Chiral reagents

Within the last decade remarkable progress has been made with highly stereoselective addition reactions to C = C and C = 0 double bonds using chiral reagents. These reagents include ... 

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Fig. 2.6. Dependence of enanhomeric excess on relative rate of reaction and extent of conversion with a chiral reagent in kinetic resolution. [Reproduced from J. Am. Chem. Soc. 103 6237 (1981) by permission of the American Chemical Society.]...

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

Most enzyme-catalyzed processes, such as the examples just discussed, are highly enantioselective, leading to products of high enantiomeric purity. Reactions with other chiral reagents exhibit a wide range of enantioselectivity. A fiequent objective of the smdy... 

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 hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

Fluorinations of enolates with chiral reagent D (Table 3a) give moderate degrees of enantiomeric excess [671 (equation 43). 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

With the use of chiral reagents a differentiation of enantiotopic faces is possible, leading to an enantioselective reaction. The stereoselective version of the Michael addition reaction can be a useful tool in organic synthesis, for instance in the synthesis of natural products. 

With this epoxidation procedure it is possible to convert the achiral starting material—i.e. the allylic alcohol—with the aim of a chiral reagent, into a chiral, non-racemic product in many cases an enantiomerically highly-enriched product is obtained. The desired enantiomer of the product epoxy alcohol can be obtained by using either the (-1-)- or (-)- enantiomer of diethyl tartrate as chiral auxiliary ... 

Clearly it is advantageous to be able to use achiral starting materials and a chiral reagent to induce an asymmetric reaction, thus obviating the need to attach and remove a chiral auxiliary and permitting the recovery and reuse of the chiral reagent. 

Table 1.10 Chiral reagent 75 in asymmetric Darzens reactions. Ph Ph...

Of course, the key limitation of the ylide-mediated methods discussed so far is the use of stoichiometric amounts of the chiral reagent. Building on their success with catalytic asymmetric ylide-mediated epoxidation (see Section 1.2.1.2), Aggarwal and co-workers have reported an aza version that provides a highly efficient catalytic asymmetric synthesis of trans-aziridines from imines and diazo compounds or the corresponding tosylhydrazone salts (Scheme 1.43) [68-70]. 

I.3.2.3.3.I. With Chiral Reagents, Bearing a Stereogenic Center... 

Many of the chiral allylboron reagents discussed in Section 1.3.3.3.3.1.4. have been utilized in double asymmetric reactions with chiral aldehydes. Chiral 2-(2-butenyl)-3.5-dioxa-4-boratri-cyclo[5.2.1.02-6]decanes were among the first chiral reagents of any type to be used in double asymmetric reactions52a,b. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

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. 

Reagent 4 is the most selective ( )-2-butenylboron reagent available for application in demanding cases of mismatched double diastcrcosclcction. considerably more so than the chiral reagents discussed in Section 1.3.3.3.3.1.5. It is noted that the mismatched double asymmetric reactions are often very slow, particularly in the most stereochemically demanding eases, and the reactions of 11 and 15 with 4 are thus performed at 4 kbar pressure12 25. 

There is one report of a chiral reagent based on allylaluminum chemistry1 2 3 4 5 10. Bis(2-methyl-propyl)-2-propenylaluminum is treated with tin(II) triflate and chiral diamine ligand 4 to give a reagent, presumably a chiral allyltin species, that reacts with aldehydes at — 78 "C. Good enantioselectivity (80 -84% ee) is obtained with aromatic aldehydes, but with aliphatic aldehydes the selectivity is somewhat lower (53-64%)10. 

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