Reductive amination using

Protected pyrazoline derivatives 429 can be transformed by conventional ozonolysis methodology to the corresponding aldehydes 430, then the Cbz protecting group is removed and the intramolecular reductive amination using... 

N. Mohr and H. Budzikiewicz 107) described another example of an asymmetric reductive amination using a (S)-proline moiety as chiral inductor. 

This reaction refers to the case when a ketone or aldehyde is reductively aminated, using ammonium formate or another amine salt of formic acid. 

In other reports, /i-cyclodcxtrins have been used to induce asymmetry in borohydride reduction of ketones,166 a diastereoselective reduction has been controlled167 by a real lyltricarbonyl iron lactone tether , a phosphinamide has been combined with a dioxaborolidine unit as an activated, directed catalyst for ketone reduction,168 reductive amination using benzylamine-cyanoborohydride converts 3-hydroxy ketones into syn-1,3-amino alcohols,169 l-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propan-l-one has been reduced diastereoselectively,170 and production of chiral alcohols via (i) Itsuno-Corey and Brown procedures171 and (ii) lithium aluminium hydride modified by chiral nucleophiles172 has been reviewed. 

The synthesis is straightforward except for the Krapcho method (NaCl in wet DMSO) of decarboxylating one ester in a malonate 39 without hydrolysing the other. After the condensation this was used again to give the ketone 34 and finally the reductive amination used NH4OAc and NaB(CN)H3 as discussed in chapter 4. 

The phenols need to be protected as their methyl ethers 67 and functionalisation by SeC>2, as described earlier in this chapter, gives the keto-aldehyde 68. To get 65 we should have to reduce the ketone in the presence of the aldehyde but the workers at Boehringer discovered a shortcut reductive amination using hydrogenation reduced both the imine (from i-PrNH2 and the aldehyde) and the ketone to give 69 and hence, by deprotection, metaproterenol 64. Notice that the aldehyde in 68 is more electrophilic than the conjugated ketone so it forms the imine needed for reductive amination. 

An alternative method for reductive amination uses hydrogenation (hydrogen gas with a metal catalyst) to reduce the imine in the presence of the carbonyl compound. 

L-6-Hydroxynorleucine is a key intermediate used for the synthesis of a vasopepti-dase inhibitor. It was synthesized from 2-keto-6-hydroxyhexanoic acid by reductive amination using beef liver GluDH and GDH from Bacillus sp. for regeneration of NADH (Fig. 36) [155]. The educt of the reaction, 2-keto-6-hydroxyhexanoic acid is in equilibrium with 2-hydroxytetrahydropyran-2-carboxylic acid. 

Allysine ethylene acetal is synthesized from the corresponding keto acid by reductive amination using phenylalanine dehydrogenase (PDH) from Thermoacti-nomyces intermedius ATCC 33205 combined with FDH from C. boidinii SC13822 for the regeneration of NADH (Fig. 39). 

Fig. 39 Conversion of 5-(l,3-dioxolan-2-yl)-2-oxo-pentanoid acid to allysine ethylene acetal by reductive amination using phenylalanine dehydrogenase (PDH) and formate dehydrogenase (FDH) for cofactor recycling...

An alkylation by reductive amination using aldehyde 253 in the presence of sodium triacetoxyborohydride in 1,2-dichloroethane afforded the adamantyl compound 253, which after further deprotection produced an A, A -disu Instituted guanidine derivative 254 interesting for potential biological activity (Scheme 105 <2000JME2362>). 

Donsbach [2] prepared 3,3-diarylpropylamines by hydroformylation/hydro-carbonylation followed by reductive amination using (acetylacetonate)dicar-bonylrhodium as illustrated below, beginning with 4-hydroxybenzoic acid, ethyl ester. 

With a 1° or 2° amine as starting material, reductive amination is used to prepare 2° and 3° amines, respectively. Note the result Reductive amination uses an aldehyde or ketone to replace one H atom on a nitrogen atom by an alkyl group, making a more substituted amine. 

Another route to the formation of piperidine heterocycles is cyclization via reductive amination utilizing various hydride sources. The scheme below depicts a bis reductive amination, using sodium triacetoxyborohydride as the hydride source, to generate exo- l% and endo- 19 azabicyclo[3.2.1]octane amino acids in moderate yields <06JOC8467>. 

General guidelines for choice of reagent for reductive amination use LiAlH4 when the imine or oxime is isolated. Use Na(CH3COO)3BH in solution when the imine or iminium ion is not isolated. Alternatively, catalytic hydrogenation works in most cases. 

Now a difficulty emerged. They wanted to carry out the resolution on a large scale but enantio-merically pure 6 is expensive. The solution was to make it themselves from previously resolved cheap 2. The obvious route is reductive amination using benzaldehyde and the only danger is racemisation of the intermediate imine 7. They found that the imine 7 did not racemise as it was prepared in toluene but that some racemisation took place when NaB(CN)H3 was used for the reduction. The solution was to use catalytic hydrogenation and they prepared 53 kg batches of optically pure 7 in 98% yield by this method and used that to resolve the hydroxy acid 5. 

Fig. 32 A basic wedge-structureobtained by reductive amination used by Turbull and coworkers [225]...

Racemic compounds containing a carbonyl function can serve as good models for the study of diastereoselective reductive aminations using achiral amines as educts. Intermediates in these reactions ate imines. The related racemic amines are obtained with relatively low diastereose-lectivity11-14. 

The asymmetric reductive amination using ( + )-(/ )- or (—)-(S,)-l -phenylcthylamine as the chiral auxiliary has also been used in the synthesis of several cw-bicyclic lactams and amines32. 

The 6-bromodeoxy-tri- O -benzyl-pyranoside 44 was heated in a mixture of acetic acid and zinc dust to give 45, which directly underwent reductive amination using benzylamine and NaBH3CN to afford 46 (Scheme 9). Intramolecular aminomercuration of 46 with mercuric trifluoroacetate afforded bromomercurials 48 (61%) and 47 (39%). Reductive... 

Synthesis from aldonolactones The synthesis of p-homonojirimycin (2) from tetra-(9-benzyl-D-glucono-1,5-lactone (56) (Scheme 8) was achieved by treatment of the latter with (methoxymethoxy)methyl lithium to give the a-D-gluco-heptulose derivative 57, which underwent reduction with LiAlITj to produce a mixture of heptitols 58 (1 1 ratio). Oxidation of 58 using Swern oxidation (DMSO-TFAA) gave the heptodiulose 59. Compound 59 was immediately submitted to reductive amination using ammonium formate in the presence of sodium cyanoborohydride to produce 60 in 50% yield from 58. Removal... 

Preparation of Allysine Ethylene Acetal by Reductive Amination Using... 

Preparation of L-6-Hydroxynorleucine by Reductive Amination Using Amino Acid Dehydrogenase... 

Preparation of AttvsiNE EiMYtENF AcETAt by Reductive Amination Using Phenyeaeanine Dehydrogenase... 

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