David E. Chavez

Highly Enantioselective Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of α,β‐Unsaturated Aldehydes

Simple, α,β-unsaturated aldehydes are excellent substrates in the hetero-Diels-Alder reaction with inverse electron demand, catalyzed by the Cr(III)-Schiff base complex I in the presence of 4-Ǻ molecular sieves and without solvent. The resulting dihydropyrans are obtained with high enantio- (89-98% ee) and diastereoselectivity (> 95% de) and in good yields (40-95%).

Total Synthesis of Fostriecin (CI-920)**

Fostriecin (CI-920, 1; see Scheme 1) is a structurally interesting antitumor agent that was first isolated in 1983 by scientists at Warner Lambert-Parke Davis.[1] It displays in vitro activity against a broad range of cancerous cell lines as well as in vivo antitumor activity,[2] and it appears to operate by a novel mechanism involving inhibition of the mitotic entry checkpoint.[3] In this context, fostriecin is a potent inhibitor of protein serine/threonine phosphatases, and it is in fact the most selective protein phosphatase inhibitor identified to date (104 times greater affinity for the protein phosphatases PP2A and PP4 versus PP1).[4] It was not until 1997 that a correct and complete stereochemical assignment of fostriecin was made by Boger and coworkers,[5] and that was followed very recently by a report of the first total synthesis from the same group.[6] Certainly, the development of a practical synthetic route to fostriecin is warranted based on its interesting biological properties. In addition, clinical trials carried out at the National Cancer Institute were halted early in Phase I over concerns about the stability and purity of the natural material.[7] A flexible synthetic route to 1 could serve as a basis for the discovery of analogues with similar biological but more desirable physical properties. In addition, the structure of fostriecin poses an assortment of interesting challenges to an efficient synthetic design, including the presence of the unsaturated lactone,[8] the C8 ± C11 triol monophosphate component, and the conjugated Z,Z,E-trienol unit. Herein we report a new total synthesis of fostriecin. Our approach integrates highly effective asymmetric catalytic reactions to generate key chiral building blocks, and efficient coupling reactions to enable their convergent assembly. The synthetic plan involves assembly of four fragments (2 ± 5) of similar complexity (Scheme 1). Epoxyketone 3 plays a central role in our strategy, serving not only as the source of

Energetic Chromophores: Low-Energy Laser Initiation in Explosive Fe(II) Tetrazine Complexes.

The synthesis and characterization of air stable Fe(II) coordination complexes with tetrazine and triazolo-tetrazine ligands and perchlorate counteranions have been achieved. Time-dependent density functional theory (TD-DFT) was used to model the structural, electrochemical, and optical properties of these materials. These compounds are secondary explosives that can be initiated with Nd:YAG laser light at lower energy thresholds than those of PETN. Furthermore, these Fe(II) tetrazine complexes have significantly lower sensitivity than PETN toward mechanical stimuli such as impact and friction. The lower threshold for laser initiation was achieved by altering the electronic properties of the ligand scaffold to tune the metal ligand charge transfer (MLCT) bands of these materials from the visible into the near-infrared region of the electromagnetic spectrum. Unprecedented decrease in both the laser initiation threshold and the mechanical sensitivity makes these materials the first explosives that are both safer to handle and easier to initiate than PETN with NIR lasers.

Laser Initiation of Fe(II) Complexes of 4-Nitro-pyrazolyl Substituted Tetrazine Ligands

The synthesis and characterization of new 1,2,4-triazolyl and 4-nitro-pyrazolyl substituted tetrazine ligands has been achieved. The strongly electron deficient 1,2,4-triazolyl substituted ligands did not coordinate Fe(II) metal centers, while the mildly electron deficient 4-nitro-pyrazolyl substituted ligands did coordinate Fe(II) metal centers in a 2:1 ratio of ligand to metal. The thermal stability and mechanical sensitivity characteristics of the complexes are similar to the conventional explosive pentaerythritol tetranitrate. The complexes had strong absorption in the visible region of the spectrum that extended into the near-infrared. In spite of having improved oxygen balances, increased mechanical sensitivity, and similar absorption of NIR light to recently reported Fe(II) tetrazine complexes, these newly synthesized explosives were more difficult to initiate with Nd:YAG pulsed laser light. Specifically, the complexes required lower densities (0.9 g/cm3) to initiate at the same threshold utilized to initiate previous materials at higher densities (1.05 g/cm3).

Two-Photon Absorption in Conjugated Energetic Molecules.

Time-dependent density functional theory (TD-DFT) was used to investigate the relationship between molecular structure and the one- and two-photon absorption (OPA and TPA, respectively) properties of novel and recently synthesized conjugated energetic molecules (CEMs). The molecular structures of CEMs can be strategically altered to influence the heat of formation and oxygen balance, two factors that can contribute to the sensitivity and strength of an explosive material. OPA and TPA are sensitive to changes in molecular structure as well, influencing the optical range of excitation. We found calculated vertical excitation energies to be in good agreement with experiment for most molecules. Peak TPA intensities were found to be significant and on the order of 10(2) GM. Natural transition orbitals for essential electronic states defining TPA peaks of relatively large intensity were used to examine the character of relevant transitions. Modification of molecular substituents, such as additional oxygen or other functional groups, produces significant changes in electronic structure, OPA, and TPA and improves oxygen balance. The results show that certain molecules are apt to undergo nonlinear absorption, opening the possibility for controlled, direct optical initiation of CEMs through photochemical pathways.