Imines stereoselective additions

A parallel solution-phase asymmetric synthesis of a-branched amines has been reported by Ellman and coworkers based on stereoselective addition of organomag-nesium reagents to enantiomerically pure tert-butanesulfinyl imines [156]. Micro-wave heating was utilized in two of the steps of this synthesis of asymmetric amines, both for the imine formation and for the resin capture (Scheme 7.128). 

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2-63). 

Stereoselective addition of organometallics to C=N bond is not fully understood due to a number of difficulties. First, imines are not as electrophilic as... 

Stereoselective addition to carbonyl groups is a powerful tool in organic synthesis and has received a great deal of attention. Addition to imines can be equally as powerful, but has received much less attention. Denmark and co-workers first introduced the use of bis(oxazoline) ligands in the addition reactions of imines.The most successful ligand has been the modified bu-box ligand 182. This ligand was used both stoichiometrically and catalytically in the reaction between various imines and several alkyllithium species. Selected examples are summarized in Table 9.32 (Fig. 9.54). 

The stereoselective addition of allylmetal reagents to imines is one of the most important reactions in organic synthesis for carbon-carbon bond formation [118, 129] (Scheme 8.59). 

Hashimoto, Y. Takaoki, K. Sudo, A. Ogasa-wara, T. Saigo, K. Stereoselective addition reaction of organolithium reagents to chiral imines derived from erythro-2-amino-l,2-diphenylethanol. Chem. Lett. 1995, 235-236. 

A direct stereoselective addition of an activated imine to jS-keto phosphonates in the presence of a chiral copper(II) catalyst has been developed 83... 

The reaction of imines with 2-pyridyl thioesters in the presence of aluminium tribromide or ethylaluminium dichloride afforded /ra r-3,4-disubstituted azetidin-2-ones < 1996T2583>. Similar stereoselective addition of silylketene thioacetals to imines is known in the presence of Lewis acids <1996T2573>. An indium-mediated reaction of ethyl bromoacetate with imines yielded 3-unsubstituted azetidin-2-ones in reasonable yields (Equation 195) <2000J(P1)2179>. 

Stereoselective addition of a chiral cyclic phosphite to a cyclic imine was applied to the synthesis of phosphonic analogs of d- and L-penicillamine41. Enantiomerically pure dioxaphospholane oxide 6 underwent addition to 2,5-dihydro-2,2,5,5-tetramethylthiazole in the presence of boron trifluoride as a catalyst. The diastereomeric adducts 7, obtained in a 2 1 ratio, were easily separated on silica gel and their configuration assigned by X-ray analysis the (4/ )-isomer was shown to be the major diastereomer. Hydrolysis of each diastereomer gave pure enantiomers of phosphopenicillamine 841. 

STEREOSELECTIVE ADDITION AND SUBSTITUTION REACTIONS 10.3.1 Additions to Glycosyl Imines and Other Nucleophilic Additions... 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

Although the level of enantioselectivity observed in this study was modest, this contribution has documented for the first time the use of a dialkylzinc reagent for the stereoselective addition of a carbon nucleophile to the imine function. 

A few examples of stereoselective additions of organomagnesium or -cerium reagents to imines bearing a chiral arenechromium tricarbonyl or dieneiron tricarbonyl residue have been described [539, 1197], Reactions of allylmetals with an oxime bearing a chiral ether functionality can be stereoselective provided that the oxime displays the E configuration [1198],... 

A full paper has appeared on the preparation of P-chiral fullerenephosphinites reported last year. A series of functionalised alkylphenylphosphinic acids has been synthesised by addition of in situ prepared bis(trimethylsilyl) phenylphos-phonite (12) to a range of electrophiles, e.g. (IS). Stereoselective syntheses of the four diastereomers of phosphothreonine have been described which are based on the stereoselective addition of diethyl trimethylsilyl phosphite (14) to protected lactaldehyde (15) or its imine. A similar procedure gave access to phosphomycin... 

The stereocontrolled synthesis of 1,2-aminols is of interest due to the utility of these substances as efficient synthons for a variety of natural products. A highly stereoselective addition of lithium alkyls or Grignard reagents to the 0-protected a-hydroxy-A-trimethylsi-lylimines generated in situ constitutes the path for the preparation of these 1,2-aminols. Thus, the addition-elimination reaction of lithium hexamethylsilylamide with aldehyde 129, easily obtained in two steps from 103, leads to the a-OTBS-A -TMS-imine 130 (Scheme 30). 

Yoon et al. [33] found that thiourea catalyst with an amine function promotes the stereoselective addition of a range of nitroalkanes to aromatic A-butoxycarbonyl (A-Boc) imines. In the Mannich reaction of nitroethane (Table 9.12) high enantioselectivity, but low yield, is observed when urea is used (run 1), whereas thiourea affords the adduct in >95% yield with 92% ee (run 2). It should be noted that addition of powdered molecular sieves is necessary for reproducible results. 

Rhodium-catalyzed chelation-assisted C—H bond functionalization reactions (enantioselective annulation of aryl imines, dihydropyridine synthesis from imines and ahcynes, one-pot synthesis of pyridines from imines and alkynes, 2-arylpyridine alkylation with imines) 12ACR814. Synthesis of pyridine and dihydropyridine derivatives by regjo- and stereoselective addition to N-activated pyridines 12CRV2642. 

It is also noteworthy that Ricci and co-workers have disclosed phase nitro-Mannich (or aza-Henry) reaction using Al-Carbamoyl imines generated in situ from a-amido Sulfones using phase-transfer catalysts [78]. Ricci s direct use of a-amido sulfones as acceptors has also inspired developments in aminocatalysis as described vide infra. Here the 7/-benzyl quininium chloride catalyst has a dual function by generating the corresponding Al-carbamoyl imines in situ and next activate the nucleophile for the highly stereoselective addition (Scheme 4.17). 

A similar reaction mechanism could be assumed for the aza-Henry reaction catalyzed by urea 38 [46], In this particular case, the sulfinyl group acts both as an acidifying agent and a chiral controlling element, and allows the stereoselective addition of nitroethane to aromatic and, in two instances, aliphatic N-Boc imines (Scheme 29.21). 

The intermediate 139 formed following the addition of z-butylmagnesium chloride to the nitrile 138 was then treated with sulfoxide 137 to afford the sulfinyl ketimine 140. " Diastereoselective addition of hydride to the chiral imine 140 in the presence of Ti(0 Pr)4 afforded the chiral amine 142. This reaction may proceed via a closed-transition state (e.g., 141) in which the sulfoxide coordinates to the metal center and directs the stereoselective addition of hydride, as has been proposed for related reactions.Treatment of the sulfoxide 142 with acid and base effected removal of the auxiliary. 

SCHEME 47.23. Stereoselective addition of a P-nucleophile to imine in the synthesis of iminosu gar phosphonates. 

Among numerous studies employing this auxiliary [26], Davis enantiose-lective synthesis of (-)-agelastatin A (88), a cytotoxic tetracyclic marine alkaloid, is noteworthy (Scheme 11.13) [77]. In this synthetic endeavor, the major u,p-syn diamino ester 87 was obtained in 73% isolated yield through the dia-stereoselective addition of N-protected glycine enolate 85 to a,/S-unsaturated p-toluenesulfmyl imine 86. 

An conceptually different approach using the chiral Bronsted acid catalyst 306 (Equation 33) was devised by Johnston [192]. This catalyst effected the stereoselective addition of nitroalkane 305 to N-Boc-protected imine 304 to provide the syn adduct 307 in 7 1 dr and 90 % ee. Interestingly, the pfC of 306 has been determined to be 5.8, thus indicating that this catalyst is not sufficiently acidic to protonate the imine 304 [193]. The inherent simplicity in the catalyst structure 306 is truly remarkable, given its ability to effect control over the stereochemical outcome of such addition reactions. 

Since alkenes are relatively impotent precursors to aziridines, especially with regard to stereoselective reactions, substantially greater advances have been made in this field by means of the addition reactions between imines and a range of car-bene equivalents. 

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