A Highly Active Polymer-Supported Catalyst for Asymmetric Robinson Annulations in Continuous Flow

Abstract

ABSTRACT:The preparation through Robinson annulation of enantiopure building blocks with both academic and industrial relevance, such as the Wieland-Miescher and Hajos-Parrish ketones, has suffered from important drawbacks, such as the need of high catalyst loading or extremely long reaction times. Here we report a heterogeneized organocatalyst based on Luo's diamine for the fast and broad-scope enantioselective Robinson annulation reaction. The polystyrene-supported diamine 19a enables the high-yield, highly enantioselective preparation of a wide scope of chiral bicyclic enones under mild conditions, with reaction times as short as 60 minutes (batch) or residence times of 10 minutes (flow). In contrast with its homogeneous counterpart 19b, the catalytic resin 19a experiences a notable increase in catalytic activity with temperature in 2-MeTHF (a ten-fold decrease in reaction times without erosion in enantioselectivity is observed from room temperature to 55 ºC). The scope of the transformation in batch has been illustrated with 14 examples, including examples only reported in poorly enantioenriched (22n) or in racemic form (22k). Enantiopure 22k has been used as starting material for a straightforward formal synthesis of the antibiotic and antifeedant sesquiterpene (−)-isovelleral (24). The heterogeneized catalyst 19a admits extended recycling (10 cycles) and has been used to develop the first asymmetric Robinson annulations in continuous flow. The potential of the flow process is illustrated by the large scale preparation of the Wieland-Miescher ketone (65 mmol in 24 h operation, TON of 117) and by a sequential flow experiment leading to a library of eight enantioenriched diketone compounds. KEYWORDS : Robinson annulation, Continuous flow, Heterogeneized catalysts, Wieland-Miescher ketone, Hajos-Parrish ketoneThe Hajos-Parrish-Eder-Sauer-Wiechert (H-P-E-S-W) reaction to access chiral bicyclic enones, via an intramolecular aldol reaction, is one of the most well-known organocatalytic processes. 1 Reported in 1971 by two independent industrial research groups, this L-proline-catalyzed process enables the isolation of enantioenriched Wieland-Miescher (W-M, 1) and Hajos-Parrish (H-P, 2) ketones (Figure 1). 2 While high enantioselectivity was achieved for the H-P ketone (2), the W-M ketone (1) was obtained with moderate enantioselectivity. In both cases, prolonged reaction times were required. Enantioenriched W-M and H-P ketones provide access to a broad variety of sesquiterpenoids, diterpenoids and steroids. 1b,3 Biological activities of these compounds include antimicrobial, anticancer, antiviral and antineurodegenerative effects. 3 For these reasons, since 2000, following the seminal work by List and Barbas on the use of proline as a catalyst for enantioselective aldol reaction, 4 there has been a resurgent interest in achieving more efficient routes for these catalytic processes. 5 As a result, several new organocatalysts have emerged for the synthesis of these bicyclic enones. 3a-b Among them, most structures ...

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…However, the synthetic methods for these ketones have some defects such as high catalyst loading and very long reaction times (from 10 h to 7 d). Recently, Pericàs and co‐workers used an immobilized chiral vicinal‐diamine promoted Robinson annulation reaction to construct W‐M and H‐P ketones in very short reaction times (1–2 h). In this article (Scheme ), they compared the catalytic activity with homogeneous catalyst 88 , homogeneous analog 89 , and heterogeneous catalyst 90 .…”

Catalytic Enantioselective Flow Processes with Solid‐Supported Chiral Catalysts

“…A synthetic sequence that hinged on the preparation of a chiral aziridine furnished 17 (without triazole linker in this case) in six steps from tert ‐leucine. To our delight, going from room temperature to 55 °C with resin 17 , did not affect the ee's, but the reaction times were reduced by a 10‐fold . Strikingly, its homogeneous analogue 16 did not show such a significant improvement when heating up, indicating that the interplay of polymer and temperature generates a special situation.…”

Assessing the Recyclability of Supramolecularly Assembled Organocatalytic Species: A Theoretical Insight

“…[11] On the other hand, we have recently reported the covalent immobilization onto polystyrene of Luo's diamine [12] leading to an extremely active catalyst for the enantioselective Robinson annulation. [13] Our initially reported supramolecular catalysts [10] suffered, however, from poor recyclability and we considered that replacement of the cyclodextrin host by a cucurbituril (CB) could solve this problem. We present in this manuscript an attempted improvement of the catalyst recycling methodology described above via replacement of the β-cyclodextrin part with a cucurbit[7]uril (CB[7]) host.…”