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Topic: Catalytic enantioselective conjugate additions, and cycloadditions
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1
Key Concepts: Regioselectivity and Catalysis
1.1
Regioselectivity
1,2- vs 1,4-Addition: α,β-unsaturated carbonyl compounds are ambident electrophiles. The incoming
nucleophiles can attack either the C=O or C=C bonds
O
O
O
Nu
X
Nu
X
1,2addition
R
X
1,4addition
R
R
Nu
The regioselectivity is determined by a combination of the nature of R, X and of the nucleophile:
more
reactive
carbonyl
O
O
Cl
less
reactive
carbonyl
+
NH3
1,2-addition only
NH2
O
O
+ NH3
OMe
1,4-addition only
OMe
H2N
Fleming, Molecular Orbitals and Organic Chemical Reactions, 2010, p 188
This selectivity can be described by the Klopman-Salem equation and Hard-Soft Acid-Base theory:
Klopman, JACS, 1968, 223
HSAB theory is a useful means of classifying the reactivity of nucleophiles + electrophiles, and serves as a
good “rule-of-thumb”:
Pearson, JACS, 1963, 3533; Pearson, J. Chem. Ed., 1968, 581
Relevance to 1,4-conjugate addition: Properties of Acrolein
Charge Distribution:
Frontier Orbitals:
.51
.59
LUMO
-.48
Compare butadiene with acroleinO
-.39
+.23
-.58
.59
HOMO
-.3 O
.48
LUMO coefficients correspond with
increased reactivity of b-carbon
-.35
-.34
-.41
Oxygen atom makes
b-carbon
more positive
O
+.48
Significantly more
positive charge on C=O
carbon
LUMO calculations: Houk, JACS, 1973, 4094. Charges: Tidwell, JOC, 1994, 4506
These factors provide tremendous potential not only for the control of the regioselectivity, but also
for the catalysis.
1.2
Common methods for achieving catalytic 1,4-conjugate additions
1
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A catalyst is employed to control the regioselectivity (and ideally also the enantioselectivity) of the addition to
only one of the reactive sites of an ambident molecule.
1.2.1 LUMO-Lowering by Lewis Acid Catalysis
Classic Example: Diels-Alder reactions are strongly influenced by HOMO-LUMO interactions. Dramatic rate
acceleration by AlCl3 catalysis observed 50 years ago:
Yates, JACS, 1960, 4436
The LUMO-lowering effect of Bronsted or Lewis acids has been calculated – again on acrolein as an
example:
O
+2.5 eV
LUMO
O
H
O H
-6.5 eV
O
O
H
LUMO
-14.5 eV
HOMO
LUMO coefficients correspond with
increased reactivity of b-carbon
O H
-23.7 eV
HOMO
Houk, JACS, 1973, 4094
1.2.2 LUMO-Lowering by Catalytic Formation of Iminium Ions
A more recent discovery - analogy between Lewis acid-activated unsaturated aldehydes and unsaturated
iminium ions
O
O
Lewis Acid
H
O
R1
H
R
N
H
O
R
R
R1
R2
• HX
N
R2
R1
X
H
(organic molecule)
- H 2O
LA
H
H
(typically cationic
metal)
R
LA
N
R2
H
R
R
• Lewis acid complexation
is LUMO-lowering
• C=O and C=C bonds become
more electrophilic
• Iminium ions are positively
charged
• Should be more electrophilic
than parent aldehyde
MacMillan, JACS, 2000, 4243
1.2.3 Catalytic Generation of Soft Nucleophiles by Transmetallation:
By addition of catalytic amounts of other metals, the regioselectivity of organometallic addition to unsaturated
carbonyls can be altered. This was first observed in the case of Grignard reagents: Without the addition of
Cu salts the 1,2-addition products (and derivatives thereof) are formed exclusively. When Cu salts are
present in catalytic amounts, the 1,4-addition product is favored.
HO
+
Et2O, 5 °C
O
CuCl (1 mol %)
+
Me
Me
42%
Me
O
Me
Me
MeMgBr
HO
Me
48%
0%
Me
O
+
+
MeMgBr
Et2O, 5 °C
Me
7%
Me
Me
Me
0%
1,2-Addition Products
83%
Me
Me
1,4-addition
Kharasch, JACS, 1941, 2308
1.2.4 Catalytic Generation of Soft Anions with Chiral Bases
Deprotonating weak acid with a chiral base can form a chiral ion pair that is significantly more nucleophilic
than the neutral starting material:
2
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Wynberg, JACS, 1981, 417
2
Catalytic, Enantioselective Conjugate Additions
2.1
LUMO lowering
2.1.1 Lewis acid activation
Important Considerations
Lewis acid binding to carbonyl oxygen is reversible and dynamic – for ligand and substrate design this must
be taken this into account. Therefore, ligands and substrates are equipped with extra coordination sites to
control these aspects to limit the number of possible transition states in the enantiodetermining step. The
number of coordination sites is determined by the metal ion.
Lone pair isomers + sigma bond conformers
L*
L*
LA
O
C-LA sigma bond rotation
L*
L*
LA
O
R2
R2
L 1*
R1
R1
- anti lone pair
- s-trans conformer
- syn lone pair
- s-trans conformer
O
LA
L2*
L2*
O
R2
L*
O
R1
L 1*
R2
R1
LA
LA
R1
L*
L*
L*
R2
LA
O
R1
- anti lone pair
- s-cis conformer
R2
- syn lone pair
- s-cis conformer
2.1.1.1 C2-Symmetric Bis(Oxazoline) (“Box”)-Based Complexes:
Cu-Bis(Oxazoline) complexes are a versatile ligand/metal combinations for a large variety of reactions
(including conjugate additions and cycloadditions). The best results are obtained with substrates bearing two
coordination sites to the Cu atom (they can form stable 5- or 6-membered ring chelates with the chiral Cu
complex).
C2-symmetry limits number
of diastereomeric TS
Me
Me
O
Chiral centre
from amino acids
O
N
N
Cu
R TfO OTf R
O
Bidendate ligand for
strong chelation and
rigid structure, forces
Cu(II) to adopt a
distortet
square-planar
geometry
RO
Cu
O
O
OR
R
Cu
X
R
6-Membered Chelate:
Alkylidene Malonates
5-Membered Chelate:
a-ketoesters, a-hydroxyketones
ketophosphonates etc
Works best on bidendate acceptors
that can attach to metal with two-point binding
Weakly coordinated,
easily displaced counterion
Evans, Acc. Chem. Res., 2000, 325
Mukaiyama-Michael addition of silyl-ketene thioacetals proceed with very high selectivity; isolation of Culigand-malonate complex showed distorted square-planar geometry; Cu-malonate in a boat conformation
with shielded Re face
3
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Me
Me O
O
Me
Me
N
Me
N
Cu
O
MeO
O
H
Me
Me
Me
OMe
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R
TMSO
St-Bu
Me
2+
Me
O
O
N
O
t-Bu
O
OTMS
MeO
N
Cu
2 SbF6- t-Bu
(10 mol %)
OMe +
HFIP, -78 °C
t-BuS
O
R
R = Ph, 91%, 93% ee
R = 2-MeOPh, 92%, 99% ee
R = Cy, 95%, 95% ee
R = i-Pr, 93%, 93% ee
CO2Me
t-BuS
CO2Me
R
Evans, JACS, 1999, 1994
6-Membered chelates based on imide frameworks places the electrophilic center roughly in the equatorial
plane of the square planar complex and closer to the bulky t-Bu group of the ligand. Note that the oxazolidine
moiety is installed in the substrate to provide a second coordination site for the Cu complex (It can be
transformed to a variety of carboxylic acid derivatives in following steps):
OTMS
Top face shielded
t-BuS
O
Me
O
EtO2C
Me
O
N
Cu
Me
O
Me
Me
Me
N
-
t-Bu
O
CO2Et O
MeS
OTMS
Me
Me O
O
O
N
Cu
O
N
O
N
Me
N
73%, 99:1 syn:anti, 99% ee
EtO2C
2 SbF6
(10 mol %)
MeS
O
N
2+
O
N
t-Bu
t-BuS
Me
O
O
CO2Et O
O
O
Me
Me
Me
Me
Bottom face exposed
90%, 5:95 syn:anti, 90% ee
Evans, JACS, 2001, 4480
Activated unsaturated carbonyls that form 5-membered ring chelates have also been developed. αKetoesters are highly electron-withdrawing and make particularly reactive electrophiles:
Jørgensen, ACIE, 2001, 160
Other metal-ligand complexes based on oxazoline frameworks are known. For example, Mg2+-catalyzed
addition of hydrazines to imides provides pyrazolidinones:
Sibi, JACS, 2007, 4522
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Higher oxidation state metals, for example Sc3+, can be more Lewis acidic but require an extra coordinating
group to occupy 3 of 6 open sites in the octahedral geometry (in contrast to the previously mentioned
square-planar geometry): Pyridine-bis(oxazoline) ligands (“PyBox”) are used:
OTf
O
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O
O
N
O
X
R
N
N
N
N
Sc
TfO
OTf
OTf
O
Sc
Re face
blocked
N
O
X
R
Si face
open
Evans, JACS, 2007, 10029
This complex is an excellent catalyst for enantioselective Friedel-Crafts-type addition to unsaturated
acylphosphonates- useful ester surrogates:
O
N
+
O
R
R
O
(10 mol %)
Me
OMe
CH2Cl2, -78 °C; then
DBU, MeOH
O
P
MeO
O
N
N
N
Sc
TfO
OTf
OTf
N
Me
R = Me, 75%, 97% ee
R = Ph, 85%, 80% ee
OMe
Evans, JACS, 2003, 10078
2.1.1.2 Other Classes of Catalysts for Electrophile Activation:
The first catalytic, enantioselective Mukaiyama-Michael reaction used a BINOL-Ti oxide complex to add to
cyclic ketones:
O
O
O
O
OTMS
Ph
+
( )n
Ti O
S
Ph
(20 mol %)
PhCH3, -78 °C
( )n
O
Ph
n = 1, 75%, 90% ee
n = 2, 76%, 70% ee
n = 3, 33%, 40% ee
S
Ph
Mukaiyama, Chem. Lett. 1994, 97
Bandini and Umani-Ronchi were the first to demonstrate that one-point binding could also provide high
enantioselectivity in the Friedel-Crafts alkylation: (In contrast to the previously mentioned transformations
with well-defined coordination geometries). A chiral Salen ligand (Salen from salicylaldehyde and
ethylenediamine) with bulky tert-butyl groups was employed, which creates a well-defined chiral geometry
around the Al atom.
Bandini, JOC 2004, 7517
An improved version giving better selectivities using 3,3`-disubstituted-BINOL Zirconium complexes was
described (Note: The bulky 3,3’-Br substitutents on the BINOL are necessary for a high chiral induction):
5
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Br
OH
+ Zr(OtBu)4
OH
N
H
Br
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R
O
(20 mol % each)
+
Ar
CH2Cl2, rt
O
N
H
Indoles: 54-91%, 72-97% ee
Pyrroles: 84-97%, 65-99% ee
Ar
R
Pedro, OL, 2007, 2602
In addition to Lewis acid catalysts, Brønsted acid catalysts also promote this type of reaction:
Rueping, ACIE, 2008, 593
2.1.2
Iminium catalysis
- For these reaction to occur, α,β-unsaturated aldehydes (sometimes ketones) are required for the formation
of the iminium ions. (This is in contrast with the metal-catalyzed reactions in Section 2.2 where unsaturated
aldehydes are difficult substrates.) Therefore, the nucleophile has to be unreactive with the aldehyde (or
ketone) in the absence of a catalyst to prevent an unwanted background reaction from occurring.
Electrophilicity of iminiums is greater than that of aldehydes - importantly, the groups, which provide the
chiral environment, are also LUMO lowering, leading to enhanced reactivity.
Relative electrophilicity E of selected iminium ions
O
O
Ph
Me
N
Ph
Ph
N
N
N
N
N
OTMS
Me
Me
R
LUMO
lowered energy
Ph
Ph
-10.3
-9.8
Ph
Ph
-8.6
Ph
-8.2
-7.2
Electrophilicity E
Catalytic cycle: Formation of iminium, addition of nucleophiles, followed by protonation of enamine and
hydrolysis- generates and requires molecule of water for catalyst turnover
Iminium catalytic cycle in nucleophilic addition to cinnamaldehyde
Ph
O
H
H
Ph
HNR2* · HX
Ph
H
H2 O
NR2*
H
X
H
O
Nu
NuH
H
Ph
H
NR2*
NuH H
X
Mayr ACIE 2008, 47, 8723
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- Equilibrium between E/Z isomers leads to Curtin-Hammett control of product distribution- addition to E
isomer faster than to Z
Asymmetric Induction
E/Z-equilibrium and preferential attack on E-isomer
R'
R'
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N
Nu
R
faster
(E)
R
R
Nu
(Z)
Me
O
N
Me
N
Me
H
R1
R1
Me
Me
(E)
x
R'
R'
x
N
NH
Nu
Me N
O
slower
R (Z)
N
x
major product
N
N
Nu
E/Z :9:1
x
Me
O
N
NH
x
R
x
Me N
O
R1
R
Nu
minor product
N
N
Nu
x
Nu
Steric repulsion leads to high energy
of both transition states
MacMillan Model
R1
Nu
Houk Model
Seebach Hev. Chim. Acta 2009, 92, 1, Hev. Chim. Acta 2009, 92, 1225, Hev. Chim. Acta 2010, 93, 1, Hev. Chim. Acta
2010, 93, 603, MacMillan JACS 2000, 122, 4243 & Houk JACS 2006, 128, 3543
- Enantioselective Friedel-Crafts alkylations
MacMillan JACS 2002, 123, 4370
- Enantioselective Mukaiyama-Micheal reactions employing 2-siloxyfurans as nucleophiles to furnish
butenolide structures. Here, the nature of the catalyst governs the regioselectivity: Lewis acid-based
catalysts will lead to the 1,2-addition products (1,2-diol derivatives, Mukaiyama-Aldol), whereas
organocatalytic approaches (iminium catalysis) will lead to the corresponding 1,4-addition products
(Mukaiyama-Michael).
MacMillan JACS 2003, 125, 1192
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Treatment of 2-siloxyfurans with a variety of ,-unsaturated aldehydes afforded syn-butenolide adducts with
high diastereoselectivity and high enantioselectivity. Significantly, the use of different cocatalyst and solvent
provided the opposite diastereomer with same enantioselectivity.
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This methodology was applied in the synthesis of spiculisporic acid and 5-epi-spiculisporic acid
MacMillan JACS 2003, 125, 1192
- Enantioselective Michael reactions of ,-unsaturated ketones:
Jørgensen ACIE 2003, 42, 4055
- Conjugate reduction, formally, a H- is added in a 1,4-fashion to ,-unsaturated aldehydes. To render this
process stereoselective, a β,β’-disubstituted aldehyde has to be used.
In the following case, the Hantzsch ester (a dihydropyridine) is employed as the hydrogen source. It gets
oxidized to a pyridine, thereby formally releasing an equivalent of H2. (compare also with nature’s reducing
agent NADH, which essentially works via the same principle)
MacMillan JACS 2005, 127, 32
- Asymmetric counteranion directed catalysis (ACDC).
In this conjugate reduction of α,β-unsaturated aldehydes, the chiral 3,3’-BINOL derived phosphoric acid
serves as the counterion to the iminium ion formed in situ. Electrostatic interactions keep the phosphate in
close proximity to the electrophile, so that a face selection is induced. Important to note is that the bulky 3,3’substituents on the BINOL are essential for asymmetric induction to occur.
8
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List ACIE 2006, 45, 4193
,-unsaturated ketones: Neither ACDC catalysts nor chiral imidazolidinone catalysts gave good yields or
enantioselectivies in the conjugate reduction of ,-unsaturated ketones. A novel class of catalytic salts, in
which both anion and cation are chiral was developed by List.
List JACS 2006, 128, 13368
2.2
Catalytic Generation of Soft anions
2.2.1 Soft anions by transmetallation of hard anions
A wide variety of organometallic compounds can transfer their substituents (e.g. alkyl- or aryl ligands) to
other catalytically active metals. Thereby, the reactivity of these substituents to be transferred can be altered.
(see also section 1.2.3. : Transmetallation of a ‘hard’ Grignard reagent RMgBr to ‘soft’ copper leads to a shift
of 1,2-addition to 1,4-addition) Many different organometallic reagents are either commercially available or
can be prepared readily, therefore, the general approach to use them as alkyl- or aryl-donors for conjugate
addition through transmetallation is attractive.
2.2.1.1 Copper-catalyzed addition of Grignard reagents
Some characteristics of Cu-catalyzed enantioselective 1,4-conjugate addition of Grignard reagents are:
Grignard reagents have a relatively high reactivity. The competition of fast, uncatalyzed
background 1,2-carbonyl addition and 1,4-addition.
Unlike in iminium catalysis, α,β-unsaturated aldehydes cannot be employed because of their
high reactivity. Ketones, esters and thioesters have to be employed.
+
Chiral copper complexes based on phosphine-, phosphoramidite- and NHC-ligands are well
known and available
+
Many Grignard reagents are commercially available, and inexpensive
Alexakis and Baeckvall, Chem. Rev. 2008, 8, 2796,
Feringa, Chem. Rev. 2008, 8, 2824 & ACIE 2010, 40, 2486.
Good results with respect to yields and enantioselectivites are obtained with Cu/ferrocenyl-ligand complexes.
Important to note is the fact that both cyclic and acyclic substrates give good stereoselectivities. This
catalytic system works best for linear, unfunctionalized Grignard reagents. To introduce a chiral center with a
methyl group (from MeMgBr), which is the most frequent pattern in natural products, one needs to use the
more reactive thioesters instead of esters.
9
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- Mechanism of the enantioselective 1,4 addition of ,-unsaturated carbonyl compounds promoted by
copper complexes of chiral ferrocenyl diphosphine. The reaction is believed to run via a Cu-π-complex
followed by a formation of a Cu-σ-complex. The transfer of R to the α,β-unsaturated carbonyl compound was
found to be the rate-determining step.
Feringa JACS 2006, 128, 9103
Results with ferrocenyl-based bisphosphine ligands
Thioesters employed in these reactions show a more “ketone-like” reactivity and can be easily used in followup reactions, e.g. in a direct transformation to aldehydes. The aldehydes can then be employed to construct
another α,β-unsaturated thioester via Horner-Wadsworth-Emmons reaction, which allows the conjugate
addition to be carried out iteratively. Up to seven chiral methyl groups have been introduced using this
method in the synthesis of phthioceranic acid.
10
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- Similarly good results in terms of enantioselectivities can be obtained with BINAP-derived catalysts. This
catalyst system requires higher temperatures than the ferrocenyl-derived one, but has a broader nucleophile
scope. In contrast to the ferrocenyl-based system, one does not need to employ a thioester to achieve good
enantioselectivities with MeMgBr.
2.2.1.2
Cu-Catalyzed Conjugate Addition of C-Zn and C-Al Nucleophiles + Application to All-Carbon
Quaternary Centres
A recent addition to enantioselective conjugate additions is the formation of very sterically hindered,
quaternary all carbon centres by asymmetric conjugate addition to β,β’-disubstituted carbonyl compounds.
As these substrates are less reactive due to their steric hindrance, more reactive organometallic reagents
like trialkylaluminum reagents are employed. One of the first examples used highly reactive
trialkylaluminums as nucleophiles with a Cu/phosphoramidite catalyst:
Me
Me
Ar
O
Chiral Carbenes O
Angewandte
Chemie
Me
P N
DOI : 10.1002/ anie.200604511
Me
Ar
Quaternary
Me
A ll-Carbon
Stereogenic Centers by Enantioselective CuMe
Catalyzed
Conj ugate A dditions Promoted
by a Chiral N-H eterocyclic
O
R = Me, R` = Et, 97% ee
Carbene* * (4 mol %)
O
+
AlR`3
R
R = Et, R` = Me, 94% ee
CuTC (2 mol %)
M . Kevin Brown, Tricia L . M ay, Carl A . Baxter, and A mir H . R
H oveyda*
= i-Bu, R` = Me, 93% ee
R`
Et2O, -30 °C, 18 h
The design of new chiral catalysts for enantioselective synthesis of all-carbon quaternary stereogenic centers is a critical
and challenging objective in modern chemistry.[1] Such
catalysts must be enantio-differentiating but also especially
active because the desired reactions involve additions of
carbon nucleophiles to sterically congested electrophilic sites.
H erein, we disclose a readily available chiral N-heterocyclic
carbene (NH C) that can be used to promote the catalytic
asymmetric conjugate addition (A CA ) [2] of organozinc
reagents to cyclic g-keto esters [Eq. (1)] ; these transformations give rise to the enantioselective formation of all-carbon
R
R = (CH2)2CH=CH2, R` = Me, 95% ee
Alexakis, ACIE, 2005, 1376 & Chem. Commun. 2010, 46, 7295.
Dialkylzinc nucleophiles are more functional group compatible than trialkylaluminums- additions to enones
with β-ester groups proceed without acyl substitution and with complete regiochemistry for the more
hindered site. A chiral NHC-Ag complex was employed as catalyst in this case.
O
+
( )n
CO2Me
R2Zn
NHC-Ag complex
(2.5 mol %)
O
(CuOTf)2•PhH
quaternary
centers that bear a readily functiona(2.5
mol stereogenic
%)
[3–5]
lizable carboxylic ester substituent in up to 95% ee.
In
nearly all of the catalytic A CA reactions (one exception), the
Et
-30 °C
( )n
2O,
new
chiral NH C (Cu complex generated
COin2situ)
Me delivers
significantly higher efficiency and asymmetric induction than
R
the previously reported systems.
We began our investigation by examining the ability of Cu
complexes generated from the reaction of 1[5a] and 2[5c]
(Scheme 1) with (CuOTf) 2·C6H 6 in promoting the A CA of
M e2Z n to five- and six-membered ring g-keto esters 4 and 5
(Table 1). With cyclopentenone 4a as the substrate and in the
presence of binaphthyl-based 1 and (CuOTf) 2·C6H 6
[* ] M. K. Brown, T. L. May, Dr. C. A. Baxter, Prof. A. H. Hoveyda
Department of Chemistry
Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
Fax: (+ 1) 617-552-1442
E-mail : amir.hoveyda@bc.edu
11
[* * ] We are grateful to the NIH (GM-47480) and the NSF (CHE0213009) for financial support. We thank Professor A. Alexakis
(University of Geneva) for generously sharing unpublished results
n = 1, R = Me, 61%, 91% ee
n = 1, R = Ph, 72%, 81% ee
n = 2, R = Me, 89%, 89% ee
n = 2, R = i-Pr, 57%, 73% ee
n = 2, R = Ph, 82%, 93% ee
NHC-Ag
Complex
Scheme 1. Previously
reported 1 and 2 and the new chiral NHC
complex 3.
Hoveyda, ACIE, 2007, 1097
(2.5 mol % ), less than 10% conversion is detected after 24 h
(Table 1, entry 1). When biphenyl complex 2 is used, there is
only 15% conversion and 6 is formed in 30% ee (Table 1,
entry 2). With six-membered ring enone 5a, Cu-based complexes derived from 1 and 2 (Table 1, entries 4–5) promote the
A CA of M e2Z n more efficiently (60% and > 98% conversion) and with improved enantioselectivity (73% ee and
33% ee), but only in comparison to the reactions of cyclopentenone 4a and not at synthetically useful levels.
Faced with the inferior activity and asymmetric induction
provided by the Cu complexes of 1 and 2, we set out to
identify a more effective chiral catalyst. This initiative led us
to discover that complex 3,[6] a sulfonate-containing chiral
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Non-cyclic unsaturated carbonyls are less reactive than cycloalkenones, thus double activation of the alkene
is common. Meldrum’s acid derivatives (2 electron withdrawing groups) have been employed as activated
α,β-unsaturated carbonyl compounds for the addition of dialkylzinc reagents with a Cu/phosphoramidite
complex as catalyst.
Fillion, JACS, 2006, 2774
Recently Hoveyda reported asymmetric conjugate additions of aryl- and alkylaluminum reagents to ,disubstituted acyclic enones.
Hoveyda ACIE, 2013, 52, 8156.
2.2.1.3 Conjugate reduction
A Chiral copper-hydride catalyst is prepared in situ for the asymmetric conjugate reduction of ,unsaturated carbonyl compounds. As in the case of the organocatalytic conjugate reduction (compare
section 2.1.2), “H-“ is the nucleophile that is added in a 1,4-fashion. As stoichiometric reducing agents,
silanes (compounds bearing a Si-H bond) are employed. PMHS is a side-product of silicone production, thus
inexpensive and widely available.
Buchwald JACS 2003, 125, 11253
Lipshutz and Krause, Chem. Rev. 2008, 208, 2916
12
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Bode Research Group
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2.2.1.4 Rh-Catalyzed Asymmetric Addition of Boronic Acids and their Derivatives
Hayashi and Miyaura described the Rh-catalyzed addition of aryl boronic acids to unsaturated ketones in
1998 - since that time this field has developed greatly. Even though boronic acids are not “organometallic”
reagents in a strict sense, they do transmetallate. This stems from the fact that the C-B bond is polarized in a
similar fashion like a C-Mg bond in a Grignard reagent. This enables the R group from a boronic acid to be
transferred to a metal. Boronic acids are readily available and the reaction with Rh catalysts shows a high
functional group tolerance as well as mild reaction conditions.
Hayashi, JACS, 1998, 5579
Mechanistic studies revealed the importance of water to help catalyst turnover and hydroxide to facilitate
transmetallation and allow lower reaction temperatures:
*
O
Ph2P
PPh2
PhB(OH)2
Rh
H O
O H
(transmetallation
at 35 °C)
Rh
Ph
H2 O
Ph2P
PPh2
*
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Lipshutz JACS 2004, 126, 8352
*
Ph2P
O
*
PPh2
Rh
Ph2P
PPh2
Rh
O
P
Ph
Ph
Ph
P
O
Ph (S)
(key aryl Rh species)
si face attack
O
*
Ph2P
PPh2
Rh
O
Ph
Hayashi, JACS, 2002, 5052 & Chem. Rev. 2003, 103, 2829.
An important discovery is that chiral dienes can be used as ligands rather than chiral phosphines- this leads
to far more reactive catalysts. The reactions can be carried out at much lower reaction temperatures.
Hayashi, JACS, 2003, 11509
Diene ligands can provide exquisite chemo- and enantioselectivity - additions to unsaturated aldehydes
proceed by 1,4-addition, not 1,2. This is in stark contrast to a Rh/phosphine catalyst, which furnishes the 1,2additon product exclusively.
13
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Carreira, JACS, 2005, 10851 & Miyaura, J. Org. Chem. 2000, 65, 4450
Other boron-based reagents can also be used. Most importantly, potassium trifluoroborate salts which are air
and moisture stable and easy to prepare and handle:
O
Me
O
O
OMe
O
Me
Me
Ph
Ph
(85%, 96% ee)
(51%, 91% ee)
Ph
(99%, 93% ee)
Me
O
X
+ RBF3K
( )n
(2.2 mol %)
[Rh(C2H4)2Cl]2 (1.0 mol %)
KOH (2.2 mol %)
O
O
O
X
Et3N, PhCH3, H2O, rt
( )n
Ph
R
(84%, 84% ee)
Ph
(80%, 82% ee)
Darses, OL, 2009, 3486
The use of tetraarylborate salts allows synthesis of all-carbon quaternary centers. The coordination of Ar3B
to the carbonyl is proposed to assist activation of the electrophile to enable attack on the hindered β-position.
One drawback of this methodology is that only one of four aryl groups can be transferred:
Ar3B
Me
Ar4BNa
via
O
Me
(2.5 mol %)
R2
MeOH, Dioxane, 60 °C
R3
Me
Ph
Me
Ph
R3
94%, 91% ee
Rh
Cl
R1
R2
O
O
O
O
R1
+ Ar Rh
R1
R2
O
Me
+
O
O
Ar
R3
Ph
Ar
R
Me
R = Me, 83%, 98% ee
R = CO2Me, 80%, 98% ee
Ar = 4-MeC6H4, 73%, 91% ee
Ar = 3-ClC6H4, 65%, 97% ee
Hayashi, JACS, 2009, 13588
Boron nucleophiles can transmetallate with other soft metals beside rhodium.1,4-Additions of aryl-boronic
acids to ,-unsaturated aldehydes have been performed with a combination of Pd and amine catalysts.
Ibrahem & Cordova ACIE, 2013, 52, 878.
2.2.1.5 Overview of some methods for conjugate additions
14
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X
Nu
= CR
- allylSiR3
(Nu = allyl)
- Silyl-thioketene
acetals
- Aryls (FriedelCrafts-type)
- Carbamates
= OR
= NR
(oxazolidinones,
imides)
= CO2R
= COH(CH3)2
= NR (Imides)
= P(O)(OMe)2
= imidazoles
= CR
= CR
Ligand
Cu
BOX
Mg
Sc
BOX
PyBOX
- Ti-BINOL
- oxazaborilidine
Al
BINOL
One-point
binding
Salen
Zr
BINOL
One-point
binding
One-point
binding
- Hydrazines
- Aryls (FriedelCrafts-type)
- Silyl(thio) ketene
acetals
- Aryls (FriedelCrafts-type)
- Aryls (FriedelCrafts-type)
= CR
http://www.bode.ethz.ch/
Catalyst
Lewis Acid catalyzed
Cu
BOX
Organocatalysis
- Aryls (Friedel- Imidazolidinone
Crafts-type)
- Silylenolethers
(Mukaiyama-type)
- Hydride: “H-“
(conjugate red.)
- Hydride: “H-“
- chiral BINOLChiral counterions
(conjugate
based
needed for ketones
reduction)
phosphoric acids
Organometallic nucleophiles
- R-B(OH)2
Rh
BINAP or chiral
R = aryl
diene (lower temp)
=H
= CR (more
difficult)
=H
= CR
= CR (ketones)
= OR
= H (difficult)
= CR
= OR
= SR
= CR
= CR
Comments
2-point binding
of substrate to
catalyst
“ACDC”
- RMgBr
R = alkyl
(mostly
unfunctionalized)
- R3Al
R = alkyl (mostly
unfunctionalized)
- R2Zn
Cu
Josiphos-type or
BINAP
1,2- vs 1,4addition can be
done by choice
of catalyst
Can be done
iteratively
Cu
Phosphoramidites,
NHC
Quaternary
centers
Cu
- Hydride “H-“
(from silanes)
Cu
Phosphoramidites,
NHC
BINAP, Josiphos
Quaternary
centers
Conjugate
reduction
= CR
= OR
= NR
2.2.2 Generation of soft anions by deprotonation
2.2.2.1 Deprotonation of terminal alkynes
Terminal alkynes are relatively acidic (pKa ~ 23 in H2O) and are easily deprotonated by weak bases in the
presence of π-acidic Lewis acids such as Cu. However, alkynes often act as “dummy ligands” as they are
poor nucleophiles; in the first catalytic, asymmetric alkyne addition, highly reactive electrophiles were used to
overcome this poor reactivity:
Ph
Et
HN
Et
N
OH
N
MeO
O
PPh2
H
O
O
O
R = i-Pr, 94%, 95% ee
R = Cy, 81%, 94% ee
R = Et, 83%, 82% ee
R = Ph, 64%, 83% ee
Cu(OAc)2 H2O (cat)
O
O
R
O
+
Ph
Na-(+)-ascorbate
H2O, 0 °C
O
R
Ph
Carreira, JACS, 2005, 9682
15
Update to 2013
Bode Research Group
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Alkyne1,4-addition to less electrophilic substrates can be carried out at elevated temperatures. Unfortunately
alkyne dimerization is a common side reaction, which can be avoided using very bulky and electron-rich
phosphine ligands.
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O
O
PAr2
O
PAr2
O
H
O
+
R1
(5.5 mol %)
[Rh(OAc)(C2H4)]2
(2.5 mol %)
O
R1
Dioxane, 80 °C
R2
R2
Si(i-Pr)3
Si(i-Pr)3
R1 = Ph, R2 = Me, 99%, 91% ee
R1 = 2-Furyl, R2 = Me, 99%, 93% ee
R1 = Me, R2 = Me, 90%, 95% ee
R1 = Me, R2 = C5H11, 90%, 97% ee
t-Bu
Ar =
OMe
t-Bu
Hayashi, JACS, 2008, 1577
2.2.2.2 Deprotonation of nitroalkanes and malonates
Nitroalkanes (pKa ~ 10 in H2O) are readily deprotonated by weak bases - use of a bulky chiral cation gives
high enantio- and diastereoselectivity in conjugate additions. Note that the chiral catalyst has to carry bulky
3,3’-substituents in order to achieve high ees. Malonates (pKa ~ 13 in H2O) are the classic Michael donors.
Br
Ar
O
O
1 mol % cat
Cs2CO3 (3 equiv)
H
+
( )n
R
NO2
PhCH3, -20 °C
O
O
N
NO2
R
O
Ar
O
Ar =
NO2
NO2
Ph
CO2Et
NO2
O
99%, 95:5 dr, 93% ee
99%, 89:11 dr, 90% ee
O
NO2
Me
Me
94%, 95:5 dr, 80% ee
94%, 88:12 dr, 85% ee
F
F
Maruoka, OL, 2005, 5143
Maruoka, OL, 2005, 3195
2.3
Dual Activation of Nucleophiles and Electrophiles
2.3.1 3,3`-Disubstituted BINOL Catalysts in Conjugate Additions of Boronic Acids
Extensive computational studies by Goodman suggest that BINOL-derived boronates are more Lewis acidic
than the parent boronates as the twisted orientation limits B-O interactions. Subsequently, this adduct with
the ketone has a lower lying LUMO and a higher energy HOMO than the adduct of the parent boronate.
Therefore, this is an example of a ligand-accelerated reaction.
16
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I
-1.796 eV
Me
MeO
MeO
LUMO
O
-2.885
LUMO
B
3.333 eV
4.626 eV
O
O
I
Me
Ph
-6.218 eV
-6.422 eV
Me
O B
Me
Ph
HOMO
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HOMO
Dual activation by HOMO raising and LUMO lowering
Goodman, JOC, 2008, 5078
This concept has been shown to be practical in synthetic applications:
Chong has demonstrated that BINOLs catalyzed the addition of alkynylboronates to unsaturated ketones;
the proposed catalytic cycle is based on ligand exchange around the boron atom:
Chong, JACS, 2005, 3244
Similarly high enantioselectivities were observed for attack of alkenylboronates- a six-membered ring
transition state was proposed to explain the sense of addition:
I
OH
R4
R3
OH
R4
R5
B(OMe)2
I
+
4 Å MS, CH2Cl2
reflux
O
R1
R3
R5
R2
O
R1
R2
81-96%, 94-99.5% ee
Chong, JACS, 2007, 4908
2.3.2 Al-Salen Catalyzed Conjugate Additions to Unsaturated Imides
Jacobsen has made extensive use of salen ligands for enantioselective conjugate reactions - in the initial
report on addition of hydrazoic acid (pKa 4.72 in H 2O), high ee was obtained for addition to β-alkylsubstituted imides. This was proposed to occur through a one-point binding, Lewis acid activation:
(R,R)-Salen
N
N
Back face t-Bu
hindered
NCOPh
Al
t-Bu
O
O
N
R
H
+
HN3
Ph
O
N3 O
t-Bu
H
t-Bu
t-Bu
(5 mol %)
PhCH3, CH2Cl2, -40 °C
N3
R
O
O
N
Ph
H
R = alkyl, 96-99%, 95-95% ee
R = Ph, 58%, 60% ee
R
O
N Al
N
t-Bu
O
O
t-Bu
Front face H
exposed
t-Bu
Jacobsen, JACS, 1999, 8959
In the conjugate addition of cyanide to imides, high enantioselectivity was obtained for β-alkyl substrates but
β-aryl ones showed no reactivity. An important observation was a 2nd order rate dependence on catalyst
concentration, evidence for a bimetallic catalytically active species.
17
Update to 2013
Bode Research Group
O
N
R1
Ph
H
+
TMSCN
i-PrOH
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O
(S,S)-SalenAlCl
(10 mol %)
PhCH3, rt
in-situ
HCN
O
CN
O
R
N
Ph
H
R = alkyl, 70-96%, 87-98% ee
R = Ph, vinyl, no reaction
[SalenAlCl] in (M)2 • 104
Jacobsen, JACS, 2003, 4443
Therefore, a new ligand was designed which contains two Al-salen groups tethered together - dramatic rate
acceleration and higher ee’s were observed. Importantly, previously unreactive electrophiles could be used.
O
N
Al
t-Bu
O
Dimer Salen
(5 mol %)
O
N
Cl
Ph
O
N
H
O
Ph
TMSCN, i-PrOH
TBME, 50 °C
O
t-Bu
O
t-Bu
( )n
t-Bu
Ph
t-Bu
O
Cl
O
N
H
Me
TMSCN, i-PrOH
TBME, 50 °C
O
CN
N
H
O
Ph
65% conv
95% ee
Ph
O
CN
47% conv
95% ee
N
H
Me
O
Al
N
Ph
Dimer Salen
(5 mol %)
O
O
t-Bu
O
O
N
Ph
O
N
H
Dimer Salen
(5 mol %)
Me
t-Bu
TMSCN, i-PrOH
TBME, 50 °C
O
Ph
O Me
N
H
CN
32% conv
t-Bu 92% ee
Formation of Salen-CN as more reactive nucleophile, and Salen-Imide as more reactive electrophile
Jacobsen, ACIE, 2008, 1762
18