•ARTICLES• https://doi.org/10.1007/s11426-020-9768-x. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Silicon-mediated enantioselective synthesis of structurally diverseα-amino acid derivatives

Jun-Han Ma1, Li Li1, Yu-Li Sun1, Zheng Xu1, Xing-Feng Bai2, Ke-Fang Yang1, Jian Cao1,Yu-Ming Cui1, Guan-Wu Yin1 & Li-Wen Xu1,2*

1Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, and Key Laboratory of OrganosiliconMaterial Technology of Zhejiang Province, Hangzhou Normal University, Hangzhou 311121, China;

2State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute (SRI) and Lanzhou Institute of Chemical Physics(LICP), University of Chinese Academy of Sciences (UCAS), Lanzhou 730000, China

Received January 20, 2020; accepted May 7, 2020; published online May 27, 2020

The catalytic asymmetric synthesis of novel and chiral amino acid derivatives with unconventional chemo-, diastereo-, andenantio-selectivity remains a paramount challenge. Herein we reported a novel protocol for the use of highly enantioselectivecopper-catalyzed cycloaddition of α,β-unsaturated acylsilanes as a springboard reaction for the facile synthesis of structurallydiversified pyrrolidines and complicated α-amino esters by desilylation. The newly developed process could provide a widerange of synthetically useful acylsilane-substituted pyrrolidines (ASiP) in high yields and excellent diastereo- and enantio-selectivities with Cu/(R)-XylBINAP complex as the catalyst. And the downstream desilylation transformation enables to expandthe potntial applications of 1,3-dipolar cycloaddition in the construction of structurally unique amino acid derivatives, in whichan unprecedented and concerted fluoride anion-promoted C–X (X=H, Si, N, C) bond cleavage occurred to the enantioselectiveconstruction of aldehyde-substituted pyrrolidines, linear cinnamaldehyde or alkene-substituted amino esters in high ee values.

(3+2) cycloaddition, asymmetric catalysis, acylsilane, pyrrolidine, amino aldehyde, amino acids

Citation: Ma JH, Li L, Sun YL, Xu Z, Bai XF, Yang KF, Cao J, Cui YM, Yin GW, Xu LW. Silicon-mediated enantioselective synthesis of structurally diverse α-amino acid derivatives. Sci China Chem, 2020, 63, https://doi.org/10.1007/s11426-020-9768-x

1 Introduction

The silicon, one of the most abundant elements in the earth,is playing more and more important part in material chem-istry and organic synthesis. In the field of silicon-mediatedorganic synthesis (SiMOS), one of the core issues is themanipulation ability of the formation and cleavage of Si–Cbond that inaccessible from nature [1]. Significantly, it re-mains a paramount challenge of achieving highly chemo-,diastereo-, or enantio-selectivity. Through the molecular le-vel of design and transformation of silicon-containing mo-lecules, SiMOS has been recognized as a rising strategy to

the construction of organosilicon or complicated organicmolecules in a privileged model [2]. In this regard, acylsi-lanes are known to be the unique, non-intuitive silyl ketones[3] and represented a class of synthetically useful and ex-tremely important structural motifs in organosilicon chem-istry [4]. Usually, acylsilanes are recognized as the maskedaldehydes and unconventional acyl anion precursors in theselective synthesis of novel carbonyl compounds [5,6].Moreover, acylsilanes can exhibit their beneficial to suppressthe potential side or undesired reactions during the trans-formations and/or as the weakly coordinating substrates inC–H functionalization, because they are much more steri-cally congested compared with the precursor aldehydes [7–9]. Furthermore, the thermally or photochemically induced

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*Corresponding author (email: liwenxu@hznu.edu.cn)

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Brook rearrangements (1,2-silicon-to-oxygen migrations) ofacylsilanes [10], enabled to construct some complicatedstructures or natural products via the potential cascade re-actions in the development of synthetic methodology [11–14]. Although the application of acrysilanes in C–C bondformation attracted considerable synthetic interests [15–17],the use of α,β-unsaturated acylsilanes in chiral synthesisappeared more attractive [18–20]. To date, most of trans-formations of α,β-unsaturated acylsilanes based on the re-duction of carbonyl moiety but not the bifunctionalization ofC=C double bond. Recently, Leyssens and Riant et al. [21]reported a copper-catalyzed 1,2-hydroborylation of α,β-un-saturated acylsilanes, in which the chiral α-hydroxysilaneswere enantioselectively generated in the presence of chiralMeO-biphep under room temperature. Based on the Brookrearrangement, (3+2) and (3+4) annulations were proven tobe effective for the facile preparation of carbocycles oroxygen-based heterocycles [22,23], while attempts to applythis strategy with difunctionalization of α,β-unsaturatedacylsilanes remained underlying. To the best of our knowl-edge, no example of catalytic asymmetric (3+2) cycloaddi-tion of α,β-unsaturated acylsilanes via 1,3-dipolarcycloaddition has been reported to date.Undoubtedly, discovery of the catalytic asymmetric (3+2)

cycloaddition reaction of azomethine ylides and EWG-acti-vated alkenes (EWG=electron-withdrawing group) providedan atom-economic process for the construction of numerousfive-membered amino acid derivatives (Figure 1, Eq. (A1))and its azaheterocyclic cores-containing molecular scaffoldsthat become a complementary method to the enantioselectivesynthesis of amino acids by alkylation of glycine aldiminoesters or its analogues (Figure 1, Eq. (A2)) [24–27]. Sinceacylsilanes are often considered as the masked aldehydes[5,6], we were intrigued with the possibility of preparing thealdehyde-containing pyrrolidines by utilizing the aforemen-tioned 1,3-dipolar (3+2) cycloaddition, which is an importantatom-economical strategy for the enantioselective construc-tion of N-heterocycles based on carbon-carbon bond for-mation [28–30]. However, there is no report on the catalyticasymmetric (3+2) cycloaddition of α,β-unsaturated acylsi-lanes with glycine-derived azomethine ylides (Figure 1, Eq.(B)) and no related transformations for the ring-openingprocess of pyrrolidines to the construction of linear aminoacid derivatives. It should be noted that, the catalyticasymmetric synthesis of novel and chiral amino acid deri-vatives with unconventional chemo-, diastereo-, and enantio-selectivity is still a challenging research area.Our initial purpose is to develop a new workable reaction

process for the potential enantioselective (3+2) cycloadditionof α,β-unsaturated acylsilanes with glycine-derived aldiminoesters to access chiral acylsilane-containing pyrrolidines(ASiP), which could be acted as a springboard for thesynthesis of novel amino aldehydes and its derivatives

through facile desilylation process. Fortunately, the initialexperiments proved that the ASiP could be served as thestarting material for the preparation of amino aldehydes andtheir analogues by the fluoride anion-promoted desilylationof acylsilane moiety. Interestingly, further investigationsrevealed an unexpected discovery that the desilylation ofacylsilane-containing pyrrolidines in the absence of waterdisclosed a new access to a wide range of previously in-accessible amino acid derivatives, including α,β-unsaturatedaldehyde-containing amino esters, linear cinnamaldehyde-substituted amino acid derivatives, or alkene-containingamino esters, in good yields and enantioselectivies throughprecise adjustment of C–X (X=H, Si, N, C) bond cleavage.

2 Experimental

2.1 General procedure for the synthesis of product 3via copper-catalyzed 1,3-dipolar (3+2) cycloaddition of 1and 2

(R)-XylBINAP (7.3 mg, 0.01 mmol) and Cu(CH3CN)4PF6(2.2 mg, 0.006 mmol) were dissolved in 2 mL dry THF un-der N2 atmosphere, and stirred at room temperature about0.5 h. Iminoesters 2 (0.30 mmol) and K2CO3 (2.8 mg,0.02 mmol) were added sequentially, then acylsilane 1(0.20 mmol) was added. Once starting material was con-

Figure 1 Catalytic asymmetric synthesis of structurally diverse aminoacid derivatives from glycine aldimino esters: from (A) catalytic asym-metric (3+2) cycloaddition (metal catalysis) to (B) silicon-mediatedsynthesis of amino acid derivatives by fluoride-catalyzed desilylation andring-opening processes of acylsilane-containing pyrrolidines (color online).

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sumed (monitored by thin layer chromatography (TLC)), themixture was filtered through celite and the filtrate was con-centrated to dryness, then the residue was purified by columnchromatography to give the corresponding addition product,which was then directly analyzed by chiral high performanceliquid chromatography (HPLC) to determine the en-antiomeric excess.

2.2 General procedure for the silicon-mediated synth-esis of amino aldehyde derivative 7 initiated by fluoride-catalyzed desilylation

To a solution of 4 (0.1 mmol) in dimethyl sulfoxide (DMSO)(2 mL), iodomethane (MeI) (0.12 mmol) under N2 atmo-sphere, and tetrabutylammonium fluoride (TBAF) (1 M,0.2 mmol) were added. The resulting mixture was stirred atroom temperature for 2 h and quenched by the addition ofwater (2 mL). The aqueous phase was extracted twice withethyl acetate (EA). The combine organic extracts were wa-shed three times with brine, dried over anhydrous Na2SO4and concentrated in vacuo after filtration. Purification bysilica gel column chromatography gave product 7.

2.3 General procedure for the silicon-mediated synth-esis of amino acid derivative 8 initiated by fluoride-cat-alyzed desilylation

To a stirred solution of 4 (0.1 mmol) and DMSO (2 mL),TBAF (1 M, 0.01 mmol) was added. The resulting mixturewas stirred at room temperature for 2 h and quenched by theaddition of water (2 mL). The aqueous phase was extractedtwice with ethyl acetate (EA). The combined organic extractswere dried over Na2SO4 and the solvent was removed underreduced pressure. Purification by silica gel column chro-matography gave product 8.Full experimental details and the characterization of new

compounds 3–8 are provided in the supporting information(Supporting Information online).

3 Results and discussion

For the initial attempts to functionalize the α,β-unsaturatedacylsilanes at the carbon-carbon double bond, the cycload-dition of 3-phenyl-1-(trimethylsilyl)prop-2-en-1-one (1a)and methyl 2-(benzylideneamino)acetate (2a) were chosenas a model reaction in the presence of Ag/Xing-Phos catalystsystem that has been identified as a highly effective in theasymmetric (3+2) cycloaddition of glycine aldimino esterswith activated alkenes, including nitroolefins, chalcones, andmethyl cinnamates [31–33]. Unfortunately, under the stan-dard reaction conditions as shown in Table S1 (SupportingInformation online), low diastereoselectivity and moderate

enantioselectivity of desired product 3a were achieved in thepresence of Ag/Xing-Phos catalyst system (up to 74% ee and74:26 d.r.). Therefore, it should be commented on differentreactivity by the comparison of α,β-unsaturated acylsilaneswith chalcones or α,β-unsaturated ketones, whereas theanalogous chalcones showed excellent diastereo- and en-atioselectivity (>98:2 d.r., up to 96% ee) in silver-catalyzed1,3-dipolar (3+2) cycloaddition in the presence of Xing-Phos[32]. Similarly, changing the silver salt to Cu(CH3CN)4PF6led to lower yield with reverse diastereoselectivity, providingan information that the α,β-unsaturated acylsilanes exhibiteddifferent reactivity in comparison to that of enones. We at-tributed this unexpected silasubstitution effect to the natureof the long Si–C bond (1.89 Å) on the α,β-unsaturatedacylsilane compounds, and there is an slightly enhancednegative polarization at the Si-linked carbonyl oxygen atom.Inspired by our recent findings that the DTBM-Segphos

was also an alternative ligand to the asymmetric silver orcopper-catalyzed 1,3-dipolar addition when Xing-Phos wasnot effective in these reactions [34–36], we carried out fur-ther investigations on the catalytic asymmetric (3+2) cy-cloaddition of 1a and 2a in the presence of Ag/DTBM-Segphos, and gratifyingly, the experiment result showed thatthe use of Cu(CH3CN)4PF6 instead of AgOAc was beneficialto the enhancement of enantioselectivity and conversion inTHF (86% ee, 88:12 d.r. and 70% yield, see Table S2). Then,we choose Cu(CH3CN)4PF6 as a catalyst to explore the Cu-catalyzed cycloaddition of the α,β-unsaturated acylsilane(1a) with 2a by varying the chiral ligands and additives (orbases) as summarized in the supporting information (for theeffect of additives on diastereo- and enantio-selectivity, seethe Tables S3, S4). After screening these reaction para-meters, we determined that the (R)-XylBINAP was the bestligand to give the desired chiral silyl pyrrolidine 3a withgood yield and excellent diastereo- and enantioselectivity(>98:2 d.r. and 98% ee, see Table 1, entry 1). And otherrepresentative P-ligands evaluated in this work exhibitedinferior diastereo- and enantio-selectivities (Table 1). Theseexperimental results suggested that the C2-axial P-ligand wasbeneficial to the enhancement of the coordinated abilitybetween copper and chiral P-ligand by precise modificationof the steric repulsion and electronic properties. And theadditive or base effect revealed that K2CO3 was an idealreagent to promote the formation of reactive 1,3-dipolarspecies and subsequent cycloaddition to α,β-unsaturatedacylsilane. Finally, we confirmed that (R)-XylBINAP incombination with Cu(CH3CN)4PF6 and K2CO3 gave the de-sired product 3a with satisfying yield and excellent diaster-eo- and enantioselectivity in THF.Next, the scope of the copper-catalyzed asymmetric (3+2)

cycloaddition was investigated (Table 2). The structure ofα,β-unsaturated acylsilanes had only a minor effect on the1,3-dipolar cycloaddition (Entries 1–11), in which most of

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silyl pyrrolidines were obtained with >98:2 d.r. and >96% ee.Similarly to that of 3-phenyl-1-(trimethylsilyl)prop-2-en-1-one (1a), all of ortho-, para-, or meta-substituted aryl α,β-unsaturated acylsilanes undergo smooth cycloaddition, pro-viding the corresponding chiral acylsilane-substituted pyr-rolidines 3a–3k bearing four continuous stereocenters inmoderate to good yields with excellent enantioselectivities(up to >92% ee and >98:2 d.r.).Then, it was found that other dipolar species derived from

substituted glycine imino esters also worked well and af-forded the corresponding acylsilane-substituted pyrrolidines3l–3t in good yields with high diastereo- and enantio-selectivities (92%–98% ees). For product 3i, the corre-sponding absolute configuration of the four stereocenterswas confirmed by X-ray diffraction analysis. Notably, thepreparation of aliphatic α,β-unsaturated acylsilanes was notan easy task according to previous methods [37,38] and ac-cordingly, there was only one additional data to support thereactivity of aliphatic α,β-unsaturated acylsilane in this re-action. In addition, varying the trimethylsilyl group (TMS) to

dimethylphenylsilyl group (–SiMe2Ph) made little or nodifference on either enantioselectivity or yield (3u: 82%yield and 94% ee). Based on the experimental observationsand precedents regarding the mechanism of copper-catalyzed(3+2) cycloaddition [28–30], we proposed a cascade cata-lytic pathway for the 1,3-dipolar cycloaddition that couldexplain the stereochemistry of copper/(R)-XylBINAP in thisreaction (Figure 2).Next, we focused on the downstream group-transformation

of acylsilanes that are known to react with aqueous tetra-hydrofuran to give the corresponding aldehydes [39,40]. Asdescribed above, the standard strategy to convert the groupof acylsilanes into aldehydes or carbonyl anions typicallyinvolves the fluoride or strong bases as charged nucleophilicspecies, such as KF, tetrabutylammonium fluoride (TBAF),and cyanide anions, to promote transformations of the car-bonyl carbon of acylsilanes with various electrophilic re-agents [41,42]. Therefore, as a masked α,β-unsaturatedaldehyde, the catalytic asymmetric cycloaddition of α,β-un-saturated acylsilanes would be acted as a springboard for the

Table 1 Optimization of catalytic asymmetric (3+2) cycloaddition of 3-phenyl-1-(trimethylsilyl)prop-2-en-1-one (1a) and methyl 2-(benzylideneamino)acetate (2a)a)

Entry Variation from standard condition Yield(%)b) d.r.c) eed)

1 none 82 >98:2 98

2 L1 instead of L10 70 88:12 86

3 L2 instead of L10 60 56:44 86(72)

4 L3 instead of L10 60 95:5 68

5 L4 instead of L10 87 48:52 62(32)

6 L5 instead of L10 32 97:3 64(28)

7 L6 instead of L10 43 41:58 34(22)

8 L7 instead of L10 42 41:58 0(6)

9 L8 instead of L10 39 79:21 86(30)

10 L9 instead of L10 58 86:14 92(28)

11 K3PO4 instead of K2CO3 62 73:27 96

12 Et3N instead of K2CO3 80 75:25 98

a) The standard reaction was carried out at 0.2 mmol scale with 3 mol% Cu(CH3CN)PF6, 5 mol% P-ligand, 10 mol% base in 2 mL THF at roomtemperature for 24 h. b) Determined by 1H NMR. c) Determined by 1H NMR and confirmed by HPLC. d) Determined by chiral HPLC, and the number inparentheses is the ee value of minor isomer.

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synthesis of chiral aldehyde-substituted pyrrolidines that areinaccessible from direct 1,3-dipolar cycloaddition of α,β-unsaturated aldehyde. In addition, whereas above methodsprovide access to enantiopure acylsilane-substituted pyrro-lidines 3 or its N-protected derivatives 4, a general method tosynthesize aldehyde-substituted pyrrolidines is not yetavailable. Thus we checked the desilylation/hydrolysis ofacylsilane-substituted pyrrolidines 4 to give aldehyde-substituted pyrrolidines 5a–5j in the presence of TBAF inTHF/H2O. As shown in Figure 3, good levels of chemos-electivity were achieved under standard reaction conditions,and the ee values of product 5maintained the same level thatconfirmed by chiral amino alcohol 6b after reduction (97%ee). Therefore, the desilylation/hydrolysis of various sub-stituted acylsilane-substituted pyrrolidines 4 made no dif-ference on enantioselectivity. And the X-ray structure of 5d

further supported that the continuous four-seterocenters ofaldehyde-substituted pyrrolidines was reserved without lossof stereoselectivity.Given the synthetic potential of desilylation of acylsilane-

substituted pyrrolidines in the construction of aldehyde-containing pyrrolidines 5 in a convergent fashion (Figure 3),we want to develop a new alkylation reaction processes withsuch unique acylsilane-containing pyrrolidines in the pre-sence of MeI. Interestingly and unexpectedly, when we uti-lized MeI to trapp the anion equivalent that derived from 4awith the presence of TBAF in anhydrous DMSO, a new typeof reaction was detected, in which the linear and N-methylamino aldehyde 7a was obtained by ring-opening procedurein good yields (63%). In general, the five-membered ring ofpyrrolidines is quite stable and the ring-opening cleavage ofcyclic amines to linear molecules was needed to be per-

Table 2 Copper-catalyzed asymmetric cycloaddition of α,β-unsaturated acylsilanesa)

Entry R Ar Yield(%)b) ee (%)c) d.r.d)

1 Ph Ph 3a: 82 98 >98:2

2 p-CF3Ph Ph 3b: 50 92 >98:2

3 p-ClPh Ph 3c: 71 96 >98:2

4 p-MePh Ph 3d: 83 98 >98:2

5e) p-BrPh Ph 3e: 60 98 >98:2

6 p-EtPh Ph 3f: 40 98 95:5

7 o-FPh Ph 3g: 74 96 >98:2

8 o-ClPh Ph 3h: 67 96 >98:2

9 o-BrPh Ph 3i: 77 96 >98:2

10 o-CF3Ph Ph 3j: 53 92 >98:2

11 m-ClPh Ph 3k: 52 98 95:5

12 Ph p-FPh 3l: 65 96 >98:2

13 Ph p-ClPh 3m: 65 92 >98:2

14 Ph p-BrPh 3n: 76 92 >98:2

15 Ph p-MePh 3o: 72 98 98:2

16 Ph p-MeOPh 3p: 62 96 92:8

17 Ph o-MePh 3q: 56 92 >98:2

18 Ph 2-naphthyl 3r: 72 92 >98:2

19 Ph m-MePh 3s: 64 98 >98:2

20 Ph m-BrPh 3t: 54 94 >98:2

21f) Ph Ph 3u: 82 94 >98:2

22 n-Pr Ph 3v: 59 0 >98:2

a) Unless otherwise noted, the reactions were carried out with 0.2 mmol of 1 and 2 (1.5 equiv.), catalyst (3 mol%), ligand (5 mol%) and base (10 mol%) in2.0 mL of THF (2 mL) under room temperature for 24 h. b) Isolated yield. c) Determined by HPLC. d) Determined by 1H NMR. e) Gram scale catalyticcycloaddition reaction (7 mmol substrate) led to 1.91 g product 3e with 62% yield, 93% ee, and >98:2 d.r. f) For the silicon-based group [Si], the use ofSiMe2Ph instead of SiMe3.

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formed under harsh conditions [43]. Notably in this case, thereaction conditions are quite mild, and there is no need ofadditional metal catalysts and oxidant agents to break thefive-membered ring of pyrrolidines. In addition, it was foundthat the amount of TBAF could be reduced to 10 mol% andthe yield was also good in anhydrous DMSO. Besides TBAF,the anhydrous solvent is a key factor to this reaction becausethe use of other solvents, such as THF, DCM, and EtOAc,resulted in poor chemoselectivity (several unidentified side-products were detected) and low yield (99:1 d.r. that confirmed by 1H NMR (coloronline).

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hyper-valent silicon intermediate. 2) Decarboxylation: thedesilylation resulted in the C–C bond cleavage in the anhy-drous DMSO, and COwas detected in this reaction. 3) Retro-aza-Michael reaction [45]: in both reaction systems showedin Figures 5 and 6, the use of TBAF in anhydrous DMSOresulted into ring-opening or retro-aza-Michael reaction, inwhich the different outcome is the nucleophilic addition ofnitrogen to MeI or trimethylsilyl (TMS) group.Based on these exciting observations regarding the

downstream transformations of acylsilane-substituted pyr-rolidines 4 to 7, we believed that the feature structure of 4 hasthe ability to facilitate the intramolecular hydride transfer orproton exchange [46] during the desilylation of acylsilane-initiated ring-opening procedure, and it would be a key stepfor the formation of aldehyde moiety of products 7. Then weinvestigated the transformation of deuterated substrate D-4aunder the optimized reaction conditions (Figure 6, eq. (1)).The H/D exchange experiment revealed that the H atom onaldehyde moiety of 7 was generated from the C4-H on pyr-rolidine ring of 4a (100% deuterium C5-D reserved on theproduct 7a). As a result, subsequent retro-aza-Michael re-action by β-elimination [47] and nucleophilic methylationresulted in the corresponding D-labeled product 7a. Simi-larly, the in situ generation of hypervalent Si–F complex

makes the C–C bond cleavage easily afford the alkene-containing amino acid derivative 8a that formed via dec-arbonylation and retro-aza-Michael reaction (Figure 6, Eq.(2)). In these transformations, the DMSO can enhance thenucleophilic ability of fluoride anion, which could be sup-ported by the change of 19F NMR (see Supporting In-formation online). Thus we checked this reaction to elucidateother possibility of hydride transfer in the presence of D-labeled water (D2O) and solvent (DMSO-d6). As shown inFigure 6 (Eqs. (2, 3)), when 10% of D2O or 200% of D2Owas used, 7% or 36% D-labeled product 7d was detectedrespectively. In addition, the DMSO-d6 was proved to bestable and did not provide hydride source in this process(Figure 6, Eq. (4)). And other experimental results for thetransformation of 4d to 8a are suggested to be not a radicalreaction but to take place through fluoride anion- promotedSi–C bond cleavage, in which the Brook rearrangement canbe triggered with C–H, C–N, and C–C bond activation tofurnish a wide range of amino acid derivatives.Therefore, for the desilylation of acylsilane-substituted

pyrrolidines 4 and related downstream transformations togive products 5–8 that showed in above figures, we proposedpossible pathways in Figure 7 for the formation of structu-rally diverse amino esters bearing aldehyde or alkene moiety

Figure 4 The reaction of chiral acylsilane-containing pyrrolidines 4 withMeI promoted by TBAF in anhydrous DMSO. Synthesis of cinnamalde-hyde-substituted linear amino ester derivatives 7 initiated by an unexpectedand concerted fluoride anion-catalyzed desilylation of 4 via C–X (X=Si, N)bond cleavage. The ratio of Z/E is >99:1 for all the products (color online).

Figure 5 The desilylation reaction of chiral acylsilane-containing pyrro-lidines 4 promoted by TBAF in anhydrous DMSO (without MeI). Catalyticsynthesis of alkene-substituted linear amino ester derivatives 8 in anhy-drous DMSO initiated by an unexpected and concerted fluoride anion-promoted desilylation of 4 via C–X (X=Si, N, C) bond cleavage (coloronline).

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on the basis of previous reports on the mechanism of desi-lylation of acylsilanes [4,17,39,48] as well as the NMRanalysis (Figures S6–S14). Especially for the unexpectedformation of linear amino ester derivatives 7 and 8, the ring-opening procedure will be very interesting, and it is probablyundergo through penta-coordinated anionic silicate inter-mediate (I)-activated β-elimination and subsequent hydridetransfer, methylation, or decarboxylation, as shown in Eqs.(2, 3) of Figure 7. For example, the transformation of 4 to 7would be completed by initial β-elimination (retro-aza-Mi-chael) and subsequent trapping of nitrogen anion inter-mediate III with MeI (Eq. (2)). Notably, the experimentalresults showed in Figure 6 supported that hydrogen atom ofaldehyde on product 7 came from the hydrogen of positionC4, and the intramolecular hydride transfer could be im-pacted by additional water during the work-up. This in-formation revealed that the β-elimination occurred before thestep of proton transfer in this reaction. Similarly, in the ab-sence of MeI, the hypervalent Si-intermediate I formed by areaction of TABF and 4 (the addition of fluoride on the si-licon) is proposed to be favorable to the retro-aza-Michaelreaction in anhydrous DMSO, which will smoothly inducedecarbonylation to give intermediate IV with the release ofacylsilane group (see Eq. (3) in Figure 7). Subsequently, thedesilylated intermediate IV is able to form the desired pro-

duct 8 during work-up procedure. Although the desilylation-initiated β-elimination of acylsilane-substituted pyrrolidines4 is understandable based on the experimental results, morestudies will be continuous undergoing in our laboratory togain more accurate realization of present reaction mechan-ism.

4 Conclusions

In the case of catalytic asymmetric cycloaddition as aspringboard to the construction of structurally diverse aminoacid derivatives, we have successfully developed a novelprotocol for highly enantioselective cycloaddition of α,β-unsaturated acylsilanes with glycine imino esters mediatedby copper/(R)-xylBINAP catalyst system. In this newly de-veloped methodology, a wide range of aromatic α,β-unsaturated acylsilanes could be directly coupled with sub-stituted glycine imino esters to generate synthetically usefulacylsilane-substituted pyrrolidines in high yields and ex-cellent diastereo- and enantioselectivities. Because of themulti-skilling acylsilane group, the silicon-mediated cataly-tic asymmetric 1,3-dipolar (3+2) cycloaddition could be re-cognized as a masked springboard to construct structurallydiversified N-protected amino aldehydes and their deriva-tives with at least two stereocenters. Representative versionof the transformations of acylsilane-substituted pyrrolidines

Figure 6 The transformation of D-4a and related experiment on thecatalytic transformation of 4d in the presence of D-labeled water or DMSO(DMSO-d6). The determination of the unexpected 1,2-hydrogen transferprocess (color online).

Figure 7 Proposed pathways for the acylsilanes as anion equivalents inthe transformations of 4 to aldehyde-substituted pyrrolidines or its deri-vatives under different reaction conditions. Path A: the desilylation trans-formations of acylsilane-substituted pyrrolidines 4 in THF/H2O; path B: thereaction of chiral acylsilane-containing pyrrolidines 4 with MeI promotedby TBAF in anhydrous DMSO; path C: the desilylation reaction of chiralacylsilane-containing pyrrolidines 4 promoted by TBAF in anhydrousDMSO (without MeI) (color online).

8 Ma et al. Sci China Chem

was completed by fluoride anion-promoted/catalyzed desi-lylation in aqueous THF, which gave the multi-substitutedpyrrolidines bearing aldehyde moiety and with four adjacentstereocenters in good yields. More importantly, anhydrousreaction conditions led to an unexpected finding on the de-termination of a concerted fluoride anion-promoted C–Xbond cleavage (X=Si, N, C) via desilylation/ring-openingretro-aza-Michael reaction/methylation, providing a privi-leged approach to the construction of the high ees’ linearcinnamaldehyde or alkene-substituted amino ester deriva-tives, which were almost inaccessible from previous reportedprotocols. A special intermediate was proposed with the aidof fluoride anion during the reaction. Fluoride anion pro-moted ring-opening retro-aza-Michael reaction and thesubsequent nucleophilic methylation or decarbonylation.Further investigation of the reaction mechanism of thefluoride anion-activated ring-opening reaction and relatedprocesses of intramolecular β-elimination on the backbone ofacylsilane-substituted pyrrolidines are currently ongoing inour laboratory.

Acknowledgements This work was supported by the National NaturalScience Foundation of China (21773051, 21702211, 21703051), ZhejiangProvincial Natural Science Foundation of China (LZ18B020001,LQ19B040001, LY18B020013), and the Hangzhou Science and TechnologyBureau of China (20180432B05). The authors thank K.Z. Jiang and X.Q.Xiao for their assistance on the MS and X-ray analysis, the technicians ofour group, and the members of our NMR, MS and HPLC departments fortheir excellent service. L.-W. Xu also thank Prof. X.Q. Hu (Zhejiang Uni-versity of Technology) and Prof. Y. Lu (National University of Singapore)for their help and discussion in this work.

Conflict of interest The authors declare no conflict of interest.

Supporting information The supporting information is available online athttp://chem.scichina.com and http://link.springer.com/journal/11426. Thesupporting materials are published as submitted, without typesetting orediting. The responsibility for scientific accuracy and content remains en-tirely with the authors.

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Silicon-mediated enantioselective synthesis of structurally diverse α-amino acid derivatives 1 Introduction2 Experimental2.1 General procedure for the synthesis of product 3 via copper-catalyzed 1,3-dipolar (3+2) cycloaddition of 1 and 22.2 General procedure for the silicon-mediated synthesis of amino aldehyde derivative 7 initiated by fluoride-catalyzed desilylation2.3 General procedure for the silicon-mediated synthesis of amino acid derivative 8 initiated by fluoride-catalyzed desilylation

3 Results and discussion4 Conclusions