lecture 30 - enamine and iminium organocatalysis
TRANSCRIPT
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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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