Almost one-third of all proteases can be classified as serine proteases, named for the nucleophilic Ser residue at the active site. This mechanistic class was originally distinguished by the presence of the AspHis-Ser “charge relay” system or “catalytic triad”.1 The Asp-His-Ser triad can be found in at least four different structural contexts, indicating that this catalytic machinery has evolved on at least four separate occasions.2 These four clans of serine proteases are typified by chymotrypsin, subtilisin, carboxypeptidase Y, and Clp protease (MEROPS nomenclature;3 Table 1). More recently, serine proteases with novel catalytic triads and dyads have been discovered, including Ser-His-Glu, Ser-Lys/His, His-Ser-His, and N-terminal Ser.2 Several of these novel serine proteases are subjects of accompanying articles in this issue. This article will review recent work on the mechanism and specificity of chymotrypsin-like enzymes, with the occasional references to pertinent experiments with subtilisin. Chymotrypsin-like proteases are the most abundant in nature, with over 240 proteases recognized in the MEROPS database.3 * E-mail: hedstrom@brandeis.edu; phone: 781-736-2333; FAX: 781-736-2349. 4501 Chem. Rev. 2002, 102, 4501−4523

Serine protease mechanism and specificity

Molecular recognition of protein-ligand complexes : applications to drug design

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking University, 202 Chengfu Road, 098#, Beijing 100871, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 200060, China

Transition-Metal-Free Coupling Reactions

Tosylhydrazones are useful synthetic intermediates that have been used in organic chemistry for almost 60 years. The recent discovery of a palladium-catalyzed cross-coupling reaction involving a tosylhydrazone coupling partner has triggered renewed interest in these reagents. This reaction shows nearly universal generality with regard to the hydrazone and can be employed for the preparation of polysubstituted alkenes. In the course of this research, novel metal-free C-C and C-O bond-forming reactions have been discovered. Since tosylhydrazones are readily prepared from carbonyl compounds, these transformations offer new synthetic opportunities for the unconventional modification of carbonyl compounds. This Minireview discusses all of these new reactions of a classic reagent.

Tosylhydrazones: new uses for classic reagents in palladium-catalyzed cross-coupling and metal-free reactions.

New economic and environmentally benign methods for achieving carbon–carbon bond formation are in constant demand. Here, a remarkably efficient and functional-group-tolerant, metal-free reductive cross-coupling of carbonyl compounds with boronic acids is described.

Metal-free carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones

The reaction of trialkylboranes with diazoacetone. A new ketone synthesis

Alkylation of diazoacetonitrile and ethyl diazoacetate by organoboranes. Synthesis of nitriles and esters

Reaction of organoboranes with diazo esters and diazo ketones in the presence of deuterium oxide. A New synthesis of .alpha.-deuterio- and .alpha., .alpha.-dideuterio esters and ketones

Electronic and Steric Effects in Monosubstituted Ferrocenes as Determined by Relative Site Reactivities and Desilylation

All of the acetylalkylferrocenes have been synthesized and obtained in a highly pure state. The infrared and NMR spectrum of each of these compounds has been determined, and the results tabulated. It has been shown that NMR spectroscopy provides a convenient tool in elucidating the structure of substituted ferrocenes. It is particularly useful in distinguishing between 1,2-and 1,3-disubstituted structures, a situation where infrared has its greatest limitations. A series of shielding constants has been developed for a variety of ferrocene substitu-ents. These enable one to predict with considerable precision the chemical shifts of a variety of protons bonded to the ferrocene nucleus.

John Hooz

Papers

The reaction of trialkylboranes with diazoacetone. A new ketone synthesis

Alkylation of diazoacetonitrile and ethyl diazoacetate by organoboranes. Synthesis of nitriles and esters

Reaction of organoboranes with diazo esters and diazo ketones in the presence of deuterium oxide. A New synthesis of .alpha.-deuterio- and .alpha., .alpha.-dideuterio esters and ketones

Electronic and Steric Effects in Monosubstituted Ferrocenes as Determined by Relative Site Reactivities and Desilylation

The Use of NMR Spectroscopy as a Structural Probe in Ferrocene Chemistry