A-chiral amines

Nitrogen chirality may also be produced by the action of an achiral peroxyacid on a Schiff base containing a chiral amine (75JOC3878). In this case the oxaziridine contains a configurationally known centre of chirality relative to this, absolute configurations of the centres of chirality at nitrogen and carbon, and thus the complete absolute configuration of the molecule, can be determined (see Section 5.08.2.2). 

In some reactions intramolecular chalcogen nitrogen interactions may lead to stereochemical control. For example, selenenyl bromides react with C=C double bonds, providing a convenient method of introducing various functional groups. The reaction proceeds readily, but affords a racemic mixture. The modified reagent 15.22 contains a chiral amine in close interaction with the selenium atom. It reacts with olefins affording up to 97% ee of isomer A (Scheme 15.2). ... 

CH2=CHCH2CH2C02CH2CN, 3-methyl-3-pentanol, Subtilisin Carlsberg. These conditions were used to resolve a chiral amine (43% yield, 97% ee). ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

High enantioselectivities may be reached using the kinetic controlled Michael addition of achiral tin enolates, prepared in situ, to a,/i-unsaturated carbonyl compounds catalyzed by a chiral amine. The presence of trimethylsilyl trifluoromethanesulfonate as an activator is required in these reactions236. Some typical results, using stoichiometric amounts of chiral amine and various enolates are given below. In the case of the l-(melhylthio)-l-[(trimethylsilyl)thio]ethene it is proposed that metal exchange between the tin(II) trifluoromethanesulfonate and the ketene acetal occurs prior to the 1,4-addition237,395. 

A small library of thiazolidinones 138 has been prepared mixing directly a primary amine (as the HCl salt), an aldehyde and mercaptoacetic acid in EtOH in the presence of Hiinig s base and molecular sieves (120 °C for 30 min) [88]. Working with a chiral amine, a 1 2 mixture of diastereoisomers was obtained (Scheme 49). 

A number of (S)- or (R)-2-aminoamides were independently obtained by running reactions between chiral 2-bromoamides 1 and an achiral primary or secondary amine, in both sets of conditions (ref. 5). Accordingly, either a diastereoisomeric mixture or a single diastereoisomer in high diastereoisomeric excess, resulted respectively when an (S,R)- or (S)-2-bromoamide is treated with a chiral amine, again in the two sets of conditions. 

Moreover, a dramatic increase of the reaction rate was observed when the coupUng of aromatic imines mediated by samariiun diiodide was carried out in the presence of both water and a tertiary amine or tetramethylethylene-diamine (TMEDA) [29], causing the almost instantaneous formation of the 1,2-diamine, although with undetermined diastereoselectivity. Similarly, the samarium diiodide promoted reductive coupling of iminiiun ions formed in situ by reacting ahphatic aldehydes with secondary amines and benzotriazole occurred at temperatures as low as - 70 °C [30]. Even in this case a mixture of diastereomers with undetermined ratio was obtained nevertheless, the item of diastereoselectivity induced by a chiral amine (auxiliary) is worthy of investigation. 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

Diketimines can be prepared by condensation of 1,2-diketones with 2 equiv of an amine, or 1 equiv of a 1,2-diamine, by azeotropic removal of water. Either a chiral diketone or a chiral amine/diamine can be used in order to obtain a chiral diimine. In both cases, the use of 1,2-diamines is expected to provide better stereocontrol, because of the rigidity of the derived cyclic diimines. For example, the reaction of camphor 1,2-diketone 275 and racemic 1,2-diphenylethylenediamine (d,l)-26 gave the diimine 276 as a mixture of two diastereomers (Scheme 45) [138]. Reduction of 276 with sodium borohydride followed by hydrogenolysis of the N substituents afforded the camphordiamine, which was isolated as the dihydrochloride... 

Disubstituted triazolium salts are prepared from alkyl or aryl hydrazines via an oxadiazolium salt 28 (Scheme 16). Addition of a chiral amine on this salt resulted in a ring opening - ring closure reaction affording the triazolium salts 29. 

Treatment of a chiral amine with phosgene is the cheapest way to prepare symmetrical ureas [29]. Nevertheless, due to the toxicity and reactivity of that reagent, it can advantageously be replaced by triphosgene [30] or l,l -carbonyldiimidazole [31-34] or other derivatives such as l,l -carbonyldi-2(lH)-pyridinone [35]. This procedure can be extended to thiophosgene (Scheme 1) and its thio-analogues, such as l,l -thiocarbonyldi-2(lH)-pyridinone to produce thioureas [36] chiral diamines can thus be transformed into the corresponding monoureas or monothioureas. 

Hirrlinger B, A Stolz (1997) Formation of a chiral hydroxamic aid with an amidase from Rhodococcus erythropolis MP50 and subsequent chemical Lessen rerarrangement to a chiral amine. Appl Environ Microbiol 63 3390-3393. 

Scheme 2.9 gives some examples of use of enantioselective catalysts. Entries 1 to 4 are cases of the use of the oxazaborolidinone-type of catalyst with silyl enol ethers and silyl ketene acetals. Entries 5 and 6 are examples of the use of BEMOL-titanium catalysts, and Entry 7 illustrates the use of Sn(OTf)2 in conjunction with a chiral amine ligand. The enantioselectivity in each of these cases is determined entirely by the catalyst because there are no stereocenters adjacent to the reaction sites in the reactants. 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

In 1980, Hengtges and Sharpless published a seminal report that dihydroxylation occurred in a good enantioselective manner when the reaction was carried out in the presence of a chiral amine, dihydroqunidine acetate (DHQD-Ac) or dihydroquinine acetate (DHQ-Ac). DHQD and DHQ are diastereomers to each other, but they behaved like enantiomers in this reaction (Scheme 42).167... 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

A final example, from the work of Trost (49), represents the only case in which an intramolecular Michael reaction has been catalyzed by a chiral amine. When the achiral cyclohexanone is treated with (- )-quinine and heated in toluene solution, the bicyclic ketone is formed in 83% chemical and 30% enantiomeric yield (eq. [8]). 

These results may be compared with those of the experiments of Schwartz and Carter (64) and Cohen (65a) with fl-phenylglutaric anhydride. [See also the more recent results of Fujita and co-workers with meso-2,4-dimethylglutaric acid (65b).] The former group showed that a chiral amine could discriminate between attack at the pro-(/J) and pro-(S) carbonyl groups of the anhydride. The two diastereomers were formed in a ratio of 3 2, with optical purities of about 20%. 

The use of chiral auxiliaries has been developed into elegant three-step sequences to achieve high ee s (Figure 2). In the general scheme a ketone is derivatized with a chiral amine. Low temperature lithiation and alkylation followed by hydrolysis produces the alkylated ketone in moderate to excellent ee s. The auxiliaries most often used are (S)-valine tert-butyl ester (Koga), l-amino-2-methoxymethylpyrrolidine (Enders) and (S)-2-amino-1-... 

Methylcyclopropanone hemiacetal (4) undergoes an asymmetric Strecker reaction to give IR, 25 )-(- -)-a/to-norcoronic acid (5) in good yield and high de. The induction depends on the use of a chiral amine [e.g. (5 )-a -methylbenzylamine] to control the face on which the intermediate iminium cation (6) is attacked. 

In 1998, Page and coworkers reported a series of dihydroisoquinoline-related iminium salts which can be readily synthesized in three steps from a chiral amine (Scheme 14) [140-143], Among the catalysts tested for asymmetric epoxidation, iminium salts 74 were found to be efficient catalysts (Fig. 24, Table 7, entries 2, 4-6, 17-19). Iminium salts 74a can epoxidize 4-phenyl-1,2-dihydronaphthalene in up to 63% ee (Table 7, entry 17). 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Gastaldi et al. discovered that in situ racemization of a chiral amine 59 was mediated by the addihon of thiyl radicals (Scheme 2.29). Combinahon with CALB... 

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