Stereoselectivity proline-catalyzed reactions

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

Aliphatic aldehydes are more difficult substrates because the presence of two enolizable carbonyls results in decreased reaction selectivity. Such aldehydes may be used as acceptors in the proline-catalyzed reaction with acetone, but as expected, only branched aldehydes give good yields and stereoselectivities [14, 50]. The best results are obtained using Wennemers tetrapeptide 18 (Table 3.1) [25a]. 

The introduction of a halogen at the a-position in an acceptor aldehyde influences the course of the cross-aldol reaction by imposing steric constraints and by activating the carbonyl group towards electrophilic attack [144]. As a result, a-haloaldehyde preferentially reacts as an acceptor in L-proline-catalyzed reactions, affording aldols with rzwft-stereoselectivity. 

A highly stereoselective proline-catalyzed acetone aldol reaction has recently been used in the synthesis of sugar derivatives such as 141 (Scheme 4.28) [124]. 

Interestingly, the stereoselectivity of reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde vere first predicted by using density functional theory calculations on models based on Houk s calculated transition state of the Hajos-Parrish-Eder-Sauer-Wiechert reaction [125]. The transition states of inter- and intramolecular aldol reactions are almost super-imposable and readily explain the observed enantiofacial selectivity. Relative transition state energies vere then used to predict the diastereo- and enan-tioselectivity of the proline-catalyzed reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde. The predictions are compared vith the experimental results in Scheme 4.30. The good agreement clearly validates the theoretical studies, and provides support for the proposed mechanism. Additional density functional theory calculation also support a similar mechanism [126, 127]. 

Figure 17.6 Generally employed transition state models for the stereoselectivity-controlling bond formation in proline-catalyzed reactions. Reproduced from Reference [24] with permission from John Wiley Sons.

The key to partnership between theory and experiments in organocatalysis rests with the ability of the former to precisely identify the transition states responsible for stereoselectivity. In the following section, some prototypical organocatalytic reactions are presented wherein the computational methods were impressively successful. There are more exciting applications wherein a priori predictions were attempted ahead of experimental verification. As a prelude to in silica catalyst design, a comparison between the computational predictions of the stereochemical outcome and the experimentally observed enantiomeric excess values for a representative set of proline-catalyzed reactions (Scheme 17.13) is compiled in Table 17.1. 

Scheme 17.13 Selected examples of proline-catalyzed reactions where the enantiomeric excess has been predicted by using DFT computations with enamines in the stereoselective bond formation.

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

Although experimental support exists for one proline molecule in the transition state of proline-catalyzed intramolecular aldol reactions was later developed [6, 51], reaction rates and stereoselectivities are not fully explained by a simple transition-state model. For example, the insoluble portion of the catalyst cannot participate in the catalysis. However, when a catalyst with a low enantiopurity is used, the solubilized portion of the catalyst can have a higher enantiopurity (i.e., racemic... 

Not only does acetone undergo a highly enantioselective aldol reaction, but hydroxy acetone exhibits excellent stereoselectivity to produce the anti-aldol products 75 (Scheme 2.3d). For example, L-proline catalyzed the aldol reaction between hydroxy acetone and cyclohexanecarbaldehyde to furnish the anti -diol in 60% yield with a greater than 20 1 diastereomeric ratio. The enantiofacial selectivity of the anti-isomer was higher than >99%. Diastereoselectivities are very high with a-substituted aldehydes, whereas low selectivities are recorded in reactions with aromatic aldehydes and with a-unsubstituted aliphatic aldehydes. It is noteworthy that the levels of enantiofacial selectivity for the anti -aldol products... 

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... 

Houk s involvement in proline-catalyzed asymmetric induction began in a similar way. Occasionally something very interesting appears in the literature, especially so if it is amendable to elucidation by computational methods, Houk recalls. We are especially interested in synthetic methods where the experimentalist is unclear of just how things work. This was Ihe case with the proline work. We saw the work of Barbas and List on the aldol reaction, and we were aware of the Hajos-Parrish reaction. So we started computations on simple models, and then looked at the Hajos-Parrish reaction, and we came upon an explanation for its stereoselectivity. This was all done without communicating with any of the experimentalists. ... 

Sharma, A. Sunoj, R. Enamine versus oxazolidinone What controls stereoselectivity in proline-catalyzed asymmetric aldol reactions , Angew. Chem. Int. Ed. 2010, 49, 6373-6377. 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

Bahmanyar, S., Houk, K. N. Origins of Opposite Absolute Stereoselectivities in Proline-Catalyzed Direct Mannich and Aldol Reactions. Org. Lett. 2003, 5, 1249-1251. 

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