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).     

Convergent assembly of the spiroacetal subunit of didemnaketal B

A highly convergent synthesis of the C9-C28 spiroacetal subunit of didemnaketal B has been accomplished. Assembly of the C9-C15 alkylborate and C16-C21 enol phosphate by means of Suzuki-Miyaura coupling and acid-catalyzed cyclization of the derived dihydroxy enol ether enabled a rapid and efficient construction of the spiroacetal subunit. The C22-C28 side chain was incorporated via Nozaki-Hiyama-Kishi coupling to complete the synthesis.     

Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B

The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.     

A nonsymmetric pincer-catalyzed Suzuki-Miyaura arylation of benzyl halides and other nonactivated unusual coupling partners

The catalytic activity of a PCN-type palladium pincer complex is evaluated in the construction of C(sp(2))-C(sp(2)) and C(sp(2))-C(sp(3)) bonds by Suzuki-Miyaura cross-couplings employing nontypical substrates such as benzyl halides, alpha-haloenones, or alkylboronic acids as coupling partners. Most of the reported reactions are achieved in aqueous media, with all of the advantages implied.     

Total syntheses of epothilones B and d

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.     

Nitrosylated iron-thiolate-sulfinate complexes with {Fe(NO)}6/7 electronic cores: relevance to the transformation between the active and inactive NO-bound forms of iron-containing nitrile hydratases

The five-coordinated iron-thiolate nitrosyl complexes [(NO)Fe(S,S-C6H3R)2]- (R = H (1), m-CH3 (2)), [(NO)Fe(S,S-C6H2-3,6-Cl2)2]- (3), [(NO)Fe(S,S-C6H3R)2]2- (R = H (10), m-CH3 (11)), and [(NO)Fe(S,S-C6H2-3,6-Cl2)2]2- (12) have been isolated and structurally characterized. Sulfur oxygenation of iron-thiolate nitrosyl complexes 1-3 containing the {Fe(NO)}6 core was triggered by O2 to yield the S-bonded monosulfinate iron species [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]- (R = H (4), m-CH3 (5)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2(2-) (6), respectively. In contrast, attack of O2 on the {Fe(NO)}7 complex 10 led to the formation of complex 1 accompanied by the minor products, [Fe(S,S-C6H4)2]2(2-) and [NO3]- (yield 9%). Reduction of complexes 4-6 by [EtS]- in CH3CN-THF yielded [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]2- (R = H (7), m-CH3 (8)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2- (9) along with (EtS)2 identified by 1H NMR. Compared to complex 10, complexes 7-9 with the less electron-donating sulfinate ligand coordinated to the {Fe(NO)}7 core were oxidized by O2 to yield complexes 4-6. Obviously, the electronic perturbation of the {Fe(NO)}7 core caused by the coordinated sulfinate in complexes 7-9 may serve to regulate the reactivity of complexes 7-9 toward O2. The iron-sulfinate nitrosyl species with the {Fe(NO)}6/7 core exhibit the photolabilization of sulfur-bound [O] moiety. Complexes 1-4-7-10 (or 2-5-8-11 and 3-6-9-12) are interconvertible under sulfur oxygenation, redox processes, and photolysis, respectively.     

X-ray Structure of 1- (3' -Phenyl-4' -morpholinyl-2' 5' - dithiole-1' - ylidene)-3, 4-biscarboethoxy-2-thionaphthalene

1INTR0DUCTIONa-Thiocarbonylthioformamideshavebeensynthesizedsince1980[l-23,however,thereisn0reP0rtofthesecomP0undsrelatedtheirpropertiesandreactivities(3).Ac-cordingtothepublishedpapers('-",adithioketone,adithioesterandadithioth-ioesteraresnitablefort4 2JcycloadditionwithalkenicandacetylenicdienophileS.Wewanttoknowwhethera-thiocarbonylthioformamideshavethesamecharacters,thereforethereactionofathiobenzoylthioformmorpholine(1)withdiethylacetylenedicarboxylate(2)wasexplored.Theredultsshowth…     

Total synthesis of amphidinolide J

The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.     

Reversible and irreversible higher-order cycloaddition reactions of polyolefins with a multiple-bonded heavier group 13 alkene analogue: contrasting the behavior of systems with π-π, π-π*, and π-n+ frontier molecular orbital symmetry

The heavier group 13 element alkene analogue, digallene Ar(iPr(4))GaGaAr(iPr(4)) (1) [Ar(iPr(4)) = C(6)H(3)-2,6-(C(6)H(3)-2,6-(i)Pr(2))(2)], has been shown to react readily in [n + 2] (n = 6, 4, 2 + 2) cycloaddition reactions with norbornadiene and quadricyclane, 1,3,5,7-cyclooctatetraene, 1,3-cyclopentadiene, and 1,3,5-cycloheptatriene to afford the heavier element deltacyclane species Ar(iPr(4))Ga(C(7)H(8))GaAr(iPr(4)) (2), pseudoinverse sandwiches Ar(iPr(4))Ga(C(8)H(8))GaAr(iPr(4)) (3, 3(iso)), and polycyclic compounds Ar(iPr(4))Ga(C(5)H(6))GaAr(iPr(4)) (4) and Ar(iPr(4))Ga(C(7)H(8))GaAr(iPr(4)) (5, 5(iso)), respectively, under ambient conditions. These reactions are facile and may be contrasted with other all-carbon versions, which require transition-metal catalysis or forcing conditions (temperature, pressure), or with the reactions of the corresponding heavier group 14 species Ar(iPr(4))EEAr(iPr(4)) (E = Ge, Sn), which give very different product structures. We discuss several mechanistic possibilities, including radical- and non-radical-mediated cyclization pathways. These mechanisms are consistent with the improved energetic accessibility of the LUMO of the heavier group 13 element multiple bond in comparison with that of a simple alkene or alkyne. We show that the calculated frontier molecular orbitals (FMOs) of Ar(iPr(4))GaGaAr(iPr(4)) are of π-π symmetry, allowing this molecule to engage in a wider range of reactions than permitted by the usual π-π* FMOs of C-C π bonds or the π-n(+) FMOs of heavier group 14 alkyne analogues.     

Reactions of arachno-6,8-C2B7H12- with electron deficient olefins: syntheses of cyano-substituted carboranes

The syntheses of new cyano-substituted derivatives of arachno-6,8-C(2)B(7)H(13) have been achieved through the addition reactions of the arachno-6,8-C(2)B(7)H(12)(-) (1-) anion with cyano-activated olefins. The reaction of PSH+1- with tetracyanoethylene (TCNE) yielded the unusual bridging compound PSH(+)endo-6-endo-7-[micro(2)-(C(CN)(2))(2)]-arachno-6,8-C(2)B(7)H(12)(-) (PSH+2-)) resulting from cycloaddition of the TCNE at the C6-B7 edge of the anion. Consistent with its hypho skeletal electron count, an X-ray crystallographic study and DFT/GIAO calculations confirm 2(-) has a more open structure than 1-. The reaction of 1- with acrylonitrile resulted in the formation of endo-6-(NCCH(2)CH(2))-arachno-6,8-C(2)B(7)H(11)(-) (3-), which, upon acidification, afforded endo-6-(NCCH(2)CH(2))-arachno-6,8-C(2)B(7)H(12) (3) in high yield. X-ray crystallographic and DFT/GIAO studies established that the cyanoethyl fragment in 3 is substituted at the endo-position of the C6 cage-carbon. Heating 3 in THF at 50 degrees C or in toluene at 110 degrees C resulted in the quantitative isomerization of the cyanoethyl-substituent from the endo- to the exo-position at C6 to yield exo-6-(NCCH(2)CH(2))-arachno-6,8-C(2)B(7)H(12) (4). This is the first example of an endo to exo isomerization to be observed at a cage-carbon of a carborane. While heating 3 resulted in isomerization to 4, heating 3- in the presence of a small amount of 3 yielded the new ethylene-bridged 10-vertex tricarbaborane micro(6,9)-(CH(2)CH(2))-arachno-5,6,9-C(3)B(7)H(11) (5) resulting from reduction of the 3- pendant nitrile group, followed by deammination and carbon insertion.     

C?C Cross‐Coupling Reactions of O6‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O6‐Deprotection Procedure

Reaction conditions for the C? C cross‐coupling of O⁶‐alkyl‐2‐bromo‐ and 2‐chloroinosine derivatives with aryl‐, hetaryl‐, and alkylboronic acids were studied. Optimization experiments with silyl‐protected 2‐bromo‐O⁶‐methylinosine led to the identification of [PdCl₂(dcpf)]/K₃PO₄ in 1,4‐dioxane as the best conditions for these reactions (dcpf=1,1′‐bis(dicyclohexylphosphino)ferrocene). Attempted O⁶‐demethylation, as well as the replacement of the C‐6 methoxy group by amines, was unsuccessful, which led to the consideration of Pd‐cleavable groups such that C? C cross‐coupling and O⁶‐deprotection could be accomplished in a single step. Thus, inosine 2‐chloro‐O⁶‐allylinosine was chosen as the substrate and, after re‐evaluation of the cross‐coupling conditions with 2‐chloro‐O⁶‐methylinosine as a model substrate, one‐step C? C cross‐coupling/deprotection reactions were performed with the O⁶‐allyl analogue. These reactions are the first such examples of a one‐pot procedure for the modification and deprotection of purine nucleosides under C? C cross‐coupling conditions.     

Total synthesis of (−)-dictyostatin, a microtubule-stabilising anticancer macrolide of marine sponge origin

An efficient convergent synthesis of the anticancer marine macrolide (−)-dictyostatin is described that proceeds in 4.6% yield over 27 steps. Most of the stereocentres were configured using substrate control, making use of a common building block to install the C12-C14 and C20-C22 stereotriads, with a lactate boron aldol reaction employed to construct a C4-C10 β-ketophosphonate as utilised in the pivotal Still-Gennari HWE coupling step with a fully elaborated C11-C26 aldehyde. Following introduction of the (2Z,4E)-dienoate, a modified Yamaguchi macrolactonisation and deprotection delivered the requisite 22-membered macrocyclic lactone.     

Au(i)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide pyrazolo[1,5-a]pyridines

Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated adducts were further converted to 6-arylpyrazolo[1,5-a]pyridines via Suzuki-Miyaura coupling reaction and 6-cyanopyrazolo[1,5-a]pyridine by Ullmann condensation reaction. One of the cyclization adducts, 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine, was converted to a p38 kinase inhibitor, 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine, in two steps.     

Homodinuclear iron thiolate nitrosyl compounds [(ON)Fe(S,S-C6H4)2 Fe(NO)2]- and [(ON)Fe(SO2,S-C6H4)(S,S-C6H4)Fe(NO)2]- with {Fe(NO)}7-{Fe(NO)2}9 electronic coupling: new members of a class of dinitrosyl iron complexes

Reaction of Fe(CO)2(NO)2 and [(ON)Fe(S,S-C6H3R)2]- (R = H (1), CH3 (1-Me))/[(ON)Fe(SO2,S-C6H4)(S,S-C6H4)]- (4) in THF afforded the diiron thiolate/sulfinate nitrosyl complexes [(ON)Fe(S,S-C6H3R)2 Fe(NO)2]- (R = H (2), CH3 (2-Me)) and [(ON)Fe(S,SO2-C6H4)(S,S-C6H4)Fe(NO)2]- (3), respectively. The average N-O bond lengths ([Fe(NO)2] unit) of 1.167(3) and 1.162(4) A in complexes 2 and 3 are consistent with the average N-O bond length of 1.165 A observed in the other structurally characterized dinitrosyl iron complexes with an {Fe(NO)2}9 core. The lower nu(15NO) value (1682 cm(-1) (KBr)) of the [(15NO)FeS4] fragment of [(15NO)Fe(S,S-C6H3CH3)2 Fe(NO)2]- (2-Me-15N), compared to that of [(15NO)Fe(S,S-C6H3CH3)2]- (1-Me-15N) (1727 cm(-1) (KBr)), implicates the electron transfer from {Fe(NO)2}10 Fe(CO)2(NO)2 to complex 1-Me/1 may occur in the process of formation of complex 2-Me/2. Then, the electronic structures of the [(NO)FeS4] and [S2Fe(NO)2] cores of complexes 2, 2-Me, and 3 were best assigned according to the Feltham-Enemark notation as the {Fe(NO)}7-{Fe(NO)2}9 coupling (antiferromagnetic interaction with a J value of -182 cm(-1) for complex 2) to account for the absence of paramagnetism (SQUID) and the EPR signal. On the basis of Fe-N(O) and N-O bond distances, the dinitrosyliron {L2Fe(NO)2} derivatives having an Fe-N(O) distance of approximately 1.670 A and a N-O distance of approximately 1.165 A are best assigned as {Fe(NO)2}9 electronic structures, whereas the Fe-N(O) distance of approximately 1.650 A and N-O distance of approximately 1.190 A probably imply an {Fe(NO)2}10 electronic structure.     

二、三分枝甘露糖簇衍生物的合成

采取一种有效途径合成了二、三分支的甘露糖簇分子．甘露糖经烯丙苷化、乙 酰基保护后，将其烯丙基的双键氧化得到带有羧基连接臂的甘露糖衍生物，然后再 分别与l，6-己二胺和三(2-氨乙基)胺进行缩合反应，最后脱掉保护基，得到二分 枝甘露糖簇化合物6和三分枝甘露糖簇化合物8．     

4J(COCCH) and 4J(CCCCH) as probes of exocyclic hydroxymethyl group conformation in saccharides

[structure: see text] 1H NMR spectra of aldohexopyranosyl rings containing 13C-enrichment at either C1 or C3 reveal the presence of long-range 4J(C1,H6R/S) and 4J(C3,H6R/S) whose magnitudes depend mainly on the O5-C5-C6-O6 torsion angle. Using theoretical calculations (density functional theory, DFT; B3LYP/6-31G*) and conformationally constrained experimental model compounds, the magnitudes and signs of 4J(C1,H6R/S) and 4J(C3,H6R/S) have been established, and their dependencies on the geometry of the C1-O5-C5-C6-H6R/S and C3-C4-C5-C6-H6R/S coupling pathways, respectively, were determined. The latter dependencies mimic that observed previously for 4J(HH) in aliphatic compounds such as propane. DFT calculations also showed that inclusion of non-Fermi contact terms is important for accurate predictions of 4J(CH) values. Application to methyl alpha- and beta-D-glucopyranosides reveals different rotameric distributions about their hydroxymethyl groups, with the beta-anomer enriched in the gt rotamer, in agreement with recent multi-J redundant coupling analyses. 4J(C1,H6R/S) and 4J(C3,H6R/S) are expected to complement other recently developed J-couplings for the assignment of hydroxymethyl group conformation in oligosaccharides containing 1,6-glycosidic linkages.     

Transition metal mediated organic synthesis: The synthesis of moracin M.

The Palladium catalysed cross coupling of 2-halo- or metallo-benzofurans with both 5-metallo- or halo-resorcinol tricarbonyl chromium(O) complexes and the uncomplexed resorcinols, has been evaluated and in consequence, moracin M has been synthesised in good yield by the cross coupling of 6-(t-butyldiphenylsiloxy)-2-trimethylstannylbenzofuran with 5-iodoresorcinolbis(triisopropylsilyl) ether and fluoride ion deprotection of the product.     

Total synthesis of rhizoxin D,a potent antimitotic agent from the fungus Rhizopus chinensis

Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the beta carbon of the (Z)-alpha,beta-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired beta-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from delta-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.     

C60-induced alkyne-alkyne coupling and alkyne scission reactions of a tungsten tris(diphenylacetylene) complex

Reaction of W(NCMe)(η(2)-PhC≡CPh)(3) with C(60) affords W(η(3)-NC(Me)C(60))(η(4),η(2)-C(6)Ph(6)) (2) and W(≡CPh)(NCMe)(η(2)-C(60)) (η(3),η(2)-C(5)Ph(5)) (3). The hexaphenylbenzene species of 2 shows an η(4)-butadiene + η(2)-olefin bonding mode and the nitrile carbon is inserted into one 6:5-ring junction of C(60). Compound 3 contains an η(3),η(2)-pentaphenylcyclopentadienyl and a benzylidyne group from 2 + 2 + 1 cyclization and scission reactions of the diphenylacetylene ligands.