Alan C. Spivey

Catalysis of the Asymmetric Desymmetrization of Cyclic Anhydrides by Nucleophilic Ring-Opening with Alcohols

The single symmetry-breaking transformation of a relatively simple meso compound can provide highly expedient access to a wide variety of usefully functionalized chiral building blocks. Recent advances in asymmetric desymmetrization, through the development of tertiary amines as nonenzymatic catalysts for the ring opening of meso cyclic anhydrides with alcohols [for example, see Eq. (1)], are discussed here.

ASYMMETRIC CATALYSIS OF ACYL TRANSFER BY LEWIS ACIDS AND NUCLEOPHILES. A REVIEW

INTRODUCTION .............................................................................................................................. 333 I. CHIRAL LEWIS ACID CATALYSIS ........................................................................................ 334 11. CHIRAL NUCLEOPHILE CATALYSIS ................................................................................. 338 CONCLUSIONS ................................................................................................................................ 3.56 REFERENCES ................................................................................................................................... 3.57

SYNTHESIS OF ATROPISOMERIC ANALOGUES OF DMAP

Abstract A method for the preparation of 7-aryl derivatives ofN-methyl-5-azaindoline involving Suzuki cross-coupling is described. Certain biaryls prepared in this manner exhibit atropisomerism. In particular, azaindoline11 is shown to be configurationally stable at room temperature and to catalyse efficiently the esterification of 1-methylcyclohexanol with Ac2O.

Enantioselective Desymmetrization of meso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of Polyhydroxylated Celastraceae Sesquiterpene Cores

Crude plant extracts of the Celastraceae have been valued since antiquity for their stimulant, appetite suppressive, antiarthritic, antibacterial, insect repellent, and memoryrestorative properties.[1] Pervasive among the secondary metabolites isolated from this class of plants is a large family of polyhydroxylated sesquiterpene esters having a dihydro-bagarofuran skeleton.[2] Many members of this family, particularly esters of three polyhydroxylated agarofurans: euonyminol, 4b-hydroxyalatol, and 14-deoxyalatol, exhibit significant biological activity. These include: triptogelins A-1/A-6[3a] and celhin A[3b] (antitumor), wilfortrine[4] (immunosuppressive), wilforine[5] (insecticidal), and celangulin[6a] and cathedulins E-3/E-4/E-5[6b] (insect antifeedant). Additionally, hypoglaunine B and related macrocyclic lactone derivatives of euonyminol have recently been shown to display significant anti-HIV activity[7] (Scheme 1).

Study of the influence of the non-pyridyl nitrogen hybridisation on the stability of axially chiral analogues of 4-(dimethylamino)pyridine (DMAP)

Abstract This study investigates and explains the differences in rotational energy barriers between two series of atropisomeric biaryl derivatives of DMAP, using computational methods to determine the rotational energy barriers of a large number of compounds. A theoretical investigation of the rotational barriers of an asymmetric nucleophilic catalyst determined the most configurationally stable DMAP analogue. The rotational barriers of DMAP derivatives are from ab initio RHF/STO-3G (for conjugated amines), and semi-empirical PM3 calculations. The enantiomerisation energies are from energy scans around the Ar–Ar bond of each molecule, and are then compared to experiment. The theoretical rotational energies, for each series of DMAP derivatives, show a trend within the series. This allows prediction of the rotational energies for compounds, which have not been determined experimentally. The calculations show that the difference in barriers to rotation, between the series, reflects the difference in hybridisation of the non-pyridyl nitrogen in the transition state structures.

Atropisomeric α-methyl substituted analogues of 4-(dimethylamino)pyridine: synthesis and evaluation as acyl transfer catalysts

The regioselectivity of α-metalation–methylation of N-BF3 adducts of 4-(dimethylamino)pyridines as a function of β-substitution is examined in attempts to prepare configurationally stable atropisomeric derivatives (I and II) having an α-methyl substituent and a β-biaryl stereogenic axis. The activity of some of these derivatives as catalysts for acyl transfer is examined and the kinetic resolution of 1-(1-naphthyl)ethanol catalysed by α-methyl chiral DMAP (−)-24 is reported. A rationale for the reduced stereoselectivity of this catalyst relative to its non-α-substituted analogue (−)-1 is also proposed.

The Importance of Lys-352 of Human Immunoglobulin E in FcϵRII/CD23 Recognition

The interaction of immunoglobulin E (IgE) with its low affinity receptor (FcϵRII/CD23) plays a central role in the initiation and regulation of type I hypersensitivity responses. We have previously identified the importance of amino acid residues in the A-B loop of the Cϵ3 domain of human IgE and implicated a region close to the glycosylation site at asparagine 371 as contributing to IgE-CD23 interaction. These residues were now targeted by site-directed mutagenesis. The IgE-CD23 interaction was assessed by semiquantitative flow cytometry. Replacement of the entire Cϵ3 A-B loop (residues 341–356) with the homologous rat IgE sequence resulted in complete loss of human CD23 recognition, as did replacement of residues 346–353, indicating that class-specific effector residue(s) are contained within these eight amino acids. Lysine 352 within the A-B loop was identified as contributing directly to human CD23 interaction. Mutation to the rodent homologue glycine or glutamate resulted in a significant reduction in binding compared with native IgE, whereas conservative substitution with arginine effected a small, but statistically significant, enhancement of CD23 binding. Mutation of the Cϵ3 glycosylation site at asparagine 371 to threonine or glutamine did not significantly affect CD23 recognition. Our results yield new insights into the structural basis of the hIgE-CD23 interaction and hold promise for the rational design of drugs that can manipulate IgE-mediated regulation of the allergic response.

Synthesis of C2-symmetric analogues of 4-(pyrrolidino)pyridine: new chiral nucleophilic catalysts

The syntheses of a series of enantiomerically pure C2-symmetric 4-(pyrrolidino)pyridine (PPY) derivatives by SNAr of 4-halo-/4-phenoxypyridines and by cyclocondensation from 4-aminopyridine are described. Preliminary results pertaining to their use as catalysts for acylative kinetic resolution of 1-phenylethanol are also presented. A single-crystal X-ray analysis of PPY If is reported.

A new germanium based linker for solid phase synthesis of aromatic compounds

An efficient three-step synthesis of germyl linker precursor 4 is described which enables a simple two step immobilisation of lithiated aromatics to Argogel™ polymer; cleavage from the polymer support via ipso-degermylation with TFA, ICl, Br2 and NCS provides protio-, iodo-, bromo- and chloro- aryls, respectively.

Structure/function studies on IgE as a basis for the development of rational IgE

Since the discovery of antibodies of the immunoglobulin (1g)E isotype some 30 years ago,. their pivotal role in mediating type I hypersensitivity responses has been extensively documented (1, 2). In normal adults, the plasma levels of IgE rarely exceed 100 pg/l, but are elevated in allergic and parasitic disease, and compelling evidence suggests that an IgE response protects against parasitic infestations (3-5). In industrialized societies and in developing countries, the incidence of allergic and asthmatic disorders has dramatically increased during this century, particularly over the past three decades. Epidemiologic surveys indicate that allergic manifestations now afflict more than a quarter of the population in industrialized countries, with 10% of children suffering from asthmatic airway inflammation (6, 7). Pollutants in the air such as diesel exhaust particles, and oxygen radicals produced by engine emissions or cigarette smoke have been implicated as adjuvants, enhancing IgE synthesis (8, 9), Other observations point to a connection between the decline of infectious diseases and the rise in allergic manifestations (10). Furthermore, repeated exposure to substances at the workplace can lead to the development of allergies. Agricultural workers show adverse responses to a widely ranging number of plant and animal allergens, bakers asthma is a well-documented occupational hazard, latex hypersensitivity in health-care workers has become a serious problem in recent years, and employees in the detergent industry report a high incidence of allergic reactions to biologic detergents (11). The socioB. A. Helm, 1. Sayers, E. A. Padlan, J. E. McKendrick3, A. C. Spive