9S-Dihydroerythronolide

Crimmins s TiCL -mediated asymmetric aldol condensation protocol was used in the enantioselective total synthesis of (9S)-dihydroerythronolide A (68)25 (Scheme 2.lx). Swern oxidation of the primary alcohol 69 provided the aldehyde 70 in almost quantitative yield, which underwent asymmetric aldol condensation with the titanium enolate of (A )-4-bcnzyl-3-propionyloxa/,olidin-2-onc (26M) in the presence of (-)-sparteine to afford the aldol adduct desired (71) as a single diastereomer. 

Our synthesis of (9S)-dihydroerythronolide A, which constitutes a formal synthesis of erythronolideA (226), depends on a key aldol reaction between the racemic aldehyde 244 and imide auxiliary 245 (Scheme 9-66) [84]. In this reaction, the auxiliary overrides any aldehyde facial bias, thus leading to an equimolar mixture of separable syn adducts 246 and 247. These two compounds were then processed separately and together provide five of the ten necessary stereocenters of erythronolideA (C9 will be oxidized). This synthesis also features the thioalkyla-tion of silyl enol ether 248 giving ketone 249, a process which can be compared with the Mukaiyama addition to aldehydes. Presumably, Felkin selectivity controls the Cii stereocenter while the mixture of C12 epimers was not detrimental as epi-merization could be effected in the subsequent elimination step. 

Tone, H, Nishi, T, Oikawa, Y, Hikota, M, Yonemitsu, O, A stereoselective total synthesis of (9S)-9-dihydroerythronolide A from D-glucose, Tetrahedron Lett., 28, 4569-4572, 1987. 

A more complex hydroxy acid is lactonized in a synthesis of (9S)-9-dihydroerythronolide A, albeit in low yield (equation 128). By acid treatment (356) is deprotected to give the desired target molecule. The presence of jp -centers in the seco-acid obviously facilitates lactonization, as shown by the preparation of the mycinolide V precursor (357 equation 129). A mixed carbonate is used in the synthesis of the tylonolide precursor (358 equation 130). ° In general, DMAP catalysis is helpful in the ring closing step in most cases. 

Kinoshita s erythronolide synthesis is based on the preparation of (9S)-9-dihydroerythronolide A (76), which is constructed from the three chiral segments, Ci-Cg (69), C7-C9 (70) and C10-C13 (72). 

Compound 89 was converted into 91 through epimerization at C5 of the ketone 90. The aldehyde 93 reacted with the lithium enolate of ethyl trityl ketone to give the desired aldol 94 as a sole product, which was converted into the (R)-sulfoxide 95 through the epimerization of the (S)-sulfoxide. The lithiated 95 was added to the ketone 91, followed by desulfurization and desilylation, to give the adduct 96. The seco-acid derived from 96 was cyclized by Corey s method followed by deprotection to give (9S)-9-dihydroerythronolide B, which was converted to erythronolide B (55) after 3,5-0-benzylidenation, oxidation and debenzylidenation. 

---