Diastereoselectivity alkylation

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Enolates from l-acyl-2-pyrrolidinemethanols (A -acylprolinols) and their ethers are alkylated diastereoselectively, usually providing products in good to excellent diastereomeric ratios1-4. The most commonly employed auxiliaries are (S)-2-pyrrolidinemethanol (L-prolinol, 1), (S)-a,a-dimethyl-2-pyrrolidinemethanol (2) and (S)-2-(alkoxymethyl)pyrrolidines 3. For the preparation of these and the corresponding A -acyl derivatives, see Appendix. 

For benzyloxymethyl electrophiles, titanium enolates are superior to the corresponding lithium enolates in both yield and alkylation diastereoselectivity (eq 11). Unfortunately, the analogous p-methoxybenzyl-protected (3-hydroxy adducts cannot be obtained by this method. In other cases the titanium methodology complements the corresponding reactions of the lithium and sodium enolates for SNl-like electrophiles. It is noteworthy that imides may be selectively enolized under all of the preceding conditions in the presence of esters (eq 12). 

As shown in Scheme 34, a rather profound solvent effect on dienolate alkylation diastereoselectivity has been noted for the steroidal enone (71). Such large solvent effects have not been documented for other systems. Possible explanations based upon the position of the transition state along the reaction coordinate and/or specific solvation of the dienolate have been advanced to account for preferential axial alkylation in benzene and equatorial alkylation in t-butyl alcohol.However, in view of the fact that the degree of aggregation of the dienolate as well as the structure of the aggregates may be modified considerably in going from one solvent to the other, rationalization of the results is difficult. 

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. 

For the alkylation of enolates, chromium tricarbonyl complexes of aromatic compounds (benchrotrenes) are useful, as they make simple aromatic compounds chiral. Thus, enantiomer-ically pure (indanone)tricarbonylchromium (2R)-25 has been prepared by resolution of the racemic benchrotrene derivative with cinchonidine and oxidation of the alcohol to the ketone with manganese dioxide60. The chiral ketone is alkylated diastereoselectively via the enolate, leading to the f.vo-2-methyl derivative (2/ )-25 which has been used in enolate alkylations and annulation reactions (Section D.1.5.2.4.). If necessary, complete isomerization to the endo-methyl compound can be achieved by treatment with base. 

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. 

The highly regio- and diastereoselective addition of an alkyl and an arylthio group to an olefinic double bond ( carbosulfenylation ) is achieved with arenesulfenyl chlorides and alkyl-chloro-titanium(IV) species (Reetz reagent, from R2Zn/TiCU 5 1 M. T. Reetz, 1987, 1989), Use of the more bulky 2,4,6-triisopropylbenzenesulfenyl chloride improves the yield of the highly versatile alkyl aryl sulfide products. 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

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. 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

Stockman has reported the preparation of alkyl-, aryl-, and vinyl-disubstituted aziridines with good diastereoselectivities and in good yields through treatment of tert-butylsulfmylimines with the ylide 119, derived from S-allyl tetrahydrothio-phenium bromide (Scheme 1.39) [64]. A range of substrates were tolerated, including heterocyclic, aromatic, and aliphatic substrates (Table 1.16). 

Unlike regular aziridine-2-carboxylic esters, aziridine-2-carboxylic thioester 174 (Scheme 3.62) forms stable carbanions at the 2-position upon treatment with base [13b, 122]. Thus, electrophilic alkylations of aziridine 174 afforded products 175. The reactions were highly diastereoselective, affording 175 in moderate to good... 

A similar but asymmetric variant of the reaction, involving the radical addition of alkyl iodides and trialkylboranes to chiral azirine esters derived from 8-phenyl-menthol and camphorsultam, in the presence of a Cu(i) catalyst, has subsequently been reported [64]. The diastereoselectivity of the addition is variable (0-92% de)... 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

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