A Combined Chemical - En zymatrc Synthesis of 3 - Deoxy - D - arabino - heptulosonic Acid 7 - Phosphate I

3-Deoxy-o-arabino-heptulosonic acid 7-phosphate (DAHP) has been synthesized from N-acetyl-n/l-aspartate p-semialdehyde and dihydroxyacetone phosphate in four steps with an overall yield of 13%. The key step generates the required threo stereochemistry by using rabbit muscle aldolase (E.C.4.1.2.13) as catalysl. 3-Deoxy-o-arabino-heptulosonic a id 7-phosphate (DAHP, l) is an important intermediate in the shikimic acid pathway, standing at the crossover point from the sugar phosphates to the cyclitols that eventually are transformed into the aromatic amino acids.3-5 This cascade of transformations is initiated by the conversion of DAHP (l) to dehydroquinate (DHQ, 2), catalyzedby dehydroquinate synthase (DHQ synthase) (eq I ) d e h y d r o q u i n a t e synthase ( r ) D A H P ( 1 ) DIJO (2) The inhibit ion of this reaction, and the result ing disruprion of aromatic amino acid biosynthesis in plants, provides the basis for the activity of certain herbicides.6 The development of new plant growth regulators of this type would be facilitated by a convenient synthetic route to DAHP; such a route might also allow for the preparation of structural analogues of DAHP. Most of the previous chemical syntheses of DAHPT-rl have employed 2-deoxy-o-glucose (a relatively costly carbohydrate at $17/g) as the starting material. The most efficient of these synthesesr0 requires eight steps and proceeds in 6Vo overall yield. Recently, Frost and co-workersl2 have used an enzymatic system to produce DAHP from o-fructose. Despite the efficiency of this methodology (85Vo conversion of o-fructose to DAHP) the cost and sensitivity of the enzymes involved are such that this method is not a practical one for the production of DAHP. This paper explores a new approach to the synthesis of DAHP that uses rabbit muscle aldolasel3-tt (8.C. 4.1.2.13) to catalyze formation of the C4-C5 bond. This aldol condensation generates these two chiral (l ) Supported by NIH Grant GM 30367 . (2) N.J.T. was a Royal Society Research Fellow, 1985-1987. (3) Haslam, E. The Shikimate Pathway. Wiley: New York, 1974. (4) Ganem, B. Tetahedron 1978, 34,3353. (5) Robinson, J. A.; Gani, D. Nat. Prod. Rep. 1985, 2,293. (6) Hardy, R. W. F.;Giaquinta, R, T. Bioessays 19t4, l, l52. (7) Sprinson, D. B.; Rothschild, J.; Sprecher, M. J. Biol. Chem.1963, 238, 3 1 7 0 . (8) Hermann, K.M.; Pol ing, M. D. J. Bio l . Chem. 1975,250,68t l . . (9) Trigalo, F.; Level, M.; Szabo, L. J. Chem. Soc., perkin Trans. I 1975, 600. Trigalo, F.; Szabo, L. Methods Enzymol.1975,41, pt. 8,9j. (10) Frost, J. W.; Knowles, J. R. Biochemistry 1984, 23,4465. (l l) Adlersberg, M.; Sprinson, D. B. Carbohydr. Res. 1984, 127, g. (12) Reimer, L. M.; Corley, D. L.; Pompliano, D. L.; Frost, J. W. J. Am. Chem. Sac. 1986. /08. 8010. (13) Wong, C.-H.; Whitesides, G. M. J. Org. Chem. 1983, 48, 3199. (14) Durrwachter, J. R.; Drueckhammer, D. G.;Nozaki, K.; Sweers, H. M.; Wong, C.-H., I . Am. Chem. Soc. 1986, 108, i812. (15) Bednarski, M. D.;Waldmann, H. J.: Whitesides. G.M. Tetrahedron Irtt. 19t6, 27. 5807 . Scheme I. Synthesis of DA[{P, I