral centres has been synthesized. Chemical structures were analysed by NMR. Liquid crystal phases were characterized by differential scanning calorimetry, optical polarizing microscopy, and X-ray diffractometry. The behaviour of the liquid crystalline phases was investigated as a function of spacer units and differing terminal asymmetric moieties. It was found that phase transition temperatures decreased with increasing length of the oligooxyethylene spacer unit. Differing terminal asymmetric moieties led to differing mesophase phenomena. Furthermore, a wide temperature range (including room temperature) of a chiral smectic C phase was achieved.     

Synthesis and characterization of halogen-containing ferroelectric liquid crystals and side chain liquid crystalline polymers

A new series of ferroelectric liquid crystals and side chain liquid crystalline polymers based on halogen-containing chiral centres has been synthesized. Chemical structures were analysed by NMR. Liquid crystal phases were characterized by differential scanning calorimetry, optical polarizing microscopy, and X-ray diffractometry. The behaviour of the liquid crystalline phases was investigated as a function of spacer units and differing terminal asymmetric moieties. It was found that phase transition temperatures decreased with increasing length of the oligooxyethylene spacer unit. Differing terminal asymmetric moieties led to differing mesophase phenomena. Furthermore, a wide temperature range (including room temperature) of a chiral smectic C phase was achieved.     

Studies directed toward the total synthesis of azaspiracid: stereoselective construction of C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments

[reaction: see text] The efficient entry to the C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments of azaspiracid is outlined. The C(1)-C(12) portion is constructed using a key asymmetric allenyl borane addition to the corresponding alpha,beta-unsaturated aldehyde. The synthesis of the C(13)-C(19) portion utilizes an Evans asymmetric alkylation followed by Sharpless asymmetric dihydroxylation. In addition, a novel solution to the mismatched effects of a neighboring chiral oxazolidinone during a Sharpless dihydroxylation is detailed.     

Stereo selective synthesis of C3–C12 fragment of iriomoteolide-1a

A convergent and flexible synthetic route for the synthesis of C3–C12 fragment of iriomoteolide-1a is described. The key steps are: Mannich reaction, Keck asymmetric allylation, Sharpless asymmetric epoxidation and cross-metathesis protocol.     

Gemini表面活性剂联接基团对合成硅基介孔材料结构的影响

考察了Gemini表面活性剂不同联接基团对介孔结构的影响, 通过改变联接基团碳链的长度和在联接基团中加入苯基和羟基改变链的柔性和亲水性, 可改变表面活性剂在两相界面的头基面积和电荷分布, 形成不同的表面活性剂溶液结构, 并通过自组装过程控制生成不同介孔材料的孔结构. 当联接基团链长为4~8个碳时, 得到六方相孔道结构, 而当碳链长度增加为10~12个碳时, 形成立方相孔道结构, 其中以GEM16-6-16为模板, 形成了高度有序的MCM-41, 以GEM16-12-16为模板, 则得到高度有序的MCM-48. GEM16-3(OH)-16可合成出层状结构, 但有序性较低. GEM16-(1-Ar-1)-16的cmc较低, 在水溶液中溶解度极低, 当加入共溶剂乙醇时, 得到了空心球结构.     

Towards the synthesis of Palmerolide A: asymmetric synthesis of C1–C14 fragment

The synthesis of a C1–C14 fragment of a marine cytotoxic natural product Palmerolide A is described. The key steps involved in this synthesis are deoxygenative rearrangement of an alkynol followed by an asymmetric dihydroxylation of a diene ester and CBS-reduction.     

Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.     

The direct amino acid-catalyzed asymmetric incorporation of molecular oxygen to organic compounds

We have disclosed the direct catalytic incorporation of 1O2 to aldehydes. The unprecedented amino acid-catalyzed asymmetric alpha-oxidation of aldehydes with molecular oxygen or air proceeded with high chemoselectivity and was a direct entry for the synthesis of both enantiomers of terminal diols. The results demonstrated that simple amino acids accomplished catalytic asymmetric oxidations with molecular oxygen or air, which has previously been considered to be in the domain of enzymes and chiral transition-metal complexes. The efficiency of the catalytic process may warrant the existence of an ancient pathway for the synthesis of hydroxylated organic compounds.     

Asymmetric synthesis of diastereomeric diaminoheptanetetraols. A proposal for the configuration of (+)-zwittermicin a

[structure: see text] A proposed absolute configuration for the 7 stereocenters in (+)-zwittermicin A is described based on asymmetric synthesis of six diastereomeric 2,6-diamino-1,3,5,7-heptanetetraols corresponding to the C9-C15 segment, pairwise 13C NMR chemical shift difference analysis of the models with the natural product, interpretation of enantiospecificity of the serine loading domain of the zwittermicin A biosynthetic gene cluster, and degradation of the natural product.     

Asymmetric Addition of Diethylzinc to Aldehydes Using SPINOL Derivatives

Lewis acid catalyzed enantioselective carbon-carbon bond formation is one of the most interesting challenges in catalytic asymmetric synthesis. A convenient route for this synthesis is the addition of organozinc to aldehydes.[1]1,1'-Spirobiindane-7,7'-diol (SPINOL), a new reported C2 symmetrical diol, was recently proven to be an excellent framework for chiral ligands.[2] In this paper, interestingly, we describe the preparation of SPINOL derivatives and application of these ligands to asymmetric addition of diethylzinc to aldehydes as model reaction. Previously, an improved method for the resolution of C2-symmetric spirocyclic SPINOL was presented with crude menthyl chloroformate as resolving reagent.[3] Then (R)-SPINOL with C2-symmetric spirocyclic framework was applied in the asymmetric diethylzinc addition to aromatic aldehydes, which induced high conversions and moderate enantioselectivities for the production of chiral secondary alcohols. Further work of other SPINOL derivative ligands for asymmetric diethylzinc addition to aromatic aldehydes and developing further new SPINOL-based Lewis acid catalyzed asymmetric synthesis are underway.     

Studies towards the synthesis of epothilone A via organoboranes

Studies towards the synthesis of epothilone A via organoboranes have been described. A modified procedure for the large-scale preparation of B-gamma,gamma-dimethylallyldiisopinocampheylborane from prenyl alcohol has been developed. This reagent, upon reaction with various aldehydes, provides the corresponding alpha,alpha-dimethylhomoallylic alcohols in high enantioselectivities. The application of this reagent for the synthesis of the C1-C6 subunit of epothilone has been demonstrated. Alternatively, inter- and intramolecular asymmetric reduction protocols have also been utilized for the synthesis of the C1-C6 subunit of epothilone A. The synthesis of the C7-C21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using alpha-pinene-derived reagents has also been described.     

Asymmetric crotylation reactions in synthesis of polypropionate-derived macrolides: application to total synthesis of oleandolide

Complete details of a convergent asymmetric synthesis of oleandolide (1), the aglycon of the macrolide antibiotic oleandomycin, is described. The synthesis has been achieved through the assembly and coupling of the left- and right-hand subunits 12 and 38, respectively. These subunits were prepared from chiral silane-based asymmetric crotylation reactions to control the stereochemical relationships. The left- and right-hand subunits (C1-C7 and C8-C14) were brought together through a Pd(0)-catalyzed sp3-sp2 cross-coupling reaction between the zinc intermediate 40 and vinyl triflate 38 to give 27. This product was converted to seco acid 42a and cyclized to lactone 35 under Yamaguchi conditions. This material was then epoxidized with m-chloroperbenzoic acid (m-CPBA) to install the correct C8 epoxide as a single diastereomer, which after a short deprotection sequence completed the synthesis of oleandolide.     

Asymmetric formal synthesis of schulzeines A and C

The asymmetric formal synthesis of schulzeines A and C is described. Key features of the synthesis include the efficient and stereoselective construction of the benzoquinolizidine skeleton via the aza-Claisen rearrangement-induced ring expansion of the 1-vinyl-N-glycyl-isoquinoline, which was prepared by the highly enantioselective asymmetric allylation of the 8-benzyloxy-substituted dihydroisoquinoline and by the acid-catalyzed transannulation of the resulting 10-membered lactam.