Catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides: diastereo- and enantioselective synthesis of imidazolidines

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  • Catalytic asymmetric homo-1,3-dipolar cyylides: diastereo- and enantioselective sy

    Ren-Yi Zhu, Cong-Shuai Wang, Fei Jiang, Feng Shi , ShSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic C

    tricchiateenicto 9idazste

    azomethine ylides to unsaturated bonds haerful tool to access chiral nitrogenous hetexisted in numerous natural products and apharmaceutical relevance.1 As a result,

    d in thtron-de scaffoselect1,3-DCgen do

    at the precursorserated from alde-nitrogen

    es via homDCs under the catalysis of CPA, thus affording chiral imidazowith multiple stereogenic centers (Scheme 1). In this appazomethine ylides would act as both 1,3-dipoles and diphiles to perform diastereo- and enantioselective homo-1,3-DCs,which have not been reported so far during the development ofcatalytic asymmetric 1,3-DCs of azomethine ylides.

    Herein we report the rst catalytic asymmetric homo-1,3-DCsof azomethine ylides, which assemble aldehydes and 2-aminomal-onates in a highly ordered reaction sequence to efciently

    N R3R1

    R2

    H

    N

    NHR

    1

    R2

    R3

    ArR

    only a few enantioselectivetransformations are available

    Cat.*

    Cat.* **

    N

    Ar

    R*imineazomethine ylide

    imidazolidine

    pyrolidine

    (2)

    Corresponding author. Tel./fax: +86 (516) 83500065.E-mail address: fshi@jsnu.edu.cn (F. Shi).

    Tetrahedron: Asymmetry xxx (2014) xxxxxx

    Contents lists availab

    Tetrahedron:

    journal homepage: www.elstereoselective imidazolidines, we envisioned thof azomethine ylides, that is, the aldimines genhydes and amino-esters would serve as carbonAbonds to react with the same azomethine ylid

    EWGR4

    R5 R6

    NR1

    R2

    R3

    EWG

    R6

    R5 R4

    many enantioselectivetransformations are available**

    * *olefin

    (1)http://dx.doi.org/10.1016/j.tetasy.2014.03.0080957-4166/ 2014 Elsevier Ltd. All rights reserved.

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.008doubleo-1,3-lidinesroach,polaro-volves the use of imines derived from anilines and aldehydes asdipolarophiles as reported by Gong et al. and Wang et al. (Eq. 2).3

    as dipolarophiles.We have already established a series of 1,3-DCs of azomethine

    ylides to electron-decient olens7 or alkynes8 with excellentenantioselectivity using chiral phosphoric acids (CPAs)9 as cata-lysts. Inspired by this success and with the aim of synthesizing

    previous work on catalytic asymmetric 1,3-DCs:transformations have been develope1,3-DCs of azomethine ylides to electo the formation of chiral pyrolidinin sharp contrast, only a few enantifound for the catalytic asymmetricto electronically poor carbonAnitrove proven to be a pow-erocyclic motifs, whichrticial molecules withmany enantioselectivee catalytic asymmetricecient olens, leadingolds (Eq. 1).2 However,ive variants have beens of azomethine ylidesuble bonds, which in-

    natural products, bioactive compounds, and important catalystsor ligands in organic synthesis. For example, as illustrated inFigure 1, fumiquinazolines A and B I are natural alkaloids.4 Com-pounds IIIV possess antipyretic, anticonvulsant, and aldosereductase inhibitory activities, respectively.5 Compounds VVIIare well known organocatalysts or ligands, which have enabled avariety of enantioselective transformations.6 Therefore, this trans-formation is highly desirable for the stereoselective construction ofthe imidazolidine moiety and remains a challenge with regard tothe limited examples employing carbonAnitrogen double bonds1. Introduction

    Catalytic asymmetric 1,3-dipolar cycloadditions (1,3-DCs) of

    On the other hand, the catalytic asymmetric 1,3-DCs of azome-thine ylides to imines would allow for the creation of a chiral imi-dazolidine skeleton, which constitutes the core structure of manya r t i c l e i n f o

    Article history:Received 22 January 2014Accepted 7 March 2014Available online xxxx

    a b s t r a c t

    The rst catalytic asymmelished via SPINOL-derivedhydes and 2-aminomalonscaffolds with two stereog81% yield, all >20:1 dr, uptically important chiral imfour new bonds in a singlecloadditions of azomethinenthesis of imidazolidines

    u-Jiang Tuhemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, China

    homo-1,3-dipolar cycloadditions of azomethine ylides have been estab-ral phosphoric acid-catalyzed pseudo four-component reactions of alde-s, resulting in the stereoselective construction of chiral imidazolidinecenters in generally high yields and with good stereoselectivities (up to

    3% ee). This protocol provides easy access to synthetically and pharmaceu-olidines via the formation of one ring system, two stereogenic centers, andp.

    2014 Elsevier Ltd. All rights reserved.

    le at ScienceDirect

    Asymmetry

    sevier .com/locate / tetasy

  • an

    gens

    ort

    AsyNN

    TsSMe

    O

    O

    OR

    antipyretic

    N

    NNH

    O

    O

    Me

    N

    OH

    NH

    MeO

    H

    fumiquinazoline A and B

    NH

    NO

    Me

    Me

    Me

    Bn

    MacMillan's catalyst

    BnI

    II

    VJo

    Figure 1. Selected natural alkaloids, bioactive compounds, and imp

    this work: the first catalytic asymmetric homo-1,3-DCs

    N

    CO2R

    R1

    RO2C

    N

    CO2RCO2R

    R1

    +Homo-1,3-DCs

    CPAN

    NH

    CO2R

    CO2R

    RO2C

    RO2C R1

    R1*

    *

    CPA

    stereoselective formationof imidazolidines

    2 R.-Y. Zhu et al. / Tetrahedron:construct chiral imidazolidines with two stereogenic centers inhigh yields (up to 81%) and with good stereoselectivities (all>20:1 dr, up to 93% ee). This approach also takes advantage of apseudo four-component reaction, which forms one ring system,two stereogenic centers, and four new bonds in a single step.

    2. Results and discussion

    The initial experiments to test our hypothesis started with apseudo four-component reaction of 4-nitrobenzaldehyde 1a anddiethyl 2-aminomalonate 2a in the presence of various BINOL-de-rived CPAs 4 at 25 C in chloromethane (Table 1, entries 17).Although these reactions afforded the desired imidazolidineproduct 3aa, the yield was rather low, which indicated that thehomo-1,3-DCs of azomethine ylides were challenging because ofthe relatively low activity of azomethine ylides acting as dipolaro-philes. The preliminary screening of catalysts also revealed thatCPAs 4f and 4g could give product 3aawith higher enantioselectiv-ity than others (entries 6 and 7 vs 15). Changing CPA 4f to H8-BINOL-derived CPA 5a with the same 3,30-substituents of theBINOL backbone improved the enantioselectivity to 69% ee, butwithout any improvement in the yield (entry 8). Recently, SPI-NOL-derived CPAs have been recognized as a type of chiralBrnsted acids that possess higher capability in enantioselectivecontrol than their BINOL-based analogues.10 Hence, we changedthe H8-BINOL backbone of catalyst 5a to a SPINOL scaffold and em-ployed this type of spiro-CPA 6a to the same reaction. As expected,this structurally more rigid catalyst 6a enabled the model reactionto proceed in a much more efcient and enantioselective manner,affording imidazolidine 3aa in 68% yield and 87% ee (entry 9). Inthe presence of CPA 6a, the screening of molecular sieves (MS)

    R1 CHO + H2NCO2R

    CO2R

    Scheme 1. The design of catalytic asymmetric homo-1,3-DCs of azomethine ylides.

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: Asymmwere subsequently performed, which showed that 4 MS wasmuch superior to 3 and 5 MS, both in terms of reactivity andenantioselective control (entry 9 vs 10 and 11).

    Next, other reaction parameters including solvents, tempera-ture, and catalyst loading were optimized to further improve theenantioselectivity (Table 2). The screening of solvents (entries15) found that chloroform was the most suitable one, enablingthe model reaction to proceed in a high yield of 74% and with anexcellent enantioselectivity of 90% ee (entry 3). With regard tothe temperature (entries 6 and 7), we found that 40 C gave thebest performance in providing product 3aa in 76% yield and 91%ee (entry 6). However, increasing the catalyst loading was detri-mental to the enantioselectivity of the reaction without any obvi-ous improvements in the yields (entries 8 and 9). The most suitablereaction conditions are found in entry 6.

    With the optimal reaction conditions in hand, we next investi-gated the substrate scope of the catalytic asymmetric homo-1,3-DCs of azomethine ylides. As shown in Table 3, this protocol wasamenable to a wide range of aromatic, heteroaromatic aldehydes1a1m and different amino-esters 2a,2b, providing chiral imidaz-olidines 3 with structural diversity in generally acceptable yieldsand with good stereoselectivities. Most of the electronically pooraldehydes proved to be suitable substrates in giving the homo-1,3-DCs with high enantioselectivities (8093% ee, entries 15, 8,

    O

    N

    N

    O

    O

    OEt

    Ph

    Me**

    ticonvulsant

    O

    NHHN

    O

    O

    F

    OH

    inhibiting aldose reductase

    NH

    NMe

    CO2HN

    HN

    NN

    NH

    Bn

    Ph

    Ph

    Ph

    Bn

    Ph

    PyBidine ligand

    III IV

    VI VII

    en's catalyst

    ant catalysts or ligands containing a chiral imidazolidine skeleton.

    mmetry xxx (2014) xxxxxx10, and 1417). Nevertheless, for some of the benzaldehydessubstituted with electron-withdrawing groups, the enantioselec-tivities were moderate (entries 6, 7, and 9), which indicated thatthe electronic nature of the substituents might have an eff

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