Total synthesis of the polyether antibiotic ionomycin

Evans, David A.; Dow, Robert L.; Shih, Thomas L.; Takacs, James M.; Zahler, Robert

doi:10.1021/ja00169a042

Cited by 239 publications

(97 citation statements)

References 6 publications

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“…Another earlier asymmetric route to reduced polypropionates involved diastereoselective conversion of chirons derived from natural sources (8). However, the methods most frequently used now involve either ␣-alkylation of chiral enolates (2,(9)(10)(11)(12) and related nucleophiles (13) or conjugate addition to chiral ␣,␤-unsaturated carboxamides (14,15). Despite the fact that these methods require at least one, and often more than one, equivalent of chiral reagents, some of them, in particular the protocol of Myers et al (11,12), may be viewed as the current benchmarks.…”

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confidence: 99%

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Negishi

Tan²,

Liang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

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An efficient and general method for the synthesis of reduced polypropionates has been developed through the application of asymmetric carboalumination of alkenes catalyzed by dichlorobis(1-neomenthylindenyl)zirconium [(NMI) 2ZrCl2]. In this investigation, attention has been focused on those reduced polypropionates that are ␣-monoheterofunctional and either -ethyl or -n-propyl. The reaction of 3-buten-1-ol with triethylaluminum (Et 3 Al) or tripropylaluminum ( n Pr3Al) in the presence of (NMI)2ZrCl2 and isobutylaluminoxane gave, after protonolysis, (R)-3-methyl-1-pentanol as well as (R)-and (S)-3-methyl-1-hexanols in 88 -92% yield in 90 -92% enantiomeric excess in one step. These 3-monomethyl-1-alkanols were then converted to two stereoisomers each of 2,4-dimethyl-1-hexanols and 2,4-dimethyl-1-heptanols via methylalumination catalyzed by (NMI) 2ZrCl2 and methylaluminoxane followed by oxidation with O 2. The four-step (or three-isolation-step) protocol provided syn-2,4-dimethyl-1-alkanols of >98% stereoisomeric purity in Ϸ50% overall yields, whereas (2S,4R)-2,4-dimethyl-1-hexanol of comparable purity was obtained in 40% overall yield. Commercial availability of (S)-2-methyl-1-butanol as a relatively inexpensive material suggested its use in the synthesis of (2S,4S)-and (2R,4S)-2,4-dimethyl-1-hexanols via a three-step protocol consisting of (i) iodination, (ii) zincation followed by Pd-catalyzed vinylation, and (iii) Zr-catalyzed methylalumination followed by oxidation with O 2. This three-step protocol is iterative and applicable to the synthesis of reduced polypropionates containing three or more branching methyl groups, rendering this method for the synthesis of reduced polypropionates generally applicable. Its synthetic utility has been demonstrated by preparing the side chain of zaragozic acid A and the C11-C20 fragment of antibiotics TMC-151 A-F. O ligo-and poly(alkene)s with methyl groups bonded to alternating carbon atoms in the main chain (compound 1 in Fig. 1) are important structural units in both polymer materials chemistry (1) and natural products chemistry. The latter includes those reduced polypropionates that contain (i) two methylbranched asymmetric carbon centers, such as zaragozic acid A (compound 2 in Fig. 1) (2), and (ii) three methyl-branched asymmetric carbon centers, such as antibiotics TMC-151 A-F (compound 3 in Fig. 1) (3). The degree of polymerization of poly(propylene) usually exceeds 10 3 . As a consequence, most of the methyl-branched carbon centers may be considered to be ''virtually achiral,'' rendering their absolute configuration practically insignificant. On the other hand, their relative stereochemistry, termed tacticity, is of crucial importance in various respects. In the cases of reduced polypropionates, where the degree of polymerization is mostly Ͻ10, typically 2-4, both absolute and relative configurations of compound 1 (Fig. 1) are critically important. It is therefore essential to construct each methyl-bearing asymmetric carbon center with the correct absolute configurati...

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mentioning

confidence: 99%

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Negishi

Tan²,

Liang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

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“…However, methyltriphenoxyphosphonium iodide gave rise to allylic iodide 14 in good yield. 19,20 Since the double bond of 14 can undergo isomerization during flash chromatography, iodide 14 was used crude for the subsequent alkylation of propionyloxazolidinone 21 15. Using standard conditions, that is deprotonation of 15 with NaN(SiMe 3 ) 2 in THF followed by addition of iodide 14 furnished compound 16 in 71% yield based on alcohol 13.…”

Section: Resultsmentioning

confidence: 99%

Concise route to defined stereoisomers of the hydroxy acid of the chondramides

2008

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The use of Kobayashi vinylogous aldol reaction in the reaction with acetaldehyde led to anti-aldol product 11. After reductive removal of the chiral auxiliary, the primary alcohol was converted to the allyliodide 14. This compound could be engaged in an Evans alkylation reaction, leading eventually to hydroxy acid 19. Inclusion of a Mitsunobu inversion reaction on the sequence starting with ent-11 led to hydroxy ester 30, featuring a 6,7-syn-configuration. These hydroxy acids should help to elucidate the correct stereostructure of the chondramide depsipeptides.

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“…This character, especially its high affinity for Ca 2+ ions, has made it an important molecule in neurochemistry research. 4 Three total syntheses of ionomycin have been published; Evans (1990), 5 Hanessian (1990) 6 and Lautens (2002), 7 each with different strategies for the synthesis of the anti, anti, anti dipropionate fragment (boxed in Fig. 4).…”

Section: Introductionmentioning

confidence: 99%

“…Evans et al published the total synthesis of ionomycin also in 1990, 5 based on the chiral auxiliary strategy (oxazolidinone) for creating the first asymmetric centers (Scheme 2). Aldol addition of the boryl enolate derived from crotonimide 14 with aldehyde 15 provided the crystalline syn, a-vinyl adduct 16.…”

Section: Introductionmentioning

confidence: 99%

Polyketide stereotetrads in natural products

Koskinen¹,

Karisalmi²

2005

Chem. Soc. Rev.

128

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Natural products (or secondary metabolites) remain as the most important source for discovery of new and potential drug molecules. With high resolution data of their structures, and the advancement of synthesis possibilities, analysis of the natural products based on their specific structural features is valuable to those entering the field. In this tutorial review we attempt such an analysis indicating the salient features of the structural classes with examples of the synthesis of each one of them. As the particular class of natural products, we have chosen polyketides.

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Total synthesis of the polyether antibiotic ionomycin

Cited by 239 publications

References 6 publications

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

Concise route to defined stereoisomers of the hydroxy acid of the chondramides

Polyketide stereotetrads in natural products

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