Tandem 1,5-diastereoselectivity

Aluminum oxide catalyzed addition of ethyl nitroacetate to racemic 2,3-cpoxy aldehydes 7 affords substituted 4,5-dihydroisoxazole 2-oxides through a regio- and stereospecific tandem nitroaldol cyclization process. High diastereoselectivities are observed in the reaction of cis-epoxyaldehydes to yield the ethyl, vi7 -4.5-dihydro-4-hydroxy-5-( I -hydroxyalkyl)-3-isoxazole-carboxylate 2-oxides, with tram configuration at the ring positions, whereas reactions of trans-and 3,3-disubstituted 2,3-epoxyaldehydes proceed with lower selectivities28. 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Tandem transesterification and diastereoselective intramolecular 1,3-dipolar cycloaddition of a-methoxycarbonylnitrones with chiral allyl alcohols give polycyclic compounds in one step with high stereoselectivity (Scheme 8.14).76 Transition state Ain Scheme 8.14 is more favorable than B because B has severe steric interaction (allylic 1,3-strain).77... 

Inter [4+2]/inter [3+2] The tandem intermolecular [4+2]/intermolecular [3+2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers, which can be controlled by the choice of the stereochemistry of each component and the Lewis acids. The nitronate derived from 2-nitrostyrene and 1-trimethylsilyloxycyclohexene reacts with methyl acrylate to give the nitroso acetal in good yield and high diastereoselectivity (Eq. 8.107).154... 

When a-tethered nitroalkenes bearing three or four methylene chains and ester-activated dipolarophiles react with vinyl ethers, spiro mode tandem cycloaddition takes place to give tricyclic spiro nitroso acetals in good yield and high diastereoselectivity (Scheme 8.46).184... 

The third member of the tandem inter [4+2]/intra [3+2] cycloaddition family is classified as the bridge mode, in which the dipolarophile is attached to the dienophile. Simple, 1,4-pentadi-enes as well as 2-alkoxy-l,4-pentadienes can function effectively as dienophiles and dipolarophile combinations with excellent chemical selectivity and regio- and diastereoselectivity. Hydrogenation of the bridged nitroso acetals produces hydroxymethylated derivatives in high diastereo- and enantioselectivity (Eq. 8.116).185... 

A sequential cycloaddition, tandem cycloreversion-cycloaddition process is more efficient than the direct cycloaddition, especially in case of aliphatic aldehydes, where the corresponding ylides are rather unstable. The cycloreversion strategy lowers the concentration of the free ylide in the reaction mixture and avoids side reactions such as self-condensation of this reactive species. In some cases, this tandem cycloreversion-cycloaddition sequence provides improved chemical yields without any loss of diastereoselectivity. For example, compound 476 treated with methyl fumarate, methyl maleate, and methyl acrylate provides acceptable yields of compounds 477-479 (Scheme 80) <2000S1170, 2002S1885>. 

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... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

The zinc chloride-mediated tandem Mukaiyama aldol-lactonization reaction of aldehydes 21 and thiopyridylketene acetals 22 gave mainly the trans isomer 23. However, if the catalyst is stannic chloride and the reaction is carried out at -78 °C, then the cyclization is highly diastereoselective and yields the cis-isomer 24 <990L1197>. 

The first total synthesis of (T)-arteannuin M was accessed using a tandem oxy-Cope/ene reaction.87 Divinylcyclohexanol 138 was heated in toluene and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give compound 140 as a single diastereomer in 55-60% yield (Scheme 28). The diastereoselectivity is controlled by the pseudo-equatorial position of the alkyl group in the transition state 139. 

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]. 

A direct comparison of the stereochemical efficiency of the fragmentation reaction versus the tandem reaction (Scheme 53) was studied by Porter et al. as a function of the steric effect based on the Taft parameters for different substituents [146]. In general, the tandem reactions perform better and provide higher levels of ee s than the fragmentation reactions. This effect could be due to the tinbromide by-product catalyzing a non-stereoselective process as has been uncovered by the same authors (vide supra) and by Sibi and Ji in their diastereoselective studies [147]. 

In a similar fashion, allylboronates can be used as allylation reagents under hydroformylation conditions. Thus condensed 1,5-oxazadecalin systems are achieved via tandem hydroformylation/allylboration/hydroformylation sequences starting from an N-allyl-y-amidoallylboronate (Scheme 23) [77,78]. The aldehyde obtained from a regioselective hydroformylation undergoes diastereoselective intramolecular allylboration to give an intermediate al-lylic alcohol derivative. The reaction does not stop at this stage, since this... 

Complete control of the diastereoselectivity of the synthesis of 1,3-diols has been achieved by reagent selection in a one-pot tandem aldol-reduction sequence (see Scheme l). i Anti-selective method (a) employs titanium(IV) chloride at 5°C, followed by Ti(OPr )4, whereas method (b), using the tetrachloride with a base at -78 °C followed by lithium aluminium hydride, reverses the selectivity. A non-polar solvent is required (e.g. toluene or dichloromethane, not diethyl ether or THF), and at the lower temperature the titanium alkoxide cannot bring about the reduction of the aldol. Tertiary alkoxides also fail, indicating a similarity with the mechanism of Meerwein-Ponndorf reduction. 

Diastereoselective tandem conjugate addition of both oxygen- and nitrogen-centred nucleophiles (potassium phthalimide, TsNHK, MeONa, and MesSiOK) to the novel (IN)-lO-camphorsulfonic acid-derived nitroalkenes (139 R = Me, Pr, and... 

The Ir(lll) complex also funchoned as a catalyst in a tandem Nazarov cyclization-Michael addition. The reaction of monocyclic a-alkylidene-P-keto-y.b-unsaturated ester with nitroalkene gave bicyclic cyclopentenones which possessed an alkyl side chain, with high yield and diastereoselectivity (Scheme 11.36) [47]. 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

Hydroformylation reactions have been shown to be amenable to use in tandem or domino reaction sequences. In one elegant example, alkene 36 was subjected to rho-dium(I)-catalyzed hydroformylation, and the resulting aldehyde underwent smooth intramolecular allylboration (Scheme 5.14) [19]. This produced a new terminal alkene which underwent a second hydroformylation to provide, after workup,lactols 37 in 80% yield and with excellent diastereoselectivity. 

The tandem silylformylation/allylsilylation reaction is particularly well suited to the synthesis of skipped polyol motifs such as are found in the oxopolyene macroHdes. The synthesis of protected triol 43 (an intermediate in the mycoticin A formal synthesis described above see Scheme 5.18) relied on an application of this methodology. Thus, homoallylic alcohol 76 was transformed into triol 77 in 55% overall yield and >10 1 diastereoselectivity (Scheme 5.27) [23]. Selective protection of the triol to give 43... 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

The same authors later reported that although sterically hindered lithium dialkylamides do not react under the normal conditions, they do undergo an unusual 1,6-addition to the oxazolinylnaphthalene 511 in the presence of excess HMPA (8-10 equiv)." ° These reactions are also diastereoselective to afford the trans tandem adduct as the major product (Scheme 8.166). A dimeric lithium... 

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