Aminoalkyl and Related Acids

9 Aminoalkyl and Related Acids. - Diethyl (l-aminoalkyl)phosphonates have been prepared by reduction of the oximes of (l-oxoalkyl)phosphonates with NaBH4 in the presence of NiCla or MoOa and diethyl (2-amino-2-arylethyl)-phosphonates by hydrogenation of the methyl ethers or acetates of the oximes of the corresponding 2-oxo esters.  

The addition of hydrogenphosphonates or related compounds to imines or their trimers continues to be a widely employed procedure. Noteable is the observation that whereas the addition of hydrogenphosphonates to (193) require a period of heating at 90 °C for appreciable reaction to occur, sonication of reaction mixtures produces immediate addition to form (194). Interest has tended to be centred around the potential for stereochemical control of the addition through modification to the stereochemistry of the hydrogenphospho-nate or other phosphorus intermediate, or in the use of selected imines. Slight control was observed in the addition of (25,4i )-(195) to (196) the products, (197), exhibited diastereoisomeric ratios of 40-45 60-55. Modest diastereo-selectivity was also observed in reactions between (198) and (199) leading to 

The addition of lithium diethyl phosphite to the imines (201) from (/ )-(—)- -amino-l-phenyl-2-methoxyethane gave mixtures of (202) and (203) in the ratios of 110 1 to 7 1, but mostly around 50 1. The sequence was completed by hydrogenolytic removal of the benzylic group, when the product (1-aminoalkyl)-phosphonic diesters had e.e.s of 96-99%. The diastereoisomeric ratios within (205), obtained from the chiral sulfoxides (204) and diethyl (lithiomethyl)phos-phonate, varied from 4.9 1 (R = PhCH=CH) to 9.2 1 (R = 2-thienyl), but the ratio also depended, to some extent, on the nature of the phosphonate alkyl group.  

In planning a general enantioselective route to (l-aminoalkyl)phosphonic acids, French workers originally considered the alkylation of (212) (R = H), but this procedure led to products of only moderate e.e.s. Newer work has now considered the preparation and use of the perhydro-l,4,2-oxazaphosphorine 

The amidation of a-hydroxyallylic phosphonates (2IS) with nitriles in the presence of trifluoromethanesulfonic acid proceeds with high ( )-stereoselectivity and with moderate to good yields of (216) [R = H, R = Me or Ph R = Me, = Ph R R = (CH2)n, n = 2-4 R = Me or Ph]. Mannich reactions between diethoxyphosphinoylacetic acid, a primary amine, and formaldehyde, have been used for the preparation of (217).  

The Beckmann rearrangement of oxime mesylates initiated by TiCU has been applied to the preparation of 1,2-dehydro-1-aminoalkylphosphonates, e.g. 201, through trapping of the intermediate with triethyl phosphite. Oximes of a-ketophosphonates are often difficult to reduce to the corresponding 1-aminoalk- 

The Rh acetate catalysed decomposition of dimethyl a-diazobenzylpl-ospho-nate (204) in the presence of primary amines and amides offers a simple route to the corresponding a-aminophosphonates. 1-Aminocycloalkylphosphonates 205 have been synthesised from the corresponding cycloalkylphosphonate via electrophilic azidation of the phosphonate carbanion followed by catalytic hydrogenation.  

Phosphono analogues 206 of glutathione have been prepared as inhibitors of glutathione 5-transferases. 1-Aminophosphonate structures have potential as haptens in a number of areas and examples of such compounds reported include 207 and 208. The A-hydroxy-l-aminophosphonates 208 were prepared from 

Various solid-phase syntheses have been reported including the phosphinic acid dipeptide analogues 209 which were constructed by coupling the appropriate Wang Resin-bound amino acid to the phosphinate carboxylic acid 210 using Fmoc chemistry. Similar phosphinate carboxylic acid derivatives (211) protected at phosphorus as their 1-adamanyl esters have also been used in solid-phase synthesis directed towards zinc metallo protease inhibitors.  

Reagents i, DEAD, PhaP, THF, room temp. ii, TFA, CH2CI2 

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Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonate derivatives. The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(0Et)2 and P(OEt)3 in ionic liquids. TaCb-Si02 has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-... 

Aminoalkyl and Related Acids. Various 1-aminoalkylphosphonic acids (313) have been obtained in high yield by microwave assisted reaction of ammonium hypophosphites (314) with aldehydes (Scheme 83). ... 

By contrast, the reactions of the amino group in (aminoalkyl)phosphonic and related acids are, in principle, relatively simple and few in number, interest in the acids, as a class, residing in their biochemical properties. Their diazotization leads to (diazoalkyl)phos-phonic derivatives, and the protection of the amino group by acylation (as acetyl, benzoyl... 

As already shown for dihydrothiazole-containing cyclic peptides (Section 6.8.5.2.2.2), basically two different synthetic routes are used for the introduction of dihydrooxazoles into cyclic peptides. In the first one, 2-(aminoalkyl)dihydrooxazole-4-carboxylic acids and related derivatives are synthesized,t554 571,572 589 590 then incorporated directly into the linear precursors, which are finally cyclized by standard protocols.1541.554.567.569.5711 Again the main disadvantage to this synthetic approach is the facile racemization of the dihydrooxazole syn-thon. Therefore, the preferred method is the production of the oxazolidine ring in the preassembled cyclic peptide. For this purpose various methods have been proposed. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

The creation of diastereoisomeric molecules which are epimeric at phosphorus presents no fundamental difficulties. Such molecules are readily available by means of reactions between the dichlorides RP(=Z)Cl2 (Z = O, S or Se) and an appropriate chiral difunctional compound. Many reactions that lead to such products were indicated in the previous chapter in connection with the synthesis of enantiomers of, particularly, (l-aminoalkyl)phos-phonic acids and related compounds. With regard to the preparation of diastereoisomeric thio- or seleno-phosphoryl compounds epimeric at phosphorus, the chiral reactants first used were modified carbohydrates and, less successfully, simple mono- or di-substituted diols. The latter provided simple monocyclic 1,3,2-dioxaphospholanes and 1,3,2-dioxaphosphorinanes which could provide (a) chiral centre(s) on (a) ring carbon atom(s), but also generated compounds epimeric at phosphorus their inconvenience often lay in lack of availability of cheap starting materials. In the case of the carbohydrates, the substrates were readily available from cheap starting materials thus, methyl 2,3-di-(9-methyl-... 

The roundabout route to 57 via 56 was required because attempted direct replacement of a-halide by hydroxide or (trimethylsilyl) oxide had failed in a model compound. In view of the instability of (a-aminoalkyl)boronic esters toward deborona-tion, described in a subsequent section, it is plausible that an (a-hydroxyalkyl)boronic ester might deboronate similarly if the hydroxyl group was deprotonated by base, though (a-hydroxyalkyl)boronic ester 57 and related compounds are stable under neutral or acidic conditions. (Trimethylsilyl)oxide apparently failed because the pinanediol oxygens migrated faster than the silyloxide from boron to carbon [41]. 

Attempts to convert the Akacyl derivatives of the moderately stable a-amino sulfonic acids by turning them into sulfonyl chlorides and then directly to sulfonamides have failed it appears that the critical requirement for C-S bond rupture is related to a sufficient activation of the sulfonate. 1061 Any synthetic approach to the desired sulfonamide derivatives which utilizes N-protection of aminomethane sulfonic acid as the initial step seems to offer little likelihood of success. In the context of the overactivation of the sulfonyl group of N-protected aminoalkyl sulfonic acid, (l-elimination of the S02C1 is favored over the corresponding sulfonamide, with amines acting merely as bases, not as nucleophiles (Scheme 24). 107 ... 

The Mannich reaction l and the related a-aminoalkylations of nucleophilic anions of weak acids are also examples of MCRs of type I,t whereas ring closures to heterocycles, e.g. the Hantzschf l and Radziszewkit l reactions, correspond to MCRs of type II. The Asinger reactiont sometimes belongs to type I and in some other cases to type II MCRs. 

In 1960, Hellmann and Opitz l realized that the majority of the previously discussed named reactions and other related processes are all a-aminoalkylations of nucleophilic compounds of sufficiently weak acids, corresponding to MCRs of type I, or they have secondary reactions of type II that are followed by the formation of heterocycles [the Hell-mann-Opitz three-component reaction (HO-3CR),t Scheme 2]. In 1921, Passerinih 47] jjj. troduced his three-component reaction (P-3CR), which involves the reaction of a carboxylic acid 7, a carbonyl compound 1, and an isocyanide 10, to form (via rearrangement of the first-formed product 11) an a-carboxy-substituted alkanamide 12 (Scheme 2). This was the first example of a MCR of type II that involved an isocyanide. 

An eneamine derivative (30) prepared from compound 11 can be acylated with phosgene and the resulting acid chloride 31 then converted to the desired amides 25 (Eq. 6).17,22 23 This sequence of reactions also proved useful for preparing 3-aminoalkyl esters and 3-aminoalkylamides related to 25.24... 

Accordingly, the Ugi reaction is closely related to the Mannich reaction and may be classified as an a-aminoalkylation. However, at the same time, a special type of Ugi reaction, the formation of a-acylami-nocarboxamides (42g) by 4CC of carboxylic acids and primary amines with carbonyl compounds and isocyanides, resembles the Passerini reaction (see Section 4.6.2). 

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