Research Summary. Lei Jiao, Ph.D. in Chemistry

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1 esearch Summary Lei Jiao, Ph.D. in Chemistry My research focused on three aspects of organic chemistry: developing new reactions, mechanistic study on organic reactions (both experimental and computational), and total synthesis of natural products. The aim of the research is to develop novel and synthetically useful reactions, and to understand them at the molecular level. The major lines of my research are summarized as follows: Studies on the stereochemistry of the Staudinger [ + ] ketene-imine cycloaddition. iming to figure out the relationship between the substrate structure and stereochemical outcome (cis or trans) of the Staudinger reaction, this study consisted of a series of carefully designed ammett analyses as well as other experiments. generic stereochemical model of the Staudinger reaction was proposed based on the experimental findings, and the substituent electronic/steric effects were rationalized. hodium-catalyzed cycloaddition chemistry of vinylcyclopropane derivatives. esearch under this topic constituted the major part of my Ph.D. thesis. variety of intra- and intermolecular cycloaddition reactions of vinylcyclopropane (VCP) derivatives under h(i)-catalysis were developed, delivering six- to eight-membered carbocycles embedded in a bicyclic or tricyclic structure. Total syntheses of several polycyclic natural products were achieved using these reactions as the key skeleton-building step. The reaction mechanism was investigated by DFT computation. egioselective C- alkylation reaction on heterocycles. -eterocycles, including indole and pyrrole, were employed as ideal substrates in a palladium-catalyzed norbornene-mediated alkylation process. egioselective direct alkylation on C (for indole) or C5 (for C-substituted pyrrole) was achieved by employing primary alkyl bromides as the alkylation reagent. The reaction mechanism was investigated in detail, and the alkylation reaction was successfully applied to the synthesis of structurally complex spidosperma alkaloids. The research corresponding to the first two areas was completed at Peking University from 00 to 00 under the supervision of Profs. Jiaxi u (the Staudinger reaction) and Zhi-iang Yu (rhodium catalysis). The contributions of my collaborators, who have co-authored the related publications, are greatly acknowledged (Dr. Yong Liang, Mr. Changxia Yuan, Dr. Siyu Ye, and Mr. Mu Lin). The research on heterocycle C- activation was conducted at Technical University of Munich in Prof. Thorsten ach s laboratory during my lexander von umboldt postdoctoral fellowship (starting from 00).

2 . Studies on the Stereochemistry of the Staudinger eaction bjective: The Staudinger ketene-imine [ + ] cycloaddition reaction of unsymmetric ketenes and imines delivers β-lactam products with different relative configurations (cis or trans). The dependence of the observed stereochemical outcome on substrate structure has been a long-standing problem and no general and comprehensive rationalization was provided. We are interested in establishing a generic stereochemical model for the Staudinger reaction by detailed mechanistic investigations. esults: We first established a model reaction as the platform on which all studies were done. α-diazocarbonyl compounds were employed as the ketene precursor to cleanly generate monosubstituted ketenes under thermal conditions via Wolff rearrangement. series of Staudinger reaction with different electronic/steric substituents on either ketene or imine (i.e.,,, and ) were conducted and the cis/trans ratios of the cis k corresponding β-lactam k trans k k a cis- -lactam products were measured. + k y correlating the d k ' C k cis/trans ratios to the k electronic nature of D trans- -lactam ketene or imine substituents using ammett analysis, we figured out that the electronic substituents on both ketene and imine moieties controls the competition between direct cyclization of zwitterionic intermediate C (k, leads to cis product) and isomerization of the imine moiety in intermediate C (k, leads to trans product), and these competitive pathways finally determine the diastereoselectivity. This model addresses the stereochemical issues in the Staudinger reaction and provides a simple way to T PhS rationalize or predict the stereochemical catalyst free + PhS stereospecific outcome of a given Staudinger reaction. This acyclic and cyclic imines C PhS C yield 7099% research is highly evaluated and cited as one of the key references in the Staudinger reaction in many followed publications. PhS PhS C cat. h (c) 4 C nu Sn, I, 00 C (±) or Zn, c, 60 C C (±) major 6796% yield stereospecific 7097% yield trans : cis up to >95:5 Two synthetic projects were derived from this mechanistic study, utilizing phenylthio diazoacetates as ketene precursors in the synthesis of β-lactam derivatives, especially

3 bicyclic β-lactams. The advantages of this method are the clean generation of phenylthio-substituted ketenes and their high-yielding cycloadditions with various imines, as well as facile removal of the phenylthio functionality. The Staudinger reaction between unsymmetric disubstituted ketenes and imines has a more complicated stereochemical scenario, which was investigated by a combined experimental DFT-Calculated Potential Energy Surface and computational study. Since imine can (on LYP/6-G(d) Level) G sol (98 K) kcal/mol TS-in TS-out TS-out TS-in 8.8 approach the disubstituted ketene from both sides, the. 9.0 preference for imine attack exerts influence on the stereochemistry of the reaction. 0 I-out Previous literature reports -.5 I-in proposed exclusive torquoelectronic effect control of the stereoselectivity. owever, donor-out pathway donor-in pathway based on this study, we pointed out that the relative activation energy barrier of imine-to-ketene attack and ring-closure in both donor-in and donor-out pathways is another important control factor of stereochemistry. In certain cases the stereochemistry of the Staudinger reaction is not controlled by the torquoselectivity, which can be well understood by the proposed mechanistic model. Publications resulting from this research area:. rigin of the elative Stereoselectivity of the β-lactam Formation in the Staudinger eaction. Lei Jiao, Yong Liang, and Jiaxi u* J. m. Chem. Soc. 006, 8, Catalyst-Free, igh-yield, and Stereospecific Synthesis of -Phenylthio β-lactam Derivatives. Lei Jiao, Yong Liang, Qianfeng Zhang, Shiwei Zhang, and Jiaxi u* Synthesis 006, Versatile thod for the Synthesis of -lkoxycarbonyl β-lactam Derivatives. Lei Jiao, Qianfeng Zhang, Yong Liang, Shiwei Zhang, and Jiaxi u* J. rg. Chem. 006, 7, ew Insights into the Torquoselectivity of the Staudinger eaction. Yong Liang, Lei Jiao, Shiwei Zhang, Zhi-iang Yu,* and Jiaxi u* J. m. Chem. Soc. 009,,

4 . hodium-catalyzed Cycloaddition Chemistry of Vinylcyclopropane Derivatives bjective: Vinylcyclopropane (VCP) was reported to participate in cycloaddition reactions with π-components under transition-metal catalysis. With a long-standing interest in this field, we hope to explore novel and synthetically useful cycloaddition reactions of VCPs by designing new VCP substrates with different substitution patterns. Complex polycyclic cycloadducts bearing various functional groups are target products. esults: series of novel VCP-participated cycloadditions were realized under h(i)-catalysis. The VCP motif functions as either a three-carbon component or a five-carbon component, and other cycloaddition components can be a π-component (alkene, alkyne, and allene) or carbon monoxide. These cycloadditions have found use in organic synthesis, as demonstrated by applications in the synthesis of polycyclic natural products. vinylcyclopropane (VCP) h(i) (C) [(5+)+]/aldol [+] [+] [(+)+] (±)-hirsutene (±)--desoxyhypnophilin C (±)-hirsutic acid C (±)- -agarofuran The first project in this area is the development of a tandem h(i)-catalyzed [(5 + ) + ]/aldol reaction and its application in the synthesis of linear triquinane natural products. specially designed -ene-vcp substrate with a silyloxyl group on the C-position of cyclopropane moiety was employed. Therefore, directly after the h(i)-catalyzed [(5 + ) + ] cycloaddition via intermediate, an intramledular aldol condensation could be triggered on intermediate to construct the linear triquinane structure. The tandem process proceeded with excellent diastereocontrol, delivering the linear tricyclic cycloadduct as a sole diastereomer. C C cat. [h(c) ] h TS Concise and efficient syntheses of C 80 C TS 6% hirsutene and -desoxyhypnophilin were then achieved by further manipulations steps on this cycloadduct. This tandem [(5 + ) + ]/aldol reaction could also work on TS (±)-hirsutene 4steps several other -ene-vcp substrates to generate a series of structurally versatile linear triquinane compounds. (±)--desoxyhypnophilin The intramolecular cycloaddition of a series of -ene-vcp substrates, in which the alkene unit was tethered to the C-position of VCP with a,-trans configuration, was studied following the previous project. Unexpectedly, trans--ene-vcps exhibited an intriguing intramolecular cycloaddition mode under h(i)-catalysis, undergoing a [ + ] 4

5 [h(c) ] (5 mol %) cycloaddition, rather than a [5 + ] cycloaddition, toluene, 90-0 C, or to afford cis-fused bicyclic cyclopentanes in good [h(c) ] (5 mol %) 50-80% yield gtf (0 mol %) toluene, 0 C 8examples yields. pparently, the cyclopropane moiety of VCP cyclized with the alkene to form the [h(c) ] (5 mol % ) five-membered ring, leaving the vinyl moiety Ts Ts toluene, 90 C (75%) intact. owever, the reaction did not occur when 9% ee h(i) 9% ee vinyl moiety was absent, indicating the role of VCP as an integrated cycloaddition partner. Ts Ts Ts During this reaction the stereochemistry of VCP is C C conserved, as indicated by the complete transfer h h or C h of chirality from an optically active C trans--ene-vcp substrate to the corresponding [ + ] cycloadduct, which is consistent with the proposed reaction mechanism. The next reaction discovered is this line is the intramolecular [ + ] cycloaddition of -ene/yne-vcps. cationic h(i)-phosphine complex, [h(dppp)]sbf 6, was found to be an efficient catalyst for the cycloaddition between the C=C or C C bond and the cyclopropane unit in -ene/yne-vcp substrates. This cycloaddition delivered bicyclic cyclopentane and cyclopentene derivatives in good yields, which bear a vinyl-substituted quaternary bridgehead stereocenter. The reaction mechanism has been studied by DFT calculation. Similar to other VCP-participated cycloadditions, the reaction is initiated by the formation of π-allyl rhodium species. The π-component tethered to the C-position of VCP was placed proximal to C and distal to Cβ in intermediate. Then alkene/alkyne insertion into the C-h bond generates intermediate, which is the rate- and stereochemistry-determining step in this reaction. eductive elimination in intermediate between C and the terminal carbon of the π-component forges the second C C bond to deliver the [ + ] cycloadduct. follow-up study on the -ene/yne-vcp participated cycloaddition revealed the potential of these substrates to undergo carbonylative cyclization. In a C atmosphere, -yne/ene-vcps underwent a carbonylative [( + ) + ] cycloaddition in the presence of [h(c) ] catalyst. icyclic cyclohexenone/cyclohexanone products were obtained in good yields, rendering a homologous Pausen-Khand reaction. This reaction was believed to proceed in a similar mechanism to the [ + ] cycloaddition of -ene/yne-vcps via intermediates and. In the presence of C, intermediate undergoes C complexation and insertion, followed by reductive elimination to deliver the carbonylative cycloadduct. When a -yne-vcp substrate bearing a preexisted stereogenic center was employed, the [( + ) + ] cycloaddition proceeded with a good diastereocontrol to afford the bicyclic cyclohexenone in a good yield. The cycloadduct served as a key intermediate in the total synthesis of 5

6 C h(i) C h. Ce,a 4, 0 C. Mgr TF, 0 C (9%, steps) C/ :4 [h(c) ] (5 mol %) toluene, 70 to 80 C 9examples 60-90% yield C h C C/ :4 [h(c) ] (5 mol %) toluene, 80 C (86%, dr 5:) C C C h C -agarofuran furanoid sesquiterpene natural product α-agarofuran. In this research field, VCP has been recognized as a multifunctional component to participate in various cycloadditions to construct functionalized five- to eight-membered carbocycles under h(i)-catalysis. The exploration of unprecedented cycloaddition modes of VCP derivatives by tuning their substitution pattern has resulted in fruitful achievements, which constituted the major part of my Ph.D. thesis. Publications resulting from this research area:. Tandem h(i)-catalyzed [(5+)+] Cycloaddition/ldol eaction for the Construction of Linear Triquinane Skeleton: Total Syntheses of (±)-irsutene and (±)--Desoxyhypnophilin. Lei Jiao, Changxia Yuan, and Zhi-iang Yu* J. m. Chem. Soc. 008, 0, h(i)-catalyzed Intramolecular [+] Cycloaddition of trans-vinylcyclopropane-enes. Lei Jiao, Siyu Ye, and Zhi-iang Yu* J. m. Chem. Soc. 008, 0, h(i)-catalyzed Intramolecular [+] Cycloadditions of -Ene-, -Yne- and -llene-vinylcyclopropanes. Lei Jiao, Mu Lin, and Zhi-iang Yu* Chem. Commun. 00, 46, h(i)-catalyzed [(+)+] Cycloaddition of -Yne/Ene-Vinylcyclopropanes and C: omologous Pauson-Khand eaction and Total Synthesis of (±)--garofuran. Lei Jiao, Mu Lin, Lian-Gang Zhuo, and Zhi-iang Yu* rg. Lett. 00,, Formal Total Synthesis of (±)-irsutic cid C Using the Tandem h(i)-catalyzed [(5+)+] Cycloaddition/ldol eaction. Changxia Yuan, Lei Jiao, and Zhi-iang Yu* Tetrahedron Lett. 00, 5, Density Functional Theory Study of the chanisms and Stereochemistry of the h(i)-catalyzed Intramolecular [+] Cycloadditions of -Ene- and -Yne-Vinylcyclopropanes. Lei Jiao, Mu Lin, and Zhi-iang Yu* J. m. Chem. Soc. 0,, Vinylcyclopropane Derivatives in Transition-tal-Catalyzed Cycloadditions for the Synthesis of Carbocyclic Compounds. (JCSynopsis paper) Lei Jiao and Zhi-iang Yu* J. rg. Chem. 0, 78,

7 . Palladium-Catalyzed egioselective C lkylation on eterocycles bjective: Direct C functionalization on heterocycles receives much attention from the synthetic community. Compared with direct C arylation and alkenylation, the corresponding alkylation reaction has been far less developed and is in a high demand. The aim of the present research is to invent reactions that regioselectively introduces an alkyl group to a heterocycle, particularly biorelevant -heterocycles. lkyl halides are the preferred alkyl source amongst others due to their facile availability, and the use of non-activated common alkyl halides are expected. esults: The research in this area was inspired by a previously established method for ortho-alkylation of aryl halides (the Catellani reaction). In this Pd(0)-catalyzed process, norbornene is employed as a transpositional cocatalyst that inserts into the formed aryl Pd(II) bond and dictates the formation of a reactive palladacycle intermediate to activate the ortho-position of the aryl halide substrate. n the other hand, the C activation chemistry enabled direct formation of palladated heterocycle species from a heterocycle and a Pd(II) complex. The combination of heterocycle C activation and the Catellani chemistry resulted in a new chemical transformation enabling direct regioselective alkylation on heterocycles. Indole was the first heterocycle investigated in this research, which cat. Pd(II), K C + r was found to undergo smooth DM,, C alkylation with primary alkyl Pd(II) norbornene norbornene Pd(II) bromides in the presence of a Pd(II) catalyst, norbornene, and a base. The alkyl group was regioselectively Pd II L trapped palladacycle intermediate Pd II rl introduced to the C-position of L C indole, leaving the intrinsic active Pd II C-position L intact. The reaction C C r proceeds well with both electron-rich and electron-deficient - indoles, C together with a number of alkyl TS 59% yield 58% yield 8% yield 56% yield bromides bearing various functionalities. C-substituted indoles can C u also participate in the reaction, albeit with a diminished reactivity. 6% yield 86% yield 90% yield detailed mechanistic study revealed that the reaction proceeds through - palladation, aminopalladation of norbornene, palladacycle formation, oxidative addition of an alkyl bromide, reductive elimination, norbornene elimination, and depalladation via intermediates,, and C. The key palladaheterocycle intermediate was isolated in a trapped form, whose structure was confirmed by D analysis. In a kinetic study the dependence of initial rate on substrate concentration was investigated, which is in agreement with a rate-determining oxidative addition step. 7

8 This reaction has been successfully applied to the syntheses of two spidosperma alkaloids, aspidospermidine and goniomitine. oth natural products have an alkyl group connected to the C-position of the indole core, which is envisioned to be introduced by the present indole alkylation method. In the synthesis of aspidospermidine, indole was alkylated by ethyl 4-bromo--ethylbutanoate to give a -alkylated indole intermediate. Starting from this compound, aspidospermidine was synthesized by ring-formation reactions and functional group modifications. This nine-step route to aspidospermidine ranked among one of the shortest synthetic route, giving rise to an overall yield of 5%. r C Pd (C) norbornene, K C DM, (0.5M) 70 C, r (65%) C C C C, a 4,0 C DIl- C,-78 C c-tf- :: rt (79%, steps) (±)-aspidospermidine The synthesis of goniomitine relied on the -alkylation of a -substituted indole substrate, TS protected tryptophol. lkyl iodide was used instead of the corresponding bromide, and the key,-disubstituted indole intermediate was obtained in a good yield. Further transformations, including δ-lactam formation, modification, and reduction, led to goniomitine in a good overall yield (7 steps from tryptophol, 5% overall). The brevity of both syntheses is largely attributed to the direct -alkylation reaction of indole. Given that the alkylation reaction involves the aminopalladation of norbornene by - indole, we have made an effort to apply this chemistry to other - heterocycles. Pyrrole was found to be the next heterocycle category compatible to this Pd(II)/norbornene cocatalyzed alkylation process. Electron-deficient pyrrole derivatives with C- or C,C-substitution participated in the alkylation reaction with alkyl bromides under slightly modified conditions to produce the C5-alkylation product in good yields. This reaction well complements the established pyrrole alkylation protocol and provides an efficient approach to advanced alkylpyrrole intermediates. Exploration of the potential of other heterocycles to undergo this type of direct alkylation is ongoing in the research group. Publications resulting from this research area:. Palladium-Catalyzed Direct -lkylation of Indoles by orbornene-diated egioselective Cascade C ctivation. Lei Jiao and Thorsten ach* J. m. Chem. Soc. 0,,

9 . Pd(II)-Catalyzed egioselective -lkylation of Indoles via a orbornene-diated C ctivation: chanism and pplications. Lei Jiao, Eberhardt erdtweck, and Thorsten ach* J. m. Chem. Soc. 0, 4, Palladium-Catalyzed Direct C lkylation of Electron-Deficient Pyrrole Derivatives. Lei Jiao and Thorsten ach* ngew. Chem. Int. Ed. 0, 5, egioselective Direct C- lkylation of Indoles and Pyrroles by a Palladium/orbornene- Cocatalyzed Process. (Synthesis PSP paper) Lei Jiao and Thorsten ach* Synthesis 0, doi: DI: 0.055/s