Straigthening out the stereochemical numbering system

29 0307-4412(95)00159-X

Straightening System

Out the Stereochemical

had the two numbers seen on the left and on the right side of I in Figure 1). Numbering

VASEK A MEZL Department of Biochemistry UniversiQ of Ottawa Ottawa, Ontario Canada KlH 8M5

Introduction - Development of the stereochemical numbering (sn) system Hirschmann was the first to propose a nomenclature that unambiguously designated any prochiral group.’ His method consisted in viewing a prochiral centre, Caabc, from the side opposite the lower priority substituent among b and c (priority according to the RS system) and then using a counterclockwise direction of rotation to assign the first of the two identical substituents the lower number. In keeping with the RS system, Hirschmann’ maintained the priority of R over S in his rules. However, his system was designed to keep the numbering of glycerol consistent with the numbering derived from labelling studies with L-glyceraldehyde. Although not stated, this choice meant that the stereochemical numbering of prochiral carbon chains would proceed from thepr0-S group to the pro-R group (numbering on the left side of the structures in Figure l), thereby reversing the conventional R over S priority of the RS system. In the classic paper describing the relsi nomenclature for the sides of trigonal carbons, Hanson’ pointed out that the Hirschmann convention meant that a pro-S ligand would have the lower numbering, yet his interpretation of the conventions in use at that time was that the carbon chains could be numbered so that either the pro-R or the pro-S end had the lower numbering and he illustrated this with a glycerol structure that was numbered from both ends (each carbon

IUPAC-IUB Recommendations This ambiguity was resolved by the report of the IUPACIUB commission on Biochemical Nomenclature of Lipids’ which in section 1.2 presented the Hirschmann numbering of glycerol as the stereospecific numbering system for glycerol (sn system, now referred to as stereochemical numbering). This discussion document” (later incorporated into the approved recommendations’4) listed Hirschmann’s original paper’ as the basic reference for this system and it showed examples of sn-numbered glycerol; it did not however define a general sn numbering system (as had been proposed by Hirschmann) or base the numbering of sn-glycerol on the priorities of the RS system. The subsequent IUPAC recommendations for nomenclature in stereochemistry4 affirmed the priority of pro-R over pro-S. This again created ambiguity for those using Hirschmann’s numbering method’ for other compounds. Englard and Hanson5 identified this problem and numbered citrate starting at the pro-R end (see right side of II), basing their numbering on the general principle that since R has priority over S, when general stereochemical numbering is needed, the R or pro-R substituent should therefore be given the lower number. They noted that this had been done after consultation with Hirschmann and that this reversed the earlier practice.’ A subcommittee on Biochemical Nomenclature of the National Academy of Sciences-National Research Council (USA) approved this principle and published a recommendation.6 This document, written by Hirschmann and Hansen,6 clearly defined a general sn numbering system and it noted that giving priority to pro-R over pro-S reversed the original Hirschmann convention. This proposal emphasized that glycerol must be numbered from pro-S to pro-R as an exception authorised by IUPAC for specialized fields. This proposal was never formalized by IUPAC-IUB. As

pro-S

pro-R 5

1 2

3

H-k-OH HO-C-H ' H-C-OH A pro-R I

3

4

2

3

1

2 1

COOH I H-C-H I HOOC-C-OH

1

2 3

H-C-H I COOH

4 5

pro-S II

Figure 1 Application of sn proposals to glycerol (I) and to citrate (II). On the left of each structure is the numbering according to the original Hirschmann proposal,’ the right shows the numbering that would be obtained by starting at thepro-R end. Bold type indicates the numbering that must be used for glycerol as IUPAC approved sn-glyceroli and the numbering that is recommended6 for sn numbered citrate (see text). Note: While the two ends of citrate can be numbered with the proposed sn nomenclature, the systematic name” for citric acid is 2-hydroxypropane-1,2,3-tnkarboxylic acid

BIOCHEMICAL EDUCATION 24(l) 1996

30

noted earlier, IUPAC had never approved a general sn numbering system, it had only approved a specific numbering for glycerol called sn-glycero1.‘4 Therefore, at the present time a IUPAC approved general sn system does not exist. The sn numbering system in biochemistry textbooks The stereospecific use of the prochiral ends of glycerol and of citrate is a key concept that is presented in most biochemistry texts, yet a nomenclature to designate these groups is usually not given. In fact, few textbooks present structures in a manner that is consistent with stereochemical priorities; among 30 basic biochemistry textbooks that were examined (including’-“), only three textbooks7-9 consistently orient the structure of the key prochiral intermediate, citrate, going from pro-R to pro-S (see II) in keeping with the Hirschmann and Hansen proposa16 and only one textbook’ correctly explains this sn system. Two other biochemistry textbooks”*‘l do explain a general sn numbering system. However, in keeping with the original Hirschmann proposal,’ they give the direction of numbering backwards, stating that the carbons are numbered beginning with the end of the chain that occupies the pro-S position (numbering on the left side of II). Since most textbooks do not number symmetrical carbons when discussing stereospecific reactions, the lecturer is left with comparing the ‘top carbon’ to the ‘bottom carbon’ or the ‘red carbon’ to the ‘black carbon’. . . Additional problems in comprehension can be expected from a recent text’* that simply states that s11-means a numbering system that differentiates the numbering of a compound from other approaches, such as the RS system, when in fact the proposals for sn numbering have always been an application of the RS system.‘~2,5,6

nomenclature system should be simple yet be able to describe most situations that are encountered. A general Sn-system’.z.5,6 is very convenient for situations where the direction of numbering depends solely on steric differences however the current ambiguity associated with sn numbering needs to be eliminated. For this to occur, it should be realized that the system proposed by Hirschmann’ was updated6 and only the procedure described by Hirschmann and Hansen6 should be used (numbering in bold type on I and II). To avoid the propagation of the problems’“,” created by citing only the original Hirschmann paper’ or sn-glycerol,3x14 authors should cite the Hirschmann and Hansen proposal6 when s11numbering is used for a molecule other than glycerol. This document6 provides a clear and updated description of the method proposed by Hirschmann, while fully acknowledging Hirschmann’s contribution to stereochemistry. As noted earlier, authors should realize that this sn system is still only a proposal and not a IUPAC approved procedure. Recommendation for the presentation of sn numbering Since .WZnumbering is a simple application of the RS system, it can be presented to students along with the RS system.‘,” This will provide students and lecturers with a simple method to designate the ends of symmetrical molecules. Textbooks that limit themselves to discussing the prefix in sn-glycerol, should not present sn-glycerol as an example of the sn numbering system. Instead they should point out that glycerol is a special numbering situation (as are the inositols16), possibly by adding that, for glycerol, SIZ-not only means stereochemically numbered but also specially numbered! References

Need for sn numbering in biochemistry Stereochemical numbering is rarely encountered as it is only used for structures that can not be numbered with the standard chemical nomenclatures. However, in the life sciences, several key molecules of this type are encountered even in basic studies (glycerol, citrate, tartarate) and as metabolism is studied in more detail, a nomenclature is needed for the stereochemistry of a number of symmetrical chiral or prochiral groups that are encountered in linear (eg diaminopimelic acid and 3-hydroxy-3-methyl glutarate) and in cyclic (eg quinic and dipicolinic acids) molecules. The need for SIZnumbering will increase with the synthesis of new symmetrical molecules for probing the specificity of enzymes and for assessing the results of protein engineering.13 Recommendation for the use of s12numbering The purpose of nomenclature is to provide an unambiguous means of communicating information. Ideally a

BIOCHEMICAL EDUCATION 24(l) 1996

1 Hirschmann, H (1960) J Viol Chem 235, 2762-2767 2 Hanson, K R (1966) J Am Chem Sot 88,2731-2742 3 IUPAC-IUB Commission, The Nomenclature ofLipids (1967) J Biol Chem 242,4845-4849 4 IUPAC, Nomenclature of Organic Chemistry Section E. Fundamental Stereochemistry (1970) Biochim Biophys Acta 208, l-44 5 Englard, S and Hanson, K R (1969) Methods Enzymol 13, 567-601 6 Hirschmann, H and Hanson, K R (1971) Eur JBiochem 22, 301-309 7 Rawn, J D (1989) Biochemistry, Neil Patterson 8 White, A, Handler, P, Smith, E L, Hill, R L, Lehman, I R (1977) Principles of Biochemistry, sixth edition, McGraw-Hill 9 Mahler, H R and Cordes, E H (1971) Biological Chemistry, second edition, Harper & Row, New York 10 Voet, D and Voet, J G (1990) Biochemistry, John Wiley & Sons, New York 11 Metzler, D E (1977) Biochemistry: The Chemical Reactions ofLiving Cells, Academic Press, New York 12 Zubay, G (1993) Biochemistry, W C Brown, Dubuque 13 Jones, J B (1993) Aldrich Chimia Acta 26, 105-112 14 IUBMB (1992) Biochemical Nomenclature and Related Documents, second edition, pp 180-191, Portland Press, London 15 IUPAC (1979) Nomenclature of Organic Chemistry, fourth edition, C-402.1, Pergamon Press, Oxford 16 IUB Nomenclature Committee, Numbering of atoms in myo-inositol (1989) Biochem J 258, l-2