Small-molecule chiral hydrogen-bond donors have emerged as important organocatalysts for the activation of Lewis basic electrophiles—such as imines, nitroolefins, and carbonyl compounds—toward nucleophilic addition.1 In this context, we recently discovered that pyrrole-bearing thiourea derivatives (e.g. 1) catalyze highly enantioselective N-acyl-Pictet-Spengler and Mannich-type reactions to provide products in high ee’s.2 Reactivity patterns in these additions were found to be consistent with an SN1 pathway, and we proposed a mechanism involving thiourea-assisted chloride dissociation from a transient α-chloroamide (2) to generate a reactive N-acyliminium chloride-thiourea complex 1·Cl-·3 (Scheme 1).2c The ability to engage highly reactive cationic species in this manner presents exciting new possibilities for asymmetric catalysis. Herein we report the successful application of this mode of activation to catalyst-controlled enantioselective additions to oxocarbenium ions.
Scheme 1.
Enantioselective addition to reactive cationic species: hydrogen-bond catalysis by anion-binding
The reactions of oxocarbenium ions play an important role in the synthesis of complex natural products, and in the chemistry of carbohydrates in particular. Numerous methods for Lewis-acid mediated substrate-controlled diastereoselective additions to substituted oxocarbenium ions have been identified.3,4 On the other hand, enantioselective addition reactions to prochiral oxocarbenium ions are almost completely undeveloped.5,6 A catalyst system capable of inducing stereocontrol in nucleophilic additions to cyclic oxocarbenium ions would be of considerable significance. With the goal of applying the principle of H-bond donor catalysis by anion-binding to transformations involving oxocarbenium ions, we targeted the addition of carbon-centered nucleophiles to cyclic glycosyl donors.7 Whereas α-chloroamides (e.g. 2) are generally unstable, glycosyl chlorides (e.g. 4) are often isolable and more easily manipulated. Under the thiourea-catalyzed reaction conditions, use of glycosyl chlorides would allow direct access to putative intermediate ion pair 5.
For exploratory studies, 1-chloroisochroman 7 was selected as a model substrate and prepared by treatment of known methyl acetal 68 with BCl3 (0.33-0.4 equiv), followed by purification by vacuum distillation.9,10 At -78 °C in TBME, conditions under which 7 does not undergo spontaneous reaction with silyl ketene acetal 8a, catalyst 1011 was found to promote clean substitution to generate ester 9a in 63% ee (Table 1, entry 1).
Table 1.
Thiourea-catalyzed addition of 8a to 1-chloroisochroman (7) to give ester 9a
| entry | catalyst | conversion (%)a | ee (%)b |
|---|---|---|---|
| 1 | 10 | 88 | 63 |
| 2 | 11 | 69 | 54 |
| 3 | 12 | 97 | 73 |
| 4 | 13 | 78 | -41 |
| 5 | 14 | 96 | 81 |
| 6 | 15 | 98 | 85 |
| 7 | 16 | 59 | 42 |
Determined by 1H NMR analysis of crude reaction mixtures relative to an internal quantitative standard.
Determined by HPLC analysis using commercial chiral columns.
Systematic evaluation of a variety of thioureas revealed that both the bis(trifluoromethyl)aniline and the tertiary benzyl amide components were important for achieving useful reaction rates at low temperatures.12 Incorporation of an additional stereogenic center within the benzyl amide imparted a measurable detrimental (mismatched) or complementary (matched) influence on enantioselectivity: (S,S)-11 induced reaction with diminished (54%) ee and lower conversion while (R,S)-12 afforded 9a in 73% ee (Table 1, entries 2 and 3). Reasoning that the conformations available to the benzyl amide may be tied closely to reaction enantioselectivity, we hypothesized that appropriately constrained amide components might prove advantageous. Indeed, 2-phenylpyrrolidine-derived thiourea (R,S)-14 provided ester 9a in 81% ee.13 Catalysts lacking an aryl group in the amide component (e.g. 16, entry 7) induced slower reaction rates and diminished enantioselectivity. This observation, taken together with the relative rates and enantioselectivities of catalysts 11/12 and 13/14, suggests that the aromatic group may engage in stabilizing interactions between the catalyst and oxocarbenium ion or silyl ketene acetal in the rate-determining transition state. Pursuant to this possibility, evaluation of several catalysts with varying aryl substitution led to the identification of fluoroaryl catalyst 15 as optimal.12
With the identification of a suitable catalyst, the substrate scope of this transformation was explored (Table 2 and Figure 1). Thiourea 15 induced high ee’s in additions of the commercially available methyl acetate-derived silyl ketene acetal 8b to a variety of isochroman derivatives. The substituted chloroisochromans were prepared from the corresponding methyl acetals and used directly without purification in a one pot, two-stage procedure. Saponification of ester 9a provided the corresponding carboxylic acid, which was found to be levorotatory, and therefore assigned as the (S)-enantiomer by comparison to previously published data.14 Symmetric tetrasubstituted silyl ketene acetals afforded addition products with uniformly high enantioselectivities (Figure 1). When conducted on a 5 mmol scale using 5 mol% of catalyst 15, ester 18a is produced in 95% yield (1.1 gram) and 91% ee (TON = 19, TOF > 3 h-1).
Table 2.
Enantioselective addition of silyl ketene acetal 8b to provide substituted isochromans
| entry | R | time (h) | product | yield (%)a | ee (%)b |
|---|---|---|---|---|---|
| 1 | H | 6 | 9b | 87 | 85 |
| 2 | 5-Me | 7.5 | 9c | 71 | 90 |
| 3 | 6-Me | 7.5 | 9d | 82 | 84 |
| 4 | 7-Me | 7.5 | 9e | 82 | 87 |
| 5 | 6-F | 21 | 9f | 70 | 90 |
| 6 | 6-OMe | 22 | 9g | 96 | 74 |
Isolated yield (based on 6) after silica gel chromatography.
Determined by HPLC analysis on commercial chiral columns.
Figure 1.
Addition of tetrasubstituted silyl ketene acetals to provide substituted isochromans.
The successful enantioselective catalysis of silyl ketene acetal addition to racemic 1-chloroisochromans raises interesting mechanistic questions. The products are isolated in >50% yield in good-to-excellent ee’s that were found to remain constant over the course of the reaction. These data indicate that the described reaction is a dynamic kinetic resolution, with racemization of 7 being either spontaneous or catalyst-induced.15 Addition of 10 mol% n-Bu4NCl resulted in complete inhibition of the reaction, as would be expected in the context of a chloride-binding mode of action of 15 in these substitutions.16 Reaction rates and enantioselectivities were observed to be dependent on the concentration and nature of the silyl ketene acetal. While the observation of SN2 kinetics requires that the nuceophile is engaged in the rate-determining step, it is consistent with a oxocarbenium chloride-thiourea complex as the reactive electrophilic species.17,18
This work brings oxocarbenium ions into the realm of viable electrophilic substrates for asymmetric catalysis. Taken together with our previously described reactions of N-acyliminium ions, thiourea catalysis by anion-binding provides a general mechanism for enantioselective additions to cationic intermediates. We anticipate that this mode of catalysis will find use in related reactions of oxocarbenium ions, such as diastereoselective glycosyl-bond formation, and this is the focus of ongoing research.19
Supplementary Material
Acknowledgment
This work was supported by the NIGMS (GM-43214), by predoctoral fellowship support to A.G.D. from the NSF, and postdoctoral fellowship to S.E.R. from the NIH. We thank Dr. Kevin Campos (Merck Process) for helpful discussions and generous donations of N-boc-2-arylpyrrolidine derivatives.
References
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