Valine chiral auxiliary from

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

A decisive improvement in the stereoselective performance of the Ugi reaction was achieved by the use of 1-ferrocenylalkylamines, in particular, l-ferrocenyl-2-methylpropylamine. as the inducing chiral auxiliary 18, S7. The iminc formed from the (/ )-enantiomer and isobutyralde-hyde reacts at — 78 °C with tm-butyl isocyanidc and benzoic acid to give the (S )-valine derivative with a diastereoselectivity of about 100 1. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

To circumvent side reactions and racemization of the chiral auxiliary in metalation reactions of cyclohexanone imines derived from the tert-butyl esters of valine and tm-leucine, deprotonation is performed using LDA at low temperatures (— 78 °C, THF, 0.5 h). 

Valine and tert-leucine derived cyclohexanone imines were hydrolyzed with 5% aqueous citric acid in an ice bath under vigorous stirring for 25 minutesi-17. From the acidic layer 67% of the chiral auxiliary was recovered3. Aldimines13. acyclic ketimines10, and cyclic polymer-... 

The chiral auxiliary (the a-amino ester 4) is regenerated and can be separated from the desired amino ester 3 by distillation or chromatography. (S)- or (/ )-Valine (R2 = z -Pr) is commonly used as the chiral auxiliary. The corresponding bis-lactimether (with R3 = H or CH3) is commercially available as the Schollkopf-Hartwig reagent 6. 

Instead of alanine and valine, several other chiral auxiliaries have been used, such as tert-leucine13, leucine14 and isoleucine15. In some cases diastereomeric excesses may be higher with the dihydropyrazines 5 and 6, derived from 0,0-dimethyl-alkylation with 3-bromo-propyne gives a de of 60% with (2S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine (3), in contrast to 85% de with 516 and >95% de with 613. 

Symmetrical hw-Iactim ethers of type (187) — built up from two identical amino acids — do have one disadvantage, inherent in the system only 50% of the chiral auxiliary — in this case (S)-alanine — is recovered the other 50 % is first racemized via (188) and finally incorporated in the product (189). To avoid this disadvantage Schollkopf et al. have developed methods to synthesize mixed bw-lactim ethers, starting from two different amino acids, e.g. (S)-valine and (R,S)-alanine. Thus, the authors obtained cyclo [(S)-val-(R,S)-ala] and prepared the related h/.s-lactim ether... 

From an industrial chemist s point of view the use of proline, phenylalanine, valine, and other commercially available amino acids, is fine. To date, however, tert.-(S)-leucine is still an exotic compound. It should also be noted that the recycling of the chiral amino acid moiety is of importance for possible technical processes. On the other hand, the recovery of the chiral auxiliary sometimes does not make sense, especially in syntheses which the require the use of stochiometric amounts of expensive reagents, e.g. LDA. 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

Asymmetric aldol reactions5 (11, 379-380). The lithium enolate of the N-propionyloxazolidinone (1) derived from L-valine reacts with aldehydes with low syn vs. anti-selectivity, but with fair diastereofacial selectivity attributable to chelation. Transmetallation of the lithium enolate with ClTi(0-i-Pr)3 (excess) provides a titanium enolate, which reacts with aldehydes to form mainly the syn-aldol resulting from chelation, the diastereomer of the aldol obtained from reactions of the boron enolate (11, 379-380). The reversal of stereocontrol is a result of chelation in the titanium reaction, which is not possible with boron enolates. This difference is of practical value, since it can result in products of different configuration from the same chiral auxiliary. 

Itsuno s amino alcohol (70), prepared from L-valine, is an extremely efficient auxiliary for enantioselective reduction of aryl alkyl ketones using BH3. The corresponding alcohols are obtained in up to 100% ee using BH3 and 0.5 equiv. of (70) in THF at 30 °C. Reduction of dialkyl ketones affords (R)-carbinols in 55-73% ee. Halomethyl t-butyl ketones are also converted to the corresponding (5)-carbinols in high optical purity (Scheme 15). Immobilized amino alcohol (70) permits reduction in a continuous flow system. 1-Phenylpentanol of 90% ee was prepared by this catalytic process in almost 1000% chemical yield based on the quantity of chiral auxiliary used. ... 

But, in the second example, a green chiral auxiliary has been attached to one of the starting materials. It contains another stereogenic centre and is enantiomerically pure—it was, in fact, made by a chiral pool strategy from the amino acid (S)-valine (see below). You can see that it has quite an effect on the reaction—the extra stereogenic centre means that there are now two possible diastereoiso-meric endo products, but only one is formed. 

The most versatile chiral auxiliaries should also be available as both enantiomers. Now, for the valine-derived one here, this is not the case—(J )-valine is quite expensive since it is not found in natrue. However, by starting with the natruaUy occruring (and cheap) compound norephedrine, we can make an auxiliary that, although not enantiomeric with the one derived from (S)-valine, acts as though it were. Here is the synthesis of the auxiliary. 

Perhaps the simplest of the isoquinoline alkaloids is salsolidine. It has been synthesized by asymmetric alkylation of 6,7-dimethoxytetrahydroisoquinoline using either a formamidine ° or oxazoline chiral auxiliary. Scheme 25 illustrates the recently published Organic Syntheses preparation of salsolidine on a 5 g scale. It is of interest to note that, in this and all subsequent examples of asymmetric alkylation of tetrahydroisoquinolines, formamidines derived from L-valine afford (IS)-tetrahydroisoquinolines, while oxazolines derived from L-valine afford the (lf )-enantiomer. The reason is simply the opposite orienta-... 

Good asymmetric induction occurs with the Evans valine-derived chiral auxiliary (as in 284, see chapter 27) which reacts in alkylation style on the face of the enolate away from the t-Pr group. The products 285 give a-hydroxy-acids 286 on hydrolysis. 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

The reactions of ketene acetals with Schiff bases derived from (S)-valine esters 1.59 (R = /-Pr) under TiCl4 catalysis are highly selective, but the chiral auxiliary has not been removed [264], Engler and coworkers [1532] performed the asymmetric [2+2]-cycloaddition of 2-methoxy-l,4-benzoquinone with 1-arylpro-penes substituted by electron-donating groups. These reactions occur at -78°C when catalyzed by chiral titanium complexes derived from 2.50 (R = Me, Ar = R = Ph). Cycloadducts are obtained with a good selectivity (Figure 9.6). 

In 1980, Kelly Rein began an investigation into the use of an oxazoline chiral auxiliary to effect ditistereoseleetive additions of Grignard reagents based on the Seebaeh discovery. The initial effort 46 used an oxazoline auxiliary derived from valine (Table 53, entry 5), one that we had used previously in studies of asymmetric alkylations of... 

Substituted morpholines 65-68 have been used as chiral auxiliaries for the formation of chiral dienophiles after IV-acylation with acrylic acid (Section D. 1.6.1.1.1.1.2.1.). The auxiliaries are obtained from amino acids (especially valine) via benzyl amino alcohols by cyclization of the AMiydroxyethyl derivative40. 

O-Alkylation of dioxopiperazines with oxonium salts yields bislactim ethers, e.g. 4, which are used as reagents for the asymmetric synthesis of amino acids (bislactimether method, Schollkopf 1979). The chiral bislactim ether 4 is converted into the 6 r-anion 5 (under kinetic control) by n-butyllithium. Alkylation proceeds with high stereoselectivity (greater than 95%). Acid hydrolysis of the alkylation product 6 leads to (unnatural) (R)-mnno acids 7 and recovery of the chiral auxiliary (5)-valine, from which the starting material dioxopiperazine 3 was derived [160]. 

Reactions of imines derived from valine tert-butyl ester with Brassard s diene proceed highly stereoselective in the presence of Lewis acids, such as EtAlCl2, at low temperature. Removal of the chiral auxiliary is achieved via a Curtius rearrangement. 

This reaction was first reported by Schollkopf in 1979. It is a synthesis of an unnatural nonproteinogenic amino acid from the lithiated enolate equivalent of a simple amino acid (e.g., glycine, alanine and valine), which involves the diastereoselective alkylation of the lithiated bis-lactim ether of an amino acid with an electrophile or an Aldol Reaction or Michael Addition to an o ,jS-unsaturated molecule and subsequent acidic hydrolysis. Therefore, the intermediate of the bis-lactim ether prepared from corresponding amino acids is generally referred to as the Schollkopf bis-lactim ether, " Schollkopf chiral auxiliary, Schollkopf reagent, or Schollkopf bis-lactim ether chiral auxiliary. Likewise, the Schollkopf bis-lactim ether mediated synthesis of chiral nonproteinogenic amino acid is known as the Schollkopf bis-lactim ether method, Schollkopf bis-lactim method, or Schollkopf methodology. In addition, the reaction between a lithiated Schollkopf bis-lactim ether and an electrophile is termed as the Schollkopf alkylation, while the addition of such lithiated intermediate to an Q ,j8-unsaturated compound is referred to as the Schollkopf-type addition. ... 

The synthesis of 11-methoxymacroline 350 (239) required 6-methoxy-D-tryptophan 359, which was prepared by Larock s Pd-catalyzed heteroannulation of iodoaniline 360 and the propargyl compound 361 (prepared in turn from the Schollkopf chiral auxiliary derived from L-valine), followed by removal of the chiral auxiliary, and N(l)-methylation (Scheme 28). The 6-methoxy-D-tryptophan 359 was then transformed into the pentacyclic sarpagine derivative 362, via the 11-methoxytetracyclic ketone 354, following the same protocol as that employed in the A -methylsarpagine synthesis (vide... 

---