The Diels-Alder reaction - Massey gjrowlan/stereo2/ Organic Chemistry The Diels-Alder reaction • Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings • Normally DA

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  • 123.702 Organic Chemistry

    The Diels-Alder reaction

    Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings Normally DA is highly regioselective (as seen above) It is controlled by the relative sizes of the p orbitals in the LUMO & HOMO involved More accurately referred to as the orbital coefficients In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity

    and a faster reaction

    1

    NMe2

    +CO2Me

    NMe2CO2Me

    NMe2CO2Me

    HOMO LUMO

    Me

    +CO2Me

    +

    MeCO2Me

    Me

    CO2Memajor minor

    Me+

    CHO

    Me

    CHO+

    Me CHO

    toluene, 120C, no catalystbenzene, 25C, SnCl4

    5996

    ::

    414 Lewis acid improves

    selectivity

    regioselectivity often follows simple electronic argument (consider which C is +ve or ve)

    +

    +

    +

    +

    +

    +

    +

    +

    +

  • 123.702 Organic Chemistry

    B

    A

    D

    C B

    AH

    HDHC

    H AC

    DB

    exo

    exo

    B

    AH

    DHCH

    H AC

    DB

    endo

    B

    A

    D

    Cendo

    B

    AC

    D

    Endo vs. exo selectivity

    Endo transition state & adduct is more sterically congested thus thermodynamically less stable

    But it is normally the predominant product The reason is endo transition state is stabilised by orbital overlap of the group on

    C or D with the diene HOMO; an effect called secondary orbital overlap

    The reaction is suprafacial and we observe that the geometry of the diene & dienophile is preserved

    2

    favoured

    secondary orbital overlap

  • 123.702 Organic Chemistry

    Diels-Alder reaction

    The cube method is a nice way to visualise the relative stereochemistry

    Finally, remember that the dienophile invariably reacts from the less hindered face If you are a little rusty on the Diels-Alder reaction either re-read your lecture notes or

    any standard organic text book

    3

    draw a cube

    add the diene

    add dienophile (endo product has

    substituents directly under diene)

    remember other substituents

    present

    do reaction (make new

    bonds)

    A

    B CD B

    A

    CD B

    AH

    H

    HH C

    D

    A

    B

    should be able to see relative stereochemistry

    CD

    A

    B

    H

    HH

    H CD

    HH

    HHB

    A

    OMe

    NO2

    +

    HMeO

    H

    O2N NO2

    H

    HMeO

  • 123.702 Organic Chemistry

    + O N O

    O

    MeMe

    single(ish) diastereoisomer

    Et2AlClR

    R = H 86% deR = Me 90% de>98% endo

    achiral diene

    ON

    O

    MeMe

    O

    R

    chiral dienophile

    Cl

    O

    OHN

    O

    MeMe

    (S)-valine derivative

    R

    1 : 1 mixture of enantiomers

    O OBn

    +

    O OBnCl

    O BnOH

    OBn

    O

    achiral diene

    +

    achiral dienophile +

    Chiral auxiliaries on the dienophile

    One diastereoisomer is formed - the endo product But mixture of enantiomers If we add a chiral auxiliary then there are two possible endo diastereoisomers But one predominates - thus we can prepare a single enantiomer

    4

    O OBn

    BnOH

    single enantiomer

    R

  • 123.702 Organic Chemistry

    ON

    O

    MeMe

    OAl

    Et Et

    NO

    Et2Al O

    OH

    MeMe

    Et2AlCl2

    ON

    O

    MeMe

    O

    NO

    Et2Al O

    OH

    MeMe

    NO

    Et2Al O

    OH

    MeMe

    Explanation of diastereoselectivity

    Coordination to the Lewis acid activates dienophile The rigid chelate governs reactive conformation (s-cis) as s-trans disfavoured iso-Propyl group blocks bottom face Dienes approach maximises secondary orbital overlap and favours endo product

    5

    lower face blocked

    s-cis favoured

    s-trans disfavoured

  • 123.702 Organic Chemistry

    Me Me

    NS O

    R

    O O TiLn

    Me Me

    NS

    OO

    O

    R +TiCl478C

    RH

    NOO2S

    MeMeR = H 99% deR = Me >97% de>98% endo

    Camphor-derived auxiliary

    A range of auxiliaries can be utilised Most give good diastereoselectivities

    6

    Me Me

    NSO2 O

    R

  • 123.702 Organic Chemistry

    Me

    O

    O MeMe

    BnO

    CO2R

    H

    BnO

    Me

    O

    O MeMe

    HH

    OBn

    BnOMe

    O

    O MeMe

    AlCl3+

    Chiral auxiliaries II

    It is possible to attach the chiral auxiliary to the diene as well

    7

    O

    O OH

    O

    OOMe

    H Ph +B(OAc)3

    O

    O

    OHO

    O

    H

    H

    MeO

    H Ph

    >95% deendo

    phenyl group blocks lower face

    diene approaches from the top

  • 123.702 Organic Chemistry

    Chiral auxiliary controlled DA in total synthesis

    Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA) Note how it sets up 4 stereocentres and the central ring of ()-stenine ()-Stenine is isolated from Stemona family of subshrubs is a constituent of a variety

    of Eastern folk medicines This synthesis is by Morimoto Y, Iwahashi M, Nishida K, Hayashi Y, Shirahama H,

    Angew. Chem. Int. Ed. Engl., 1996, 35, 904

    8

    S S

    PMBO

    N

    O

    OO

    Me

    Ph

    Me2AlCl

    S S

    HO

    NR2*

    H

    PMBON

    O

    H

    H

    MeO

    HMe

    H

    ()-stenine

  • 123.702 Organic Chemistry

    Chiral catalysis and the Diels-Alder reaction

    The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out

    The aluminium catalyst above has been utilised in enolate chemistry (aldol) reaction and is very effective in this Diels-Alder reaction

    9

    MeON

    O

    O

    Me

    Br+cat.

    N

    O

    O

    Me

    Br

    H

    H

    MeO

    >97% ee

    NAl

    N

    Me

    SO2CF3F3CO2S

    Me

    Me Me

    Me

  • 123.702 Organic Chemistry

    i. KOHii. HCl

    O

    H

    H

    O

    OH

    + HOEt

    O

    O

    cat 2-5mol%

    72%97%ee

    O

    CO2Et

    H

    MeH

    HO

    R2N

    HO N

    MeH

    O

    O

    same as

    Me Me

    OOCu

    N N

    OO

    O N Me

    MeMe

    MeMeMe

    Me

    2+NO Me

    OO

    +

    N

    OMe Me

    N

    O

    MeMe

    Me MeMe

    Me

    CuTfO OTf

    cat 5-10mol%92%

    97%ee

    Bis(oxazoline)-based catalysts & the DA reaction

    Bis(oxazoline) ligands (Box) are amongst the most versatile & well used ligands known Simply prepared from amino alcohols (& hence amino acids) Here used in both DA and the equally useful HDA

    10

    Diels-Alder reaction

    Hetero-Diels-Alder reaction (HDA)

  • 123.702 Organic Chemistry

    TBSO

    OBn

    +

    TBDPSO

    O

    H

    NCr

    O

    Me

    O Cl

    NCr

    O

    Me

    O

    TBDPSO H

    O

    TBSO

    OBnneat, 25C64%

    97%ee

    O

    OBn

    OTBDPSTBSO

    Catalytic enantioselective HDA in total synthesis

    From the synthesis of (+)-ambruticin by Ping Liu and Eric N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 10772

    11

    TESO

    Et

    +

    OTBS

    O

    HMe

    ent-catneat, 25C

    64%97%ee

    O

    Et

    OTBSTESO

    Me

  • 123.702 Organic Chemistry

    Catalytic enantioselective HDA in total synthesis

    (+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium cellulsoum

    It has shown activity against Coccidioides immitis the cause of coccidioimycosis...

    12

    OCO2H

    OHOH

    Me MeO

    Me

    Et

    Me(+)-ambruticin

  • 123.702 Organic Chemistry

    OMeN

    N

    Et

    ArO Me

    N

    NMeO

    OMeEt

    96% eeendo / exo >200 : 1

    cat. (20%)HClO4

    OMe

    +Et

    O COEt

    OMe

    Organocatalysis and the Diels-Alder reaction

    Organic secondary amines can catalyse certain Diels-Alder reactions The reaction proceeds via the formation of an iminium species This charged species lowers the energy of the LUMO thus catalysing the reaction In addition one face of dienophile is blocked thus allowing the high selectivity

    13

    NH

    NMe

    Ph

    O

    O Me

  • 123.702 Organic Chemistry

    Organocatalysis and total synthesis

    The marine metabolite solanapyrone D is a phytotoxic polyketide isolated from the fungus Altenaria solani

    14

    CHO

    Me

    MeCHOH

    H

    Me

    H

    H

    O

    OMe

    O

    H

    O

    solanapyrone D

    cat 20mol%

    71%>20:1 dr90%ee

    N

    NH

    Bn t-Bu

    MeO

  • 123.702 Organic Chemistry

    TFA

    OPh

    OO

    O

    TBS

    Me

    OH

    O

    HPh

    H

    N N

    PhPh

    TfTf

    TBSO

    MeO

    TBSO

    OMe O

    HO

    Ph+1. cat. (10%)2. TFA

    O

    OPh

    O87% ee

    Organocatalysis and the Diels-Alder reaction

    This is an example of a hetero-Diels-Alder reaction The aldehyde is the dienophile We have to use a very electron rich diene The amine catalyst acts as a Lewis acid via two hydrogen bonds

    15

    OPh

    OO

    O

    TBS

    MeH

    NH H

    N

    Ph Ph

    Tf Tf

  • 123.702 Organic Chemistry

    O

    Ph

    NMeMe

    TBSOO

    HO H O H O

    H

    Ph

    HO

    TBSO

    NO

    H Ph

    MeMe

    +1. cat. (10%)2. AcCl

    O