Asymmetric amination

M.E. Van Dort, Y.W. Jung, P.S. Sherman, M.R. Kilbourn, D.M. Wieland, Fluorine for hydroxy substitution in biogenic amines Asymmetric synthesis and biological evaluation of fluorine-18-labeled beta-fluorophenylalkylamines as model systems, J. Med. Chem. 38 (1995) 810-815. 

Figure 5.4 Structural formulae showing tertiary (lidocaine (lignocaine), bupivacaine) and secondary (prilocaine) amines. Asymmetrical carbon atom.

A new C3-symmetric chiral phase-transfer catalyst that offers multipoint inteaction with a nucleophile has been described (Scheme 7.6) [23]. Thus, various quaternary ammonium salts were prepared through the ring opening of optically active epoxides, followed by quaternization of the resulting amines. Asymmetric benzylation of Schiff s base 20 in the presence of catalyst 24—26 yielded (S)-21 with moderate enantioselectivity. As expected, the C3-symmetric catalyst R,R,R)-26a provided... 

Zirconaaziridines react with unsaturated C-C bonds such as (1) olefins and acetylenes [20], and with unsaturated C-X bonds such as (2) aldehydes and imines [20], (3) heterocumulenes [21,43,49],and (4) carbonates [21,22,43,50] (Scheme 5). The products generated upon workup are a-functionalized amines. Asymmetric transformations can be carried out when a chiral zirconaaziridine or inserting reagent is used optically active allylic amines and amino acid esters have been prepared, and the details of these transformations will be discussed. 

Amidines, N-(l,2,4-thiadiazol-5-yl)-, rearrangement, 56, 103 Amidoximes, 1,2,4-oxadiazol-3-yl-, rearrangements, 56, 55 Amidyl radicals, see Radicals, nitrogen Amination, asymmetric, of carboxylic acids by chiral nitroso compds, 57, 41 Amines, catalysis of 3-acyl-1,2,4-oxadiazole arylhydrazone rearrangement by, 56, 87 Amines, thionitroso-, formation, 55, 20 Aminium cation radicals, see Radicals, nitrogen... 

Regioselectivity Anions of allyl silanes Anions of allyl sulfides Anions of allyl ethers Anions of allyl amines Asymmetric allylic amines Allyl Carbamates... 

Interfdci l Composite Membra.nes, A method of making asymmetric membranes involving interfacial polymerization was developed in the 1960s. This technique was used to produce reverse osmosis membranes with dramatically improved salt rejections and water fluxes compared to those prepared by the Loeb-Sourirajan process (28). In the interfacial polymerization method, an aqueous solution of a reactive prepolymer, such as polyamine, is first deposited in the pores of a microporous support membrane, typically a polysulfone ultrafUtration membrane. The amine-loaded support is then immersed in a water-immiscible solvent solution containing a reactant, for example, a diacid chloride in hexane. The amine and acid chloride then react at the interface of the two solutions to form a densely cross-linked, extremely thin membrane layer. This preparation method is shown schematically in Figure 15. The first membrane made was based on polyethylenimine cross-linked with toluene-2,4-diisocyanate (28). The process was later refined at FilmTec Corporation (29,30) and at UOP (31) in the United States, and at Nitto (32) in Japan. 

Alkyl dimethyl and dialkylmethyl tertiary amines are commercially available. These amines are prepared by reductive methylation of primary and secondary amines using formaldehyde and nickel catalysts (1,3,47,48). The asymmetrical tertiary amines are used as reactive intermediates for preparing many commercial products. 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaHy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphoms [7723-14-0] produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-Hthiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has Httie commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Sulfonyloxazindines as aprollc neutral oxidizing reagents oxidainn of amines, sulfides, selenides and asymmetric oxidation. 

Although unsynunetrically substituted amines are chiral, the configuration is not stable because of rapid inversion at nitrogen. The activation energy for pyramidal inversion at phosphorus is much higher than at nitrogen, and many optically active phosphines have been prepared. The barrier to inversion is usually in the range of 30-3S kcal/mol so that enantiomerically pure phosphines are stable at room temperature but racemize by inversion at elevated tempeiatuies. Asymmetrically substituted tetracoordinate phosphorus compounds such as phosphonium salts and phosphine oxides are also chiral. Scheme 2.1 includes some examples of chiral phosphorus compounds. 

An asymmetric synthesis has used the reduction of imonium salts to optically active tertiary amines with lithium aluminum alkoxy hydrides derived from optically active alcohols (538,539). 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

With the success in Lewis acid-catalyzed thiol conjugate addition reactions mentioned above, we further tried to apply the J ,J -DBFOX/Ph-nickel(II) aqua complex catalyst to the catalyzed asymmetric conjugate addition reactions of hydroxyl-amines [88, 89]. However, after some preliminary examinations, we found that... 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

To control the stereochemistry of 1,3-dipolar cycloaddidon reacdons, chiral auxiliaries are introduced into either the dipole-part or dipolarophile A recent monograph covers this topic extensively ° therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddidon can be divided into three main groups (1) chiral allyhc alcohols, f2 chiral amines, and Hi chiral vinyl sulfoxides or vinylphosphine oxides. 

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