Cyclization diastereoselective

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

A related approach consists in the generation of endocyclic iminium ions from fV-acylaminals 209. As in the previous case, their treatment with boron trifluoride induces a diastereoselective cyclization, and thiazolo[3,4- ]pyridines 210 are isolated in good yields (Scheme 59) <2001EJ01267>. Alkenes can also participate and react well with the intermediate... 

Scheme 35 Diastereoselective cyclization of a pair of diastereomeric substrates...

Scheme 36 Diastereoselective cyclization of a further pair of diastereomeric amines...

The total asymmetric syntheses of natural (lS,2S)-norcoronamic 72a and of (lS,2S)-coronamic acid 73 have been obtained from the diastereoselective cyclization of chiral non-racemic 2-(Ar-benzylideneamino)-4-chlorobutyronitriles [98] but one of the shortest syntheses of these attractive amino acids was based on the diastereoselective palladium(0)-catalyzed alkylation and S cyclization of l,4-dichlorobut-2-ene by the anion of 2-aminoacetonitrile derivatives [99]. On the other hand, diastereoselective palladium(0)-catalyzed azidation of chiral non-racemic 1-alkenylcyclopropyl esters provide non-natural (lk,2S)-norcoro-namic acid, enantiomerically pure [100]. 

Titanium-catalyzed cyclization/hydrosilylation of 6-hepten-2-one was proposed to occur via / -migratory insertion of the G=G bond into the titanium-carbon bond of the 77 -ketone olefin complex c/iatr-lj to form titanacycle cis-ll] (Scheme 16). cr-Bond metathesis of the Ti-O bond of cis- iij with the Si-H bond of the silane followed by G-H reductive elimination would release the silylated cyclopentanol and regenerate the Ti(0) catalyst. Under stoichiometric conditions, each of the steps that converts the enone to the titanacycle is reversible, leading to selective formation of the more stable m-fused metallacycle." For this reason, the diastereoselective cyclization of 6-hepten-2-one under catalytic conditions was proposed to occur via non-selective, reversible formation of 77 -ketotitanium olefin complexes chair-1) and boat-1), followed by preferential cyclization of chair-1) to form cis-11) (Scheme 16). 

Like in other chiroptical switches (Section 5.3.1), solvent polarity was found to play an important role. Diastereoselective cyclization was observed in THF and toluene, but not in nonpolar solvents such as n-hexane. Upon photoexcitation, diarylethenes 24 (Scheme 11) can adopt a planar and a twisted conformation, and photocyclization only proceeds through the planar conformation. In the case of chiral diarylethene 27a, there are two diastereomeric planar conformations leading to the diastereomers of the cyclic product 27b. The stereoselectivity in the photocyclization process is enhanced because of a decrease in the excited state energy of the unreactive twisted form, providing a relaxation pathway for the less favorable planar diastereoisomer in more polar solvents. Chiral photochromic diarylethenes are among the most prominent photoswitches known today, featuring nondestructive read-out, excellent reversibility, and the potential for construction of switchable molecular wires and modulation of liquid crystalline phases (see Section 5.5.3).[40,411... 

Scheme 4.14. Chiral auxiliary approach to diastereoselective cyclizations.

On the other hand, alkenyl aryllithiums can undergo diastereoselective cyclizations in very good yields. Pedrosa and coworkers163 reported that chiral 2-(o-bromophenyl)-substitutedperhydro-l,3-benzooxazines 281, initially transformed to the aryllithium derivative, gave the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle (Scheme 87). By adding 2 equivalents of TMEDA to the aryllithium derivative 1,3-benzooxazines 281 prepared at —90 °C,... 

A diastereoselective cyclization of a 5-hexenyl radical linked to a carbohydrate scaffold was reported by Enholm et al. [171]. The authors used (+ )-isosorbit and ( —)-D-xylose as the chiral auxiliaries. The a,p-unsaturated bromo ester 262 derived from (-h )-isosorbit was reacted with tributyltinhydride and Lewis acids. The influence of the reaction temperature and of the solvent on the yield and stereoselectivity of the cyclization were also examined. Best results were obtained when ZnCl2 was used as Lewis acid at — 78°C (Scheme 10.85). The cyclization furnished the ester... 

The use of chelation to direct the stereochemical outcome of intramolecular additions of allylsilanes to -dicarbonyl compounds can provide excellent levels of diastereoselectivity. Cyclizations of this type proceed at low temperature under mild reaction conditions and are highly chemoselective, providing routes to highly functionalized five-, six- and seven-membered rings (10 100b and 100c Scheme 47). For the cases examined, SnCU and FeCls proved to be less effective than TiCU in the cyclization of ethyl 2-alkyl-2-alkanoyl-4-(trimethylsilyl)methyl-4-pentenoate(99 n = 1 Table 13). ... 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization of 175, which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid (see Eq. (13.55)). The enantioselective variant simply utilizes an achiral template 188 in conjunction with a bulky chiral binol-derived aluminum Lewis acid 189 (Eq. (13.59)) [75]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid, providing a yield of 63%. 

Diastereoselective cyclizations are possible [73], in particular when the outcome of the stereochemistry is set by the configuration of a cylic ring junction (Fig. 10). The stereochemistry-determining insertion step proceeds via the less encumbered transition state providing a single diastereoisomer. 

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