Cycle-Specific Catalysis Cascades

SCHEME 1.86 Organocatalyzed hydrofluorination reactions by cycle cascade catalysis. 

Transfer hydrogenation followed by alkylation of oc,P-unsaturated aldehydes mediated by a combination of cycle-specific catalysts of 115 and ent-196 was also developed [135]. 

It is believed that monofunctional imidazolidinones are optimal for iminium catalysis but without the necessary structural features to participate in bifunctional enamine catalysis (e.g., activation of electrophiles via electrostatic interaction). Conversely, proline has proved to be an enamine catalyst for which bifunctional activation is a standard mode of operation aCTOss a variety of transformation types, yet it is generally ineffective as an iminium catalyst with enals or enones. Therefore, a combination of imidazoUdinone and proline may provide a dual-catalyst system that could fully satisfy the chemoselectivify requirements for cycle-specific catalysis [136]. 

SCHEME 1.88 Noninterpenetrating star polymer for one-pot cascade catalysis. 

Star polymers 200 and 202 cannot penetrate each other s core and therefore are expected to maintain their catalytic integrity. On the other hand, small-molecule reagents and catalysts can freely diffuse to the core of the star polymers. MacMillan s imidazolidinone can diffuse to the core of the acid star polymer 200 to form the desired salt 201, which is an optimal iminium catalyst. Electrostatic attraction should retain 199 within the core of 200 during catalysis. The presence of strong acid p-TSA (alone or paired with imidazolidinone 199) diminishes the ability of 202 to effect iminium catalysis. Additionally, a hydrogen-bond donor catalyst 203 

---

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

SCHEME 1.89 Aza-Michael/Mannich cascade by cycle-specific catalysis. 

Perhaps the most important point in these studies was the discovery that two discrete amine catalysts could be employed to enforce cycle-specific selectivities (Scheme 3.18) [20]. Conceptually, this achievement demonstrates that these cascade-catalysis pathways can be readily modulated to afford a required... 

Cycle-specific cascade catalysis in natural product synthesis... 

Iminium-enamine cycle-specific cascade catalysis... 

Cycle-Specific Cascade Catalysis in Natural Product Synthesis... 

As mentioned above, the development of elegant approaches based on cascade catalysis, which was inspired by nature s biosynthetic proficiency for the rapid synthesis of molecular complexity, has been considered as a new tool for target-oriented synthesis. The implementation of cycle-specific cascade catalysis also provides a... 

Enamine (/Dienamine)-Iminium Cycle-Specific Cascade Catalysis... 

The enamine (/dienamine)-iminium cycle-specific cascade catalysis is an important constituent of amine-catalyzed cascade reactions [10]. This strategy has been explored extensively and also applied to natural product synthesis. One such example is the total synthesis of dihydrocorynantheol, which was first isolated from the bark of Aspidosperma marcgravianum in 1967 [29]. This indole alkaloid is a member of the corynantheine and was found to exhibit antiparasitic, antiviral, or analgetic activities, which have attracted considerable attention from the synthetic community. Among those reported total syntheses, Itoh et al. developed a Mannich-Michael cascade reaction catalyzed by L-proline 52 for the total synthesis of ent-dihydrocorynantheol 54 (Scheme 3.8) [30], The cascade reaction of 3-ethyl-3-buten-2-one 51 with dihydro-P-carboline 50 catalyzed by 30mol% of (S)-proline afforded the tetracyclic core structure 53 in 85% yield. Excellent stereoselectivity was achieved in this cascade reaction (99% enantiomeric excess and almost complete diastereomeric control). Therefore, this organocascade reaction could lead expeditiously to construction of the core structure, which enabled the authors to accomplish the total synthesis of enl-dihydrocorynantheol 54 in just five steps. 

By merging a transition metal-catalyzed reaction with an organocatalytic cascade sequence into a cycle-specific cascade catalysis, Simmons et al. developed a new... 

---