Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Asymmetric 1,3-Dipolar Cycloaddition Reactions

Recent Developments of Transition-State Analogue Glycosidase Inhibitors of Non-Natural Product Origin

Thionation reactions of lawesson's reagents

TADDOLs, which contain two adjacent diarylhydroxymethyl groups in a trans relationship on a 1,3-dioxolane ring, can be prepared from acetals or ketals of tartrate esters by reaction of the latter with aromatic Grignard reagents. They are extraordinarily versatile chiral auxiliaries. Here, a historical review of the subject is followed by discussion of the preparation of TADDOLs and analogous systems, including TADDOLs with N-, P-, O-, and S-heteroatom ligands appropriate for metals. Crystal structure analysis reveals that the heteroatoms on the diarylmethyl groups are almost always in close proximity to each other, joined together by H-bonds, and predisposed to form chelate complexes in which the metallic centers reside in propeller-like chiral environments. Applications of TADDOL derivatives in enantioselective synthesis extend from utilization as stoichiometric chiral reagents or in Lewis acid mediated reactions, to roles in catalytic hydrogenation and stereoregular metathesis polymerization. Derivatives and complexes based on the following metals have so far been investigated: Li, B, Mg, Al, Si, Cu, Zn, Ce, Ti, Zr, Mo, Rh, Ir, Pd, Pt. The number of stereoselective reactions already accomplished with TADDOLs is correspondingly large. It is also easy to prepare TADDOL derivatives that are readily polymerizable and graftable, and to transform them into immobilized solid-phase catalysts. The result is catalysts, simply or dendritically immobilized in polystyrene or on silica gel and characterized by unexpected stability even after multiple use in titanium TADDOLate mediated reactions. TADDOLs show further unusual characteristics that make them useful for applications in material science and supramolecular chemistry: they are the most effective doping agents known for phase transformations of achiral (nematic) into chiral (cholesteric) liquid crystals. The TADDOL OH group that is not involved in intramolecular H-bonding shows a strong tendency to associate intermolecularly with H-bond acceptors. In the process of crystallization this leads, enantioselectively, to the formation of inclusion compounds that lend themselves to the separation of racemic mixtures not otherwise suited to the classical method of crystallization through diastereomeric salts. The high melting points of TADDOLs even make possible the resolution of racemates by distillation! Host-guest compounds formed between TADDOLs and achiral partners can serve as platforms for enantioselective photoreactions. It seems safe to predict that many more applications will be discovered for the TADDOLs and their derivatives. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.

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TADDOLs, Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries

A highly diastereo- and enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of 3-((E)-2‘-alkenoyl)-1,3-oxazolidin-2-ones with nitrones has been developed. A series of TiX2−TADDOLate...

A Highly Diastereoselective and Enantioselective Ti(OTos)2−TADDOLate-Catalyzed 1,3-Dipolar Cycloaddition Reaction of Alkenes with Nitrones

Studies on organophosphorus compounds XLVII preparation of thiated synthons of amides, lactams and imides by use of some new p,s-containing reagents

Aliphatic and aromatic aldehydes can be converted to acyl azides by treatment with iodine azide at 0-25 degrees C. If the reaction is performed at reflux Curtius rearrangement occurs and carbamoyl azides are obtained in 70-97% yield from the aldehyde. The reaction was shown to have a radical mechanism.

Radical azidonation of aldehydes.

(3,4-trans-4,5-trans)-4,5-dihydroxy-3-hydroxymethylhexahydropyrida-zine (16) was synthesized in four steps from 2,4-pentadienol (22) and 4-phenyl-triazolin-3,5-dione (18) in an overall yield of 32%. In the first step a Diels-Alder reaction between 18 and 22 gave (π)-2-hydroxymethyl-8-phenyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3-trans-3,4-trans)-3,4-dihydroxy-2-hydroxy-methyl-8-phenyl-1,6,8-triazabicyclo[4.3.0]-nonane-7,9-dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of α-and β-glucosidase, isomaltase and glyco-gen phosphorylase, while galactosidases and α-mannosidase were not inhibited. The inhibition of β-glucosidase is independent of pH, and was found to be due to unprotonated 16.

1-Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.

I. Thomsen

Papers

A Highly Diastereoselective and Enantioselective Ti(OTos)2−TADDOLate-Catalyzed 1,3-Dipolar Cycloaddition Reaction of Alkenes with Nitrones

Studies on organophosphorus compounds XLVII preparation of thiated synthons of amides, lactams and imides by use of some new p,s-containing reagents

Radical azidonation of aldehydes.

1-Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage

Enantiospecific synthesis of 1-azafagomine.