Metalated Nitriles:  Chelation-Controlled Cyclizations to <i>cis</i> and <i>trans</i> Hydrindanes and Decalins

Fleming, Fraser F.; Vu, Viet Anh; Shook, Brian C.; Rahman, Moshfiqur; Steward, Omar W.

doi:10.1021/jo062270r

Cited by 22 publications

(15 citation statements)

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“…Cyclizations of β-hydroxy nitriles have exploited this strategy by forming internally chelated nitrile anions that selectively cyclize to trans - and cis -decalins depending on the stereochemistry of the adjacent hydroxyl-bearing carbon (Scheme 3). 22 Simply deprotonating the β-hydroxy nitrile 11 at low temperatures and warming, triggers a facile, completely stereoselective cyclization to the trans -decalin 13 whereas the diastereomeric β-hydroxy nitrile 14 cyclizes to the cis -decalin 16 under identical conditions. The divergent stereoselectivity is consistent with cyclization through internal chelates simplistically viewed as pyramidal, nitrile anions 12 and 15 .…”

Section: 1 Introductionmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cisfused hydrindanes, decalins, and bicyclo [5.4.0] undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis-and transhydrindanes, decalins, and [5. 4. 0] undecanes, and reveals the key geometric requirements for intramolecular S N 2 and S N 2′ displacements. IntroductionMetalated nitriles are nucleophilic chameleons, readily adapting to the local environment by adopting different structures. 2 X-ray crystallographic analyses of metalated nitriles 3 show two main structural classes: N-metalated nitriles in which the metal coordinates to the nitrile nitrogen, 4 and C-metalated nitriles 5 in which the metal is bound to the formally anionic carbon (Figure 1, 1 and 2, respectively). Crystallographically derived bond lengths for N-and Cmetalated nitriles reveal only a slight weakening of the C≡N triple bond (1.15-1.20 Å), relative to the C≡N bond length of neutral nitriles (1.14 Å), 6 indicative of a predominant inductive stabilization 7 of the negative electron density. Consistent with the inductive stabilization are short C-CN bonds 8 stemming from an electrostatic contraction between the formal anion and the powerful electron-withdrawing nitrile group. 9 Moderating the ligand or metal environment exerts a pronounced influence on the site of coordination in metalated nitriles. The solid-state N-and C-palladated nitriles 1 and 2 10 differ rather modestly in their structural features, essentially in the nature of the phosphine ligand, but exhibit completely different coordination modes to the same nitrile! 7 Li NMR reveals basically the same structural trends for metalated nitriles in solution; a preference for N-or C-metalation that depends intimately on ligand and solvent, 11 and minimal delocalization of the anion into the carbon-nitrogen triple bond. 9 Differences in the site of metal coordination relay into different reactivity modes for N-and C-metalated nitriles. For example, reductive elimination from the N-palladated nitrile 1 is ten Correspondence to: Fraser F. Fleming. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers th...

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Section: 1 Introductionmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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“…Similarly, utilization of cyclopentanone 176 with ketone 177 led to formation of hydrindene 178 in 78% [102]. Other examples have appeared in the literature [103][104][105][106]. In a similar vein as the Michael additions, the Morita-Bayliss-Hillman under phosphine or transition metal catalysis has been shown to provide similar results to Michael addition strategies (see Scheme 26).…”

Section: Cyclization Strategies To Hydrindane Coresmentioning

confidence: 80%

“…Similarly, utilization of cyclopentanone 176 with ketone 177 led to formation of hydrindene 178 in 78% [102]. Other examples have appeared in the literature [103][104][105][106].…”

Section: Cyclization Strategies To Hydrindane Coresmentioning

confidence: 95%

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

Eddy

Ichalkaranje

2016

Molecules

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Abstract:The bicyclo[4.3.0]nonane scaffold, commonly known as a hydrindane, is a common structural motif found in many terpenoid structures and one that remains a challenge for synthetic chemists to elaborate with appropriate regio-and stereo-selectivity. Over the course of the study of terpene natural products, the elaboration of the hydrindane structure has seen progress on the utilization of both old and newer methods to achieve the desired outcomes. This review seeks to serve as a general overview of these methods, and detail specific examples.

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“…The strategy was based on the highly selective alkylations of cyclic nitrile anions in which the anion geometry is enforced by internal complexation. [34] Experimentally, sequentially deprotonating the hydroxy nitriles 30 and 31 [35] with excess LDA, followed by addition of methyl iodide installs the quaternary center with a modest preference for 34a and 35a. [36] The diastereoselectivity is consistent with preferential alkylation from the nitrile anions 32Ј and 33Ј in which the alkoxy lithium is complexed to the nitrile [37] π-electrons with an additional lithium-π interaction with the benzene ring [38] (Scheme 7).…”

Section: Third Generationmentioning

confidence: 99%

Metalated Nitriles: Internal 1,3‐Asymmetric Induction

Fleming

Liu

2009

Eur J Org Chem

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Stereoselective alkylations of acyclic, metalated nitriles are intimately controlled by a remote stereocenter. Probing the optimal steric demand through alkylations with a series of substituted pentanenitriles reveal the fundamental requirements for 1,3-asymmetric induction. Relaying these requirements into a predictive model suggests that the stereoselectivity arises from a preferential electrophilic attack on the more stable diamond lattice conformation of the metalated nitrile. Using this strategy a series of metalated alkanenitriles 1.IntroductionConformational control is a central prerequisite for stereoselective asymmetric synthesis.[1] A time-proven stereocontrol strategy, whose origin is often equated with the beginning of stereoselective synthesis, [2] is to employ conformationally constrained cyclic enolates that bias electrophile trajectories.[3] Underpinning stereoselective transformations within carbocycles is the ability to accurately predict the reactive conformation, a concept whose seminal importance was recognized in the 1969 Nobel Prize for "The Principles of Conformational Analysis." [4] The conformational bias in six-membered rings usually rests on a preference for avoiding steric compression. 1,3-Diaxial interactions, [5] the steric compression between two axial substituents on a cyclohexane ring, is essentially the cyclic equivalent of the destabilizing syn-pentane interaction encountered in linear hydrocarbons (Figure 1, compare 1 and 2). The centrality of the syn-pentane interaction is readily appreciated by imposing the carbon backbone of pentane onto a diamond lattice, a carbon scaffold in which the dihedral angles around carbon-carbon bonds are assumed to approximate the ideal found in diamond. Overlaying conformationally mobile chains onto a diamond lattice provides a valuable concept for readily identifying the lowenergy conformations of acyclic chains without recourse to computational methods. Seminal advances in acyclic conformational analysis reveal how substituents on flexible hydrocarbon chains can favor surprisingly few well-defined conformations.[7] For example, the syn-2,4-dimethylpentane motif, 3 (Figure 2), has facile rotation around the two core bonds but exhibits a strong substituent-dependent preference for one of two conformations 3Ј or 3ЈЈЈ to avoid conformations with syn-pentane interactions (3ЈЈ or 3ЈЈЈЈ).[8] The preference for conformer 3Ј or 3ЈЈЈ depends on the relative steric demand of the substituents R 1 , R 2 , and Me. Although a precise measure of the interactions between these substituents and the syn-axial-like methine proton (see symbols in Figure 2) is compromised by the facile relaxation of substituents away from a perfect diamond lattice conformation, the steric interactions approximate the corresponding A values determined for substituted cyclohexanes (Figure 1). [9] Numerous natural products incorporate the 2,4-dimethylpentane structural motif leading to one favored solution conformation.[7b] For example, in solution the nitrile-containing natural pr...

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Metalated Nitriles: Chelation-Controlled Cyclizations to cis and trans Hydrindanes and Decalins

Cited by 22 publications

References 63 publications

Metalated nitriles: stereodivergent cation-controlled cyclizations

Metalated nitriles: stereodivergent cation-controlled cyclizations

Methodology for the Construction of the Bicyclo[4.3.0]nonane Core

Metalated Nitriles: Internal 1,3‐Asymmetric Induction

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