Dipolarophiles auxiliaries

To control the stereochemistry of 1,3-dipolar cycloaddidon reacdons, chiral auxiliaries are introduced into either the dipole-part or dipolarophile A recent monograph covers this topic extensively ° therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddidon can be divided into three main groups (1) chiral allyhc alcohols, f2 chiral amines, and Hi chiral vinyl sulfoxides or vinylphosphine oxides. 

The asymmetric synthesis of six-membered cyclic nitronates with the use of dipolarophiles containing auxiliaries was studied in more detail. Chiral vinyl ethers are most commonly used for this purpose. This process is schematically shown in Scheme 3.182. 

Elsewhere, Faita et al. (438) bound the Evans chiral auxiliary to Wang or Merrifield resin for use as a dipolarophile in cycloadditions with C,N-diphenyl-nitrone. Yields on both resins are significantly reduced in comparison to the solution phase reaction (43-20% compared to 95%) but are unaffected by addition of magnesium perchlorate or scandium triflate catalyst. A one-pot process has been reported by Hinzen and Ley (439) that oxidizes secondary hydroxylamines to the... 

A second strategy to control facial selectivity involves the use of chiral sultams and lactams as auxiliaries for the dipolarophile (120-123). Cycloaddition of 132 with a variety of substituted nitronates provides up to 9 1 selectivity of the major diastereomer (Table 2.38). However, substitution at the a-position of the dipolarophile leads to a reduction in stereoselectivity (entry 5). Assuming an s-cis conformation of the dipolarophile, it is proposed that the major isomer arises from an endo approach of the nitronate to the Re face of the dipolarophile (Fig. 2.13). This is supported by X-ray crystallographic analysis of one of the cycloadducts, which resides in a conformation similar to the proposed transition state. However, this analysis assumes that the silyl nitronate is only reacting through the... 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

Similar facial selectivity has been observed in nitronates derived from chiral vinyl ethers (69), as well as from nitronates prepared with a chiral Lewis acid, which lack any bias from a chiral auxiliary (66). Even in the absence of a substituent at C(4), as in the nitronate 287, there remains a high facial selectivity upon the addition of a dipolarophile (Eq. 2.28) (84). Both RHE and B3LYP calculations for the approach of a dipolarophile to the nitronates 289 and 290 show at least a... 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

The first diastereoselective synthesis of a tetrahydrothiophene derivative was reported by Karlsson and Hdgberg (32,95). The parent ylide la was added to a variety of C,C-dipolarophiles (79) bearing (—)-(15)-2,10-camphorsultam as the chiral auxiliary group to exclusively give trans-cycloadducts 80a,b with high diastereoselectivity [diastereomeric ratio (dr) 9 1], (Scheme 5.28). 

Another approach to obtain pure enantiomers of isoxazolines involves the use of chiral acrolein aminals, formed with A.A -substituted diaminodiphenylethanes (194). Thus, with this chiral imidazolidinyl auxiliary in the p-position, and with unsaturated esters serving as the dipolarophile, benzonitrile oxide afforded only one regioisomeric cycloadduct with good stereoselectivity (194) (Scheme 6.40). When the analogous A,A -dimethyl auxiliary was chosen, excellent stereoselectivity was accompanied by poor regioselectivity (194). 

A new dipolarophile bearing a chirality-controlling heterocyclic auxiliary at the p-position is readily accessible from (5)-A -benzylvalinol and methyl ( )-4-oxo-2-propenoate. However, the dipolarophile is available only as an 86 14 equilibrium mixture of trans and cis stereoisomers (Scheme 11.20) (84). When this is used without separation in the reaction with the Al-hthiated azomethine ylide derived from methyl (benzylideneamino)acetate in THE at 78 °C for 3.5 h, a mixture of two diastereomeric cycloadducts (75 25) was obtained in 82% yield. These two cycloadducts are derived from the trans and cis isomers of acceptor, indicating that both cycloadditions were highly diastereoselective. 

The most common method for inducing asymmetry in 1,3-dipolar cycloadditions is by the application of chiral 1,3-dipoles, chiral dipolarophiles, or both, the latter always being the case for intramolecular reactions (5). First the reaction of chiral 1,3-dipoles will be described, then the reactions of chiral dipolarophiles, and finally the intramolecular reactions. In this chapter we have chosen to treat the diaster-eoselective reactions employing chiral auxiliaries separately in Section 12.3. 

Chiral auxiliaries are very often applied for induction of asymmetry in 1,3-dipolar cycloadditions. For most of the reactions described in this section, recovery of the chiral auxiliary has been demonstrated, but for some reactions the chiral moiety has the potential to be recovered, although it was not performed. Most frequently, the chiral auxiliary is connected to the dipolarophile, very often as a,p-unsaturated esters or amides. In a few cases, auxiliaries have been attached to the 1,3-dipole. 

Chiral furanones (butanolides) such as 191 have been used as dipolarophiles in various 1,3-dipolar cycloadditions. The chiral 4-substituted butanolide 190 was prepared from 191 and the chiral auxiliary menthol (Scheme 12.55) (310,311). The single diastereomer 191 is obtained by crystallization and epimerization of the other diastereomer, as the amount of 191 in solution decreases. 1,3-Dipolar... 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

Poor (<4% de) to modest (56% de) amounts of diastereofacial selection is observed in the cycloaddition of nitrile oxides to optically active acrylates. The plan in each case, of course, was to use a chiral auxiliary which would preferentially shield one of the two ir-faces of the dipolarophile. Of the auxiliaries used, the sulfonamide esters derived from (+)-camphorsulfonyl chloride worked best, the menthyl esters derived from (-)-menthol the poorest (<4% de). As illustrated in Table 19, changes in both temperature and solvent had either no or little affect on the product ratios. Unlike Diels-Alder reactions, the addition of Lewis acids, specifically Et2AlCl, EtAlCh and TiCL, resulted in significant decreases in both the rate of cycloaddition and isolated yield, without an appreciable change in diastereomer ratio. ... 

The tandem inter-[4+2]/intra-[3+2] cycloaddition process involving dienylsilyloxy nitroalkene 540 and chiral vinyl ether 541 in the presence of methylaluminium bis(2,6-diphenylphenoxide) (MAPh) as Lewis acid afforded the single cycloadduct 542 in 66% yield. On a preparative scale, a lower yield (49%) of the purified product was obtained (Scheme 126) <2001JOC4276>. The two-atom linker between the nitronate and the dipolarophile moieties in 540 and the configuration of the chiral auxiliary phenylcyclohexanol could be chosen to obtain the adduct 542 with the relative and absolute configuration at the newly formed stereocenters, as required in the pyrrolizidine alkaloid (-l-)-l-epiaustraline. 

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