lecture 30 - enamine and iminium organocatalysis

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  • 7/28/2019 Lecture 30 - Enamine and Iminium Organocatalysis

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    December 2, 2011

    Enamine and Iminium Organocatalysis

    Scope of Lecture

    Eugene E. Kwan

    Key Questions

    proline aldolreactions

    enamine and iminiumorganocatalysis

    NH

    CO2H

    detection ofenamines

    1+rate lawanalysis

    List-Houk model

    and alternativesenantioselectivereduction ofiminium ions

    enantioselectiveDiels-Alderreactions

    cascadeorganocatalysis

    SOMO and photoredoxcatalysis

    Helpful References

    1. "The Advent and Development of Organocatalysis."Macmillan D.W.C. Nature2008, 455, 304-307.

    2. "Theory of Asymmetric Organocatalysis..." Houk, K.N. et al. Acc. Chem. Res. 2004, 37, 558-569.

    3. "Enamine Catalysis Is a Powerful Strategy..." List, B.Acc. Chem. Res.2004, 37, 548-557.

    4. "Iminium Catalysis." Pihko, P.M. et al. Chem. Rev. 2007, 107, 5416-5470.

    5. "Organocatalytic Cascade Reactions..." Enders, D. et al. Nature Chemistry2010, 2, 167-178.

    I thank Dr. Rob Knowles and Dr. Jaclyn Henderson for

    some helpful discussions and material for the preparationof this lecture.

    H

    O

    Br

    CO2Et

    CO2Et 83% yield, 95% ee

    H

    O

    CO2Et

    CO2Etvisible light(fluorescent bulb)

    organocatalyst (20 mol%)Ru(bpy)3Cl2 (0.5 mol%)2,6-lutidine, DMF, 23 C

    +

    H

    O

    iPr

    NHPMPN

    H CO2Et

    PMPH

    O

    Me

    +

    Me

    NH

    COOH

    Me

    Me Me

    O O

    Me H+ Me

    O

    Me

    OHNH

    CO2H

    why aturnover?

    OMe

    H

    OMe

    O

    Cl

    Cl

    Cl

    Cl

    Cl

    ClOMe

    O

    H

    Me

    Cl

    EtOAc, 50 C

    20 mol% catalyst

    +

    86% yield14:1 dr, 99% ee

    (1) Proline vs. Mannich Reactions

    (2) Organocascade Reactions

    (3) Organo-SOMO/Photoredox Catalysis

    mechanism?

    mechanism?

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Predicting the Future

    Society: What technologies will be important in the future?

    Organic Chemists: What new developments are going topropel the field forwards?

    People have been trying to predict the future of technology forquite a while. Unfortunately, they are very bad at it. In 1977,Ken Olson, CEO of Digital Equipment Corporation, a maker oflarge mainframe computers, famously said this at a conventionof the World Future society:

    "There is no reason for any individual to have a computer inhis home." ("Bill Gates: The Path to the Future." Gaitlin, J .Perennial Currents, 1999. ISBN: 0-38080-625-8, pg 39).

    But why are people so bad at it? The writer Vernor Vingeproposes that the creation of superhuman intelligence will leadto a breakdown in our ability to predict the future in what hecalls a "singularity." In a more restrictive usage, technologicalsingularities are breakthroughs beyond which technologicalprogress becomes so fast that it makes any predictions of thefuture become impossible. Moore's Law is the classic example:

    Wikipedia

    Somewhat more controversial is the idea of accelerating change.Acccording the futurist Ray Kurzweil, paradigm shifts areoccurring exponentially more frequently, and will soon lead to"change so rapid and profound it represents a rupture in thefabric of human history":

    Now, before superintelligent AIs become our inscrutableoverlords, or the fabric of history ruptures, we will need to dosome organic chemistry. In 1990, Seebach considered thefuture of organic chemistry ("Organic Synthesis--Where Now?"

    ACIEE199029 1320) and wrote:

    "The primary center of attention for all synthetic methods willcontinue to shift towards catalytic and enantioselectivevariants..."

    This has certainly been true. However, he also felt that:

    "The discovery of truly new reactions is likely to be limited tothe realm of transition metal organic chemistry, which willalmost certainly...[deliver] miracle reagents..."

    This foreshadowed things like olefin metathesis, but did notreally predict the explosion of interest in organocatalysis.

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Predicting the FutureAs Macmillan points out, mentions of the word "organocatalysis"have truly exploded in the literature (ISI Web of Knowledge, ref 1):

    Macmillan writes (ref 1):

    "Why was organocatalysis so long overlooked as an area ofresearch?...One perspective worth considering is that it isimpossible to overlook a field that does not exist yet...researchers cannot work on a problem that has not beenidentified."

    This may be a bit harsh, but there is a ring of truth to it. InSeebach's defense, hardly any of the reactivity that will be

    discussed in the first part of this lecture (proline aldol andMannich reactions, reductions of-unsaturated iminium ions,enantioselective Diels-Alder reactions) are actually new. Rather,they are "simply" enantioselective variants of old reactions.However, in the second part of the lecture, I will show you somegenuinely new reactivity in the context of SOMO catalysis.

    The seminal work in this area came simultaneously from Hajosand Parrish (JOC197439 1615) at Hoffmann-La Roche, and

    Eder, Sauer, and Weichert at Schering AG (ACIEE197110496). They reported that proline catalyzed this cyclization:

    Et O

    O

    O

    3 mol% L-proline

    (Eder and co-workers used harsher conditions involvingperchloric acid at elevated temperatures, but accomplished thesame transformation.) Other amino acids, methylated proline,and pipecolic acid are either ineffective catalysts or give lowenantioselectivity.

    As usual, these intramolecular reactions preceded the inter-molecular versions by quite a bit. In 2000, List and Barbas

    showed that intermolecular proline-catalyzed reactions canwork (JACS2000122 2395):

    Me

    OHO

    Et

    OHO

    O

    O

    71%, 99% ee

    MeO

    O

    O3 mol% L-proline

    52%, 74% ee

    OO

    NO2

    30 mol%L-proline

    +

    NO2

    O OH

    68%, 76% ee

    The mechanism of these reactions is proposed to be analogousto how type I aldolases work (Bachrach, Section 5.3):

    LysNH2 +

    O LysN

    -H2O

    LysNH +

    R H

    OLys

    NH O

    R

    +H2O

    Lys NH2 +

    O OH

    R

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    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    Kinetics of Intermolecular Proline Aldo l Reactions"Kinetic and Mechanisitic Studies of Proline-Mediated Direct

    Aldol Reactions." Blackmond, D.G. et al. Bioorg. & Med. Chem.Lett. 2009, 19, 3934-2937.

    "The Elusive Enamine Intermediate in Proline-Catalyzed AldolReactions: NMR Detection..." Gschwind, R.M. et al. ACIE2010, 49, 4997-5003.

    Despite some recent controversy (see below), there is now littledoubt that enamines are the nucleophilic species in these

    reactions and that C-C bond formation is rate-limiting.

    Gschwind and co-workers have looked at the self-aldolization ofpropionaldehyde under synthetically relevant conditions (20 mol%L-proline in d6-DMSO at 300 K) with real-time NMR:

    Me

    O

    H +

    Me

    O

    H

    OH O

    H+

    O

    H

    In agreement with previous studies, two diastereomeric aldoladdition products are formed, along with some condensationproduct. Over the course of the reaction:

    When the catalyst loading is raised to 100%, the total amount ofthe intermediates rises from 8% to 25-30%, allowing for accuratequantitation. As others have noted before, oxazolidinones aredetectable. But now, the enamine is detectable:

    (1) The enamine is E-configured and s-trans, regardless of[enamine]. Incidentally, this is the same conformation thatHouk predicts is reactive (see discussion below).

    N

    Me

    CO2H

    Es-trans

    (2) NMR exchange spectroscopy ("EXSY") is a technique thatallows the rate of interconversion between equilibratingspecies to be measured, so long as the exchange rate issuitable (for a more precise definition, you will have to waituntil Chem 117 next semester). If two peaks have a"crosspeak" then there is exchange. The volume of thecrosspeak is related to the rate of exchange.

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    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    Kinetics of Intermolecular Proline Aldol ReactionsHere is a schematic for the exchange equilibria:

    Regardless of how enamine is formed, this is the proposedkinetic scheme for intermolecular proline aldol reactions (tomaintain consistency with previous lectures, we're using a newset of letters to denote the various chemical species now):

    O

    Me

    H

    N

    Me

    CO2H

    NH

    CO2H+N

    Me

    CO2

    A IE

    N

    Me

    O

    O

    N

    Me

    O

    O

    Oa

    Ob

    (3) The iminium ion is spectroscopically invisible. Ob is morestable than Oa.

    (4) The dotted arrows represent crosspeaks. Note that exchangeis not found betweenA and E.

    (5) The authors suggest that means that enamine only comesfrom oxazolidinones Oa and Ob, perhaps through an E2mechanism. To bolster their claim, they show that:

    rate (Oa toA)

    rate (Oa to E)

    rate (Ob toA)

    rate (Ob to E)

    is differentthan

    the argument being that the partitioning toA and E should notdepend on the starting point if a common intermediate I exists.

    ,

    ?

    C

    CK

    K

    (CK)'

    A

    CKA

    PK1

    K2

    k3

    KI

    Q: Does this fit the observed kinetic data?

    To answer this question, we need to draw a 1+rate law for this.This is more complicated than the 1+rate laws we haveconsidered. For example, step 1 produces water as well asCK and it reasonable to think that additional water would shiftthis equilibrium left towards starting materials. Assuming product

    release is irreversible,

    Assuming that we can ignore any catalysis (perhaps by water)

    of oxazolidinone formation, one can see that K1 and KI will bemerged into some smaller apparent equilibrium constant K1'.

    1 2 3 2 T

    1 1 I 1 22

    2 2 2

    [H O][K][A][C]

    [K] [K] [K] [A][H O] 1

    [H O] [H O] [H O]

    K K kv

    K K K K K

    NH

    CO2H

    N CO2H NO

    O

    H

    O

    R

    Me Me

    O

    H2O

    N

    Me

    CO2OH

    R

    H2O

    O

    Me

    OH

    R

    Me MeMe

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Kinetics o f Intermolecular Proline Aldol Reactions

    1 2 3 2 T

    ' '

    2 1 1 2

    [H O][K][A][C][H O] [K] [K] [A]

    K K kvK K K

    if addition=rds,

    rate is approximatelypropotional to

    Similarly, [H2O] no longer appears in the numerator, since waterwill not speed up the reaction if aldol addition is rate-limiting.Additionally, the K2 term is small, so it does not appear in thedenominator. (1) does correspond to the power law above. Tosee this for [H2O], hold other concentrations constant (x=[H2O]):

    0.7 0.6 0.92 T[H O] [K] [A] [C]v k

    Note that for a multi-step reaction, the exponents do not implythe molecularity of any particular step. Suppose the enamineformation is rate-limiting. In that case, the reaction becomeselementary and the rate law is (the pre-equilibrium assumptionfor step 1 is no longer valid since it's now the "last" step):

    T

    '

    2 1

    [K][A][C]

    [H O] [K]K

    T'

    2 1

    [K][A][C] 1

    [H O] [K]K x c

    This is a bit less than negative first order in water, depending onhow big c is. Finally, let y = [K], and we get:

    (1)

    T'

    2 1

    [K][A][C][H O] [K]

    yK d y

    before the rate-determining step, slowing down the reaction.Increasing the amount of ketone increases the amount of thisintermediate. However, because both water and ketone areincorporated before CK goes to product in a multi-step process,their kinetic orders have magnitudes less than one.

    Further EvidenceUntil a few years ago, the idea that these reactions go throughenamine intermediates was itself controversial. Even thestoichiometry of the transition state was unclear. Here weresome of the leading proposals for the Hajos-Parrish reaction:

    HO

    Me

    OHN

    HCO2

    Houk model

    Hajos model

    NO

    Absorbing K1 and KIgives this expression:

    Experimentally, it has been determined that the rate can befitted to an approximate power law expression:

    C CK / (CK)' CKA

    if enamine

    formation=rds,rate law is

    Since the reaction is about first order in aldehyde, this can bediscounted. (Neither water nor aldehyde take the reactionforwards to product, so they don't appear in the numerator.)What if aldol addition is rate-limiting?

    O

    O

    H

    N

    O

    O

    H

    H

    O

    O

    H

    crystal surface

    O

    Swaminathanmodel

    N

    Me

    NCO2

    OH

    HR

    Agami model

    The Hajos and Houk models have the same stoichiometry, sowe cannot distinguish between them with kinetics. Thesereactions work in compeletely homogeneous media, so theSwaminathan model is unlikely.

    Q:How can the number of prolines in the TS be determined?

    O

    O

    1 T[K][C]k

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    ee (Product)

    ee (Product)

    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Further Evidence

    The classic experiment is to examine the relationship between

    catalyst enantiopurity and the product enantiopurity. This iscalled a nonlinear effects experiment. Despite some initialreports by Agami that these were involved in the Hajos-Parrishreaction, very careful studies showed that there is no sucheffect (Houk/List JACS2003125 16):

    If the homochiral catalyst-catalyst complexes are less reactivethan heterochiral (meso) complexes, then the line would becurved upwards (asymmetric amplification). Similarly, ee isunchanged with dilution (more dilute = aggregation less likely):

    From microscopic reversibility arguments, the fact that the retro-aldol reaction is first-order in proline means that the forwardaldol reaction is also first-order. This also has the advantage ofdefinitively being related to the C-C bond forming step:

    Finally, performing the reaction in 18O-labeled water givesincorporation of the label at the ketone. This is required by the

    mechanism, which generates an iminium ion which must behydrolyzed by solvent (List PNAS2004101 5839):

    Me

    OMe

    O

    O

    25 mol%(S)-proline

    3 vol% H218O

    DMSO under Ar

    four days

    Me

    OHN

    O2C

    Me

    OH18O

    This excludes the Hajos model, whichdoes not proceed via an iminium ion.

    (Initial reports were to the contrary, butcareful experiments give incorporation.)

    40% 50% 10%

    + +

    Me

    18O

    Me

    N

    HO2C

    HO

    Me

    OHN HCO2

    O O O

    O

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    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    The Houk-List Model for Stereoselectivity

    All of this evidence points to a one-proline enamine mechanism.

    Houk considered a variety of intermolecular reactions, bothselective and unselective, and List measured their enantio-selectivities (JACS2003125 2475). One considered reaction:

    Me Me

    O O

    Me H+

    proline

    Me

    O

    Me

    OH

    A variety of parameters were looked at:

    NHO2C N CO2H

    syn or anti enamine

    R

    O

    H

    Re or Si faceof aldehyde

    enamine-aldehyde rotamers

    As it turns out, unless the carboxylic acid and the aldehyde areengaged in hydrogen bonding, the incipient alkoxide is not

    effectively stabilized, and therefore the TS is very high in energy.

    The computations (B3LYP/6-31G*) led to this "metal-free"Zimmerman-Traxler model:

    O H

    NMe

    O

    OH

    Me

    O H

    NH

    O

    OMe

    Me

    favored disfavored (+1.0 kcal)

    Thus, anti-enamines are preferred, as is an equatorial aldehyde.Here are two equivalent renderings of the favored TS:

    This is the lowest energy TS leading to the minor product:

    Selectivity is predicted to be lower with cyclohexanone, sincethis makes both the equatorial and axial aldehyde conformersequally bad:

    O H

    NMe

    O

    OH0.0 kcal/mol +0.5 kcal/mol

    O H

    NH

    O

    OMe

    attraction between negativelycharged oxygen and positively

    charged N-C-H hydrogen atom

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    0 1 2 3 4

    0

    2

    4

    6

    8

    predictedselectivity(kcal/mol)

    observed selectivity (kcal/mol)

    y =1.7 xR =0.93

    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    The Houk-List Model for StereoselectivityOf course, the computations are useless if they don't agree withreality. In general, the correlation is good, although the predictedselectivities are a bit too high:

    The Hajos-Parrish reaction seems to work along similar lines(HoukACIE200443 5766). The favored transition state is:

    Houk also examined the uncatalyzed and Hajos pathways:

    O

    MeO

    O H

    uncatalyzed TS(+10.2 kcal)

    Me

    OHN

    HCO2

    OH

    carbinolamine intermediate(+12.4)

    Since the carbinolamine leading up to the Hajos TS is already

    higher in energy than the uncatalyzed TS, Houk concludes theHajos model is incorrect.

    If you don't believe any of this, the results for the closely relatedproline-catalyzed Mannich reactions are very compelling. Let'sapply the same model to this reaction (Houk OL 20035 1249):

    Me Me

    O O

    H+

    S-proline

    Me

    O

    iPr

    NHPMP

    OMe

    NH2

    +Me

    Me

    E imines are more stable than Z imines, so this gives this TS:

    N H

    NH

    OORMe

    PMP

    Indeed, this gives the correct facial selectivity and explains whythe sense of induction is turned over from the aldol reaction. Notethat for donor aldehydes, this favors syn-Mannich products:

    R

    N H

    NH

    OOR

    PMP

    RH

    O

    CO2Et

    NHPMP

    R

    So how can one obtain anti-Mannich products?

    N

    H CO2Et

    PMP

    H

    O

    R

    +

    90%, 93% ee

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    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    Mannich ReactionsA different catalyst turns out to be highly anti-selective:

    H

    O

    iPr

    NHPMP

    70%, 94:6 anti:syn>99% ee

    N

    H CO2Et

    PMP

    H

    O

    Me

    +

    Me

    NH

    COOH

    Me

    This catalyst was designed by computations, which predictedthis transition state (Houk/Barbas JACS2006128 1040):

    NR NPMP

    EtO2C

    Me

    HO

    O

    Deletion of the methyl group reduces selectivity by about 1 kcal.

    Oxazolidinone Intermediates?Despite the success of the List-Houk mechanistic framework,Seebach and Eschemenmoser have proposed an alternatepathway that involves oxazolidinones (Helv Chim Acta200790 425). Here is the List-Houk mechanism:

    NH

    CO2H

    N CO2H NO

    O

    H

    O

    R

    Me Me

    O

    H2O

    N

    Me

    CO2OH

    R

    H2O

    O

    Me

    OH

    R

    In that manifold, oxazolidinones are thought to be unproductiveand "parasitic." In the Seebach-Eschenmoser scheme, theoxazolidinone can open to an enamine carboxylate, which isproposed to be the nucleophilic species:

    NH

    CO2H

    N CO2

    NO

    O

    H

    O

    R

    O

    H2OH2O

    O OH

    R

    H

    B:

    BH

    NO

    O

    HO

    R

    Me MeMe

    Me

    B

    (1) The enamine carboxylate might arise from an E2 eliminationas depicted, or perhaps by deprotonation of the iminium ionformed from proline and acetone.

    (2) The carboxylate is proposed to assist the nucleophilicity ofthe enamine (similar to halolactonization):

    N

    H

    Me

    O

    O

    E+

    (3) From various X-ray structures and calculations, it's beensuggested that the concave/convex shape of these

    structures might give rise to high stereoselectivity.

    N H

    NH

    OOR

    Me

    PMP

    R

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    Chem 106E. Kwan Lecture 31: Enamine and Iminium Organocatalysis

    Oxazolidinone Intermediates?

    (4) It's been suggested that the 9-membered hydrogenbonds required by the List-Houk model areimplausible. However, the usual proscriptionagainst such rings is based on the transannularinteractions in medium-sized cycloalkanes.Gellmann has shown that these H-bonds are, in fact,quite plausible (JACS1990, 112, 8630; CSD: PAGTIA):

    NO O

    O

    H

    (5) However, in DMSO, a lot of these hydrogen bonds do getdisrupted (DMSO is a very good H-bond acceptor). However,

    it seems plausible that in a transition state, H-bonding to aninternal donor might be feasible due to entropic effects.Noncovalent interactions are also generally stronger intransition states, since they're more polarized.

    (6) The Seebach-Eschenmoser proposal does not takeadvantage of intramolecular general acid catalysis, and soan alkoxide is formed. Although DMSO is very polar, it is nota hydrogen bond donor, so the alkoxide is expected to be

    quite unstable. From the ground state side, the enaminecarboxylate is not expected to be very well stabilized either.

    Sunoj has looked at the relative energetics of both mechanismscomputationally using a variety of methods (ACIE201049 6373).

    List-Houk (correct enantio- and d iastereoselectivity)

    Seebach-Eschenmoser (correct ee, incorrect dr)

    predicted ee

    B3LYP/6-31+G**

    MP2/6-31+G**

    M05-2X/6-31+G**

    predicted dr

    experimental ee: 99%; dr: 4:1 anti:syn

    >99 >99 98.5

    5.4:1 1.2:1 1:1.7

    predicted ee

    predicted dr

    95 >99 >99

    1:3.9 1:4.6 1:2

    So both models get the enantioface right, but the predictions ofdiastereoselectivity are better with the List-Houk enamine model.More compelling are the substantially higher barriers for the

    Seebach oxazolidinone pathway (by about 11 kcal/mol):

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Enamine vs. Iminium Activation Modes

    O H

    NMe

    OOHMe

    Q: Why is proline a catalyst for aldol reactions?

    i.e., Why does it lower the activation barrier?(1) general acid catalysis: COOH

    stabilizes forming alkoxide

    (2) enamine activation

    - most isolated carbonyl groups in ketones and aldehydes havevery low enol content; the catalyst increases the amount of"enol" available

    - actually, it's an enamine, not an enol; on the Mayr scale,enamines are much more reactive

    N

    O

    OEt OEtOEt

    OEt

    - enols are not available on the scale, but this shows that youneed approximately two oxygens to equal one nitrogen!

    OTMS

    5.41(s=0.91)

    9.81(s=0.81)

    12.06(0.80)

    3.92(s=0.90)

    4.23(s=1.00)

    If enamines are more nucleophilic, it's reasonable to expectthat iminiums ions are more electrophilic. This is similar to howLewis acids or hydrogen bond donors activate carbonyl groups:

    O activation

    O

    N N

    S

    H

    R R

    H

    OMLn

    NR R

    increasing covalency

    These are all LUMO-lowering strategies. While organocatalyticactivation may not be as powerful in increasing reactivity as Lewis

    acid catalysis, it can be an advantage in getting catalyst turnover.Iminium ions are so easily hydrolyzed by water, they are

    generally considered to be in equilibrium with their carbonylcounterparts. MacMillan has taken advantage of this for Diels-Alder reactions (JACS2000 122 4243):

    OAc+

    O

    H

    20 mol% cat

    MeOH/H2Ort

    OAc

    CHO

    11:1 endo:exo72%, 85% ee

    N

    NH

    O Me

    BnMe

    Me

    cat

    This also works with -unsaturated ketones (JACS20021242458), but requires a different catalyst:

    Me+

    O

    20 mol% cat

    20 mol% HClO4EtOH, 30 C

    Me

    COEt

    11:1 endo:exo72%, 85% ee

    N

    NH

    OMe

    Bncat

    Me

    Me

    Note that, in contrast to proline aldol reactions, these occurin protic media, where there may be some hydrophobicacceleration. Exactly how selectivity is obtained here is still upfor debate (HoukAcc Chem Res200437 558). Instead, I willdiscuss what's known about models for organocatalytic transferhydrogenation (reviews: MacMillanAcc Chem Res2007401327; AdolfssonACIE200544 3340).

    Me

    O Me

    NH

    CO2EtEtO2C

    Me MeHantzsch ester

    These reactions were developed as a synthetic analog tonatural hydride reductions which occur with NADH or FADH2.-Disubstituted aldehydes can be reduced effectively(MacMillan JACS2005 127 32, ListACIE200544 108) withHantzsch esters as the hydride source:

    H H

    +

    NR2*

    RAr

    NR2*

    RAr

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    O

    H20 mol% cat

    Hantzsch esterPhMe, 30 C

    96% conv., 75% ee

    N

    NH

    O Me

    tBu

    catMePh TFA

    O

    H

    MePh

    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Organocatalytic Hydride Reductions

    The convergence of E and Z starting materials to the sameproducts suggests a Curtin-Hammett scenario where adienamine intermediate can rotate to isomerize the olefins:

    Bn

    An anomalous case (see below) is this tert-butyl catalyst:

    O

    H20 mol% cat

    Hantzsch esterCHCl3, 30 C

    91%, 93% ee

    N

    NH

    O Me

    tBu

    cat

    MePh TFA

    O

    H

    MePh

    Under slightly different conditions, the reaction improves:

    O

    H 20 mol% catHantzsch esterdioxane, 13 C

    77%, 90% ee

    N

    NH

    O Me

    tBu

    catMePh TCA

    O

    H

    MePhBn

    advantages: bench-stable reagent; a good alternative tohydrogenation (usually needs optimization) or copper-basedhydrides (unreliable); E and Z isomers converge to the sameproduct

    disadvantages: the Hantzsch pyridine is a stoichiometricbyproduct, which must be removed by chromatography (acid-base extraction doesn't work); the Hantzsch pyridine is quitea large reagent for delivering just one hydrogen

    An initial result:

    N

    CO2EtEtO2C

    Me Me

    byproductHantzschpyridine

    N

    N

    O Me

    H

    Ar Me

    N

    N

    O Me

    H

    Ar

    N

    N

    O Me

    H

    ArMe

    fast slow

    O

    H

    MeAr

    O

    H

    MeAr

    Stereochemical Model

    NN

    PhMe

    O

    Me

    H3C CH3CH3

    (1) In the left-hand rotamer, the bulky tert-butyl group ensuresthat the benzyl group rotates over the -face of theelectrophile, making the hydride reagent come from thebottom.

    (2) Both the attractive /cation- interactions and repulsivesteric interactions (as the carbons pyramidalize) areexpected to become more important in the transition state.

    What controls the stereoselectivity? Having established thefavored iminium ion geometry, we must now consider twoiminium ion rotamers:

    NN

    MePh

    O

    Me

    H3C CH3CH3

    betterthan

    or cation-interaction?

    preferred attack

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    N

    NH2

    O Me

    Me

    Me

    N

    N

    O Me

    Me

    Me

    Ph

    H

    The ground state conformational preferences of these systemshave been studied (Tomkinson et al. OL200911 133). TheX-ray structures shown below are similar to the solution phasestructures, as shown by NMR studies. Here is an X-raystructure of a free imidazolidinone catalyst (CSD: POPRES):

    Bn

    Bn

    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Organocatalytic Hydride Reductions Calculations show the penalty for rotating the benzyl group inthe ground state of the iminium ion is about 1 kcal/mol--verysmall. I doubt these ground state pictures tell us much about

    the transition state; the fact that the benzyl group doesn't seemto be covering the -face very effectively in the X-ray structureis meaningless.

    The anomaly is that the catalyst which only has a tert-butylgroup is still very selective:

    This is the X-ray structure of the corresponding iminium ion

    (CSD: DOSKIG01). Note the rotation in the benzyl group:

    NN

    PhMe

    O

    Me

    H3C CH3CH3

    still preferred (?)

    I don't have a good explanation for this. Enones also work inthis chemistry, but with a slightly different system (MacMillanJACS2006 128 12662; Houk OL200911 4298):

    O

    Bu

    20 mol% cat

    Et2O, 0 CNH

    CO2tButBuO2C

    Me Me

    H H

    +

    O

    Bu

    82%, 90% ee

    The product can be explained by this model, but it might not be

    right (see the Houk paper):

    NN

    Bu

    O

    Me

    preferred attack

    O

    Me

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    Q: Why can't we make taxol in ten steps?

    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Organocatalytic Cascades

    "Strategies to Bypass the Taxol Problem..." Walji, A.M.;

    MacMillan, D.W.C. Synlett2007, 10, 1477-1489.

    Taxol is a potent anticancer agent used in the treatment oflung, ovarian, breast, neck, and other cancers, with sales of $1.6billion US in 2000. Until 1993, taxol had to be extracted fromthe bark of the pacific yew tree and prepared via semi-synthesis.Now, BMS uses cultured Taxus cells in a fermentation process.Taxol is extracted and purified directly from the broth.

    Analysts estimate that the world will need 1 040 kg of taxol/yearby 2012. Despite our best efforts, total synthesis is clearly notup to the job:

    Each of these groups used cutting-edge chemical methodologyand very clever synthetic logic, but none of their routes is evenremotely amenable to a large-scale process route. This problem

    is certainly not unique to taxol.

    Here's what I think the biggest problem is: the complexity ofmolecules scales exponentially with size, but thecomplexity in troduced by a synthetic sequence scales evenless than linearly with its length.

    MacMillan points out that the yield of a synthetic sequence also

    drops exponentially with its length. A somewhat unsatisfactory,literal explanation is that the total yield is just the product of theyields of every step. But why don't reactions give 100% yield?

    (1) The reactions are intrinsically "dirty" and give side productswhich account for the remainder of the mass balance.

    (2) Purification is "lossy."

    J ust how lossy is purification? Hudlicky has recently done somesimple experiments (Synlett201018 2701) which show that, ingeneral, one cannot expect more than a ca. 94% yield for anygiven reaction which involves workup and chromatography.

    AcO

    Me

    HO OBz

    O

    OHO

    OAcO

    O

    OH

    BzHN

    H

    mass recovery

    filtration

    aqueous extraction

    fraction collection

    separation

    1001.7 mg

    978.6 mg

    985.0 mg

    980.1 mg

    This is bad news if you want to use a sequence of 37 steps.The top synthesis, Wender's, already has an average yield of85%, suggesting that there is nothing wrong with the reactions

    themselves; they're simply not generating enough complexityper step.

    O

    O

    OH

    Nicolaou(1994)

    51 steps

    Me Wender(1997)

    37 steps0.4% overall yield

    H

    O

    Me

    Kuwajima(1998)

    47 steps

    NH2

    O

    HO OH

    Mukiyama

    (1999)38 stepsO

    OMe

    47 steps

    Danishefsky

    (1995)

    Me

    MeMe

    MeO

    Holton(1994)

    41 steps

    (1000 mg scale)

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Organocatalytic CascadesMacMillan proposes that we circumvent the defects of "stop-and-go" synthesis by combining several steps into one step. For

    example, consider this sequence (JACS2005127 15053):

    This represents the merging of two catalytic cycles. First, thecatalyst forms an iminium ion with the aldehyde (A), whichundergoes a Friedel-Crafts alkylation. Then, the producttautomerizes into a nucleophilic enamine (B), which is chlorinated.

    (1) This reduces the number of purifications required, which isgood. However, simply performing reactions in a cascade,rather than stop-and-go sense does not by itself improve theintrinsic yield of a reaction.

    (2) Cascade reactions are not new. In fact, we've already seenquite a few such reactions in the course already. However,

    most of them are diastereoselective in nature. For example,this cascade reaction was discussed in Lecture 10 on page 14:

    Me

    PhMe

    Ph

    Me

    HOoxy-Cope/carbonyl-ene

    OMe

    H

    OMe

    O

    Cl

    Cl

    Cl

    Cl

    Cl

    ClOMe

    O

    H

    Me

    Cl

    EtOAc, 50 C

    N

    N

    MeON

    Bn

    tBu

    20 mol% catalyst

    Me

    N

    N

    MeON

    Bn

    tBu

    Me

    O

    Me

    A

    B

    Cl

    O

    Me

    +

    Without catalyst, one is at the mercy of the complex energylandscape that is intrinsic to the reaction; there is noguarantee that the desired reaction lies on the minimumenergy path. Nor is it guaranteed that there is only oneminimum energy path, such that the reaction will be "clean"and have no other side products. So using a tunable

    catalyst is a real advantage in that sense.

    (3) One complaint about this chemistry is that it makes stringsof stereocenters efficiently, but is relatively ineffective atbuilding structural complexity. Is this true? You decide.

    This area has been reviewed recently: "OrganocatalyticCascade Reactions..." Enders, D. et al. Nature Chemistry

    2010, 2, 167-178. Here is another example from the Hayashigroup for the synthesis of oseltamivir (ACIE200948 1304):

    86% yield14:1 dr, 99% ee

    RO

    O

    H

    tBuO2CNO2

    + NH

    PhPh

    OTMS

    Michael addition

    Cs2CO3

    P CO2EtO

    EtOEtO

    conjugate addition/HWE olefination

    NO2

    tBuO2C

    RO CO2Et

    5 mol%

    5:1 drundesireddiastereomer

    The first step uses a silylated Hayashi-J orgenson diarylprolinol

    catalysts. Unfortunately, the second step delivers the incorrectstereocenter at the nitro group. (All of this occurs in one pot.)

    O

    H

    NO2

    tBuO2C

    RO

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Organocatalytic Cascades

    NO2

    tBuO2C

    RO CO2Et

    OMe

    H

    O

    Me

    OTMS

    Me

    O

    O

    O

    Me

    H

    O

    OH

    MeH

    Me

    O

    H

    O

    Me

    OH

    OMe

    O

    O

    O

    H

    OMe

    O

    NHO2C

    Me

    type I/type IIcross-metathesis

    (Grubbs II)

    Me

    O

    N

    NO Me

    tBu

    Ph

    +

    H

    selective foriminiumcatalysis

    three sequentialone-pot operations

    Friedel-Craftsalkylation

    (imidizolidinone)

    ketone aldol(proline)

    selective forenaminecatalysis

    64%, 95% ee,5:1 dr

    Fortunately, a hetero-conjugate addition/epimerization strategy,followed by some other manipulations delivers Tamiflu in 57%

    overall yield from the nitroalkene, which is pretty good. Overall,there are nine reactions, three separate one-pot operations, andone column chromatography purification.

    TolSH

    70%

    NO2

    tBuO2C

    RO CO2Et

    STol

    =

    tBuO2C

    O2N

    RO CO2Et

    STol

    1. TFA2. (COCl)2,

    cat.DMF

    3. NaN3NO2

    RO CO2Et

    STol

    O

    N3

    1. AcOH/Ac2O2. Zn/TMSCl

    3. NH3; K2CO3

    one-pot

    one-pot

    no purificationpurified byflash chromatography

    NH2

    AcHN

    RO CO2Et

    oseltamivir(82% from A)

    A

    (1) The second one-pot procedure sequentially cleaves the tert-butyl ester, converts the liberated carboxylic acid into theacyl chloride, and displaces the chloride with azide.

    (2) The third one-pot procedure first converts the acyl azide intothe amine via a Curtius rearrangement. The advantage ofthese conditions is that the reaction occurs at ambienttemperatures. The amine is trapped by acetic anhydride.Zinc then reduces the nitro group. Finally, ammonia isadded to chelate the zinc, and potassium carbonate initiatesa retro-conjugate addition to generate the olefin.

    Obviously, this is a very nice synthesis, but the fact that theconjugate addition is not catalyst controlled means that its drisat the mercy of the various stereocenters present:

    O

    H

    NO2

    tBuO2C

    ROP CO2Et

    O

    EtOEtO+

    NO2

    tBuO2C

    RO CO2Et

    5:1 drundesireddiastereomer

    A more sophisticated "cycle-specific" strategy is to use more

    than one catalyst at the same time (MacMillanACIE2009484349). This requires the catalysts be orthogonal:

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Stereoselectivity in CascadesA common feature in these cascade reactions is that they givevery high overall enantioselectivities, even if the component

    reactions are not very enantioselective. How is this possible?

    Consider a two-step cascade in which the first step produces anx : 1-x enantiomeric ratio of products, where x is the molefraction of R configuration produced at stereocenter 1. Similarly,step 2 has a selectivity ofy:

    startingmaterial

    step 1

    selectivityx

    xR1

    (1-x) S1

    step 2

    selectivityy

    xyR1-R2

    x(1-y) R1-S2

    (1-x)yS1-R2(1-x)(1-y) S1-S2

    If this seems a bit abstract, maybe revisiting this example willhelp:

    OMe

    H

    OMe

    O

    Cl

    Cl

    Cl

    Cl

    Cl

    ClOMe

    O

    H

    Me

    Cl

    EtOAc, 50 C

    20 mol% catalyst

    +

    86% yield14:1 dr , 99% ee

    stereocenter 1

    stereocenter 2

    The Fridel-Crafts alkylation is step 1, and has some intrinsicenantioselectivity x. The chlorination is step 2, and has another

    intrinsic selectivityy.

    (1) Without a loss in generality, suppose that the R1-R2 productis the desired one. How much of it is formed? A molefraction ofxy.

    (2) Where does the enantiomer of the desired product, S1-S2,come from? It comes from an incorrect first step, followed

    by an incorrect second step. Hence, a mole fraction of(1-x)(1-y) is formed. Since 1-x and 1-y are small fractions

    (i.e., less than 1), multiplying them together gives an evensmaller number.

    (3) The enantiomeric ratio of the product is therefore xy dividedby (1-x)(1-y). Division by a very small number between 0and 1 increases the size ofxy by a lot. This is why theenantiomeric ratio of the product is very large.

    (4) The enantiomeric ratio of the product can be big, even if theenantioselectivity of the component steps is not that great.For example, suppose steps 1 and 2 have ee's of 80%.That would be considered good, but great. In our language,this would mean x = y = 0.9. This gives an enantiomericratio of 81:1, or an ee of 97.6% (which, for one step, wouldbe considered excellent).

    Thus, it is relatively easy to get almost enantiopure product:

    0.5 0.6 0.7 0.8 0.9

    1

    2

    4

    8

    16

    32

    64

    128

    256

    enantiomericratioofproduct

    selectivity for second step (y)

    x=0.9

    x=0.8

    x=0.7

    x=0.6

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    SOMO Act ivation

    So far, we've seen a variety of activation modes:

    O

    RH

    RNR2

    enamine:more

    nucleophilic

    O

    RH

    RN

    iminium:more

    electrophilic

    OH-AO MLn O

    RH

    O

    RH R

    M = H (acid catalysis)M = metal (Lewis acid

    catalysis)

    more electrophilic

    hydrogen bonding

    more electrophilic

    O

    RH

    R

    OHRN

    RN

    NHC carbonyl anionmore nucleophilic

    O

    ROR

    R

    O

    N

    or R

    ORN

    RN

    NHC carbonylpseudohalide

    more electrophilic

    nucleophili c catalysismore electrophilic

    or

    Nuc:

    O

    ROR

    HO

    RB:

    base catalysis

    Q: What's in between an enamine and an iminium?

    "Enantioselective Catalysis Using SOMO Activation."MacMillan et al. Science2007, 316, 582-585.

    MacMillan's clever idea is that enamines are very electron rich,and therefore more easily oxidized than amines or iminiums:

    H

    O

    TMS

    NH

    NOMe

    PhtBu

    20 mol%

    CAN (2 equiv.)NaHCO3, DME

    24h, 20 C

    H

    O

    75% yield, 94% ee

    N

    R

    R

    O

    H

    +NH

    -H2O

    H

    N

    RH

    +2 e-

    9.8 eV8.8 eV7.2 eV

    N

    RH

    -1 e-N

    RH

    N

    RH

    (The ionization potentials are shown in bold; the lower thenumber, the easier it is to oxidize.) Oxidation of the enamineproduces a radical cation, which is an ambident electrophile:

    enamine radical cationmore reactive

    In the jargon of organocatalysis, this is "SOMO activation"--the generation of a singly occupied molecular orbital which canundergo many subsequent reactions. One of the first exampleswas an aldehyde allylation, which is very useful synthetically:

    +

    CAN is ceric ammonium nitrate (NH4)Ce(NO3)6, which is

    a strong oxidant (even stronger than Cl2!) which reacts togenerate a chiral enamine radical cation.

    H

    R

    R

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    H

    O NH

    NOMe

    Ph

    tBu

    20 mol%

    CAN (2 equiv.), H2ODTBP, acetone,

    24h, 20 C

    Ph

    OTMS

    74% yield,93% ee

    H

    O

    Ph

    O

    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    SOMO Activation

    stereochemical model

    NN

    O

    Me

    H3C CH3CH3

    R+

    (Historical Note: This use of stoichiometric CAN for similarreactions was previously reported by Narasaka (Chem Lett1992 2099.)

    Aldehydes can be coupled with enolate equivalents, which

    produces umpolung 1,4-dioxygenated relationships (MacMillanJACS2007129 7004): (DTBP = 2,6-di-tert-butylpyridine)

    nucleophilesapproachfrom below

    cationinteractionbetween benzyl group

    and allyl radical cation?

    +

    If the nucleophile is allyltrimethylsilane, then this produces:

    N

    R

    N

    R

    TMS

    The regioselectivity can be explained by a radical version ofthe -silicon effect; donation of the Si-C bonds into the radicalis good. (However, the -silicon effect for radicals is much lessthan for carbocations.) The radical gets oxidized to the

    carbocation (which is why two equivalents of CAN are required),and then base comes in and does a Peterson olefination.

    Si

    CH3

    CH3CH3

    -silyl radicalstabilized bySiC to n*Cdonation

    N

    R

    Si

    CH3

    CH3CH3

    -1 e-:B

    CAN

    N

    RH2O

    OR

    H H H

    HH

    (catalystsubstituentsomitted)

    CN

    Me

    Me CN

    H

    H H

    HO

    CN

    Me

    Me

    CNO

    N

    NOMe

    NaptBu

    Cu(OTf)2NaTFA/TFA

    iPrCN/DME23 C

    CN

    CNMeMe

    [Ox]- H2O

    - 1e-

    N

    NOMe

    NaptBu

    CN

    CNMeMe

    [Ox]- catalyst

    - H+, - 1e-

    56%, 92% ee

    A dramatic demonstration of the power of this activation modeto produce complex architectures as well as stereodefined

    arrays is this cascade polyene cyclization (MacMillan JACS2010132 5027):

    CAN is ineffective here due to an inner-sphere nitrate transfer.It is interesting that both the yield and ee go up when the arylgroup on the catalyst changes from phenyl to naphthyl. To me,

    this strongly suggests an enhanced cation- interaction witha larger aromatic surface.

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    Chem 106E. Kwan Lecture 34: Enamine and Iminium Organocatalysis

    Cascade Reactions

    In the previous examples, the radical produces by the couplingreaction gets oxidized to a carbocation, which is then eliminated.

    What happens if we intercept the carbocation with an internalnucleophile first? Good stuff (Macmillan JACS2010132 10015):

    Ph

    OMe

    +

    O

    H

    NH

    NOMe

    PhtBu

    20 mol% catTFA

    Fe(phen)3(SbF6)3Na2HPO4, THF10 C, 12 h

    OMeO

    H

    Ph

    First, the aldehyde is alkylated by styrene to give a stablebenzylic radical. Then, oxidative radical-polar crossover givesa carbocation which is engaged in Friedel-Crafts alkylation:

    OMeO

    H

    Ph

    -1 e-

    OMeO

    H

    Phalkylation,

    thenelimination

    76%, >20:1 dr94% ee

    (1) The diastereoselectivity is rationalized based on a chair TS.

    (2) The yield includes 7% ortho-coupled product.

    (3) Because the selectivity of the second step is largely basedon the conformational preferences of the substrate, the eemainly reflects the enantioselectivity of the first step, whilethe dr mainly reflects the diastereoselectivity of the secondstep.

    (4) Thus, the inherent enrichment in ee that is commonplace inlargely catalyst-controlled reactions is bypassed here.

    Photoredox Catalysis

    The use of stoichiometric oxidants is undesirable in terms ofatom economy, the ability of the substrate to tolerate oxidizing

    conditions, purification, etc. The latest advance is to use aphotosensitized metal-ligand complex as the redox shuttle.This is particularly convenient, as visible light can be used asthe energy source (MacMillan Science2008322 77):

    H

    O

    Br

    CO2Et

    CO2Et83% yield, 95% ee

    H

    O

    CO2Et

    CO2Etvisible light(fluorescent bulb)

    organocatalyst (20 mol%)

    Ru(bpy)3Cl2 (0.5 mol%)2,6-lutidine, DMF, 23 C

    +

    N

    NO Me

    Me tBu

    CO2Et

    CO2Et

    .

    N

    NO Me

    Me tBu

    EtO2C

    EtO2C

    N

    NO Me

    Me tBu

    EtO2CEtO2C

    *Ru(bpy)32+

    Br

    CO2Et

    CO2Et

    Ru(bpy)3+

    Ru(bpy)32+

    light

    SET

    SET

    [O]

    -1 e-

    The blue cycle is started by sacrificing a few molecules ofenamine. Thereafter, it is driven by oxidation of the productradical (A) to an iminium ion and reduction of the bromomalonate (B) to its corresponding malonate radical. Thus,

    every equivalent of product formed requires one turn of theblue cycle.

    B

    A

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