Claisen Self-Condensation of Lactones in the Synthesis of Ionizable Lipids.

The Claisen self-condensation of lactones can be carried out safely and efficiently under Mukaiyama conditions, in the presence of TiCl4 and triethylamine. The primary Claisen products can be elaborated to various derivatives or converted directly into dihydroxyketones. Such compounds are valuable educts for the synthesis of ionizable lipids for the delivery of nucleic acid therapeutics and can now be accessed through a concise, economical, scalable route that avoids more technically challenging reaction sequences.

Utility of 2-Diphenylphosphoryloxy-1,3-Dienes in Multicomponent Hetero-Diels-Alder Reactions to Construct Functionalized Six-Membered Nitrogen Heterocycles.

The utility of 2-diphenylphosphoryloxy-1,3-dienes for the construction of substituted six-membered nitrogen heterocycles is presented. These dienes undergo boron trifluoride-promoted aza-Diels-Alder reactions when reacted with imines or related species formed in situ using aldehydes and amine derivatives. The stability of the dienes allows this three-component reaction to be carried out with no special precautions to eliminate water or air. Thirty-one examples of this process are presented. The usefulness of the enol phosphate functional group is highlighted in further reactions after the cycloaddition step to generate functionalized piperidenes or pyridines.

Copper(I) Complexes of Pyridine-Bridged Phosphaalkene-Oxazoline Pincer Ligands.

The synthesis of enantiomerically pure pyridine-bridged phosphaalkene-oxazolines ArP═C(Ph)(2,6-C5H3NOx) (1, Ar = Mes/Mes*, Ox = CNOCH(i-Pr)CH2/CNOCH(CH2Ph)CH2) is reported. This new ligand forms a κ(P), κ(2)(NN) dimeric complex with copper(I) (7) that dissociates into a cationic κ(3)(PNN) monomeric complex upon addition of a neutral ligand {[1a·CuL]OTf (8a-e): L = PPh3 (a), P(OPh)3 (b), 2,6-lutidine (c), 4-DMAP (d), 1-methylimidazole (e)}. The P-Cu bond lengths in 8 are influenced by the π-accepting/σ-donating properties of L, and this can be observed by changes in the δ(31)PP═C NMR shift. The donor-acceptor properties in complexes of type 8 have also been investigated by UV/vis spectroscopy and density functional theory calculations.

Phosphaalkene-oxazoline copolymers with styrene as chiral ligands for rhodium(I).

The radical-initiated copolymerization of phosphaalkene-oxazoline, MesP[double bond, length as m-dash]C(Ph)CMe2Ox [1, Ox = CNOCH(iPr)CH2] with different loadings of styrene affords poly(methylenephosphine-co-styrene)s [2a (1 : S = 1 : 2): Mw = 7400 g mol(-1), PDI = 1.1; 2b (1 : S = 1 : 5): Mw = 18 000 g mol(-1), PDI = 1.2; 2c (1 : S = 1 : 10): Mw = 16 000 g mol(-1), PDI = 1.3]. Copolymers 2a-2c are demonstrated as viable macromolecular ligands for rhodium(i). By comparison with the crystallographically characterized model P,N-bidentate complex, [Mes(Me)P-CH(Ph)CMe2Ox·Rh(cod)]BF4, the polymer complexes [2·Rh(cod)]BF4 were prepared. The macromolecular metal complexes were characterized by GPC {for [2a·Rh(cod)]BF4: Mw = 14 000 g mol(-1), PDI = 1.2}, UV/Vis spectroscopy, (1)H, (13)C and (31)P NMR spectroscopy. Integration of the (31)P NMR spectra of mixtures of 2 and [Rh(cod)2]BF4 permitted the determination of the mol% of incorporation of monomer 1 in copolymer 2 (2a: 17%; 2b: 5%; 2c: 4%). These results compared favorably with those determined by elemental analysis (2a: 17%; 2b: 6%).

Annulated isoxazoles via [3 + 2] cycloaddition of alkenyl bromides and oximoyl chlorides and Ag(I) promoted elimination.

Substituted salicylaldehydes are converted to fused tetracyclic isoxazoles through a synthetic sequence incorporating substitution of 2-bromo-2-cyclohexen-1-ol, formation of an oxime function, conversion to an oximoyl chloride, intramolecular [3 + 2] cycloaddition, and elimination of an equivalent of hydrogen bromide using silver(I) carbonate. Six examples of this sequence are presented.

DMAP promoted tandem addition reactions forming substituted tetrahydroxanthones.

Substituted tetrahydroxanthones are constructed using a DMAP-promoted tandem nucleophilic addition process. The reaction yields range from 39% to 73%. Disubstituted tetrahydroxanthones are generated as a ∼2.3:1 mixture of diastereomers favoring the formation of the trans-isomer.

Paradoxical activation of an inwardly rectifying potassium channel mutant by spermine: "(b)locking" open the bundle crossing gate.

Intracellular polyamines are endogenous blockers of inwardly rectifying potassium (Kir) channels and underlie steeply voltage-dependent rectification. Kir channels with strong polyamine sensitivity typically carry a negatively charged side chain at a conserved inner cavity position, although acidic residues at any pore-lining position in the inner cavity are sufficient to confer polyamine block. We have identified unique consequences of a glutamate substitution in the region of the helix bundle crossing of Kir6.2. Firstly, glutamate substitution at Kir6.2 residue F168 generates channels with intrinsic inward rectification that does not require blockade by intracellular polyamines or Mg(2+). In addition, these F168E channels exhibit a unique "spiked" tail phenotype, whereby large decaying inward tail currents are elicited upon spermine unbinding. This contrasts with the time-dependent recovery of current typically associated with blocker unbinding from ion channels. Interestingly, Kir6.2[F168E] channels exhibit a paradoxical biphasic conductance-voltage relationship in the presence of certain polyamines. This reflects channel blockade at positive voltages, channel stimulation at intermediate voltages, and exclusion of spermine from the pore at negative voltages. These features are recapitulated by a simple kinetic scheme in which weakly voltage-dependent spermine binding to a "shallow" site in the pore (presumably formed by the introduced glutamate at F168E) stabilizes opening of the bundle crossing gate. These findings illustrate the potential for dichotomous effects of a blocker in a long pore (with multiple binding sites), and offer a unique example of targeted modulation of the Kir channel gating apparatus.

Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3.

Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 µM in OCT1, ~170 µM in OCT2, and ~60 µM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine-like OCT-targeted drugs.

Total synthesis of cladoniamide G.

The total synthesis of cladoniamide G, a cytotoxic compound against MCF-7 breast cancer cells (10 µg/mL), was accomplished. Key steps in the sequence include oxidative dimerization of 3-acetoxy-5-chloroindole and a tandem process incorporating three steps: bimolecular carbonyl addition, lactam formation, and carbamate removal.

Enantiomerically pure phosphaalkene-oxazolines (PhAk-Ox): synthesis, scope and copolymerization with styrene.

The design of a synthetic route to a class of enantiomerically pure phosphaalkene-oxazolines (PhAk-Ox) is presented. The condensation of a lithium silylphosphide and a ketone (the phospha-Peterson reaction) was used as the P=C bond-forming step. Attempted condensation of PhC(=O)Ox (Ox = CNOCH(iPr)CH(2)) and MesP(SiMe(3))Li gave the unusual heterocycle (MesP)(2)C(Ph)=CN-(S)-CH(iPr)CH(2)O (3). However, PhAk-Ox (S,E)-MesP=C(Ph)CMe(2)Ox (1 a) was successfully prepared by treating MesP(SiMe(3))Li with PhC(=O)CMe(2)Ox (52 %). To demonstrate the modularity and tunability of the phospha-Peterson synthesis several other phosphaalkene-oxazolines were prepared in an analogous manner to 1 a: TripP=C(Ph)CMe(2)Ox (1 b; Trip = 2,4,6-triisopropylphenyl), 2-iPrC(6)H(4)P=C(Ph)CMe(2)Ox (1 c), 2-tBuC(6)H(4)P=C(Ph)CMe(2)Ox (1 d), MesP=C(4-MeOC(6)H(4))CMe(2)Ox (1 e), MesP=C(Ph)C(CH(2))(4)Ox (1 f), and MesP=C(3,5-(CF(3))(2)C(6)H(3))C(CH(2))(4)Ox (1 g). To evaluate the PhAk-Ox compounds as prospective precursors to chiral phosphine polymers, monomer 1 a and styrene were subjected to radical-initiated copolymerization conditions to afford [{MesPC(Ph)(CMe(2)Ox)}(x){CH(2)CHPh}(y)](n) (9 a: x = 0.13n, y = 0.87n; GPC: M(w) = 7400 g mol(-1) , PDI = 1.15).

Gold(I)-catalyzed intramolecular tandem addition/Friedel-Crafts reactions between acyclic enamides and 1-arylalkynes.

Electron-deficient acyclic enamine derivatives react with electron-rich 1-arylalkynes using cationic gold(I) species as catalysts in an intramolecular process to form annulated 1-amido-substituted indene derivatives as the major products. Yields for this process range between 21% and 98%. In some cases, a two-step process that includes a subsequent alkene isomerization is needed.

Chiral phosphaalkene-oxazoline ligands for the palladium-catalyzed asymmetric allylic alkylation.

Enantioselective catalysis in moderate to excellent yields and ee's has been accomplished using a phosphaalkene-based ligand system. Specifically, the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate using a chiral P(sp(2)),N(sp(2)) ligand proceeds with a variety of malonate nucleophiles in 73-95% yield (79-92% ee).

Enamides and enesulfonamides as nucleophiles: formation of complex ring systems through a platinum(II)-catalyzed addition/Friedel-Crafts pathway.

Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an 1-arylalkynyl fragment undergo a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to form nitrogen-containing polycyclic structures. Regioselectivity in the initial addition of the enesulfonamide or enamide nucleophile to the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation of products resulting from an initial 6-endo cyclization. Twenty-three examples of this process are presented.

A synthetic approach to the fusicoccane A-B ring fragment based on a Pauson-Khand cycloaddition/Norrish type 1 fragmentation.

A synthetic approach to the A-B ring system within the fusicoccane family of diterpenes is presented. Key steps in this approach are a diastereoselective Pauson-Khand reaction, a Norrish 1 photofragmentation, a Charette cyclopropanation, and a ring-closing metathesis process.

Synthetic studies toward halichlorine: complex azaspirocycle formation with use of an NBS-promoted semipinacol reaction.

The investigations of a synthetic route incorporating a NBS-promoted semipinacol rearrangement to the 6-azaspiro[4.5]decane fragment within halichlorine ( 1) are presented. A convergent approach was pursued, utilizing two chiral, enantiomerically enriched building blocks, 2-trimethylstannyl piperidene 10 and substituted cyclobutanone 19. Noteworthy synthetic operations in this study include the following: (a) a highly diastereoselective NBS-promoted semipinacol reaction that established four stereogenic centers in ketone 25 and (b) the use of a N- p-toluenesulfonyl-2-iodo-2-piperidene as a precursor to a basic organometallic reagent, which was critical to the success of the coupling of fragments 10 and 19.

Platinum(II)-catalyzed cyclizations forming quaternary carbon centers, using enesulfonamides, enecarbamates, or enamides as nucleophiles.

Cyclic enesulfonamides, enecarbamates, or enamides tethered to an alkyne cyclize readily with use of platinum(II) chloride. This reaction generates quaternary-substituted carbon centers within simple spiro-fused or more complex tri- and tetracyclic heterocyclic ring systems. The yields for this process range from 50% to 83%. [reaction: see text].

Pyrrole synthesis catalyzed by AgOTf or cationic Au(I) complexes.

Either silver trifluoromethanesulfonate or a mixture of gold(I) chloride, silver trifluoromethanesulfonate, and triphenylphosphine catalyze the formation of pyrroles from substituted beta-alkynyl ketones and amines. The reactions proceed by using 5 mol % of catalyst with yields of isolated pyrroles ranging from 13% to 92%. Sixteen examples are used to compare the effectiveness of each catalyst.

A synthetic approach toward nitiol: construction of two 1,22-dihydroxynitianes.

Synthetic work toward the total synthesis of nitiol has culminated in the construction of two epimeric hydroxylated derivatives, the 1,22-dihydroxynitianes. Key stereodefining steps in the construction of the A-ring fragment (13) were the use of a siloxy-epoxide rearrangement reaction, a Pauson-Khand reaction, a Norrish 1 photochemical cleavage reaction, and a highly regio- and stereoselective hydrostannylation reaction of an ynoate. The stereochemistry of the synthetically challenging C-ring fragment (20) was established using an Ireland-Claisen reaction and a Grubbs ring-closing metathesis process as key steps. The 12-membered B-ring of the nitiane skeleton was constructed using a copper-promoted Stille cross-coupling and a Kishi-Hiyama-Nozaki carbonyl addition reaction. Unfortunately, the carbonyl addition reaction produced hydroxyl functionality that could not be selectively removed. Consequently, a synthesis of epimeric 1,22-dihydroxynitianes, which are compounds that are structural hybrids of two natural products, nitiol and variculanol, was completed.