Diastereomeric mixture control

Treatment of the optically active formaldehyde dithioacetal monoxide with ethyl benzoate in the presence of sodium hydride gives the benzoylated product as a diastereomeric mixture in a thermodynamically controlled (65 35) ratio66. 

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

The longer degree of conjugation of the phenanthroline ligands in these complexes causes a bathochromic shift at the ti-ti band and the different nuclearity shows the 1 2 3 ratio of the extinction coefficient of the ti-ti as well as the MLCT bands. To avoid diastereomeric mixtures the authors established the first controlled synthesis of stereochemically defined multinuclear Ru(ll) complexes [59]. 

Perhydropyrrolo[l,2-fc]isoxazoles result from 1,3-dipolar cycloaddition of cyclic nitrones with alkenes. The high regio- and stereoselectivity of this cycloaddition has been used to control the stereochemistry in the synthesis of natural products. As one example, pyrroline N-oxide (70) and 3,4-dimethoxystyrene gave a diastereomeric mixture of pyrroloisoxazoles (71) and (72), in nearly quantitative yield with preferential formation of (71). 

Elaboration of 2-isoxazolines via their 4-endo-anions has been studied as a method to synthesize y-amino alcohols (78TL3129,3133,81AG(E)601,603). When the 5-methyl-3-phenyl-2-isoxazoline (527) was deprotonated with LDA/HMPA and methylated with methyl iodide, the tra 5-4,5-substituted isoxazoline (528) was formed predominantly (trans-.cis = 12 1). Reduction of this isoxazoline with lithium aluminum hydride proceeded with steric approach control to provide a diastereomeric mixture of y-amino alcohols (529, 530 Scheme 116). The 5-substituent was found to exhibit a greater steric influence on this reaction than the 4-substituent. 

Hydrazones have also been used as azomethine imine precursors to achieve cycloadditions.157 Proto-nated hydrazones act under suitable conditions as quasi-azomethine imines in polar [3+ + 2] cycloadditions. Thus, r.cetaldehyde phenylhydrazone (201) was found to react with styrene in the presence of sulfuric acid in a regiospecific manner to give pyrazolidine (203 Scheme 47) as a diastereomeric mixture.157 The most commonly used azomethine imine has a phenyl group attached to one end of the dipole and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl group does not lower the energy of the LUMO as much as it raises the energy of the HOMO. With electron-deficient di-polarophiles like methyl acrylate, the reaction is dipole HOMO-controlled, and mixtures can be expected. In fact, a 1 1 mixture of regioisomers was obtained in the reaction of (201) with acrylonitrile (equation 9).157... 

The initial a-addition adduct from the reaction of methyl (S)-2-isocyano-4-methylpentanoate 232 and protected (S)-alaninal 233 further reacted with benzoic acid to furnish 234 as a diastereomeric mixture. The stereochemistry of the resulting benzoyl-protected alcohol was inconsequent since the latter functionality is oxidized during the course of the synthesis using pyridinium dichromate to afford the a-oxoamide in the final target. In general, however, in isocyanide MCRs the control of the newly created stereogenic center is problematic and separation of diastereomeric mixtures cannot be avoided. A recent report by Denmark and Fan on a catalytic asymmetric variant of this reaction therefore represents an interesting development [119]. 

Recently, Oppolzer s group reported on the synthesis and use of a new sulfinylating agent,107 the /V-sulfinyl sultam 82, as part of a broad program on the use of the versatile bornane-10,2-sultam 81 in asymmetric synthesis.108 The condensation of p-TolSOCI with 81 in THF, using dimethylaminopyridine (DMAP) as catalyst, gave the /V-(p-tolylsulfinyl)bornane- 10,2-sultam as a 6.2 1 diastereomeric mixture. Crystallization of the mixture from E O/hexane afforded pure 82 in 77% yield. X-ray analysis showed the absolute configuration at the sulfinyl sulfur to be (/ ). The reaction has been shown to be kinetically controlled, in contrast to the results obtained when n-BuLi was used instead of DMAR In the latter case, the reaction was under thermodynamic control, in accord with the result obtained by Evans with iV-sulfinyl oxazolidinone (Scheme 25). 

An inspection of the stereochemistry at C-2 for the iminosugars revealed that the reductive amination with Pd/C was highly diastereoselective. Interestingly, as already stated [15, 18, 20, 34], we found that the hydrogen was added to the face opposite to the C-4 hydroxyl group, regardless of the relative stereochemistry of the other substituents. Hence, the stereochemistry observed at C-2 was controlled exclusively by the configuration at C-4. An exception was found for the reductive amination of compound 7. In this case, there was no face selectivity and a circa 1 1 diastereomeric mixture was obtained. 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

Control experiments with 19a showed that in the absence of olefins hydrodimers were also formed but the reaction rate was reduced by about 90 %. Either the CdS itself (under photocorrosion) or the solvent must be involved in the oxidative step of this reaction. Accordingly, irradiation of CdS in a solution of 19a in different alcohols transforms the imine at different rates and the corresponding addition products 22a-e and the hydrodimer 23 are isolated (Figure 31). Except for methanol and 2-propanol, the products are racemic diastereomeric mixtures which are isolated in low yields (5-20 %) they are often mixed with the two-electron reduction product A-4-chlorobenzyl-4-chloroaniline. The major product in all reactions is the hydrodimer 23, obtained in yields of 10 % (MeOH), 28 % (BuOH), 29 % (PrOH), 42 %... 

If the initial addition (A, Scheme 3) is essentially irreversible, the net stereoselectivity can be controlled by interactions that exist in the transition state for the Michael addition. However, if there is not a rapid intervening process (cyclization or proton transfer), the initial dipolar adducts would be expected to reform starting materials at an appreciable rate (vide supra). Based on the reports described previously, a significant possibility exists that this initial addition is reversible, at least in most cases. If indeed step A is reversible or if the configuration of 3.1 is not stable to reaction conditions, then the net stereoselectivity can be determined by the relative stability of the dias-tereomers of 3.1 or by the relative rates of the diastereomeric transition states for some subsequent reaction (e.g., B-F).+ For example, selectivity could be induced by preferential cyclization (paths D and E) or by selective proton transfer (path B) from one of the components of the initial diastereomeric mixture (3.1). Also, it is possible that selective protonation (path F) of enamine 3.5 could give the observed products. This prospect is less likely as the generation of enamine 3.5 is disfavored by allylic strain considerations. 

Methoxy-substitutedcyclohexa-2,5-dienones 3 regioselectively afford diastereomeric mixtures of 4-methoxybicyclo[3.1.0]hex-3-en-2-ones 4, again most probably due to electronic control.105 106... 

A recent paper, however, revealed a successful attempt to control the regioselectivity of the reaction to prepare racemic eryrAro-sphingosine and ceramids. Hino et alP reported that the reaction of ( )-hexa-dec-2-enal with 2-nitroethanol in triethylamine at room temperature gave a diastereomeric mixture of 1,2-addition products (40) and (41) in 70% overall yield, while the reaction in methanol-potassium carbonate gave a mixture of compounds (42 50%) and (43 12%). Both these compounds are derived from a Michael adduct intermediate (Scheme 7). Previously, it was observed that the reaction of hexadec-2-ynal with 2-nitroethanol (equation 15) in methanol in the presence of potassium carbonate at room temperature gave a mixture of diastereomeric nitrodiols (44) and (45) in 80% yield. 

It is well known that the tricarbonylchromium-complexed benzylic anions and cations are stabilized due to overlapping between d-orbital of the chromium and p-orbital of the benzylic carbon [1]. Tricarbonylchromium complexes of a-te-tralone and a-indanone having a carbonyl group at the side chain underwent a deprotonation of the exo-benzylic protons by treatment with base to give the stereo-controlled tricyclic compounds (Eqs. 1 and 2) [2]. In these cases, Robinson annulation products were formed in less than 10% yield. Also, base treatment of benzyl ether chromium complex having a chlorine at the side chain 3 gave cyclization product as a diastereomeric mixture (Eq. 3) [3]. 

The reduction of a diastereomeric mixture of enantiomerically pure /3-keto sulfoxides (7) furnished one of the four possible isomers with good overall stereoselectivity (90%), when carried out under conditions which favor epimerization of the a chiral center (eq 16). This outcome derives from a chelation-controlled reduction (involving the sulfoxide oxygen) coupled with a kinetic resolution of the two diastereoisomers of (7). ... 

The mechanism begins with the addition of a silyl-substituted carbanion 14 to a carbonyl compound 15 an aqueous work-up then leads to a diastereomeric mixture of yff-hydroxyalkylsilanes, often isolable and sometimes separable. The stereo-selectivity of the reaction can be controlled by the steric demands of the silyl group the use of more sterically demanding silyl groups results in the erythro isomer as the major product. 

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