Petasis condensation

If ri, t2, f3, f4 and rs represent the molecular weights of fragments Ri through R5, then the general expressions for Emw and AE for the Petasis condensation are given by... 

Returning to the example sequence in Scheme 4.7 and using the minimum values of AE determined and setting the reaction yields also as minimum values, it is possible to evaluate the probabilities that each reaction will have an RME of at least 0.618 and also the probability that both reactions will achieve it simultaneously. Figures 4.10 and 4.11 illustrate the relevant regions in the graphs. We can conclude that the probabilities for the Petasis condensation and the coupling reaction are 77% and 94%, respectively. Since the reactions are independent of each other, that is, the individual probabilities are mutually exclusive, the combined probability that both reactions will have RME values of at least... 

Kumagai, N., Muncipinto, G., Schreiber, S.L. (2006) Short Synthesis of SkeletaHy and Stereo-chemicaUy Diverse Small Molecules by Coupling Petasis Condensation Reactions to Cyclization Reactions. Angewandte Chemie Jnternational Edition, 45, 3635-3638. 

An outstanding example of a branching pathway exploited complementary cyclisation reactions to yield alternative molecular scaffolds (Scheme 1.5). A four-component Petasis condensation reaction was used to assemble flexible cyclisation precursors e.g. 14). Alternative cyclisation reactions were then used to yield products with distinct molecular scaffolds Pd-catalysed cyclisation (- 15a) enyne metathesis (- 15b) Ru-catalysed cycloheptatriene formation (- 15c) Au-catalysed cyclisation of the alcohol onto the alkyne (- 15d) base-induced cyclisation (- 15e) Pauson-Khand reaction 15f) and Miesenheimer [ 2,3]-sigmatropic rearrangement (not shown). Four of these cyclisation reactions could be used again to convert the enyne 15e into molecules with four further scaffolds (17a-d). In addition, Diels Alder reactions with 4-methyl-l,2,4-triazoline-3,5-dione converted the dienes 15b, 17a and 17d... 

Kumagai N, Muncipinto G, Schreiber SL (2006) Short synthesis of skeletally and stereochemically diverse small molecules by coupling Petasis condensation reactions to cyclization reactions. Angew Chem Int Ed 45 3635-3638... 

The Schaus group also reported related reactions involving asymmetric allyl-boration of acyl imines [59], asymmetric three component Petasis condensation reaction of secondary amines/glyoxylates/alkenyl boronates [60], as well as addition of aryl, vinyl, and alkynyl boronates to acyl imines (Fig. 15) [61]. In the later reaction, a two point coordination transition state was proposed to account the observed facial selectivity. 

In contrast to its intermolecular counterpart, an intramolecular Borono-Mannich reaction (Petasis condensation) has been found to proceed with exclusive anti stereoselectivity. The aza-Cope/Mannich reaction has been reviewed. Unprecedented nucleophilic tribromomethylation of Al-t-butanesulfinylimines by bro-moform enables the synthesis of enantiomerically pure a-tribromomethyl amines and 2,2-dibromoaziridines. ... 

Conceptually this new three-component reaction resembles the methods applied by Steglich, Enders et al. [8a] and Yamamoto et al. [8b], who treated the preformed iminoesters 26 and 29 at low temperature with the electron-rich olefins 27 and 30, respectively [9]. However, the use of boronic acid derivatives appears to be a versatile method with a great deal of potential. As Petasis and Zavialov note at the end of their paper, unprotected amino acids and peptides, aryl boronic acids, and chiral boronates can also participate in their three component condensation [7a]. Transition metal catalysis also... 

Petasis (borono-Mannich) condensation (Scheme 91) [353] To piperazinetrityl resin (32 mg, 0.030 mmol, loading 0.95 mmol g ) weighed out in a 10-mL Teflon fritted vessel was added a solution of glyoxylic acid monohydrate (0.032 mmol) in dry THE (2 mE). The suspension was allowed to mix under N2 at r. t. for 2 h. An excess of DEAM-PS boronic ester (120 mmol) was then added, followed by THP/EtOH 8 3 (v/v) (1.5 mE). The suspension was mixed under N2 at 55 °C for 48 h and then cooled at r.t. The resin mixture was filtered and washed as follows ... 

The Petasis reaction is a mild multicomponent reaction that allows the conden sation of a boronic acid, an amine, and a carbonyl derivative to generate an allylic amine. Although several diastereoselective Petasis reactions have been reported [106], the first catalytic asymmetric reaction was described in 2008 (Scheme 1.29) [107]. It was shown that the condensation proceeds in high yields and enantiomeric excesses, affording the corresponding protected a vinylglycine derivatives. 

The key skeleton of 120 was constructed via the Petasis-Ferrier rearrangement [17], established by Smith as a powerful, stereocontrolled entry to ci5-2,6-disubstituted tetrahydropyran (Scheme 24) [18,19]. Brown asymmetric allylation of the known aldehyde 124 [69] installed the C-11 asymmetric center in 91% ee to give 125 after silylation. Oxidative cleavage of the terminal alkene, followed by silylation, delivered the /8-hydroxy ester 126, which was condensed with aldehyde 127 mediated by TMSOTf (but the actual catalyst was found to be TfOH) to furnish an inseparable mixture of the... 

The Petasis method involves the use of organoboron compounds to produce a side chain on a Mannich product derived from the imine condensation product between an amine and an a-ketocarboxylic acid. Thus, as shown in Scheme 12.64, as an example of this three-component reaction, when the styrylboronic acid derived from the reaction of phenylacetylene with catecholborane was allowed to react with glyoxylic acid (CHOCO2H) and (5)-2-phenylglycinol, a single diastereomer was isolated, which gave an enantiomerically pure (7 )-homophenylalanine hydrochloride on reduction. This procedure is limited only by the availability of the components. 

The development of a short synthetic route to the dihydropyran framework of zanamivir congeners was then achieved by coupling the Petasis three-component condensation to this novel iron(m)-promoted one-pot cascade of deprotection - C-C double bond isomerization -cyclization - oxazoline formation. The entire sequence could also be applied to aldehydes 44 and 47 to furnish, in a few steps, the corresponding alcohols 45 and 48 or amines 46 and 49 (Scheme 13). 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

In 2003, Portlock and coworkers [53a] demonstrated that the Petasis borono Mannich (three-component) condensation can be performed in tandem with the Ugi (four-component) condensation to provide access to six-dimensional libraries of compounds with application in the drug discovery area. 

An inherent advantage of the Petasis borono-Mannich reaction is the ability to conduct reactions in a three-component fashion, since the imine or iminium ion intermediates can be formed in situ from the condensation of either primary or secondary amines with the corresponding aldehydes or ketones. The operational advantages of such a three-component coupling approach, combined with the practical benefits outlined above, render the Petasis borono-Mannich reaction particularly desirable for parallel synthesis applications and in the generation of combinatorial libraries. In-... 

The Petasis reaction is a multicomponent condensation occurring between boronic acids, amines and aldehydes. The asymmetric version of this reaction is very attractive for the synthesis of chiral a-amino acids.In this context, Schaus and Lou reported the use of chiral biphenols as organocatalysts for the asymmetric Petasis reaction of ( )-diethyl styrylboronate with secondary amines and ethyl glyoxylate. The corresponding a-amino esters were obtained in high yields and enantioselectivities of up to 97% ee by using a vaulted biaryl phenol such as (5)-VAPOL as the organocatalyst in the presence of 3-A molecular sieves (Scheme 2.59). 

Many other fascinating examples of organocatalysis have been presented in a recent monograph and reviews [6, 11, 12], In its original form, the Petasis reaction was developed as a three-component, non-catalytic condensation of amine, aldehyde and vinyl boronic acid (Scheme 8.2) [13, 14],... 

Broad biological potential of enantiopure 1,2-dihydroquinolines prompted the recently reported organocatalytic, asymmetric Petasis reaction, catalyzed by chiral biphenols [31]. Since it was observed that chiral biphenol derivatives XXVI-XX-VIII serve as proficient catalysts for asymmetric reactions involving boronates [32, 33], the authors postulated that they could be used as ligands in multi-component condensation reactions, and the Petasis reaction in particular. 

Synthesis of Petasis-Ferrier union/rearrangement substrates usually involves the condensation of bis-silylated p-hydroxy acid 169 and aldehyde 94 to afford dioxanone 170 (Scheme 45, Eq. 1) [89, 90]. Carbonyl olefination (typically using Cp2TiMe2) followed by treatment with a Lewis acid (often alkyl aluminum... 

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