Amines diastereoselective synthesis

For the preparation of enantiopure amines, diastereoselective synthesis using a chiral auxiliary can be a viable approach. In this concept, in the first step a chiral intermediate is formed by reaction of a prochiral substrate with the chirality transfer agent. The key second step is a diastereoselective reaction. This is followed by cleavage of the chiral auxiliary to give the product amine. This concept is illustrated in Figure 25.1. 

More recently, Carreira reported a [Fe(TPP)Cl]-catalyzed diastereoselective synthesis of trifluoromethyl-substituted cyclopropane in aqueous media [56]. The carbene precursor trifluoromethyl diazomethane is difficult to be handled, generated in situ from trifluoroethyl amine hydrochloride, and reacts with styrene in the presence of [Fe(TPP)Cl] to give the corresponding cyclopropanes in high yields and with excellent diastereoselectivities (Scheme 12). 

Nenajdenko VG, Reznichenko AL, Balenkova ES (2007) Diastereoselective Ugi reaction without chiral amines the synthesis of chiral pyrroloketopiperazines. Tetrahedron 63 3031-3041... 

This alkylation strategy has been successfully implemented to the diastereoselective synthesis of a number of biologically active compounds,17 19 32 72 73 including the orally active HIV protease inhibitor Crixivan (>95% de)17-19 and nucleoside antibiotic (+)-sinefungin (51) (>99% de).72 The C-6 amine stereochemistry of (+)-sinefungin was set by a highly diastereoselective allylation of (lS,2/ )-l-amino-2-indanol-derived oxazolidinone 52 (Scheme 24.10). 

Scheme 1.11. Diastereoselective synthesis of a Cgo-scandine conjugate by tandem reaction sequence involving a photoinduced addition of a tertiary amine and a [2 + 2] cycloaddition. The structure of the product includes a noninherently chiral functionalization pattern in addition to stereogenic centers in the alkaloid moiety.

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Diastereoselective synthesis of homoallylic amines. The Diels-Alder adducts (2) formed from 1,3-dienes and 1 undergo basic hydrolysis to a single unsaturated sulfonamide (3) via a concerted rctro-cnc reaction. 

Kunz and coworkers reported the application of an immobilized chiral galacto-sylamine in diastereoselective synthesis of piperidine and amino acid derivates [14]. Preparation of the galactosylamine auxiliary from 1,6-hexandiol and P-D-galactopyranosyl azide (1) required a six-step synthesis protocol. The precursor 2 was loaded onto a polymer bound silane. Reduction of the azide function gave the corresponding immobilized amine 3 (Scheme 12.2). 

Reductive N-N cleavage of hydrazines. A diastereoselective synthesis of chiral a-amino aldehydes (4) from glyoxal involves an intermediate dimethylhydrazone (1), which reacts with an alkyllithium to provide an a-substituted N, N -dimethylhydrazine (2). The mildest method for cleavage of hydrazines to primary amines (3) involves hydrogenolysis catalyzed by Raney nickel at 30-50°. This Raney nickel reductive cleavage is markedly improved by sonication and proceeds at atmospheric pressure of H2 at 20° in CH3OH in yields of 66-84% with no racemization or debenyzlation. ... 

Scheme 14.21 Enantio- and diastereoselective synthesis of homoallylic fragments. CHAPTER 15 [2,3]-REARRANGEMENTS OF AMMONIUM ZWITTERIONS Scheme 15.1 Sigmatrnpic 12.31-rearrangements of reactive ammonium zwitterioas. Scheme 15.2 Meisenheimer s original report of an amine N-oxide rearrangement. Scheme 15.3 12.31- and ri.21-Meisenheimer rearrangements of amine jV-oxides.

A new efficient and stereoselective synthesis of furo[2, 3 5,6]pyrano[4,3-i)]quinoline derivatives and has been achieved by intramolecular hetero Diels-Alder reactions of aldimines generated in situ from aromatic amines and the O-allyl derivative of the chiral sugar derived aldehyde in acetonitrile in the presence of a catalytic amount (10 mol%) of BiCl3. The products are formed with extremely high (>95%) trans-selectivity in good to excellent yields (Equation 20) [38a]. The authors have also carried out the diastereoselective synthesis of new hexahydropyrazolo[4, 3 5,6]thiopyrano[4,3-t>] in the similar conditions [38b]. 

The Strecker reaction of a dial with an amine and hydrogen cyanide, to produce a cyclic a,a -dicyanoamine, involves HCN addition to a cycUc imino nitrile intermediate as the final step. A highly diastereoselective synthesis of dihydro-5//-dibenz[c, ]azepines (80) from the biphenyldicarboxaldehyde exploits the chiral twist of the biaryl axis to achieve stereoselection. ... 

Azetidines are compounds of interest in the field of agricultural and pharmaceutical chemistry. They are also useful as monomers and cross-linkers in polymer industry. Due to ring strain associated with it, azetidines are also useful S5mthons in organic chemistry. The common methods for S5mthesis of azetidines are cyclizations of y-amino alcohols, y-amino halides, 3-amino allenes, reactions of 1,3-dielectrophiles with amines, metal-catalyzed cyclizations in diazocarbonyls, cycloaddition reactions, and reduction of 2-azetidinones. There are several reports in literature on the S5mthesis of azetidines in aqueous media. A diastereoselective synthesis of azetidines is reported by the reaction of azazirconacyclopentane derivatives with iodine followed by treatment with aqueous potassium carbonate [26]. 

SCHEME 42 A diastereoselective synthesis of 1,2,3,4-tetrahydroquinolines from the reaction of l-vinylpyrrolidinone-2-one with amines. 

The reaction of l-vinylpyrrolidinone-2-one 124 or l-vinylazepan-2-one with aromatic amines 125 on refluxing in water leads to a diastereoselective synthesis of 2-methyl-4-amino-l,2,3,4-tetrahydroquinolines 126 in moderate to good yields (Scheme 42) [95]. No catalyst or any other additive is required for the reaction. The formation of products has been explained by an equilibrium between l-vinylpyrrolidinone-2-one 124 and its corresponding iminium ion 127 in water under reflux (Scheme 43). The active iminium ion could be easily attacked by anilines to form another intermediate 128, which subsequently be transformed into imine 129 with elimination of 2-pyrrolidinone. Finally, imine 129 xmdergoes an aza-Diels-Alder type cycloaddition with another molecule of l-vinylpyrrolidin-2-one forming the desired products. The reaction of a representative 128 with 1-vinylpyr-rolidin-2-one under similar conditions affords the 1,2,3,4-tetrahydroquinoline, which supports the proposed mechanism. 

In Section 5.3.1, an example of the typical reactivity of a-oxo-ketenes as 1-oxa-dienes in inverse demand oxa-Diels-Alder reactions was presented. It was recently discovered that in the presence of 1-aza-dienes, a-oxo-ketenes can also react as dienophiles in microwave-assisted aza-Diels-Alder cycloadditions, and this reactivity was exploited for the diastereoselective synthesis of a series of a-spiro-8-lactams (Scheme 5.4). Paralleling the three-component approach presented in Section 5.3.1, the microwave irradiation at 140 °C for 15 minutes of a 1 1 1 mixture of the 5,5-dimethyl-2-diazocyclohexan-l,3-dione 1, benzyl-amine, and cinnamaldehyde furnished the a-spiro-8-lactam... 

Stereoselective Reductive Amination Using Chiral Amines as Auxiliary In 2004, Alexakis and coworkers reported on the diastereoselective synthesis of... 

Carson CA, Kerr MA. Diastereoselective synthesis of pyrro-hdines via the Yh(OTf)3 catalyzed three-component reaction of aldehydes, amines and 1,1-cyclopropanediesters. J. Org. Chem. 2005 70 8242-8244. 

A study on the diastereoselective synthesis of a-fluorinated -amino acids by a-fluorination has been presented. The diastereomeric excess (up to 94%) and yield in these reactions have been found to be influenced by both the size of the amino acid side chain and the nature of the amine protecting group. 

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