Phosphoramidite addition

A range of bis(tetrachlorocatecholato)spirophosphoranides 91 and 92 have been prepared from diones <2002EJ03580>. Careful fine-tuning of the polarity of the solvent mixture was required for the precipitation of the dimethylammonium salts of the spirophosphoranides. A Cj-symmetric spirophosphoranide 93 with three different bidentate ligands was also prepared. The synthesis required the addition of the dione to a phosphoramidite generated... 

A variety of substrates has been used in this type of conjugate addition reaction with trialkyl phosphites, with assorted proton sources.361 384 Other types of trivalent phosphorus reagents without acidic (or conjugate base of acidic) sites have also been used successfully for this conjugate addition process, including triaryl phosphites (without dealkylation),369 phosphoramidites,385 389 phospho-nites,363 380 390 and phosphinites.360 380... 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

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. 

With chiral phosphoramidite (S,R,R) 29, 3-ethylcyclohexanone, 3-ethylcycloheptanone, and 3-ethylcyclooctanone were obtained with >97% ee s.37,39 (R,R,R)-32 also showed excellent enantioselectivity in the addition of Et2Zn to both 2-cyclohexenone (93% ee) and larger ring enone as 2-cyclopenta-decen-l-one (95% ee).40... 

Feringa and co-workers applied chiral phosphoramidite ligand (S,R,R)-67 in the conjugate addition of dimethylzinc to acyclic unsaturated malonates 68 and obtained up to 98% ee (Scheme 22).71... 

The enantioselective conjugate addition of dialkylzinc to nitroalkenes using other phosphoramidite,79,79a 83a sulfonamide,84 and binaphthol-based thioether ligands65 has also been studied in the past few years. Particularly noteworthy are the efficient chiral monodentate phosphoramidite ligands (S,R,R)-29 and (A,A)-55 developed by Feringa et al. and Alexakis et al., respectively, for this reaction. (S,R,R)-29 provided excellent enantioselectivities (up to 98% ee) for acyclic nitroalkenes (Scheme 25).80 It also worked well for other nitroolefin substrates such as 3-nitrocoumarin 7068 and methyl 3-nitropropenoate 7185. 

Alexakis et al. showed that under optimized experimental conditions, the enantioselectivity of the Cu-catalyzed conjugate addition of dialkylzinc to cyclic nitroolefin was improved to 95% with both (A,A)-55 and (R,S,S)-29.79,79a Biphenol-based phosphoramidite ligand (S,S)-55 also provided acyclic nitroalkenes adducts with 95-96% ee.42... 

Ojima and co-workers found that chiral monodentate phosphoramidite (S,R,R)-35 was highly effective for the enantioselective conjugate addition of diethylzinc to acyclic nitroalkenes (up to 99% ee).86... 

The use of monodentate phosphoramidites in enantioselective hydrogenation was first reported in 2000, together with reports on the use of phosphites and phospho-nites [15]. Phosphoramidites are prepared in a variety of ways, but the most common route is the treatment of a diol with PC13, followed by addition of an amine [60, 61]. MonoPhos (29a), the first reported phosphoramidite used as a ligand, is prepared from BINOL and HMPT in toluene [62]. Phosphoramidites, especially... 

Zhou et al. have reported extensively on the use of a spiro-biindanediol as the backbone in the ligands 35a-f (Scheme 28.11, SIPHOS) [70]. Excellent results are obtained for a variety of substrates, and recently a full report has appeared on the use of these ligands [71]. Synthesis of the diol backbone requires a number of steps, including a resolution [72]. An additional and successful spiro-diol-derived phosphoramidite 39 has recently been disclosed by the group of Zhang [73]. 

There is one more report on the synthesis of a library of phosphorus ligands on solid phase. Waldmann et al. prepared a library of phosphoramidites on beads (Fig. 36.5), but these were only applied in enantioselective C-C-bond formation. In fact, as two ligands need to be bound to the catalyst, the use of an immobilized monodentate ligands should most likely be avoided unless the proximity between the ligands is sufficiently close. In addition, crosslinking by the metal may have a negative impact on the permeability of the polymer for the substrate. 

In 1996, Feringa and co-workers (164) reported the use of binaphthol-derived phosphoramidite 232a as a ligand for the copper-catalyzed conjugate addition. Addition of 2 equiv of 232a to Cu(OTf)2 forms an effective catalyst for the selective... 

Although addition of activated phosphoramidite to hemiacetals of manno-pyranoses under thermodynamic control has been reported to deliver exclusively a-phosphates in some cases,43 anomeric mixtures with preponderance of a-anomer have been reported in other examples.10,44 Since formation of phosphorotetrazolidite is a rate-limiting step of the process, initial activation of phosphoramidite followed by addition of nucleophilic hemiacetal should accelerate condensation and favour the formation of the thermodynamic a-product. Indeed, reaction of hemiacetal 101 with dibenzyl phosphorotetrazolidite assured exclusive a-selectivity of the resulting glycosyl phosphate 102.43 The accumulation in the reaction mixture of mildly acidic 1H-tetrazole, which is liberated upon reaction of tetrazolidite with hydroxylic component, could also favour predominant formation of the a-phosphate (Scheme 18, A). Conventional hydrogenolysis afforded the a-mannosyl phosphate 103. 

Phosphoramidites 13, derived from 2,2 -binaphthol, proved to be versatile ligands for copper-catalyzed 1,4-additions of Et2Zn to chalcone and 2-cyclohexenone (Scheme 7.9) [37]. 

Scheme 7.9. Copper-catalyzed 1,4-addition to cyclohexenone and chalcone, with phosphoramidites as chiral ligands.

A breakthrough was achieved with chiral phosphoramidite (S, R, i )-18, in which a C2-symmetric (S)-binaphthyl unit and a C2-symmetric (R, R)-bis-(l-phenylethyl)-amine unit are present (Scheme 7.10), resulting in the enantioselective catalytic 1,4-addition of Et2Zn to 2-cyclohexenone (6) with >98% ee [38]. 

The presence of two ligands in the active catalyst is proposed on the basis of the optimum ligand-to-copper ratio of 2 and the nearly identical selectivities of monodentate and bidentate phosphoramidites in the 1,4-addition of Et2Zn to 2-cydohexenone [45]. 

The X-ray structure of the Cut complex 21 of phosphoramidite 14 provides additional insight into a possible mechanism for stereocontrol (Fig. 7.3). The formation of the L2CuEt-enone complex involves substitution of the iodide in 21 for the alkyl moiety and of one of the ligands for the -coordinated enone. Coordination of RZnX results in the bimetallic intermediate 19 (Fig. 7.3). The absolute configuration of the two phosphoramidite ligands and the pseudo-C2-symmetric arrangement dictate the formation of (S)-3-ethyl-cyclohexanone. 

Pfaltz introduced phosphite ligands 22, with BINOL and chiral oxazoline units, which gives excellent enantioselectivities [47]. In phosphoramidites 14 and 15 (Scheme 7.9) the structure of the amine moiety is crucial, but substituents at the 3,3 -positions of the BINOL unit had only minor influences on the enantiose-lectivity of the 1,4-addition to cyclohexenone. In contrast, the introduction of the two 3,3 -methyl substituents in ligand 22 increased the ee drastically from 54% to 90%. 

Scheme 7.13. TADDOL-based phosphoramidite ligands in the catalytic 1,4-addition.

Optically active cyclopentanes are among the structural units most frequently encountered in natural products such as steroids, terpenoids, and prostaglandins. Not unexpectedly, the development of a highly enantioselective catalytic 1,4-addition reactions to 2-cyclopentenones has proven to be a challenging goal. In contrast with the high enantioselectivity observed in the copper-phosphoramidite-catalyzed 1,4-... 

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