A-amino aldehyde

An important extension of the Knorr pyrrole synthesis developed by Cushman utilizes ketone enolates and BOC-protected a-amino aldehydes and ketones. Two examples (37, 38) are shown. 

The Friedlander quinoline synthesis combines an a-amino aldehyde or ketone (1) with another aldehyde or ketone with at least one methylene a to the carbonyl (2) to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat. 

The addition of an achiral organometallic reagent (R M) to a chiral carbonyl compound 1 (see Section 1.3.1.1.) leads to a mixture of diastercomers 2 (syn/anti) which can be either racemic, or enantiomerically enriched or pure, depending on whether the substrates are race-mates or pure enantiomers. This section incorporates only those reactions starting from optically pure a-amino aldehydes, however, optical purity of the starting material has not been demonstrated in all cases. 

Nucleophilic addition reactions to A -monoprotected a-amino aldehydes 1 (Table 20) represent the beginning of the worldwide interest in peptide isosteres for the preparation of certain specific enzyme inhibitors (e.g., aspartylproteinase inhibition). Some examples of this reaction type show a relatively low diastereofacial selectivity, especially when the reactions are per-... 

The second important group of configuralionally stable bis-protected a-amino aldehydes are the V-dibenzvl derivatives 5, easily prepared from amino acids in a three-step procedure65. These aldehydes react with various nucleophiles to normally provide the nonchelation-con-trolled adducts in high diastereoselectivity. This anti selectivity is observed when diethyl ether or telrahydrofuran is used as reaction solvent. Certain Lewis acidic nucleophiles or additives, such as tin(IV) chloride, in dichloromethane as solvent force chelation and therefore provide the. syn-adducts, once again with a high diastereoselectivity. 

The cyanohydrin-forming addition of cyanide or cyanide equivalents (e.g.. cyanotrimethylsilane) to optically active a-amino aldehydes occurs diastereoselectively. 

The extent of the stereoselectivity depends on the protection of the nitrogen and also on the catalyzing Lewis acid. However, the monoprolected a-amino aldehydes 1 (R3 = H) show good to excellent chelation-controlled syn preference, independent of the Lewis catalyst employed6fi S9. 

For the monoprotected a-amino aldehydes, the best results in yield and stereoselectivity were obtained under kinetic control conditions which gave the expected sw-com pounds. The addition of tin(lV) chloride did not result in increased syn selectivity, and the use of boron trifluoride diethyl ether complex did not provide the ann -isomer as the major product. 

On the contrary, in the latter case, a total loss of stereoselectivity occurs68. TV-Bis-benzyl-a-amino aldehydes 1 (R = R3 = Bn) under the assistance of boron trifluoride, zinc bromide or tin(lV) chloride lead to the nonchclation-controlled adducts preferentially, whereas titanium(IV) chloride or magnesium bromide result in chelation control70. In some cases, the O-trimcthylsilyl cyanohydrins arc the primary products, but the workup procedure usually provides the desily-lated products. 

Alternatively, Cushman has devised a facile route to pyrroles by the reaction of Boc-a-amino aldehydes or ketones 14 with the lithium enolates of ketones 15 to afford aldol intermediates 16 which cyclize to pyrroles 17 under mild acidic conditions <96JOC4999>. This method offers several advantages over the Knorr since it employs readily available Boc-a-amino aldehydes or ketones and utilizes simple ketones instead of the p-diketo compounds or p-keto esters normally used in the Knorr. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

This route has been widely exploited because of the availability of a-amino azomethine compoimds from natural (S)-a-amino acids, through the corresponding a-amino aldehydes, which are configurationally stable provided that the amino function is suitably protected. Moreover, some a-amino acids are available with the R configuration and a number of enzymatic and chemical transformations have been described for the preparation of optically active unnatural a-amino acids. Overall, the route suffers from the additional steps required for protection/deprotection of the amino function and, in the case of hydrazones and nitrones, cleavage of the N - N or N - O bond. 

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. 

N-substituted and N,N-disubstituted chiral a-amino nitrones are also available from the corresponding a-amino aldehydes. In a first study, it was shown that the addition of phenylmagnesium bromide to N-Boc derivatives exclusively gave the syn N-Boc a-aminohydroxylamines with good yields, but... 

Metal-catalyzed asymmetric addition of dialkyl phosphites to aldehydes (Pudovik reaction) has been extensively developed since the initial reports in 1993 by Shibuya. Scheme 5-25 illustrates the use of TiCh to promote diastereoselective addition of diethyl phosphite to an a-amino aldehyde. 

Scheme 5-25 Titanium-promoted hydrophosphonylation of an a-amino aldehyde...

An efficient route for the synthesis of the Phe-Phe hydroxyethy-lene dipeptide isostere precursors utilized for the design of potential inhibitors of renin and HIV-protease was developed. The key step is the zinc-mediated stereoselective allylation of A-protected a-amino aldehydes in aqueous solution (Eq. 8.32).70 NaBF4/M (M = Zn or Sn) showed facilitating allylation of a variety of carbonyl compounds in water, and a-and y-addition products of crotylations could be alternatively obtained under the control of this novel mediator (Eq. 8.33).71... 

Diastereoselective allylation under aqueous Barbier conditions of a-amino aldehydes with the chiral building block (Ss)-3-chloro-2-(p-tolylsulfinyl)-l-propene to give enantiomerically pure sulfinyl amino alcohols in good yields and with high diastereoselectivity was reported (Eq. 8.34).73... 

Similarly, chiral nitrones (61a—c) and (62a—c) were obtained from the corresponding a-amino aldehydes (209, 210), nitrones (63a,b) from p-amino-a-hydroxy aldehydes (211), and chiral nitrones (64) and (65) from IV-fluorenyl-methoxycarbonyl (/V-Fmoc) amino acids and /V-Fmoc-dipeptides (Fig. 2.6) (212). 

Reactions of Vmylation and Ethynylation Vinylation and ethynyla-tion of nitrones using vinyl (137, 202, 563, 564) and ethynyl (199, 213, 219) organometalic reagents is a convenient method for synthesizing various nitrogen-containing compounds such as a-amino aldehydes, a-amino acids, amino... 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

Stereoselective allylation of aldehydes is another preferred strategy for the synthesis of appropriate intermediates for the total synthesis and introduction of hydroxy functionalities. Park and co-workers <2003S2473> proposed a synthesis of castanospermine 228 through a key indium-mediated allylation in the presence of (+)-cinchonine of an a-amino aldehyde 247 derived from D-glucono-O-lactone (Scheme 53). 

This reaction is applicable to the reduction of a-amino acids to optically active a-amino aldehydes with high yields (Scheme 27) [53]. 

A library of piperazine containing fused azepine-tetrazoles 183 was built by Nixey et al. via Ugi reaction in the solution phase [55]. This library comprises an example of a building block introduced piperazine (Scheme 32). The reaction of A-Boc-a-amino aldehyde 184, methyl isocyanoacetate 185, substituted piperazines 186, and trimethylsilylazide 181 in methanol, followed by acid treatment, proton scavenging, and reflux affords bicyciic azepine-tetrazoles 183. This efficient protocol with three diversity points can be used to generate arrays of biologically... 

Since a-branched aldehydes gave rather higher asymmetric induction (Scheme 6.166), Nagasawa et al. extended the biphasic strategy to the diastereoselective Henry reaction of nitromethane with enantiomerically pure (S)-configured N,N -dibenzyl protected a-amino aldehydes and a-hydroxy aldehydes protected as silyl ethers. The screening reaction (Scheme 6.169) demonstrated a match/mismatch... 

Scheme 6.169 Screening reaction to identify (R,R)-configured guanidine-thiourea 186 as matching catalyst for the anti-diastereoselective and enantioselective Henry reaction of (S)-a-amino aldehydes with nitromethane.

Utilizing 10mol% of (R,R)-guanidine-thiourea catalyst 186 under optimized biphasic condihons for the Henry reaction [224] of (S)-a-amino aldehydes with nitromethane furnished the corresponding nitroalcohols 1-6 in yields ranging from 33 to 82% and with excellent diastereoselechvities (up to 99 1 anti/syn) and enanhoselectivihes of the major isomer (95-99% ee) (Scheme 6.171) [328]. 

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