Amine-catalyzed Aldol Reactions

Modem Aldol Reactions. Vol. 1 Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis. Edited by Rainer Mahrwald 

Copyright 2004 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30714-1 

Other interesting organocatalysts of the aldol reaction, for example simple tertiary amine Bronsted bases and phase-transfer type quaternary ammonium salts [34-36]. Mechanistically related class I aldolases and catalytic antibodies have been fundamentally important in the development of the reactions described belotv and are discussed in another chapter of this book. 

Although aminocatalysis of the aldol reaction via enamine intermediates is an important enzymatic strategy and several bioorganic studies of the subject have appeared, applications in preparative organic synthesis, particularly in intermolecular aldol addition reactions, have been published only sporadically. Despite the often-used Mukaiyama-aldol reaction of enol ethers and Stork s vell-developed enamine chemistry [37, 38], aldolizations of preformed enamines are rare. One report describes Le vis acid-catalyzed aldolizations of preformed enamines vith aldehydes that furnish aldol addition products [39]. Aldol condensation reactions of preformed enamines vith aldehydes have also been described [40]. Only enamine-catalytic aldolizations, vhich are primary and secondary amine-catalyzed aldol reactions, vill be discussed in this chapter, ho vever. 

Some amine-catalyzed aldolizations in aqueous buffers. 

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For a previous related work on the achiral amine-catalyzed aldol reaction, see S. Bahmanyar, K. N. Hour,/. Am. Chem. Soc. 2001, 123, 11273-11283. 

A few theoretical studies of oxetanes and oxetanones have been reported since CHEC-II(1996). Building upon a study of the oxetane- -HCl complex studied by rotational spectroscopy, MP2 calculations were used to investigate the axial and equatorial HCl arrangement, and to try and explain why for oxetane- -HCl only one conformer was observed <2001CPL250, 2002CPL123>. The amine-catalyzed aldol reaction via enamine intermediates has been explored using density functional theory (DFT) (B3LYP/6-31G ) and conductor-like polarizable continuum model... 

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

Examples of amine-catalyzed aldol reactions are shown in Table 6.10. For all entries, the mole percent of amine nsed was generally 10-20 percent. While, in some cases, yields may be poor, generally the yields are qnite acceptable. 

We begin by examining the computational results for the intermolecular amine-catalyzed aldol reaction. The most likely mechanisms posit an enamine intermediate that then attacks an aldehyde to produce the aldol product. Boyd and coworkers ° examined this entire reaction pathway for the reaction of acetone and... 

The preference for the amine-catalyzed aldol reaction to go through a TS having the features of 53a or 55a is now called the Houk-List model. This type of TS has three major characteristics (1) proton transfer from the carboxylic acid to the incipient alcohol concomitant with the formation of the C-C bond (TS D of Scheme 6.8) (2) the enamine is in the anti orientation and (3) the aldehyde substituent is anti to the enamine carbon. 

Bahmanyar, S. Honk, K. N. Transition states of amine-catalyzed aldol reactions involving enamine intermediates Theoretical studies of mechanism, reactivity, and stereoselectivity, J. Am. Chem. Soc. 2001,123,11273-11283. 

Bahmanyar, S., Houk, K. N. (2001). Transition States of Amine-Catalyzed Aldol Reactions Involving Enamine Intermediates Theoretical Studies of Mechanism, Reactivity, and Stereoselectivity. Journal of the American Chemical Society, 123(45), 11273-11283. 

The amine-catalyzed aldol reaction between ketone donors and a-disubstituted aldehydes normally proceeds much more easily and with excellent enantios-electivity, which was demonstrated impressively in the synthesis of the southern part of the highly cytotoxic potential anticancer drug epothilone B (29) 47,48) by Avery and Zheng (49) (Scheme 8). In this case (/ )-proline was the catalyst of choice to introduce the secondary alcohol group in high enantioselectivity early in the synthesis sequence. 

Scheme 28.30 Magnetically supported amine-catalyzed aldol reactions.

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

Amine-catalyzed aldol reaction enhanced by Si02 was reported by Kubota and coworkers in 2003 [8]. In the reaction of 4-nitrobenzaldehyde with acetone catalyzed by piperazine, the addition of mesoporous silica FSM-16 induced the increase in yield of the product from 5% to 91%. Several secondary amines were used as catalysts. In addition, the authors also investigated the amine-immobilized silicas... 

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