# Synthesis of enantiomerically pure amino acids

Valérie Rolland, L. Pappalardo, Jean-Marie Receveur, Mehdi Sadoune, Yves

Vidal, Philippe Viallefont, Marie-Louise Roumestant

► To cite this version:

Valérie Rolland, L. Pappalardo, Jean-Marie Receveur, Mehdi Sadoune, Yves Vidal, et al.. Synthesis of enantiomerically pure amino acids. A.GAYATHRI. Recent Research Developments in Synthetic Organic Chemistry, 2, S.G. Pandalaï, pp.35-47, 1999, 81-86846-43-3. hal-04712628

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Recent
Research
Developments
in

Synthetic
Organic
Chemistry

Vol. 2 - 1999

Managing Editor
S. G. PANDALAI

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(Salt Lake City)

RECENT RESEARCH DEVELOPMENTS IN
SYNTHETIC ORGANIC CHEMISTRY

Published by Transworld Research Network

1999; Rights Reserved

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ISBN : 81 - 86846 - 43 - 3

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CONTENTS

<table><tbody><tr><td>Silyl- and stannylcupration of unactivated multiple bonds: Scope and synthetic applications<br>A. Barbero and F. J. Pulido</td><td>1</td></tr><tr><td>Radical cyclizations. Synthesis of oxa- and aza-heterocyclic compounds<br>Janine Cossy</td><td>23</td></tr><tr><td>Synthesis of enantiomerically pure amino acids<br>L. Pappalardo, J. M. Receveur, V. Rolland, M. Sadoune, Y. Vidal, Ph. Viallefont and M. L. Roumestant</td><td>35</td></tr><tr><td>Use of natural products in pest management; Synthetic studies on pheromones and antifeedants<br>François-Didier Boyer, Josiane Beauhaire, Giang Vo Thanh, Charles Desccons Jr., Martine Letteré, Anne-Claire Hervier, Yvain Roué, Paul-Henri Ducrot</td><td>49</td></tr><tr><td>Lexitropsin peptides conjugated to aromatic amino acids and β-lactam antibiotics: Synthesis and DNA binding properties<br>Mark Frasier, Vanessa Swartz and Kevin M. Church</td><td>69</td></tr><tr><td>Recent developments in the synthesis of indolocarbazoles, topoisomerase I inhibitors<br>M. Prudhomme, F. Anizon and P. Moreau</td><td>79</td></tr></tbody></table>
# Synthesis of enantiomerically pure amino acids

L. Pappalardo, J.M. Receveur, V. Rolland, M. Sadoune, Y. Vidal, Ph. Viallefont and M.L. Roumestant

UMR 5810, LAPP Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cédex 5, France

Natural and unnatural α-amino acids are used in practically all areas of the physical and life sciences. They are not only « building blocks » for peptides, proteins and other natural products but also they are used extensively in the pharmaceutical, agrochemical and food industries. They have also been utilized in total synthesis both as sources of chirality in final products and as chiral auxiliaries, reagents and catalysts for asymmetric synthesis.

Because of this widespread use, a great number of methods for both the small and large scale preparation of natural as well as structurally diversified α-amino acid derivatives were reported (1). They can be classified in three methods :

-Enantioselective synthesis in which the two important ways of introducing chirality into a molecule are catalytic asymmetric synthesis and the use of chiral auxiliaries.

- Enantiospecific synthesis starting from «the chiral pool»

- Resolution methods

This review focuses on the syntheses principally carried out in the laboratory for the obtention of α-amino acids and α-aminophosphonic acids by enantioselective synthesis using as chiral auxiliary 2-hydroxypinan-3-one 1, by enantiospecific synthesis using as starting material commercially available or laboratory made chiral

building blocks and by resolution methods.

## I- Enantioselective synthesis: 2-hydroxypinan-3-one as chiral auxiliary

This chiral auxiliary is very attractive because easily obtained by permanganate oxidation (2) of (+) or (-) α-pinene which are commercial inexpensive products. Recently Krishnamurthy et al.(3) reported an other method which involves the diastereoselective dihydroxylation of α-pinene using potassium osmate and NMO (N-methylmorpholine N-oxide) and subsequent oxidation to the hydroxy ketone by DMSO activated by pyridine. SO₂. The two enantiomers of 2-hydroxypinan-3-one are now commercially available. Twenty years ago Yamada (4) showed that 2-hydroxypinan-3-one was an effective chiral auxiliary for the enantioselective synthesis of α-amino acid derivatives ; he described the synthesis of four α-amino acids by stereoselective alkylation of the dilithio salt of the ketemine (d.e. 66 to 83%).

In the laboratory we have used this chiral auxiliary to synthesize a great number of non proteinogenic mono and disubstituted α-amino acids (5) starting from Schiff bases 2 or from oxazinone 5 by reaction with different electrophiles.(Scheme 1)
<figure><img src="image_2.png" /><figcaption>Scheme 1</figcaption></figure>

### 1 - Schiff bases

Schiff bases of methyl glycinate or monosubstituted α-aminoesters 2 were easily prepared in good yields by reaction of 2-hydroxypinan-3-one with α-aminoesters in refluxing toluene in presence of BF₃, Et₂O. Starting from monosubstituted α-aminoesters the two

chromatography and this method allowed the obtention of the two enantiomerically pure isomers (6) after cleavage of the imine function using citric acid or a very mild agent : boric acid.

We have prepared numerous enantiomerically pure compounds by reaction of enolates of chiral Schiff bases 2 with different electrophiles (7) (alkyl halogenides, saturated and unsaturated alkenes, etc.).
alkylation reactions we were interested in investigating the factors influencing the steric course of the reaction (5b) and in particular:

- the nature of the base

- the nature of the alkylating agent

- the steric encumbrance of the ester substituent

- the substituent R present on the Schiff base before alkylation.

Several bases were used (LDA, LTMP, Li (N Si Me₃)², *tert*-BuOK). The chemical yields were not affected by the base, however in most cases the lithiated amines gave the best diastereoselectivity excepted in the case of sulfenylation reactions (8), the sulfenylating agent being disulfide, where *tert*-BuOK produced the best results.

Concerning the alkylating agent, the diastereoselectivity was better for the non activated one than for activated ones. Concerning the ester substituent R¹, the first results in the laboratory (5a) were obtained with methyl esters because the methoxy group was very useful to determine the diastereomeric excesses (d.e) by ¹H N.M.R. During the study on the synthesis of optically pure monosubstituted α-amino acids at an industrial scale, we noticed that the chemical yield was not dependent on R₁ but the d.e. was related to the size of the ester group and for R¹ = *tert*-Bu an excellent d.e (>98%) was obtained compare to R¹ = CH₃ (d.e 50 to 69%).

However for the synthesis of disubstituted α-amino acids both chemical yield and d.e were dependent on R¹; so starting with α-monosubstituted amino esters (R≠ H) the *tert*-Bu group cannot be used, the chemical yield was very poor, however the *i*-Bu group gave good results.

Moreover alkylation in the reverse sequence preferentially gave the same Schiff base diastereomer

(5). For example aminoesters of the same configuration were obtained starting from the Schiff base of phenylalanine methyl ester and introducing a methyl substituent and starting from the Schiff base of alanine methyl ester and introducing a benzyl substituent.

The chirality of the aminoester (R<sup>±</sup> H) played a prominent role on the course of the reaction (9) and the results obtained in this study clearly showed that the alkylating agent was not only «spectator» of the aggregates (10) of the lithium enolates previously formed approaching them by a definite face but it entered these aggregates and changed them before reaction of alkylation.

Two models were proposed in the literature to rationalize the results, the monomeric one described first by Yamada (4) and the dimeric one reported by Solladie-Cavallo (11) and were discussed later by Matsumoto et al.(12).

These two models didn't take into account the role of the electrophile.

More recently we applied this methodology to the synthesis of non proteinogenic α-amino acids.

Enantiomerically pure (2R, 5R) and (2R, 5S) 5-hydroxypipecolic acid (13) 6a, 6b were prepared, with the aim of introducing them into various peptides as replacements of the homologs D or L-4-hydroxyproline. (Scheme 2)

In order to develop new specific glutamate analogues(14) 7 at metabotropic glutamate receptors, Diels-Alder 1,4-ionic and radical reactions were performed starting from (2S) 4-methylene glutamic acid easily obtained in a three short step synthesis using as key reaction the diastereoselective alkylation of glycinate Schiff base (R=H) with methyl 2-bromomethyl acrylate. (Scheme 3)

(2S, 3R,4S) 4-hydroxyisoleucine has been described as a new insulinotropic compound (15) this secretagogue
<figure><img src="image_3.png" /><figcaption>Scheme 2</figcaption></figure>

may be considered as a novel drug with potential interest for the treatment of non insulinodependant diabetes mellitus. We prepared (2S, 4S) and (2R, 4R)-γ-hydroxynorvalines(16) 8 which can be considered as analogues of 4-hydroxyisoleucine; moreover these trifunctionalized chiral synths can be used as new chiral building blocks in combinatorial chemistry. (Scheme 3)

<figure><img src="image_4.png" /><figcaption>Scheme 3</figcaption></figure>

2-hydroxypinan-3-one was also used in the enantioselective synthesis of monosubstituted α-aminophosphonic acids (17) and in particular for the obtention of enantiomerically pure phosphonic analogue of homoserine (18) which was easily transformed into homoserine lactone (19) 10, a new pseudopeptide unit considered as hapten for eliciting catalytic antibodies. (2S, 3R, 4R) ethoxycarbonylcyclopropylglycine 9, constrained amino acid, was also synthesized (20), the key-step involving 1,4-addition of the chiral enolate to ethyl-4 bromocrotonate. (Scheme 4)

The enantiospecific synthesis (21) of several α-aminophosphonic esters like phosphonic analogues of vinyl glycine 12, DABA (diaminobutyric acid) 13, homophenylalanine 14, homoquisqualic acid 15 starting from easily available chiral building blocks 11a, 11b was achieved in good yields. (Scheme 5)

In spite of the potential synthetic power of
<figure><img src="image_5.png" /><figcaption>Scheme 4</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Scheme 5</figcaption></figure>

stereoselective protonation of enolates this subject did not attract great interest until recently (22). The pioneering work on the « deracemization « of amino acid derivatives by enantioselective protonation of the corresponding enolates was carried out by L. Duhamel (23)

In the laboratory we examined the potential of

diastereoselective protonation (24) of enolates of chiral Schiff bases (R≠H). For deprotonation several bases have been tested (LDA, LiHMDS, tert-BuOK, KHMDS), tert-BuOK was most suitable among the bases examined. Protonation was attempted by different proton sources (H₂O, CH₃CO₂H, NH₄Cl/H₂O,...) the best results were obtained using a saturated solution of NH₄Cl (Yields 92 to 96%; d.e 79 to > 98%) starting from 2-hydroxypinan-3-one of S)-chirality, (R) amino esters were obtained.

This method has been extended to non natural α-amino acids and particularly to the synthesis of 7-azatryptophan 16 which is a potential fluorescent probe, azatyrosine 17 which is known as an antibiotic and anticarcinogenic compound and to tribromo and trichlorophenyl alanine 18 which are interesting precursors for the labelling of biologically active peptides. Racemic aminoesters (azatyrosine, tribromophenyl alanine methyl esters) were obtained by alkylation of methyl N-diphenylmethylene glycinate with the corresponding bromides easily prepared from commercially available materials.
Racemic azatryptophan methyl ester was obtained by reaction of azagramine on diethyl N-acetyl aminomalonate in the presence of NaOH in refluxing toluene using Robison's (25) method. From these racemic aminoesters, reaction with 2-hydroxypinan-3-one yielded the chiral Schiff bases which were deprotonated by tert-BuOK in THF and reprotonated by

a saturated solution of $NH_4Cl$. In these conditions azatyrosine and tribromophenyl alanine Schiff bases were obtained in good yields and excellent d.e. (>98%) where as 7-azatryptophan was prepared only in 66% d.e. (Scheme 6)

This last compound (26) was synthesized enantiomerically pure by enzymatic resolution of the N-

<figure><img src="image_7.png" /><figcaption>Scheme 6</figcaption></figure>

17:R=a

18:R=b

19:R=c

acetyl derivative by Aspergillus genus acylase.

## I - 2 1,4-oxazinone

1,4-oxazinone 4 was easily prepared (7) in two steps by esterification of 2-hydroxypinan-3-one by Boc or Z glycine followed by cleavage of the protecting group and spontaneous cyclisation in 65% overall yield. The same procedure starting from racemic monosubstituted N-Boc α-amino acids led to optically pure oxazinones (27) in 48% overall yield after two successive resolutions, partial resolution during the ester formation followed by complete resolution during the cyclisation to form the oxazinone.

Alkylation of 4 using tert-BuOK as base allowed the synthesis of amino acids 5 in high enantiomeric excess (7). Moreover the potassium enolate of 4 reacted rapidly with aldehydes (acetaldehyde propionaldehyde, benzaldehyde) at -78°C and in very good yields (85%) to

afford the dehydro compound 19a resulting from the spontaneous dehydration of the intermediate aldols. ¹H NMR spectra showed that only the Z configuration was present or very preponderant (90/10). The same reaction starting from formaldehyde gave a poor yield and the best method to obtain 19b was the reaction of Eschenmoser's salt on oxazinone 4 in $CH_2Cl_2$ (84% yield).

These dehydro compounds allowed the synthesis of a large variety of enantiomerically pure α-amino acids using cycloaddition or 1,4-addition reactions.

Cyclopropanic α-amino acids were obtained by cycloaddition with diazomethane (28) or by reaction with Corey's ylide (29).

Diels-Alder reactions on the two dehydro compounds 19a (R=Me) 19b (R=H) in the presence of a Lewis
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

1) BF₃.Et₂O (1.2eq) r.t/24 or 48h/CH₂Cl₂

2) MeOH/Na (10eq)

3) 1M HCl /THF/H₂O propylene oxide

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>Scheme 7</figcaption></figure>
acid at room temperature using as dienes: 3-methylbutadiene, 2,3-dimethylbutadiene and cyclopentadiene led to the cycloadducts in good yields (50-60%) and excellent diastereoselectivity (30). Among the Lewis acids that were tested ($TiCl_4$, $Et_2AlCl$, $BF_3$, $Et_2O$) $BF_3$, $Et_2O$ produced the best results; in the presence of $TiCl_4$ 19a was isomerised (Z to E). (Scheme 7)

To obtain α-amino acids, cleavage of the oxazinone ring was achieved using two procedures: cleavage of both ester and imine functions by 6M HCl (one step procedure) or cleavage of the ester function by MeONa in refluxing MeOH followed by treatment of the imine with 1M HCl (two steps procedure). The S configuration of the spiranic carbon established by X ray diffraction confirmed as expected that the diene

approached the opposite face to the gem dimethyl group.

To our knowledge the dehydro compounds are the first dienophiles inducing a total stereoselectivity with acyclic or cyclic dienes allowing an easy access to cyclic α-amino acids in enantiomerically pure form.

We have also studied 1,4-addition reactions on compound 19b; 1,4 radical reactions were unsuccessful, only reduction products were obtained. On the contrary the reaction of organocuprates (dimethyl, dibutyl, diphenyl) led to the 1,4-addition products in 50 to 73% yield. In each case only one stereoisomer was detected by ¹H NMR in $C_6D_6$ showing that the organocuprate attacked the less shielded face opposite to the gem dimethyl group. (Scheme 8)

<figure><img src="image_13.png" /><figcaption>Scheme 8</figcaption></figure>

Finally we examined the tandem reaction: 1,4 addition followed by reaction with an electrophile like an aldehyde. In this case also only one compound was obtained with total control of the chirality on the two carbons.

This recent result opens up the opportunity to obtain a great variety of enantiomerically pure α-disubstituted functionalized amino acids.

## II - Enantiospecific synthesis

A general method (31) was elaborated in the laboratory, for the synthesis of optically pure α-amino

esters by reaction of organocuprates with tosyl and halogeno derivatives of L-serine and L-homoserine. (Scheme 9)

<figure><img src="image_14.png" /><figcaption>Scheme 9</figcaption></figure>

This reaction was very performant starting from homoserine derivatives (n=2) and allowed the obtention of different α-amino esters in enantiomerically pure form and was successfully extended to the synthesis of γ-
hetaaryl a-amino acids (32) using organocyanocuprates.

In contrast with serine derivatives an elimination reaction
was the major process and the percentage
(substitution/elimination) depended on the nature of the
leaving group and the amine protecting group however
the substitution product was predominant (31) when
Y=Ts and X = I.

Been engaged in a program of synthesis of a-amino
acids of the quisqualate family, neuroexcitatory
aminoacid, we have prepared quisqualic acid 20
precursors 21 and analogues 22, by reaction of
nucleophiles on iodohomoserine and synthetic
equivalents of serine.

R or S quisqualic acid 20 was prepared (33) starting
from R or S serine via Garner's aldehyde (34) in 17%
overall yield.

To prepare compound 21a, we preferred using a
synthetic equivalent of serine, N-protected a-amino β-
lactone, which was easily obtained in stereochemically
pure form by Mitsunobu type cyclisation using a
modified procedure of Vederas (35). Nucleophilic
opening of this lactone by N-ethoxycarbonyl N-
benzyloxythiourea prepared by condensation of O-
benzylhydroxyl amine on ethoxycarbonyl isothiocyanate
led to the desired product in 40% yield. The reaction of
23 on iodohomoserine tert-butyl ester led to the
substitution product which after silmultaneous cleavage

<figure><img src="image_15.png" /></figure>

20

<figure><img src="image_16.png" /></figure>

21 a: n=1

21 b: n=2

<figure><img src="image_17.png" /></figure>

22

<figure><img src="image_18.png" /></figure>

23

<figure><img src="image_19.png" /></figure>

21a

<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /></figure>

21b

<figure><img src="image_22.png" /></figure>

22

<caption>Scheme 10</caption>
of tert-butyl and Boc groups led to amino acid (36) with an overall yield of 60%. The reaction of 4-phenyl-1,2,4-oxadiazolidine-3,5-dione, prepared using Steibrunn's (37) procedure, on iodohomoserine t-butyiester led to the desired substitution compound 22 in 70% yield. (Scheme 10)

### III - Resolution methods

Engaged in a program of synthesis of insulino stimulant amino acids we planed to synthesize pyrazolyl alanine 24 which is a natural compound first isolated from the pressed juice (38) and the seeds of watermelon (Citrullus vulgaris) (39) and has subsequently been found in other cucurbit plants ; it presents hypoglycemic properties. Needing appreciable quantities of the two enantiomerically pure isomers for biological activity studies, we envisaged a short and practical synthesis in two steps of either enantiomer of β-pyrazolylalanine which could be performed on gram scale.

Reaction of an excess of pyrazole (3 eq) on

commercially available methyl-2 acetamidoacrylate in CH3 CN at 60°C in the presence of K2CO3 led directly to potassium salt of N-acetyl-β-pyrazolylalanine in 90% isolated yield. Resolution of N-acetyl β-pyrazolyl alanine with an acyclase from Aspergillus genus was very performant and allowed the obtention of the two enantiomerically pure enantiomers (enantiomer purity being checked on chiral Crown Pack CR+). (Scheme 11)

This method was extended with success to the synthesis of β-triazolyl, β-azaindolyl alanine and quisqualic acid.

In certain cases the purification was very tedious and it was difficult to separate the excess of nucleophile so we turned out to a solid phase synthesis (40) which facilitated the purification. Wang resin was selected because of an easy acidic cleavage ; Mitsuhobu reaction was the best method for anchoring of N-acetamidoacrylic acid. For 1,4-addition reaction best yields (75-80%) were obtained at room temperature

<figure><img src="image_23.png" /><figcaption>Scheme 11</figcaption></figure>
<figure><img src="image_24.png" /><figcaption>Scheme 12</figcaption></figure>

$CH_3CN$ in the presence of $K_2CO_3$ using 6 equivalents of nucleophile. (Scheme 12)

## IV Conclusion

The different methods used for the synthesis of enantiomerically pure α-aminoacids and α-aminophosphonic acids, enantioselective synthesis, enantiospecific synthesis, racemic resolution permitted the easy access to a large variety of compounds (monosubstituted, disubstituted, alicyclic, cyclic, with functionalities) with total control of chirality on one or several carbons.

The experimental conditions were very mild and avoided partial racemisation during the synthesis. The chiral auxiliary 2-hydroxy pinan-3-one and its derivative the oxazinone were easily available, cheap. The ketone was quantitatively recovered and can be recycled.

The enantiospecific synthesis starting from γ-iodohomoalanine and the racemic resolution starting from 2-acetamido acrylic acid (or ester) are, very performant and rapid methods for the obtention of γ and β substituted α-amino acids.

## References

1. Williams R.M. 1989. Synthesis of optically active α-amino acids. In organic chemistry series, Baldwin, J.E., Magn P.D. (Eds); Pergamon Press, Oxford, Vol.7 Duthaler R.O. 1994. Tetrahedron 50, 11539

2. Schmidt, H 1960. Chem. Ber. 93, 2485.

Carlson, R.G., Pierce J.K., 1971. J. Org. Chem. 36, 2319.

3. Krishnamurthy V., Landi J.J. Jr and Roth P. 1997. Synthetic Commun. 27, 853.

4. a) Yamada S.I., Oguri T, Kawai N, Shioiri T., 1976.

J. Chem. Soc., Chem. Commun. 136. b) Oguri T., Kawai N., Shioiri T and Yamada S.I. 1978. Chem. Pharm. Bull., 26, 803.

5. a) Bajgrowicz J.A., Cossec B., Pigière Ch., Jacquier R. and Viallefont Ph. 1983. Tetrahedron Lett. 24, 3721.

b) Tabcheh M., El Achqar A., Pappalardo L., Roumestant M.L., Viallefont Ph. 1991. Tetrahedron 47, 4611.

6. Bajgrowicz J.A., Cossec B., Pigière Ch., Jacquier R., Viallefont Ph. 1984. Tetrahedron Lett. 25, 1789.

7. El Achqar A., Boumzebra M., Roumestant M.L. and
Viallefont Ph. 1988. Tetrahedron 44, 5319.

8 - Bentama A., Hoarau S., Pappalardo L., Roumestant M.L. and Viallefont Ph. 1994. Amino Acids, 7, 105.

9 - El Achqar A., Roumestant M.L. and Viallefont Ph. 1988. Tetrahedron Lett., 29, 2411.

10 - Seebach D. 1988. Angew. Int. Ed. Engl. 27, 1624.

11 - Solladie-Cavallo A. Simmon M.C. 1989. Tetrahedron Lett. 30, 6011.

Solladie-Cavallo A. Simmon-Wermeister M.C. 1993. Organometallics 12, 3743.

12 - Matsumoto T. Shioiri T. Osawa E. 1996. Tetrahedron 52, 5961 and 52, 5971.

13 - Hoarau S. Fauchère J.L., Pappalardo L., Roumestant M.L. and Viallefont Ph. 1996. Tetrahedron Asymmetry, 7, 2585.

14 - a) Receveur J.M., Roumestant M.L., Viallefont Ph. 1995. Amino Acids, 391.

b) Receveur J.M., Guiramand J., Recasens M., Roumestant M.L., Viallefont Ph and Martinez 1998.J. Bioorg. Med. Chem. Lett. 8, 127.

15- Sauvaire Y., Petit P., Broca C., Manteghetti M. Baissac Y., Fernandez-Alvarez J., Gross R., Roye M., Leconte A., Gomis R., Ribes G. 1998.Diabetes 47, 206.

16 - Jacob M., Roumestant M.L., Viallefont Ph. and Martinez J. 1997. Synlett 691.

17 - Jacquier R., Ouazzani F., Roumestant M.L., Viallefont Ph. 1988. Phosphorus Sulfur, 36, 73.

18 - Ouazzani F., Roumestant M.L., Viallefont Ph., El Hallaoui A. 1991. Tetrahedron Asymmetry 2, 913.

19- Ryglowski A., Lazaro R., Roumestant M.L., Viallefont Ph. 1996. Synthetic Commun. 26, 1739.

20- Hannour S., Roumestant M.L., Viallefont Ph., Riche Cl., Martinez J., El Hallaoui A., Ouazzani F. 1998. Tetrahedron Asymmetry in press

21 - a) Alami A., Ouazzani F., Roumestant M.L., Viallefont Ph. and El Hallaoui A. 1992. Amino Acids, 2, 189. b) Hannour S., Roumestant M.L., Viallefont Ph, Martinez J., Ouazzani F., El Hallaoui A. 1998.

Phosphorus Sulfur and Silicon, in press.

22 - Reviews a) Duhamel L., Duhamel P., Launay J.C., Plaquevent J.C. 1984.Bull. Soc. Chim. Fr. II - 421. b - Fehr C. 1991. Chimia 45, 253. c - Fehr C. 1996. Angew. Chem. Int. Ed. Engl. 35, 2566.

23 - Duhamel L., Plaquevent J.C. 1978. J. Am. Chem. Soc. 100, 7415.

24 - Tabcheh M. Guibourdenche C., Pappalardo L., Roumestant M.L. and Viallefont Ph. 1998. Tetrahedron Asymmetry 9, 1493.

25 - Robison M.M., Robison B.L., 1955. J. Am Chem. Soc 77, 457.

26 - Lecointe L., Rolland-Fulcrand V., Roumestant M.L., Viallefont Ph. and Martinez J. 1998. Tetrahedron Asymmetry 9, 1753.

27 - Calmes M., Daunis J., Escale F., Jacquier R., Roumestant M.L. 1994. Tetrahedron Asymmetry 5, 1643.

28 - Alami A., Calmes M., Daunis J., Escale F., Jacquier R., Roumestant M.L., Viallefont Ph. 1991. Tetrahedron Asymmetry 2, 175.

29- Calmes M., Daunis J., Escale F. 1996. Tetrahedron Asymmetry, 7, 395

30 - Sadoune M., Vidal Y., Roumestant M.L., Viallefont Ph., Martinez J. Tetrahedron submitted.

31 - Bajgrowicz J.A., El Hallaoui A., Jacquier R., Pigière Ch., Viallefont Ph., 1985. Tetrahedron 41, 1833.

32- El Marini A., Roumestant M.L., Pappalardo L., Viallefont Ph. 1989. Bull. Soc. Chim. France 554.

33 - Guibourdenche C., Roumestant M.L., Viallefont Ph. 1993. Tetrahedron Asymmetry 4, 2041.

34- Garner P., Min Park J. 1987. J. Org. Chem. 52, 2361.

35 - Arnold L.D., Kalantar T.H., Vedera J.C. 1985. J. Am. Chem. Soc. 107, 7105.

36 - Alami A. Guibourdenche C., Roumestant M.L., Viallefont Ph. unpublished results.
37 - Steibrunn G. 1962. Chem. Abstr. 57, 8741 h

38 - Shinano S., Kaya T. 1957.J. Agric. Chem. Soc. Japon 31, 759.

39 - Noe F.F. and Fowden L. 1965. Phytochemistry 4, 935.

40 - Barbaste M., Rolland-Fulcrand V., Rouméant M.L., Viallefont Ph., Martinez J. 1998. Tetrahedron Lett. in press.