Stereoinvertive Nucleophilic Substitution at Quaternary Carbon Stereocenters of Cyclopropyl Ketones and Ethers

Chen, Xu; Marek, Ilan

doi:10.1002/ange.202203673

Cited by 4 publications

(2 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is what was observed for 2b (Figure 1A). Similarly, during the preparation of this manuscript, Marek reported similar reactions involving CPC cations [40][41][42] and showed that phenyl-containing substrates, when reacted with highly nucleophilic trialkylaluminum compounds at lower temperatures, provide the homoallyl products without any epimerization. 40 This supports our conclusion of a CPC/homoallyl kinetic competition as the driver of the selectivity.…”

Section: Figure 1 Free Energies In Kcal/molmentioning

confidence: 75%

Cyclopropylcarbinyl-to-homoallyl carbocation equilibria influence the stereospecificity in the nucleophilic substitution of cyclopropylcarbinols

Larmore

Champagne

2023

Preprint

View full text Add to dashboard Cite

The synthesis of quaternary homoallylic halides and trichloroacetates from cyclopropylcarbinols, as reported by Marek in 2020 (J. Am. Chem. Soc. 2020, 142, 5543-5548), is one of the few reported examples of stereospecific nucleophilic substitution involving chiral bridged carbocations. However, for the phenyl-substituted substrates the stereoselectivity of the reaction is poor and a mixture of diastereomers is obtained. In order to understand the nature of the intermediates involved in this transformation and explain the loss of selectivity for certain substrates, we have performed a Density Functional Theory investigation of the reaction mechanism at the DLPNO-CCSD(T)/Def2TZVPP level of theory. Our results indicate that cyclopropylcarbinyl cations are stable intermediates in this reaction, while bicyclobutonium structures are high-energy transition structures and as such are not involved, regardless of the substitution pattern on the substrate. Instead, multiple rearrangement pathways of cyclopropylcarbinyl cations have been located, including rotations around their π-bonds and ring openings to homoallylic cations. Importantly, the relative energies of these homoallylic cations and of the activation barriers to reach them are correlated to the nature of the substituents. While direct nucleophilic attack on the chiral cyclopropylcarbinyl cation is kinetically favored for most systems, the rearrangements become competitive with nucleophilic attack for the phenyl-substituted systems, leading to a loss of selectivity through a mixture of rearranged carbocation intermediates. As such, it appears that stereospecific reactions of chiral cyclopropylcarbinyl cations depend on the ability of these cations to access homoallylic structures, from which selectivity is not guaranteed.

show abstract

Section: Figure 1 Free Energies In Kcal/molmentioning

confidence: 75%

Cyclopropylcarbinyl-to-homoallyl carbocation equilibria influence the stereospecificity in the nucleophilic substitution of cyclopropylcarbinols

Larmore

Champagne

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…For instance, Feringa, Houk and Fujita reported in 2018 that cycloheptenyl bromide III undergoes an enantiospecific rearrangement to its cyclohexenyl derivative IV under Lewis acid catalysis, a process that involves CPC cation V. 44 Similarly, Marek has published a series of reports starting in 2020, discussing how cyclopropylcarbinols VI form homoallylic products VII with high diastereoselectivity, as long as no aromatic substituent is located at the R 3 or R 4 positions. [45][46][47][48][49][50] Our group studied this system computationally and showed that CPC intermediate VIII is responsible for the observed selectivity. 51 This cation only rearranges faster than nucleophilic trapping when R 3 is an aryl substituent, which enables a classical homoallylic cation to intervene, leading to reduced specificity.…”

mentioning

confidence: 99%

Substituent effects on the equilibria between cyclopropylcarbinyl, bicyclobutonium, homoallyl, and cyclobutyl cations

Larmore,

Champagne

2023

Preprint

View full text Add to dashboard Cite

The cyclopropylcarbinyl (CPC) and bicyclobutonium (BCB) structures of the C4H7+ cation have been proposed as intermediates in various synthetic transformations forming cyclopropylcarbinyl, cyclobutyl, or homoallyl products. It has recently been recognized that such cations, when generated from chiral electrophiles, are themselves chiral and can react with nucleophiles stereospecifically. However, the CPC and BCB cations are in equilibrium with each other and with other related structures such as the cyclobutyl (CB) and homoallyl (HA) cations, from which stereospecificity is not guaranteed. Currently, the effect of substitution on the composition of cation mixtures containing CPC/BCB/CB/HA cations is not understood, precluding the prediction and control of the major products generated from such cations. Using Density Functional Theory and DLPNO-CCSD(T) calculations, we have studied the electronic and steric effects on the equilibria between mono- and polysubstituted C4H7+ cations. Our results indicate that electron-donating groups at the C1 position favor CPC structures, while BCB/CB structures are favored for the C2 position and HA structures for the C3/C4 positions. Electron-withdrawing groups yield shallower potential energy surfaces where many related structures are energetically accessible. Strong Hammett correlations (σ+) are observed for the various substituent effects, which appear to be additive in nature. In addition, BCB cations with more substituents are energetically destabilized compared to CPC cations, except with donating substituents at the C2 position. This work provides a predictive model for the major structures observed in mixtures of CPC/BCB/CB/HA cations, for given substituent patterns.

show abstract

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters

2022

View full text Add to dashboard Cite

An efficient method for the stereoselective construction of tertiary CÀ O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.

show abstract

Stereoinvertive Nucleophilic Substitution at Quaternary Carbon Stereocenters of Cyclopropyl Ketones and Ethers

Cited by 4 publications

References 104 publications

Cyclopropylcarbinyl-to-homoallyl carbocation equilibria influence the stereospecificity in the nucleophilic substitution of cyclopropylcarbinols

Cyclopropylcarbinyl-to-homoallyl carbocation equilibria influence the stereospecificity in the nucleophilic substitution of cyclopropylcarbinols

Substituent effects on the equilibria between cyclopropylcarbinyl, bicyclobutonium, homoallyl, and cyclobutyl cations

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters

Contact Info

Product

Resources

About