Chris P. Miller

A short, stereospecific synthesis of dihydrooxazoles from serine and threonine derivatives

Abstract Cyclization of serine and threonine derivatives with Burgess reagent provides a one-step, streospecific access to 4,5-dihydrooxazoles. Noteworthy features of this new methodology include mild experimental conditions, and the absence of β-lactam, aziridine, or dehydroamino acid side products.

An investigation of the Mitsunobu reaction in the preparation of peptide oxazolines, thiazolines, and aziridines

Abstract The diisopropyl azodicarboxylate-triphenylphosphine mediated cyclization of serine and allo-threonine derivatives provides peptide oxazolines, whereas cyclization of threonine containing substrates leads to N-acyl aziridines. In the thiopeptide series, only thiazolines are obtained. The presence of a moderately strong base is necessary for the formation of aziridines from threonine peptides.

Thiolysis of oxazolines: A new, selective method for the direct conversion of peptide oxazolines into thiazolines

A direct oxazoline→thiazoline conversion can be realized by thiolysis of oxazolines with H2S in methanol/triethylamine, followed by cyclodehydration with Burgess reagent. This protocol is high-yielding, chemoselective, and essentially free of racemization for C(5)-unsubstituted and trans-4,5-disubstituted peptide oxazolines. Thioamide intermediates are obtained regioselectively, thus the thiolysis of oxazolines offers an alternative to the thiation of peptides with Lawessons reagent.

Synthesis of Cyclopeptide Alkaloids by Cyclooligomerization of Dipeptidyl Oxazolines

Abstract Cyclodehydration of Cbz-valylthreonine methyl esters with Burgess reagent provides access to cis - and trans -oxazoline segments for cyclooligomerization reactions. The ratio of 12-, 18-, 24-, and larger-ring macrocycles obtained in this process is kinetically controlled and dependent on the relative stereochemistry of the backbone α-carbons. A network of bifurcated hydrogen bonds rigidifies the peptidyl oxazoline strand and positions the valine side chains in either pseudoaxial or pseudoequatorial orientations. In the former case, transannular strain prevents the formation of 12-membered cyclopeptide alkaloids. Several X-ray structures illustrate the conformational preferences in this family of marine natural product analogs.

A new synthesis of α-methylserine by nucleophilic ring-opening of N-sulfonyl aziridines☆

Abstract Conversion of tritylated 2-methylglycidol to the corresponding aziridine occurs by Staudinger cyclization of the intermediate azido alcohol. After N -sulfonylation with Ses-Cl and ring-opening with benzyl alcohol, oxidation of the primary alcohol provides N , O -bisprotected α-methylserine directly suitable for repetitive peptide synthesis. This sequence represents a general enantioselective protocol for the synthesis of α-methylserine and other α,α-disubstituted amino acids.

A highly efficient, one-pot synthesis of benzo[b]fluoren-10-ones

Abstract 5,11-Dioxa- and 5-oxa-11-thiabenzo[b]fluoren-10-ones were prepared via a one-pot procedure initiated by the reaction of salicylates or thiasalicylates with ortho fluoro-α-bromoacetophenones in the presence of cesium carbonate. The reactions proceeded in good yield and the final products were obtained without chromatography. The reaction presumably proceeds via a sequential intermolecular alkylation, intramolecular acylation sequence concluded by an intramolecular, ipso-fluoro substitution.

Chapter 15. Targeting the estrogen receptor with SERMs

Publisher Summary This chapter describes the targeting of the estrogen receptor with selective estrogen receptor modulators (SERMs). Most non-steroidal selective estrogens share a common pharmacophore consisting of two aryl groups separated by two atoms, often in a stilbene type arrangement. SERMs typically bear a third aryl group possessing a 4-aminoethoxy substitution. It has been demonstrated that small structural modifications to SERM molecules often results in large differences in both in vitro and in vivo potency as well as tissue selectivity. The 2-phenyl substituted indole has been used as a non-steroidal estrogen scaffold. Conversion of these indole estrogen agonists to compounds with improved selectivity profiles was accomplished through the introduction of aliphatic side chains originating from the 1-position and often terminating with amines, such as ZK-119010. The approval of raloxifene for the treatment and prevention of osteoporosis in postmenopausal women illustrates the value of SERMs for the treatment of at least one of the maladies associated with this patient population.

A simplified route to a key intermediate in the synthesis of the Chinese nootropic agent huperzine A

An efficient one-pot, three-component process for the preparation of 2-pyridones from a carbonyl compound, ammonia, and methyl propiolate has been found which provides ready access to a key intermediate in the synthesis of huperzine A.