GUESTAUTHOR Kenneth R. Hanson The Connecticut Agricultural Experiment Station New Haven
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Textbook Errors,
39
The Configuration of (-)-Shikimic Acid and Certain Biochemically Related Compounds
Studies on bacteria, moulds, yeasts, and higher plants have shown that the benzene rings present in a large group of natural products are derived from the same cyclohexane intermediate 6dehydroquinic acid I1 (8). This group includes the amino acids phenylalanine and t.yrosine; 2-aminobenzoic acid (from which tryptophan is formed) (0)and 4-aminobenzoic acid (a building unit of folic acid); and &mono-, 3,4-di-, and 3,4,5-trihydroxybenzoic acids ( 6 , 7 ) . The above aromatic compounds are themselves involved in the biogenesis of alkaloids, flavonoids, rotenoids, lignans, tannins, and the natural polymers melanin and lignin. In view of the importance of this route of aromatic biosynthesis, it is unfortunate that t,he structures of 5dehydroquinic acid I1 and t,he closely associated acids quinic I, 5-dehydroshikimic 111, shikimic IV, and 5phosphoshikimic should frequent,ly be represented as the mirror images of their established structures. In more than one text the same compound is to be found in both its correct and mirrored form, while in other texts' an ambiguous notat,iou is employed. This error also appears in reviews and in original biochemical and chemical papers, including papers on the widely distributed plant constituent chlorogenic acid (3-0-caffeoylquinic acid) (10). The student may, therefore, be pardoned if he infers that t,he relationship of these compounds to the stereochemical reference point D(+)glyceraldehyde VI is not known (lla). It is the purpose of this paper to summarize the chemical and biochemical evidence for this correlation.
Chemical Evidence
Shikimic Acid. Studies of the simple derivatives of shikimic acid established the relative configurations of the three asymmetric centers in the molecule. In order to decide among the four possible structures (IV, VII, and their mirror images), H. 0. L. Fischer and Gerda Dangschat carried out the sequence of reactions summarized in Figure 1 (12). The products of the degradation are consistent only with the structure IV for shikimic acid. Thus if stucture VII were correct the
Figure 1. Correlation of rhikimic o d d with D-sugars ( 1 21: 0, KMnOl, neutral solution; b, NoOH; c, HIOli d, B n , HOAc, AgOAc; e, H1, Ni; f, boiling HOAc. C-1 to C-6 in IV ore equivalent to C-1 to C-6 in the Rnol loclone.
sugar produced would possess a D-Zyzo instead of a Darabo configuration. The products of the degradation, 2-deoxy-D-arabo-hexono-y-lactone and the trimethyl ether of this compound, were compared with authentic materials synthesized from 2-deoxy-D-arabo-hexose (2deoxygh~cose).~Transformations of the intermediates in this degradation provided supplementary evidence that the double bond is in the assigned position.
I n the discussion of Figures 1 to 4, the convention is used that heavy lines represent bonds above theplane of the paper, and dott,ed lines bonds below the plane of the paper. For the sugars, the horizontal bonds are to be read as being above the plane of the paper (Emil Fischer convention) (22).
Quinic Acid. As in the case of s h i k i c acid IV, Dangschat and Fischer first determined the relative configurations of the various asymmetric centers in the
Suggestions of material suitable for this column and guest columns suitable for publication directly are eagerly solicited. They should he sent with as many details as possible, and particularly with references to modern textbooks, t o Karol J . Mysels, Department of Chemistry, University of Southern Celifornia, Los Angeles 7, California. ' Since t h e purpose of this column is t o prevent the spread and continuation of errors and not the evaluation of individual texts, the source of errors discussed will not he cited. The error must occur in a t least two independent standard hooks t o bepresented.
'The rules of carbohydrate nomenclature adopted by the American Chemical Society are, a t the time of writing, being revised. It is possible that in the future the prefix "deoxy" will cease t o be treated alphaheticdly hut will form part of the root name eg. D-nrabd2-deoxyhexose in place of 2-deoxy-Dambo-hexose. In this event the operational preiix "deoxy" and the name of the structure operated upon will be juxtaposed and the configurational ambiguity in the usage mabo-hexose removed. The writer is indebted t o a referee for drswing his attention t o this matter.
Volume 39, Number 8, August 1962
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molecule. They then transformed quinic acid into shikiiic acid (Fig. 2 ) , thus demonstrating that quinic acid-not its enantiomorph-is represented by I (IS). The relationship between the two compounds has been further subst,ant,iated by the work of Grewe and his associates a t the University of Kiel, Germany. A
Figure 2. Correlation of quinir acid with shikimic acid 113): a,p-toluene~vlphonylchloride in pyridine 154-65% yield); b. NoOH.
second independent conversion of I into IV as in Figure 3 (14), and a conversion of IV into I have been achieved. In converting I into IV, bot,h groups of workers were fortunate in obtaining t,he double bond in t,he desired I,6 position. The conversion of IV into I was effected
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COO
Am,,
b
dns
dac
Figure 3. Correlation of quinic ocid with rhikimic ocid (141: 0 , NoBHIOCHs)J, note ocetde wandering; b, POCIa in pyridine 194% yield); c. minus ocetyl (Zemp16nl; d , trityl; e, pius ocetyl; f, minus trityl; g, Cr0~.
by Grewe and Lorenzen (1953) in the following manner (15): When IV was treated with bromine, transaddition to the double bond t,ook place and a dibromo compound with a configuration a t C-1, ident,ical to that of I (Br in place of OH), was isolated in 84% yield. The 1-Br atom was then replaced by OH to give a 6hromoquinic acid (Br-COOH cis), the configuration a t C-1 being ret,ained through the neighboring group action
of the presumably axial 6-Br atom (Ilb). The lactone of this product on hydrogenation gave I. The over-all yield for t,he conversion was great,er than .5O%. 5-Dehydropuinic Acid and 5-Deh~/droshilcimicAcid. When these compounds were first isolated from culture filtrates, only 100-mg quantities were available for chemical invcstigat,ion. Grewr. and Jeschke, however, have shown that klrhydroqninic acid I1 may be obtained in surprisingly high yield by the oxidation of quinic acid (16). They have thus made 11, and hence 5-dehydroshikimic acid 111, availahlc in any desired quant,it,y. Indeed, it appears t,hat I1 was prepared in this manner by Hesse in 1859 (17). The gerreralizat,ion that axial-OH groups are more readily oxidized than eqnalorial-OH groups (Ilc) may be used to account for t,he preferpntial oxidat,ion of the 5-OH arouD . of I (see brlo!~~). The st,udirs of G r e w and Jeschke have further substantiat,ed thr st,ruct,ures proposed by Davis and his associates (18. 10). In I k w e 4. various t,ransformat,ions invol;ing compounds I1 and 111 are represented. The int,erconvcrsion of I and I1 under non-alkaline conditions ~stablishesthat t,he -OH groups of I1 are in the same configurat,ion as in I , while t,he conversion of VIII into the lactone I X establishes that the 3-OH group was not oxidized in converting I to 11. Cleavage of VIII by HIOn demonstrates that -OH groups on adjacent carbon atoms are present in VIII. I t follows that the ket,o group of I1 is a t position 5. The fact that, I and IV readily form isopropylidene derivatives wit,h acetone, whereas I1 fails to form such a derivative under standard conditions, is in agreement with the trans-configuration assigned to the adjacent. -OH groups of 11. The conversion of I1 into 111 and 111 into IV confirms the position of the keto group in I1 and establishes the configuration of the -OH groups in 111. I t is of interest that the biological conversion of I into IV can be so closely duplicated by chemical means. Biochemical Evidence
The finding that 3-deoxy-2-0x0-D-arabo-heptonic acid 7-(dihydrogen phosphate) V is converted into I1 by cellfree extracts of E. coli in the presence of reduced nicotinamide adenine dinucleotide provides a furt,her correlation between t,he compounds under discussion and D(+)-glyceraldehyde (1). The structure of V has been
Fiaure 4. Chemical tranrfarmotionr invalvina 5dehydroqvinic and 5dehydrorhikimic acidr: a, Pt, 0 2 lover 50% yield) 171, also HNOI ot O0 163y0 yield)ll6l,and Brg,H?O160% yield) 117);b.PtOl,H1 1le.s than 25% vviidl: c 0.1 N HCI. 100' or Am-
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.
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~~.
116); f, heof, or boil with conc. HCl for 2 0 seconds l i 8 . 191; g, PtOz. H?,HrSO~IZN);h.Acr0; i, HI06 1161: R = Me., ,i., CH-NI, Ac.,O. . . . .k.,~ - .~ - ,HCIOI. HOAc: R H, i, AclO, pyridine (18); Ill forms crystalline derirmtirer with corbonyl reagents.11 gives only noncry~tollinemoterid (18. 19).
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420 / Journol of Chemical Education
