Enolates diastereoselective alkylation

Removal of the unsaturated side-chain appendage from C-8 in 22 provides diol lactone 23 and allylic bromide 24 as potential precursors. In the synthetic direction, a diastereoselective alkylation of a hydroxyl-protected lactone enolate derived from 23 with allylic bromide 24 could accomplish the assembly of 22, an intermediate that possesses all of the carbon atoms of PGF2o- It was anticipated that preexisting asymmetry in the lactone enolate would induce the... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

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>. 

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

Six-Membered Ring (exo-Cyclic). The diastereoselective alkylation reactions of exo-cyclic enolates involving 1,2-asymmetric inductions are anti-inductions. In Scheme 2-2, there are two possible enolate chair conformations in which the two possible transition-state geometries lead to the major diaster-eomer 9e (where the substituent takes the equatorial orientation). However, for the case in which R = methyl and X = alkoxyl or alkyl, one would expect the... 

Scheme 2-5 is one of such examples in which stereoelectronic control has to be taken into account in diastereoselective alkylation of substituted cyclohexanone enolates.12... 

The diastereoselective alkylation reaction of endo-cyclic five-membered ring enolates exhibits good potential for both 1,3- and 1,2-asymmetric induction. In Scheme 2-6, the factor controlling the alkylation transition state is steric rather than stereoelectronic, leading to an auh-induction.13... 

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-... 

TABLE 2-5. Diastereoselective Alkylation Reaction of the Lithium Enolates Derived from Imides 22 and 23... 

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). 

Scheme 27 Diastereoselective alkylation of propargyl alcohols with silyl enol ethers, allyl silanes and electron-rich arenes...

Clavepictines A and B were prepared using a variety of effective reactions on the piperidine ring, such as a silver-promoted cyclization of an aminoallene intermediate, diastereoselective alkylation, and cross coupling of an enol triflate <99JA10012>. 

Intramolecular diastereoselective alkylation of the exocyclic enolate derived from compound 6 results in cyclization yielding bicyclic 7 in 94%. 

Diastereoselective alkylations of fi ve-membered ring enolates generally proceed with high levels of 1,2- and 1,3-asymmetric induction. The alkylation is controlled by steric rather than stereo-electronic factors. Thus, attack of the electrophile is directed to the sterically less hindered 7t-face of the enolate system1. 

Diastereoselective alkylations of seven-membered and larger ring ketone enolates have been performed1. High selectivity has been observed in a number of cases84 85, for example, in the preparation of cycloalkanones 45, 47, and 49. 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

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) . 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

Diastereoselective alkylation of tartaric acid. The enolate (2) of the acetonide of dimethyl (R, R)-tartrate (1) can be generated with LDA in THF-HMPT at — 70° and is sufficiently stable for alkylation with allyl and benzyl halides, but not with other simple alkyl halides, and for addition to acetone (60% yield). The main products (3) of allylation and benzylation have the /ranr-configuration, and thus the substitution occurs with retention of configuration.7... 

The origin of the diastereoselective alkylation of enolates of oxazolopiperidones (2) and (3) has been studied by means of theoretical calculations and experimental (g) assays.18 For the unsubstituted oxazolopiperidone, the alkylation with methyl chloride is predicted to afford mainly the exa product, a finding further corroborated from the analysis of the experimental outcome obtained in the reaction of the racemic oxazolopiperidone. However, such a preference can be drastically altered by the presence of substituents attached to the fused ring. 

After reaction of the excess lithium with isoprene the enolate is alkylated with allyl bromide diastereoselectively from the less hindered face, opposite to the axial methyl group at the bridge head, to provide allyl ketone 3 as the single diastereomer. 

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. 

The Novartis Institute for BioMedical Research in Basel, Switzerland, and the University of Hull, UK, performed the diastereoselective alkylation of metal-stabilized enolates using a pressure-driven microreactor at — 100°C, whereby increased conversions and diastereoselectivity were observed compared to the batch process [20]. 

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]. 

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