Review on asymmetric cycloaddition reactions at phosphorus (III) atom

The asymmetric hetero-Diels-Alder reactions are one of the most powerful methods for the construction of optically active mono-and polycyclic heterocycles with extensive synthetic applications. At the present time the phospha-Diels-Alder reactions still received much less attention, despite its potential utility to obtain P -chiral cyclic phosphines for use in asymmetric homogeneous catalysis. This review is a comprehensive account of asymmetric cycloaddition reactions including trivalent phosphorus atom in phosphalkenes, phospholes, heterophospholes and other P (III) species as prochiral motif. This original synthetic strategy is of interest for the synthesis of polycyclic and caged P -chiral phosphines and subsequent ligand design for asymmetric catalysis.


Introduction
2][3] The simultaneous formation of two carbon-carbon or carbon-heteroatom bonds leads to the creation of up to four stereogenic centers in a single step from achiral dienophiles and dienes, making this one of the most fascinating and elegant methods in asymmetric organic synthesis.8] In the last decade the scope of this reaction has been extended to phosphorus (III) compounds, in spite of the low availability of a P=C bond compared to a C=C bond.

Asymmetric Cycloaddition Reactions with Chiral Dienes
The planarity and high reactivity of 1,2-diphospholes 9-10 allow to control the stereoselectivity in cycloaddition reactions using the principle of diastereotopic face differentiation by employing a P=C double bond as prochiral motif.The formation of two diastereomers was clearly observed in the [4+2] cycloaddition reaction of 1-((1R,2S,5R)-menthyl)oxymethyl-1,2-diphosphole (1a) as chiral diene with non-chiral maleic anhydride (Scheme 1).During the reaction in the temperature range from -30 °C to +60 °C a small diastereomeric excess of 2` and 2`` (30-46% de) was observed. 113][14] An analysis of the structure of 1-(+)-neomenthyl-3,4,5-triphenyl-1,2-diphosphacyclopenta-2,4-diene (1b) indicated that steric shielding of one side by the bulky isopropyl group causes a preferential approach of the dienophile from the opposite side resulting in one attractive and one repulsive pathway of the [4+2] cycloaddition reaction.This study approves that getting closer of the chiral inductor with the dienic system of 1,2-diphospholes leads to an increase of stereochemical outcome (de) of hetero-Diels-Alder reaction.

Asymmetric Cycloaddition Reactions with Chiral Dienophiles
The principle of stereotopic face differentiation was successfully applied to P=C bond of 1-mono-and 1,2diphospholes and became an effective synthetic approach for highly selective synthesis of P-chiral phosphines from readily available starting materials.An efficient and highly stereoselective asymmetric Diels-Alder reactions of 1H-8, 9 and 2H-monophospholes 10 with the chiral dienophile (5R)-(l-menthyloxy)-(5H)-furanone (MOxF) allowed to generate multiple stereogenic centers resulting in P-chiral 7-phosphanorbornenes 21 11 and 1-phosphanorbornenes 12 (Scheme 4). 22The observed reaction pathway has been supported by theoretical calculations showing that the cycloaddition reaction between 2H-phosphole 10 and MOxF is of normal electron demand. 23The [4+2] cycloaddition products were converted to their air stable sulfur derivatives, which were isolated and the endo-and exo-isomers were separated by column chromatography.The phosphorus atom in the obtained cycloadducts 11 and 12 was easily desulfurized to give the corresponding P(III)-species, which were further functionalized and yielded different bidentate phosphines.
The Diels-Alder reaction of phospholes with various dienophiles in the coordination sphere of chiral Pdcomplexes was proposed as a method for the synthesis of chiral phosphines. 29The chiral (S)-ortho-(1dimethylaminoethyl)-naphthalene palladium (18) was complexed with 3,4-dimethyl-1-phenylphosphole (9b), and then involved into the Diels-Alder reaction with various dienophiles (N,N-dimethylacrylamide, diphenylvinylphosphine, styrene, and others) to result in diastereoisomers of endo-amidophosphanorbornene complexes 19.It should be noted that [4+2] cycloaddition reactions of 1H-monophospholes 9 in the coordination sphere of Pd-complexes 18 proceeded under milder conditions (25-80 °C) compared to uncoordinated 1Hmonophospholes (140-150 °C).The stereoselectivity of the reaction was moderate (up to 50% de), but diastereoisomers were easily separated by chromatography or recrystallization to yield a library of enantiopure bicyclic caged phosphines 20 with 40-85% yields after decomplexation with KCN or 1,2bis(diphenylphosphino)ethane (Scheme 7, right).It was shown that the stereochemical course of the [4+2] cycloaddition depends on the presence of silver perchlorate or tetrafluoroborate in the reaction medium. 30Therefore, it is possible to select either the exo-or the endo-cycloaddition reaction pathways by controlling the number of coordination sites on the ortho-Pd naphthylamine template 18.In the endo-cycloaddition pathway, the kinetically stable chloro-ligand is coordinated to the neutral template, but in the exo-cycloaddition pathway, the kinetically labile perchlorato ligand forms a cationic intermediate, which coordinates simultaneously onto the chiral template during the course of cycloaddition reaction.Therefore, the reaction of 18 with 3,4-dimethyl-1-phenylphosphole (9b) in the presence of AgClO4 led to the formation of only one enantiopure cycloaddition products 21 and phosphines exo-22 with 99% de (Scheme 7, left). 31] Scheme 8.The asymmetric Diels-Alder reactions between diphenylvinylphosphine and Ndiphenylphosphinopyrrole or 3-diphenylphosphinofuran.

Conclusions
The principle of diastereotopic face differentiation by employing a P=C double bond of phosphalkenes, phospholes, heterophospholes and other P(III) species as prochiral motif in [4+2] cycloaddition reactions was successfully used in the synthesis of P-chiral polycyclic phosphines.Although first results reveal moderate yield and enantioselectivity in asymmetric catalysis, the original synthetic strategy for these new enantiopure P-chiral ligands are of interest for the synthesis of polycyclic and caged chiral phosphines and subsequent ligand design for asymmetric catalysis.][43]