Flexible strategy for syntheses of spirooxindoles using palladium-catalyzed carbosilylation and Sakurai-type cyclization

The intramolecular carbosilylation of N-[2-(1,3-butenyl)aryl]carbamoyl chloride has been investigated. The reaction with hexamethyldisilane proceeds smoothly in the presence of a catalytic amount of [Pd(η(3)-allyl)Cl](2) to give oxindoles with an allylsilane functional group in good yield. The subsequent subjection of the products to a Sakurai-type reaction provides more advanced tricyclic spirooxindoles by controlling the stereochemistry of three contiguous stereogenic centers.     

Total synthesis of (+/-)-lysergic acid, lysergol, and isolysergol by palladium-catalyzed domino cyclization of amino allenes bearing a bromoindolyl group

Ergot alkaloids and their synthetic analogs have been reported to exhibit broad biological activity. We investigated direct construction of the C/D ring system of ergot alkaloids based on palladium-catalyzed domino cyclization of amino allenes. With this biscyclization as the key step, total synthesis of (+/-)-lysergic acid, (+/-)-lysergol, and (+/-)-isolysergol was achieved.     

Design, syntheses, and studies of supramolecular porphyrin-fullerene conjugates, using bis-18-crown-6 appended porphyrins and pyridine or alkyl ammonium functionalized fullerenes

Photoinduced electron-transfer processes in cis and trans functionalized bis-18-crown-6 porphyrin self-assembled with fullerene functionalized with pyridine or alkylammonium cation entities are reported. The structural integrity of the newly formed supramolecular conjugates was accomplished by optical absorption and emission, electron spray ionization mass, electrochemistry, and semiempirical PM3 calculations. A 1:2 stoichiometry of the supramolecular porphyrin:fullerene conjugates was deduced from these studies. The conjugates revealed stable "two-point"' binding involving metal-ligand coordination and alkylammonium cation-crown ether binding or only the latter type of binding depending upon the functionality of the fullerene and metal ion in the porphyrin cavity. The effect of the variation on free energy changes of charge separation and the charge recombination was achieved by varying the metal ion in the porphyrin cavity. The charge-separation rates (k(CS)) determined from the picosecond time-resolved emission studies were generally higher for the cis bis-crown functionalized porphyrins than those of the corresponding trans ones. A comparison of the k(CS) values reported earlier for 1:1 porphyrin-fullerene conjugates with a similar self-assembly mechanism suggested that employing a higher number of acceptor entities improves the electron-transfer rates. The calculated charge-recombination rates (k(CR)) were 2-3 orders of magnitude smaller than the k(CS) values, suggesting the occurrence of the charge recombination process in the Marcus inverted region. The lifetimes of the radical ion pair (tau(RIP)) ranged between 46 and 233 ns indicating charge stabilization in the studied conjugates.     

Divergent syntheses of L-733, 060 and CP-122721 from functionalized pieridinones made by one-pot tandem cyclization

An efficient diastereoselective approach to access trans-5-hydroxy-6-substituted 2-piperidinones skeleton has been developed through one-pot intramolecular tandem process of O-benzyl protected aldimine 11 with Grignard reagents. The diastereoselectivity of substitution at C-6 position of 2-piperidinone was controlled by α-benzyloxy group. In addition, the utility of this straightforward cascade process is demonstrated by the asymmetric syntheses of (+)-L-733, 060 (2) and its 2-substituted analogue 3, as well as (+)-CP-122721 (5).     

New stereo- and regiospecific synthesis of humulene by means of the palladium-catalyzed cyclization of haloalkenylboranes

We describe a new stereo- and regiospecific synthesis of humulene, the major sesquiterpene of hops, by means of the palladium-catalyzed cyclization of haloalkenylboranes derived from geranyl halides $\text{via}$ 4 principal steps.     

Total syntheses of (-)-methyl atis-16-en-19-oate, (-)-methyl kaur-16-en-19-oate, and (-)-methyl trachyloban-19-oate by a combination of palladium-catalyzed cycloalkenylation and homoallyl-homoallyl radical rearrangement

Asymmetric total syntheses of (-)-methyl atis-16-en-19-oate (1c), (-)-methyl kaur-16-en-19-oate (2c), and (-)-methyl trachyloban-19-oate (3c) have been achieved by employing a hybrid strategy of palladium-catalyzed cycloalkenylation and homoallyl-homoallyl radical rearrangement. The common synthetic intermediate 5 was prepared from 2-allylcyclohexanone (4) with 98% ee using d'Angelo's asymmetric Michael addition. A series of functional group modifications in 5 via palladium-catalyzed cycloalkenylation led to (+)-14, which had already been prepared by us as racemate. (-)-Methyl atis-16-ene-19-oate (1c) was generated via homoallyl-homoallyl radical rearrangement. On the other hand, Wolff-Kishner reduction of 18 followed by esterification yielded (-)-methyl kaur-16-en-19-oate (2c) together with (-)-methyl trachyloban-19-oate (3c).     

New reagents for the synthesis of a series of ferrocenoyl functionalized copper and silver chalcogenolate complexes

A series of silylated ferrocenoyl chalcogenide reagents, FcC(O)ESiMe(3) (E = S, Se, Te; Fc = ferrocene), can be prepared in very good yield from FcC(O)Cl and LiESiMe(3). These reagents are used in the preparation of triphenylphosphine-ligated copper and silver ferrocenoyl thiolate and selenolate complexes, [M(4)(E{O}CFc)(4)(PPh(3))(4)], (M = Cu, Ag; E = S, Se) and [Cu(2)(mu-Se{O}CFc)(2)(PPh(3))(3)] from solubilized copper(i) and silver(i) acetate. The structures of these complexes have been determined via single-crystal X-ray diffraction. The driving force for these reactions is the thermodynamically favorable formation and elimination of AcOSiMe(3). The synthesis and characterization of both starting reagents and cluster complexes are discussed.     

New Heck coupling strategies for the arylation of secondary and tertiary amides via palladium-catalyzed intramolecular cyclization

A new synthetic protocol has been developed for the arylation of secondary and N-alkylated amide Heck precursors by the implementation of the palladium-catalyzed intramolecular Heck reaction strategies.     

Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.     

Regioselective C-H functionalization directed by a removable carboxyl group: palladium-catalyzed vinylation at the unusual position of indole and related heteroaromatic rings

The palladium-catalyzed oxidative vinylation of indole-3-carboxylic acids with alkenes effectively proceeds via directed C-H functionalization and decarboxylation to produce the corresponding 2-vinylated indoles. Similarly, pyrrole-, furan-, and thiophenecarboxylic acids also undergo decarboxylative vinylation.     

Convenient magnesiation of aromatic and heterocyclic rings bearing a hydroxy group in presence of LiCl

The reaction of various iodophenols with MeMgCl in presence of LiCl followed by the addition of i-PrMgCl provides the corresponding magnesiated magnesium phenolates as THF soluble reagents; this approach can be extended to heterocyclic compounds bearing a hydroxy group like pyridines and quinolines.     

A new solid phase approach for rapid syntheses of oligonucleotides bearing a 3′-terminal phosphate group

Synthesis of pentanucleotide ApTpCpTpTp containing a 3′-terminal phosphomonoester group was accomplished with the help of the new phosphate-solid phase link 2-(4-carboxyphenyl-mercapto)ethanol; a similar molecule, 2-benzylsulfonylethanol, revealed interesting features as a temporary 3′-phosphate protecting group.     

A dearomatizing, thionium ion cyclization for the synthesis of functionalized, azaspirocyclic cyclohexadienones

Thionium ions, generated by the addition of thiols to N-benzylglyoxamides, undergo a dearomatizing spirocyclization. The alkyl or arylsulfanyl group introduced during the thionium ion cyclization can act as a synthetic handle and a stereochemical control element during modifications of the azaspirocyclic frameworks (R(F) = CH(2)CH(2)C(8)F(17)).     

Highly selective cascade couplings for the syntheses of functionalized piperidinones and bispidines

Efficient cascade couplings to synthesize functionalized piperidinones 1 and bispidines 2 and 3 have been developed. Simple modifications to the reaction conditions allow for the highly controlled and selective formation of each compound. In addition, the cis isomer of 1 can be selectively obtained under acidic conditions, while the preparation of the corresponding trans isomer can also be readily realized through a base-catalyzed, dynamic crystallization-driven process.     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).     

The development of efficient protocols for the palladium-catalyzed cyclization reactions of secondary amides and carbamates

[formula: see text] With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamate precursors, offering significant improvements to currently existing methodology.     

(N,N-Diisopropylcarbamoyloxy)-methyl p-tolyl sulfone: preparation and application for the syntheses of 1,2-diols

1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-methane (CbOCH₂Ts, Cb=N,N-diisopropylcarbamoyl) was readily prepared from p-TolSH, paraformaldehyde and CbCl. With the dual activation of CbO- and Ts-substitutions, deprotonation of CbOCH₂Ts could be effected not only by n-BuLi, but also by Grignard reagents. Upon deprotonation, the title compound adds to various carbonyl structures. By choosing proper organometallic reagents for consecutive steps, the addition intermediate undergoes in situ conversions to efficiently yield regioselectively O-Cb protected and unprotected 1,2-diols.     

3-Methoxalylchromones--versatile reagents for the regioselective synthesis of functionalized 2,4'-dihydroxybenzophenones, potential UV-filters

The reaction of 1,3-bis-silyl enol ethers with 3-methoxalylchromones affords a great variety of functionalised 2,4'-dihydroxybenzophenones. These products are formed by a domino Michael/retro-Michael/Mukaiyama-aldol reaction. The synthesized compounds are promising candidates for the synthesis of the novel UV-A/B and UV-B filters.     

Synthesis, cellular uptake of, and cell photosensitization by a porphyrin bearing a quinoline group

A tetraphenyl porphine linked to a 7-chloroquinoline (5,10,15,20-tetraphenyl-1-3-[4-(4-aminobutyl)7-chloroquinoline] propioamidoporphine, TPPQ) was synthesized and examined as a potential photosensitizer for photodynamic therapy (PDT) of proliferative diseases. With respect to haematoporphyrin, TPPQ is a good in vitro photodynamic sensitizer producing singlet oxygen in 1% Triton X100 solutions. As with other hydrophobic porphyrins used in PDT, blood lipoproteins strongly bind TPPQ. Thus one low density lipoprotein (LDL) can incorporate 25 TPPQ molecules and 17 TPPQ molecules are taken up by one high density lipoprotein (HDL). Cell delivery of TPPQ using HDL or human serum albumin (HSA) as carrier is rather weak. However, an efficient TPPQ delivery to human skin fibroblasts is observed, partly aided by receptor-mediated endocytosis of LDL. Fluorescence spectroscopy shows that the cellular localization of TPPQ is both carrier and time dependent. During its delivery with LDL, TPPQ does not significantly impair the endocytosis of LDL-receptor complexes. After delivery with LDL, TPPQ is as efficient as other haematoporphyrin derivatives used in the PDT of cancers in photosensitizing human skin fibroblasts.     

Selective mono-alkylation and arylation of aromatic dihalides by palladium-catalyzed cross-coupling with the Grignard and organozinc reagents

Dibromobenzene, dibromothiophenes, dichloro- and dibromopyridine are highly selectively mono-alkylated and arylated with Grignard or organozinc reagents in the presence of palladium complexes as catalysts.