Esters tartrate

An achiral reagent cannot distinguish between these two faces. In a complex with a chiral reagent, however, the two (phantom ligand) electron pairs are in different (enantiotopic) environments. The two complexes are therefore diastereomeric and are formed and react at different rates. Two reaction systems that have been used successfully for enantioselective formation of sulfoxides are illustrated below. In the first example, the Ti(0-i-Pr)4-f-BuOOH-diethyl tartrate reagent is chiral by virtue of the presence of the chiral tartrate ester in the reactive complex. With simple aryl methyl sulfides, up to 90% enantiomeric purity of the product is obtained. 

The reaction of diethyl tartrate with sulfur tetrafluonde at 25 °C results in replacement of one hydroxyl group, whereas at 100 °C, both hydroxyl groups are replaced by fluonne to form a,a -difluorosuccinate [762] The stereochemical outcome of the fluonnation of tartrate esters is retention of configuration at one of the chiral carbon atoms and inversion of configuration at the second chiral center [163,164, 165] Thus, treatment ofdimethyl(+)-L-tartrate with sulfur tetrafluonde gives dimethyl meso-a,a difluorosuccinate as the final product [163, 164], whereas dimethyl meso tartrate is converted into a racemic mixture of D- and L-a,a -difluorosuccmates [765] (equation 80)... 

Recent optimization studies reveal that the yield of 2-(2-propenyl)-1,3,2-dioxaborolane-4,5-di-carboxylate esters (i.e., the tartrate ester modified allylboronates) is improved by using triiso-propyl borate as the borylating agent1. The improved yields are directly related to the increased efficiency of the preparation of the intermediate allylboronic acid. 

The tartrate ester modified allylboronates, the diisopropyl 2-allyl-l,3,2-dioxaborolane-4,5-di-carboxylates, are attractive reagents for organic synthesis owing to their ease of preparation and stability to storage71. In the best cases these reagents are about as enantioselective as the allyl(diisopinocampheyl)boranes (82-88% ee with unhindered aliphatic aldehydes), but with hindered aliphatic, aromatic, a,/l-unsaturated and many a- and /5-alkoxy-substituted aldehydes the enantioselectivity falls to 55-75% ee71a-b... 

It has been observed, however, that the enantioselectivity of reactions of tartrate ester modified allylboronates with metal carbonyl complexes of unsaturated aldehydes are significantly improved compared with the results with the metal-free, uncomplexed aldehydes72. Two such examples involve the (benzaldehyde)tricarbonylchromium complex and the hexacarbonyl(2-... 

The tartramide-based reagents, 10-allyl-3,6-dibenzyl-9,ll-dioxa-3,6-diaza-10-borabicyclo[6.3.0]-undecane-2,7-diones, are significantly more enantioselective than the parent tartrate ester derivatives7lb 73. Unfortunately, they have poor solubility at — 78 =C and consequently reactions times are long and conversions are often poor. The full scope of this tartramide reagent system awaits the development of a more soluble auxiliary. 

The procedures for the reactions of the boronate tartrate esters and tartramides are similar71 13. The reactions of tartramides are much slower (typically 2 4 days) due to their poor solubility in toluene at —78 °C, and these reactions were therefore quenched at —78 °C by the addition of excess sodium borohydride in ethanol to consume any unreacted aldehyde before the reactions were allowed to warm above — 78°C73. 

The matched double asymmetric reactions with (7 )-l and (a.R,S,S)-2 provide the (S,Z)-diastereomer with 94% and 96% selectivity, while in the mismatched reactions [(S)-l and (aS,R,R)-2] the (S.Z)-diastereomer is obtained with 77% and 92% selectivity, respectively. Interestingly, the selectivity of the reactions of (/ )-2,3-[isopropylidenebis(oxy)]propanal and 2 is comparable to that obtained in reactions of (7 )-2,3-[isopropylidenebis(oxy)]propanal and the much more easily prepared tartrate ester modified allylboronates (see Table 7 in Section 1.3.3.3.3.1.5.)41. However, 2 significantly outperforms the tartrate ester allylboronates in reactions with (5)-2-benzyloxypropanal (Section 1.3.3.3.3.1.5.), but not the chiral reagents developed by Brown and Corey42-43. 

The epoxidation of allylic alcohols can also be effected by /-butyl hydroperoxide and titanium tetraisopropoxide. When enantiomerically pure tartrate ligands are included, the reaction is highly enantioselective. This reaction is called the Sharpless asymmetric epoxidation.55 Either the (+) or (—) tartrate ester can be used, so either enantiomer of the desired product can be obtained. 

The mechanism by which the enantioselective oxidation occurs is generally similar to that for the vanadium-catalyzed oxidations. The allylic alcohol serves to coordinate the substrate to titanium. The tartrate esters are also coordinated at titanium, creating a chiral environment. The active catalyst is believed to be a dimeric species, and the mechanism involves rapid exchange of the allylic alcohol and /-butylhydroperoxide at the titanium ion. 

Sharpless epoxidation involves treating an allylic alcohol with titanium(IV) tetraisopropoxide [Ti(0-/Pr)4], tert-butyl hydroperoxide [t-BuOOH], and a specific enantiomer of a tartrate ester. 

The enantioselectivity of the reaction results from a titanium complex among the reagents that includes the enantiomerically pure tartrate ester as one of the ligands. 

The use of tartrates as chiral auxiliaries in asymmetric reactions of allenyl bor-onic acid was first reported by Haruta et al.69 in 1982. However, it was not for several years that Roush et al.,70 after extensive study, achieved excellent results in the asymmetric aldol reactions induced by a new class of tartrate ester based allyl boronates. 

The asymmetric induction cannot be explained simply by steric interaction because the R group in the aldehyde is far too remote to interact with the tartrate ester. In addition, the alkyl group present in the tartrate ligand seems to have a relatively minor effect on the overall stereoselectivity. It has thus been proposed that stereoelectronic interaction may play an important role. A more likely explanation is that transition state A is favored over transition state B, in which an n n electronic repulsion involving the aldehyde oxygen atom and the /Mace ester group causes destabilization (Fig. 3-6). This description can help explain the stereo-outcome of this type of allylation reaction. 

The Sharpless epoxidation is a popular laboratory process that is both enantioselective and catalytic in nature. Not only does it employ inexpensive reagents and involve various important substrates (allylic alcohols) and products (epoxides) in organic synthesis, but it also demonstrates unusually wide applicability because of its insensitivity to many aspects of substrate structure. Selection of the proper chirality in the starting tartrate esters and proper geometry of the allylic alcohols allows one to establish both the chirality and relative configuration of the product (Fig. 4-1). 

In 1980 a useful level of asymmetric induction in the epoxidation of some alkenes was reported by Katsuki and Sharpless121. The combination of titanium (IV) alkoxide, an enantiomerically pure tartrate ester and tert-butyl hydroperoxide was used to epoxidize a wide variety of allylic alcohols in good yield and enantiomeric excess (usually >90%). This reaction is now one of the most widely applied reactions in asymmetric synthesis131. 

In 1980, Katsuki and Sharpless[1] reported that, with the combination of a titanium(IV) alkoxide, an enantiomerically pure tartrate ester [for example (+)-diethyl tartrate ((+)-DET) or (+) di-iso-propyltartrate ((+)-DIPT)] and tert-butyl hydroperoxide, they were able to carry out the epoxidation of a variety of allylic alcohols in good yield and with a good enantiomeric excess (Figure 5.1). 

The tartrate esters can be used as obtained from Aldrich Chemical Co. or Fluka Chemical Corp. If the yield and/or the enantiomeric excess is/are... 

Table 5.1 Catalytic asymmetric epoxidation of allylic alcohols using a combination of titanium wopropoxide. enantiomerically pure tartrate ester ((+)-DET or (+)-DIPT) and rerr-butyl hydroperoxide (yield and enantiomeric excess, according to the relevant publication). ...

Table 6 Chirality effects in the dimerization of homologous tartrate esters... 

If optimal conditions are desired for a specific asymmetric epoxidation.variation of the tartrate ester is likely to be a useful exercise. 

One of the first attempts to extend polymer-assisted epoxidations to asymmetric variants were disclosed by Sherrington et al. The group employed chiral poly(tartrate ester) hgands in Sharpless epoxidations utilizing Ti(OiPr)4 and tBuOOH. However, yields and degree of stereoselection were only moderate [76]. In contrast to most concepts, Pu and coworkers applied chiral polymers, namely polymeric binaphthyl zinc to effect the asymmetric epoxidation of a,/9-unsaturated ketones in the presence of terPbutyl hydroperoxide (Scheme 4.11). 

The use of tartrate esters was an obvious place to start, especially since both enantiomers are readily available commercially and had already found widespread application in asymmetric synthesis (Figure 11) (e.g.. Sharpless asymmetric epoxidation).23.24 Reagents 36-38 are easily prepared and are reasonably enantioselective in reactions with achiral, unhindered aliphatic aldehydes (82-86% ee) typical results are given in Figure 12.3c,h Aromatic and a,p-unsaturated aldehydes, unfortunately, give lower levels of enantioselection (55-70% e.e.). It is also interesting to note that all other C2 symmetric diols that we have examined (2,3-butanediol, 2,4-pentanediol, 1,2-diisopropylethanediol, hydrobenzoin, and mannitol diacetonide, among others) are relatively ineffective in comparison to the tartrate esters (see Table ll).25... 

Our development of the tartrate ester modified allylboronates c.h suggested to us that many of these problems could be avoided by using the reaction of a chiral aldehyde and a chiral allylboronate as a means of establishing the stereochemistry of the sugar backbone. This strategy has been used in our synthesis of the AB disaccharide unit of olivomycin A (Figures 16, 17).3 ... 

We began these studies with the intention of applying this tandem asymmetric epoxidation/asymmetric allylboration sequence towards the synthesis of D-olivose derivative 63 (refer to Figure 18). As the foregoing discussion indicates, our research has moved somewhat away from this goal and we have not yet had the opportunity to undertake this synthesis. This, as well as the synthesis of the olivomycin CDE trisaccharide, remain as problems for future exploration. Because it is the enantioselectivity of the tartrate ester allylboronates that has limited the success of the mismatched double asymmetric reactions discussed here, as well as in several other cases published from our laboratorythe focus of our work on chiral allyiboronate chemistry has shifted away from synthetic applications and towards the development of a more highly enantioselective chiral auxiliary. One such auxiliary has been developed, as described below. 

Dimethyl allylboronates (e.g., 17,18) are sensitive to hydrolysis, and the allylboronic acids are unstable in the presence of O2. The pinacoi and tartrate esters, however, are quite stable and many have been purified by distillation. We routinely monitor the isomeric purity of the crotyl reagents by capillary GC analysis (ref 3e). 

Use of tartrate esters as chiral auxiliaries in the asymmetric reactions of allenyl boronic acid also have been reported Ikeda, N. Aral, I. Yamamoto, H. J. Am. Chem. Soc. 1986,108, 483 Haruta, R. Ishiguro, M. Ikeda, N. Yamamoto, H. Ibid. 1982,104, 7667. 

Originally, it was proposed that lone pair repulsions between one of the tartrate ester carbonyl oxygens and the aldehyde oxygen in transition structure 60 were responsible for the preference for transition structure 59 and the consequent enantiofacial selectivity (Scheme 5). Recent theoretical calculations. 

The most extensively developed allylboron reagents for enantioselective synthesis are derived from tartrate esters.40... 

The enantioselectivity is consistent with cyclic transition states. The key element determining the orientation of the aldehyde within the transition state is the interaction of the aldehyde group with the tartrate ester substituents. 

The orientation of the reactants is governed by the chirality of the tartrate ester. In the transition state, an oxygen atom from the peroxide is transferred to the double bond. The... 

This method has proven to be an extremely useful means of synthesizing enantiomerically enriched compounds. Various improvements in the methods for carrying out the Sharpless oxidation have been developed.48 The reaction can be done with catalytic amounts of titanium isopropoxide and the tartrate ester.49 This procedure uses molecular sieves to sequester water, which has a deleterious effect on both the rate and enantioselectivity of the reaction. Scheme 12.9 gives some examples of enantioselective epoxidation of allylic alcohols. 

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