Stereoselective formal [3 + 3] cycloaddition approach to cis-1-azadecalins and synthesis of (-)-4a,8a-diepi-pumiliotoxin C. evidence for the first highly stereoselective 6pi-electron electrocyclic ring closures of 1-azatrienes

Evidence is described here to support that a highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes is a key step in formal [3 + 3] cycloaddition or annulation reactions of chiral vinylogous amides with alpha,beta-unsaturated iminium salts. This would represent the first highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes. We have also unambiguously demonstrated that these specific ring closures are reversible, leading to the major diastereomer that is also thermodynamically more stable, and that a rotation preference likely also plays a role. A synthetic application is illustrated here to stereoselectively transform the resulting dihydropyridines to cis-1-azadecalins with unique anti relative stereochemistry at C2 and C2a, leading to synthesis of epi isomers of (-)-pumiliotoxin C.     

Total synthesis of ageladine A, an angiogenesis inhibitor from the marine sponge Agelas nakamurai

[reaction: see text] A 12-step total synthesis of the tricyclic heteroaromatic marine metabolite ageladine A has been achieved using a 6pi-azaelectrocyclization and a Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloropyridine as key steps.     

Development of a one-pot asymmetric azaelectrocyclization protocol: synthesis of chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines

[reaction: see text] A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via Stille-Migita coupling, 6pi-azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes, vinyliodides, and cis-aminoindanol derivatives. Based on the method, chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines, bearing a variety of aromatic substituents at the C-2 position, have been prepared.     

Development of highly stereoselective asymmetric 6pi-azaelectrocyclization of conformationally flexible linear 1-azatrienes. from determination of multifunctional chiral amines, 7-alkyl cis-1-amino-2-indanols, to application as a new synthetic strategy: formal synthesis of 20-epiuleine

The highly stereoselective asymmetric 6pi-azaelectrocyclization was achieved as a general synthetic method based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-alkyl-cis-1-amino-2-indanol derivatives which are effective chiral amines. The 7-alkyl-substituted 2-indanol moiety of the cyclized products was efficiently removed by the novel manganese dioxide oxidation under remarkably mild conditions, and the method was successfully applied to the formal synthesis of optically active 20-epiuleine.     

Total synthesis of epoxyquinols A, B, and C and epoxytwinol A and the reactivity of a 2H-pyran derivative as the diene component in the Diels-Alder reaction

Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCl(4)-mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6pi-electrocyclization, and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction composed of oxidation, 6pi-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6pi-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized by a similar cascade reaction composed of the four successive steps: oxidation, imine formation, 6pi-azaelectrocyclization, and Diels-Alder dimerization.     

Ruthenium-catalyzed cycloisomerization-6pi-cyclization: a novel route to pyridines

[reaction: see text] Herein we report a method for the synthesis of substituted pyridines. The unsaturated ketones and aldehydes derived from the cycloisomerization of primary and secondary propargyl diynols in the presence of [CpRu(CH3CN)3]PF6 (1) are converted to 1-azatrienes which in turn undergo a subsequent electrocyclization-dehydration to provide pyridines with excellent regiocontrol.     

Highly stereoselective asymmetric 6pi-azaelectrocyclization utilizing the novel 7-alkyl substituted cis-1-amino-2-indanols: formal synthesis of 20-epiuleine

Highly stereoselective asymmetric 6pi-azaelectrocyclization was achieved with generality, based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-alkyl-cis-1-amino-2-indanol derivatives as the effective novel chiral amines. Furthermore, the chiral auxiliaries of the cyclized products obtained were efficiently removed by the novel manganese dioxide oxidation under remarkably mild conditions, and the method was successfully applied to the formal synthesis of optically active 20-epiuleine.     

Novel synthesis of the ocular age pigment A2-E: new method for substituted pyridine synthesis via azaelectrocyclization

[reaction: see text] The formal synthesis of the ocular age pigment A2-E was achieved by the efficient one-pot preparation of the substituted pyridine, which involves the aza-6pi-electrocyclization of the Schiff base derived from (E)-3-carbonyl-2,4,6-trienal followed by oxidation.     

Total synthesis of (-)-gambierol

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B --> AB --> ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which SmI(2)-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh(3))(4)/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1).     

Asymmetric synthesis of a chiral building block for cyclopentanoids: a novel enantioselective synthesis of preclavulone A

A new asymmetric approach to the hydroxylactone (+)-(3aR,4R,6aS)-4-(hydroxymethyl)-3a,4-dihydro-3H-cyclopenta[b]furan-2(6aH)-one (1), a key synthetic building block for cis-1,2-disubstituted five-membered ring derivatives (i.e., isoprostanes, jasmonates, and clavulones), has been described. A remarkable control of the absolute and relative configuration of the three stereocenters was achieved. Thus, the use of the Trost's asymmetric allylic alkylation strategy secured highly enantioenriched (R)-3-(nitromethyl)cyclopent-1-ene (13), which was smoothly converted to (R)-cyclopent-2-enecarboxylic acid (15) in excellent yield and high enantiomeric purity (>98% ee). 6-exo-trig atom-transfer radical cyclizations of ((R)-cyclopent-2-enyl)methyl 2-iodoacetate (12) produced exclusively the desired cis-fused delta-lactone (4aR,7aR)-hexahydro-5-iodocyclopenta[c]pyran-3(1H)-one (11), which was subsequently elaborated to hydroxylactone 1 through a stereocontrolled Pd(II)-mediated lactonization reaction. En route to preclavulone A, a putative elusive intermediate in the biosynthesis of clavulones, the synthetic utility of compound 1 was demonstrated. The key feature in this synthesis was the installation of the lower side chain via the Knochel organozinc sp3-sp C-C coupling protocol.     

Stern-Gerlach experiments of one-dimensional metal-benzene sandwich clusters: Mn(C6H6)m (M = Al, Sc, Ti, and V)

A molecular beam of multilayer metal-benzene organometallic clusters Mn(C6H6)m (M = Al, Sc, Ti, and V) was produced by a laser vaporization synthesis method, and their magnetic deflections were measured. Multidecker sandwich clusters of transition-metal atoms and benzene Scn(C6H6)n+1 (n = 1, 2) and Vn(C6H6)n+1 (n = 1-4) possess magnetic moments that increase monotonously with n. The magnetic moments of Al(C6H6), Scn(C6H6)n+1, and Vn(C6H6)n+1 are smaller than that of their spin-only values as a result of intracluster spin relaxation, an effect that depends on the orbital angular momenta and bonding characters of the orbitals containing electron spin. While Ti(C6H6)2 was found to be nonmagnetic, Tin(C6H6)n+1 (n = 2, 3) possess nonzero magnetic moments. The mechanism of ferromagnetic spin ordering in M2(C6H6)3 (M = Sc, Ti, V) is discussed qualitatively in terms of molecular orbital analysis. These sandwich species represent a new class of one-dimensional molecular magnets in which the transition-metal atoms are formally zerovalent.     

Total synthesis of nor-1,6-germacradien-5-ols

The first total synthesis of (+/-)-nor-1,6-germacradien-5-ols is described. The synthetic route involves the RCM methodology for the ring formation and a selective 1,2 addition of MeLi to cyclodecenone. By altering the order of the last synthetic steps, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-(5S*,8R*)-16 and -(+/-)-(5S*,8S*)-16 were obtained. The synthetic strategy via cyclodecenone offers the possibility of preparing different analogues of the title compounds through addition of other nucleophiles. Moreover, nor-germacrene D could be accessed from the target molecule by methylenation of its carbonyl moiety. (+/-)-nor-1,6-Germacradien-5-ol [(+/-)-(1E,5S*,6E,8S*)-2] was synthesized in eight steps from isovaleric acid. The 10-membered ring was formed by RCM, and the tertiary alcohol moiety was introduced in the last step via a highly diastereoselective addition of MeLi to (+/-)-(1E,6E)-1,6-cyclodecen-5-one (+/-)-E,E-5. Addition of MeLi to cyclodecenone (+/-)-Z,E-5 also occurred with complete selectivity to provide (+/-)-(1Z,5S*,6E,8S*)-2. A slightly different synthetic pathway was also explored, in which the order of the final synthetic steps was switched: the enone formation and the addition of MeLi were conducted prior to the cyclization. When the hydroxy group was protected as a TBS ether, the newly formed olefin had exclusively Z configuration. Thus, TBSO-protected (+/-)-(1Z,6E)-nor-1,6-germacradien-5-ols (+/-)-16 were obtained as a 1:1 (5S*,8S*)/(5R*,8S*) mixture. The NMR spectra of these two diastereomers confirmed the relative stereochemistry of natural (-)-1,6-germacradien-5-ol (1) at C5 and C8.     

A DFT Investigation on Hydrogen Adsorption Based on Alkali-metal Organic Complexes

Using density functional theory calculation based on the B3LYP method,we have studied the interactions of H2 molecules with alkali-metal organic complexes C6H6-nLin(n = 1～3),C6H5Na and C6H5K.A significant part of the electronic charge of M s orbital(Li 2s,Na 3s,K 4s) is donated to phenyl and is accommodated by H2 bonding orbital.For all the complexes considered,each bonded alkali-metal atom can adsorb up to five H2 in molecular form with the mean binding energy of 0.59,0.55 and 0.56 eV/H2 molecule for C6H6-nLin(n = 1～3),C6H5Na and C6H5K,respectively.The kinetic stability of these hydrogen-covered organometallic complexes is discussed in terms of energy gap between HOMO and LUMO.It is remarkable that these alkali-metal organic complexes can store up to 23.80 wt% hydrogen.Therefore,the complexes studied may be used as hydrogen storage materials.     

Mechanistic insights into triterpene synthesis from quantum mechanical calculations. Detection of systematic errors in B3LYP cyclization energies

Most quantum mechanical studies of triterpene synthesis have been done on small models. We calculated mPW1PW91/6-311+G(2d,p)//B3LYP/6-31G* energies for many C30H51O+ intermediates to establish the first comprehensive energy profiles for the cationic cyclization of oxidosqualene to lanosterol, lupeol, and hopen-3beta-ol. Differences among these 3 profiles were attributed to ring strain, steric effects, and proton affinity. Modest activation energy barriers and the ample exothermicity of most annulations indicated that the cationic intermediates rarely need enzymatic stabilization. The course of reaction is guided by hyperconjugation of the carbocationic 2p orbital with parallel C-C and C-H bonds. Hyperconjugation for cations with a horizontal 2p orbital (in the plane of the ABCD ring system) leads to annulation and ring expansion. If the 2p orbital becomes vertical, hyperconjugation fosters 1,2-methyl and hydride shifts. Transition states leading to rings D and E were bridged cyclopropane/carbonium ions, which allow ring expansion/annulation to bypass formation of undesirable anti-Markovnikov cations. Similar bridged species are also involved in many cation rearrangements. Our calculations revealed systematic errors in DFT cyclization energies. A spectacular example was the B3LYP/6-311+G(2d,p)//B3LYP/6-31G* prediction of endothermicity for the strongly exothermic cyclization of squalene to hopene. DFT cyclization energies for the 6-311+G(2d,p) basis set ranged from reasonable accuracy (mPW1PW91, TPSSh with 25% HF exchange) to underestimation (B3LYP, HCTH, TPSS, O3LYP) or overestimation (MP2, MPW1K, PBE1PBE). Despite minor inaccuracies, B3LYP/6-31G* geometries usually gave credible mPW1PW91 single-point energies. Nevertheless, DFT energies should be used cautiously until broadly reliable methods are established.     

Divergent synthesis of cytotoxic styryl lactones from D-xylose. The first total synthesis of (+)-crassalactone C

A new divergent approach to (+)-goniofufurone (1) and 7-epi-(+)-goniofufurone (2), as well as the first total synthesis of crassalactone C (3), has been achieved starting from D-xylose. In a preliminary bioassay, all three natural products 1, 2, and 3 showed remarkable in vitro antiproliferative activities against K562, Raji, and HeLa neoplastic cell lines.     

Total synthesis of (+)-kalafungin using a tandem Michael-Dieckmann approach

A stereoselective synthesis of the antibiotic kalafungin 1 is reported. A key step involved the tandem Michael-Dieckmann reaction between methyl 2-methoxy-6-methylbenzoate 11 and the α,β-unsaturated lactone (R)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methoxy-5,6-dihydropyran-2-one 10, which was prepared from (S)-aspartic acid. The C5 alkyl substituent was introduced by the use of methylmagnesium bromide and subsequent stereoselective reduction. A sequence of oxidations followed by acid-catalyzed epimerization delivered (+)-kalafungin 1.     

Simple, general, and efficient synthesis of meso-substituted borondipyrromethenes from a single platform

An unprecedented synthesis of 8-substituted-borondipyrromethenes is described starting from 8-thiomethylbodipy 1. Aryl, heteroaryl, alkenyl, and organometallic boronic acids smoothly reacted with 1 in the presence of a catalytic amount of Pd(0) and a stoichiometric amount of Cu(I)-2-thienylcarboxylate under neutral conditions to give the corresponding Bodipy analogues in good to quantitative yields (20 examples). A remarkable reactivity was observed in some cases, e.g., ferrocenylboronic acid gave the product in 98% isolated yield after only 10 min at 55 degrees C.     

一步法合成二甲醚整体式催化剂的制备及反应性能研究

以蜂窝陶瓷为载体、γ-Al₂O₃为惰性涂层、C301/HZSM-5为活性组分制备出一种整体式合成二甲醚催化剂。BET、XRD和SEM分析结果表明,活性组分均匀负载在载体表面上,催化剂具有良好的结构和织构特点。在固定床反应器中考察了整体式催化剂上CO加氢一步法合成二甲醚的反应性能,并与C301/HZSM-5颗粒（粉末）催化剂进行了比较。在温度260℃、压力4.0MPa、合成气空速1500mL/(g·h)的条件下,整体式催化剂上CO转化率达到79.62%,二甲醚选择性为70.58%,分别比C301/HZSM-5颗粒催化剂高出7.78%和9.44%。100h的稳定性实验结果表明,整体式催化剂可以保持较高的活性和选择性,而颗粒状催化剂的活性有明显的下降。
     

De novo synthesis of a methylene-bridged Neu5Ac-alpha-(2,3)-gal C-disaccharide

A general strategy toward the synthesis of C-ketosides of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2. The key strategic element of this novel approach is a stereoselective, 6-exo-trig selective, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open chain aldehyde 5a obtained from D-glucono-delta-lactone by chain elongation. Subsequent C1-incorporation using Tebbe-reagent, formation of a cyclic carbonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively cyclized in a 6-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after deacetylation, could be regioselectively tetrabenzoylated with benzoyl cyanide. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41, which was reduced with hydrogen and Pearlman's catalyst. Concomitant removal of the benzyl ethers and subsequent saponification of all ester moieties successfully completed the de novo synthesis of the desired methylene bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2.     

Halichondrin B: synthesis of a C1-C14 model via desymmetrization of (+)-conduritol E

[reaction: see text] A model C1-C14 segment (1) of halichondrin B was synthesized from (+)-conduritol E (7) in 18 steps and 2.9% overall yield. Key features of the synthesis include the novel ozonolytic desymmetrization of C(2)-symmetric diol 6, the early-stage construction of the C-ring which accompanies installation of the crucial C12 stereocenter, and the use of an enol ether C14-ketone surrogate as a precursor to the CDE-"caged" ketal.