9-dihydroerythronolide

Macrolactonization.1 High dilution is usually essential for macrolactonization, but the 14-membered lactone, 9-dihydroerythronolide A (3), can be obtained in almost quantitative yield by lactonization of the seco-acid 2 via the mixed anhydride formed with 2,4,6-trichlorobenzoyl chloride (1) with triethylamine and 4-dimethyl-... 

Although the majority of sulfides used as precursors to organolithiums have been thioacetals or sulfides bearing other a-substituents, the usefulness even of simple phenylsulfides related to 56 was demonstrated in the synthesis of dihydroerythronolide A by Stork,74 which used a sulfide intermediate 59 in the conversion of an alcohol to a Grignard reagent. 

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. 

Another example which shows how subtle changes in a protecting group can dramatically alter the ground state conformation of a molecule, and hence its reactivity, comes from the synthesis of dihydroerythronolide A by Stork and... 

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. 

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. 

Hoffmann and co-workers demonstrated [242, 2431 the utility of (Z)-211 several times in their synthesis of (95)-dihydroerythronolide A, a known precursor of erythronolide A (Fig. 11-30) [251, 252],... 

Oxidative cleavage of arylmethylene acetals offers another method for the transformation of an arylmethylene acetal to a mono-protected diol. For example, benzylidene acetals of 1,2- and 1,3-diols undergo ozonolytic cleavage rapidly at -78 °C at rates that compete with cleavage of alkenes to give a benzoate ester [Scheme 3.71]. The reaction is not restricted to benzylidene acetals since ethyli-dene and /erf-butylmethylidene acetals also cleave rapidly. The reaction was creatively exploited by Stork and Rychnovsky in the closing stages of their synthesis of dihydroerythronolide A when it was used to unmask a 1,2-diol protected as a 2-methyl-l,3-dioxolane in the presence of a 2-methyl-l,3-dioxane. It is noteworthy that a 1,3-dioxane function cleaved very much slower [Scheme 3.72). 

DCC-DMAP has been used in the synthesis of depsipeptides. Macrocyclic lactones have been prepared by cyclization of hydroxy carboxylic acids with DCC-DMAP. The presence of salts of DMAP, such as its trifluoroacetate, is beneficial in such cyclizations, as shown for the synthesis of a (9. -dihydroerythronolide. Other macrolactonizations have been achieved using 2,4,6-Trichlorobenzoyl Chloride and DMAP in Triethylamine at rt or Di-2-pyridyl Carbonate (6 equiv) with 2 equiv of DMAP at 73 °C. ... 

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). 

Stork s synthesis of dihydroerythronolide A illustrates the usefulness of the butenolide template route to polypropionate sequences. 

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. 

A quick analysis of 9(S)-dihydroerythronolide A 19 shows that 7 of the 11 stereocenters could be created using reagent control of diastereoselectivity by crotylboration reactions. The stereogenic centers at C6 and C12 having a tertiary alcohol function are presently outside the scope of stereoselective crotylboration reactions. Here we have to rely on other methods. For instance, the use of lactic acid enolates developed by Seebach [28] appeared attractive to generate the tertiary centers both at C6 and Cl2. 

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