α -Amino acid derivatives with a C α -P bond in organic synthesis

α -Amino acid derivatives with a C α -P bond have been used for a wide range of chemical transformations, including synthesis of many kinds of bioactive compounds, e


Introduction
Chemical literature deals with the four most important kinds of α-amino acid derivatives with a C α -P bond: esters of N-acyl-α-triphenylphosphonio-α-amino acids 1, the most important of which are N-acyl-α-triphenylphosphonioglycinates (1a, R 3 = H), phosphonium ylides derived from glycine with the nitrogen atom incorporated into a β-lactam ring 2, α-(dialkoxyphosphoryl)glycinates 3 and their analogues with a tertiary nitrogen atom included into a β-lactam structure 4 (Figure 1).The great interest in these compounds is due to their many applications in organic synthesis.3][4][5] Recently, their applications in the synthesis of α,β-dehydro-α-amino acids in the Wittig reaction, 6 as well as their transformation to N-acyl-α-(dialkoxyphosphoryl)glycinates 3b, have also been described. 7Ylides 2 have been applied in Woodward's synthesis of β-lactam antibiotics since 1978. 8At the present time, α-(dialkoxyphosphoryl)glycinates derived from β-lactams 4 are being used for this purpose.α-(Dialkoxyphosphoryl)glycinates 3 have been gaining importance since 1973, when they were used for the first time by Ratcliffe and Christensen for the synthesis of β-lactam antibiotics. 9,10owadays, they have become the crucial synthetic tool for the synthesis of α,β-dehydro-αamino acids, dehydropeptides and glycopeptides in the Wadsworth-Emmons reaction.
The present review deals with the methods of synthesis, the properties and synthetic applications of the α-amino acid derivatives with a C α -P bond, mentioned above.

Scheme 1
In 1996 a simple and effective method for synthesizing 4-phosphoranylidene-5(4H)oxazolones 5 from N-acylglycine was described. 11,12The method consists in the transformation of N-acylated glycine into the corresponding 5(4H)-oxazolone 6 followed by the phosphorylation of this compound in situ with dibromotriphenylphosphorane or dibromotributylphosphorane in the presence of triethylamine (Scheme 2).
The most convenient method of synthesizing N-acyl-α-triphenylphosphonioglycinates (1a, X = BF 4 ) consists in treating a solution of phosphoranylideneoxazolones 5 in methanol with an ethereal solution of tetrafluoroboric acid. 2,4An alternative synthesis of N-acyl-αtriphenylphosphonioglycinates with an iodide counterion (1a, X = I) consists in the reaction of 4phosphoranylidene-5(4H)-oxazolone 5 with acetyl iodide in acetonitrile, followed by the reaction of the acylation product with methanol. 2,4The synthesis of N-acyl-α-triphenylphosphonio-αamino acids 1b with an alkyl substituent at the α-position by alkylation of phosphoranylideneoxazolones 5 with alkyl halides, 12,13 followed by the opening of the oxazolone ring with methanol or methanol in the presence of an acidic catalyst (Scheme 3), has been described, too.

N-Acyl-α-triphenylphosphonio-α-amino acid esters -properties and application in synthesis
3][4] They are easily accessible from N-acylglycine even on a kilogram scale (Scheme 2 and 3).These features, as well as their diversified reactivity, make them interesting reagents in organic synthesis.
In 1983 Kober and Steglich noticed that the treatment of N-benzoyl-αtriphenylphosphonioglycinate 1a (R 1 = Ph, X = Br) with triethylamine results in the formation of the corresponding 1,2-di(acylamino)fumaric acid diester 7. Based on this observation, they assumed that N-benzoyl-α-triphenylphosphonioglycinate, in the presence of triethylamine, was transformed to a mixture of the corresponding N-acyliminoacetate 8 and N-acyl-αtriphenylphosphoranylideneglycinate 9, which reacted slowly with each other to the fumaric acid derivative 7 (Scheme 4). 1 This hypothesis has been confirmed experimentally by Mazurkiewicz and Grymel, who demonstrated spectroscopically that the treatment of N-acyl-α-triphenylphosphonioglycinates 1a (R 1 = t-Bu, Ph; X = BF 4 ) with bases resulted in the immediate disappearance of the starting ester.Detailed analyses of 1 H-and 13 C-NMR spectroscopic data led to the conclusion that the reaction mixture contained the corresponding phosphonium ylide derived from glycine 9 and N-acyliminoacetate 8, which remained in an equilibrium (Scheme 4). 14Attempts to isolate ylide 9 and N-acyliminoacetate 8 from the reaction mixture failed, probably because of the instability of both these compounds. 14Both components of the equilibrium mixture are highly reactive compounds, which makes N-acyl-α-triphenylphosphonioglycinates an interesting starting point in organic synthesis.

ROCHN
Thus, N-acyl-α-triphenylphosphonioglycinates react as precursors of phosphonium ylides 9 with aliphatic or aromatic aldehydes in the presence of Et 3 N in the Wittig reaction in mild conditions yielding the corresponding α,β-dehydro-α-amino acid derivatives 10 in good or even very good yields (Scheme 4). 63][4] The especially interesting displacement of the triphenylphosphonium group with dimethylphosphite or trimethyl phosphite, which transforms N-acyl-α-triphenylphosphonioglycinates 1a into N-acyl-α-(dialkoxyphosphoryl)glycinates 3b will be discussed in Section 4.1.3 of this paper.
Thus, N-acyl-α-triphenylphosphonioglycinates may be considered to be synthetic equivalents of the glycine α-cation.If N-acyliminoacetate 8 or ylide 9 are not caught in their reaction with a nucleophile or a carbonyl compound, respectively, the ylide reacts as a nucleophile with Nacyliminoacetate, which eventually gives dimethyl 1,2-di(acylamino)fumarate. 1,14 Similarly as in the case of N-acyl-α-triphenylphosphonioglycinates 1a, N-acyl-αtriphenylphosphonio-α-amino acid esters 1b with an alkyl substituent at the α-position under the influence of triethylamine undergo immediate transformation to the corresponding ester of α-(N-acylimino)alkanecarboxylic acid 12; however in such a case, as is to be expected, esters 12 are the only primary reaction product.If esters 12 possess a hydrogen at the β-position, they can undergo tautomerization to the corresponding α,β-dehydro-α-amino acid derivatives 10, which can be isolated in good yields (Scheme 5). 4,14The addition of a nucleophile results, in this case, in a double functionalization of the glycine α-position with an alkyl group and a nucleophilic agent. 4

Phosphorus ylides derived from glycine with a nitrogen atom incorporated into a β-lactam ring
β-Lactam ring-containing compounds, such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenems, belong to the most important and most famous class of antibiotics. 15,16They are derivatives of parent systems such as cephem, carbacephem, oxacephem, penem and carbapenem (Figure 2).
ARKAT USA, Inc.As has already been mentioned, attempts to isolate phosphonium ylides 9 derived from N-acyl-α-triphenylphosphonioglycinates failed, because they are generated from the corresponding phosphonium salts simultaneously with N-acyliminoacetates 8, and react easily with the latter compounds to 1,2-di(acylamino)fumarates 7 (Scheme 4).On the other hand, a special class of relatively stable phosphonium ylides 2 derived from glycine, with the nitrogen atom incorporated into a β-lactam ring, is well known.Their stability is probably caused by the lack of hydrogen at the nitrogen atom in the parent phosphonium salts, which makes it impossible to form an iminoacetic acid derivative.The discussed ylides are widely used for the synthesis of bicyclic β-lactam antibiotics.One of the earliest methods of synthesizing them, described by Woodward, consists in the treatment of the corresponding β-lactams 14 with glyoxylic acid esters [17][18][19][20][21][22] or their hemiacetals, 8,23,24 which yields the corresponding αhydroxyglycine derivatives 15.The latter compounds react with thionyl chloride, followed by their reaction with triphenylphosphine in the presence of bases.β-Lactam antibiotics 16 derived from penem-3-carboxylic acid (Z = S) 8,19,23,24 and carbapenem-2-carboxylic acid (Z = CH) 21 were synthesized using this method (Scheme 6).

Synthesis, properties and application of α-(dialkoxyphosphoryl)glycinates
Since 1973, when Ratcliffe and Christensen used α-(dialkoxyphosphoryl)glycinates 3 in the synthesis of cephalosporins, 9,10 again and again, new information has appeared in the literature devoted both to the methods of synthesizing these important compounds and their application in organic syntheses.

Synthesis of α-(dialkoxyphosphoryl)glycinates
As the number of described methods of synthesizing α-(dialkoxyphosphoryl)glycinates 3 is considerable, these methods will be further on classified in this paper, depending on which of the three bonds of the C α atom is formed the last, as follows: -formation of the C α -COOR bond, -formation of the C α -N bond, -formation of the C α -P bond.

Scheme 10
Amination with O-mesitylenesulfonylhydroxylamine, carried out in DME in the presence of sodium hydride gives the expected α-(diethoxyphosphoryl)glycinates in about 40% yield. 26The explosive properties of O-mesitylenesulfonylhydroxylamine are the main drawback of this method. 26hloramine in the presence of sodium hydride or potassium t-butoxide was also used for the amination of diethoxyphosphorylate 25 giving the amination product 3a in 24-84% yields (Scheme 10). 27This method does not seem to be a suitable process for large scale preparations, because of the difficulty of generating the hazardous chloramine in a large quantity. 27][30] Electrophilic amination of the α-position of diethoxyphosphorylacetates can also be performed in a few steps, e.g. by the reaction of the enolate anion derived from the ester 25 with ethyl nitrite, followed by the reduction of the obtained oxime 26 with zinc in acetic acid or aluminum amalgam (Scheme 11). 27,31The low yield of the oxime synthesis is the main limitation of this method.

Scheme 11
It has also been shown that the reaction of the enolate anion of t-butyl diethoxyphosphorylacetate (25, R = t-Bu) with tosyl azide in 1,2-dimethoxyethane at 0 o C leads to the corresponding diazo derivative 27 with a yield of 81% (Scheme 12). 27Subsequent catalytic hydrogenation of the latter compound using 10% palladium on charcoal in methanol gave the desired amination product 3a in a good yield. 27iazo derivatives of diethoxyphosphorylacetates 27 were also used as precursors of rhodium carbenoids in N-H insertion reactions catalyzed by rhodium (II) acetate. 323][34] It should be noted, that both tosyl azide and diazo compound 27 are potentially explosive.40% yield R = Et 50 -80% 32 88 -93% 33,34

Scheme 12
The amination of diethoxyphosphorylacetates can also be carried out via the azido derivative 29 (R = Et), which was obtained in the reaction of the corresponding starting compound 25 with trifluoromethanesulfonyl azide in a yield of 40%. 35Catalytic hydrogenation of the azide 29 gave the corresponding α-(diethoxyphosphoryl)glycinate 3a in a 90% yield (Scheme 12). 35

Formation of the C α −P bond
Several methods of synthesizing α-(diethoxyphosphoryl)glycinates by the formation of a C α -P bond have also been described.One of them consists in the addition of diethyl phosphite to the ARKAT USA, Inc.
Schiff base 30 in the presence of sodium hydride.The addition product 3c was then catalytically hydrogenated to the corresponding α-(diethoxyphosphoryl)glycinate 3a in a quantitative yield (Scheme 13).

Scheme 22
The α-(diethoxyphosphoryl)glycinate moiety was synthesized by N-acylation of β-lactam with ethyl oxalyl chloride followed by the reaction of the obtained oxamate 45 with triethyl phosphite and bromotrimethylsilane, the mechanism of which is analogous to the one shown in Scheme 14.
A similar method was used for the synthesis of fused tricyclic carbapenems, which bear the name "trinems"(Scheme 23). 15,46 O