Reductive amination/lactamization

The Painter group developed another approach to tetramates (e.g., 320) that involved the reductive amination of y-oxobutenoates (e.g., 319) in the presence of primary amines (Scheme 81 2002S869). Unsaturated dicarbonyl 319 was prepared in three steps by the phosphine-catalyzed Michael addition of benzyl alcohol to butynoate 318, desilylation, and oxidation of the resulting primary alcohol with 2-iodoxybenzoic acid (IBX). Treatment of 319 with tert-butylamine followed by sodium borohydride gives the O-benzyl tetramate 320 via a reductive amination—lactamization. 

Among the anionic/reduchve domino transformations, one of the most often encountered is the reductive amination of a carbonyl compound being followed by the formation of a lactam. As did many others before, Abdel-Magid and coworkers used this approach for the synthesis of y- and 6-lactams as 2-949 from either ketone 2-944 and amine 2-945 or amine 2-946 and ketone 2-947 via 2-948, employing sodium triacetoxyborane (Scheme 2.212) [484]. 

The numerous synthetic approaches relied principally on the formation of a 5-substituted proline ester by reductive amination followed by cyclization of the lactam ring. 

Reduction of lactams to amines resembles closely the reduction of amides except that catalytic hydrogenation is much easier and was accomplished even under mild conditions. a-Norlupinone (l-azabicyclo[4.4.0]-2-oxodecane) was converted quantitatively to norlupinane (l-azabicyclo[4.4.0]decane) over platinum oxide in 1.25% aqueous hydrochloric acid at room temperature and atmospheric pressure after 16 hours [1122]. Reduction of the same compound by electrolysis in 50% sulfuric acid over lead cathode gave 70% yield [1122]. 

Reduction of lactams (cyclic amines) 9-40 Reduction of lactones (cyclic ethers)... 

Reductive amination amides and lactams.1 The a-nitro ketone 1, prepared as shown, on reduction with NaBH4 in the presence of ammonia gas is converted into the amide 2 in 30% yield. 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

Compared to t.l.c. results the effective yields in the two step process seem to be much better than if the products are isolated and purified. There are indications that during chromatography, some of the nitro lactams are destroyed. In competition with this reductive amination/ring enlargement reaction is the enamine expansion route, discussed at the beginning of this Chapter (Scheme VII/6). Therefore the imine in this sequence must be reduced immediately after its formation. 

This protocol led to the diamine 46, which also represents a protected amino sugar (2,4-diamino-2,4-dideoxy-L-xylose). Interestingly, the direct reductive amination of 47 was followed by in situ cyclization to afford the lactam 48 as the major diastereomer. 

Conditions normally suitable for Leuckart-Wallach reductive amination (90 % formic acid and A-methylformamide at 170 °C) converted 4-azacholest-5-en-3-one (144) into the 5a-saturated lactam (145). A 17-oxo-group was simultaneously converted into the 17j8-A-methylformamido-derivative. 

Various accounts report the synthesis of heterocyclic androstane derivatives. 17)8-Acetoxy-4-oxa-androst-2-ene (215) has been prepared in three steps from the hemiacetal (214). Since various 4-aza-steroids exhibit antimicrobial activity, several new 4-aza-androstanes have been prepared. The reduction of ring a enamine lactams, such as 4-aza-androst-5-ene-3,17-dione (216a), under conditions of the Leuckart-Wallace reductive amination, provided 17/ -(iV-methyl-... 

Gheorghe et al. make use of sodium cyanoborohydride as a hydride source in the synthesis of 5-arylpiperidines <06OL1653>. Kellehar and Kelly report the formation of a spiro -lactam using sodium borohydride in the key reductive amination step <06TL3005>. 

In summary, a broad range of large-scale applicable biocatalytic methodologies have been developed for the production of L-amino acids in technical quantities. Among these industrially feasible routes, enzymatic resolutions play an important role. In particular, L-aminoacylases, L-amidases, L-hydantoinases in combination with L-carbamoylases, and /l-lactam hydrolases are efficient and technically suitable biocatalysts. In addition, attractive manufacturing processes for L-amino acids by means of asymmetric (bio-)catalytic routes has been realized. Successful examples are reductive amination, transamination, and addition of ammonia to rx,/fun-saturated carbonyl compounds, respectively. 

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. 

Thus, we first discuss thermodynamics, paying attention to features that are important for polymer synthesis (e.g., dependence of equilibrium monomer concentration on polymerization variables) then we describe kinetics and thermodynamics of macrocyclization, trying to combine these two related problems, usually discussed separately. In particular we present the new theory of kinetic enhancement and kinetic reduction in macrocyclics. Thereafter, we describe the polymerization of several groups of monomers, namely cyclic ethers (oxiranes, oxetanes, oxolanes, acetals, and bicyclic compounds) lactones, cyclic sulfides, cyclic amines, lactams, cyclic iminoethers, siloxanes, and cyclic phosphorus-containing compounds, in this order. We attempted to treat the chapters uniformly we discuss practical methods of synthesis of the corresponding polymers (monomer syntheses and polymer properties are added), and conditions of reaching systems state and reasons of deviations. However, for various groups of monomers the quality of the available information differ so much, that this attempt of uniformity can not be fulfilled. 

Reduction of lactams Tertiary lactams are transformed into tertiary amines. 9-BBN holds an advantage over borane because it does not complex with amines and therefore no excess reagent is required. 

Diazabicyclo[4.3.0]nonene-based peptidomimetics with a quaternary chiral centre are prepared via intramolecular condensation of A -aminopropyl-y-lactam [27]. Reductive amination of oxazolidinone aldehydes with A -monoprotected propylenediamine give A -phthalimidopropyl lactams however, trials of cyclization to bicyclic amidines after deprotection under dehydration conditions are unsuccessful. To solve this problem, the phthalimides are converted to thiolactams with Lawesson reagent. Deprotection followed by treatment with mercury (11) chloride (HgCl2) yields desired cyclic amidines (Scheme 3.14). 

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