Increasing complexity of a diterpene synthase reaction with a single residue switch

Terpene synthases often catalyze complex reactions involving intricate series of carbocation intermediates. The resulting, generally cyclical, structures provide initial hydrocarbon frameworks that underlie the astonishing structural diversity of the enormous class of terpenoid natural products (>50,000 known), and these enzymes often mediate the committed step in their particular biosynthetic pathway. Accordingly, how terpene synthases specify product outcome has drawn a great deal of attention. In previous work, we have shown that mutational introduction of a hydroxyl group at specific positions within diterpene synthase active sites can "short circuit" complex cyclization and/or rearrangement reactions, resulting in the production of "simpler"' diterpenes. Here we demonstrate that the converse change, substitution of an Ile for Thr at the relevant position in a native pimaradiene synthase, leads to a dramatic increase in reaction complexity. Product outcome is shifted from the tricyclic pimaradiene to a rearranged tetracycle, aphidicol-15-ene. Thus, the nature of the residue at this position acts as a true switch for product outcome. In addition, the ability of aliphatic residue substitution to enable a more complex reaction emphasizes the importance of substrate conformation imposed by a largely inert active site. Furthermore, the profound plasticity of diterpene synthases exemplified by this single residue switch for product outcome is consistent with the screening/diversity-oriented hypothesis of natural products metabolism.     

Rearrangements in Scholl Reaction

Rearrangements in Scholl reaction are mostly serendipitous. The design of molecular precursors is what seems to guide the course of rearrangement. This review consolidates different classes of precursors used in Scholl reaction and their accompanying rearrangements that include aryl migration, migration followed by cyclization and skeletal rearrangements involving ring expansion, ring contraction and both, under the reaction conditions. The attempt in collating heretofore-reported examples in this review is to guide designing appropriate precursors to predictably achieve complex molecular structures or nanographenes or defect-nanographenes via rearrangement.     

Biomimetic cationic polyannulation reaction catalyzed by Bi(OTf)3: cyclization of 1,6-dienes, 1,6,10-trienes, and aryl polyenes

Nonactivated trienes and aryltrienes were cyclized into polycyclic compounds in good to excellent yields under bismuth triflate catalysis in a biomimetic fashion. The reaction showed broad applicability and allowed for the formation of functionalized bicyclic to tetracyclic structures from simple precursors in one pot. For some specific substrates, the cyclization was followed by a methyl shift as encountered in terpenoid biosynthesis.     

Electrophilic and nucleophilic enzymatic cascade reactions in biosynthesis

The biosynthesis of cyclic terpenoids and polyethers involves enzyme-initiated cascade reactions for ring formation. While the former are obtained by electrophilic cascades through carbenium ions as intermediates, cyclic polyethers are formed by nucleophilic cascade reactions of (poly)epoxide precursors. These mechanistically complementary pathways follow common principles via (i) triggering of the cascade by forming a reactive intermediate ('initiation'), (ii) sequential 'proliferation' of the cyclization and finally (iii) 'termination' of the cascade. As analyzed in this concept paper, the multiplicity of precursors, combined with various initiation and termination routes and kinetically favored or disfavored cyclization modes accounts for the enormous diversity in cyclic terpenoid and polyether scaffolds. Although the essential role of enzymes in the triggering of these cascades is reasonably well understood, remarkably little is known about their influence in proliferation reactions, especially those implying kinetically disfavored (anti-Markovnikov and anti-Baldwin) routes. Mechanistic analysis of enzymatic cascade reactions provides biomimetic strategies for natural product synthesis.     

Synthesis of Cyclic Fragrances via Transformations of Alkenes,Alkynes and Enynes: Strategies and Recent Progress

With increasing demand for customized commodities and the greater insight and understanding of olfaction, the synthesis of fragrances with diverse structures and odor characters has become a core task. Recent progress in organic synthesis and catalysis enables the rapid construction of carbocycles and heterocycles from readily available unsaturated molecular building blocks, with increased selectivity, atom economy, sustainability and product diversity. In this review, synthetic methods for creating cyclic fragrances, including both natural and synthetic ones, will be discussed, with a focus on the key transformations of alkenes, alkynes, dienes and enynes. Several strategies will be discussed, including cycloaddition, catalytic cyclization, ring-closing metathesis, intramolecular addition, and rearrangement reactions. Representative examples and the featured olfactory investigations will be highlighted, along with some perspectives on future developments in this area.     

Electrostatic effects on (di)terpene synthase product outcome

Terpene synthases catalyze complex reactions, often forming multiple chiral centers in cyclized olefin products from acyclic allylic diphosphate precursors, yet have been suggested to largely control their reactions via steric effects, serving as templates. However, recent results highlight electrostatic effects also exerted by these enzymes. Perhaps not surprisingly, the pyrophosphate co-product released in the initiating and rate-limiting chemical step provides an obvious counter-ion that may steer carbocation migration towards itself. This is emphasized by the striking effects of a recently uncovered single residue switch for diterpene synthase product outcome, whereby substitution of hydroxyl residues for particular aliphatic residues has been shown to be sufficient to "short-circuit" complex cyclization and/or rearrangement reactions, with the converse change further found to be sufficient to increase reaction complexity. The mechanistic hypothesis for the observed effects is hydroxyl dipole stabilization of the specific carbocation formed by initial cyclization, enabling deprotonation of this early intermediate, whereas the lack of such stabilization (i.e. in the presence of an aliphatic side chain) leads to carbocation migration towards the pyrophosphate co-product, resulting in a more complex reaction. This is further consistent with the greater synergy exhibited between pyrophosphate and aza-analogs of late, relative to early, stage carbocation intermediates, and crystallographic analysis of the monoterpene cyclase bornyl diphosphate synthase wherein mechanistically non-relevant counter-ion pairing between aza-analogs of early stage carbocation intermediates and pyrophosphate is observed. Thus, (di)terpene synthases seem to mediate specific reaction outcomes, at least in part, by providing electrostatic effects to counteract those exerted by the pyrophosphate co-product.     

Gold(I)-catalyzed cyclizations of 1,6-enynes: alkoxycyclizations and exo/endo skeletal rearrangements

Gold(I) complexes are the most active catalysts for alkoxy- or hydroxycyclization and for skeletal rearrangement reactions of 1,6-enynes. Intramolecular alkoxycyclizations also proceed efficiently in the presence of gold(I) catalysts. The first examples of the skeletal rearrangement of enynes by the endocyclic cyclization pathway are also documented. Iron(III) is also able to catalyze exo and endo skeletal rearrangements of 1,6-enynes, although the scope of this transformation is more limited. The gold(I)-catalyzed endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII, HgII, or RhI catalysts.     

Synthesis of seven-membered carbocyclic rings via a microwave-assisted tandem oxyanionic 5-exo dig cyclization-claisen rearrangement process

Appropriately substituted 1-alkenyl-4-pentyn-1-ol systems, readily prepared from simple starting materials, serve as useful precursors to a number of substituted cyclohept-4-enone derivatives via a microwave-assisted tandem oxyanionic 5-exo cyclization/Claisen rearrangement sequence. The reactions involving terminally substituted 4-pentyn-1-ols were found to be highly stereoselective, with the alpha and beta groups in the final product showing a strong preference for the trans orientation.     

An Enyne Cope Rearrangement Enables Polycycloalkane Synthesis from Readily Available Starting Materials

Cyclohexanone‐derived Knoevenagel adducts (cyclohexylidenemalononitriles) and two different propargyl electrophiles serve as carbon sources for assembling diverse 6/7/5 tricycloalkanes, a common terpenoid framework. The sequence involves three unique reactions: 1) deconjugative propargylation, 2) one‐pot enyne Cope rearrangement/deconjugative propargylation, and 3) an allenic Pauson–Khand reaction.     

Additions to the Activated CC Triple Bond

The possibilities of additions to the activated CC triple bond are discussed with the aid of a number of examples. The additions of donors that contain no active hydrogen are generally initiated via a dipolar primary complex, which can undergo stabilization by rearrangement, cyclization, or addition reactions. Preparative aspects of these reactions are also discussed. They offer routes for the preparation of heterocycles, particularly pyrrole and thiophene derivatives.     

Synthesis of (-)-centrolobine by Prins cyclizations that avoid racemization

[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.     

Facile access to diverse all-carbon quaternary center containing spirobicycles by exploring a tandem Castro–Stephens coupling/acyloxy shift/cyclization/semipinacol rearrangement sequence

Efficient combination of two or more reactions into a practically useful purification free sequence is of great significance for the achievement of structural complexity and diversity, and an important approach for the development of new synthetic strategies that are industrially step-economic and environmentally friendly. In this work, a facile and efficient method for the construction of highly functionalized spirocyclo[4.5]decane derivatives containing a synthetically challenging quaternary carbon center has been successfully developed through the realization of a tandem Castro–Stephens coupling/1,3-acyloxy shift/cyclization/semipinacol rearrangement sequence. Thus a series of multi-substituted spirocyclo[4.5]decane and functionalized cyclohexane skeletons with a phenyl-substituted quaternary carbon center have been constructed using this method as illustrated by 24 examples in moderate to good yields. The major advantages of this method over the known strategies are better transformation efficiency (four consecutive transformations in one tandem reaction), product complexity and diversity. As a support of its potential application, a quick construction of the key tetracyclic diterpene skeleton of waihoensene has been achieved.

An efficient construction of spirocyclo[4.5]decane derivatives is developed via a Castro–Stephens coupling/1,3-acyloxy shift/cyclization/semipinacol rearrangement sequence.     

Protein splicing in cis and in trans

Intein-mediated protein splicing is a self-catalytic process in which the intervening intein sequence is removed from a precursor protein and the flanking extein segments are ligated with a native peptide bond. Splice junction proximal residues and internal residues within the intein direct these reactions. The identity of these residues varies in each intein, as groups of related residues populate conserved motifs. Although the basics of the four-step protein splicing pathway are known, mechanistic details are still unknown. Structural and kinetic analyses are beginning to shed some light. Several structures were reported for precursor proteins with mutations in catalytic residues, which stabilize the precursors for crystallographic study. Progress is being made despite limitations inherent in using mutated precursors. However, no uniform mechanism has emerged. Kinetic parameters were determined using conditional trans-splicing (splicing of split precursor fragments after intein reassembly). Several groups concluded that the rate of the initial acyl rearrangement step is rapid and Asn cyclization (step 3) is slow, suggesting that this latter step is rate limiting. Understanding the protein splicing pathway has allowed scientists to harness inteins for numerous applications.     

金催化的环化反应与钯催化的炔醇偶联/环化反应相结合用于合成多取代呋喃衍生物:串联反应的应用范围(英文)

开发了一种由金和钯催化π-活化由炔醇合成呋喃衍生物的集成方法.该合成策略是最显著的特点适用于带环辛基的底物,其适用范围比之前报道的有很大扩展.在Sonogashira反应条件下,由相应底物可直接得到环辛基呋喃.Pd在这些反应中起到2个重要作用:底物发生偶联反应的关键催化剂;通过π-活化促进炔醇中间体成环反应.该方法在一步合成3-碘呋喃反应中作用很突出,使通过偶联法进一步官能团化成为可能.我们还将AuBr_3用于多米诺成环/C-H键活化反应和无环前体的成环反应.本文结果表明,在该类成环反应中金和钯催化剂相辅相成.     

Samarium diiodide induced cyclizations of γ-, δ- and ε-indolyl ketones: reductive coupling, intermolecular trapping, and subsequent transformations of indolines

This comprehensive study describes our results of samarium diiodide induced 5-exo-trig to 8-exo-trig cyclization/alkylation sequences of 3'-acceptor-substituted indolyl ketones. All cyclization precursors were easily prepared by simple N-alkylation or N-acylation of indole derivatives with the corresponding iodo alkanones, acid chlorides, or lactones. After treatment of indolyl ketones with two equivalents of SmI(2), the generated stabilized carbanionic intermediates were trapped with different electrophiles leading to a variety of highly substituted indoline derivatives in good to very good yields. In general, the cyclization products were obtained as single diastereomers bearing a newly generated quaternary center, a common structural motif in various indole alkaloids. The relative configurations of the products were established by NOE experiments and by single-crystal analysis and follow the rules already established. Furthermore, the obtained products were subjected to a series of chemical transformations, such as oxidation, reduction, and metathesis reactions resulting in a range of interesting synthetic building blocks valuable for further applications.     

Tandem visible light-mediated radical cyclization-divinylcyclopropane rearrangement to tricyclic pyrrolidinones

Visible light promoted single electron reduction of bromocyclopropyl cyclization scaffolds enabled by photoredox catalysis initiates a novel tandem radical cyclization/sigmatropic rearrangement to generate tricyclic pyrrolidinones having considerable molecular complexity from simple, readily available starting materials. Furthermore, subtle variations to substrate structure afford a wide array of reaction diversity.     

Experimental and quantum-mechanical investigation of the vinylsilane-iminium ion cyclization

A vinylsilane-ketiminium ion cyclization involving iminium species derived from amines 6 and 7 was investigated experimentally as a possible approach to some biologically interesting 1-azaspirocycles. However, even under conditions of microwave irradiation at high temperatures no such cyclization was observed whereas (in line with previous results) the corresponding vinylsilane-aldiminium ion cyclizations were more successful. Aldiminium species substituted alpha to nitrogen displayed no diastereoselectivity in the cyclization of precursors derived from 6 while high trans diastereoselectivity could be obtained for iminium species derived from 7. Quantum-mechanical investigations of the general reaction mechanism underlined the lack of reactivity of ketiminium species and also convincingly explained the observed diastereoselectivities of aldiminium species. The calculations further revealed that (Z)-vinylsilanes cyclize via a silicon-stabilized beta-carbocation, and that any formal aza-Cope rearrangement of the starting material to an allylsilane-iminium species does not take place in a concerted fashion. However, the calculations show that the aza-Cope rearrangement precedes cyclization for the corresponding (E)-vinylsilanes, the overall reaction being energetically slightly less favoured than cyclization of the (Z)-isomers.     

Gold-catalyzed reactions of 2-alkynyl-phenylamines with alpha,beta-enones

[reaction: see text] The gold-catalyzed reaction of 2-alkynyl-phenylamines with alpha,beta-enones represents a new general one-pot entry into C-3-alkyl-indoles by sequential reactions. Gold-catalyzed sequential cyclization/alkylation, N-alkylation/cyclization, or N-alkylation/cyclization/alkylation reactions leading to different indoles can be directed by changing the 2-alkynyl-phenylamine 1/alpha,beta-enone 3 ratio and the reaction temperature. Unusual gold-catalyzed rearrangement reaction of indoles are observed at 140 degrees C. New gold-catalyzed formation of propargyl-alkyl ether under mild conditions and the hydration reaction of N-acetyl-2-ethynyl-phenylamine are reported.     

A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3+2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.     

Radical Reactions Induced by Visible Light in Dichloromethane Solutions of Hünig's Base: Synthetic Applications and Mechanistic Observations

β‐(3‐Iodopropoxy)‐substituted α,β‐unsaturated lactams, lactones, and cycloalkenones (eight examples) underwent reductive radical reactions in a dichloromethane solution of N,N‐diisopropylethylamine (Hünig's base) upon irradiation with visible light (λ=419 nm). Apart from plain reduction reactions (hydro‐de‐iodination), a significant degree of cyclization was observed in three cases. In parallel to the conversion of the substrates, the formation of intensely colored by‐products was observed. Based on mass spectrometric evidence and upon comparison with known compounds, the by‐products were identified as cyanine dyes. Their formation supports the hypothesis that irradiation of dichloromethane solutions of Hünig's base leads to the formation of radicals, which in turn can either initiate a radical reaction or combine with cyanine precursors. It was shown by deuterium‐labelling experiments, that one equivalent of dichloromethane is incorporated into the cyanine dyes and that the reductive quenching of radical intermediates is at least partially due to hydrogen abstraction from the solvent. As a consequence, a reductive cyclization of the starting materials is favored in CD₂Cl₂ solutions as shown for two β‐(3‐iodopropoxy)‐substituted tetronates, which underwent in dichloromethane almost exclusive reduction, but gave predominantly the cyclization products in CD₂Cl₂.