Enantioselective cyclisation

For instance, Kwong, Chan and coworkers have developed an operationally simple aqueous procedure for the enantioselective cyclisation of ethers such as (8.245)... 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

The synthesis of a series of chiral organophosphine oxide/sulfide-substituted binaphtholate ligands has recently been reported by Marks and Yu and their corresponding lanthanide complexes characterized. These complexes, generated in situ from Ln[N(TMS)2]3, cleanly catalysed enantioselective intramolecular hydroamination/cyclisation of 1-amino-2,2-dimethyl-4-pentene albeit with a low enantioselectivity of 7% ee (Scheme 10.82). 

The first enantioselective total synthesis of the sesquiterpenoid heliannuol D 56 has been reported by Shishido and co-workers. The key step was a base-mediated (NaOH) intramolecular cyclisation of the phenolic epoxide mixture 55 (R1 = MOM, R2 = H and R1 = H, R2 = MOM). Heliannuol D (and the eight-membered congener, heliannuol A) is an allelopathic agent isolated from cultivated sunflowers (Helianthus annuus L.SH-222) <00JCS(P 1)1807>. 

Chromans with defined stereochemistry are accessible by manipulation of dihydrochromeno[3,2-b]azete-2,8-diones 26 which result from the cyclisation of azetidine-2-carboxylic chlorides 25 <99T5567> and also from chroman-4-ones via an initial enantioselective reduction by BHj in the presence of Coreyls oxazaborolidine <99T7555>. 

An enantioselective synthesis of the methyl esters of -)-cis and (-)-tro/ i-clavicipitic esters has been achieved <99T10989>. The key cyclisation step is the acid cyclisation of the amino acid ester 20. A number of tetracyclic derivatives of the general structure 21 have also been reported <99TL5569>. 

The dithiadecalin (34) was used to provide the carbon backbone for C-3 to C-8 and C-9 to C-13. Compound (34) was obtained in an optically active form by a route involving an enantioselective (36% e.e.) aldol cyclisation catalyzed by (R)-proline71). 

Carbamates containing unsaturated substituents may undergo enantioselective anionic cyclisations (see also section 7.2.4) for example, 421 is deprotonated enantioselectively by s-BuLi-(-)-sparteine and gives the cyclopentane 422.180... 

Cyclisation with substitution of chloride was made enantioselective by Beak83 in a remarkable reaction initiated by an asymmetric deprotonation of 171 (see section 5.4 for a discussion), followed by cyclisation to 172. Yields and enantiomeric excesses were highly solvent-dependent. 

Cyclisations onto allylic ethers such as 325 give vinyl-substituted pyrrolidines in good yield.61 Enantioselective versions of similar syntheses of pyrrolidines are discussed below. 

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

A sequence of allylation, epoxidation and an acid-mediated 6-exo cyclisation converts salicylaldehydes into 2-hydroxymethyl-2-methyl-27/-[l]benzopyrans. A bicyclic chroman arising from attack of the hydroxymethyl group on the intermediate benzylic cation has been isolated <02SL322>. A twelve-step enantioselective synthesis of a 2-hydroxymethyl-2-methylchroman with an overall yield of 48% uses related methodology and introduces the chirality through an asymmetric Sharpless epoxidation <02JCS(P1)496>. 

Many further important natural product syntheses are covered by the aforementioned review. Particularly noteworthy amongst them are Hudlicky s syntheses of conduramines [522] and (+)-lycoricidine [523] since they employ enantioselective microbial oxidations of halobenzenes as source of chirality. Racemic lycoricidine has also been prepared by Martin et al. this synthesis exhibits an interesting Heck cyclisation as key step in addition to the hetero Diels-... 

A first example shows the enantioselective reductive radical cyclisation reaction of 3-(5 -iodopentylidene)-piperidin-2-one (24) (Scheme 9). After the primary cyclisation step the hydrogen abstraction leads to the formation of a stereogenic centre. The complexing agent (+)-12 was used as source of chirality (Aechtner et al. 2004 Dressel et al. 2006). 

Another substrate class for reductive radical cyclisation reactions, which was studied in our laboratories, are 4-(4 -iodoalkyl)quinolones (e.g. 27 Scheme 10). High enantioselectivities could be achieved even at 0 °C (up to 99% ee) or at ambient temperature (up to 96% ee). Furthermore, an unexpected chirality multiplication was observed with low catalyst loadings (Dressel and Bach 2006). 4-(4/-Iodobutyl)quinolone (27) can be synthesised from4-methylquinolonein three steps by alkylation with 3-/< /7-butyldimcthylsilyl(TBDMS)oxy-l-iodopropane, deprotection of the alcohol and iodo-dehydroxylation in an overall yield of 31%. 

The model in Scheme 11 explains the regioselectivity, enantioselectivity and diastereoselectivity of the reaction. In the radical cyclisation step the endo radical 28 is formed exclusively due to the high stability of the resulting benzyl radical. The approach of the alkyl radical in the complex 27 (+)-12 occurs from the sterically unhindered re face whereas the attack of the radical from the si face is blocked by the tetrahydronaphthalene shield. For the same reason the hydrogen abstraction step in the complex 28 (+)-12 takes place at the same face to form product trans-29 predominantly with high enantioselectivity. 

Bach T, Aechtner T, Neumtiller B (2002b) Enantioselective Norrish-Yang cyclisation reactions of A-( )-oxo-a>-phenylaIkyl)-substituted imidazolidin-ones in solution and in the solid state. Chem Eur J 8 2464-2475 Bach T, Grosch B, Strassner T, Herdtweck E (2003) Enantioselective [6jt]-photocyclisation reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation. J Org Chem 68 1107-1116... 

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