(+/-)-Boc-a-phosphonoglycine Trimethyl Ester

[89524-98-1]  · C10H20NO7P  · (294.24)

[synthon for a,b-dehydroamino acids (DAA) and amino acids]

Alternate Name: methyl 2-(t-butoxycarbonylamino)-2-(dimethoxyphosphinyl)acetate.

Physical Data: white solid, mp 47-48 °C.

Solubility: alcohol and most organic solvents.

Form Supplied in: Form Supplied in: available in six steps from crude glyoxylic acid.1 The first four steps2 can be carried out on a kilogram scale. Deprotection of the N-benzyloxycarbonyl-2-(dimethoxylphosphinyl)glycine methyl ester and reaction with Boc2O affords the title compound (1).

Purification: recrystallization from diethyl ether/pentane (1:1) at 0 °C.

Handling, Storage, and Precautions: reagent should be used in a fume hood.

Reaction with Aldehydes

The main use of phosphoglycinate is to synthesize a,b-dehydroamino acids (DAA) by condensation with an aldehyde in a Wittig-Horner-type olefination (2).3

In order to obtain high yields and to limit the amounts of by-products, the choice of base is critical. The use of t-BuOK, NaH, lithium diisopropylamide, or potassium hexamethyldisilazide affords yields ranging from 70 to 95%,4 along with small amounts of side-products, which are often difficult to separate from the DAA. This is of paramount importance if the next step is a metal-catalyzed hydrogenation, since the impurities can poison the catalyst. Also, in most cases, the diastereoselectivity of double bond formation is fairly low. Nevertheless, the use of DBU or NEt3 in CH2Cl2 is often superior to alkali bases, resulting in nearly quantitative yields and high diastereoselectivities (3). Addition of LiCl is not necessary and may be detrimental in terms of yields.

Also, the use of TMG 4-6 as base in THF at -70 °C to +20 °C is reported to give rise to even better Z-diastereoselectivity, yield, and product purity. All types of aldehyde can react, except 2-alkenals, which suffer decomposition in the basic reaction medium. Complex or sterically hindered aldehydes react well. The olefination is applicable to the synthesis of non-conjugated 2-amino-2,n-alkadienoic esters which can be selectively hydrogenated to give (,(- and (,(-dehydroamino acid derivatives. Also, the reaction conditions (neutral or alkaline) are compatible with aldehydes that contain acid-sensitive groups.7 Aldehydes can also be coupled to di- or tripeptides containing a phosphoglycinate unit (4).

If the reaction is applied to the synthesis of histidine or tryptophane derivatives, the nitrogen atom in the heterocyclic moiety must be protected. No racemization was observed during the olefination of the above dipeptide.

The stereocontrol of double bond geometry depends heavily on the base used during the olefination. In most cases, Z-geometry prevails. The E-isomer can be converted to the Z-isomer by means of HCl/Et2O,8 NEt3/charcoal in MeOH/CHCl3, thiophenol/AIBN/benzene at 80 °C,9 illumination10 or DBU/charcoal in MeOH/CHCl3 at 20 °C (5).3

The protecting group associated with 1 can be easily changed. N-t-butoxycarbonyl- can be replaced by N-Benzyloxycarbonyl-, N-acetyl-, N-chloroacetyl-, and N-formyl, in the fifth step of 1 without any problem and the methyl ester can be replaced by -CH2CH2TMS (TMSE). Any type of combination can be realized. Orthogonally protected phosphoglycinates have been prepared (6).11

Different protecting groups on 1 can affect the yield of the olefination (7),6 as well as the E/Z ratio. Methyl esters are preferred over ethyl esters due to their ease of hydrolysis.

Reaction with Ketones

Ketones react with 1, or its analogs, in the presence of TMG as base. Good Z-selectivity is observed. Recourse to DBU is synthetically useless since a large excess of ketone is required for the olefination to proceed.3

Related Reagents.

N-benzyloxycarbonyl-2-(diethoxyphosphinyl)glycine ethyl ester; N-benzyloxycarbonyl-2-(dimethoxyphosphinyl)glycine methyl ester; N-chloroacetyl-2-(dimethoxyphosphinyl)glycine methyl ester; N-formyl-2-(dimethoxyphosphinyl)glycine methyl ester; N-acetyl-2-(dimethoxyphosphinyl)glycine methyl ester.

1. Schmidt, U.; Lieberknecht, A.; Wild, J., Synthesis 1984, 53.
2. (a) Schmidt, U.; Liebernecht, A.; Schanbacher, U.; Beuttler, Th.; Wild, J., Angew. Chem. 1982, 94, 797. (b) Schmidt, U.; Liebernecht, A.; Schanbacher, U.; Beuttler, Th.; Wild, J., Angew. Chem., Int. Ed. Engl. 1982, 21, 776. (c) Schmidt, U.; Liebernecht, A.; Schanbacher, U.; Beuttler, Th.; Wild, J., Angew. Chem. Suppl. 1982, 1682.
3. Moglioni, A. G.; Garcia-Exposito, E.; Moltrasio, G.; Ortuno, R. M., Tetrahedron Lett. 1998, 39, 3593.
4. Schmidt, U.; Griesser, H.; Leitenberger, V.; Liebernecht, A.; Mangold, R.; Meyer, R.; Riedl, B., Synthesis 1992, 487.
5. Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J., J. Am. Chem. Soc. 1997, 119, 9897.
6. Hiebl, J.; Kollmann, H.; Rovenszky, K.; Winkler, K., J. Org. Chem. 1999, 64, 1947.
7. (a) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Bartkowiak, F., Angew. Chem. 1984, 96, 310. (b) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Bartkowiak, F., Angew. Chem., Int. Ed. Engl. 1984, 23, 318. (c) Schmidt U.; Beuttler, Th.; Lieberknecht, A.; Griesser, H., Tetrahedron Lett. 1983, 24, 3573. (d) Schmidt U.; Lieberknecht, A.; Griesser, H.; Utz, R.; Beuttler Th.; Bartkowiak, F., Synthesis 1986, 361. (e) Schmidt, U.; Lieberkneck A.; Kazmaier, U.; Griesser, H; Jung, G.; Metzger, R., Synthesis 1991, 409. (f) Schmidt, U.; Meyer, R.; Leitenberger, V.; Stabler, F.; Leiberknecht, A., Synthesis 1991, 275 .
8. Poisel, H; Schmidt. U. Chem. Ber. 1975, 108, 2547.
9. Wild, J. Diplomarbeit, Universität Stuttgart, 1982.
10. (a) Horenstein, B. A.; Nakanishi, K., J. Am. Chem. Soc. 1989, 111, 6242. (b) Kim, D.; Li, Y.; Horenstein, B. A.; Nakanishi, K., Tetrahedron Lett. 1990, 31, 7119. (c) Schmidt, U.; Wild, J., Angew. Chem. 1984, 96, 996. (d) Schmidt, U.; Wild, J., Angew. Chem., Int. Ed. Engl. 1984, 23, 991. (e) Schmidt, U.; Wild, J., Liebigs Ann. Chem. 1985, 1882 .
11. Travins, J. M.; Etzkorn, F. A., J. Org. Chem. 1997, 62, 8387.

Nicolas Cuniere

The Ohio State University, OH, USA

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