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

Organocatalysis has captured the imagination of a significant group of synthetic chemists. Much of the mechanistic understanding of these reactions has come from computational investigations or studies involving both experimental and complementary computational explorations. As much as any other area of chemistry, organocatalysis has advanced because of both empirical discoveries and computational insights. Quantum mechanical calculations, particularly with density functional theory (DFT), can now be applied to real chemical systems that are studied by experimentalists; this review describes the quantum mechanical studies of organocatalysis.

The dramatic growth of computational investigations on organocatalysis in the last decade reflects the great attention focused on this area of chemistry since the discoveries of List, Lerner, and Barbas of the proline-catalyzed intermolecular aldol reaction, and by MacMillan in the area of catalysis by chiral amino-acid derived amines. The number of reports on the successful applications of organocatalysts and related mechanistic investigations for understanding the origins of catalysis and selectivities keep growing at a breathtaking pace. Literature coverage in this review is until October 2009, except for very recent discoveries that alter significantly the conclusions based on older literature.

1.1 Computational methods for organocatalysis
Over the last two decades, DFT has become a method of choice for the cost-effective treatment of large chemical systems with high accuracy.1 Most of the studies reported in this review were carried out using the B3LYP functional with the 6-31G(d) basis set, which is a standard in quantum mechanical calculations. Nevertheless, DFT is experiencing continuing developments of new functionals and further improvements. The availability of many new functionals and, in particular, the rapidly evolving performance issues of B3LYP have stimulated extra efforts on benchmarking DFT methods for the prediction of key classes of organic reactions.2 The well-documented deficiencies of B3LYP include the failure to adequately describe medium-range correlation and photobranching effects,3,4 delocalization errors causing significant deviations in π→σ transformations,2b,5 and incorrect description of non-bonding and long-range interactions,6 which are likely to be key factors in determining stereoselectivities. Benchmark results also show that newer functionals considerably improve some of the underlying issues.2–7 Recent advances, especially in the treatment of dispersion effects, now offer more reliable models of the reaction profiles and stereoselectivities.

Most benchmarks focus on energetics rather than stereoselectivities. Systematic benchmarking for stereoselectivities requires more sophisticated techniques and averaging over conformations. To date, such benchmarking based upon stereoselectivity is available for only three reactions,8 and even there only various basis sets with B3LYP, as well as comparisons of results predicted using enthalpies and free energies. It is not possible to assign error bars for stereoselectivities for the majority of reports discussed in this review. Because stereoisomeric transition structures are very similar species, their relative energies are likely to be calculated accurately, as shown by the good agreement between calculated and experimental values.

More recently Harvey (Harvey, 2010, faraday discussions) has studied two typical organic reactions of polar species (Wittig and Morita-Baylis-Hillman reactions) at different levels of theory.2i He showed that many standard computational methods, involving B3LYP, are qualitatively useful, but the energetics may be misleading for larger reactive partners; the quantitative prediction of rate constants remains difficult. These studies suggest that although B3LYP provides valuable qualitative insight into the reaction mechanisms and selectivities, the energetics may require testing with higher accuracy methods for complex organic systems. On the other hand, Simon and Goodman found B3LYP to be “only slightly less accurate” than newer methods, and recommended its use for organic reaction mechanisms.9

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Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

TADDOLe, ihre Derivate und Analoga – vielseitige chirale Hilfsstoffe

Isocyanides are a very special class of organic compounds, which may behave as acyl anion equivalents. However, with very few exceptions, isocyanides do not react with carbonyl compounds in the absence of an acid. In this chapter, all reactions of a carbonyl compound or an acetal with an isocyanide are considered. These are processes that frequently, but not invariably, result in the incorporation of an acid residue in the final product. In the classic Passerini reaction, discovered in 1921 by Mario Passerini, the acid is always a carboxylic acid and the products alpha-acyloxy amides. A more recent variation, which is often referred to as the Passerini reaction as well, employs a variety of mineral (H+) or Lewis acids (LA) to afford alpha-hydroxy amides. These compounds may also be formed in the presence of carboxylic acids such as formic acid or trifluoracetic acid. Interactions of isocyanides with carbonyl compounds and some protic or Lewis acids can also lead to a large variety of products other than alpha-hydroxy amides, including several heterocyclic systems. These Passerini-type reactions are discussed. Acetals can also react with isocyanides in the presence of Lewis acids. The usual products are alpha-alkoxy amides.



The classic Passerini reaction is one of the oldest multicomponent reactions and is the first based on isocyanides to be discovered. This method is experiencing a growing interest. Its scope has been expanded by employing bifunctional substrates able to undergo secondary reactions. In this way, a larger variety of products can be synthesized and complex biologically active substances can be accessed quickly. Modifications that form products different from alpha-acyloxy amides or alpha-hydroxy amides, especially those leading to heterocycles, may find useful applications in synthesis.


Keywords:

Passerini reaction;
functional group compatibility;
carbonyl compounds;
isocyanides;
carboxylic acids;
intramolecular reactions;
secondary transformations;
protic acids;
acids;
Lewis acids;
acetals;
alpha-acyloxy amides;
stereochemical aspects;
solid-phase synthesis;
method comparisons;
experimental procedures

The Passerini Reaction

A NEW TYPE OF PHOSPHORIC ACID COMPOUND ISOLATED FROM BLOOD, WITH SOME REMARKS ON THE EFFECT OF SUBSTITUTION ON THE ROTATION OF l-GLYCERIC ACID

Pasteur Memorial Lecture

CLXVII.—The Grignard reaction applied to the esters of hydroxy-acids

CV.—Position-isomerism and optical activity; the comparative rotatory powers of the dibenzoyl and ditoluyltartrates

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Percy Faraday Frankland

Papers

Pasteur Memorial Lecture

CLXVII.—The Grignard reaction applied to the esters of hydroxy-acids

CV.—Position-isomerism and optical activity; the comparative rotatory powers of the dibenzoyl and ditoluyltartrates

CXXX.—The influence of various substituents on the optical activity of tartramide

XXVII.—A gasometric method of determining nitrous acid