The Kinetics of 20-Keto Reduction in 11α-Acetoxypregnane-3,20-dione by Sodium Borohydride

Garrett, Edward R.; Lyttle, Douglas A.

doi:10.1021/ja01119a515

Cited by 27 publications

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“…The kinetics of reduction of ketones by sodium borohydride are known to be second order, first order in both ketone and borohydride (1)(2)(3)7). This observation led Garrett and Lyttle (I) to propose the stepwise (nondisproportionation) mechanism, in which transfer of the first hydride is rate determining.…”

Section: T/7e Existing Evidencementioning

confidence: 99%

Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Wigfield¹,

Gowland²

1978

Can. J. Chem.

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/t,retr/ oJ'Clret~~i.s/ry, Cnr.le/otr U t r i~~e~. s i / )~, Ottcrn,tr, Otr/. , Cntrcrtltr KIS 586 Received Septernbe1.26, 1977 DONALD C. WIGFIELD and FREDERICK W. GOWLAND. Can. J. Chem. 56,786(1978).Examination of unreacted sodium borohydride after reduction of ketones by mixtures of NaBH, and NaBD, shows that it is still isotopically pure and that no detectable species NaBH,D,-, have been formed. Disproportionation of intermediates back to NaBH, therefore plays no significant role in the reduction. DONALD C. WIGFIELD et FREDERICK W. GOWLAND. Can. J. Chem. 56,786 (1978).Un examen du borohydrure de sodium qui n'a pas reagit lors de la reduction de cetones par des melanges de NaBH, et de NaBD, indique que ce dernier est encore isotopiquement pur et I'on n'a pas detecte la formation d'entites NaBH,,D,-,,. La dismutation d'intermtdiaires pour reconduire a NaBH, ne joue donc aucun r61e important.[Traduit par le journal] Little is known about the mechanism of borohydride reductions of ketones. Three major questions, of increasing level of molecular detail, exist. Firstly, given the 4:l stoichion~etry, what are the structures of the reducing agents for reduction of each of the four ketone molecules? Secondly, given the structure of the reducing agent(s), what is the mechanism of reduction: is it cyclic or acyclic; does it differ for each reducing species; what role, if any, d o the metal cation and the solvent play? Thirdly, given the reducing agent and the mechanism for each reducing species, where on the reaction coordinate d o the transition states occur: are they reactant-like, product-like, or somewhere in between? Finally, if one knew the answers to the above questions, presumably the problem of understanding the striking stereoselectivity of the reactions could at least be approached on a rational basis.With several notable exceptions (see for example refs. 1-3), investigations in this area seem to be a persistent case of the cart before the horse. Speculations concerning the cause of stereoselectivity have been discussed for over twenty years. Speculators d o not seem to have been greatly troubled by the almost total lack of knowledge of the reaction mechanism. Similarly, a good deal of effort has been expended to define the degree of hydride transfer in the transition state but the answer to this question is still unsettled. In contrast, little attention has been paid to the first two, rather more fundamental, questions posed above. The questions are not intangible and this communication is aiined a t the first of these: what is(are) the structure(s) of the reducing agent(s)? Results and Discussion The ProbletnAll four hydrides of sodium borohydride are available for reduction of simple ketones.' While there is not much doubt that the reduction is initiated by reaction of NaBH, itself with a molecule of ketone, considerable uncertainty exists about what happens then. We have recently shown that the hydroxylic solvent plays a crucial role in this first step (5, 6) and it may therefore be represented as ...

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Section: T/7e Existing Evidencementioning

confidence: 99%

Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Wigfield¹,

Gowland²

1978

Can. J. Chem.

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“…Despite the existence of kinetic approaches to quantifying steric hindrance in the reduction of carbonyls [20][21][22][23], diastereoselectivity, which is the reaction selectivity at the same reaction point in the same molecule as those in Cram's method [4], was used as the target system in this study. In contrast to the method for determining the reaction rate between substrates, the diastereoselectivity method, which re ected the reaction rate at the same reaction point, was considered to be more capable of eliminating electronic factors at the reaction point.…”

Section: Introductionmentioning

confidence: 99%

Quantification of steric hindrance by geometric calculation, prediction of the reductive selectivity of ketones, and clarification of reaction mechanism

Sakaguchi

Gotoh

2022

Preprint

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Stereoisomers often have different physiological characteristics, and stereocontrol , which includes diastereoselective reduction of carbonyls, is important in the synthesis of pharmaceuticals and natural products. Here, we have developed a model that offers features that have been difficult to achieve simultaneously using conventional methods: reflective of the experimental values of selectivity, applicable to both chained and cyclic ketones, and can quantitatively predict diastereoreductive selectivity. The method, named Moving Sphere Model (MSM), predicts diastereoreductive selectivity by quantifying steric hindrance by the overlapping volume of ketone substrate atoms and a virtual sphere moving in both reaction directions. The reaction mechanism was predicted by examining how the consistency between the calculated selectivity by MSM and the experimental values of selectivity changes when the values of the radius r of the virtual sphere and reaction direction θ are changed. Thus, a reaction mechanism in which only hydride contributes to steric hindrance was inferred for the reduction of ketones by NaBH4 in MeOH solvent. Meanwhile, for the reduction of ketones with NaBH4 in iPrOH solvent, a reaction mechanism in which the solvent introduced to the reducing agent also contributes to steric hindrance was inferred. The MSM enabled us to calculate the angle of nucleophilic attack to carbonyls based on experimental facts, to infer the reaction mechanism of the reduction of ketones with NaBH4 in alcohol solvents, and to predict the reduction selectivity of ketones with NaBH4 in MeOH solvents.

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“…Since the report of their first reduction reaction, several mechanistic studies have appeared, but the intimate molecular details remain uncertain. The complexity of the problem arises from the availability of four hydride sites, all of which ultimately react, though there is general agreement that the rate determining step (RDS) is the transfer of the first hydride . Kinetic studies of cyclic ketone reductions by NaBH 4 concluded that the rate law was first order with respect to both ketone and borohydride in an aprotic solvent.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic investigations in α‐hydroxycarbonyls reduction by BH₄^‐

Marincean

Fritz

Scamp

et al. 2012

J of Physical Organic Chem

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BH4‐, a well‐known and widely used reducing agent for carbonyl compounds, has been reported to have the ability to participate in dihydrogen bonding, an interaction with applications in catalysis, stereoselectivity and crystal engineering. Specifically, α‐hydroxycarbonyls are activated for reduction by dihydrogen bonding that occurs between BH4‐ and hydroxyl group. We explored the effect of the interaction on the mechanism of these reactions by examining their activation parameters. We found that dihydrogen bonding activates α‐hydroxycyclopentanone for reduction with NBu4BH4 by lowering the activation enthalpy by 6.6 kcal/mol. While the activation entropy is a significant component of the barrier, the changes resulting from the occurrence of dihydrogen bonding are manifested predominantly in the enthalpy term. Computational studies suggest that, while internal hydrogen bonding is allowed by the flexibility of the carbon backbone, that interaction is outweighed by dihydrogen bonding once BH4‐ is present in the system. Experimentally, a red shift of the hydroxyl frequency is observed upon addition of BH4‐ to the reaction mixture, suggesting a dihydrogen bonding interaction. The flexibility of the substrate's skeleton or the selectivity of the hydride sites in BH4‐ does not account for the lack of directing effect of the dihydrogen bonding. When a substrate with a rigid naphthalene backbone moiety, 2‐hydroxyacenaphthylen‐1(2H)‐one, is reduced, the stereochemical outcome is very similar to the one corresponding to the α‐hydroxycyclopentanone. Copyright © 2012 John Wiley & Sons, Ltd.

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The Kinetics of 20-Keto Reduction in 11α-Acetoxypregnane-3,20-dione by Sodium Borohydride

Cited by 27 publications

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Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Quantification of steric hindrance by geometric calculation, prediction of the reductive selectivity of ketones, and clarification of reaction mechanism

Mechanistic investigations in α‐hydroxycarbonyls reduction by BH₄^‐

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The Kinetics of 20-Keto Reduction in 11α-Acetoxypregnane-3,20-dione by Sodium Borohydride

Cited by 27 publications

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Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Mechanism of borohydride reductions. Evidence for lack of disproportionation in the reduction of ketones

Quantification of steric hindrance by geometric calculation, prediction of the reductive selectivity of ketones, and clarification of reaction mechanism

Mechanistic investigations in α‐hydroxycarbonyls reduction by BH4‐

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Mechanistic investigations in α‐hydroxycarbonyls reduction by BH₄^‐