Chiral phosphorus reagents

The first highly diastereoselective hydrophosphonylation of heterocyclic imines, 3-thiazolines (330) by a chiral phosphorus reagent BINOL, has been performed. The relative configuration of BINOL and the newly formed stereogenic centre in the a-amino phosphonic acid derivatives (331) have been elucidated by X-ray analysis. 

Scheme 7.5. Three types of chiral phosphorus reagents employed in asymmetric carbonyl olefination.

Pioneering studies in the area of chiral phosphorus reagents for asymmetric synthesis were reported by Bestmann (Equation 12) [68]. Treatment of phosphorus ylide 109 with 4-substituted cyclohexanones thus led to the formation of enantioenriched benzylidenecyclohexanes, such as 111 in... 

This seminal work inspired the development of chiral phosphorus reagents that furnished related products with higher optical purity. Hanessian, for example, documented the synthesis and use of chiral bicyclic phosphona-mide reagents such as 112, conveniently prepared from 1,2-diaminocyclo-hexane (Equation 13) [69]. 

In this transformation, condensation of 4-tert-butylcyclohexanone with 112 afforded olefin 114 in 90 % optical purity. In addition, these chiral phosphorus reagents were also shown to undergo diastereoselective alkylation reactions. 

A.A-Dimethylhydroxylamine reacts with 73a to give the chiral animation reagent 89 with retention of configuration at the phosphorus atom. On reacting (-)- 89 with... 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

The use of copper catalysts based on chiral phosphorus ligands to assist 1,4-additions of dialkylzinc reagents has in recent years produced major breakthroughs, with excellent enantioselectivities. A number of monodentate and bidentate phos-phoramidites, phosphites, phosphonites, and phosphines are now available as chiral ligands for alkyl transfer to a variety of cyclic and acyclic enones. So far. 

Chiral Phosphorus Compounds Koizumi et al. 251 have prepared a series of chiral organophosphorus compounds (256) in which the phosphorus atom is the asymmetric center, whereby amino acid derivatives were used as chiral auxiliary reagents. 

Intermolecular aza-Wittig reaction has been described for the one-step synthesis of pyrazolofl, 5-a Ipyrimidinc and imidazo[l,2-fc]pyrazole derivatives.37 The asymmetric synthesis of ft-quaternary azacycles has been accomplished by aza-Wittig reaction mediated by chiral phosphorus(ni) reagents.38... 

The copper-catalyzed conjugate addition reaction of organozinc reagents has reached a prominent level of success by the development of sophisticated chiral phosphorus ligands. Nickel catalysts have also been surveyed by several groups. 

Chiral chelating ligands that contain only one phosphine and another donor atom have been successful in recent years. A readily synthesized example is the phosphino-oxazoline ligand 87 shown in Scheme 31. These types of ligand can be prepared in two steps from an amino alcohol, a substituted benzonitrile and either a electrophillic or nucleophilic phosphorus reagent. They have been used in a number of asymmetric reactions. 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

Chiral phosphorus(III) reagents undergo the Pudovik reaction51,88 with good diastereoselectivity being achieved by the reaction of Spilling and co-workers diamide 52 with aldehydes (Scheme 26),107 however, research on this chiral auxiliary approach to ct-hydroxy phosphonates is now surpassed by chiral catalysis. 

It is of interest that the commercially available chiral phosphoramide shown in Fig. 7, when employed in comparison reactions, afforded no observable diastereomeric differentiation either by P- or H-NMR spectroscopy [121]. This result may be rationalized on the fact that the monocyclic reagent has only two chiral centers while li possesses three. Moreover, the chiral centers in li are held rigidly in place, thus perhaps providing an enhanced chiral phosphorus environment. 

The chlorophosphine boranes 97 are efficient starting reagents for the synthesis of various classes of P-chiral phosphorus compounds. Reactions of chlorophosphine boranes 97 with nucleophiles, such as carbanions, phenoxides, phenylthiolates, or amides, leads to the formation of corresponding organophos-phorus compounds 100-103 in yields of 53-99% and with up to 99% ee. This method was also used for the preparation of various classes of symmetric and asymmetric P-chiral ligands useful for asymmetric reactions, catalyzed by complexes of transition metals (Scheme 31) [52, 60, 61]. 

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