Diastereoselective synthesis

Diastereoselective synthesis of pyrrolidine derivatives using chiral and non-racemic A-cyanomethyloxazolidines 99CSR383. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

Diastereoselective synthesis, particularly of piperidine derivatives using chiral and nonracemic A-cyanomethyloxazolidines 99CSR383. 

The reaction was applied to the diastereoselective synthesis of acyloxiranes from a-chloroalka-nals and -alkanones, for example7 ... 

In contrast to the 2-butenylboranes, 2-butcnylboronates have found widespread application in acyclic diastereoselective synthesis owing to their ease of preparation (Section 1.3.3.3.3.1.1.), configurational stability and highly stereoselective reactions with aldehydes3 4. The results of reactions of substituted allylboronates and representative achiral aldehydes are summarized in Table 1. 

The reactions of allylboronates 1 (R = H or CH3) may proceed either by way of transition state 3, in which the a-substituent X adopts an axial position, or 4 in which X occupies an equatorial position. These two pathways are easily distinguished since 3 provides 7 with a Z-olefin, whereas 4 provides 8 with an E-olefinic linkage. There is also a second fundamental stereochemical difference between these two transition states 7 and 8 are heterochirally related from reactions in which 1 is not racemic. That is, 7 and 8 arc enantiomers once the stereochemistry-associated with the double bond is destroyed. Thus, the selectivity for reaction by way of 3 in preference to 4, or via 6 in preference to 5 in reactions of a-subsliluted (Z)-2-butenylboronate 2, is an important factor that determines the suitability of these reagents for applications in enantioselective or acyclic diastereoselective synthesis. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

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.). 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

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-... 

An example of stereocontrol by high pressure is given by the regio- and diastereoselective synthesis of hydrophenanthrenones [18] which are useful intermediates for synthesizing diterpenes and steroids, by EtAlCli-catalyzed cycloadditions of heteroannular bicyclic dienone 50 with (E)-piperylene (24) and 2,3-dimethyl-1,3-butadiene (51) (Scheme 5.4). 

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. ... 

The key step in the diastereoselective synthesis of model insect antifeedant 152 starting from a-cyclocitral 148 was the INOC reaction of oxime 149 or nitro alkane 150 to the isoxazoline 151 (Eq. 15) [42]. 

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

Scheme 21 Diastereoselective synthesis of Ci- and C2-symmetric 1,2-diamines by addition of organometallic reagents to enantiopure a-aminoimines...

Scheme 26 Diastereoselective synthesis of C2-epimers of 2,3-diamino-4-hydroxybutanal and 2,3-diamino-4-hydroxybutanoic acid...

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). 

Scheme 44 Diastereoselective synthesis of protected 1,2-diamines from glyoxal Ramp hy-drazone...

More recently, Carreira reported a [Fe(TPP)Cl]-catalyzed diastereoselective synthesis of trifluoromethyl-substituted cyclopropane in aqueous media [56]. The carbene precursor trifluoromethyl diazomethane is difficult to be handled, generated in situ from trifluoroethyl amine hydrochloride, and reacts with styrene in the presence of [Fe(TPP)Cl] to give the corresponding cyclopropanes in high yields and with excellent diastereoselectivities (Scheme 12). 

Suggest a method for diastereoselective synthesis of the following compounds ... 

Lam et al. applied the copper catalyst system to the diastereoselective synthesis of 4-hydroxypiperidin-2-ones, such as 130, 132 and 134... 

A diastereoselective synthesis of the model insect antifeedant related to 12-hydroxyazadi-radione starting from a-cyclocitral has been reported. [The key steps involve INOC and a Stille... 

This methodology was applied successfully also for the diastereoselective synthesis of a series of P-stereogenic (o-hydroxyaryl)diazaphospholidine - borane complexes 250-257 (yields ranging from 40 to 86%) via the reaction sequence shown in Scheme 61 with a one-pot formation of the appropriate (o-bromoaryloxy) diazaphospholidine-borane complexes 242-249 in yields ranging from 70 to 92% (Scheme 61) [93],... 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

Also in 2001, Azizian described a one-pot diastereoselective synthesis of 2-sub-stituted l,l,2,3,3aa,3b) ,4,5,6,8,8aa-decahydro-8-(spiro-3-indolino-2-one)pyrrolo[3,4-b] pyrrolizine-l,3-dione (151) in good yield and diastereomeric excess using microwave irradiation (Scheme 9.46). 

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>. 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

A diastereoselective imine alkylation and a palladium-catalysed biaryl coupling were important steps in the diastereoselective synthesis of 6,7-dihydro-5//-dibenz[c,e]azepines (Scheme 7) starting from (R)-l-(2-methoxyphenyl)ethylamine. Selection for the... 

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