Chelation-Controlled Diastereoselective Reduction of α-Fluoroketones

Mohanta, Pramod K.; Davis, Todd A.; Gooch, Jeremy R.; Flowers, Robert A.

doi:10.1021/ja052546x

Cited by 51 publications

(21 citation statements)

References 16 publications

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“…s, 1H), 3.82 (m, 1H), 4.49 (m, 1H); 13C NMR (CDCl3, 75.5 MHz) 16.7, 17.9, 70.9, 94.2. Data is in agreement with literature values …”

Section: Methodssupporting

confidence: 92%

“…Given the ability of fluorine to form hydrogen bonds, perhaps the low selectivity of 1-F is due to chelation control not seen with the other halides. This issue can be addressed directly, as Flowers et al have looked at the reduction of 1-F both with and without chelation control For the latter, they saw little selectivity, consistent with our results. For the former, they found very high anti selectivities, counter to our result.…”

Section: Resultsmentioning

confidence: 99%

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Felkin–Anh is not enough

Rosenberg

Kelly

2014

J of Physical Organic Chem

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The understanding of the electronic effects of the diastereoselective addition of a nucleophile to a polar substituted aldehyde or ketone is not complete, with several theories competing to explain the data. For numerous hydride reductions of 3‐X‐2‐butanones (X = F, Cl, Br), the selectivity for the major syn isomer is significantly and consistently higher for X = Br than for X = F. This result is rationalized as a shift in mechanism from Cornforth (X = F) to Felkin–Anh (X = Br). The experimental data is well modeled by ab initio calculations for the addition to these ketones by BH3, but not by other nucleophiles such as LiH or LiAlH4. The energetic ordering of the BH3 transition states largely follows the trends for the ground state ketones. Here, consistent with electrostatic arguments, the anti orientation of the C―X and CO bonds is always lower in energy than the syn arrangement. The gauche conformer is intermediate between these two, becoming gradually lower in energy as X increases in size. The hyperconjugative interaction invoked by the Felkin–Anh model provides only a modest stabilization of the relevant transition states as judged by NBO analysis. Copyright © 2014 John Wiley & Sons, Ltd.

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“…s, 1H), 3.82 (m, 1H), 4.49 (m, 1H); 13C NMR (CDCl3, 75.5 MHz) 16.7, 17.9, 70.9, 94.2. Data is in agreement with literature values …”

Section: Methodssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Felkin–Anh is not enough

Rosenberg

Kelly

2014

J of Physical Organic Chem

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“… Supplementary Materials: Materials and Methods Figures S1-S18 Tables S1–3 Scheme S1 References (46–60) …”

mentioning

confidence: 99%

Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Walker

Thuronyi

Charkoudian

et al. 2013

Science

179

156

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Organofluorines represent a rapidly expanding proportion of molecules used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems and show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be introduced site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

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“…It cannot be ruled out that the neutral imine is trapped directly, possibly in association with Lewis acids – metals or H-bond donors. 21-24 …”

Section: Discussionmentioning

confidence: 99%

Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the CarcinogenN-Nitrosomorpholine by Inorganic and Biological Reductants

Koissi

Fishbein

2013

Chem. Res. Toxicol.

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3-Hydroperoxy-N-nitrosomorpholine in buffered aqueous media in the presence of calf thymus DNA was treated with a phosphine reductant to generate the transient α-hydroxynitrosamine and subsequent diazonium ion that alkylated the DNA, as previously reported. Subsequent addition of hydride donors, for 30 min, followed by acid hydrolysis of the mixture allowed detection and quantification of 6-(2-(2-((9H-purin-6-yl)amino)ethoxy)ethoxy)-9H-purin-2-amine, the reduced cross-link formed from deposition, via the diazonium ion, of a 3-oxa-pentanal fragment on O6-Gua, and condensation with N6-Ade, presumably in the vicinity. Decreasing temperature of the reactions and decreasing pH modestly increased the yields of trapped crosslink. Among three borohydride reductants, NaNCBH3 is superior, being ∼4 times more effective on a molar basis, as opposed to a hydride equivalent basis, than NaBH4 or Na(AcO)3BH. For trapping with NaNCBH3, it is deduced that the reaction likely occurs with the iminium ion that is in protonic equilibrium with its conjugate base imine. In an experiment in which the hydroperoxide was decomposed and NaNCBH3 was introduced after various times, the amount of cross-link was observed to increase, nearly linearly, by about four-fold over one week. These data indicate that there are a minimum of 2 populations of cross-links, one that forms rapidly, in minutes, and another that grows in with time, over days. Reduced nicotinamide co-factors and ascorbate are observed to effect reduction (over 3 days) of the cross-links confirming the possibility that otherwise reversible cross-links might be immortalized under biological conditions.

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Chelation-Controlled Diastereoselective Reduction of α-Fluoroketones

Cited by 51 publications

References 16 publications

Felkin–Anh is not enough

Felkin–Anh is not enough

Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the CarcinogenN-Nitrosomorpholine by Inorganic and Biological Reductants

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