Cascade sequence

Figure 25-8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone FFA, free fatty acids.) Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is "switched off" by removal of the stimulating hormone the action of lipase phosphatase the inhibition of the lipase and adenylyl cyclase by high concentrations of FFA the inhibition of adenylyl cyclase by adenosine and the removal of cAMP by the action of phosphodiesterase. ACTFI,TSFI, and glucagon may not activate adenylyl cyclase in vivo, since the concentration of each hormone required in vitro is much higher than is found in the circulation. Positive ( ) and negative ( ) regulatory effects are represented by broken lines and substrate flow by solid lines.

An efficient one-pot synthesis of mikanecic acid derivatives was accomplished from allylic phosphonates, ClC02Et, and aqueous HCHO (Eq. 12.38).100 The overall process involves a cascade sequence linking together metalation-alkoxycarbonylation, Homer-Wadsworth-Emmons,... 

An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 <06T5338 06JA15114>. 

The reaction sequence outlined in Scheme 20.30 for the preparation of the chlorinated enyne-allenes was successfully adopted for the synthesis of the C44H26 hydrocarbon 251 having a carbon framework represented on the surface of C60 (Scheme 20.50) [83]. Condensation of the monoketal of acenaphthenequinone (243) with the lithium acetylide 101 afforded the propargylic alcohol 244. On exposure to thionyl chloride, 244 underwent a cascade sequence of reactions as described in Scheme 20.30 to furnish the chloride 248. Reduction followed by deprotection produced 250 to allow a repeat of condensation followed by the cascade transformation and reduction leading to 251. 

Thermolysis of benzoenyneallene (113) in cyclohexadiene at 75 °C produced the cycloaromatized adduct (116) in 22% yield. A biradical is believed to form through a cascade sequence involving an initial Myers cyclization. Trapping of the aryl radical centre in (114) with the tetrarylallenic moiety intramolecularly affords (115), having two triaryl radical centres. Hydrogen abstraction from cyclohexa-1,4-diene by (115)... 

It is instructive to note that the biochemistry of the reactions that initiate the visual cascade and the glycogenolytic cascade is similar. The cyclic AMP-dependent protein kinase complex comprises the regulatory and catalytic components (R and C) for which the regulatory signal is the concentration of cyclic AMP. This binds to the regulatory component of the kinase (the R subunit) which then dissociates from the R-C complex. The C is now catalyti-cally active and catalyses the initial reaction in a cascade sequence which leads to activation of the target protein (phosphorylase). 

It is clear that, as understanding of the underlying principles of both iminium ion and enamine catalysis improves, the trae power of these cascade sequences will be fully exploited. It can be expected that introduction of subsequent independent catalytic cycles will add to the complexity and applicabihty of these processes and provide highly regulated cascades that mimic the power of enzymatic pathways. 

We have already considered regulatory cascades initiated respectively by the (3 and a2 adrenergic receptors. The effect of these cascades on glycogen phos-phorylase is outlined on the left side of Fig. 11-4. One branch of the cascade sequence begins with release of... 

The synthesis of A-fused tricyclic (3-lactams involving a radical cascade sequence in enyne 2-azetidinones 114 and 115 bearing a methylenecyclopropane unit has been reported [82]. Slow addition of Bu3SnH/AIBN to a refluxing solution of 114 gave tricyclic vinylstannane 116 as a single stereoisomer in 42% yield, whereas cyclization of 115 under identical conditions gave fused heterocycles 117 and 118 in 73 and 11% yield, respectively, in all three cases via a 7-endo cyclization. Treatment of vinyl stannanes 117 and 118 with PPTS in dichloromethane yielded a common tricyclic product 119 (Scheme 40). 

SCHEME 23. First attempt atthetropoloisoquinoline-forming cascade sequence. 

SCHEME 25. Second attempt at the tropoloisoquinoline-fbrming cascade sequence. Preparation of pareitropone. 

Lewis acid-mediated endo -cyclization of trimethylsilylmethylenecyclopropylimines provides a stereoselective route to indolizidines via a novel cascade sequence including (g) a [l,2]-hydride shift (Scheme 56).91... 

The number of similar cyclizations, including tandem and cascade sequences where an SnH reaction is a key step, has been considerably increased. As a rule, they are easily performed allowing at times the synthesis of complex polynuclear heterocycles in one step. The present paper, which summarizes about 130 articles on this topic, shows SnH cyclizations to be a very promising strategy for heterocyclic ring annulations. 

Complex multi-step cyclizations when the SNH reaction initiates several other processes sometimes including repeated SNH reactions, classified as cascade sequences (96CRV137). 

As in the above tandem reactions, cascade sequences of this type are normally initiated by an SNH reaction. They differ from the former by having a larger number of stages and greater variety. Practically always this complexity is caused by involvement of functional groups, as a rule, via redox processes. For some time such cascades were known only for nitro derivatives of arenes and hetarenes. However, recently some novel substrates and cascade sequences have been discovered. 

Radical cyclization of 405 led to the dimethylene tricyclic /3-lactam 406 in a cascade sequence of steps. Radical procedures have been used extensively and have the advantages of stereoselectivity in the cyclization step from relatively simple starting materials. A disadvantage is the sometimes relatively low yield <1999TL5391, 2000TL10347>. Other examples of the use of radical cyclization processes are given in Sections 2.04.11.1.1 (ii), 2.04.11.2.2, 2.04.11.3, and 2.04.11.4. 

Alcaide et al. have used their methanesulfonate route to fused /3-lactams in a cascade sequence of reactions, including an intramolecular Diels-Alder reaction to obtain tetracyclic compounds (Scheme 17) <2003JOC3106>. 

It was envisioned that the addition of an indole derived from a tryptamine to the activated iminium ion, arising from imidazolidinone catalyst 3 and an a,p-unsaturated aldehyde, would generate a C(3)-quaternary carbon-substituted indo-lium ion. As a central feature this intermediate cannot undergo re-aromatization by means of proton loss, in contrast to the analogous 3-H indole addition pathway. As a result, 5-exo-heterocyclization of the pendant ethylamine would provide the corresponding pyrroloindoline compounds. In terms of molecular complexity, this cascade sequence should allow the rapid and enantioenriched formation of stereochemically defined pyrroloindoline architecture from tryptamines and simple a,/i-unsaturated aldehydes. 

This reactivity proved to be a general process, providing the unique products in moderate yields following cyclopropanation and immediate treatment with silver tetrafluoroborate. These structures revealed that a cascade sequence was proceeding stereoselectively in every case to furnish a single product as the result of conrotatory 4jt electrocyclization, electrophilic aromatic substitution at the least hindered position on the arene moiety (para to the MeO) in favor of six-membered ring formation, and desilylation with protonation from the exo face of the bicyclic product. Dehydrochlorination to form a second cationic intermediate did not occur in this case, due to structural restrictions imposed by the bridged architecture of 81. 

The cascade sequences presented herein demonstrate unprecedented modes of reactivity in Nazarov chemistry that are initiated by the silver(I)-promoted ring opening of halocyclopropanes. The ease with which the gem-dichlorocyclopropanes can be prepared, the relatively mild reaction conditions, and the efficiency of these processes make these substrates attractive intermediates for an application in natural product synthesis. 

Sofikiti, N., Tofi, M., Montagnon, T., Vassilikogiannakis, G. and Stratakis, M. (2005) Synthesis of the spirocydic core of the prunolides using a singlet oxygen-mediated cascade sequence. Organic Letters, 7 (12), 2357-2359. 

Abstract This review gives an insight into the growing field of transition metal-catalyzed cascades. More particularly, we have focused on the construction of complex molecules from acyclic precursors. Several approaches have been devised. We have not covered palladium-mediated cyclizations, multiple Heck reactions, or ruthenium-catalyzed metathesis reactions because they are discussed in others chapters of this book. This manuscript is composed of two main parts. In the first part, we emphasize cascade sequences involving cycloaddition, cycloisomerization, or ene-type reactions. Most of these reaction sequences involve a transition metal-catalyzed step that is either followed by another reaction promoted by the same catalyst or by a purely thermal reaction. A simple change in the temperature of the reaction mixture is often the only technical requirement to go from one step to another. The second part covers the cascades relying on transition metalo carbenoid intermediates, which have recently undergone tremendous... 

The cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

Nicolaou KC, Montagnon T, Snyder SA (2003) Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem Commun 5 551... 

A cascade approach to isoindole-1-phosphonates 9 starting from from o-alkynyl benzylamides was reported <07OL465>. The cascade sequence presumably involved a 5-exo-dig cyclization, a [1,3]-alkyl shift (or aza-Claisen), and aromatization. 

A new general synthesis of substituted formylpyrroles 106 has been developed starting from ketones and 4-formyloxazoles. The aldol adducts undergo a cascade sequence of reactions which ends with the formation of a pyrrole. The reaction is intended as a vinylogous extension of the Comforth reaction, hydrolysis of formyloxazoles, and allows the synthesis of a large series of 4-and 5-substituted 2-formylpyrroles <07OL1875>. 

---