Methyl a-Phenylglycinate

[6591-61-3]  · C9H11NO2  · Methyl a-Phenylglycinate  · (MW 165.21) (.HCl)

[15028-40-7]  · C9H12ClNO2  · Methyl a-Phenylglycinate Hydrochloride  · (MW 201.67)

(synthesis of b,g-unsaturated ketones from carboxylic acids and substituted allylic alcohols)

Physical Data: hydrochloride (RS)-form: mp 224 °C.1

Solubility: hydrochloride: insol ether; sol H2O, alcohol, benzene.

Form Supplied in: hydrochloride: colorless crystals.

Preparative Method: from a-phenylglycine and methanol.1,2

General Discussion.

Methyl a-phenylglycinate is used as a reagent for the conversion of carboxylic acids into b,g-unsaturated ketones.3,4 For this purpose, the acid is linked to the amino group of the a-amino acid ester and the resulting methyl N-acyl derivative is transesterified with an appropriate allylic alcohol, e.g. geraniol (eq 1). On treatment with Triphenylphosphine/Hexachloroethane/Triethylamine5 the geranyl N-acyl-a-phenylglycinate is cyclized to a 5-(geranyloxy)oxazole intermediate which immediately rearranges to the 5(2H)-oxazolone via a Claisen-aza-Cope sequence.6 Subsequent reductive cleavage of the oxazolone ring by Chromium(II) Acetate/H3PO2 in DMF7 yields the b,g-unsaturated ketone. This three-step procedure offers a novel effective means to accomplish nucleophilic acylation with carboxylic acids. Alternatively, the geranyl N-acyl-a-phenylglycinate can be synthesized from the preformed amino acid geranyl ester, which can be stored in the form of its hydrochloride.4

Whereas the scope of this reaction is nearly unlimited with respect to the carboxylic acid, the choice of the allylic alcohol requires attention. Thus with prenyl alcohols,4 cinnamyl derivatives,8 and 2,4-dienols,4 the sequence proceeds smoothly and in high yields. In the case of crotyl9 and 3-phenylpropargyl derivatives,10 the formation of the 5(2H)-oxazolone requires elevated temperatures and longer reaction times. Simple allyl esters cannot be used for the chain elongation because the cyclization step in this case leads to stable 4-allyl-5(4H)-oxazolones.3

The a-phenylglycine technique constitutes an efficient alternative to the use of organometallic reagents for the conversion of carboxylic acid derivatives into b,g-unsaturated ketones.11 The mild reaction conditions and absence of strong bases allow even the use of sensitive carboxylic acids, as is illustrated by the conversion of O-acetyl protected D-gluconic acid into C-farnesyl a-D-glucopyranoside (eq 2).4 Isomerization of the b,g-unsaturated ketone to the conjugated enone, a notorious problem with other procedures,12 is not observed, and stereogenic centers in the a-position to the carboxyl group maintain their stereochemical integrity.4,13 During the chain elongation, the configuration at the trisubstituted double bond is conserved.14 This is of importance for the attachment of terpenoid chains to carboxylic acids,4 e.g. in the synthesis of 12-oxosqualene from farnesoic acid and farnesol (eq 3).7 Interestingly, both diastereomers of cinnamyl alcohol afford the (E)-b,g-unsaturated ketone (eq 4).9 In the case of secondary cinnamyl alcohols, the reaction proceeds with complete transfer of chirality (eq 5).10

The chain elongation via allyl N-acyl-a-phenylglycinates can be used for the conversion of carboxylic acids into b-keto aldehydes, 1,3-diketones, and b-keto esters, and heterocycles derived therefrom.8,13 The general procedure is outlined in eq 6 for the synthesis of a C-nucleoside.8

Related Reagents.

Ethyl N-Benzylideneglycinate; Methyl N-Benzylidenealaninate.

1. Kossel, A. CB 1891, 24, 4145.
2. Duhamel, L.; Plaquevent, J.-C. BSF(2) 1982, 75.
3. Engel, N.; Kübel, B., Steglich, W. AG(E) 1977, 16, 394.
4. Wild, H.; Mohrs, K.; Niewöhner, U.; Steglich, W. LA 1986, 1548.
5. Appel, R.; Schöler, H. CB 1977, 110, 2382.
6. Kübel, B.; Höfle, G.; Steglich, W. AG(E) 1975, 14, 58.
7. Niewöhner, U.; Steglich, W. AG(E) 1981, 20, 395.
8. Klein, U.; Steglich, W. LA 1989, 247.
9. Steglich, W. Chemistry for the Future; Grünewald, H., Ed.; Pergamon: Oxford, 1984, p 211.
10. Fischer, J.; Kilpert, C.; Klein, U.; Steglich, W. T 1986, 42, 2063.
11. O'Neil, B. T. COS 1991, 1, Chapter 1.13.
12. Reetz, M. T.; Wenderoth, B.; Urz, R. CB 1985, 118, 348.
13. Klein, U.; Mohrs, K.; Wild, H.; Steglich, W. LA 1987, 485.
14. Fischer, J.; Steglich, W. AG(E) 1979, 18, 167.

Wolfgang Steglich & Stefan Jaroch

Universität München, Germany

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