Facial selectivity lactones

In 1,4-conjugate additions toward cyclic unsaturated lactones, facial selectivity... 

Cyclo-reversions proceed readily in reactions of enantiopure D7i and D7i ent with cyclic (551) and acyclic (585) nitrones. The sulfinyl group in lactones D7i and D7i ent controls the Jt-facial selectivity and is also controller of the endo/exo selectivity (Scheme 2.274) (788). 

The alternative strategy of using d,v-aminoindanol as a chiral auxiliary on the Michael donor has also been explored.81 Chiral amide enolates were reacted with a,P-unsaturated ester 70, and the resultant adducts were reduced and cyclized to 8-lactones 73 to determine the facial selectivity on the Michael acceptor. It is interesting that protected amino alcohol 71 did not lead to significant diastereofacial discrimination, whereas 72 afforded lactone 73 with high 4-(,S )-selectivity (Scheme 24.15). 

The rather low reactivity of the 3-p-tolylsulfinyl acrylates (they do not react with furan even under forcing conditions) prompted the search for more reactive dienophiles. In this context, pyridylsulfinyl derivatives proved to be more efficient than the arylsulfinyl ones. Thus, menthyl-3-(2-pyridylsulfinyl)propenoates 14a and 14b were prepared from (+)-menthyl propiolate in low yields [34]. Their reactions with cyclopentadiene proceed smoothly in the presence of Et2AlCl at -70°C to afford just one endo diastereoisomer 15a or 15b [35] (in the absence of the catalyst the 7r-facial selectivity for the endo approach was lower than that observed for the p-tolylsulfmyl derivatives [10c]). These compounds were transformed into 16a or 16b [36] respectively (Scheme 8), both allowing the synthesis of the bicyclic lactone 17 (known as Ohno s lactone), a key intermediate in Ohno s synthesis of (-)-aristeromycin and (-)-neplanocin A [37]. 

The latter reaction was further described by Koizumi et al. [86b] with slightly different results (lower facial selectivity for the exo-approach), in connection with the enantiodivergent synthesis of fused bycyclo [2,2,1] heptane lactones 91 (see Scheme 47). The key step of this transformation was the regioselective DIBAL reduction of only one of the two ester groups in the adducts, followed by... 

O Scheme 26) [196]. Tetra-0-acetyl-D-galactono-l,4-lactone 75 yields 3-deoxylactone 77 through the unsaturated lactone 76. Because of the facial selectivity in the hydrogenation, the 2-acetate group in the product is always cis to the side chain. 2,3-Unsaturated aldono-lactones can also be saturated by 1,4-reduction with tributyltin hydride, copper(I) iodide, and trimethylsilyl chloride [197]. Under these conditions other isolated olefins are not affected. 

The facial selectivity of (43) was found to be 1.75 1 from the ratio of aldol products (48) and (49) obtained by the reaction with the achiral boron enolate (50). The latter is structurally similar to reagents (37) and (38). These experiments confirm again the validity of the rule of double asymmetric synthesis. The product (44) can be further converted through a sequence of reactions to provide (+)-Prelog-Djerassi lactonic acid (51 Scheme 27) (i) trimethylsilylation (ii) hydroboration with thexylborane (single asym-... 

A series of alkenes 20, derived from amino acids, react with the dienol 21a to give adducts 22. Formation of the additional lactone and lactam rings occurs prior to isolation of the product. A complete facial selectivity, but only moderate (22a) to low (22b and 22c) yields are obtained9. To prevent lactone ring formation several protected derivatives of dienol 21 were reacted with alkylidene malonic ester 20a. Only diene 21g reacts in an acceptable yield and selectivity10. 

Another example presented by this group involved the reduction of ( )-3-hydroxy-5-phenyl-2-pentanone with Sml2 in the presence of ethyl crotonate to afford jjn-y-lactone in excellent yield and diastereoselectivity at three contiguous stereocenters (Scheme 6) [19, 20], Cram cyclic model K was used to explain the selectivity in the formation of the first new stereogenic center. Subsequent coordination of the ethyl crotonate ester group to the Sm" was responsible for the facial selectivity during the formation of the second center [20]. 

Third, the diastereotopic facial selectivity between the olefin and the ketyl is determined by the biaryl stereochemistry. This stereocontrol element, set earlier via a kinetic resolution of racemic lactone ( )-28, provided an enantiomerically enriched atropisomer (98% ee) that was carried throughout the synthesis without loss of stereochemical integrity. 

The low stereoselectivity observed with unsaturated lactones 56, even for very large substituents, cannot be explained easily, because an increase of the size of substituents has very little effect on the composition of the reaction mixture, when a total facial selectivity is observed for the corresponding cyclopentenone 59 in the presence of vinyl carbonate. 

A very active area of research in S Ar chemishy is in the field of asymmehic synthesis. This chemistry involves a unique set of electrophiles—those in which a chiral environment must exist near the electrophilic reaction site. In most cases, these asymmetric synthetic reactions are accomplished with a chiral electrophile or a chiral catalyst (or counterion) in tight coordination to the electrophile. For example, Stadler and Bach used a chiral electrophile (36) in an S Ar reaction leading to the natural product (-)-podophyllotoxin 38 (Scheme 1.10) [31]. With planar sp carhocation centers, facial selectivity may be controlled by neighboring groups, in this case the adjacent vinyl group on the lactone 36. The Friedel-Crafts chemistry provides intermediate 37, which is then converted to (-)-podophyllotoxin (38) as a single enantiomer. 

Facial selectivity in Diels-Alder reactions has also been studied using theoretical methods. Poirier et al. have studied reactions of ethylene with 5-substituted cyclopenta-dienes (12) and have shown that the major factor responsible for determining the facial selectivity is the deformation of the addends at the transition states, and not the direct interaction between the diene and the dienophile. For reactions between cyclopentadiene and chiral butenolides (13) the most favorable diastereoisomer corresponds to the attack of the diene at the less sterically hindered face of the lactone. Steric interaction between the addends is also reflected in geometry distortions at the transition states. 

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