Erythronolides aldehydes

The best conditions for the a-regioselective coupling of a chiral, highly substituted, lithiated allyl sulfide to a chiral aldehyde were carefully worked out for the key step in an erythronolide B total synthesis108. 

The combination of the (S)-enolate 2 with aldehyde 1 is one of the key steps in the syntheses of the macrolide aglycone 6-deoxy-erythronolide B131 and tylonolidc16. 

The next step to erythronolide A is the coupling of fragments A and B. Asymmetric aldol reaction of aldehyde 2 with a lithium enolate generated from... 

The C27-C35 segment 238 was prepared from 32 (O Scheme 30), which is the synthetic intermediate of erythronolide A. Oxidative cleavage of 32 gave aldehyde 251, which was subjected to aldol reaction with TBDMS-enol ether and TiCl4 to provide 252. Hydrolysis of thioester and deacetalization with TFA were accompanied by furanose-to-p)ranose interconversion and... 

Development of a novel route to the C-7 to C-13 portion e.g. 122) of erythronolides A and B (i.e. 121a and 121b) by Burke makes use of a stereoselective addition of an isopropenyllithium-derived cuprate to homochiral aldehyde (123) as a first, key step (Scheme 20). Formation of allylic alcohol (124) as the major product presumably reflects a 3 chelation controlled pathway vide supra) Subsequent handling of (124), which included as the second critical step a dioxanone to dihydropyran enolate Claisen rearrangement, produces three key subunits, including (122). 

Stereoselective addition of a dithiane anion to chiral 2-methyl-3-trimethylsilyl-3-buterud combined with the stereoselective addition of a Grignard reagent to the chi a-alkoxy ketone affords a practical method for the construction of a,y-dimethyl-a,3-dihydroxy compounds, useful intermediates for the synthesis of erythronolides (Scheme 33). -Hydroxy cartmxylic esters were synthesized by the addition of ethyl l,3-dithiolanyl-2-carboxylate enolate to a chiral aldehyde, followed by desulfurization. ... 

In a synthetic effort directed toward a segment of erythronolide A, the addition of (2) to aldehyde (22) gave, after treatment with MeMgBr/CuI, an approximately 80 20 mixture of ring-opened products (23) and (24 equation ll). Interestingly, direct alkylation of this aldehyde (as a mixture of double bond isomers) with ethyllithium gave an 18 82 mixture of adducts. The factors responsible for the complementary face selectivity shown by (2) versus ethyllithium are unclear. Comparisons are particularly difficult due to the fact that most organolithium additions to carbonyl compounds are irreversible, kinetically controlled processes, whereas reactions of (2) can be reversible. 

As with all reactions with phosphonates, these conditions are sensitive to the steric environment of the carbonyl and phosphonate. In a reaction directed at intermediates for synthesis of the erythronolides, Paterson and cowoilcers found that the unsubstituted phosphonate (188) added in 82% yield in the presence of molecular sieves (equation 48). When R was methyl the reaction failed with DBU because of competitive elimination of OSiMe2Bu. Model studies with the phosphonate and isopropyl aldehyde were successful, providing the alkene in 78% yield in an ratio of 8 1. The Roush-Masamune... 

Danishefsky, S., Larson, E., Askin, D., Kato, N. On the scope, mechanism and stereochemistry of the Lewis acid catalyzed cyclocondensation of activated dienes with aldehydes an application to the erythronolide problem. J. Am. Chem. Soc. 1985, 107, 1246-1255. 

A unique approach to the stereochemical complexities of erythronolide A was developed by Deslongchamps as outlined in Scheme 2,19. The methyl ester of erythronolide A seco acid (212) was dehydrated to form the cyclic ketal 213. A multistep oxidation of the side chain then gave aldehyde 214 which, when condensed with the zirconium enolate of methyl propionate, afforded a 10 1 ratio of aldol diastereomers, the major being 213. Furthermore, aldehyde 214 could easily be converted into the y-lactone 215. 

The conversion of 235 to erythronolide A is still under investigation but will most probably involve the protection of the C-9 carbonyl, oxidation of the olefin to the aldehyde, and thiopropionate aldol reaction (a la Woodward). 

Reagent (27) has been used in a synthesis of the C-l,C-7 segment of erythronolide A, as shown in equation (108).144 Addition of the lithium enolate of (27) to chiral aldehyde (165) provides aldols (166) and (167) in a ratio of approximately 6 1. [The initial report that this aldol reaction gives a stereoisomer ratio of approximately 15 1 was subsequently found to be in error (ref. 144b).]... 

The other aspect of the aldol condensation to be considered in using this reaction for the construction of compounds such as erythronolide-A is diastereoface selection. That is, in many cases one will want to carry out aldol condensations on aldehydes already having one or more chiral centers. The carbonyl faces in these molecules are diastereotopic, rather than enantiotopic, and there... 

Martin used a tin-coupling reaction in a synthesis of erythronolide A.302 Keto-aldehyde 463 reacted with the crotyltin compound shown, in the presence of BF3 to give a 66% yield of the syn-diastereomer (464), along with 16% of the anti-diastereomer. 

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. 

During a synthesis of erythronolide A, carried out by our group at Marburg, we needed the chiral aldehyde 35 as starting material. Perusal of the list of commercially available chiral starting materials [13] suggested a synthesis of lactone 36 from D-fructose (Scheme 4.8). With this in mind, aldehyde 35 was prepared from fructose in eight steps [16]. 

In anticipation of the final carbon-carbon bond construction that is required to prepare the intact seco acid of erythronolide B using a directed aldol reaction to form the C(10)-C(l 1) bond, it was first necessary to prepare the requisite chiral aldehyde 80. Although the synthesis of 80 had been previously reported, we elected to devise an alternative route to access this material that commenced with the addition of the chiral boron enolate 37 0 to propionaldehyde to furnish 81 (Scheme 12). The sequential protection of the secondary hydroxyl group and removal of the chiral auxiliary gave 82, which was then converted to 80 by over-reduction followed by reoxidation under Swem conditions. 

Upon examination of the reactions outlined in Schemes 9, 11, and 12, it is evident that the present route to the seco acid of erythronolide B is remarkably concise, involving a longest linear sequence of a mere 14 chemical operations from the commercially available 2-ethylfuran (64). Even counting the steps required for the preparation of the aldehyde 80, the total number of operations is only 19. We anticipate that the analogous aldol reaction of the enolate derived from 79 with the... 

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