Stereoselective Synthesis of Pyrans from Epoxyalkenes: Dual Catalysis with Palladium and Brønsted Acid.

We describe regio- and stereoselective cycloisomerizations of alcohols tethered to epoxyalkenes, to construct alkene-substituted pyrans. These transformations are best catalyzed by Pd(PPh3)4 in the presence of phosphite ligands, and with diphenylphosphinic acid as an essential Brønsted acid cocatalyst for activation of the epoxyalkene.

Gram-scale, chemoselective synthesis of N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC).

N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) is a potent activator of the TrkB receptor in mammalian neurons and of interest because of its potential therapeutic uses. In the absence of a commercial supply of HIOC, we sought to produce several grams of material. However, a synthesis of HIOC has never been published. Herein we report the preparation of HIOC by the chemoselective N-acylation of serotonin, without using blocking groups in the key acylation step.

Stereospecific Cu(I)-Catalyzed C-O Cross-Coupling Synthesis of Acyclic 1,2-Di- and Trisubstituted Vinylic Ethers from Alcohols and Vinylic Halides.

CuI and trans-N,N'-dimethylcyclohexyldiamine catalyze the single-step C-O bond cross-coupling between 1,2-di- and trisubstituted vinylic halides with functionalized alcohols, producing acyclic vinylic ethers. This stereospecific transformation selectively gives each of the (E)- and (Z)-vinylic ether products from the corresponding vinyl halide precursors. This method is compatible with carbohydrate-derived primary and secondary alcohols and several other functional groups. The conditions are mild enough to reliably generate vinylic allylic ethers without promoting Claisen rearrangements.

A Tropomycin-Related Kinase B Receptor Activator for the Management of Ocular Blast-Induced Vision Loss.

Pressure waves from explosions or other traumatic events can damage the neurons of the eye and visual centers of the brain, leading to functional loss of vision. There are currently few treatments for such injuries that can be deployed rapidly to mitigate damage. Brain-derived neurotrophic factor (BDNF) and activation of its receptor tropomycin-related kinase B (TrkB) have neuroprotective effects in a number of degeneration models. Small molecule activators of TrkB, such as N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC), cross the blood-brain and blood-retina barriers after systemic administration. We characterize the effects of blast-induced ocular trauma on retinal and visual function. We show that systemic administration of HIOC, a potent small molecule activator of the BDNF/TrkB receptor, preserves visual function in mice exposed to ocular blast injury. The HIOC treatment for one week preserves visual function for at least four months. The HIOC treatment effectively protected vision when the initial dose was administered up to 3 h after blast, but not if the initial treatment was delayed for 24 h. We provide evidence that the therapeutic effect of HIOC is mediated by activation of BDNF/TrkB receptors. The results indicate that HIOC may be useful for managing ocular blast injury and other forms of traumatic optic neuropathy.

Biomimetic syntheses from squalene-like precursors: synthesis of ent-abudinol B and reassessment of the structure of muzitone.

We achieved the stereoselective syntheses of two different structural patterns corresponding to the enantiomers of the marine natural products abudinol B and muzitone, by developing two-directional tandem biomimetic cyclizations of polyepoxides of squalene analogues in which one alkene was functionalized as an enolsilane. In the course of this work, we demonstrated that the structure of muzitone was misassigned.

Total synthesis of the sphingolipid biosynthesis inhibitor fumonisin B(1).

The first total synthesis of the sphingolipid biosynthesis inhibitor fumonisin B(1) has been achieved. This convergent synthesis utilizes oxonia Cope rearrangements to prepare two key homoallylic alcohols, which are then functionalized to the primary components A and B for cross-coupling. Other highlights of our approach include a new and efficient synthesis of the diprotected tricarballylic acid C and a global deprotection strategy as the final step.

Stereo- and regioselective synthesis of squalene tetraepoxide.

Squalene tetraepoxide, a putative biosynthetic precursor to a variety of oxacyclic triterpenoid natural products, has been efficiently synthesized by anionic coupling of two farnesol-derived diepoxides, which have arisen from electronic control of the regioselectivity in organocatalytic enantioselective epoxidations.

Sequential exo-mode oxacyclizations for the synthesis of the CD substructure of brevenal.

We describe a novel strategy for synthesizing the CD bicyclic ether substructure of the fused polycyclic ether natural product brevenal. This product arises from a three-step sequence beginning with (1) regio- and diastereoselective iodoetherification of an acyclic diene-diol, followed by (2) alkene metathesis with an epoxyalkene synthon, concluding with (3) palladium-catalyzed cycloisomerization. Despite the modest yield and long reaction period for the cycloisomerization step, these studies provide valuable insights into the nature of byproducts generated and the mechanisms by which they form. This work demonstrates a portion of a larger synthetic strategy for constructing the pentacyclic core of brevenal from an acyclic precursor.

Alkynylation of Pentose Derivatives with Stereochemical Fidelity: Implications for the Regioselectivity of Alkynyl Diol Cycloisomerizations to Cyclic Enol Ethers.

This work characterizes a previously undetected epimerization in the preparation of alkynyl diols from pentose precursors utilizing the Ohira-Bestmann reagent. Lithium trimethylsilyldiazomethane (Colvin reagent) additions to the d-ribose and d-lyxose-derived benzylidene acetals provide the respective alkynyl diol stereoisomers, without epimerization. Regioselective tungsten-catalyzed cycloisomerizations of the d-ribose- and d-lyxose-derived alkynyl diols yield rigid bicyclic pyranose glycals, confirming the stereochemical fidelity of the Colvin alkynylation process.

Modular synthesis of the C9-C27 degradation product of aflastatin A via alkyne-epoxide cross-couplings.

A modular approach to the synthesis of complex polyketide natural products is demonstrated for the synthesis of the C9-C27 degradation product from aflastatin A. The product of the cross-coupling of C23-C27 terminal alkyne with C17-C22 epoxide underwent functionalization of the resulting internal alkyne, which was then coupled similarly with C9-C16 epoxide. This synthesis concluded with regio- and stereoselective addition of methyl onto the internal alkyne followed by stereoselective hydroboration-oxidation.

Stereo- and regioselective glycosylations to the bis-C-arylglycoside of kidamycin.

In explorations toward the total synthesis of the antitumor anthrapyran natural product kidamycin, the regioselective introduction of aminosugars angolosamine and vancosamine as C-arylglycosides has been accomplished onto hydroxylated anthrapyran aglycones. Specifically, the 9,11-dihydroxylated anthrapyran A undergoes sequential glycosylations with angolosamine synthon B and vancosamine synthon C to regio- and stereoselectively afford bis-C-glycoside D corresponding to the C-glycoside pattern of kidamycin.

Fischer carbene catalysis of alkynol cycloisomerization: application to the synthesis of the altromycin B disaccharide.

[reaction: see text] The tungsten-catalyzed cycloisomerization of alkynyl alcohols can be conducted without using photochemistry, using a stable tungsten Fischer carbene as the precatalyst for this transformation. A variety of alkynyl alcohols undergo cycloisomerization under these conditions to provide endocyclic enol ethers of five-, six-, and seven-membered ring sizes. The utility of this method is further demonstrated in the stereoselective synthesis of the disaccharide substructure of altromycin B.

Synthesis of the ABC Substructure of Brevenal by Sequential exo-Mode Oxacyclizations of Acyclic Polyene Precursors.

Exploratory studies on the sequential exo-mode oxacyclizations of acyclic polyene precursors have provided a substantial substructure of brevenal, including the fused tricyclic polyether with stereochemical patterns consistent with the AB and BC ring fusions. The synthesis of acyclic substrates featured two variations of Cr(II)/Ni(II) couplings for preparing 1,1-disubstituted allylic alcohols. A sequence of iodine-promoted cycloetherification, base-promoted intramolecular conjugate addition, and mercury-promoted cycloetherification produced the tricyclic substructure.

Synthesis of 1-deoxysphingosine derivatives with conformationally restricted pyrrolidinediol head groups.

[structure: see text] A family of cyclic 1-deoxysphingolipid derivatives of structure 4 has been designed and synthesized, which may serve as tumorigenesis suppressors for various cancers. Compound 4 is a second-generation analogue developed from sphingosine (1), in which a hydroxyl substituent is moved from C1 to C5 and a methylene is added for conformational rigidity between the C2-nitrogen substituent and C4. The synthetic chemistry for pyrrolidine ring closure at C3-C4 features ring-closing metathesis followed by hydroboration-oxidation.

Synthesis of the saccharomicin fucose-aglycon conjugate and determination of absolute configuration.

[reaction: see text] Schmidt glycosylation of the appropriately protected 3,4-dihydroxycinnamate methyl ester with 2,3,4-triacetoxyfucopyranosyltrichloroacetimidate gives aryl glycoside in high yield and diastereoselectivity. 2-Sulfation of fucose, installation of taurine, and global deprotection of the remaining protecting groups affords the fucose-aglycon conjugate of saccharomicin. This synthesis which arises from L-fucose also establishes the absolute configuration of the reducing terminus of the saccharomicin oligosaccharide.

Synthesis of the aglycones of altromycins and kidamycin from a common intermediate.

The aglycone structures 1 and 2, respectively corresponding to the antitumor antibiotic natural products altromycin and kidamycin, have been efficiently synthesized from a common advanced intermediate 3. A series of Claisen condensations and aromatizations affords the anthracene section of 3, followed by annulation of the pyrone ring. The functional groups of 3 can be manipulated for enantioselective introduction of the epoxide side-chain of altromycin aglycone 1, as well as synthesis of the kidamycin aglycone 2. [reaction: see text]

Synthesis of the branched C-glycoside substructure of altromycin B.

Tungsten-catalyzed cycloisomerization of alkynyl alcohols including 8 provides only the endocyclic enol ether (11) as a key intermediate for the branched C-glycoside substructure (2) of altromycin B. A sequence of Stille cross-coupling reaction and regio- and stereoselective functional group transformations affords each C13-diastereomer of the branched C-arylglycoside (2a and 2b). [reaction: see text]

1-Deoxy-5-hydroxysphingolipids as new anticancer principles: an efficient procedure for stereoselective syntheses of 2-amino-3,5-diols.

[reaction: see text]. Enantioselective preparation of the linear homoallylic alcohol I allows efficient formation of the 2-amino-3,5-diol moiety present in several biologically active compounds, including 1-deoxy-5-hydroxysphingosine analogue IV, which has exhibited excellent biological activity against colon cancer. The conversion of I into IV involves a sequence of enantioselective epoxidation of the O-tert-butoxycarbonyl derivative of I, followed by regioselective and stereospecific oxacyclization of II to introduce differentiated oxygens in III.

Stereoselective synthesis of L-oliose trisaccharide via iterative alkynol cycloisomerization and acid-catalyzed glycosylation.

[formula: see text] The synthesis of an all-alpha L-oliose diastereomer of digitoxin provides valuable insights into the generality and protective-group dependence of acid-catalyzed glycosylations of glycals to 2-deoxycarbohydrates.

Stereoselective synthesis of d-desosamine and related glycals via tungsten-catalyzed alkynol cycloisomerization.

Stereoselective synthesis of d-desosamine diacetate ester (iii, R = Ac) was achieved from the glycal (ii). generated by tungsten carbonyl-catalyzed cycloisomerization of the corresponding amino-alkynol (i). A wide variety of N-substituents (R, R') are compatible with the cycloisomerization, provided that at least one R or R' is an acyl derivative.