Phosphoramidite chiral

The copper-catalyzed enantioselective Michael addition of organometallic reagents to enones was the first successful application of phosphoramidite chiral ligands in catalysis [4, 43]. Since this early report, substantial enhancement of the enantioselectivity and/or of the substrate scope has been achieved through an untiring effort to optimize the ligand structure [5a, 44]. 

Scheme 5.5 Hydrovinylation of styrene with a preformed phosphoramidite chiral nickel catalyst activated by Inlj.

Chirahty at the phosphoms is an unavoidable problem in all phosphorothioate syntheses. The phosphoramidite method produces a mixture of both the and the diastereomers having a small excess of the isomer (53). Although some progress has been made in the chiral synthesis of dinucleoside phosphorothioates, low yields have limited the utility of these approaches. The chiral center may be eliminated by replacing the other, nonbridging oxygen with sulfur. Avoidance of the chirahty problem is one reason for the interest in phosphorodithioates. 

Phosphine(s), chirality of, 314 Phosphite, DNA synthesis and, 1115 oxidation of, 1116 Phospholipid, 1066-1067 classification of, 1066 Phosphopantetheine, coenzyme A from. 817 structure of, 1127 Phosphoramidite, DNA synthesis and, 1115 Phosphoranc, 720 Phosphoric acid, pKa of, 51 Phosphoric acid anhydride, 1127 Phosphorus, hybridization of, 20 Phosphorus oxychloride, alcohol dehydration with. 620-622 Phosphorus tribromide, reaction with alcohols. 344. 618 Photochemical reaction, 1181 Photolithography, 505-506 resists for, 505-506 Photon, 419 energy- of. 420 Photosynthesis, 973-974 Phthalic acid, structure of, 753 Phthalimide, Gabriel amine synthesis and, 929... 

Pineschi and Feringa reported that chiral copper phosphoramidite catalysts mediate a regiodivergent kinetic resolution (RKR) of cyclic unsaturated epoxides with dialkylzinc reagents, in which epoxide enantiomers are selectively transformed into different regioisomers (allylic and homoallylic alcohols) [90]. The method was also applied to both s-cis and s-trans cyclic allylic epoxides (Schemes 7.45 and 7.46,... 

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. 

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... 

Although disubstituted alkynes are used successfully as two-carbon components in chromium-mediated and -catalyzed [6 + 2]-reactions, the use of terminal alkynes produces a [6 + 2 + 2]-reaction (Section 10.13.3.7). Buono and co-workers have discovered that when a cobalt catalyst is employed, several monosubstituted alkynes can be used in [6 + 2]-cycloadditions with cycloheptatriene (Scheme 35). The use of a chiral BINOL-phosphoramidite cobalt complex affords an enantioselective [6 + 2]-cycloaddition reaction (Equation (18)).121... 

Very recently, Reetz, Ma and Goddard reported phosphoramidites based on BINOL bearing a single ortho-substituent (Scheme 28.10) [69]. These ligands are also chiral on phosphorus, such that the synthesis results mostly in diastereo-mers which have to be separated. In several cases, however, one of the diaster-eomers was formed exclusively. Some of the ligands afford high ee-values in the hydrogenation of methyl N-acyl dehydroalanine and dimethyl itaconate. 

Phosphoramidite ligands based on TADDOL (36) and on D-mannitol (37) [74] have also been used (Scheme 28.11). However, the enantioselectivities reported for the hydrogenation of a-dehydroamino acids and itaconates were generally lower compared to the ligands based on BINOL. A different strategy is the use of ligands 38a-g based on the achiral diol catechol, and chiral amines [75]. 

In contrast to dehydro a-amino acids, the hydrogenation of acetylated /1-dehy-droamino acid derivatives has only recently been of industrial interest and, accordingly, no applications on a larger scale have yet been reported. Several ligands such as certain phospholanes or phosphoramidites might have industrial potential, but until now these have only been tested on model substrates under standard conditions [50]. Chiral Quests TangPhos and Binapine (Fig. 37.10) have been shown to hydrogenate several acetylated dehydro / -amino acid derivatives with ee-values of 98-99% and TONs of 10000 at r.t., 1 bar [3, 47]. 

Copper-catalyzed enantioselective SN2 substitution of propargyl oxiranes in the presence of chiral phosphoramidites F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold, B. L. Feringa, Tetrahedron Lett. 1999, 40, 4893—4896. 

Phosphoramidites are probably the most versatile ligands in this series as in amidites the substituents at the nitrogen atom are in close proximity to the metal centre and also the substituents could carry chiral centres. In Figure 4.22 we have depicted the simplest derivative, named Monophos , which is highly efficient for asymmetric hydrogenation but for a variety of other reactions as well. The ligand is much easier to make than most, if not all, chiral bidentate phosphine ligands and surely commercial applications will appear. 

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]. 

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%. 

We have recently discovered that phosphoramidite 18 is also an excellent ligand for copper-catalyzed kinetic resolution of chiral 2-cyclohexenones (Scheme 7.15). Chiral 2-cyclohexenones are attractive building blocks for a variety of natural products, but their synthesis usually requires multistep routes from chiral starting materials [65]. The development of the new kinetic resolution was the product of two impor-... 

When an alkyl and an alkoxy moiety are present at the 4-position of the dienone (Scheme 7.17(b)), desymmetrization during the 1,4-addition produces two stereocenters in a single step. The chiral copper-phosphoramidite catalyst derived from... 

Alexakis, employing various chiral trivalent phosphorus ligands, has recently described Cu(OTf)2-catalyzed 1,4-additions of Et2Zn to a number of nitroalkenes (Scheme 7.22) [77]. TADDOL-based phosphonite 82 gave the highest ees for ar-ylnitroalkenes (up to 86%), whereas phosphoramidite 18 is the ligand of choice for alkylnitroalkenes [ees of up to 94%). 

The moderate ees obtained with the copper arenethiolate ligands discussed above prompted a search for new chiral ligands for use in asymmetric allylic substitution reactions. The binaphthol-derived phosphoramidite ligand 32, used successfully by Feringa et al. in copper-catalyzed 1,4-addition reactions [37], was accordingly tested in the reaction between 21 and n-BuMgl. 

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