Enantioselective reductive multicomponent coupling reactions between isatins and aldehydes

A reductive coupling of two different carbonyls via a polar two-electron reaction mechanism was developed and the stereochemical outcome of this multicomponent process is precisely controlled by a chiral triaminoiminophosphorane.

At the outset, we envisaged the possibility of catalytic generation of an a-oxycarbanion from a carbonyl substrate and its rapid and selective trapping with another carbonyl compound to form 1,2-diols. For substantiating this hypothesis, polarity reversal of a particular carbonyl group is of critical importance and we sought to take advantage of the phosphonate-phosphate (phospha-Brook) rearrangement to achieve this requisite process. Thus, a base-catalyzed sequence of Pudovik addition and phosphonate-phosphate rearrangement between ketone 1 and dialkyl phosphite was projected to lead to carbanion 2. The interception of this key intermediate by aldehyde 3 would afford mono-protected diol 4 through dialkoxyphosphinyl migration (Figure 1b). 9 A crucial departure from prior art is the fully intermolecular nature of the coupling and the need for the phosphite to exhibit complete selectivity between the two carbonyl reactants. We reasoned that the crucial chemoselectivity issue underlying this mechanistic framework, viz. the selective generation of a-oxycarbanion 2 from ketone 1, would be ensured by the inherent reversibility of Pudovik reaction and the reluctance of the aldehyde Pudovik product to undergo phospha-Brook rearrangement. In addition, absolute stereochemical guidance in the C-C bond-forming event could be provided by the conjugate acid of a suitable chiral base. In providing the conceptual blueprint for this scenario, we focused our attention on the exceptional electrophilicity and utility of a-dicarbonyls. 9d-g,10 Steps were initially taken to assess the feasibility of the proposed reaction in a racemic sense using achiral bases such as potassium tert-butoxide (KO t Bu). Initial trials with diethyl phosphite as the stoichiometric reductant indicated that the reaction proceeds most cleanly and efficiently when a protecting group is used on the isatin. Benzyl, allyl, and methyl protecting groups were examined using 20 mol% KO t Bu in THF at 0 C ( Table 1, (AE)-4a-(AE)-4c). Under these conditions, the reactions were complete in minutes with no observable intermediates (if the aldehyde is omitted from the reaction, the Pudovik-phospha-Brook product can be observed, however). 9f These experiments revealed that the benzyl protecting group provided the highest isolated yield and diastereoselectivity. We subsequently veried that para-tolualdehyde is not capable of phospha-Brook rearrangement when treated with diethyl phosphite and 20 mol% KO t Bu: only the Pudovik adduct was observed, implying that it is the isatin that is undergoing polarity reversal as we expected.
We then briey studied the scope of the racemic reaction. The reaction gives consistently good yields for various aryl aldehydes incorporating substituents of different electronic properties (Table 1, (AE)-4d-(AE)-4g). At the current level of optimization, alkyl aldehydes and Boc-protected imine electrophiles were not well tolerated and only provided messy reactions. 11 The substitution pattern of the isatin was also examined; we found that the racemic reaction is reasonably exible in terms of isatin electronics ((AE)-4h-(AE)-4k).
Efforts were next directed to the development of the enantioselective variant. 12 We were encouraged to nd that when we used the chiral iminophosphorane (C1), we obtained the secondary phosphate 4a with appreciable enantioenrichment (er 89.5 : 10.5), although the diastereoselectivity was poor (Table 2, entry 1). Gratifyingly, we found that upon lowering the temperature to À78 C, phosphate 4a was obtained in 82% yield, 15 : 1 diastereoselectivity and an er of 96.5 : 3.5 (entry 2). Using the same temperature, we proceeded to evaluate the effect of the catalyst structure (entries 3 to 6), but ultimately concluded that a-branching in ligand substituent R is essential for promoting the desired transformations and the valinederived iminophosphorane C1 was optimal in terms of stereoselectivity and chemical yield.
The disparity between the stereoselectivities at 0 C and À78 C prompted us to investigate the reversibility of the carboncarbon bond formation via crossover experiments in that temperature range (Table 3). When racemic phosphate (AE)-4a was subjected to standard conditions in the presence of 4-uorobenzaldehyde, signicant incorporation of that component in the form of phosphate 4a-F was observed at 0 C and À40 C, but no crossover was observed at À78 C. These data support the hypothesis that the increase in enantioselectivity at À78 C is not only a consequence of more rigorous facial discrimination of both substrates but also shutting down a stereoablative retro-aldol process that is operative at higher temperatures.
Using the optimized conditions, we evaluated the scope of the asymmetric reaction by initially looking at various isatins. Table 1 Three component reductive coupling: racemic a a All reactions were run on 0.2 mmol scale, using 1.1 equiv. of dialkylphosphite and 5.0 equiv. of aldehyde. % Yields refer to isolated yields. All d.r. and % yield values are the averages of two trials. Reactions were run until complete as adjudged by TLC. b % Yield determined by crude 1 H NMR using mesitylene as an internal standard. Products derived from apparent retro-reaction signicantly diminished the isolated yield; therefore, this substrate was not selected for further study.
While electron-decient 5-halogenated isatins were well accommodated under the optimized conditions, use of dimethyl phosphite was indispensable for completion of the reactions with 5-methyl and methoxy isatins probably because of the slow phospha-Brook rearrangement ( Table 4, 4h-4m). 13 6-Chloro and 7-uoro isatins were also smoothly converted into the reductive coupling products of high stereochemical purity using appropriate phosphite (4n and 4o). The absolute stereochemistry was determined at this stage by an X-ray diffraction study of phosphate 4j (Fig. 2). 14 For exploration of aldehyde generality, we selected 5-bromo isatin as a coupling partner in consideration of its high reactivity and advantage of having an additional functional handle at the aromatic nuclei. As included in Table 4, various para-   substituted aromatic aldehydes were tolerated and relatively electron rich aldehydes exhibited higher reactivity and selectivity (4p-4t). Hetero-substituents at the meta-position slightly affected the stereochemical outcome (4u-4w). For sterically demanding ortho-substituted aldehydes, dimethyl phosphite was needed to accelerate the reaction and virtually complete stereocontrol could be achieved (4x-4z).
In summary, we have developed a highly stereoselective, fully organic multicomponent coupling reaction between isatins and aldehydes with dialkyl phosphite as an economical reductant. The advantages of extending the reductive coupling into a twoelectron manifold are manifest, and the mechanistic framework established herein may be applicable to other stereoselective reductive carbon-carbon bond constructions. Efforts to exploit this reaction paradigm in other systems are ongoing in our laboratories. Fig. 2 ORTEP diagram of 4j (ellipsoids displayed at 50% probability. Calculated hydrogen atoms except for that attached to the stereogenic carbon atom are omitted for clarity. Black: carbon, red: oxygen, purple: phosphorous, blue: nitrogen, vermilion: bromine, white: hydrogen).