Total synthesis of both (+)-compactin and (+)-mevinolin.  A general strategy based on the use of a special TiCl3/C8K mixture for dicarbonyl coupling

Clive, Derrick L. J.; Murthy, K. S. Keshava; Wee, Andrew G. H.; Prasad, J. Siva; Silva, Gil Valdo José da; Majewski, Marek; Anderson, Paul C.; Haugen, Richard D.; Heerze, Louis D.

doi:10.1021/ja00228a067

Cited by 54 publications

(5 citation statements)

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“…The lactol oxidation using various oxidation methods such as Br 2 /BaCO 3 [103], N -iodosuccinimide [104], Ag 2 CO 3 [105], Pt/C-O 2 [106], RuCl 2 (PPh 3 ) 3 /cyclohexanone [107], MnO 2 [108], or NaOCl/AcOH [60] was described before. Aiming toward a scalable and sustainable process we tested several process options in order to use the whole-cell DERA reaction mixtures in a straightforward manner (Table 2).…”

Section: Resultsmentioning

confidence: 99%

A Highly Productive, Whole-Cell DERA Chemoenzymatic Process for Production of Key Lactonized Side-Chain Intermediates in Statin Synthesis

Ošlaj¹,

Jérôme²,

Orkić³

et al. 2013

PLoS ONE

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Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole-cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2-substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L−1 h−1 (up to 50 g L−1 h−1) with >80% yield and >80% chromatographic purity with titers reaching 100 g L−1. Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins.

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Section: Resultsmentioning

confidence: 99%

A Highly Productive, Whole-Cell DERA Chemoenzymatic Process for Production of Key Lactonized Side-Chain Intermediates in Statin Synthesis

Ošlaj¹,

Jérôme²,

Orkić³

et al. 2013

PLoS ONE

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“…A variety of different ring sizes are obtained by the coupling procedure, illustrating the power and generality of the method. Five-membered rings are formed in the hirsutene (entry 5) and strigol (entry 17) syntheses; six-membered rings are formed in the isokhusimone (entry 4), compactin (entry 18), and estrone (entry 19) syntheses; eight-membered rings are formed in the taxane (entry 13), fusicoccane (entry 15), and ceroplastol (entry 16) syntheses; ten-membered rings are formed in the helminthogermacrene (entry 7), bicyclogermacrene (entry 8), and lepidozene (entry 9) syntheses; an eleven-membered ring is formed in the humulene synthesis (entry 10); a twelve-membered ring is formed in the verticillene (entry 6) synthesis; fourteen-membered rings are formed in the casbene (entry 11), cannithrene II (entry 20), and sarcophytol B (entry 21) syntheses; and a fifteen-membered ring is formed in the flexibilene (entry 12) synthesis.…”

Section: B Synthesis Of Unusual Moleculesmentioning

confidence: 99%

Carbonyl-coupling reactions using low-valent titanium

McMurry¹

1989

Chem. Rev.

1,056

422

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“…8), including the synthesis of olefin, 2 , through the intramolecular coupling reaction of carbonyl substrate, 1 , with the presence of acetal (Table 2). 11 Another unpublished experiment conducted by McMurry and Matz showed that tetrahydropyran ether, 4 , were obtained from the intermolecular coupling of two acetals, 3 . 13 Moreover, Sander and Dehmlow successfully synthesized 1-( cis -4′,5′-dihydroxycycloheptylidene)- cis -4,5-dihydroxycycloheptane, 6 , through McMurry coupling of the cis -4,5-dibenzyloxycycloheptanone compound, 5 .…”

Section: Functional Group Compatibilitiesmentioning

confidence: 99%

“…Various McMurry system, namely TiCl 3 /K, 6,7 TiCl 3 /Li, 7 and TiCl 3 (DME) 1,5 /Zn–Cu 8 were tested to find the best system for preparing the low-valence titanium reagent. Other systems were also tested and reported by another researcher, such as TiCl 4 /Zn/pyridine, 9 TiCl 3 /C 8 K, 10,11 TiCl 4 /C 8 K/pyridine, 10 and TiCl 4 /Mg (Hg)/pyridine. 10 Various uses of organometals other than titanium for carbonyl coupling reactions such as zirconium, hafnium, niobium, tantalum, chromium, molybdenum, tungsten, iron, manganese, rhenium, lanthanide, and actinide groups have also been explored and briefly summarized by Kahn and Rieke.…”

Section: Introductionmentioning

confidence: 99%