Pavel Nagorny

Chiral Phosphoric Acid-Catalyzed Enantioselective and Diastereoselective Spiroketalizations

Catalytic enantioselective and diastereoselective spiroketalizations with BINOL-derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions.

Toward Fully Synthetic Homogeneous β-Human Follicle-Stimulating Hormone (β-hFSH) with a Biantennary N-Linked Dodecasaccharide. Synthesis of β-hFSH with Chitobiose Units at the Natural Linkage Sites

A highly convergent synthesis of the sialic acid-rich biantennary N-linked glycan found in human glycoprotein hormones and its use in the synthesis of a fragment derived from the beta-domain of human Follicle-Stimulating Hormone (hFSH) are described. The synthesis highlights the use of the Sinay radical glycosidation protocol for the simultaneous installation of both biantennary side-chains of the dodecasaccharide as well as the use of glycal chemistry to construct the tetrasaccharide core in an efficient manner. The synthetic glycan was used to prepare the glycosylated 20-27aa domain of the beta-subunit of hFSH under a Lansbury aspartylation protocol. The proposed strategy for incorporating the prepared N-linked dodecasaccharide-containing 20-27aa domain into beta-hFSH subunit was validated in the context of a model system, providing protected beta-hFSH subunit functionalized with chitobiose at positions 7 and 24.

Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: In vivo and mechanistic studies on the migrastatin core ether analog

A significantly simpler analog of the natural product migrastatin, termed migrastatin ether (ME), has been prepared and evaluated. Both in vivo and in vitro studies indicate that ME exhibits a concentration-dependent inhibitory effect on migration of breast cancer cells.

Recent Advances in the Synthesis of Natural 2-Deoxy-β-glycosides

This report provides an overview of the recent synthetic efforts directed toward the assembly of complex 2-deoxy-β-glycoside-containing natural products landomycin A, apoptolidin A, digitoxin, lomaiviticin A, incednine, and versipelostatin. In particular, the intention of this review is to cover the work published since the earlier reports on this topic by Lowary and Hou (2009) and Franck and Marzabadi (2000).

Chiral Phosphoric Acid Directed Regioselective Acetalization of Carbohydrate-Derived 1,2-Diols†

In control: A chiral phosphoric acid catalyst significantly enhances or completely overrides the inherent regioselective acetalization profiles exhibited by monosaccharide-derived 1,2-diol substrates. This study represents the first example of chiral-catalyst-directed regio- and enantioselective intermolecular acetalizations, which are complementary to existing methods for substrate-controlled functionalization of polyols.

Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin

Migrastatin is a biologically active natural product isolated from Streptomyces that has been shown to inhibit tumor cell migration. Upon completion of the first total synthesis of migrastatin, a number of structurally simplified analogs were prepared. Following extensive in vitro screening, a new generation of analogs was identified that demonstrates substantially higher levels of in vitro inhibitory activity, stability and synthetic accessibility when compared to the parent natural product. Herein, we describe two promising ether-derivative analogs, the migrastatin core ether (ME) and the carboxymethyl-ME (CME), which exhibit high efficacy in blocking tumor cell migration and metastasis in lung cancer. These compounds show an in vitro migration inhibition in the micromolar range (IC50: ME 1.5 to 8.2 μM, CME 0.5 to 5 μM). In a human small-cell lung carcinoma (SCLC) primary xenograft model, ME and CME compounds were found to be highly potent in inhibiting overall metastasis even at the lowest dosage used (degree of inhibition: 96.2% and 99.3%, respectively). Together these very encouraging findings suggest that these analogs have promise as potent antimetastatic agents in lung cancer.

Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S(N)1-like, S(N)2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = -2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value.

Total Synthesis of the α-Subunit of Human Glycoprotein Hormones: Toward Fully Synthetic Homogeneous Human Follicle-Stimulating Hormone

Described herein is the first total chemical synthesis of the unique α-subunit of the human glycoprotein hormone (α-hGPH). Unlike the biologically derived glycoprotein hormones, which are isolated as highly complex mixtures of glycoforms, α-hGPH obtained by chemical synthesis contains discrete homogeneous glycoforms. Two such systems have been prepared. One contains the disaccharide chitobiose at the natural N-glycosylation sites. The other contains dodecamer oligosaccharides at these same sites. The dodecamer sugar is a consensus sequence incorporating the key features associated with human glycoproteins.

Thiophosphoramide‐Based Cooperative Catalysts for Brønsted Acid Promoted Ionic Diels–Alder Reactions

Significance: The Nagorny group reports an ionic [4+2] cycloaddition between α,β-unsaturated acetal dienophiles 1 and dienes 2 to afford Diels–Alder adducts 3 in moderate to excellent yields. The reaction is promoted by a cooperative catalytic system involving a strong Brønsted acid [PTSA (p-toluenesulfonic acid)] and a triple hydrogen bond donor thiophosphoramide (A). NMR and computational studies suggest that the key feature of the catalytic system is the strong interaction between A and the sulfonate anion. Comment: Ionic [4+2] cycloadditions (Gassman’s cycloadditions) have proven to be efficient complements to traditional Diels–Alder reactions when challenging unactivated substrates are involved. The authors report a variety of these reactions, which interestingly do neither require a Lewis acid nor a highly ionic medium for the generation of the reactive separated ion pair. The same objective is achieved by a cooperative catalytic system in which the sulfonic acid generates the oxocarbenium species and in which the thiophosphoramide co-catalyst ensures the formation of separated, highly reactive counterions via three hydrogen bonds to the sulfonate anion. PhMe, 0 °C

On the emerging role of chemistry in the fashioning of biologics: synthesis of a bidomainal fucosyl GM1-based vaccine for the treatment of small cell lung cancer.

The synthesis of the novel small cell lung cancer (SCLC) fucosyl GM1-based vaccine construct, featuring insertion of the HLA-DR binding 15 amino acid sequence derived from Plasmodium falciparum, is described. The resultant glycopeptide has been synthesized in an efficient manner. Finally, successful conjugation of the glycopeptide to the keyhole limpet hemocyanin (KLH) carrier protein completed the preparation of the vaccine.