Synthesis (and Alternative Proof of Configuration) of the Scyphostatin C(1‘)−C(20‘) Trienoyl Fragment

Hoye, Thomas R.; Tennakoon, Manomi A.

doi:10.1021/ol0058386

Cited by 60 publications

(33 citation statements)

References 21 publications

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“…One of the earliest methods for the preparation of terminally differentiated 2,4-dimethyl-1,5-pentane derivatives involves enzyme-catalyzed desymmetrization of 2,4-dimethyl-1,5-pentanediols (5). At the current level of development, however, the method suffers from low overall yields and long procedures for the synthesis of ␣-activated and -protected 2,4-dimethyl-1,5-pentanediols, which reportedly require six to eight steps and lead to 6-8% overall yields from diethyl ␣-methylmalonate and ethyl 2-bromo-2-methylpropionate for preparing the syn-dimethyl isomers (6,7). The preparation of the anti-dimethyl isomers is even less satisfactory, proceeding in seven to eight steps and leading to Ͻ2% overall yields (7).…”

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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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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“…Accordingly, several studies were conducted in the beginning of 2000 to determine the absolute configuration of scyphostatin and to synthesize related inhibitors, with low molecular weight, primarily as molecular tools to investigate the enzymatic mechanism of the various isoforms of sphingomyelinases (Saito et al 2000;Hoye and Tennakoon 2000;Izuhara and Katoh 2001;Runcie and Taylor 2001). It was found that scyphostatin inhibits shear stress-induced but not ceramide-induced activation of Src-like kinase and concomitant tyrosine phosphorylation of plasma membrane protein, thus confirming the hypothesis on the key role of NSMase and its downstream product ceramide in mechanosignaling (Czarny and Schnitzer 2004).…”

Section: Scyphostatinmentioning

confidence: 99%

Fifty years of drug discovery from fungi

2011

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For the past 50 years, fungal secondary metabolites have revolutionized medicine yielding blockbuster drugs and drug leads of enormous therapeutic and agricultural potential. Since the discovery of penicillin, the first β-lactam antibiotic, fungi provided modern medicine with important antibiotics for curing life threatening infectious diseases. A new era in immunopharmacology and organ transplantation began with the discovery of cyclosporine. Other important drugs or products for agriculture derived from or inspired by natural products from fungi include statins, echinocandins and strobilurins. Moreover, fungal biotransformation of steroids for the industrial production of steroidal hormones represents one of the key successes in biotechnology. Given that estimations of fungal biodiversity exceed by far the number of already identified species, chances to find hitherto unidentified fungal species and novel bioactive fungal products are still high. Thus, further compounds with medicinal or agricultural potential from less investigated fungal taxa can be expected in the years to come.

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“…The azide was reduced to the amine that was coupled with 332 (prepared as described by Hoye and Tennakoon [161]) and desilylated to give 351. Bromoetherifica-tion with NBS gave bromide 347, which was debrominated, oxidized and hydrolyzed to yield 348.…”

Section: Syntheses Of Scyphostatinmentioning

confidence: 99%

Enantioselective Synthesis of Natural Epoxyquinoids

Pandolfi

Schapiro²,

Heguaburu³

et al. 2013

COS

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Natural products play an important role as a source not only of potential therapeutic drugs but also of starting materials for semisynthetic new medicines. The epoxyquinoid family, composed by cyclohexane epoxides and related structures, exhibit these characteristics without doubt.Since 2004, significant efforts have been devoted to the stereocontrolled synthesis of these molecules with different and interesting strategies. More than 50 works on this field have been published during this period of time. In addition, many of these polyoxygenated cyclohexenoids exhibit diverse and impressive bioactive shapes. This review aims to analyze the recent advances in the enantioselective processes that have been performed for the total syntheses of these target molecules. It includes a wide range of methodologies for the introduction of chirality either enzymatic or chemical ones. This summarizes microbial preparation of starting materials, lipase kinetic resolutions, use of compounds from the chiral pool, use of chiral auxiliaries and asymmetric catalysis. In a special section, syntheses of scyphostatin are also included.

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Synthesis (and Alternative Proof of Configuration) of the Scyphostatin C(1‘)−C(20‘) Trienoyl Fragment

Cited by 60 publications

References 21 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

Fifty years of drug discovery from fungi

Enantioselective Synthesis of Natural Epoxyquinoids

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