Lactones stereoselective reduction

Compound 59 was prepared in six steps starting from iV-(/>-methoxybenzyl)glycine ethyl ester and (i )-O-acetyl-atrolactic chloride, as reported in Section 11.11.7.3. Stereoselective reduction of 59 with BH3 at the carbonyl in position 8 (the only ketone among the other carbonyls) gave compound 60 in high diastereomeric purity (>95%). This diol was further opened in basic conditions and lactonized (Scheme 5) to produce an omuralide analogue 61 which can be potentially selective for proteasome inhibition <20010L1395>. 

Similarly, exposure of stannyl lactol to PhI(OAc)2 4 led to oxidative ring expansion yielding the trans unsaturated lactone stereoselectively, presumably via 1,4-fragmentation induced by reductive elimination of iodobenzene [Eq. (46)] [83]. 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

To demonstrate the versatility of his S3mthesis strategy Yamada used ketoester 151 as relais substance to S3mthesize two further picrotoxane alkaloids isolated from Dendrobium species, nobilonine (90) and 2-hydroxydendrobine (87) (Scheme 14) (84). Monobromination of 151 with bromine in dioxane and subsequent treatment with water resulted in hydroxy-y-lactam 152, whereas attempts to hydroxylate 151 by Barton oxidation led to rearrangements. Chemo- and stereoselective reduction with zinc borohydride converted 152 into the en fo-alcohol. To counterbalance the unfavorable conformational equilibrium this alcohol had to be converted into the alcoholate to achieve lactonization. Chemoselective reduction of the hydroxylac-tam moiety of lactone 153 again followed Borch s protocol, which led in this case to boron complexed amino compounds necessitating successive acid treatment to obtain racemic 2-hydroxydendrobine (87) in low yield accompanied by dendrobine (82). 2-Hydroxydendrobine (87) was converted into nobilonine (90) by Eschweiler-Clark methylation. 

Stereoselective reduction of an enone lactone was a key step in the construction of the 20-hydroxyec-dysone side chain. Totally different mixtures of products were obtained when the reduction was carried out with sodium borohydride or by catalytic hydrogenation (Scheme 30). In all cases, the 1,4-reduction mode is preferred. With borohydride, however, this process is followed by a subsequent reduction of the saturated ketone and base-catalyzed rearrangement of the 5-lactone into a y-lactone. 

Lactone. Various fungi, including Bakers yeast and Geotrichum candi-dum, have been shown to produce optically active lactones, useful chiral synthon, via the stereoselective reduction of suitable unsaturated precursors (42). Figure 15 shows the production scheme for a chiral, substituted diketone, a synthon for optically active carotenoids. 

Chiral lactones were synthesized by stereoselective reduction reactions with a carbohydrate auxiliary [178]. The benzyl protected 3,6-anhydro-a-D-glucopyranoside 279 was acylated with acid halide 280, and the product 281 was reduced with Zn(BH4)2 (Scheme 10.91). The alcohol 282 was obtained with a high diastereomeric excess (96 4). Cleavage from the auxiliary by... 

R.S. Coleman and co-workers have developed a stereoselective synthesis of the 12-membered diene and triene lactones characteristic of the antitumor agent oximidines I and II, based on an intramolecular Castm-Stephens coupling. The effectiveness of this protocol rivals the efficiency of standard macrolactonization. The stereoselective reduction of the internai alkyne afforded the 12-membered ( ,Z)-diene lactone in good yield. 

Calcium borohydride is generated in methanol or ethanol from CaCl2 and NaBH [BR3]. It reduces esters to alcohols, leaving acid salts intact, thus allowing the formation of lactones from hemiesters [LRl] (Section 3.2.5). It has also been used in stereoselective reduction of a,p-epoxyketones [TF2] (Section 3.2.4). 

Enamines are hydrogenated over Pt catalysts and on Pd-on-carbon. A completely stereoselective reduction of lactone 6 is achieved over Rh. ... 

The same authors have developed an alternative metiiod for the synthesis of 6)8-eudesmanolides from santonin (Scheme 15) [26]. The epimerization process at C(6) consisted of the LiAlH4 reduction of the trans-6oc- actone moiety in compound 122, followed by selective protection of the hydroxyl groups at C(3) and C(12), oxidation of C(6) to give compound 128, and stereoselective reduction of the carbonyl group by attack with sodium borohydride from the less hindered a-side. Re-lactonization was achieved by oxidation, after prior deprotection of the C(12)-hydroxyl group, with RuH2(Ph3P)4 or tetra- -propylammonium... 

Based on our experiences with the NHC-catalyzed synthesis of dihydropyra-nones, we thought it conceivable that ot,p-unsaturated enol ester 51a could be converted to the iridoid cyclopenta[c]pyran core (i.e., 52a) (Scheme 11). In turn, it was envisaged that the required unsaturated enol ester 51a could be prepared via acylation of methyl formyl acetate (53a) with enantioenriched acyl chloride 54. The NHC-catalyzed rearrangement would only prove viable if it proceeded with chemoselectivity, due to the presence of additional ester functionality in enol ester 51a, and stereoselectively, to provide the correct diastereomer of 52a for the natural product. Although it was unclear whether these selectivities could be achieved, or whether the reaction would proceed with substrates annulated about the a,p-unsaturation, it was envisaged that this study would, at the very least, allow the limitations of the NHC catalysis to be examined. From the iridoid core 52a, completion of the total synthesis would require the chemo- and stereoselective reduction of the lactone to the lactol, followed by glycosylation. 

The preparation and chemical properties of levoglucosenone as well as its use in the total synthesis of natural products have been reviewed, and the stereoselective reduction of 3-bromolevoglucosenone to l,6-anhydro-3-bromo-3,4-dideoxy-P-D-rAreo-hex-3-enopyranose 1 has been effected using zinc borohydride. The known lactone 2 has been converted into the aldosulose derivative 3, a degradation product from the ansamycin antibiotic (+)-trienomycin A. This confirmed that the fragment of the natural product was the enantiomer of 3. ... 

Ley, S.V., and G. Meek, Synthesis of P-Dimorphecolic Acid Exploiting Highly Stereoselective Reduction of a Side-Chain Carbonyl Group in a it-Allyltricarbonyl Iron Lactone Complex, J. Chem. Soc. Perkin Trans. I, 1125-1130 (1997). 

---