Cycloisomerization

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Cycloisomerization is any isomerization in which the cyclic isomer of the substrate is produced in the reaction coordinate. The greatest advantage of cycloisomerization reactions is its atom economical nature, by design nothing is wasted, as every atom in the starting material is present in the product. In most cases these reactions are mediated by a transition metal catalyst, in few cases organocatalysts and rarely do they occur under thermal conditions. These cyclizations are able to be performed with excellent levels of selectivity in numerous cases and have transformed cycloisomerization into a powerful tool for unique and complex molecular construction. [1] Cycloisomerization is a very broad topic in organic synthesis and many reactions that would be categorized as such exist. Two basic classes of these reactions are intramolecular Michael addition and Intramolecular Diels–Alder reactions. Under the umbrella of cycloisomerization, enyne and related olefin cycloisomerizations are the most widely used and studied reactions. [2]

Contents

Intramolecular Michael addition

A rather intuitive route to cyclic isomers is the intramolecular conjugate addition to α,β–unsaturated carbonyls (intramolecular Michael addition or IMA). Competent Michael acceptors include conjugated enones, enals or nitroalkene derivatives and examples of other acceptors are sparse. [3] Despite IMA reactions being ubiquitous in synthesis, very few examples of asymmetric IMA transformations exist. [2]

Thiourea catalysts with pendant chiral backbones have shown to activate systems with tethered nitroalkane and ester motifs to induce asymmetric IMA. [3] [4] The utility of this transformation was demonstrated in the synthesis of cyclic γ– amino acid precursors (figure 1). [3] It is proposed that activation occurs via H–bonding of both the nitronate and the ester to the thiourea catalyst and explains the interesting selectivity for the E–ester. [3]

Figure1cycloedit.png

A functional stereodivergent organocatalyzed IMA/lactonization transformation in the synthesis of substituted dihydrofurans and tetrahydrofurans has been studied for its ability to construct important structural motifs in numerous natural products (figure 2). [5] When ethers such as 3 are subject to (S)–(–)–tetramisole hydrochloride (4) catalyst the result is the syn–2,3–substituted THF while the complementary anti–product is easily accessible via a Cinchona alkaloid catalyst such as 7. [5]

Figure2editcycloisom.png

Intramolecular Diels–Alder

Intramolecular Diels–Alder (IMDA) reactions pair tethered dienes and dienophiles in a [4+2] fashion, the most common being terminal substitution. These transformations are popular in total synthesis and have seen a wide spread use in advance to numerous difficult synthetic targets. [6] One such use is the application of an enantioselective IMDA transformation in the asymmetric synthesis of the marine toxin (–)–isopulo’upone (10). [7]

Figure3cyclosiom.png

The synthesis of (–)– isopulo’upone demonstrated the utility of cationic Cu(II)bis(oxazoline) complex catalyzed IMDA reactions to give bicyclic products with as many as four neighboring stereogenic centers (figure 3). [7] A rather recent application of IMDA reactions in complex molecule synthesis is the IMDA approach to the tricyclic core of palhinine lycopodium alkaloids, a class of natural products isolated from nodding club moss. [8]

N–heterocyclic carbenes (NHCs) are an emerging class of organocatalysts that are able to induce Umpolung reactivity as well as normal polarity transformations, however until recently these have not been broadly used in total synthesis due to limited substrate scope. [9] An interesting expansion in the use of these organocatalysts is the NHC catalyzed olefin isomerization/IMDA cascade reaction to give unique bicyclic scaffolds. [10] [11] Dienyl esters such as 11 were transformed into substituted bicyclo[2.2.2]octanes via an isomerization step stabilized by a hemiacetal azolium intermediate (13). [11] The activation barrier of isomerization of 1,3–hexadiene through a [1,5]–shift is 41 Kcal mol–1 and is expected to increase with conjugation to the ester, thus uncatalyzed isomerization is unlikely. [11] This provides the advantage of bypassing a high barrier of activation, providing access to previously unobtainable IMDA derivatives.

Figure4cycloisom.png

Enyne cycloisomerization

Enyne cycloisomerization, an alkyne variant of the Alder-ene reaction (figure 5), is an intramolecular rearrangement of 1,n–enynes to give the corresponding cyclic isomer.

Figure5cycloisom.png

Although the rearrangement may occur under thermal conditions, the scope of the thermal rearrangement is limited due to the requirement of high temperatures, thus transition metals such as Au, Pd, Pt, Rh and Ir are often employed as catalysts. [2] As synthesis quarrels to build complex structural motifs in the presence of inductive, stereoelectronic and steric demands this rearrangement has recently been developed as a robust method for constructing carbo– and heterocyclic scaffolds with excellent chemo–, regio– and diastereoselective outcomes. [2]

There is not a single mechanism that can be used to describe enyne cycloisomerizations as the mechanism depends on reaction conditions and catalyst selection. [2] [12] Intermediates of the metal catalyzed cycloisomerization in which the metal coordinates the alkyne or alkene activating either or both are possible and are shown in figure 6.

Figure6cycloisom.png

Activation of the alkyne by complexation with the metal leading to an η2–metal intermediate such as 18 opens up the alkyne to nucleophilic attack and engenders carbocation intermediates. This Pull–push reactivity is important for understanding reactions mediated by π–acids. Complexation of the alkyne to the metal fragment depletes electron density in the bond (‘pull’), in concert with the ability of the metal to back donate (“push”) arouses the observed consecutive electrophilic and nucleophilic character to the vicinal carbon atoms of the alkyne (figure 7).

Figure7cycloisom.png

Metallacycle intermediates (19) are the result of the simultaneous complexation and activation of both partners. Hydrometallation of the alkyne giving a vinyl metal species that may in turn carbometalate the olefin is also possible (20). An example of a 1,6–enyne cycloisomerization proceeding through an η2–activated metal intermediate is given in figure 8, [13] which is common for enyne cycloisomerizations mediated by Pt or Au due to their π–acidic nature. Notably, in this example chirality transfer takes place in which the absolute stereochemistry of the enyne (26) controls stereochemistry of the product (27). [13]

Figure8cycloisom.png

Au and Pt mediated enyne cycloisomerization

Alkyne activation with π–acidic metals such as Au or Pt is a conventional method in complex organic manifold synthesis, however how this activation exacts reactivity is not fully understood and thus mechanism is largely proposed on the basis of reaction outcome and theoretical calculations. [14] [15] Cationic Au(I) and Pt(II) catalyst are attractive choices as they display strong Lewis acid character and the ability to stabilize cationic intermediates while being bench stable. [16]

A versatile function of Au(I) catalyzed enyne cycloisomerization is the construction of asymmetric medium–sized rings, which is a challenge in the synthesis of ornamented molecular design. Convenient access to asymmetric 7– and 8–membered carbocycles is possible using chiral BINAP Au(I) gold catalyst, giving a wide variety of products. [17]

Figure9cycloisom.png

It is proposed that intramolecular cyclopropanation occurs via a 1,2–shift of the propargyl ester mediated by Au to give a syn–Au vinyl carbenoid species (29). [17] Computational studies show that the syn–intermediate, 29, is formed under kinetic control and it is suggested that it is in equilibrium with the thermodynamically favorable cis–intermediate which may be intercepted by a nucleophile leading to vinyl cyclopropane diene products, however this is beyond the scope of this article. [17]

Vinylcycloalkenes is another functional class of products accessible through alkyne activation of enynes with π–acidic metals. PtCl2 has been shown to catalyze the formation of a variety of exotic vinylcycloalkenes from readily accessible starting materials (figure 10). [18]

Figure10cycloisom.png

Notably, a ring expansion is observed for enynes with cyclic alkene motifs. This is rationalized by a formal insertion of the methylene group of the olefin between the two carbons of the alkyne; a mechanistic reasoning for this ring expansion has also been proposed. [19] The formation of these vinycloalkenes in concert with its ability to undergo a ring expansion was exploited to construct intermediate 36en route to streptorubin B. [18] A similar transformation is possible using cationic Au(I) complexes, however here one can select for vinycycloalkene products through a mechanism proceeding via an initial 5–exo–dig or bicyclepropanes can be produced via an initial 6–endo–dig. [20] It is suggested through DFT calculations that the 5–exo–dig cyclization is favored for Au(I) complexes as it has a lower activation barrier relative to the 6–endo–dig and indeed numerous examples of vinylcycloalkenes products produced via an initial 5–exo–dig are given (figure 11).

Figure11cycloisom.png

The reactivity can be reversed by careful selection of reaction conditions, catalyst selection and substrate. [20] The divergent reactivity of these transition metal catalyzed cyclosiomerizations further demonstrates their synthetic utility in building unique molecular skeletons.

Related Research Articles

<span class="mw-page-title-main">Ene reaction</span> Reaction in organic chemistry

In organic chemistry, the ene reaction is a chemical reaction between an alkene with an allylic hydrogen and a compound containing a multiple bond, in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position.

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

In organic chemistry, an alkyne trimerisation is a [2+2+2] cycloaddition reaction in which three alkyne units react to form a benzene ring. The reaction requires a metal catalyst. The process is of historic interest as well as being applicable to organic synthesis. Being a cycloaddition reaction, it has high atom economy. Many variations have been developed, including cyclisation of mixtures of alkynes and alkenes as well as alkynes and nitriles.

<span class="mw-page-title-main">Bamford–Stevens reaction</span>

The Bamford–Stevens reaction is a chemical reaction whereby treatment of tosylhydrazones with strong base gives alkenes. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-alkenes, while protic solvent gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis.

<span class="mw-page-title-main">Alkyne metathesis</span>

Alkyne metathesis is an organic reaction that entails the redistribution of alkyne chemical bonds. The reaction requires metal catalysts. Mechanistic studies show that the conversion proceeds via the intermediacy of metal alkylidyne complexes. The reaction is related to olefin metathesis.

A cascade reaction, also known as a domino reaction or tandem reaction, is a chemical process that comprises at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the previous step. In cascade reactions, isolation of intermediates is not required, as each reaction composing the sequence occurs spontaneously. In the strictest definition of the term, the reaction conditions do not change among the consecutive steps of a cascade and no new reagents are added after the initial step. By contrast, one-pot procedures similarly allow at least two reactions to be carried out consecutively without any isolation of intermediates, but do not preclude the addition of new reagents or the change of conditions after the first reaction. Thus, any cascade reaction is also a one-pot procedure, while the reverse does not hold true. Although often composed solely of intramolecular transformations, cascade reactions can also occur intermolecularly, in which case they also fall under the category of multicomponent reactions.

<span class="mw-page-title-main">Pauson–Khand reaction</span>

The Pauson–Khand reaction is a chemical reaction described as a [2+2+1] cycloaddition between an alkyne, an alkene and carbon monoxide to form a α,β-cyclopentenone. Ihsan Ullah Khand (1935-1980) discovered the reaction around 1970, while working as a postdoctoral associate with Peter Ludwig Pauson (1925–2013) at the University of Strathclyde in Glasgow. Pauson and Khand's initial findings were intermolecular in nature, but starting a decade after the reaction's discovery, many intramolecular examples have been highlighted in both synthesis and methodology reports. This reaction was originally mediated by stoichiometric amounts of dicobalt octacarbonyl, but newer versions are both more efficient, enhancing reactivity and yield via utilizing different chiral auxiliaries for stereo induction, main group transition-metals, and additives.

Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.

The Stetter reaction is a reaction used in organic chemistry to form carbon-carbon bonds through a 1,4-addition reaction utilizing a nucleophilic catalyst. While the related 1,2-addition reaction, the benzoin condensation, was known since the 1830s, the Stetter reaction was not reported until 1973 by Dr. Hermann Stetter. The reaction provides synthetically useful 1,4-dicarbonyl compounds and related derivatives from aldehydes and Michael acceptors. Unlike 1,3-dicarbonyls, which are easily accessed through the Claisen condensation, or 1,5-dicarbonyls, which are commonly made using a Michael reaction, 1,4-dicarbonyls are challenging substrates to synthesize, yet are valuable starting materials for several organic transformations, including the Paal–Knorr synthesis of furans and pyrroles. Traditionally utilized catalysts for the Stetter reaction are thiazolium salts and cyanide anion, but more recent work toward the asymmetric Stetter reaction has found triazolium salts to be effective. The Stetter reaction is an example of umpolung chemistry, as the inherent polarity of the aldehyde is reversed by the addition of the catalyst to the aldehyde, rendering the carbon center nucleophilic rather than electrophilic.

Carbon–hydrogen bond functionalization is a type of reaction in which a carbon–hydrogen bond is cleaved and replaced with a carbon–X bond. The term usually implies that a transition metal is involved in the C-H cleavage process. Reactions classified by the term typically involve the hydrocarbon first to react with a metal catalyst to create an organometallic complex in which the hydrocarbon is coordinated to the inner-sphere of a metal, either via an intermediate "alkane or arene complex" or as a transition state leading to a "M−C" intermediate. The intermediate of this first step can then undergo subsequent reactions to produce the functionalized product. Important to this definition is the requirement that during the C–H cleavage event, the hydrocarbyl species remains associated in the inner-sphere and under the influence of "M".

A carbometalation is any reaction where a carbon-metal bond reacts with a carbon-carbon π-bond to produce a new carbon-carbon σ-bond and a carbon-metal σ-bond. The resulting carbon-metal bond can undergo further carbometallation reactions or it can be reacted with a variety of electrophiles including halogenating reagents, carbonyls, oxygen, and inorganic salts to produce different organometallic reagents. Carbometalations can be performed on alkynes and alkenes to form products with high geometric purity or enantioselectivity, respectively. Some metals prefer to give the anti-addition product with high selectivity and some yield the syn-addition product. The outcome of syn and anti- addition products is determined by the mechanism of the carbometalation.

<span class="mw-page-title-main">Hydroamination</span> Addition of an N–H group across a C=C or C≡C bond

In organic chemistry, hydroamination is the addition of an N−H bond of an amine across a carbon-carbon multiple bond of an alkene, alkyne, diene, or allene. In the ideal case, hydroamination is atom economical and green. Amines are common in fine-chemical, pharmaceutical, and agricultural industries. Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound. The development of catalysts for hydroamination remains an active area, especially for alkenes. Although practical hydroamination reactions can be effected for dienes and electrophilic alkenes, the term hydroamination often implies reactions metal-catalyzed processes.

The Kulinkovich reaction describes the organic synthesis of cyclopropanols via reaction of esters with dialkyldialkoxytitanium reagents, generated in situ from Grignard reagents bearing hydrogen in beta-position and titanium(IV) alkoxides such as titanium isopropoxide. This reaction was first reported by Oleg Kulinkovich and coworkers in 1989.

Organogold chemistry is the study of compounds containing gold–carbon bonds. They are studied in academic research, but have not received widespread use otherwise. The dominant oxidation states for organogold compounds are I with coordination number 2 and a linear molecular geometry and III with CN = 4 and a square planar molecular geometry. The first organogold compound discovered was gold(I) carbide Au2C2, which was first prepared in 1900.

<span class="mw-page-title-main">Vinyl iodide functional group</span>

In organic chemistry, a vinyl iodide functional group is an alkene with one or more iodide substituents. Vinyl iodides are versatile molecules that serve as important building blocks and precursors in organic synthesis. They are commonly used in carbon-carbon forming reactions in transition-metal catalyzed cross-coupling reactions, such as Stille reaction, Heck reaction, Sonogashira coupling, and Suzuki coupling. Synthesis of well-defined geometry or complexity vinyl iodide is important in stereoselective synthesis of natural products and drugs.

The Danheiser benzannulation is a chemical reaction used in organic chemistry to generate highly substituted phenols in a single step. It is named after Rick L. Danheiser who developed the reaction.

In organic chemistry, hydrovinylation is the formal insertion of an alkene into the C-H bond of ethylene. The more general reaction, hydroalkenylation, is the formal insertion of an alkene into the C-H bond of any terminal alkene. The reaction is catalyzed by metal complexes. A representative reaction is the conversion of styrene and ethylene to 3-phenybutene:

Vinylcyclopropane [5+2] cycloaddition is a type of cycloaddition between a vinylcyclopropane (VCP) and an olefin or alkyne to form a seven-membered ring.

Carbonyl olefin metathesis is a type of metathesis reaction that entails, formally, the redistribution of fragments of an alkene and a carbonyl by the scission and regeneration of carbon-carbon and carbon-oxygen double bonds respectively. It is a powerful method in organic synthesis using simple carbonyls and olefins and converting them into less accessible products with higher structural complexity.

In organic chemistry, the Conia-ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene, giving a cyclic product with a new carbon-carbon bond. As initially reported by J. M. Conia and P. Le Perchec, the Conia-ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component. Like other pericyclic reactions, the original Conia-ene reaction required high temperatures to proceed, limiting its wider application. However, subsequent improvements, particularly in metal catalysis, have led to significant expansion of reaction scope. Consequently, various forms of the Conia-ene reaction have been employed in the synthesis of complex molecules and natural products.

References

  1. ↑ For a review on cycloisomerization reactions see: Enantioselective, transition metal catalyzed cycloisomerizations Angela Marinetti, Hélène Jullien and Arnaud Voituriez Chem. Soc. Rev., 2012,41, 4884-4908 doi : 10.1039/C2CS35020C, Critical Review .
  2. 1 2 3 4 5 Watson, I. D. G.; Toste, F. D. Chem. Sci. 2012, 3, 2899–2919.
  3. 1 2 3 4 Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009, 131, 16016–16017.
  4. ↑ For a review on thiourea catalysis see: Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.
  5. 1 2 Belmessieri, D.; Houpliere, A.; Calder, E. D. D.; Taylor, J. E.; Smith, A. D. Chem. Eur. J. 2014, 20, 9762–9769.
  6. ↑ Takao, K; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807.
  7. 1 2 Johnson, J. S.; Evan, D. A. J. Org. Chem. 1997, 62, 786–787.
  8. ↑ Sizemore, N.; Rychnovsky, S. D. Org. Lett. 2014, 16, 688–691.
  9. ↑ Izquierdo, J. Hutson, G. E.; Cohen, D. T.; Scheidt, K. Angew. Chem. Int. Ed. 2012, 51, 11686–11698.
  10. ↑ For a review on N–heterocyclic carbene organocatalysis cascade reactions, see: Grossman, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51, 314–325.
  11. 1 2 3 Kowalczyk, M.; Lupton, D. W. Angew. Chem. Int. Ed. 2014, 53, 5314–5317.
  12. ↑ Genêt, J. –P.; Toullec, P. Y.; Michelet, V. Angew. Chem. Int. Ed. 2008, 47, 4268–4315.
  13. 1 2 Newcomb, E. T.; Ferreira, E. M. Org. Lett. 2013, 15, 1772–1775.
  14. ↑ Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007, 46, 3410–3449.
  15. ↑ For a review on gold catalyzed enyne cycloisomerization reactions, see: Jiménez–Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350.
  16. ↑ Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403.
  17. 1 2 3 Watson, I. D. G.; Ritter, S; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056–2057.
  18. 1 2 Fürstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863–11869.
  19. ↑ Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271–2296.
  20. 1 2 Nieto–Oberhuber, C.; Muñoz, M. P.; Buñel, E.; Nevado, C.; Cμrdenas, D. J.; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 2402–2406.
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