Assignment of the Absolute Configuration of Polyfunctional

Review pubs.acs.org/CR

Assignment of the Absolute Configuration of Polyfunctional Compounds by NMR Using Chiral Derivatizing Agents J. M. Seco, E. Quiñoá, and R. Riguera* Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain Acknowledgments Dedication Abbreviations References

1. INTRODUCTION AND SCOPE Interest in determining the absolute stereochemistry of a chiral organic compound stems from the widely recognized fact that the stereochemistry often determines important properties in the chemical, physical, biological, and pharmaceutical aspects of the compounds. The need to obtain enantiomerically pure pharmaceuticals and chemicals generally has produced an enormous growth in fields such as asymmetric synthesis, asymmetric catalysis, and other processes where the availability of simple and reliable methods for the determination of enantiomeric purity and absolute configuration is a must. There are a variety of experimental techniques that can be used to determine a compound’s absolute configuration;1−5 however, one of the most widely used is without a doubt nuclear magnetic resonance2 (NMR). Other techniques include: X-ray crystallography,3 followed by chiroptical methods4 (e.g., circular dichroism (CD), optical rotatory dispersion (ORD), or specific optical rotation); however, their use is not devoid of some drawbacks and limitations related to the equipment employed, which is very specific to the method and requires special training for operation, and to the sample, which, in the case of X-ray diffraction (XRD), requires good quality monocrystals. Other methods5 include specific rotation, infrared vibrational CD (VCD), and vibrational Raman optical activity (ROA). Different approaches to the problem of determining absolute configuration have emerged recently which have been based on NMR spectroscopy.2 These techniques are very appealing because of their undoubted advantages, which include the following: (a) the instrument is available in most laboratories; (b) an in-depth understanding of the fundamentals of the method is not necessary to apply the method; (c) a small amount of sample is needed, and it can be recovered; and (d) it is applicable to both solid and liquid samples because the analysis is conducted in solution. There are two general approaches to determine absolute configurations by NMR: (a) substrate analysis without derivatization2b,c (i.e., by the addition of a chiral solvating agent (CSA)) and (b) analysis of the derivatives prepared from the substrate and the two enantiomers from a chiral derivatizing

CONTENTS 1. Introduction and Scope 2. Polyfunctional Compounds: An Outline of the Problem 3. Acyclic sec/sec-1,2- and sec/sec-1,n-Diols 3.1. Double-Derivatization Methods: MPA and 9AMA 3.2. Double-Derivatization Methods: MTPA 3.3. Single-Derivatization Methods: MPA 4. sec/sec-1,2-Amino Alcohols 5. prim/sec-1,2-Diols 5.1. prim/sec-1,2-Diols: Double Derivatization, MPA 5.2. prim/sec-1,2-Diols: Double Derivatization, 9AMA 5.3. prim/sec-1,2-Diols: Low-Temperature Single Derivatization of bis-MPA Derivatives 5.4. prim/sec-1,2-Diols: Low-Temperature Single Derivatization of bis-9-AMA Derivatives 6. sec/prim- and prim/sec-1,2-Amino Alcohols 6.1. sec/prim-1,2-Amino Alcohols, Double Derivatization, MPA 6.2. sec/prim-1,2-Amino Alcohols, Low-Temperature Single Derivatization, MPA 6.3. prim/sec-1,2-Amino Alcohols, Double Derivatization, MPA 6.4. prim/sec-1,2-Amino Alcohols, Low-Temperature Single Derivatization, MPA 7. prim/sec/sec-1,2,3-Triols, Double Derivatization, MPA 8. 13C NMR: sec/sec-Diols and sec/sec-Amino Alcohols 9. Conclusions Author Information Corresponding Author Notes Biographies © XXXX American Chemical Society

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dx.doi.org/10.1021/cr2003344 | Chem. Rev. XXXX, XXX, XXX−XXX

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agent (CDA). This second option is the most widely used to determine absolute configurations as the covalent bonding of the substrate and the auxiliary reagent produces species with a greater conformational rigidity, which in turn produces greater differences in the NMR spectra. The first approach2b,c involves procedures whereby the derivatization of the substrate whose absolute configuration is being studied is not necessary. The sample (i.e., a pure enantiomer) is analyzed by NMR in a chiral environment that is provided by a chiral solvent, or by the addition of a CSA to a nonchiral standard NMR solvent. In this approach, there is no covalent linking between the substrate and the chiral “reagent”. This apparent advantage is the origin of the method’s main limitation as the chiral environment produces very small differences in chemical shifts for the two enantiomers. Consequently, their NMR spectra are very similar; this often means that the two enantiomers must be available for comparison and no clear-cut correlations between the absolute configuration and the NMR spectra can be established. For these reasons, the usefulness of this method is practically restricted to the determination of enantiomeric purity. The second approach2a requires the derivatization of the substrate, for which there are two options: (a) the preparation of two derivatives from the two enantiomers of the chiral derivatizing agent and the substrate (double derivatization; Figure 1a), and (b) the preparation of a single derivative from the substrate and one enantiomer of the chiral derivatizing agent (single derivatization; Figure 1b).

Double-derivatization methods have a general application, and they are normally used to determine both configuration and enantiomeric composition. Single-derivatization methods can be classified into three different types. In each of these, the NMR spectrum obtained for the derivative resulting from the reaction of the substrate with the CDA at room temperature is compared with (a) the spectrum for the same derivative when registered at a lower temperature,6 or (b) the spectrum of the same derivative after forming a complex with a metal salt7 (barium, Figure 1b), or (c) the spectrum of the substrate without derivatization.8 For the first two options, the key to the methods lies in the modulation of the conformational equilibrium and the manner in which these changes are reflected in the NMR spectra. Thus, knowledge of the conformation equilibrium (from structure calculations, shielding effect, NMR spectra for variable temperatures, etc.) can be converted into an undeniably useful tool when planning new methods for the determination of absolute configuration. Thus, the empirical approach in these methods completely disappears, which gives greater rigor and assurance, meaning that determination of the configuration can be carried out with total certainty. There have been a number of significant advances in the years since the publication of the previous review that have affected both the design and application of experimental methods.2,9 The methods used in single derivatization have changed the most, and they have been the main focus of attention for researchers.6−8 As the experimental methods are simpler and because they require less substrate, this technique is particularly important in those cases where only small amounts of sample are available. The main difficulties for these methods lie in the preparation of the derivatives prior to their analysis (synthesis and purification). These stages have been reduced and simplified through the development of experimental procedures that use auxiliary reagents attached to polymeric supports.10 This has allowed the preparation process to be carried out in the NMR tubing, thereby completely eliminating the purification stages. This has been a significant improvement from the experimental standpoint. As far as NMR techniques are concerned, 1H NMR continues to be by far the most widely used technique when assigning absolute configuration. 19F NMR has been practically relegated to enantiomeric-purity11 studies, whereas 13C NMR is looked upon as an interesting alternative (mainly for studies of substrates without protons directly bonded to an asymmetrical carbon atom) or is used in conjunction with 1H NMR (double confirmation) as has been demonstrated recently.12 The configuration of substrates containing polyfunctional compounds13 has become the main objective of research in recent years, particularly as the application of methods designed for monofunctional compounds has been shown14 to be impractical for polyfunctional compounds where the simultaneous presence of a number of chiral auxiliaries produce distributions of signs in the differences in chemical shifts that do not follow the behavior of monofunctional substrates.14 This is due to the combination of the anisotropic effects produced by the presence of the different auxiliary reagents, which cause patterns in the sign distributions in the differences in chemical shifts that do not fit the models of the monofunctional compounds. These differences with respect to the monofunctional substrates do not only relate to the patterns of distribution in the differences in chemical shifts. They also relate to the protons whose signals are diagnostic, which now

Figure 1. Assignment of the absolute configuration of a secondary alcohol using MPA by double (a) and single derivatization (b). B


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are not necessarily those placed at both sides of to the asymmetric carbon (L1/L2). In some cases the diagnostic signals are those corresponding to the protons at the alpha positions of the asymmetric carbon (Hα) of the substrate or the CαH and OMe of the auxiliary reagents. All of these factors have necessitated the detailed and systematic study of polyfunctional compounds.

2. POLYFUNCTIONAL COMPOUNDS: AN OUTLINE OF THE PROBLEM Researchers often have to deal with the determination of the absolute configuration of organic compounds with complex structures that incorporate a number of asymmetric and polyfunctional carbon atoms (OH, NH). The first step in these situations is to define the relative configuration of all the asymmetric carbons,2e and then the absolute configuration of the whole molecule can be determined by ascertaining the absolute configuration for specific asymmetric carbons. To do this, asymmetric carbons are chosen that have functional groups that are susceptible to derivatization (hydroxyl, amino, and carboxyl) with the auxiliary reagents designed for the absolute configuration of monofunctional compounds2a [α-methoxyphenylacetic acid (MPA), 9-anthrylmethoxyacetic acid (9-AMA,) Boc-phenylglycine (BPG), etc.]. The problem arises when trying to apply the methods designed for monofunctional compounds; distributions of signs in the differences in chemical shifts, Δδ (ΔδRS or ΔδSR), do not conform to the predictions of the models.14 This is due to the presence of a number of auxiliary reagents in the same molecule, which cause the combination (addition/subtraction) of the anisotropic effects (shielding/deshielding) that are generated by the auxiliaries.14b This causes the distributions of signs in the differences in chemical shifts (ΔδRS or ΔδSR) to differ from the patterns observed for monofunctional compounds. This is a well-known problem, which has been discussed in a previous article,14a which details the nature and extent of the problem. It should also be added that, in the majority of cases, the problem is exacerbated by the incorrect choice of auxiliary reagent, which usually tends to be α-methoxy-α(trifluoromethyl)phenylacetic acid (MTPA). The use of this reagent is associated with a great deal of uncertainty as the outcome is conditioned by its high conformational flexibility, which combined with external factors such as the possible steric hindrance of the substrate and the polarity of the solvent15 can mean that the representative conformer, from the NMR standpoint, varies from one substrate to another. To understand the true scale of the problem, we will analyze a series of possible situations in order of increasing complexity. The hydroxy groups present in a polyfunctional compound can generally be categorized into three types: primary, secondary, and tertiary. For polyol compounds where the hydroxyl groups are bonded to asymmetric carbons (secondary hydroxyls), one of the approaches most widely used by researchers consists of simplifying the problem and trying to determine the configuration of the stereocenters bound to a hydroxyl by considering that each hydroxyl belongs to an isolated secondary alcohol. This approach is only valid for those cases where there are no interactions between the chiral auxiliaries and, therefore, there is no combination of shielding effects. Otherwise anomalous distributions of signs in the differences in chemical shifts (ΔδRS or ΔδSR) would be produced that would not allow the determination of the absolute configuration.

Figure 2. Structure of the bis-MTPA esters of the diterpenoid entpimarane (2.1).

An example of this is the diterpenoid ent-pimarane (2.1),16 whose structure is shown in Figure 2. It is a diol, with a rigid structure where the two hydroxyls bonded to asymmetric carbons are relatively far apart. The distribution of signs for values of ΔδSR that were obtained experimentally for the corresponding bis-MTPA esters is perfectly homogeneous on both sides (L1/L2) for each of the hydroxyls esterified with MTPA. In addition, the configuration of each stereocenter can be assigned using the model for secondary alcohols for each stereocenter. In this case, the simplification is valid given that (a) both MTPA esters are sufficiently separated that they do not produce a combination of shielding/deshielding effects for the two MTPA units, which is only possible because the molecule has a rigid structure; and (b) the shielding/ deshielding effect produced by the MTPA is weak,15 which is an added advantage. This type of simplification can also be applied to cases where the diol is partially rigid, provided that the two hydroxyl groups are sufficiently far apart. An example of this type of diol is the megastigmane glycoside foliasalacioside E1,17 isolated from the leaves of Salacia chinensis Linn (3.1, Figure 3). In order to determine the configuration of the two secondary hydroxyls (in positions 3 and 9), it is first necessary to carry out an enzymatic hydrolysis followed by the analysis of the bis-MTPA esters of the resulting diol, foliasalaciol E (3.2, Figure 3). The ΔδSR sign distribution that was obtained experimentally for the corresponding bis-MTPA esters (3.3) is perfectly homogeneous on both sides (L1/L2) for each of the hydroxyls esterified with MTPA [C(3) and C(9)]. Therefore, the configuration of each stereocenter can be assigned by applying the model for the secondary alcohols for each stereocenter [C(3) and C(9)]. The MTPA ester of the hydroxyl in position 3 (3.4) is prepared independently, and ΔδSR is calculated. This C


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for both MTPA units. Figure 4 shows a number of diols18 for which the ΔδSR sign distributions for each hydroxyl, when considered individually, relate to the distributions of secondary alcohols. In these cases, the configuration of each stereocenter is determined independently, as if they were monofunctional compounds. This simplification of the procedure can be applied to relatively rigid structures, in which the units of the auxiliary reagent are sufficiently far apart.

Figure 3. Foliasalacioside E1 (3.1); structures and ΔδSR values (ppm) of the MTPA derivatives of foliasalaciol E (3.2).

gives a homogeneous sign distribution, which coincides with that of the bis-MTPA ester. Identical results can be obtained if the same process is carried out for the hydroxyl in position 9 (3.5). In this case, and despite the fact that we are dealing with a more flexible diol than that shown in Figure 2, the configuration can be assigned from the ΔδSR data for the bisMTPA using the simplification mentioned previously. This is done by analyzing each hydroxyl as if it were an isolated secondary alcohol. This simplification is valid, once again, because the two MTPA units are sufficiently far apart that they do not produce a combination of shielding/deshielding effects

Figure 5. Selection of polyhydroxylated compounds containing both secondary and tertiary hydroxyls.

It is relatively easy to use this type of simplification to determine the absolute configuration of polyhydroxylated compounds containing both secondary and tertiary hydroxyls. Figure 5 shows a number of compounds19 of this type (5.1− 5.13). Determining the configuration of the secondary hydroxyls is relatively easy for these compounds given that tertiary hydroxyls do not usually react under normal esterification conditions. When there are a number of secondary hydroxyls, as in the case of iriomotelide-1a19d (5.4) and euodionosides E−D19k (5.11 and 5.12), this approach can be done provided that the hydroxyls are sufficiently far apart. Finally, another situation in which configuration is easy to determine happens when secondary and primary hydroxyls are present,20 as shown in Figure 6.

Figure 4. Selection of polyhydroxylated compounds containing secondary hydroxyls. D


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ΔδSR values for the bis-MTPA esters have a perfectly homogeneous sign distribution, which coincides with that of the MTPA ester of the secondary hydroxyl. In this instance the ΔδSR sign distribution is not altered by the presence of MTPA in the primary hydroxyl. However, there are cases in the literature20 where this additional MTPA unit in the primary hydroxyl causes anomalies. This has occurred, for instance, in the tetrahydrofuranoid lignans20i from the flower buds of Magnolia fargesii (6.9, Figure 6). In this case the homogeneity of the ΔδSR sign distribution depends on the configuration of the C(8′) carbon as shown in the values for methylene (9′). It is clear that the key factor when using this type of simplification is whether the units of the auxiliary reagent are sufficiently separated. However, this is not always the case. On many occasions it is not easy to predict a priori if the ΔδRS or

Figure 7. ΔδSR signs for the MTPA derivatives of gelomulide V and X.

ΔδSR sign distributions are going to be homogeneous and follow the models based on monofunctional substrates. The degree of uncertainty increases with the structural complexity of the compound being studied, as will be shown below. An example of this is depicted in Figure 7 for the ent-abietane diterpenes gelomulide V and X isolated from Gelonium aequoreum.22 As can be seen, these structures incorporate triols, where two of the hydroxyl groups are secondary [C(1) and C(7)] and a third is tertiary. At first sight it may appear that the hydroxyl groups attached to carbons 1 and 7 are sufficiently separated for their configuration to be determined using bis-MTPA esters, simplifying the problem and allowing the secondary alcohol model to be applied to each of the hydroxyl groups. However, the experimental ΔδSR signal distributions are not homogeneous, and they do not allow the absolute configuration to be deduced with any degree of certainty. These anomalies possibly

Figure 6. Selection of polyhydroxylated compounds containing both secondary and primary hydroxyls.

In these cases, and although the primary hydroxyl is easily esterified, the presence of another unit of the auxiliary reagent does not usually cause a major problem provided that it is sufficiently far from the auxiliary reagent that esterified the secondary hydroxyl. It should also be remembered that the esters formed by primary alcohols and auxiliary reagents such as MPA and MTPA produce useless differences in the chemical shift21 of the units substituted directly onto the asymmetric carbon (L1/L2 in the β-position of the hydroxyl). This is due to the high degree of conformational flexibility21b in the esters of primary alcohols, which means that the shielding/deshielding effects of the chiral auxiliary are not efficiently translated into differences in chemical shift.21a,b,e Generally in these cases, each of the secondary hydroxyls can be analyzed independently of each other and the Δδ sign distribution (ΔδRS or ΔδSR) can be interpreted using the models used for secondary alcohols. An example of this is provided by the acyclic diterpenes from the seeds of Carpesium triste20a (6.1, Figure 6). These compounds are a series of three diterpenes, which contain a secondary hydroxyl and one or two primary hydroxyls. To determine the configuration of the asymmetric carbon, the bis-MTPA esters of the primary and secondary hydroxyls are prepared and ΔδSR values are calculated. Finally, the MTPA esters of the secondary alcohol are prepared while the primary hydroxyls are protected with acetate. As can be seen in the data provided in Figure 6, the

Figure 8. Experimental ΔδSR sign for tris-MTPA esters of squamostatin-D, and ΔδSR sign distribution for the MTPA esters of a secondary alcohol. E


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arise because the two MTPA units are close enough for their shielding/deshielding effects to combine. The problem persists even when the molecule has a degree of conformational flexibility, as is seen in the case of squamostatin-D23 (8.1, Figure 8), an annonaceous acetogenin isolated from Annonaceae plants (Figure 8). Attempts have been made to determine the absolute configuration of stereocenters 16, 19, and 24 using tris-MTPA esters and application of the secondary alcohol model. However, the experimental ΔδSR signal distributions do not conform to those of secondary alcohols (negative for L1 and positive for L2, Figure 8). A completely anomalous distribution is obtained,23

Figure 10. ΔδSR values (ppm) for MTPA derivatives of compounds 10.1−10.5.

5-desacetylaltohyrtin A (10.3)24a annonaceous acetogenins such as sootepensin A (10.1),24b a donnaienin derivative (10.2),24c leiodolide A (10.4),24d a cytotoxic macrolide isolated from a deep-water marine sponge, Leiodermatium, and alachalasin A (10.5),24e a cytochalasin isolated from the fungus Stachybotrys charatum, among many others.2a,14a These situations also occur when the additional units of the auxiliary reagent derivatize either primary alcohols or primary amines. In these cases, given that the corresponding derivatives have a greater conformational flexibility,21b it is expected that the shielding/deshielding effects will not be transmitted as efficiently to the substrate’s protons and, therefore, will not generate this type of anomaly. However, if they are close enough to the other units of the auxiliary reagent for which they modify the conformation, they can cause additional anisotropic shielding/deshielding effects, which are attributable not only to the aromatic rings but also to the reagent’s carbonyl groups, in such a way that their combinations produce completely anomalous sign distributions (ΔδRS or ΔδSR). Figure 11 shows a number of substrates25,26a in which these effects are seen, including sponge metabolites penaresidins (11.1− 11.2),25a pyripyropene A (11.3),25b and sec/prim-amino alcohols (11.4−11.6).26a A greater problem arises when trying to apply to polyfunctional compounds the methods designed for monofunctional compounds, as the sign distributions (ΔδRS or ΔδSR) are not the same as those predicted by the models. This is because the presence of a number of auxiliary reagents in the same molecule causes the combination of anisotropic effects (shielding/ deshielding: addition/subtraction), or because some units change the conformation of the others. Whatever the reason may be, this means that the distributions of signs of the differences in chemical shifts (ΔδRS or ΔδSR) do not follow the patterns observed for monofunctional compounds. For these cases the simplifications given above are no longer useful. Therefore, it can be concluded that, except for exceptional cases, errors usually arise if one tries to assign the configuration

Figure 9. Shielding effect distribution in the tris-(S)- and (R)-MTPA esters of squamostatin-D (a, b) and expected ΔδSR signs based on models for monofunctional compounds (c).

as the signs of the ΔδSR values are identical for both sides of the asymmetrical carbons (16, 19, and 24). Therefore, the secondary alcohol model is not applicable in this case. This anomaly is caused by the combination of the shielding/ deshielding effects of the three MTPA esters present in the molecule. Figure 9 shows that the protons located between positions 16 and 24 are shielded by the MTPA in positions 16 and 19 for the tris-(S)-MTPA ester (Figure 9a) and by the MTPA in positions 24 and 19 for the tris-(R)-MTPA ester (Figure 9b). Therefore, as there is shielding in both tris-MTPA esters, it is not possible to predict the sign of the corresponding ΔδSR (Figure 9c). These types of anomalies are commonly seen throughout the literature.14a They are most often seen in situations where a molecule contains a number of auxiliary reagent units in combination with one of the following factors: (a) the auxiliary reagents are close enough to produce a combination of shielding/deshielding effects and (b) when the selected auxiliary reagent is MTPA and the steric hindrance of the substrate may modify its representative conformation as it relates to NMR. Figure 10 shows a number of examples where these circumstances may occur, including the hexa-MTPA ester of F


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Figure 11. ΔδSR values (ppm) for MTPA derivatives of compounds 11.1−11.6. Figure 12. Structure of shishididemniol A and determination of the absolute configuration of its structural fragments.

of a polyfunctional compound by treating each stereocenter as if it were an isolated monofunctional compound. It is therefore necessary to analyze the consequences of the interaction of shielding/deshielding effects from all the reagents present in the substrate, from the standpoint of NMR. There is, of course, the alternative of using selective protection of the individual stereocenters, allowing the configuration of each one to be assigned as if it were a monofunctional entity. An example that shows the extent of the difficulties that arise when determining the absolute configuration of a polyfunctional compound is the case of shishididemniol A,26 a serinolipid from a tunicate of the family Didemnidae (12.1, Figure 12). It is a structure that contains primary and secondary alcohols along with α-substituted primary amines. The stereocenters to be investigated by the derivatization methodology are carbons 2′, 10′, 2, 6, 16, and 30. To determine the configuration of stereocenters 2′ and 10′, hydrolysis is initially carried out, followed by derivatization of the hydroxyls and amines of the resulting fragment using (R)and (S)-MTPA. However, the ΔδSR sign distributions do not conform to the models for secondary alcohols nor α-substituted primary amines. Chemical shift data is then compared to that for model compounds with a known absolute configuration. The configuration of stereocenter 30 is determined from the corresponding amido esters of MTPA, despite the fact that methylene 31 shows an anomalous ΔδSR sign distribution. The configuration of stereocenter 16 cannot be assigned using MTPA esters, but after various chemical transformations it can be assigned using 2-NMA esters, although this only yields the ΔδRS signs for the methylenes of one side of the symmetrical carbon that is present six carbons away from the asymmetrical carbon. The configurations of carbons 2 and 6 are obtained from the bis-MTPA esters of the corresponding diol, but the ΔδSR sign distributions are due to the combination of the shielding/

deshielding effects of the MTPAs that esterify hydroxyls 2 and 6. Therefore, to isolate the effects of the MTPA of carbon 6 and to assign its configuration as if it were a secondary alcohol, it is necessary to carry out a number of chemical transformations and the analysis of the MTPA esters of the resulting acetonide. However, this only reveals the ΔδSR values for one of the two sides of asymmetric carbon 2. Considering all of the above, it is patently obvious that specific and systematic treatments are necessary for substrates that contain a number of derivatizable groups and a number of asymmetric centers. The following sections of this review will discuss the most relevant methods specifically designed for the determination of the absolute configuration by NMR of sec/secand prim/sec-1,2-diols; sec/sec-1,n-diols; sec/sec-, prim/sec-, and sec/prim-1,2-amino alcohols; and prim/sec/sec-1,2,3-triols (Figure 13).

3. ACYCLIC SEC/SEC-1,2- AND SEC/SEC-1,N-DIOLS 3.1. Double-Derivatization Methods: MPA and 9-AMA

There are two options to choose between when determining the absolute configuration of a sec/sec-diol: (a) assignment of the stereochemistry for each stereocenter separately while selectively protecting one and derivatizing the other and (b) assignment of all the stereocenters simultaneously, with the latter being the easiest and quickest method. It has recently been reported14b,27 that the absolute configuration of an acyclic sec/sec-1,n-diol can be accurately assigned through the comparison of the NMR spectra for the bis-(R)- and (S)-AMAA (MPA, 9-AMA, Figure 14) and MTPA esters, which yields ΔδRS values (ΔδSR in the case of MTPA) resulting from the combination of the anisotropic effects (shielding/deshielding) for the AMAA units present in the molecule. The ΔδRS values (or ΔδSR) show characteristic sign G


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Figure 15. (a) Main rotations in 1,2-diols. (b) Conformational equilibrium in AMAA esters.

Figure 13. General structures of the polyfunctional compounds studied in this review.

alcohols. This is represented by the equilibrium between the two main conformers (Figure 15b) already described for monoesters of secondary monoalcohols: sp (methoxy, carbonyl, and CαH in synperiplanar disposition) and ap (methoxy, carbonyl, and CαH in antiperiplanar form), both with the aromatic ring well-oriented for the efficient shielding of the L substituent located to the same side, and the sp being the most abundant conformer. As for the role of the rotation around the C(1)−C(2) bond, the analysis of the coupling constants (3JH1−H2) shows that there is no conformational preference around this bond, which is representative of all the diols (types A−D) (Figure 15a); in fact, the rotation depends on the configuration and structure of the substrate.

Figure 14. Stereochemistries, partial 1H NMR spectra, and ΔδRS sign distributions in the bis-AMAA-esters of sec/sec-1,2-diols.

distributions for each of the four possible configurations of the diol (types A−D, Figure 14).14b,27 The main diagnostic signals arise from the protons directly bonded to asymmetric carbons Hα(R1) and Hα(R2). The procedures for assigning the absolute configuration by NMR are based on the presence in the auxiliary reagent of an aromatic ring (or another anisotropic group) able to efficiently transmit its shielding/deshielding to the substituents of the substrate bound to the asymmetric carbon, in a selective way, that is, only to one substituent. Naturally, this requires the existence of a predominant conformation where the group affected by the anisotropic effect is located just under the shielding/deshielding influence. In the case of bis-AMAA esters (MPA and 9-AMA, Figure 15a) of sec/sec-diols, a detailed conformational analysis was performed including theoretical calculations27 [semiempirical (AM1), ab initio (HF), DFT (B3LYP), Onsager methods, and aromatic shielding effect calculations] and the experimental data27,14b (NMR, CD). The result of those studies shows that the two units of the auxiliary reagent (MPA and 9-AMA) both present the same conformational composition, basically identical to the one observed in the corresponding monoesters of secondary

Figure 16. Shielded groups in the main conformers generated by rotation around C(1)−C(2) bond in the bis-AMAA ester of a sec/sec1,2-diol.

Fortunately, of the two conformational processes, rotation around the Cα−CO bond and rotation around the C(1)−C(2) bond, only the former is relevant from the standpoint of NMR. This can be seen in Figure 16a, where in the bis-(R)-AMAA ester of the diol with the configuration shown in the figure, the groups shielded by the auxiliary reagent are the same regardless of the conformer that is formed by the rotation around the C(1)−C(2) bond. The same thing occurs in the bis-(S)-AMAA H


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ester, where the shielded groups are the same [R1, R2, Hα(R1), and Hα(R2)] regardless of the rotation around the C(1)−C(2) bond (Figure 16b). Once the most representative conformations, from an NMR standpoint, of the bis-AMAA ester of each diol (structure types A−D) are known, it is possible to predict its NMR behavior. To do this, it should be borne in mind that the two AMAA units have a synperiplanar conformation, that the rotation around the C(1)−C(2) bond does not have a great influence on the chemical shifts of the diol substituents, and, lastly, that consideration should be given to the orientation of the aromatic ring (phenyl or anthryl) of each AMAA and the direction of their anisotropic effect, shielding/deshielding. It will then be possible to predict which groups will be shielded for each of the bis-(R)- and bis-(S)-AMAA esters and, therefore, determine the identity of the groups that have diagnostically useful signals. It will also be possible to determine

Figure 17. Distribution of the shielding effects and predicted ΔδRS signs for the bis-AMAA esters of syn-sec/sec-1,2-diols.

the characteristic ΔδRS sign distributions for each of the diol configurations (types A−D). So, in a diol with a type A structure (Figure 17a), the R1 and R2 groups will be shielded in the sp conformation of the bis-(R)-AMAA ester, whereas shielding of the R1 and R2 groups as well as protons Hα(R1) and Hα(R2) will occur in the same conformation of the bis-(S)AMAA ester (Figure 17b). As R1 and R2 are shielded in both esters, it is impossible to predict in which ester they will receive the greatest shielding, which means that they are no longer diagnostic signals. On the other hand, Hα(R1) and Hα(R2) become diagnostic signals as they are more shielded in the bis(S)- than in the bis-(R)-AMAA ester and they have a positive ΔδRS (Figure 17c). If the same reasoning is applied to the enantiomeric diol with a type B structure (Figure 17d), we find that the R1 and R2 groups again cannot be used as diagnostic signals as they are shielded in both bis-AMAA esters. Once again the protons

Figure 18. ΔδRS values (ppm) for the bis-9-AMA (underlined values) and bis-MPA (plain values) esters of type A and B syn-diols (18.1− 18.13).

Hα(R1) and Hα(R2) are the diagnostic signals, and their ΔδRS values have negative signs as they are more shielded in the bis(R)- than in the bis-(S)-AMAA ester (Figure 17d). Figure 18 shows a series of bis-MPA and bis-9-AMA esters of syn-1,2-diols with type A (Figure 18a) and type B (Figure 18b) configurations along with their corresponding ΔδRS values. In all of these cases, the sign distributions are in perfect agreement with the previously described models. Again, if the same reasoning is applied to the anti-1,2-diols with type C and D structures (Figure 19), we find the following results: for type C diols of the bis-(R)-AMAA ester (Figure 19a), the R1 and Hα(R1) groups receive the greatest shielding in the representative conformation, whereas in the bis-(S)I


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Figure 20. ΔδRS values (ppm) for the bis-9-AMA (underlined values) and bis-MPA (plain values) esters of type C and D anti-diols.

Figure 19. Distribution of the shielding effects and predicted Δδ signs for the bis-AMAA esters of anti-1,2-diols.

RS

AMAA ester, the groups with the greatest shielding are R2 and Hα(R2) (Figure 19b). Therefore, R1, R2, Hα(R1), and Hα(R2) are diagnostic signals, and the ΔδRS values are negative for R1 and Hα(R1) as they are more shielded in the bis-(R)- than in the bis-(S)-AMAA ester. The ΔδRS values are positive for R2 and Hα(R2) as they are more shielded in the bis-(S)- than in the bis-(R)-AMAA ester (Figure 19c). For enantiomeric diols with a type D structure in the bis-(R)AMAA ester (Figure 19d), the most shielded groups in the representative conformation are R2 and Hα(R2), whereas in the bis-(S)-AMAA ester, the most shielded groups are R1 and Hα(R1). Therefore, R1, R2, Hα(R1), and Hα(R2) are diagnostic signals, and the ΔδRS values are negative for R2 and Hα(R2) as they are more shielded in the bis-(R)- than in the bis-(S)AMAA ester. The ΔδRS values are positive for R1 and Hα(R1) as they are more shielded in the bis-(S)- than in the bis-(R)AMAA ester. Figure 20 shows a series of bis-MPA and bis-9-AMA esters of anti-1,2-diols with type C (Figure 20a) and type D (Figure 20b) configurations along with their corresponding ΔδRS values. In all of these cases, the sign distributions are in perfect agreement with the previously described models. One of the main differences with respect to monofunctional compounds in general, and secondary alcohols in particular, is that the signals corresponding to the “alpha” position protons, Hα(R1) and Hα(R2), become diagnostic signals. This occurs because they are only affected by the auxiliary unit of the other asymmetric center, making them the key to the assignment of the absolute configuration in a sec/sec-diol. In addition the behavior, from a NMR standpoint, of the R1 and R2 groups is only important in the anti-diols (C and D) and they are unimportant in the syn-diols (A and B). As can be seen in

Figure 21. Conformational equilibrium in (R)- and (S)-AMAA esters of a secondary alcohol (a, b) and correlation of ΔδRS signs with the configuration (c).

Figure 21, the L1 and L2 groups on the AMAA esters of secondary alcohols are directly linked to the asymmetric carbon. The shielding effects of the aromatic ring of the auxiliary reagent (AMAA) selectively affect these groups, and their ΔδRS signs are correlated to the absolute configuration.28,2a For a secondary alcohol with the configuration shown in Figure 21a, L1 is more shielded in the (R)-ester than in the (S)AMAA one and it has a negative ΔδRS (Figure 21c). The L2 group, meanwhile, is more shielded in the (S)-ester than in the (R)-AMAA (Figure 21b), and it has a positive ΔδRS (Figure 21c). However, the Cα(H) proton is more subject to the J


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number of methylenes are the methylenes, the Hα(R1), and the Hα(R2), and the sign distributions coincide with those for the syn-1,2-diols.14b,27 On the other hand, the diagnostic signals for syn-1,n-diols with n > 2 and an odd number of methylenes and

influence of the anisotropic effect (shielding/deshielding) of the carbonyl of the auxiliary reagent as it is located in the molecule’s defining plane [OMe, CO, Cα(H)]. Its ΔδRS sign is the result of the weighted average of the shielding/

Figure 22. ΔδRS sign distribution for the bis-AMAA (ΔδSR for bisMTPA) esters of 1,n-diols.

deshielding effect of the carbonyl on each conformation (sp/ ap) and of the differences in sp/ap populations in both derivatives29 [(R)- and (S)-AMAA ester]. Figure 22a and b depicts the conclusions14b,27 reached above in graphical form. If the ΔδRS signs of protons Hα(R1) and Hα(R2) are equal, then the diol has a syn relative configuration. However, if the ΔδRS signs are both positive, then it is a syn-diol type A (Figure 22a), and if they are both negative, the diol is a syn-diol type B (Figure 22a). In both of these cases, the ΔδRS values for R1 and R2 have no influence when assigning the configuration. If the ΔδRS signs of protons Hα(R1) and Hα(R2) are different (one positive and the other negative), the diol will have an anti relative stereochemistry. If the ΔδRS of Hα(R1) is negative and that of Hα(R2) is positive, the configuration is a anti-type C (Figure 22b). In this case the signals corresponding to groups R1 and R2 are diagnostic signals, and the ΔδRS of R1 must be negative and that of R2 positive. However, if the ΔδRS of Hα(R1) is positive and that of Hα(R2) is negative, then the configuration is an anti-type D (Figure 22b). Once again the ΔδRS of R1 must be positive and that of R2 must be negative. For sec/sec-1,n-diols, it should first be ascertained that (a) the two AMAA units present in the substrate are in a synperiplanar conformation and (b) the rotation around the bonds that link both asymmetrical carbons does not affect the chemical shift of R1, R2, Hα(R1), and Hα(R2). Once this has been ascertained, it is possible to apply the same reasoning to determine which groups are shielded in each bis-AMAA ester, which are diagnostic signals, and what are the ΔδRS sign distributions. The results are shown graphically in Figure 22 c−f. In this case it is important to determine the number of methylenes that separate the asymmetrical carbons. The diagnostic signals in anti-1,n-diols with n > 2 and an odd number of methylenes and the diagnostic signals in syn-1,n-diols with n > 2 and an even

Figure 23. ΔδRS values (ppm) of the bis-9-AMA (underlined values) and bis-MPA (plain values) esters of 23.1 and 23.3; bis-MPA esters of onchitriol I (23.2) and bis-2-NMA esters of asimicin (23.4) and ronilliastatin-2 (23.5).

for the anti-1,n-diols with n > 2 and an even number of methylenes are R1, R2, Hα(R1), and Hα(R2), and the sign distributions coincide with those of the anti-1,2-diols.14b,27 Figure 23 shows a complete series of 1,n-diols derivatized with MPA, 9-AMA, and 2-NMA, along with their experimental ΔδRS distributions.30 The sign distributions for all these diols agree with those shown in Figure 22. It should be pointed out that other auxiliary reagents belonging to the AMAA series, such as 2-NMA or 1-NMA, behave in exactly the same manner as that described for MPA and 9-AMA, given that they have the same conformational equilibrium between the sp and ap forms and a preference for the same conformation (sp).27,28 If the ΔδRS values of the bis-2-NMA esters of rolliniastatin30b 2 (23.5, Figure 23) are analyzed in more detail, particularly those for asymmetric carbons 15 and 24, it is possible to find identical sign distributions on both sides of these two asymmetric carbons. This is one of those cases where the configuration is impossible to determine by applying the K


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Figure 25. NMR significant conformers, shielded groups, and Δδ signs distributions in the AMAA (ΔδRS) and MTPA (ΔδSR) esters of secondary alcohols. Figure 24. Structural analogy between 1,n-diols and diols containing tetrahydrofuran rings.

opposite to those obtained for the same configuration using AMAA reagents (Figure 25).15,31 When MTPA is used as the auxiliary reagent, it is common to express the shifts in the form of ΔδSR instead of ΔδRS. In these conditions, and for the same diol, the signs of ΔδSR obtained with MTPA are coincident with the signs of ΔδRS obtained with AMAA, and the general patterns represented in Figure 22 for AMAA esters are also applicable to MTPA esters by simply replacing the ΔδRS (AMAA) by ΔδSR (MTPA). In previous studies, Ichikawa32 examined the absolute configuration assignment of syn- and anti-diols using MTPA esters, but there are not many other published studies in this area. In other work, the same author33 studied the assignment of diols containing aromatic groups but found anomalies in ΔδSR sign distributions when the method was applied to nonaromatic anti-glycols. Other groups34 have analyzed the possible application to 1,3-diols, and the authors concluded that the method could only be applied to syn-1,3-diols. A more detailed analysis using the data in Figure 22 showed that it could also be applied to anti-1,3-diols. The same study describes the application of this method to six-membered cyclic systems. The majority of studies into diol configuration using MTPA esters have been carried out in the field of natural products. With the exception of the cases discussed in the previous section of this review, where the hydroxyls are sufficiently separated to allow the configuration to be determined as if the compound was an isolated secondary alcohol, configuration is assigned using the data in Figure 22 and replacing the signs of ΔδRS with ΔδSR. For example, Figure 26 shows the structures and ΔδSR values for MTPA derivatives for a series of acetogenins35 that contain 1,n-diols in their structures. From a conformational and NMR standpoint, their behavior is the same as that of type B syn-1,ndiols (n is even). The ΔδSR sign distribution for the CαH protons and the methylenes in all the examples perfectly fit the model shown in Figure 22. A more detailed analysis of the ΔδSR sign distributions around asymmetrical carbons C-24 in asimicin30b (23.4), C-20 in cis-muriosolinone26b (26.2), and C-20 in trans-muriosolinone26b (26.3) show identical signs on

secondary alcohol model to each of the two stereocenters. However, these sign distributions have meaning when the set is analyzed as a type D syn-1,8-diol (Figure 22d). We conclude this section by briefly discussing the application of the models shown in Figure 22 to polyols such as the acetogenins (also shown in Figure 23), which contain tetrahydrofuran rings (23.4 and 23.5, Figure 24) in the chains separating the hydroxyls. To model these compounds, it is necessary to remember that the equivalencies change with respect to those of the straight-chain 1,n-diols. Conformational analysis shows that the anti-1,n-diols [where n is even and which contain tetrahydrofuran (THF) rings] are equivalent to linear type B anti-1,n-diols with an odd number of methylenes and to the type B syn-1,2-diols (Figure 24a).27 As for the syn1,n-diols (where n is even and which contain THF rings), it has been found that they are equivalent to linear type D syn-1,ndiols with an odd number of methylenes, and also with the type D anti-1,2-diols (Figure 24b).27 3.2. Double-Derivatization Methods: MTPA

In the previous sections, we have described the rules relating to the absolute configuration of diols and the chemical shifts of their bis-AMAA esters (MPA, 1-NMA, 2-NMA, and 9AMA).14b,27 When a diol is derivatized with MTPA as an auxiliary, the combination of shielding/deshielding effects generated by each reagent unit is operative too. Therefore, the reasoning followed to explain and predict the Δδ in bisAMAA esters should also be of use in bis-MTPA esters, provided that the conformational differences between the AMAA and bis-MTPA esters are taken into account. These differences involve important changes in the shielding/deshielding distribution,15,31 but they can be summarized very easily. Thus, if in the (R)-AMAA ester of a secondary alcohol substituent L1 is shielded and L2 is unaffected (Figure 25a), in the corresponding (R)-MTPA ester the situation is reversed (L2 is shielded and L1 is unaffected, Figure 25c). As a result, the signs of ΔδRS obtained with MTPA are the L


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Figure 27. Structures of type D syn-1,n-diols (n is odd) and their ΔδSR values (ppm) as MTPA esters.

the same way as type D anti-1,n-diols (n is odd). In all of these cases, the ΔδSR sign distributions for the diagnostic protons, CαH and those of the R1 and R2 groups, perfectly fit the model shown in Figure 22. Although at first sight the ΔδSR sign distributions around carbons C-24 in rolliniastatin-230b (23.5), C-24 and C-15 in 2,4-cis- and trans-squamolinone36b (27.2), and mosin C36c (27.3) appear to perfectly fit the secondary alcohol model, it should be remembered that the values relating to the methylenes that separate the asymmetric carbons are completely unpredictable and are of no use when assigning a configuration. This is the case for the distribution around C-15 in rolliniastatin-2 (23.5), where the signs are identical on both sides of the asymmetrical carbon. Figure 28 shows the ΔδSR values for the MTPA derivatives of a series of substrates37 that have 1,n-diols in their structures that, from a conformational and NMR standpoint, behave in the same way as a type C syn-1,n-diol (n is odd). For all of these substrates, the ΔδSR sign distribution of the diagnostic protons, CαH and those relating to the R1 and R2 groups, perfectly fits the model in Figure 22. Figures 29 and 30 show examples of compounds38,39 where the 1,n-diols behave in a similar manner to anti-1,n (Figure 29) and where 1,n-diols behave like syn-1,n (Figure 30). In all of these cases, the ΔδSR sign distributions perfectly coincide with the models in Figure 22. The cyclic diols (Figure 31) can be considered a special case, as it is not easy to find their equivalents among the models for linear diols in Figure 22. It is therefore necessary to make a more detailed analysis of each molecule’s main conformation followed by an analysis of the shielding effects for each MTPA in order to determine the shielded groups for each derivative.

Figure 26. Structures of type B anti-1,n-diols (n is even) and their ΔδSR values (ppm) as MTPA esters.

both sides of these asymmetrical carbons, which indicates that it is not possible to determine the configuration of any of these carbons by using the secondary alcohol method. Sootepensin A24b (10.1) and donnaienin derivatives24c (10.2) shown in Figure 10 represent examples of polyhydroxylated substrates whose absolute configuration cannot be assigned using the model for secondary alcohols due to the anomalies observed in the ΔδSR sign distributions. However, the configurations of carbons C-22 and C-15 in sootepensin A24b (10.1) and C-20 and C-15 in the donnaienin derivative24c (10.2) can be successfully determined using the model shown in Figures 22 and 26, and the ΔδSR signs distributions perfectly fit those of the type B anti-1,n-diols (n is even). Figure 27 shows ΔδSR values for MTPA derivatives for a series of acetogenins36 that have 1,n-diols in their structures and which, from a conformational and NMR standpoint, behave in M


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Figure 30. Structures of syn-1,n-diols and their ΔδSR values (ppm) as MTPA esters.

Figure 28. Structures of type C syn-1,n-diols (n is odd) and their ΔδSR values (ppm) as MTPA esters.

Figure 31. ΔδSR values (ppm) of bis-MTPA esters of cyclic diols.

3.3. Single-Derivatization Methods: MPA

As has been indicated above, the absolute configuration of secondary alcohols and primary amines can be determined using simple methods that only require the preparation of one derivative of a substrate and one of the two enantiomers of the auxiliary reagent. This is followed by the analysis of the changes in the NMR spectra with temperature or before and after the addition of a barium salt.6,7,2a The feasibility of using these two approximations has also been studied for the determination of the absolute configuration of sec/sec-1,2-diols.41 It has been shown that the comparison of the NMR spectrum for one of the bis-MPA esters, either the bis-(R) or the bis-(S), at room temperature and at a lower temperature facilitates the determination of relative configuration for the 1,2-diols, distinguishing between the syn and the anti forms. However, it is only possible to determine the absolute configuration for type C and D anti-1,2diols (Figure 32). This method is possible because the bis-MPA esters of the 1,2-diols have a well-defined conformational equilibrium,27 as was indicated in the previous section. This allows identification of the two conformations, the sp and the ap, with the sp being the most stable. A decrease in temperature causes an increase in

Figure 29. Structures of type C anti-1,n-diols (n is even) and their ΔδSR values (ppm) as MTPA esters.

To do this, it is necessary to follow the steps described in Figures 17 and 19. By following this type of reasoning, it is possible to arrive at sign distribution models that are perfectly consistent with the configuration of a diol. For example, marinispolide A40a (31.1, Figure 31) contains a diol equivalent to a type C syn-1,n (n is odd), and iriomoteolide-3a40b (31.2, Figure 31) contains a diol equivalent to a type A syn-1,2-diol (Figure 31). N


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From an experimental standpoint, this method requires the preparation of one of the bis-MPA esters, either the bis-(R) or the bis-(S) form, and the record of an initial spectrum at room temperature (298 K) and a second spectrum at a lower temperature (213 K is suitable). In both cases the solvent used is a mix of CS2/CD2Cl2 (4:1). The spectra are compared, and the differences in chemical shift, ΔδT1T2, are calculated. These are defined as the difference in δ at the higher temperature minus δ at the lower temperature. The only diagnostic signals are those that correspond to groups R1 and R2 (Figure 32). In the case of the bis-(R)-MPA esters, if the ΔδT1T2 signs obtained for R1 and R2 are positive and negative, respectively, the diol is a type C anti-1,2-diol (Figure 32 and 33a). If the signs are negative and positive, respectively, it is a type D 1,2diol (Figures 32 and 33b). If both signs are positive, it is either a type A or type B syn-1,2-diol (Figures 32 and 33d). When the bis-(S)-MPA esters are used, the sign distributions are reversed. This trend has been shown experimentally for a series of diols of known absolute configuration (Figure 33). It should be stated that, as opposed to the doublederivatization method, in this case the signals corresponding to protons Hα(R1) and Hα(R2) are no longer diagnostic because, as well as being subject to the shielding/deshielding effects of the phenyls of both MPA units, shielding/deshielding

Figure 32. Diagram for the assignment of the absolute configuration of antisec/sec-1,2-diols from the ΔδT1T2 signs of the (R)-MPA derivatives.

the number of molecules in the most stable conformation, the sp, which increases the contribution of the shielding/ deshielding effects observed in the average spectrum of this conformation. The change in R1 and R2 signals in the NMR spectra as temperature decreases allows conclusions to be drawn regarding the diol’s configuration.

Figure 33. Selection of 1,2-diols and ΔδT1T2 values (ppm) of the bis-(R)- (plain values) and bis-(S)-MPA (underlined values) derivatives. O


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effects are also produced by the carbonyls of the ester groups,29 and this makes the ΔδT1T2 signs difficult to predict. To understand the relationship between the ΔδT1T2 sign distributions and the absolute configuration of the diol, it is

Figure 34. Distribution of the shielding effects in the bis-(R)-MPA esters of anti-1,2-type-C (a), anti-1,2-type-D (b), syn-1,2-type-A (c) and syn-1,2-type-B (d) diols.

necessary to analyze the conformational equilibrium, taking into account the relative stabilities and the structure of the sp/ ap conformers of the bis-MPA esters. For example, for the bis(R)-MPA ester of a type C anti-1,2-diol, the two MPA units of the sp conformation shield R1, whereas in the ap conformation R2 is shielded (Figure 34a). When the temperature decreases, the equilibrium moves toward the sp conformation and the number of molecules in this conformation increases, with a subsequent decrease in the number of molecules in the ap conformation. These changes are reflected in the NMR spectrum. As the temperature decreases, the signal corresponding to R1 moves upfield and that for R2 moves downfield. This means that ΔδT1T2 for R1 is positive and for R2 is negative (Figure 34a). By applying the same reasoning to the bis-(R)-MPA ester of a type D anti-1,2-diol (Figure 34b), the expected behavior for the change in the NMR spectra is reversed: ΔδT1T2 is negative for R1 and positive for R2. It should be taken into account that, if instead of the bis-(R)-MPA esters being analyzed it is the bis(S)-MPA ester that is analyzed, then the results are reversed. The situation is different for type A and B syn-1,2-diols and the change in the spectra with temperature is the same for both types of diols. As can be seen in Figure 34c and d, substituents R1 and R2 are shielded in both conformers sp and ap of the bis(R)-MPA ester of the type A syn-diol. Therefore, when the temperature is decreased, the signals for both groups are expected to move upfield, which translates into a positive value for their respective ΔδT1T2 values. This is the same situation

Figure 35. Partial 1H NMR spectra of the bis-(R)-MPA esters of the 4 stereoisomers of heptane-2,3-diol at different temperatures (298−183 K).

that is observed for the bis-(R)-MPA ester of the type B syndiol: ΔδT1T2 is positive for both R1 and R2 (Figure 34 c and d). For example, Figure 35 shows the change in NMR spectra with changing temperature for the bis-(R)-MPA esters for 4 stereoisomers of heptane-2,3-diol. In the type A and B syn-1,2diols, the signals corresponding to groups R1 and R2 (Me and Bu, respectively) become more shielded as temperature decreases (Figure 35a and b); therefore, it is not possible to distinguish between them. Meanwhile, in the case of the type C anti, R1 is shielded and R2 is deshielded (Figure 35c). This is reversed in the type D anti: R2 is shielded and R1 is unshielded (Figure 35d). This method allows differentiation between a syndiol and an anti-diol (relative stereochemistry), and also, if it is an anti, it is possible to distinguish between a type C and a type D (absolute stereochemistry). The literature contains a study where the single-derivatization method based in the addition of Ba2+ and designed for secondary alcohols was applied to diols. Carmeli and coP


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4. SEC/SEC-1,2-AMINO ALCOHOLS The sec/sec-1,2-amino alcohols are a type of polyfunctional compound that has many important similarities with sec/sec-1,2diols. The determination of their absolute configuration can be carried out in the same way as for diols. The configuration of the two chiral centers is determined simultaneously by analyzing the corresponding MPA amido esters without the need to carry out selective protection/deprotection protocols.43 The distribution of ΔδRS signs is the result of the combined action of both MPA moieties, and the main diagnostic signals are those relating to the Hα(R1) and Hα(R2) protons and also from R1 and R2.

Figure 37. Main rotations in the bis-MPA derivatives of sec/sec-1,2amino alcohols. Figure 36. (a) ΔδBa values (ppm) for the bis-MPA esters of pandangolide 1, isocladospolide B, and pandangolide 1a. (b) Main conformation in the complexes of the bis-(R)-MPA esters of 36.1 and 36.2 with Ba2+. (c) ΔδBa sign distribution in the (R)-MPA esters of a secondary alcohol.

The main difference between the bis-MPA derivatives of amino alcohols and those of diols is that, in amino alcohols, ester and amide bonds are present: the MPA ester is preferentially in an sp conformation, whereas the MPA amide is in an ap conformation.44 In the case of diols, both MPA units are in an sp conformation. This has been confirmed through a detailed conformational analysis (Figure 37), mainly comprising CD studies and the analysis of changes in NMR spectra with temperature (DNMR).43 As a result of this different conformational preference, the ΔδRS sign distributions of the MPA amido esters for an amino alcohol will be completely different from those of the bis-MPA esters of a diol with exactly the same spatial arrangement for the R1 and R2 groups. As in the case of the MPA esters of the diols, there is no conformational preference around the C(1′)−C(2′) link (Figure 37). Therefore, to predict the ΔδRS sign distribution, it is necessary for both MPA units to be in their preferred conformations: sp for the MPA ester and ap for the MPA amide. It will then be possible to analyze which groups are shielded in each derivative. Take as an example a type A syn-1,2-amino alcohol with the configuration shown in Figure 38. Hα(R1) and R1 groups are the most shielded in the bis-(R)-MPA derivative, while in the bis-(S)-MPA derivative it is Hα(R2) and R2 that are the most shielded. This suggests a negative ΔδRS sign distribution for Hα(R1) and R1 and a positive one for Hα(R2) and R2 (Figure 38a). Applying the same reasoning to its enantiomer, a type B syn-1,2-amino alcohol gives the opposite ΔδRS sign distribution to that above: positive for Hα(R1) and R1 and negative for Hα(R2) and R2 (Figure 38b). All the signals are diagnostic for both types of amino alcohols (types A and B). However, in the anti-1,2-amino alcohols, only the Hα(R1) and Hα(R2) protons are diagnostic signals. For example, in the bis-(R)- and bis-(S)-MPA derivatives of a type

workers 42 applied this methodology to determine the configuration of pandangolide 1 (36.2), pandangolide 1a (36.1), and isocladospolide-B (36.3) (Figure 36a). They assumed that the two MPA units present in the diol form individual complexes with Ba2+, so that each fragment of MPA adopts an sp conformation before and after forming the complex with Ba2+ (Figure 36b). They expected the same behavior as in MPA esters of secondary alcohols: the formation of the complex increases the sp conformation. Therefore, the signal corresponding to L1 moves upfield as it becomes shielded, and the L2 signal moves downfield as it becomes deshielded. This assumes a positive ΔδBa for L1 and a negative ΔδBa for L2 (Figure 36c). The ΔδBa sign distributions were consistent for the bis-MPA esters of pandangolide 1 (36.2) and isocladospolide B (36.3), but for pandangolide 1a (36.1) an anomaly was observed in one of the protons in position 2. When applying the singlederivatization methodology based on the use of Ba2+ to polyfunctional compounds, systematic studies should be carried out on a number of different substrates with a wide structural and configurational variety. Assessments were made regarding the possibility that the observed sign distributions would be the result of the different MPA units. Studies should be carried out on the geometry of possible complexes between the barium and the MPA units, which could cause variations in the direction of the shielding/deshielding effects of the MPA phenyls. Q


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C anti-1,2-amino alcohol (Figure 39a), R1 and R2 are shielded in both derivatives, making it impossible to predict the ΔδRS sign. However, only Hα(R1) and Hα(R2) are shielded in the bis-(S)-MPA derivative, which indicates a positive ΔδRS for both. In the same way, in the type D anti-1,2-amino alcohol, R1 and R2 are again shielded in both derivatives (nondiagnostic protons), whereas Hα(R1) and Hα(R2) are more shielded in the bis-(R)-MPA derivative, indicating a negative ΔδRS for both. Figure 40 shows a selection of amino alcohols (40.1−40.18) with a wide structural variety and known configurations, along with experimentally obtained ΔδRS values. In all of these cases, the distributions fit the absolute configurations, which are summarized in Figure 41a. By way of comparison, Figure 41b shows the distributions of ΔδRS signs for the bis-MPA esters of the 1,2-diols. As indicated, the ΔδRS sign distributions of an amino alcohol and a diol of the same configuration are not identical. This is also the case for the identities of the diagnostic signals, which are different for an amino alcohol and a diol of the same configuration. For example, for a type A syn-1,2-amino alcohol, all the signals are diagnostic, whereas ΔδRS values are negative for Hα(R1) and R1 and positive for Hα(R2) and R2. However, for a type A syn-1,2diol (the same configuration as the amino alcohol), the only diagnostic signals are those pertaining to Hα(R1) and Hα(R2), and both have positive ΔδRS values. These differences are due to distinct conformational preferences between the MPA esters and amides.28,44 Whereas in a diol both MPA units have the same conformation (sp),28 in an amino alcohol each MPA unit has a different conformation: sp in the MPA ester28 and ap in the MPA amide.44 This discrepancy causes the shielded groups to be different for each compound, with a change taking place in the identity of the diagnostic signals and also in the final ΔδRS value distributions. This coexistence between amide and ester auxiliary units has other important consequences, for example, for other AMAAs, such as 9-AMA, which are not very effective in determining the absolute configuration of primary amines.44 It has not been possible to establish a correlation between ΔδRS values and absolute configuration for sec/sec-amino alcohols derivatized with 9-AMA. Nor has it been possible to establish a pattern of behavior for these systems from the analysis of the changes in NMR spectra for the bis-MPA derivatives of the sec/sec-amino alcohols. This is also the case for the MPA amides of the primary amides. Therefore, the configuration of these substrates cannot be assigned following the analysis of a single derivative. Configuration can only be assigned following the preparation of the two MPA derivatives and the comparison of their NMR spectra (Figure 41c).43 Different ΔδRS signs for protons Hα(R1) and Hα(R2) indicate a syn-type amino alcohol, and equal signs indicate an anti-type amino alcohol. In the former case, R1 and R2 are diagnostic signals along with Hα(R1) and Hα(R2). For the latter case, only Hα(R1) and Hα(R2) are diagnostic signals. The configuration can be established using the signs shown in Figure 41a.

Figure 38. Distribution of the shielding effects and predicted ΔδRS signs for the bis-MPA derivatives of syn-1,2-amino alcohols.

5. PRIM/SEC-1,2-DIOLS The absolute configuration of the prim/sec-1,2-diols is basically determined through double derivatization,45 as if they are secondary alcohols. However, conformational analysis shows that their representative conformations are different depending on the configuration of the diol and the AMA. This means that each of the methylene protons (1′) experience different

Figure 39. Distribution of the shielding effects and predicted ΔδRS signs for the bis-MPA derivatives of anti-1,2-amino alcohols. R


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Figure 40. Structures and ΔδRS values (ppm) for the bis-MPA derivatives of type A syn-1,2-amino alcohols (a), type B syn-1,2-amino alcohols (b), type C anti-1,2-amino alcohols (c), and type D anti-1,2-amino alcohols (d).

shifts21 of L1/L2 substituents of the asymmetric carbon, due to their high conformational flexibility. Therefore, when assigning the absolute configuration of these systems, it is essentially the role of the secondary alcohols that is considered. Thus, the distribution of ΔδRS signs is expected to be as shown in Figure 42. The observed distributions show a close fit with this prediction, as can be seen in Figure 43a. All the protons belonging to L group show a homogeneous ΔδRS sign distribution, opposite to the methylene protons (1′). In certain cases we can see that one of the methylene protons shows a very small magnitude of the ΔδRS value (underlined values in 43.1, 43.2, 43.4, 43.11, Figure 43a), and on occasions with the opposite sign to the expected one (43.6, 43.7, 43.8, 43.10, Figure 43a). This type of anomaly is especially worrying in cases such as that of compound 43.6 (Figure 43a) in which the only two signals that could be used for diagnostics (the phenyl signals cannot be distinguished from those of MPA) should have the same sign but in fact show opposing signs. A number of studies including theoretical calculations45 (AM1, HF, and B3LYP), and experimental data [dynamic and low-temperature NMR spectroscopy, constant coupling anal-

shielding/deshielding effects depending on the configurations of the diol and the AMAA. This characteristic has allowed the development of simplified methods for determining the configuration of this type of system by solely analyzing the NMR behavior of the methylene protons.46 Until now, NMRbased methods have always analyzed the behavior of the protons situated on both sides of the asymmetric carbon (i.e., L1/L2 in monofunctional compounds) and of the protons directly bonded to the chiral center [i.e., Cα(H) in sec/secdiols]. Now this is not the case, because a correlation between the signals of a substituent (methylene) located just on one side of the asymmetric carbon and the absolute configuration46 was found. On the other hand, the conformational characteristics of the bis-9-AMA derivatives make diagnostic the signals from the CαH protons of the 9-AMA moieties. This means that the configuration of the diols can be assigned following the analysis of just one derivative47 (single-derivatization method). 5.1. prim/sec-1,2-Diols: Double Derivatization, MPA

In prim/sec-1,2-diols, one of the hydroxyls is primary and the other is secondary (chiral). The MPA esters of the primary alcohols do not produce significant differences in the chemical S


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Figure 41. General structures and ΔδRS sign distribution for the bisMPA derivatives of sec/sec-1,2-amino alcohols (a) and sec/sec-1,2-diols (b). Schematic procedure for the assignment of the absolute configuration of sec/sec-1,2-amino alcohols and sec/sec-1,2-diols (c).

Figure 43. ΔδRS values (ppm) for a selection of bis-MPA esters of prim/sec-1,2-diols (a). ΔδRS sign distribution for the bis-MPA esters of prim/sec-1,2-diols (b, c).

Figure 42. Distribution of ΔδRS signs for the MPA esters of prim/sec1,2-diols, secondary alcohols, and β-chiral primary alcohols.

ysis, selective deuteration, and circular dichroism (CD)] show that the signs that correlate with the absolute configuration are those belonging to the L group protons, the proton directly attached to asymmetric carbon H(2′), and one of the methylene protons, H(1′) (the one with the highest absolute value of ΔδRS). The ΔδRS sign distributions of this collection of protons allow the assignment of the absolute configuration of these systems with guaranteed accuracy, using the distributions shown in Figure 43b and c. Conformational analysis shows that the most important processes are those that are related to the rotations indicated in Figure 44, particularly the rotations around the C(1′)−C(2′) bonds (gauche−trans conformer, gt) and those of O−C(1′) (I and II conformers). Figure 45 shows the most representative conformers from the point of view of NMR for the bis-MPA esters of (S)-propane-1,2-diol taken as model compound (43.1, Figure 45a). Methyl (3′) is doubly shielded by the phenyls of both MPA units in the bis-(R)-MPA (Figure 45b), whereas in the bis-(S)-

Figure 44. Generation of the main conformers for the bis-(R)-MPA esters of (S)-propane-1,2-diol.

MPA it is only shielded by the MPA phenyl, which esterifies the primary alcohol (Figure 45c), and therefore its ΔδRS is negative (Figure 45d). The H(2′) proton is shielded in the bis-(R)-MPA ester by the MPA phenyl (Figure 45b), which esterifies the primary alcohol, whereas it is not affected in the bis-(S)-MPA derivative, and its ΔδRS is also negative (Figure 45d). In relation to the behavior of the methylene protons, more detailed analysis needs to be performed paying especial attention to the conformation around the O−C(1′) bond. In this way, in the T


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This conformation, which is type II in the case of (S)-propane1,2-diol, occurs in the bis-(S)-MPA. If the diol had the opposite configuration, this conformation (type II) would be found in the bis-(R)-MPA ester, and the anomalous proton would be pro-R-H(1′). Similarly, the sign distribution would be opposite if the diol had the opposite configuration (Figure 43b and c). The configuration of these diols can therefore be assigned using the double-derivatization method described previously: the two bis-MPA esters are prepared, and the chemical shift differences, ΔδRS, are calculated for the protons of the L group, the H(2′), and those of the methylene (1′). In the latter case the proton that shows the highest magnitude of ΔδRS value is always used as a diagnostic sign. If the ΔδRS of L and H(2′) is negative and that of the methylene is positive, the configuration of the diol is that shown in Figure 43c. If the signs are opposite, ΔδRS is positive for L and H(2′) and is negative for the methylene proton, the configuration of the diol is that shown in Figure 43b. As will be seen in the following sections of this review, the particular behavior shown by the methylene protons in the bisMPA esters allows the formulation of a series of simplified procedures to assign the absolute configuration of these systems. 46 This can be achieved by analyzing how a temperature change affects the NMR signals of the protons in a single bis-MPA derivative. 5.2. prim/sec-1,2-Diols: Double Derivatization, 9-AMA

The configuration of this type of diol can also be determined through the bis-9-AMA esters. Analyses of these systems have also been carried out using theoretical calculations (AM1, HF, and B3LYP), and experimental data [dynamic and lowtemperature NMR spectroscopy, constant coupling analysis, selective deuteration, and circular dichroism (CD)]. These studies show that the most representative conformers from the NMR point of view are those shown in Figure 46. In this case, the two bis-9-AMA-esters show the same conformational preference: the two 9-AMA units are in sp conformation; the preference around the C(1′)−C(2′) bond is gt, and the preference for the O−C(1′) bond is for a type II conformation [coplanar carbonyl with pro-S-H(1′), Figures 44 and 46]. This latter conformational preference is the only difference with respect to the bis-MPA esters. Taking (S)-propane-1,2-diol as a model, the following behavior is expected in the NMR spectra. The Me(3′) is more shielded in the bis-(R)-9-AMA than in the bis-(S)-9-AMA (Figure 46a), and thus, its ΔδRS will be negative (Figure 46c). As for the methylene protons (1′), the pro-R-H(1′) is shielded by the carbonyl of the 9-AMA that esterifies the primary alcohol in the bis-(R)-9-AMA ester. In the bis-(S)-9-AMA, it is once again shielded by the carbonyl and by the two anthryls of both 9-AMA units (Figure 46b). Therefore, we would expect a large, positive ΔδRS in terms of magnitude. In the pro-S-(1′), the bis-(R)-9-AMA is deshielded by the carbonyl of the 9-AMA that esterifies the primary alcohol, whereas in the bis-(S)-9AMA it is once again deshielded by the carbonyl and shielded by the anthryl of the 9-AMA, which esterifies the secondary alcohol, making its ΔδRS difficult to predict. These predictions are shown in Figure 46b and c, and as can be seen, they perfectly fit all the examples shown in Figure 47. Once again, one of the methylene protons experiences opposite shielding/deshielding effects, which makes it extremely difficult to predict its behavior in NMR, showing data that are consistently lower to that of the other proton (Figure

Figure 45. Shielded and deshielded groups in the bis-(R)- and bis-(S)MPA esters of (S)-propane-1,2-diol (b and c, respectively). ΔδRS sign distribution for the bis-MPA esters of a prim/sec-1,2-diol (d).

bis-(R)-MPA, the conformation around the O−C(1′) bond is of type I (Figures 44 and 45b), and the carbonyl bisects the two methylene protons [the carbonyl forms angles of +44° and −74° with the pro-S-H(1′) and pro-R-H(1′) hydrogens, respectively], affecting them both in the same way; this is the only influence that they receive. However, in the bis-(S)-MPA ester, the conformation around this bond is of type II (Figure 44), which means that the carbonyl is coplanar with the pro-SH(1′) hydrogen (Figures 44 and 45c). As a consequence of this, the methylene hydrogen pro-R-H(1′) is shielded by the two phenyls of both MPA units and deshielded by the carbonyl of the MPA that esterifies the primary alcohol; consequently, it shows a high, positive ΔδRS (Figure 45d). However, the pro-SH(1′), which is shielded by the phenyl of the MPA that esterifies the primary alcohol, shows the opposite effects. Its ΔδRS will be small, and its sign will be difficult to predict. Finally, it should be pointed out that the identities of both protons were established using selective deuteration experiments. In conclusion, the presence of the MPA esterifying the primary hydroxyl is sufficiently important to modify the conformation around the O−C(1′) bond in the derivative in which the phenyls of both MPA units are close together. Thus, the steric hindrance means that this bond adopts a type II conformation, which causes one of methylene hydrogens to be particularly affected by the anisotropic effects of the carbonyl. U


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It is important to highlight the fact that these differences in shielding/deshielding effects of the methylene protons (1′) allow the formulation of a simplified method to determine its configuration, in which it is only necessary to analyze the change in the signals corresponding to the CαH of the 9-AMA themselves.47 Thus, looking again at the most representative conformations, from an NMR standpoint, of the bis-9-AMA esters and, to be more precise, the shielding/deshielding effects

Figure 46. Shielded and deshielded groups in the bis-(R)- and bis-(S)9-AMA esters of (S)- propane-1,2-diol (a and b, respectively). ΔδRS sign distribution for the bis-9-AMA esters of prim/sec-1,2-diols (c and d).

Figure 48. Structure of type A and type B 1,2-diols (a). Main conformers and shielding effects for the bis-(R)- and bis-(S)-9-AMA esters of type A 1,2-diols (b and c, respectively). Idealized resonances for the methylene protons (d and e).

that the two methylene protons experience (Figure 46a and b), we can see how the results shown in the resonances of both protons can be perfectly correlated with the configuration of the diol.47 Using the (S)-propane-1,2-diol as a model, we can see that a diol with the same spatial disposition for L group and methylene as that in the (S)-propane-1,2-diol will have a type A configuration (Figure 48a). The diol with an enantiomeric disposition of these groups would be defined as type B (Figure 48a). Analyzing the conformations of Figure 46a (conformation sp-II), we can see how in the bis-(R)-9-AMA the two protons of the methylene are only affected by the shielding/deshielding of the carbonyl (Figure 48b). This occurs in such a way that the pro-S-(1′) is coplanar to the carbonyl of the 9-AMA ester that esterifies the primary alcohol and is deshielded by the carbonyl.

Figure 47. ΔδRS values (ppm) for the bis-9-AMA esters of a selection of prim/sec-1,2-diols.

47). Therefore, the method for assigning the configuration consists of preparing the two bis-9-AMA esters and calculating the ΔδRS for the protons of L group and methylene (1′). For the latter the diagnostic signal is always taken to be that from the proton that shows the highest ΔδRS value. If the ΔδRS of L is negative and that of methylene is positive, the configuration of the diol is that shown in Figure 46c. If, on the contrary, the ΔδRS is positive for L and negative for the methylene proton, the diol is that shown in Figure 46d. V


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The pro-R-(1′) is shielded by this same carbonyl. This means that the two protons resonate at relatively similar frequencies (Figure 48d). Analyzing the conformation of the bis-(S)-9-AMA ester of the same diol (sp-II conformation, Figure 46b), we can see how the pro-S-(1′), which is coplanar to the carbonyl of the 9-AMA ester that esterifies the primary alcohol, is deshielded by this carbonyl and shielded by one of the anthryls (Figure 48c), whereas the pro-R-(1′) experiences a triple shielding by the carbonyl and the two anthryls (Figure 48c). This means that

Therefore, the appearance of the methylene proton’s signals allows us to assign the configuration of a prim/sec-1,2-diol, using the simplified method described in the following paragraph. The procedure consists of preparing both 9-AMA derivatives and comparing their 1H NMR spectra. Only the zone corresponding to the resonances of the methylene protons is analyzed, as it is not necessary to assign a signal to each proton. The separation between the proton’s signals that resonate at high field and low field are calculated for the (R)-9AMA derivative, (ΔδR), and also for the (S)-9-AMA derivative, (ΔδS). If this difference is greater in the bis-(S)-9-AMA than in the bis-(R)-9-AMA, (ΔδR ≪ ΔδS), then the diol has a type A configuration (Figure 48a). On the other hand, if the separation between the signals is greater in the (R)-9-AMA derivative than in the (S)-9-AMA derivative, (ΔδR ≫ ΔδS), then the configuration is type B. It is important to note that in the case of the bis-MPA esters the differences obtained are not sufficiently large to allow this method to be used with a total guarantee of accuracy (49.2 and 43.5, Figure 49). This difference is due to the fact that the shielding effect of the phenyl is not as intense as in the case of the anthryl of 9-AMA. 5.3. prim/sec-1,2-Diols: Low-Temperature Single Derivatization of bis-MPA Derivatives

The behavior displayed by the methylene protons in the bisMPA esters allows the assignment of the absolute configurations of these systems by analyzing how the NMR signals of these protons in a bis-MPA derivative change with temperature.46 In this case, the diagnostic signals are the methylene protons. Figure 50 shows the shielding/deshielding effects suffered by each of the methylene protons in the bis-(R)-MPA esters of the two enantiomers of a prim/sec-1,2-diol that can be used as a model, in this instance, (S)- and (R)-propane-1,2-diol (types A and B, respectively, Figure 50a and b). For simplicity, all the prim/sec-1,2-diols with identical spatial disposition in the L and methylene groups identical to those of (S)-propane-1,2-diol have been denominated type A, and those that coincide with the (R)-propane-1,2-diol have been denominated type B (Figure 50a and b). The evolution of methylene protons’ signals following a reduction in temperature is as follows: (a) For a diol with configuration type A, and considering the bis-(R)-MPA ester (Figure 50a), given that the conformational equilibrium is established between the conformers sp-I and ap-I, both protons are only affected by the shielding/deshielding effect of the carbonyl. Therefore, at the lower temperature the proton that resonates in the highest field (pro-R) is lightly shielded, whereas the proton that resonates at the lowest field (pro-S) is lightly deshielded. The identity of each proton was established using selective deuteration. In terms of ΔδT1T2, calculated as δ at the highest temperature minus δ at the lowest temperature, the result will be: ΔδT1T2 > 0 for the proton that resonates at high field and ΔδT1T2 < 0 for the proton that resonates at low field. For the (S)-propane-1,2-diol, the values obtained experimentally are +0.03 and −0.11 ppm (Figure 51). (b) In the case of a type B diol, in the form of the bis-(R)MPA ester (Figure 50b), the conformational equilibrium is established between the conformers sp-II and ap-I. The hydrogen that resonates in the highest field (pro-S) undergoes triple shielding by the two phenyls of both MPA units and by the carbonyl in the most stable conformation. The sp-II

Figure 49. Partial 1H NMR spectra showing the diastereotopic methylene protons of the bis-9-AMA esters of type A and B 1,2-diols (a and b, respectively). Idem for bis-MPA esters (c).

the two protons resonate at very different frequencies (Figure 48d). If we analyze the behavior of an enantiomeric diol of the previous type, that is, type B, the behaviors are reversed (Figure 48e). This behavior is general and has been proven experimentally in a series of diols with known absolute configurations and wide structural variety. Figure 49 shows a selection of the diols studied and the experimental results. Moreover, theoretical calculations of the chemical shifts (GIAO) for the representative conformations from an NMR standpoint show a good correlation with the experimental data.47 W


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undergoes intense, effective shielding as the temperature decreases. However, the hydrogen that resonates at the lowest field (pro-R) is shielded by a phenyl and deshielded by the carbonyl in the most stable conformation. The shift that is experienced as the temperature decreases depends on which of the two is more intense, but, in whichever case, the shift that takes place will be very small. Experimentally, and in the case of the (R)-propane-1,2-diol, a ΔδT1T2 of +0.25 ppm is obtained for the hydrogen that resonates at high field and −0.03 ppm is obtained for the one that resonates at low field (Figure 51).

Figure 50. Main conformers and shielding effects in the bis-(R)-MPA esters of 1,2-diols type A and B (a and b, respectively). Idealized resonances for the methylene protons (c and d).

Figure 52. Evolution with the temperature of the methylene protons of the bis-(R)-MPA esters of prim/sec-1,2-diols.

Obviously, the trends observed in the NMR spectra for the same diols esterified with the (S)-MPA are opposite to this. This behavior has been checked for a series of diols of known absolute configurations and wide structural variety. Figure 52 shows a selection of the diols analyzed and the graphs showing the evolution of the signals for these protons with a change in temperature for the bis-(R)-MPA esters. In all the type A diols (43.1, 43.3−43.5, 43.7, 43.8, 43.10, and 43.11, Figure 52), the methylene that resonates at high

Figure 51. Evolution with the temperature of the 1H NMR spectra of the bis-(R)-MPA esters of (S)- and (R)-propane-1,2-diol (43.1 and 52.1, respectively).

X


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field shifts slightly upfield (always 0.10 ppm, then the diol has a type A absolute configuration, while if its ΔδT1T2 is

Assignment of the Absolute Configuration of Polyfunctional

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