Asymmetric addition of P-H compounds to unsaturated carbonyl derivatives

Michael addition of P-H compounds, such as phosphanes, phosphane oxides and phosphonates, is a practical tool to form P-C bonds. The stereochemistry of the newly formed compounds can be influenced either by using chiral starting materials or chiral catalysts. Since the former method is limited to the readily available optically-active derivatives, catalytic options are more common. Enantioenriched P-C compounds can have biological activity; therefore, they are pharmaceutically valuable molecules. In this paper, an overview is provided on the conjugate addition of P-H compounds according to the type of the phosphorus derivatives


Introduction
Optically-active phosphonates can be precursors of many biologically active compounds and pharmaceutically important molecules. 1 Direct addition of P-H compounds to electrophiles is one of the many methods for the preparation of such derivatives. Asymmetric conjugate addition of phosphanes to α,β-unsaturated carbonyl compounds is still challenging and has been much less developed. Products of addition can be converted to derivatives with various functional groups.
Enantioenriched organophosphorus compounds have an important role in organic chemistry since chiral phosphanes and phosphane oxides can be used as ligands or pre-ligands in metal-catalyzed reactions. 2,3 Phosphorus compounds have a wide structural diversity and various properties. Therefore, these derivatives cannot only be valuable building blocks, but also products with diverse biological activities. 1,4 The formation of a P-C bond can be straightforwardly carried out by a Michael addition of trivalent and pentavalent phosphorus species to an electron-deficient double bond. 5 Chiral phosphanes are generally synthesized in racemic form and then the stereoisomers are separated by resolution, using chiral auxiliaries or enantiopure compounds. [6][7][8] Thus, the development of efficient enantioselective catalytic methods for the synthesis of enantiomerically-enriched compounds with a chiral carbon atom having a P-C bond is highly desired. 9-11 Chiral organophosphorus derivatives can have different biological activities. For this reason, they can be used as biophosphate mimics, antibiotics, antiviral agents, and antitumor agents. 12

Asymmetric Induction Generated Without Chiral Catalysts
Selective addition of a P-H compound to an enone can be achieved by using a chiral P-compound or a chiral acceptor molecule. In the former case, the stereogenic center is closer to the active center in the catalyst. However, these methods are limited by the availability of P-stereogenic P-H compounds.
The asymmetric Michael reaction of phosphinic or aminophosphinic acids 14 with acrylate derivatives of Evans oxazolidinone-type auxiliaries 13 was carried out by Liu et al. in order to synthesize peptidomimetic compounds. 20 The diastereomeric ratio was significantly higher if the chiral Michael acceptor 13 contained a diphenylmethyl moiety (Table 5, entries 2, 4 and 6) instead of a benzyl group (Table 5, entries 1, 3 and 5).  21 Since the addition of diphenylphosphane oxide resulted in the formation of the same products 18 under the same conditions, it was assumed that an oxidationaddition sequence may be in the background. Other derivatives such as simple olefins or the amido (17carboxamido-16-ene) analogue of 16 remained unreactive under similar reaction conditions. When steroids with an exocyclic electron-deficient double bond were used, both diastereomers were formed, which were separated and identified. 22
The modification of Pincer catalyst 23 by introducing two benzoyl groups resulted in an ineffective derivative; only low enantiomeric excess could be reached in the reaction of 8 (R = Ph or Me) and diphenyl phosphane (17). 29 Pincer catalyst 24 was investigated in the Michael addition of diphenyl phosphane (17) to Nvinylimidazoles, however, it was ineffective. Meanwhile, under the same conditions, complex 28 generated significant asymmetric induction. 30 With acceptor 1 (R 1 = imidazol-1-y R 2 = Ph), 96% ee was measured in the presence of TMEDA (N,N,N',N'-tetramethylethylenediamine) ( Table 8, entry 17). When substituents were introduced into the imidazole moiety, the enantioselectivity decreased.
Complex 24 was also used in the reaction of α,β,γ,δ-unsaturated ketones with diaryl phosphanes. 31 Under optimized conditions, only the 1,4 adducts were formed with ee up to 99% (with compound 17, Table 8, entries 7-8). In the addition of diphenyl phosphane (17) to quinoline-based unsaturated compounds (e.g., 1, R 1 = quinolin-2-yl R 2 = Ph), catalyst 24 proved to be superior to complex 28 and generated enantiomeric excess up to 97% (Table 8, entry 9). 32 In the second step of the reaction, sulfur, not hydrogen peroxide, was used to prepare air-stable pentavalent P-derivatives (P=S analogues of 22). When the quinoline ring was replaced by a pyridine moiety (1, R 1 = pyridin-2-yl, R 2 = Ph), enantiomeric excess remained excellent (97% ee, Table 8, entry 10). Using complex 24, a self-breeding catalyst was developed when the product of the conjugate addition was transformed into a Pd complex, which was used in the same addition reaction as the catalyst. It was observed that enantioselectivity and yield were almost the same with the same substrate (93% ee). 33 C2-symmetric 23 and 25 and C1-symmetric 26a pincer complexes were compared in the hydrophosphination of chalcone 1 (R 1 = Ph, R 2 = Ph). 34 Catalyst 26a gave a good result under optimized conditions (82% ee, Table 8, entry 12), while only a low enantiomeric excess could be reached with complex 26c (30% ee, Table 8, entry 14). The enantioselectivity of C2-symmetric complex 25 was similar to that of C1symmetric catalyst 26a (85% ee, Table 8, entry 11). By testing a few substituted chalcones, it was found that the presence of an electron-donating substituent decreased the enantioselectivity generated by 26a. Structures analogous to 25 were synthesized and compared to pincer catalysts 26a and 26b. 35 When Cl in compound 25 was replaced by Br, it generated comparable or better enantioselectivity than 26a, while in most cases it was inferior to complex 26b. C2-symmetric pincer catalyst 27, having a modified structure compared to 25, was developed and tested in the hydrophosphination of β,γ-unsaturated-α-ketoesters. 36 A moderate ee value (66%) was measured in the case of ester 1 (R 1 = Ph, R 2 = COOiPr, Table 8, entry 16) using complex 27. The enantioselectivity generated by 27 was strongly dependent on the structure of the substrate.
A series of chiral pincer Pd-complexes with aryl-based aminophosphine-imidazoline or phosphiniteimidazoline ligands were synthesized by Hao and co-workers. 37 The structural effect of the complex was investigated and asymmetric induction was found to be highly dependent on the substituents on the imidazole ring. The most effective structure was 26b, which was tested in the hydrophosphination of chalcones. In the reaction of chalcone 1 (R 1 = Ph, R 2 = Ph), and diphenyl phosphane (17) 92% ee was measured ( Table 8, entry 13). Substitution on the aromatic rings in the acceptor only slightly influenced the enantioselectivity, although the ortho-substitution was strongly unfavorable.
A series of new chiral pincer Pd(II)-complexes bearing an imidazoline moiety were synthesized to study the structure-activity relationship. 38 Among these, 26d showed the best result (85% ee) in the conjugate addition of 1 (R 1 = Ph, R 2 = pyridin-2-yl) and diphenyl phosphane (17) ( Table 8, entry 15). Alteration of the structure of the substrate strongly affected the enantioselectivity of catalyst 26d.
A comparative study was preformed by Yang et al. to gain information about the catalytic mechanism of complexes 24 and 28. 39 It was found that the C2-symmetric pincer catalyst 24 can direct the approach of the substrate by means of the prochiral P-Ph groups, while complex 28 allows the simultaneous coordination of both reagents to the Pd center. The differences shown in the mechanism may also be behind the phenomenon that, in the case of α,β,γ,δ-unsaturated carbonyl compounds, 1,4 addition takes place with palladacycles while 1,6 addition takes place with pincer catalysts. 29,40 Catalyst 28 was used to form biologically-active chiral Pt complexes. 41 After it was used in the addition of diphenyl phosphane (17) to N-vinylbenzimidazoles, the adducts obtained were converted into new Pt complexes, the cytotoxicity of which toward cancer cell lines was investigated.
Later, catalyst 47c was investigated in the reaction of cyclic enones. 62 It was found that both diastereomers of the products were formed, but both with excellent enantiomeric excess (99% in most cases). Using tetralones (60, n = 2, R 1 = Ph or 4-Br-C6H4), the diastereomeric ratio was 2.1:1 and 3.4:1 (Table 18, entries 1 and 2). If the phenyl group in the substrate was replaced by a furan ring, diastereomers were present in 1.1:1 ratio in the product (61, n = 2, R 1 = furan-2-yl, R 2 = Et) ( Table 18, entry 3). In the case of indanones (60, n = 1, R 1 = Ph or 2,6-diMeO-C6H3 ), the diastereomeric ratio was changed to 1:2.2 and 1:6.6, respectively, while the enantioselectivity was maintained (99% in all cases, Table 18, entries 4 and 5). Substituents on the substrate had little effect on the enantioselectivity.  63 The 63 indane derivatives bearing phosphoryl groups were obtained with excellent stereoselectivity (up to > 99% ee and >99 : 1 dr) under mild conditions. While catalyst 47a and 47d proved to be highly enantioselective (97% and 99% ee, Table 19, entries 1 and 4), analogue derivatives 47b and 47c generated moderate optical purity (76% and 74%, Table 19, entries 2 and 3). Interestingly, in compound 62, when a methyl group was present next to the carbonyl functions (R 1 = Me), there was no reaction (Table 19, entry 5). The catalytic system with 47d proved to be effective when other dialkyl phosphonates were used as well as when there was a substituent on the aromatic ring.

Conclusions
By Michael addition of P-H compounds, phosphorus-containing compounds with potential biological activity can be obtained. Enantioselective catalysis is a modern and green production method of P-C chiral derivatives as well, however, this requires chiral catalysts that are efficient, robust, and widely applicable. In order to be able to plan and carry out reactions resulting in the desired products, it is necessary to know the limitations and possibilities. In several cases presented in this review, the details of effect-structure relationships can be recognized which can be useful for further catalyst research and development. In addition, the possible routes presented, leading to the preparation of P-C chiral compounds with diverse structures, may inspire new methods and newer derivatives.