Diastereoselectivity alkylations

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>. 

Diastereoselective alkylation of lactams derived from 7 -(-)-phenylglycinol is an efficient method for the preparation of various substituted piperidines <961(52)7719, 961(52)7727, 961L(37)849>. Ihe asymmetric s mthesis of a series of 2-(l-aminoalkyl)piperidines using (-)-2-cyano-6-phenyloxazolopiperidine has been described <96JOC(61)6700>. 

Catalytic RCM and Uncatalyzed Diastereoselective Alkylation of Unsaturated Heterocycles... 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

The examples shown in Scheme 5 demonstrate the potential utility of these stereoselective alkylation technologies in synthesis. Thus, preparation of rac-14 through catalytic RCM of rac-13 (85% yield) and subsequent Zr-catalyzed resolution of the resulting racemic TBS-protected oxepin affords (S)-23 after silyl group deprotection. Diastereoselective alkylation with nBuMgBr affords (S)-24... 

Scheme 5. Chiral medium-ring heterocycles that have been synthesized by catalytic RCM and resolved by the Zr-catalyzed kinetic resolution are subject to diastereoselective alkylations that afford synthetically useful materials in the optically pure form...

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... 

Scheme 2-8. Diastereoselective alkylation reactions in the norbornyl ring system.

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... 

Here again, the presence of a nitrile group at C-5 allow for a great versatility generation of an anion followed by its trapping with electrophiles allows for the introduction of an additional substituent in this position as exemplified by the diastereoselective alkylation of 331 (Scheme 90) <2005JOC4474>. 

Novel highly functionalized dipeptide isosters were synthesized via diastereoselective alkyl-arylation protocol of a glucose-derived (R)-tert-butanesulfinylimine. One of these novel sugar amino acid derivatives, a D-Ala-Ser/Thr isostere, was applied in a peptide synthesis protocol to afford a cyclic tetramer (Fig. 53).69... 

Figure 3.8 Diastereoselective alkylation of chiral fumaric acid derivatives.

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). 

The diastereoselective alkylation of dialkyl malates has been frequently used in the past [65]. However, according to the original procedure [63] (dialkyl malate, base, -78 -20 °C, then -78 °C, electrophile, then -78 0 °C, 16 h), the alkylation proceeded in average yields of about 50-60% and in diastereoselectivities in the range of 9 1 anti / syn. In our hands, application of this procedure to the reaction of benzyl bromide 23 with dimethyl malate 106 produced the alkylated compounds in only 20% yield. The yield of the alkylation was easily improved (>75%) when the ester was deprotonated with LHMDS in the presence of the electrophile at -78 °C and the reaction mixture was allowed to warm to 10 °C (Scheme 26 and Table 2). 

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

Diastereoselective alkylation of (R)-(-F)-camphor-based glycylimine (19) with 3-bromo-2-fluoropropene gave (R)-(-F)-2-amino-4-fluoropent-4-enoic acid with 38% overall yield and 90% ee after hydrolytic deprotection, or in the case of the alanylimine, (R)-(-F)-2-amino-4-fluoro-2-methyl-pent-4-enoic acid (19% overall yield, 59% ee) [49]. Deprotection under drastic conditions was accompanied by hydrolysis of the fluorovinyl moiety to give (R)-(-)-2-amino-4-oxo-pentanoic acid hydrochloride with 28% overall yield and >95% ee (Scheme 4). 

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. 

If the above reaction sequence is conducted with the /(-lactam containing a C(R R2)COOR3 group in the 1-position, rather than the methyl group, then diastereoselective alkylation in the 3-position of the lactam ring, followed by Birch reduction, gives a dipeptide. This has been exemplified in the synthesis of (5)-a-methylphenylalanyl-(7 )-a-allylalanineS-1... 

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. 

Using this procedure, enantiomerically pure cis- and /rani-isomers 8 have been prepared from (S)-alanine, (S)-phenylalanine, (7 )-phenylg1ycine, (S)-methionine and (A )-valine3. The eno-lates from these imidazolidinones have been used in diastereoselective alkylation reactions4,7- 8 (see Table 4). 

Diastereoselective alkylations of amides from the formally C2-symmetric cyclic amines 1, 3 and 4 have been studied to date, with the four-membered analog 2 not yet examined. The... 

---