Aldol reaction Of enamines

The aldol reactions of enamines may be formally considered to proceed via acyclic amino aldehyde or amino ketone forms, in spite of the fact that the cyclic enamine forms can also take part in aldol reactions. 

C. Aldolization reactions of enamines (a special case combining classes A and B). 

The hydrogen bonding catalyst turned out to be effective also for the enantiose-lective nitroso aldol reaction of enamine. Yamamoto et al. reported that treatment of enamine and nitrosobenzene with (29) furnished N-nitroso aldol products in 77-91% ee. In striking contrast, the glycolic acid derivative (31) furnished O-nitroso aldol products in 70-93% ee (Scheme 2.76) [142]. 

Scheme 10.7 Regio- and enantioselective nitroso aldol reaction of enamines.

V. Aldol Reactions of Heterocyclic Enamines and Their Importance for the... 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

Antibodies produced by this procedure were screened for their ability to react with the hapten to form the vinylogous amide 6, which has a convenient UV chromophore near 318nm, clear of the main protein absorption. Two antibodies selected in this way catalysed the expected aldol reaction of acetone with aldehyde 7 by way of the enamine 8 (Scheme 3) the remainder did not. These two effective aldolase mimics have been studied in some detail, and a crystal structure is available for (a Fab fragment of) one of them.126,281... 

Scheme 72 Asymmetric nitroso aldol reactions of achiral enamines...

This type of interesting phenomenon has also been observed in non-organometallic reactions. The Hajos-Wiechert intramolecular aldol reaction of the triketone to the bicyclic aldol exhibits a nonlinear relation between the enantiomeric purity of the (S)-proline catalyst and the en-antioselectivity (Scheme 44) (75). With the partially resolved amino acid, the cyclization affords the product in an ee lower than anticipated. The reaction occurring via an enamine intermediate again may be interpreted in terms of participation of two proline molecules in the productdetermining transition state. 

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... 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

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... 

To examine the syn/anti selectivity, Houk examined the aldol reaction of acetaldehyde and propanal with methanamine as catalyst. Reaction 6.19. The E or Z enamine can react to give syn or anti product. They located four TSs 52a-d, shown in Figure 6.22. Again, these TSs are in a half-chair conformation with internal proton transfer. The TSs involving the E isomer are lower than those with the Z isomer. The E isomer prefers to give the anti isomer (52a is 0.7 kcal mol" below 52b), while the Z isomer favors the syn product (52c is 1.4 kcal mol" below 52d) These results are consistent with experiments that show preference... 

Houk next examined the aldol reaction of cyclohexanone with benzaldehyde (Reaction 6.20) and isobutyraldehyde (Reaction 6.21) with (6)-proline as the catalyst. Four diastereomeric TSs starting from the enamine formed from cyclohexanone and proline were optimized at B3LYP/6-31G for each reaction. These transitions states, 53 and 55, are shown in Fignre 6.23. In all of these TSs, proton transfer from the carboxylic acid group to the carbonyl oxygen accompanies the formation of the new C-C bond, creating a carboxylale and alcohol product. 

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. 

An exception to the generalization that the enamine of the more hindered aldehyde acts as the nucleophilic arm in intramolecular aldol reactions of unsymmetrical dialdehydes is seen in equation (103). -2 The regioselectivity of this cyclization is apparently very high none of the other isomer was detectable by HPLC or NMR the 57% yield quoted is the overall yield of the alcohol obtained by sodium borohy-... 

In certain cases, high levels of selectivity in the asymmetric aldol reaction can be achieved in the absence of a metal salt. The amino acid proUne catalyses the aldol reaction of aldehydes or ketones (which are enolizable) with aldehydes (preferably non-enolizable or branched to disfavour enolization) to give p-hydroxy-aldehydes or ketones. For example, use of acetone (present in excess) and isobutyraldehyde gave the (3-hydroxy-ketone 81 (1.88). The reaction involves an enamine intermediate and is thought to proceed via the usual Zimmerman-Traxler chair-shaped transition state. 

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

The group of Moutevelis-Minakakis reported in 2014 the preparation and application of a series of tripeptides containing proline, phenylalanine and tert-butyl esters of different amino acids (see 36, Scheme 13.22c) for the asymmetric aldol reaction of aromatic aldehydes and various substituted ketones in both aqueous and organic medium. The authors assume in the proposed transition-state model, besides the well-known enamine activation, a stabilisation of the aldehyde via hydrogen-bond interactions of the two amide protons of the tripeptide with the carbonyl group of the aldehyde. The desired adducts were isolated in good to excellent yields and with very good diastereoselectivities and enantioselectivities. ... 

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. 

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