Diastereoselective synthesis enolates

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Using 3-substituted cyclohexanones the /rans-diastereoselective synthesis of decalones and octahydro-1 //-indenones may be achieved 164 169. This method has been applied, for instance, in the synthesis of 19-norsteroids. In a related Michael addition the lithium enolate of (R)-5-trimethylsilyl-2-cyclohexenone reacts with methyl 2-propenoate selectively tram to the trimethylsilyl substituent. Subsequent intramolecular ring closure provides a single enantiomer of the bicyclo[2.2.2]octane170 (see also Section 1.5.2.4.4.). 

Methodology for the diastereoselective synthesis of vicinal quaternary and tertiary stereo-genic centers has been developed using the lithium enolate of (4R)-4-rm-butyl-3-methyl-2-ox-etanone183 (see Section 1.5.2.4.1.2.4.). 

Consecutive Michael additions and alkylations can also be used for the diastereoselective synthesis of 5- and 6-membered ring systems. For instance when 6-iodo-2-hexenoates or 7-iodo-2-heptenoates are employed the enolate of the Michael adduct is stereoselectively quenched in situ to provide the cyclic compound with trans stereochemistry (>94 6 diastereomeric ratio). As the enolate geometry of the Michael donor can be controlled, high stereoselectivity can also be reached towards either the syn or anti configuration at the exocyclic... 

An interesting strategy for the diastereoselective synthesis of five-membered carbocycles was achieved by the reaction of alkenylcarbene complexes and lithium enolates derived from simple methyl ketones [79]. The use of more or less coordinating solvents (THF or Et20) or the presence of cosolvents such as PMDTA allows the selective synthesis of one or the other diastereoisomer of the final cyclopentene derivative (Scheme 32). 

Another example of a [2s+2sh-1c+1co] cycloaddition reaction was observed by Barluenga et al. in the sequential coupling reaction of a Fischer carbene complex, a ketone enolate and allylmagnesium bromide [120]. This reaction produces cyclopentanol derivatives in a [2S+2SH-1C] cycloaddition process when -substituted lithium enolates are used (see Sect. 3.1). However, the analogous reaction with /J-unsubstituted lithium enolates leads to the diastereoselective synthesis of 1,3,3,5-tetrasubstituted cyclohexane- 1,4-diols. The ring skeleton of these compounds combines the carbene ligand, the enolate framework, two carbons of the allyl unit and a carbonyl ligand. Overall, the process can be considered as a for-... 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

Scheme 16 Diastereoselective synthesis of 2,3-diamino esters and alcohols by the addition of achiral glycine iminoester enolates to chiral M-sulfinylimines...

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

The synthesis of the C(17)-C(24) segment also began with a diastereoselective boron enolate aldol addition. The adduct was protected and converted to an aldehyde in sequence H. The terminal diene unit was installed using a y-silylallyl chromium reagent, which generates a (3-hydroxysilane. Peterson elimination using KH then gave the Z-diene. 

Several reviews of P-lactam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions , enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of p-lactams <99MI955>. 

Diastereoselective synthesis of lactones.1 Acylation of the enolate (LDA) of the vinylogous urethane (1) results in a product (2) that on reduction with LiBH[CH(CH3)C2H5]3 (3) forms the anft-lactone (4) exclusively (equation I). This two-step synthesis of lactones is the equilvalent of an aldol condensation between... 

Scheme 14.12 Diastereoselective synthesis of ketoester from an enol lactone.

The addition of ester enolates to oi.P-unsaturated esters occurs with identical diastereoselectivity as shown for a,(3-enones this is exemplified by the diastereoselective synthesis of erythro- and threo-2,3-disubstituted glutarate esters (178 and 179). 146 -c Similarly, Yamaguchi reports a general synthesis of /ra/tJ-2-alkoxycarbonyl-l-cycloalkanepropionates (181-184) from w-halo-a,(3-unsaturated esters (180),... 

Stacking interactions in the transition state are one factor suggested for the highly diastereoselective synthesis of syn- and anfr-aldols from the reaction of an arylsulfonamidoindanyl titanium enolate with bidentate aldehydes.56... 

A diastereoselective synthesis of all. fy -2,3,6-trisubstitutcd tetrahydropyran-4-ones 1039 via an intramolecular Prins cyclization of enecarbamates 1038 with aldehydes is used during a formal synthesis of (+)-ratjadone (Equation 403) <2004JA12216>. Similarly, tetrahydropyran-4-ones bearing quaternary centres a-to the carbonyl are accessible via a Lewis acid-mediated Prins cyclization of silyl enol ether substrates <2004JA15662>. 

A useful diastereoselective synthesis of aldols using chiral 3-acyl-1,3-oxazolidine-2-thiones 30, 31, 34, and 35, was developed. As described in Section II, (4/ ,5S)-MPOT (5) and (4S)-EOT (2) were prepared. These chiral heterocycles were employed as chiral auxiliaries. As enolating reagents, tin(II)... 

The oxidation of titanium enolato complexes, derived from a transmetallation reaction of the corresponding lithium enolates with Cp2TiCl2, by dimethyldioxirane has been investigated as a general, convenient, effective, and chemo- and diastereoselective synthesis of cr-hydroxy carbonyl compounds. The Cp derivative shown in Scheme 601 results in much higher diastereoselectivities than other enolato complexes studied.1556... 

The aldol-type condensation can be extended to carbonyl equivalents such as the 4-acetoxy-2-azetid-inone (93) or similar a-acetoxylactams. The condensation of (93) with the chiral tin(II) enol ether (94) has been used in a highly diastereoselective synthesis of chiral carbapenems. 

In many cases various proton sources, solvents, auxiliaries, and conditions have been applied in order to obtain different diastereoselectivites from the protonation of nonstereogenic car-banion centers. However, only the tw o extreme diastereomeric product ratios are given in this section. In most experiments kinetically controlled protonation can be assumed. However, since the anionic substrate already carries one (or more) stereogenic center, selective equilibration at the newly formed stereogenic carbon - hydrogen center could increase the diastereoselec-tivity. Indeed, epimerization of this center is a valuable tool for diastereoselective synthesis, provided that the carbon-hydrogen bond is acidic enough (see enolates, Section 2.1.3.1). 

The HDA reaction features in a diastereoselective synthesis of c/j-2,6-disubstituted 5,6-dihydro-2//-pyrans, but this is based on the initial formation of a dihydropyran-4-one. Regio- and stereo- chemistry are controlled during the reduction to the pyranol and an ester enolate Claisen rearrangement completes the sequence <97AJC43>. 

Diastereoselective synthesis of a /3-lactam side chain precursor using a chiral imine has also been accomplished by Fujisawa and his collaborators who condensed a chiral imine with an ester enolate in a stereocontrolled way. Thus, reaction of 7.1.17 with enolate afforded the desired cislactam in 84% diastereomeric excess and 90% yield. The other enantiomer of the cis /3-lactam (diastereomeric when R is attached) was not detected (244). 

An efficient and diastereoselective synthesis of 5,6-dihydro-2H-pyran-2-acetates involves a Prins cyclization of acrylyl enol ethers mediated by TMSOTf.This strategy was used in the total synthesis of the natural compound (+)-civet (13JOC12182). Highly functionalized tricyclic dihydropy-ranopyrrolidin-2-ones are formed by a catalytic P,Y-selective Diels-Alder [4 + 2] annulation of a,P-unsaturated y-butyrolactams, in good yields and enantioselectivities (Scheme 8) (13AGE11329). 

A highly diastereoselective synthesis of azetinyl thiazolidine-2-thiones has been achieved by addition of the chlorotitanium enolates of N-acyl thiazolidine-2-thiones to O-methyl aldoximes [103], where the antV azetines product can be subsequently converted to the corresponding P-amino carbonyl compounds with retention of stereochemistry (Scheme 14.35). 

Sato, T., K. Tajima, and T. Fujisawa Diastereoselective synthesis of erythro- and threo-2-hydroxy-3-methyl-4-pentenoic acids by the ester enolate Claisen rearrangement of 2-butenyl 2-hydroxy acetate. Tetrahedron Letters 24, 729 (1983). 

SCHEME 4.38 Gold-catalyzed diastereoselective synthesis of cyclopentanone enol ether. 

The diastereoselective synthesis of p-hydroxy-a-amino esters 200 and 201 has been achieved. Use of a chiral auxiliary on the enolate component leads to good a ri-selectivity, but in the absence of this additional vehicle for stereocontrol, both syn and anti isomers 202 were produced (Scheme 42). ... 

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