Enolates chiral, diastereoselective alkylation

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Evans and Takacs23 demonstrated a diastereoselective alkylation based on metal ion chelation of a lithium enolate derived from a prolinol-type chiral auxiliary. This method can provide effective syntheses of a-substituted carbox-... 

The synthesis illustrates the utility of the chiral propionimide 38 in highly diastereoselective alkylation and aldol processes, which proceed via lithium enolate 48 and dibutylboron enolates 49 (Scheme 9.15). 

In the case of the per-O-methylated /)-D-glucopyranosyl group as chiral auxiliary, alkylation with iodomethane gave the isomeric enol ethers 2 and 3 without efficient regiocontrol in a 3-4 1 ratio. Diastereoselectivity was also moderate (d.r. 60 40-80 20). In the less polar solvent diethyl ether or toluene, induction increased (d.r. 90 10), but chemical yield decreased (34%). 

The enantiomerically pure substituted 1,2-dihydro-4(3//)-pyrimidinone 11 has been employed as a chiral auxiliary for diastereoselective alkylation reactions2. Thus, acylation, followed by enolate formation and alkylation with reactive halides such as halomethanes. (balomethyl)benzenes, 3-halopropenes and 3-halopropynes, affords the alkylation products with high diastereoselectivity (d.r. 93 7 to 99 1) . 

The physical properties of 2 were modified by introduction of polar substituents to improve both antiviral potency and hydrophilicity. These studies led to the discovery of L-689,502 (3) and L-693,549 (4), each bearing a polar, hydrophilic substituent at the para position of the P/ phenyl ring.7-9 Both compounds indeed displayed improved solubilities and antiviral potencies (Table 24.1). An inhibitor with pseudo-C2-symmetry, L-700,417 (5) was designed by rotation of the C-terminal half of 1 around the central hydroxyl-bearing carbon (Figure 24.2).10 Askin and co-workers reported a concise and practical synthesis of compounds 2-5 by diastereoselective alkylation of a chiral amide enolate derived from (I.S, 2/f)-aminoindanol.n This strategy, which efficiently used the cis-aminoindanol platform as chiral auxiliary, is fully detailed later in this chapter. 

The industrial production of Crixivan (9 H2S04) took advantage of the chirality of (IS,2R)-aminoindanol to set the two central chiral centers of 9 by an efficient diastereoselective alkylation-epoxidation sequence.17 The lithium enolate of 12 reacted with allyl bromide to give 13 in 94% yield and 96 4 diastereoselective ratio. Treatment of a mixture of olefin 13 and V-chlorosuccinimide in isopropyl acetate-aqueous sodium carbonate with an aqueous solution of sodium iodide led to the desired iodohydrin in 92% yield and 97 3 diastereoselectivity. The resulting compound was converted to the epoxide 14 in quantitative yield. Epoxide opening with piperazine 15 in refluxing methanol followed by Boc-removal gave 16 in 94% yield. Finally, treatment of piperazine derivative 16 with 3-picolyl chloride in sulfuric acid afforded Indinavir sulfate in 75% yield from epoxide 14 and 56% yield for the overall process (Scheme 24.1).17-22... 

The diastereoselective alkylation of /V-acyloxazolidinones enolates was examined first. Lithium enolates of 107 were reacted with a variety of alkyl halides, and alkylation products were formed with excellent diastereoselectivities (94-99% de). Hydrolysis gave optically pure carboxylic acids, and the chiral auxiliary was recovered for reuse almost quantitatively.105-106 Highly diastereoselective bromination was also achieved by reaction of the boron enolate of 107 with /V-bromosuccinimide (NBS) (98% de). Optically pure amino acids could be accessed by simple synthetic transformations (Scheme 24.26).106... 

Diastereoselective alkylations of enolates may occur if the enolate is chiral, i.e., surrounded by diastereotopic half-spaces. This was discussed in Section 3.4.1. In general, it is difficult to predict the preferred side of reaction of the alkylating reagent on such enolates. For cyclic enolates the situation is relatively simple, because these enolates always react from the less-hindered side. Hence, for the methylation of the enolate in Figure 13.31, the reaction with methyl iodide occurs equatorially, that is, from the side that is opposite to the axially oriented methyl group at the bridgehead. 

Diastereoselective Alkylation of Chiral Ester and Amide Enolates Generation of Enantiomerically Pure Carboxylic Acids with Chiral Centers in the a-Position... 

Side Note 13.4 presents the diastereoselective alkylation of a very special ester enolate in which one can easily understand what the stereocontrol observed is based upon. However, only very specific carboxylic acid derivatives are made accessible by those alkylations. Much more broadly applicable diastereoselective alkylations of chiral ester or amide enolates will be introduced in Figures 13.42 and 13.43. Figure 13.42 shows alkylations of a propionic acid ester—derived from an enantiomerically pure chiral alcohol—via the and Z -enolate. 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

The situation changes when chiral ester enolates or chiral amide enolates are alkylated. There, the half-spaces on the two sides of the enolate planes of the substrates are diastereotopic, and alkylating reagents can attack from one of the sides selectively (cf. discussion in Section 3.4.1). Stereogenic alkylations of such enolates therefore may occur diastereoselectively. Especially important examples of such diastereoselective alkylations are shown in Figures 10.37 and 10.38. Figure 10.37 shows the alkylation of a chiral propionic acid ester—the ester is derived from an enantiomerically pure alcohol—via the E - and Z -cnolates. Figure 10.38 shows alkylations of two propi-... 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

Thus, highly diastereoselective alkylation with the chiral tin(II) enolates 90 can readily proceed regardless of the ring size of the cyclic acylimines prepared in situ. The stereochemical outcome can be rationalized by a unified six-membered transition state 99. This can be supported by the experimental fact that the same chiral alkylation of lVl-methyl-5-acetoxy-2-pyrrolidinone with tin(II) enolate of 3-acetyl-(4S)-isopropyl-l,3-thiazolidine-2-thione (40b) gave a diastereomeric mixture of 5-alkylated products in 1 1 ratio. 

More recently Katsuki and coworkers have reported that (Z)-enolates of a-alkyl and a-heterosub-stituted amides such as (134), derived from pyrrolidine derivatives having a C2 axis of symmetry, undergo very diastereoselective alkylations with secondary alkyl and other alkylating agents in good to excellent chemical yields (Scheme 62) As with prolinol ether amide enolates, it appears that the direction of approach of the alkylating agent to the enolate (134) is controlled mainly by steric factors within the chiral auxiliary, i.e. chelation effects seem to be of little importance. 

Probably the most important and useful of all these amino acid-based chiral enolates are those of Seebach.7 The simplest is made from proline 17 simply by forming the iV, O-acetal 66 with pivaldehyde (f-BuCHO). The lithium enolate 67 is alkylated diastereoselectively with various electrophiles E+ to give one diastereoisomer of 68. 

The final fragment is a simple chiral carboxylic acid, so we need a method for its asymmetric synthesis. The most obvious choice is probably an asymmetric alkylation using Evans oxazolidinone auxiliary formation of the appropriate derivative of hexanoic acid is simple, and the enolate will be alkylated diastereoselectively by methyl iodide. You would probably take this approach if you need to make a few grams for initial studies. 

Imide enolates derived from (5)-valinol and (15,2/f)-norephe-drine and obtained by either LDA or Sodium Hexamethyldisi-lazide deprotonation (eq 24) exhibit complementary and highly diastereoselective alkylation properties. Mild and nondestructive removal of the chiral auxiliary to yield carboxylic acids, esters, or alcohols contributes to the significance of this protocol in small-and large-scale synthesis. ... 

Only one, orange, stereogenic centre remains, and its stereoselective formation turns out to be the most remarkable reaction of the whole synthesis. The centre is the one created in the planned enolate alkylation step, shown in the margin. The obvious way to make this centre is to make Y a chiral auxiliary, which would direct a diastereoselective alkylation before being removed and replaced with the amino-alcohol portion. 

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. ... 

An aldol reaction can be completed enantioselectively with an a-carbanion of the chiral carbonyl compound reacting as chiral enolate. Since the a-C atom in chiral enolate is planar, alkylation is diastereoselective because of the recognition of diastereotopic faces by the carbonyl counterpart. Alkylation of the configurationally stable tetrahedral carbanion on the a-C atom is a relatively rare case and is known as the memory of chirality. 

Seminal Work In the early 1980s, Evans introduced the use of chiral oxazolidinones as auxiliaries in asymmetric synthesis [47]. These chiral auxiliaries found use in a variety of synthetic transformations, including the diastereoselective alkylation of enolates, usually generated using a hindered... 

Regioselective and diastereoselective alkylation of the ester enolate of a 4- tert-butyloxycarbonyl)butanoyl ligand is achieved in the proximity of a chiral iron complex moiety. The alkylated carbon therein is located at the P-position of the carbonyl group of the acyliron moiety, thus having an example of a 1,4 chiral induction (Scheme 4-47). ... 

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