Yajing Lian

Rhodium-Catalyzed [3 + 2] Annulation of Indoles

An effective Rh(2)(S-DOSP)(4)-catalyzed asymmetric cyclopentannulation of indolyl rings has been developed. Depending on the substitution pattern of the indole, two distinct regioisomeric products can be generated. These studies demonstrate that rhodium-catalyzed reactions of donor/acceptor carbenoids proceeding by means of zwitterionic intermediates can be carried out with very high asymmetric induction.

The Combined C—H Functionalization/Cope Rearrangement: Discovery and Applications in Organic Synthesis

The development of methods for the stereoselective functionalization of sp(3) C-H bonds is a challenging undertaking. This Account describes the scope of the combined C-H functionalization/Cope rearrangement (CHCR), a reaction that occurs between rhodium-stabilized vinylcarbenoids and substrates containing allylic C-H bonds. Computational studies have shown that the CHCR reaction is initiated by a hydride transfer to the carbenoid from an allyl site on the substrate, which is then rapidly followed by C-C bond formation between the developing rhodium-bound allyl anion and the allyl cation. In principle, the reaction can proceed through four distinct orientations of the vinylcarbenoid and the approaching substrate. The early examples of the CHCR reaction were all highly diastereoselective, consistent with a reaction proceeding via a chair transition state with the vinylcarbenoid adopting an s-cis conformation. Recent computational studies have revealed that other transition state orientations are energetically accessible, and these results have guided the development of highly stereoselective CHCR reactions that proceed through a boat transition state with the vinylcarbenoid in an s-cis configuration. The CHCR reaction has broad applications in organic synthesis. In some new protocols, the CHCR reaction acts as a surrogate to some of the classic synthetic strategies in organic chemistry. The CHCR reaction has served as a synthetic equivalent of the Michael reaction, the vinylogous Mukaiyama aldol reaction, the tandem Claisen rearrangement/Cope rearrangement, and the tandem aldol reaction/siloxy-Cope rearrangement. In all of these cases, the products are generated with very high diastereocontrol. With a chiral dirhodium tetracarboxylate catalyst such as Rh(2)(S-DOSP)(4) or Rh(2)(S-PTAD)(4), researchers can achieve very high levels of asymmetric induction. Applications of the CHCR reaction include the effective enantiodifferentiation of racemic dihydronaphthalenes and the total synthesis of several natural products: (-)-colombiasin A, (-)-elisapterosin B, and (+)-erogorgiaene. By combining the CHCR reaction into a further cascade sequence, we and other researchers have achieved the asymmetric synthesis of 4-substituted indoles, a new class of monoamine reuptake inhibitors.

Asymmetric [4 + 3] Cycloadditions between Vinylcarbenoids and Dienes: Application to the Total Synthesis of the Natural Product (−)-5-epi-Vibsanin E

The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).

Catalyst-Controlled Formal [4 + 3] Cycloaddition Applied to the Total Synthesis of (+)-Barekoxide and (−)-Barekol

The tandem cyclopropanation/Cope rearrangement between bicyclic dienes and siloxyvinyldiazoacetate, catalyzed by the dirhodium catalyst Rh(2)(R-PTAD)(4), effectively accomplishes enantiodivergent [4 + 3] cycloadditions. The reaction proceeds by a cyclopropanation followed by a Cope rearrangement of the resulting divinylcyclopropane. This methodology was applied to the synthesis of (+)-barekoxide (1) and (-)-barekol (2).

On the Mechanism and Selectivity of the Combined C−H Activation/Cope Rearrangement

The combined C-H activation/Cope rearrangement (CHCR) is an effective C-H functionalization process that has been used for the asymmetric synthesis of natural products and pharmaceutical building blocks. Up until now, a detailed understanding of this process was lacking. Herein, we describe a combination of theoretical and experimental studies that have resulted in a coherent description of the likely mechanism of the reaction. Density functional studies on the reactions of rhodium vinylcarbenoids at allylic C-H sites demonstrate that the CHCR proceeds through a concerted, but highly asynchronous, hydride-transfer/C-C bond-forming event. Even though most of the previously known examples of this process are highly diastereoselective, the calculations demonstrate that other transition-states and stereochemical outcomes might be possible by appropriate modifications of the reagents, and this was confirmed experimentally. The calculations also indicate that there is a potential energy surface bifurcation between CHCR and the competing direct C-H insertion.

Rh2 (S-biTISP)2-Catalyzed Asymmetric Functionalization of Indoles and Pyrroles with Vinylcarbenoids

Asymmetric functionalization of N-heterocycles by vinylcarbenoids in the presence of catalytic amounts of Rh(2)(S-biTISP)(2) has been successfully developed. This bridged dirhodium catalyst not only selectively enforces the reaction to occur at the vinylogous position of the carbenoid but also affords high levels of asymmetric induction.

Combined C—H Functionalization/Cope Rearrangement with Vinyl Ethers as a Surrogate for the Vinylogous Mukaiyama Aldol Reaction

Vinyl ethers selectively undergo the combined C-H functionalization/Cope rearrangement reaction via an s-cis/boat transition state. With chiral dirhodium catalysts, products are generated in a highly diastereoselective and enantioselective fashion. This reaction can be considered as a surrogate to the traditional vinylogous Mukaiyama aldol reaction. Effective kinetic resolution has been achieved, leading to the recovery of a cyclic vinyl ether with axial chirality of high enantiomeric purity.

Rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles.

An unusual rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles is described. These studies show that (Z)-vinylcarbenoids have a greater tendency than (E)-vinylcarbenoids to react at the vinylogous position of the carbenoid rather than at the carbenoid center.

Reversal of the Regiochemistry in the Rhodium‐Catalyzed [4+3] Cycloaddition between Vinyldiazoacetates and Dienes

A regio-, diastereo-, and enantioselective [4+3] cycloaddition between vinylcarbenes and dienes has been achieved using the dirhodium tetracarboxylate catalyst [Rh2(S-BTPCP)4]. This methodology provides facile access to 1,4-cycloheptadienes that are regioisomers of those formed from the tandem cyclopropanation/Cope rearrangement reaction of vinylcarbenes with dienes.

Computationally guided stereocontrol of the combined C-H functionalization/Cope rearrangement.

Developing practical methods for C—H functionalization has attracted considerable attention from the synthetic community.[1] One of the major challenges in this field is to achieve transformations that are not only site selective, but also stereoselective.[2] One highly stereoselective intermolecular C—H functionalization method is the combined C—H functionalization/Cope rearrangement (CHCR) between allylic C—H bonds and vinylcarbenoids.[3] This transformation can generate two new stereocenters. When chiral dirhodium catalysts such as Rh2(S-DOSP)4[4] are used, the products are formed essentially as single diastereomers and in the majority of cases with >97% ee. This method has been developed into a powerful protocol for the synthesis of natural products and pharmaceutical targets.[3] In all of the studies reported to date, the stereochemistry is consistent with a reaction occurring on the s-cis conformation of the vinylcarbenoid and proceeding through a chair transition state as illustrated in [Eq. (1)]. (1) Recently, we have completed a detailed computational study of the CHCR reaction.[5] The reaction was shown to be an asynchronous process, involving an initial hydride transfer event followed by carbon-carbon bond formation. Even though all the previously reported examples of the CHCR reactions are highly diastereoselective, the calculations showed that different product outcomes are possible, depending on whether the s-cis or s-trans con of the vinylcarbenoids[6] are involved and whether the reaction proceeded through a chair or a boat transition state. Furthermore, the calculations on a model system showed that the transition states for other products were energetically accessible. In particular the s-cis chair transition state was only 2 kcal/mole more stable than the s-cis boat transition state. Inspired by the computational studies, this paper is directed towards switching the diastereoselectivity of the CHCR reaction by forcing the reaction to proceed through the s-cis boat transition state B instead of the s-cis chair transition state A (Figure 1). Figure 1 The chair and boat transition states for the CHCR reaction. In order to limit the number of potential transition states available for the CHCR reaction, the study described herein was conducted with β-siloxyvinyldiazoacetates. The carbenoid derived from E-vinyldiazoacetates has little preference for the s-trans over the s-cis configuration,[5] whereas the internal substituent in the vinylcarbenoid derived from the β-siloxyvinyldiazoacetate strongly prefers the s-cis configuration.[5] In the s-trans configuration, the siloxy group would be pointing towards the “wall” of the catalyst (Figure 2). Figure 2 The s-cis and s-trans configurations of the rhodium carbenoid derived from 1. Previous studies have shown that Rh2(S-PTAD)4 (Figure 3) is the optimum chiral catalyst for asymmetric reactions with siloxyvinyldiazoacetate 1.[7] In order to test a baseline substrate, the Rh2(S-PTAD)4 catalyzed reaction of diazoacetate 1 with the siloxycyclohexene 2a was examined [Eq. (2)]. Characterizable material was obtained by hydrolysis of the silyl enol ether of the crude product followed by conversion of the β-keto ester to the β-keto-α-diazoacetate 3a in 74% yield for the three-step sequence.[8] The β-keto-α-diazoacetate 3a was formed as a single diastereomer with 89% ee. The reaction with the bulky siloxycyclohexene 2b selectively afforded the diazoacetate 3b with even higher enantioselectivity (97% ee). The relative and absolute configuration of product 3b was unambiguously determined using X-ray crystallography.[9] Figure 3 Structures of Rh2(S-DOSP)4 and Rh2(S-PTAD)4. (2) The observed stereochemistry is consistent with the previously published examples of the CHCR reaction and would occur in a reaction proceeding through a chair transition state.[3e] An examination of the two possible transition states reveals that in the boat transition state C the remainder of the cyclohexyl ring would be pointing towards the “wall” of the catalyst, and therefore, it would be reasonable to propose that this arrangement would be unfavorable (Figure 4). Figure 4 s-Cis/boat transition state model for reaction of 1 with 2. We envisioned that a possible way to limit the steric influence of the ring would be to use a smaller ring size. Indeed, when the reaction was repeated with the siloxycyclopentene 4, two diastereomers of the CHCR product 5 were produced in a 4/1 ratio [Eq. (3)]. This is the first example of a CHCR reaction generating a mixture of diastereomeric products. (3) Further evaluation of the proposed transition states D and E related to the formation of 5, suggested that the cyclopentyl ring could be incorporated into the boat transition state E (Figure 5). Furthermore, it became evident that a 2-substituent on the cyclopentenyl ring would cause the chair transition state D to be destabilized. If this proved to be the case, then the opposite diastereomeric series of products would become accessible. Figure 5 Transition state models for reaction of 1 with cyclopentenes. The Rh2(S-PTAD)4 catalyzed decomposition of siloxydiazoacetate 1 in the presence of 1,2-disubstituted cyclopentenyl derivatives afforded the β-keto-α-diazoacetates 6–11 as summarized in Table 1. In all cases, a single CHCR product was produced with excellent diastereoselectivity (dr >30 : 1) and enantioselectivity (>97% ee). In the case of the unsymmetrical cyclopentene substrates, the resulting products, 6, 7 and 9, are derived from site selective C—H functionalization initiated at the methylene group allylic to the siloxy group. The relative and absolute configuration of 7 was unambiguously assigned by X-ray crystallography. The stereochemical configurations of products 9 and 10 were also unambiguously confirmed by X-ray crystallography of products derived from them (see supporting information). In each case, the relative configuration was consistent with a reaction proceeding through a boat transition state, and is opposite to the products 3a and 3b derived from the cyclohexene derivatives 2a and 2b. The structures of 6, 8 and 11 were tentatively assigned by assuming they are formed through a similar boat transition state. Table 1 The CHCR reactions with cyclopentenyl derivatives Normally, the CHCR reaction is influenced by the presence of other stereogenic centers in the substrate and high levels of enantiomeric differentiation have been reported.[3a–d] Consequently, we explored if a desymmetrization would be feasible in a CHCR reaction. The reaction with cyclopentene 12 successfully generated product 13 as a single diastereomer with extremely high enantioselectivity [Eq. (4)]. This represents the first example of desymmetrization in the CHCR reaction. The relative configuration of 13 inside the ring was assigned by nOe studies and was consistent with the outcome predicted by a boat transition state model (see SI), while the stereochemistry in the chain was tentatively assigned assuming a boat transition state. (4) In conclusion, the synthetic utility of the CHCR reaction has been greatly expanded by the design of substrates that will react through a boat transition state instead of a chair transition state. This has lead to the formation of the reversed diastereomeric series of products in a highly stereoselective manner. This study demonstrates the value of computational studies, not only to rationalize a new synthetic process, but also, to identify opportunities to develop new chemistry. The results showcase the synthetic potential of using carbenoid chemistry to achieve highly enantioselective C—H functionalization reactions.