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Jik Chin - One of the best experts on this subject based on the ideXlab platform.
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synthesis of enantiopure mixed alkyl aryl vicinal diamines by the diaza Cope Rearrangement a synthesis of cp 99 994
2017Co-Authors: Miji Kim, Hyun Woo Kim, Hyeseung Kim, Jik ChinAbstract:The stereoselective synthesis of mixed alkyl-aryl vicinal diamines was demonstrated by the use of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethene (hpen). A sequential addition of aryl and alkyl aldehyde to hpen gave a fused imidazolidine-dihydro-1,3-oxazine ring stereoselectively, which undergoes the diaza-Cope Rearrangement to provide mixed vicinal diimines at elevated temperature in good yields and excellent stereoselectivity. We also showed that (+)-CP-99,994 can be readily prepared by the diaza-Cope Rearrangement in overall 42% yield.
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Synthesis of Enantiopure Mixed Alkyl-Aryl Vicinal Diamines by the Diaza-Cope Rearrangement: A Synthesis of (+)-CP-99,994
2017Co-Authors: Miji Kim, Hyun Woo Kim, Hyeseung Kim, Jik ChinAbstract:The stereoselective synthesis of mixed alkyl-aryl vicinal diamines was demonstrated by the use of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethene (hpen). A sequential addition of aryl and alkyl aldehyde to hpen gave a fused imidazolidine-dihydro-1,3-oxazine ring stereoselectively, which undergoes the diaza-Cope Rearrangement to provide mixed vicinal diimines at elevated temperature in good yields and excellent stereoselectivity. We also showed that (+)-CP-99,994 can be readily prepared by the diaza-Cope Rearrangement in overall 42% yield
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Short Synthesis of Enantiopure trans-3-Arylpiperazine-2-carboxylic Acid Derivatives via Diaza-Cope Rearrangement
2012Co-Authors: Soon Ho Kwon, Sang Moon Byun, Jik ChinAbstract:An efficient synthetic method was developed for the construction of enantiomerically pure trans-3-arylpiperazine-2-carboxylic acid derivatives using diaza-Cope Rearrangement (DCR) as a key step starting from (R,R)/(S,S)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN). A complete transfer of stereochemical integrity was observed for the transformation. Piperazine ring formation from the chiral 1,2-ethylenediamine derivatives using diphenylvinylsulfonium triflate followed by oxidation using ruthenium(III) chloride monohydrate in the presence of sodium periodate provided the desired enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives.
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stereospecific synthesis of alkyl substituted vicinal diamines from the mother diamine overcoming the intrinsic barrier to the diaza Cope Rearrangement reaction
2009Co-Authors: Mima Staikova, Alan J Lough, Jik ChinAbstract:Addition of isobutyraldehyde to 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (mother diamine) cleanly gives a stable, fused imidazolidine-dihydro-1,3-oxazine ring complex. However, vigorous heating of the fused ring complex gives the diaza-Cope Rearrangement product with excellent yield and stereoselectivity. A variety of alkyl aldehydes have been used to make corresponding alkyl diamines with excellent yield and stereospecificity. DFT computation shows that the intrinsic barrier for the Rearrangement involving alkyl imines is about 7.9 kcal/mol greater than that involving aryl imines.
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stereospecific synthesis of c2 symmetric diamines from the mother diamine by resonance assisted hydrogen bond directed diaza Cope Rearrangement
2008Co-Authors: Hyun Woo Kim, Alan J Lough, Yen Thi Kim Nguyen, C P H Yen, Leonid Chagal, Moon B Kim, Jik ChinAbstract:Sixteen diphenylethylenediamine analogues including those with electron donating, electron withdrawing, and sterically bulky substituents have been prepared in good overall yields (70∼90%) and in enantiomerically pure form (>99% ee) by diaza-Cope Rearrangement reaction. A single chiral mother diamine, ((R,R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane), is reacted with appropriate aldehydes to form the initial diimines that rearrange to give all the product diimines in the (S,S) form. The daughter diamines are obtained by hydrolysis of the product diimines. Density functional theory computation shows that resonance-assisted hydrogen-bond is the main driving force behind all the Rearrangement reactions. Chiral high performance liquid chromatography and circular dichroism spectroscopy show that the highly stereospecific Rearrangement reactions take place with apparent inversion of stereochemistry.
Chun-jiang Wang - One of the best experts on this subject based on the ideXlab platform.
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catalytic asymmetric synthesis of quaternary trifluoromethyl α to e amino acid derivatives via umpolung allylation 2 aza Cope Rearrangement
2020Co-Authors: Xishang Sun, Liang Wei, Hai-yan Tao, Chun-jiang Wang, Xingheng WangAbstract:In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope Rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and e-amino acid derivatives.
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catalytic asymmetric synthesis of α trifluoromethyl homoallylic amines via umpolung allylation 2 aza Cope Rearrangement stereoselectivity and mechanistic insight
2019Co-Authors: Limin Shi, Hai-yan Tao, Chun-jiang Wang, Xishang Sun, Chong Shen, Zuofei WangAbstract:An unprecedented Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope Rearrangement of trifluoroethylisatin ketimines has been realized. The current method provides a facile access to biologically important α-trifluoromethyl-containing homoallylic amines in high yields with excellent enantioselectivity. Notably, umpolung reactivity of trifluoroethylisatin ketimine was discovered for the first time. Mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in the subsequent 2-aza-Cope Rearrangement.
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synergistic catalysis for cascade allylation and 2 aza Cope Rearrangement of azomethine ylides
2019Co-Authors: Liang Wei, Qiao Zhu, Lu Xiao, Hai-yan Tao, Chun-jiang WangAbstract:The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope Rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the Rearrangement further guided the selection of catalysts combination.
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Synergistic catalysis for cascade allylation and 2-aza-Cope Rearrangement of azomethine ylides
2019Co-Authors: Liang Wei, Qiao Zhu, Lu Xiao, Hai-yan Tao, Chun-jiang WangAbstract:Metallated azomethine ylides are commonly used for the construction of N-heterocycles and α-amino acids. Here, the authors report a synergistic Cu/Ir-catalytic system that converts aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope Rearrangement
Huw M. L. Davies - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)- Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels− Alder Reaction
2016Co-Authors: Jillian E. Spangler, Yajing Lian, Eep N. Raikar, Huw M. L. DaviesAbstract:presence of catalytic amounts of the dirhodium complex Rh2(S-DOSP)4 provides a highly enantioenriched hexacyclic product with 10 new stereogenic centers. The transformation proceeds by a cascade sequence starting with a double cyclopropanation of a benzene ring, followed by a Cope Rearrangement of a divinylcyclopropane and then an intramolecular Diels−Alder cycloaddition. The rhodium(II)-catalyzed reaction of diazo compoundsgenerates highly reactive carbenoid intermediates under very mild conditions. The energy released on formation of dinitrogen can be harnessed to generate unstable, high energy products that are often capable of initiating a cascade sequence of reactions.1,2 We have developed a number of such cascade sequences from vinyl diazoacetates, including the stereo-selective synthesis of cycloheptadienes via the tandem cyclo-propanation/Cope Rearrangement3 and the combined C−H functionalization/Cope Rearrangement/retro-Cope rearrange
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Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)-Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels–Alder Reaction
2015Co-Authors: Jillian E. Spangler, Yajing Lian, Sandeep N. Raikar, Huw M. L. DaviesAbstract:Treatment of (E)-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene with styryl diazoacetates in the presence of catalytic amounts of the dirhodium complex Rh2(S-DOSP)4 provides a highly enantioenriched hexacyclic product with 10 new stereogenic centers. The transformation proceeds by a cascade sequence starting with a double cyclopropanation of a benzene ring, followed by a Cope Rearrangement of a divinylcyclopropane and then an intramolecular Diels–Alder cycloaddition
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the combined c h functionalization Cope Rearrangement discovery and applications in organic synthesis
2012Co-Authors: Huw M. L. Davies, Yajing LianAbstract:The development of methods for the stereoselective functionalization of sp3 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 energeticall...
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computationally guided stereocontrol of the combined c h functionalization Cope Rearrangement
2011Co-Authors: Yajing Lian, Kenneth I Hardcastle, Huw M. L. DaviesAbstract: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.
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combined c h functionalization Cope Rearrangement with vinyl ethers as a surrogate for the vinylogous mukaiyama aldol reaction
2011Co-Authors: Yajing Lian, Huw M. L. DaviesAbstract: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.
Hyun Woo Kim - One of the best experts on this subject based on the ideXlab platform.
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synthesis of enantiopure mixed alkyl aryl vicinal diamines by the diaza Cope Rearrangement a synthesis of cp 99 994
2017Co-Authors: Miji Kim, Hyun Woo Kim, Hyeseung Kim, Jik ChinAbstract:The stereoselective synthesis of mixed alkyl-aryl vicinal diamines was demonstrated by the use of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethene (hpen). A sequential addition of aryl and alkyl aldehyde to hpen gave a fused imidazolidine-dihydro-1,3-oxazine ring stereoselectively, which undergoes the diaza-Cope Rearrangement to provide mixed vicinal diimines at elevated temperature in good yields and excellent stereoselectivity. We also showed that (+)-CP-99,994 can be readily prepared by the diaza-Cope Rearrangement in overall 42% yield.
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Synthesis of Enantiopure Mixed Alkyl-Aryl Vicinal Diamines by the Diaza-Cope Rearrangement: A Synthesis of (+)-CP-99,994
2017Co-Authors: Miji Kim, Hyun Woo Kim, Hyeseung Kim, Jik ChinAbstract:The stereoselective synthesis of mixed alkyl-aryl vicinal diamines was demonstrated by the use of 1,2-bis(2-hydroxyphenyl)-1,2-diaminoethene (hpen). A sequential addition of aryl and alkyl aldehyde to hpen gave a fused imidazolidine-dihydro-1,3-oxazine ring stereoselectively, which undergoes the diaza-Cope Rearrangement to provide mixed vicinal diimines at elevated temperature in good yields and excellent stereoselectivity. We also showed that (+)-CP-99,994 can be readily prepared by the diaza-Cope Rearrangement in overall 42% yield
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stereospecific synthesis of c2 symmetric diamines from the mother diamine by resonance assisted hydrogen bond directed diaza Cope Rearrangement
2008Co-Authors: Hyun Woo Kim, Alan J Lough, Yen Thi Kim Nguyen, C P H Yen, Leonid Chagal, Moon B Kim, Jik ChinAbstract:Sixteen diphenylethylenediamine analogues including those with electron donating, electron withdrawing, and sterically bulky substituents have been prepared in good overall yields (70∼90%) and in enantiomerically pure form (>99% ee) by diaza-Cope Rearrangement reaction. A single chiral mother diamine, ((R,R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane), is reacted with appropriate aldehydes to form the initial diimines that rearrange to give all the product diimines in the (S,S) form. The daughter diamines are obtained by hydrolysis of the product diimines. Density functional theory computation shows that resonance-assisted hydrogen-bond is the main driving force behind all the Rearrangement reactions. Chiral high performance liquid chromatography and circular dichroism spectroscopy show that the highly stereospecific Rearrangement reactions take place with apparent inversion of stereochemistry.
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preorganization in highly enantioselective diaza Cope Rearrangement reaction
2005Co-Authors: Haejo Kim, Hyun Woo Kim, Gamil Alhakimi, Eui June Jeong, Nirusha Thavarajah, Lisa Studnicki, Alicja Koprianiuk, Alan J Lough, Junghun Suh, Jik ChinAbstract:Crystal structure and activation entropy data indicate that H-bond directed diaza-Cope Rearrangement of chiral diimines takes place with a high degree of preorganization. CD spectroscopy and HPLC data show that there is inversion of stereochemistry for the reaction with excellent enantioselectivity.
Yajing Lian - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)- Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels− Alder Reaction
2016Co-Authors: Jillian E. Spangler, Yajing Lian, Eep N. Raikar, Huw M. L. DaviesAbstract:presence of catalytic amounts of the dirhodium complex Rh2(S-DOSP)4 provides a highly enantioenriched hexacyclic product with 10 new stereogenic centers. The transformation proceeds by a cascade sequence starting with a double cyclopropanation of a benzene ring, followed by a Cope Rearrangement of a divinylcyclopropane and then an intramolecular Diels−Alder cycloaddition. The rhodium(II)-catalyzed reaction of diazo compoundsgenerates highly reactive carbenoid intermediates under very mild conditions. The energy released on formation of dinitrogen can be harnessed to generate unstable, high energy products that are often capable of initiating a cascade sequence of reactions.1,2 We have developed a number of such cascade sequences from vinyl diazoacetates, including the stereo-selective synthesis of cycloheptadienes via the tandem cyclo-propanation/Cope Rearrangement3 and the combined C−H functionalization/Cope Rearrangement/retro-Cope rearrange
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Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)-Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels–Alder Reaction
2015Co-Authors: Jillian E. Spangler, Yajing Lian, Sandeep N. Raikar, Huw M. L. DaviesAbstract:Treatment of (E)-1-(methoxymethylene)-1,2,3,4-tetrahydronaphthalene with styryl diazoacetates in the presence of catalytic amounts of the dirhodium complex Rh2(S-DOSP)4 provides a highly enantioenriched hexacyclic product with 10 new stereogenic centers. The transformation proceeds by a cascade sequence starting with a double cyclopropanation of a benzene ring, followed by a Cope Rearrangement of a divinylcyclopropane and then an intramolecular Diels–Alder cycloaddition
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the combined c h functionalization Cope Rearrangement discovery and applications in organic synthesis
2012Co-Authors: Huw M. L. Davies, Yajing LianAbstract:The development of methods for the stereoselective functionalization of sp3 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 energeticall...
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computationally guided stereocontrol of the combined c h functionalization Cope Rearrangement
2011Co-Authors: Yajing Lian, Kenneth I Hardcastle, Huw M. L. DaviesAbstract: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.
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combined c h functionalization Cope Rearrangement with vinyl ethers as a surrogate for the vinylogous mukaiyama aldol reaction
2011Co-Authors: Yajing Lian, Huw M. L. DaviesAbstract: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.