Total synthesis of (-)-sarain A

This article describes the details of our synthetic studies toward the complex marine alkaloid sarain A. Various strategies were conceived, setbacks encountered, and solutions developed, ultimately leading to a successful enantioselective total synthesis. Our route to (-)-sarain A features a number of key steps, including an asymmetric Michael addition to install the C4'-C3'-C7' stereotriad, an enoxysilane-N-sulfonyliminium ion cyclization to set the C3 quaternary carbon stereocenter, and assemble the diazatricycloundecane core, a ring-closing metathesis to construct the 13-membered ring, an intramolecular Stille coupling to fashion the unsaturated 14-membered macrocycle, and a late-stage installation of the tertiary amine-aldehyde proximity interaction.     

Total synthesis of (+)-strictifolione

[reaction: see text] The synthesis of (+)-strictifolione was achieved from 3-phenylproprionaldehyde by using enantioselective allyltitanations to control the stereogenic centers at C6, C4', and C6' and a cross-methathesis to control the configuration of the double bond at C1'-C2'.     

Synthesis of the C1-C21 (C1'-C21') fragment of the dimeric polyketide natural product SCH 351448

[structure: see text] A convergent, stereoselective assembly of the C1-C21 (C1'-C21') fragment of SCH 351448, a 28-membered bis-lactone natural product, has been developed. A highly efficient approach to this fragment assembles 75% of the carbon skeleton and all the stereochemical elements present in the natural product. In addition, an interesting boron ligand effect on the diastereoselectivity of a key aldol reaction with methyl ketone-derived enolborinates is reported.     

The Stille reaction in the synthesis of the C37-norcarotenoid butenolide pyrrhoxanthin. Scope and limitations

The sequential Stille cross-coupling reactions of the dihalogenated gamma-alkylidenebutenolide 7 with stannanes 9 and 6 afforded the carbon skeleton of pyrrhoxanthin, a highly functionalized C7'-C8' acetylenic C37-norcarotenoid butenolide. Although the first halogen-selective Stille coupling takes place in 90% yield at ambient temperature, double isomerization of the Z,E- to the E,Z-C7'-C10' enyne, likely induced by the catalyst, accompanyied the bond formation, leading to 9'Z-20 and, ultimately, to 9'Z-pyrrhoxanthin 9'Z-1.     

New approaches towards the synthesis of the side-chain of mycolactones A and B

New approaches towards the synthesis of the C1'-C16' side-chain of mycolactones A and B from Mycobacterium ulcerans are reported. Chiral building block 4 (Fig. 2) with the correct stereochemistry was obtained starting from naturally occurring monosaccharides, i.e. D-glucose or L-rhamnose. The polyunsaturated moiety 3 was synthesized in only 3 steps from 2,4-dimethylfuran. The building blocks were connected through a Sonogashira coupling resulting in the fast and convergent assembly of an 8,9-dehydro analogue 2 of the side-chain of mycolactones A and B. The synthesis of 1 is at this stage hampered by the lack of a selective partial hydrogenation protocol for alkynes embedded in a conjugated system. Alternative strategies involving palladium catalyzed sp2-sp2 coupling between C7' and C8' or C9' and C10' (Fig. 1) were also explored.     

Measurement of five dipolar couplings from a single 3D NMR multiplet applied to the study of RNA dynamics

A new three-dimensional NMR experiment is described that yields five scalar or dipolar couplings from a single cross-peak between three spins. The method is based on the E.COSY principle and is demonstrated for the H1'-C1'-C2' fragment of ribose sugars in a uniformly 13C-enriched 24-nucleotide RNA stem-loop structure, for which a complete set of couplings was obtained for all nonmodified nucleotides. The values of the isotropic J couplings and the 13C1' and 13C2' chemical shifts define the sugar pucker. Once the sugar pucker is known, the five dipolar couplings between C1'-H1', C2'-H2', H1'-H2', C1'-H2', and C2'-H1', together with C1'-C2', C3'-H3', and C4'-H4' available from standard experiments, can be used to derive the five unknowns that define the local alignment tensor, thereby simultaneously providing information on relative orientation and dynamics of the ribose units. Data indicate rather uniform alignment for all stem nucleotides in the 24-nt stem-loop structure, with only a modest reduction in order for the terminal basepair, but significantly increased mobility in part of the loop region. The method is applicable to proteins, nucleic acids, and carbohydrates, provided 13C enrichment is available.     

Controlled direct synthesis of C-mono- and C-disubstituted derivatives of [3,3'-Co(1,2-C2B9H11)2]- with organosilane groups: theoretical calculations compared with experimental results

Mono- and dilithium salts of [3,3'-Co(1,2-C(2)B(9)H(11))(2)](-), (1(-)), react with different chlorosilanes (Me(2)SiHCl, Me(2)SiCl(2), Me(3)SiCl and MeSiHCl(2)) with an accurate control of the temperature to give a set of novel C(c)-mono- (C(c) = C(cluster)) and C(c)-disubstituted cobaltabis(dicarbollide) derivatives with silyl functions: [1-SiMe(2)H-3,3'-Co(1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))](-) (3(-)); [1,1'-mu-SiMe(2)-3,3'-Co(1,2-C(2)B(9)H(10))(2)](-) (4(-)); [1,1'-mu-SiMeH-3,3'-Co(1,2-C(2)B(9)H(10))(2)](-) (5(-)); [1-SiMe(3)-3,3'-Co(1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))](-) (6(-)) and [1,1'-(SiMe(3))(2)-3,3'-Co(1,2-C(2)B(9)H(10))(2)](-) (7(-)). In a similar way, the [8,8'-mu-(1',2'-C(6)H(4))-1,1'-mu-SiMe(2)-3,3'-Co(1,2-C(2)B(9)H(9))(2)](-) (8(-)); [8,8'-mu-(1',2'-C(6)H(4))-1,1'-mu-SiMeH-3,3'-Co(1,2-C(2)B(9)H(9))(2)](-) (9(-)) and [8,8'-mu-(1',2'-C(6)H(4))-1-SiMe(3)-3,3'-Co(1,2-C(2)B(9)H(9))(1',2'-C(2)B(9)H(10))](-) (10(-)) ions have been prepared from [8,8'-mu-(1',2'-C(6)H(4))-3,3'-Co(1,2-C(2)B(9)H(10))(2)](-) (2(-)). Thus, depending on the chlorosilane, the temperature and the stoichiometry of nBuLi used, it has been possible to control the number of substituents on the C(c) atoms and the nature of the attached silyl function. All compounds were characterised by NMR and UV/Vis spectroscopy and MALDI-TOF mass spectrometry; [NMe(4)]-3, [NMe(4)]-4 and [NMe(4)]-7 were successfully isolated in crystalline forms suitable for X-ray diffraction analyses. The 4(-) and 8(-) ions, which contain one bridging -mu-SiMe(2) group between each of the dicarbollide clusters, were unexpectedly obtained from the reaction of the monolithium salts of 1(-) and 2(-), respectively, with Me(2)SiHCl at -78 degrees C in 1,2-dimethoxyethane. This suggests that an intramolecular reaction has taken place, in which the acidic C(c)-H proton reacts with the hydridic Si-H, with subsequent loss of H(2). Some aspects of this reaction have been studied by using DFT calculations and have been compared with experimental results. In addition, DFT theoretical studies at the B3 LYP/6-311G(d,p) level of theory were applied to optimise the geometries of ions 1(-)-10(-) and calculate their relative energies. Results indicate that the racemic mixtures, rac form, are more stable than the meso isomers. A good concordance between theoretical studies and experimental results has been achieved.     

Studies toward the total synthesis of the cytotoxic sponge alkaloid pyrinodemin A

[structure: see text]. The syntheses of the proposed structure of pyrinodemin A (1) and its cis double bond positional isomer (C15'-C16') in racemic form are described. The key reaction involved an intramolecular nitrone/double bond cycloaddition. Our results suggest that neither 1 nor its double positional isomer is the correct structure of pyrinodemin A     

Synthesis of the C1'-C11' oxazole-containing side chain of leucascandrolide A. Application of a Sonogashira cross-coupling

An efficient, convergent synthesis of the C1'-C11' side chain (3) of leucascandrolide A (1) has been achieved. The key bond connection is made through the use of a palladium(0)-catalyzed Sonogashira cross-coupling between trifloyl oxazole (4) and alkynylmetal species (5).     

Total synthesis of 3',5'-C-branched nucleosides

[reaction: see text] A novel total synthesis of 3',5'-C-branched uridine azido acid has been accomplished using stereoselective aldehyde alkynylation, Ireland-Claisen rearrangement, and iodolactonization as the key reactions. Compared to traditional routes that start from carbohydrates, the present methodology is more efficient, flexible for future optimization, and provides access to both enantiomers of the products. Because the key chemistry does not involve the 3'- and 5'-C substituents, our route is a general approach to 3',5'-C alkyl nucleoside analogues.     

4 + 2]-annulations of chiral organosilanes: Application to the total synthesis of leucascandrolide A

Complete details of an asymmetric synthesis of leucascandrolide A (1) are described. The synthesis highlights the use of two diastereoselective [4 + 2]-annulations for the assembly of the functionalized bispyranyl macrolide 3. An efficient assembly and union of the oxazole-containing side chain 4 with macrolide 3 was carried out using a Mitsunobu reaction. A convergent route to the oxazole side chain was developed using a Sonogashira cross-coupling between 2-trifloyloxazole 16 and alkyne 17, which allowed for the installation of the C9'-C10' (Z)-olefin.     

Absolute configuration of scyphostatin

[reaction: see text] The absolute configuration of the side chain of scyphostatin (1) has been established. The chemical degradation of 1 gave 4 and 9, which correspond to the C7'-C12' and C13'-C16' fragments of the natural products, respectively. The spectroscopic data and [alpha]D values of both compounds were compared to those of authentic samples. The results show that the absolute configuration of 1 is 8'R,10'S,14'R.     

Carboracycles: Macrocyclic Compounds Composed of Carborane Icosahedra Linked by Organic Bridging Groups

A family of macrocyclic compounds are described, together with their precursors. These cycles are composed of icosahedral carboranes linked via their carbon vertices through 1,3-trimethylene, alpha,alpha'-1,3-xylylene, or alpha,alpha'-2,6-lutidylene groups. The compounds cyclo-(1,3-trimethylene-1',2'-closo-1',2'-C(2)B(10)H(10))(4) (6a), cyclo-(1,3-trimethylene-1',2'-closo-9',12'-dimethyl-1',2'-C(2)B(10)H(8))(4) (6b), cyclo-(1,3-trimethylene-1',2'-closo-1',2'-C(2)B(10)H(10))(3) (9), cyclo-(alpha,alpha'-1,3-xylylene-1',2'-closo-1',2'-C(2)B(10)H(10))(2) (11a), cyclo-(alpha,alpha'-1,3-xylylene-1',7'-closo-1',7'-C(2)B(10)H(10))(2) (11b), cyclo-(alpha,alpha'-1,3-xylylene-1',7'-closo-9',10'-dimethyl-1,7-C(2)B(10)H(8))(2) (11c), cyclo-(alpha,alpha'-1,3-xylylene-1',2'-closo-1',2'-C(2)B(10)H(10))(4) (12), cyclo-(alpha,alpha'-1,3-xylylene-1',7'-closo-1',7'-C(2)B(10)H(10))(3) (13), cyclo-(alpha,alpha'-2,6-lutidylene-1',7'-closo-1',7'-C(2)B(10)H(10))(2) (19), and cyclo-(alpha,alpha'-2,6-lutidylene N-oxide-1',7'-closo-1',7'-C(2)B(10)H(10))(2) (20) have been synthesized. The structures of 6a, 6b, 9, 11a, 11b, 11c, 12, and 19 have been determined by X-ray crystallography. Crystal data: for 6a, triclinic, space group P&onemacr;, a = 11.131(2) ?, b = 12.642(2) ?, c = 12.996(2) ?, alpha = 84.383(6) degrees, beta = 65.884(6) degrees, gamma = 97.292(5) degrees, Z = 1, R = 0.079; for 6b, monoclinic, space group P2(1)/a, a = 13.500(2) ?, b = 31.141(3) ?, c = 13.831(2) ?, beta = 99.90(1) degrees, Z = 2, R = 0.097; for 11a, monoclinic, space group C2/c, a = 14.5682(8) ?, b = 14.5046(8) ?, c = 16.1998(8) ?, beta = 95.631(2) degrees, Z = 4, R = 0.081; for 11b, monoclinic, space group P2(1)/n, a = 11.650(2) ?, b = 10.606(2) ?, c = 11.730(2) ?, beta = 104.951(6) degrees, Z = 2, R = 0.069; for 11c, orthorhombic, space group Pbca, a = 12.532(2) ?, b = 14.271(2) ?, c = 18.143(3) ?, Z = 4, R = 0.076; for 19, orthorhombic, space group Pcab (No. 61, standard setting Pbca), a = 11.0428(6) ?, b = 11.3785(6) ?, c = 22.533(1) ?, Z = 4, R = 0.074.     

Syntheses and structural and electrochemical characterizations of vanadatricarbadecaboranyl analogues of vanadocene and the structural characterization of the [Li(CH(3)CN)2+](6-CH(3)-nido-5,6,9-C(3)B(7)H(9-) tricarbadecaboranyl anion.

A single-crystal X-ray determination of the [Li(CH(3)CN)(2)(+)](6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-)) salt has shown that the 6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-) tricarbadecaboranyl anion has a nido-cage geometry based on an octadecahedron missing the unique six-coordinate vertex. The resulting six-membered open face is puckered, with two of the cage carbons (C6 and C9) occupying the low-coordinate cage positions above the plane of the four remaining atoms (C5, B7, B8, and B10). The Li(+) ion is centered over the open face and is solvated by two acetonitrile molecules. The reactions of the 6-CH(3)-nido-5,6,9-C(3)B(7)H(9)(-) anion with various vanadium halide salts, including VCl(4), VCl(3), and VBr(2), each resulted in the isolation of the same five paramagnetic products (2-6) of composition V(CH(3)-C(3)B(7)H(9))(2). X-ray crystallographic determinations of 2-5 showed that the complexes consist of two octadecahedral VC(3)B(7) fragments sharing a common vanadium vertex and established their structures as commo-V-(1-V-4'-CH(3)-2',3',4'-C(3)B(7)H(9))(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9)) (2), commo-V-(1-V-5'-CH(3)-2',3',5'-C(3)B(7)H(9))(1-V-4-CH(3)-2,3,4-C(3)B(7)H(9)) (3), commo-V-(1-V-5'-CH(3)-2',3',5'-C(3)B(7)H(9))(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9)) (4), and commo-V-(1-V-2-CH(3)-2,3,4-C(3)B(7)H(9))(2) (5). These complexes can be considered as tricarbadecaboranyl analogues of vanadocene, (eta(5)-C(5)H(5))(2)V. However, unlike vanadocene, these complexes are air- and moisture-stable and have only one unpaired electron. The five complexes differ with respect to one another in that they either (1) contain different enantiomeric forms of the CH(3)-C(3)B(7)H(9) cages, (2) have a different twist orientation of the two cages, or (3) have the methyl group of the CH(3)-C(3)B(7)H(9) cage located in either the 2 or 4 position of the cage. Subsequent attempts to oxidize the compounds with reagents such as Br(2) and Ag(+) were unsuccessful, illustrating the ability of the tricarbadecaboranyl anion to stabilize metals in low oxidation states. Consistent with this, both the electrochemical oxidation and the reduction of 2 were much more positive than those of the same oxidation state changes in vanadocene. The one-electron reduction of 2 is a remarkable 2.9 V positive of that of Cp(2)V.     

Catalytic, asymmetric synthesis of the C(1)(')-C(10)(') segment of pamamycin 621A

[reaction--see text] This paper describes a catalytic, asymmetric approach to the C(1)(')-C(10)(') segment of pamamycin 621A. We synthesize this segment in a convergent manner, with each of the coupling partners ultimately deriving from enantiomerically enriched methylketene dimer.     

Metallacarboranes as building blocks for polyanionic polyarmed aryl-ether materials

Polyanionic species have been obtained in high yield by a new route in the ring-opening reaction of cyclic oxonium [3,3'-Co(8-C4H8O2-1,2-C2B9H10)(1',2'-C2B9H11)] (2) by using carboxylic acids, Grignard reagents, and thiocarboranes as nucleophiles. The crystal structures of Na3(H2O)(C2H5OH)[1',3',5'-{3,3'-Co(8-O(CH2CH2O)2-1,2-C2B9H10)(1',2'-C2B9H11)}3-C6H3] and Na(H2O)[3,3'-Co(8-O(CH2CH2O)2C(O)CH3-1,2-C2B9H10)(1',2'-C2B9H11)] show that the chain contributes three or two oxygen atoms for coordination to Na(+), and interestingly, the [3,3'-Co(1,2-C2B9H11)2](-) moiety provides extra B-H coordination sites. These B-H...Na interactions in the solid state have also been confirmed by dynamic NMR studies in solution. These new polyanionic compounds that contain multiple carborane or metallacarborane clusters at their periphery may prove useful as new classes of boron neutron capture therapy compounds with enhanced water solubility and as a core to make a new class of dendrimers.     

Novel bicyclic nucleoside analogue (1S,5S,6S)-6- hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane: synthesis and incorporation into oligodeoxynucleotides

The novel bicyclic nucleoside (1S,5S,6S)-6-hydroxy-5-hydroxymethyl-1-(uracil-1-yl)-3,8-dioxabicyclo[3.2.1]octane [2'-deoxy-1'-C,4'-C-(2-oxapropano)uridine] (15), expected to be restricted into an O4'-endo furanose conformation, was synthesized from the known 1-(3'-deoxy-beta-D-psicofuranosyl)uracil 5. The phosphoramidite derivative of 15 was successfully incorporated into oligodeoxynucleotides using standard methods, and thermal denaturation studies showed moderate decreases in duplex stabilities of -2.1 and -1.5 degrees C per modification toward complementary DNA and RNA, respectively.     

Detailed mechanism for photoinduced cytosine dimerization: a semiclassical dynamics simulation

Semiclassical dynamics simulation is used to study dimerization of two stacked cytosine molecules following excitation by ultrashort laser pulses (25 fs fwhm, Gaussian, 4.1 eV photon energy). The initial excited state was found to form an ultrashort exciton state, which eventually leads to the formation of an excimer state by charge transfer. When the interbase distance, defined as an average value of C(5)-C(5)' and C(6)-C(6)', becomes less than 3 ?, charge recombination occurs due to strong intermolecular interaction, eventually leading to an avoided crossing within 20-30 fs. Geometries at the avoided crossing, with average intermolecular distance of about 2.1 ?, are in accord with CASSCF/CASPT2 calculations. Results indicate that the C(2)-N(1)-C(6)-C(5) and C(2)'-N(1)'-C(6)'-C(5)' dihedral angles' bending vibrations play a significant role in the vibronic coupling between the HOMO and LUMO, which leads to a nonadiabatic transition to the electronic ground state.     

Structural characterization of an anhydrous polymorph of paclitaxel by solid-state NMR

The three-dimensional structure of a unique polymorph of the anticancer drug paclitaxel (Taxol) is established using solid state NMR (SSNMR) tensor ((13)C & (15)N) and heteronuclear correlation ((1)H-(13)C) data. The polymorph has two molecules per asymmetric unit (Z' = 2) and is thus the first conformational characterization with Z' > 1 established solely by SSNMR. Experimental data are correlated with structure through a series of computational models that extensively sample all conformations. For each computational model, corresponding tensor values are computed to supply comparisons with experimental information which, in turn, establishes paclitaxel's structure. Heteronuclear correlation data at thirteen key positions provide shift assignments to the asymmetric unit for each comparison. The two distinct molecules of the asymmetric unit possess nearly identical baccatin III moieties with matching conformations of the C10 acetyl moiety and, specifically, the torsion angle formed by C30-O-C10-C9. Additionally, both are found to exhibit an extended conformation of the phenylisoserine sidechain at C13 with notable differences in the dihedral angles centered around the rotation axes of O-C13, C2'-C1' and C3'-C2'.     

Sulfanyl radical promoted C4'-C5' bond scission of 5'-oxo-3',4'-didehydro-2',3'-dideoxynucleosides

Treatment of C5'-aldehydes, under mildly basic conditions leads to the formation of 3',4'-didehydroaldehydes, and furfural. Sulfanyl radical addition eventually gives rise to the lactones, through C4'-C5' bond scission of the 1,2-dioxetane intermediates.