Chiral auxiliaries tandem cycloaddition

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

The choice of Lewis acid promoter for these reactions can change the sense of asymmetric induction. " For example, tandem [4 + 2]/ [3 + 2] cycloadditions (eq 4) mediated by Ti(0-i-Pr)2Cl2, followed by hydrogenolysis afforded tricyclic (-)-a-hydroxy lactam [(-)-8] in 98% ee. When mediated by methyl-aluminum-bis(2,6-diphenylphenoxide) (MAPh), the same reaction gave (+ )-8 in 93% ee. Importantly, the observed selectivity is not chiral auxiliary dependent. Rather, it is attributed to a highly endo selective cycloaddition in the case of Ti compared to high exo selectivity in the case of MAPh. 

DCP-hased Chiral Auxiliaries in Total Synthesis. DCP-based chiral auxiliaries have proven amenable to asymmetric total synthesis, including Denmark s syntheses of of the pyrrolizidine alkaloid (-)-rosmarinecine and the pentahydroxy pyrrolizidine alkaloid (+ )-casuarine. Denmark s synthesis of (+)-casuarine involves [4 + 2] cycloaddition of dienophile 15 with nitrobenzoate followed by [3 + 2] cycloaddition of the resulting nitronate 17 with a vinyl silane 18 (eq 10). During formation of the [4 + 2] cycloadduct, the relative configuration between C4 and C5 is a direct consequence of the vinyl ether geometry, while the stereochemistry at C6 is determined by the ability of the chiral auxiliary to differentiate the diastereotopic n faces (Re of Si) of the vinyl ether (termed internal diastereoselection). Thus, this tandem sequence... 

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. 

The Denmark laboratory has developed an elegant tandem [4 + 2]/[3 + 2]-cyclo-addition strategy for the synthesis of a variety of alkaloid natural products (96CR137). Nitroethylene (166) readily undergoes a Lewis acid promoted cycloaddition with vinyl ethers that contain a chiral auxiliary group to give nitronates 168... 

Denmark advanced a strategy that involves tandem cycloaddition sequences with nitronates for the asymmetric synthesis of alkaloids [73, 74). A camphor-derived auxiliary permits the preparation of chiral enol ethers (cf. 68) as the reacting partners. A noteworthy example of the complex structures that could be generated by use of 68 is illustrated in Scheme 18.15. A hetero-Diels-Alder reaction between 68 and nitronate 67 generated 69 as a 96 4 mixture of endo/exo diastereomers. The adduct then participated in an intramolecular dipolar cycloaddition at elevated temperatures to yield cycloadduct 70 as a single diastereomer (90%). The tricyclic target 72 was obtained in 88 % yield after reductive removal of the chiral auxiliary and lactam formation [74]. 

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... 

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