Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of β‐Carbolines Using Diazo Compounds as Radical Precursors

Abstract Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of β‐carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of β‐carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo‐/enantio‐selective control, and good functional group tolerance, allowing access to a variety of valuable chiral β‐carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.


Introduction
Chiral -carbolines and their derivatives are widely acknowledged as remarkable and privileged scaffolds in biologically active compounds, pharmaceuticals, and natural products (Figure 1) ref. [1].The asymmetric synthesis of chiral -carbolines has garnered significant attention due to their unique structural features, diverse potent biological activities, and their ability to DOI: 10.1002/advs.202402272access a broad range of bio-important molecules. [2]Traditionally, the asymmetric synthesis of -carbolines has primarily relied on the introduction of chirality through preinstalled chiral functional groups during the construction of the -carboline core.This strategy guides the stereochemical outcome through subsequent multistep transformations. [3]In contrast to advances in the catalytic asymmetric synthesis of enantioenriched tetrahydro--carbolines, [4] the direct enantioselective construction of chiral -carbolines using catalytic methods, particularly through the C─H functionalization process, has received comparatively less attention and remains a formidable challenge. [5]The deficiency of effective catalytic systems and appropriate transformations that permit efficient enantioselective synthesis is the cause of this constraint. [6]he Minisci-type reaction has emerged as a significant strategy for constructing complex molecules, demonstrating promising potential in the direct C─H functionalization of N-heteroarenes via radical addition to electrophilic N-heteroarenes. [7]he recent advancements in catalytic asymmetric Minisci reactions make it accessible to realize the direct enantioselective synthesis of chiral -carbolines. [8,9]Catalytic asymmetric Minisci reactions employing cooperative photoredox and chiral Brønsted acid catalysis have been achieved with various electrondeficient azaarenes, such as quinolines, isoquinolines, pyridines, and pyrimidines. [10]In 2019, Studer and colleagues explored an enantioselective three-component Minisci-type reaction of quinolines or pyridines, enamides, and -bromo carbonyl compounds as radical precursors, enabling access to chiral functionalized quinoline or pyridine derivatives in a single synthetic operation. [11]More recently, Jiang and co-workers reported a photocatalyzed asymmetric three-component Minisci-type reaction of quinoxalin-2(1H)-ones, styrenes, and 2-bromo-1-arylenthan-1ones for the enantioselective chemodivergent synthesis of two series of valuable products (Scheme 1). [12]In these cascade radical transformations, the presence of bases is essential in the catalytic system to neutralize the generated HBr, thereby suppressing the background reaction and ensuring reliable asymmetric induction.These enantioselective cascade Minisci-type reactions offer several advantages, including increased efficiency, rapid assembly of molecular diversity, and the versatile ability to access complex structures that may be challenging to synthesize through stepwise approaches. [13]However, the develop- ment of enantioselective multicomponent Minisci reactions remains in its infancy.It is important to note that such asymmetric cascade Minisci reactions present ongoing challenges, requiring compatible reactivity of each component and precise control over chemo-/stereochemistry at each step.Considering the significance of chiral -carboline derivatives, we envision a catalytic asymmetric multicomponent Minisci reaction of -carbolines utilizing diazo compounds as the radical precursors, providing  an effective, and straightforward pathway to construct valuable highly-functionalized chiral -carboline products (Scheme 1).However, several challenges need to be circumvented in this enantioselective cascade multicomponent Minisci process, including the reduced reactivity of -carbolines due to their inherently more electron-rich nature, [5,14] the highly unstable and easily decomposing nature of diazo compounds, [15] and the possible competitive side reactions involving enamides, and diazo compounds. [16]This strategy has been successfully applied in the highly efficient asymmetric synthesis of bioactive chemicals and natural products, demonstrating its effectiveness, and viability.
We proceeded to investigate the performance of various substituted N-vinylacetamides in conjunction with carboline 1a and -diazo ester 3a (Scheme 4).Other substituted N-vinylacetamides, such as N-vinylbutyramide and Nvinylcyclohexanecarboxamide, were demonstrated to be compatible in the transformation, accomplishing the enantioselective cascade Minisci reaction with good yields, and enantioselectivities (6b,6c, 71-75% yields, and 81-89% ee).N-vinylformamide could also be employed in this transformation to generate the desired product 6d with reasonable yield and decreased enantioselectivity (61% yield, 35% ee), which might be dictated by the steric effect.However, tert-butyl vinylcarbamate 2e exhibited significantly reduced reactivity, likely due to its electronic properties.Substituted N-vinylacetamide (E)-N-(prop-1-en-1-yl)acetamide 2f was demonstrated to be not suitable for this transformation and might be affected by the steric hindrance (for more details, see supporting information).

Derivatizations and Applications
1f,21] To showcase the potential applications of the enantioselective multicomponent cascade Minisci reaction of -carbolines, various transformations of the chiral -carboline products were conducted.Starting with chiral -carboline product 4d (93% ee), an intramolecular lactamization was performed under basic conditions, resulting in chiral -lactam product 7. Subsequently, -lactam 7 could be further reduced to dihydroeudistomin I 8 (82% yield, 92% ee) with complete retention of enantiomeric purity (Scheme 5A).Importantly, dihydroeudistomin I 8 could be easily transformed into alkaloid eudistomin I through treatment with N-chlorosuccinimide. [22] Reduction of the chiral -carboline product 4d (93% ee) with DIBAL-H yielded the corresponding alcohol 9, which underwent triflate formation, intermolecular annulation, and reduction of N-alkyl pyridinium salt sequence to provide a four-membered heterocyclic tetrahydro--carboline 10.Subsequent removal of the acetyl group from 10 under acidic conditions led to the formation of 1-aminoindolo[2,3-a]quinolizidine product 11 (91% ee) without erosion of the ee value (Scheme 5B).This intermediate could be employed for the convenient construction of pharmacologically interesting E-azaburnane-type compounds. [23]Chiral -carboline product 5l (95% ee) underwent intramolecular lactamization to form the -lactam compound 12, followed by selective methylation to deliver the corresponding N-Methyl carboline salt 13 with 79% yield over two steps.Subsequently, compound 13 underwent reduction using NaBH 4 , affording the corresponding tetrahydro--carboline 14 with good yield and diastereoselectivity (79% yield, >10:1 dr).Further reduction of 14 led to the formation of a pyrrolidine product.2b,24] The above-described transformations highlight the versatility and synthetic potential of this enantioselective multicomponent Minisci protocol.

Reaction Insights
To get insights into the mechanism of this enantioselective multicomponent Minisci reaction, several control experiments were performed (Scheme 6).18b] Reducing the amount of TEMPO to 1.0 equivalent produced the target product 4a with a decreased yield from 80% to 20% and compound 16 with 65% yield (Scheme 6A).18b,25] As mentioned above, 9-methyl--carboline 1q was demonstrated to be unreactive in this transformation, which might arise from the steric hindrance of substituents.Furthermore, the replacement of Nvinylacetamide 2a with N-methyl-N-vinylacetamide 2g in the reaction provided the corresponding product 6g with 19% yield and negligible enantioselectivity, indicating that the hydrogen bonding from vinylacetamide plays an essential role in the reaction activity and enantioselective control (Scheme 6C). [11]ased on the above results and previous research, [9,11,18b] we proposed the catalytic cycle described in Scheme 7. Upon exposure to blue light irradiation, the Ir(III) complex undergoes photoexcitation and generates a photoexcited *Ir(III) species, which engages in a reduction reaction of the diazo compound through a proton-coupled electron transfer (PCET) process to generate an oxidized iridium Ir(IV) species and a radical intermediate I. [26] The generated -carbonyl radical species I then undergoes intermolecular electrophilic radical addition with the enamide, leading to the formation of nucleophilic radical II.Through a bidentate binding process aided by the chiral Brønsted acid catalyst, the -aminoalkyl radical II engages in a Minisci-type addition to the protonated -carboline VII, giving rise to radical cation species IV.The radical cation IV is transformed into species V through an intramolecular deprotonation process assisted by the N-acetyl group. [19]Following additional deprotonation by an external carboline molecule, the protonated intermediate V produces the protonated -carboline VII, and radical species VI. [19] The radical species VI is oxidized by the Ir(IV) complex, followed by deprotonation, providing the target chiral -carboline product, and renewing the photosensitizer Ir(III) catalyst.

Conclusion
In summary, we have demonstrated a highly enantioselective radical cascade multicomponent Minisci reaction of -carbolines using diazo compounds as radical precursors, enabling straightforward access to a wide range of valuable highly-functionalized chiral -carbolines with good yields and high enantioselectivities (up to 83% yield and 95% ee).The cascade asymmetric Minisci protocol features its step-economy, high efficiency, and wide functional group compatibility.Noteworthy, the diazo compound has been illustrated to be an effective radical precursor in enantioselective multicomponent radical reactions.The efficiency and practicality Scheme 7. Proposed mechanism for asymmetric cascade multicomponent Minisci reaction of -carboline.
of this approach have been demonstrated by its successful application in the asymmetric syntheses of bioactive compounds and natural product.Further exploring and leveraging the potential of valuable catalytic asymmetric cascade Minisci-type reactions is ongoing research in our lab.

Table 1 .
Optimization of reaction conditions.