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Journal ArticleDOI

Phosphoramidites: marvellous ligands in catalytic asymmetric conjugate addition.

31 May 2000-Accounts of Chemical Research (AMER CHEMICAL SOC INC)-Vol. 33, Iss: 6, pp 346-353
TL;DR: The breakthrough is presented using chiral phosphoramidite ligands for copper-catalyzed dialkylzinc additions for enantioselective carbon-carbon bond formation by 1,4-addition of organometallic reagents to enones.
Abstract: The development of an efficient catalytic system for enantioselective carbon−carbon bond formation by 1,4-addition of organometallic reagents (organolithium, Grignard, and organozinc reagents) to enones is a major challenge in organic synthesis. This Account presents the breakthrough realized in this field using chiral phosphoramidite ligands for copper-catalyzed dialkylzinc additions. Applications in catalytic routes to cycloalkanones as well as tandem and annulation procedures with excellent enantioselectivities are discussed.

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University of Groningen
Phosphoramidites: Marvellous ligands in catalytic asymmetric conjugate addition
Feringa, B.L.
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Accounts of Chemical Research
DOI:
10.1021/ar990084k
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Feringa, B. L. (2000). Phosphoramidites: Marvellous ligands in catalytic asymmetric conjugate addition:
Marvellous Ligands in Catalytic Asymmetric Conjugate Addition.
Accounts of Chemical Research
,
33
(6),
346 - 353. https://doi.org/10.1021/ar990084k
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Phosphoramidites: Marvellous
Ligands in Catalytic Asymmetric
Conjugate Addition
BEN L. FERINGA
Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
Received January 31, 2000
ABSTRACT
The development of an efficient catalytic system for enantioselec-
tive carbon-carbon bond formation by 1,4-addition of organome-
tallic reagents (organolithium, Grignard, and organozinc reagents)
to enones is a major challenge in organic synthesis. This Account
presents the breakthrough realized in this field using chiral
phosphoramidite ligands for copper-catalyzed dialkylzinc additions.
Applications in catalytic routes to cycloalkanones as well as tandem
and annulation procedures with excellent enantioselectivities are
discussed.
Introduction
The challenge to develop new catalytic methods and to
replace existing synthetic procedures, which often rely on
the use of stoichiometric amounts of auxiliary reagents,
by catalytic ones has captivated the chemical community.
1
This so-called “catalytic switch” is expected to have a
profound influence on the future of fine chemical manu-
facturing and can drastically change our synthetic reper-
toire. It also has stimulated the awareness that ultimately
integrated multistep catalytic transformations might be
feasible. Few areas in chemistry have seen the pace of
progress found in asymmetric catalysis in the past de-
cades. Today a considerable number of catalytic systems
are known which provide enantioselectivities exceeding
95%.
2
Catalytic enantioselective carbon-carbon bond-
forming reactions include Diels-Alder and ene reactions,
dialkylzinc additions to aldehydes, aldol (and related)
transformations, coupling reactions, allylic substitutions,
and cyclopropanations. Among the most widely used
methods for the construction of carbon-carbon bonds are
conjugate addition reactions of carbon nucleophiles to
R,β-unsaturated compounds.
3
For instance, these addi-
tions are key steps in the synthesis of numerous biological
active compounds including steroids, prostaglandins, and
terpenes. The broad potential, combined with the large
variety of donor and acceptor compounds that can be
employed, has been a strong impetus to develop enanti-
oselective variants.
Major advances in the development of catalytic asym-
metric Michael additions
4
and enantioselective conjugate
additions of organocopper compounds with chiral non-
transferable ligands
5,6
have been reported.
However, despite numerous attempts over more than
two decades, it is only recently that chiral metal catalysts
have been found that show enantioselectivities up to the
90% level in 1,4-additions of Grignard, organolithium, or
organozinc reagents, albeit often with limited scope
2a,6
(Scheme 1).
Following Lippard’s seminal report on the asymmetric
addition of n-BuMgBr to 2-cyclohexen-1-one using a
chiral N,N-dialkylaminotropone imine copper(I) catalyst,
7
a variety of ligands were examined, and these studies
revealed that the best results are usually obtained with
copper(I) complexes with soft sulfur or phosphorus
ligands.
2a,8
Challenged by the idea to design a general and
enantioselective catalyst for this important class of reac-
tions and fascinated by the spectacular results on the 1,2-
addition of dialkylzinc reagents
9
(R
2
Zn), we started in 1986
using Zn, Ni, and Cu catalysis. In the quest for chiral
ligands and catalysts for 1,4-additions of R
2
Zn reagents,
we experienced the complex nature of many of these
catalytic systems. We decided to deviate our strategy to
uncover high reactivity first. The breakthrough came when
we introduced phosphoramidites as ligands for asym-
metric catalysis. As a result of the remarkable reactivity
and selectivity of copper complexes based on these novel
chiral ligands, the first catalytic 1,4-additions of R
2
Zn
reagents with complete enantiocontrol were realized.
10
The use of phosphoramidites in catalytic conjugate ad-
dition to cyclic and acyclic enones is the main topic of
this Account, with emphasis on the progress made by our
research group.
Dialkylzinc Reagents
Recent years have seen a remarkable revival of the use of
organozinc reagents in organic synthesis.
11
There were two
important considerations in our focus on R
2
Zn reagents:
(1) Is it possible to use an enone and an alkene as the
starting materials? (2) Are functional groups tolerated (a
feature not easily accomplished with organolithium or
Grignard reagents) (Scheme 2)?
Although R
2
Zn reagents often react sluggishly with
carbonyl compounds, effective catalysis can be achieved
by complexes based on several ligands and transition
metals. The catalytic effect has been explained by changes
in geometry and bond energy of the zinc reagents or by
transmetalation.
11
In copper-catalyzed 1,4-additions of R
2
-
Ben L. Feringa received his Ph.D. degree from the University of Groningen in
1978 with professor Hans Wynberg. He was a research scientist with Royal Dutch
Shell, both at the research center in Amsterdam and at the Shell Biosciences
Laboratories at Sittingbourne, UK, from 1978 to 1984. He joined the department
of chemistry at the University of Groningen in 1984 as a lecturer and was
appointed professor at the same University in 1988. He was visiting professor at
the University of Leuven, JSPS fellow, and 1997 recipient of the Pino gold medal
of the Italian Chemical Society. With a focus on stereochemistry, his present
research interests include organic synthesis, homogeneous (asymmetric) ca-
talysis, molecular switches and motors, self-assembly, and new organic materials.
Scheme 1
Acc. Chem. Res.
2000,
33,
346-353
346
ACCOUNTS OF CHEMICAL RESEARCH
/ VOL. 33, NO. 6, 2000 10.1021/ar990084k CCC: $19.00 2000 American Chemical Society
Published on Web 05/31/2000

Zn reagents, a key step is alkyl transfer from Zn to Cu to
generate in situ an organocopper reagent (Scheme 3),
although other formulations such as bimetallic Zn/Cu
reagents might be given.
11
The ability of organozinc reagents to undergo trans-
metalation permits their conversion in more reactive
organometallic reagents RML
n
, which has been demon-
strated with Ni,
12
Cu,
13
Pd,
14
and Ti.
15
Alkyl transfer from
diorganozinc reagents to enones can also be effected by
nickel catalysts. Enantioselective versions of these alkyl-
transfer reactions to acyclic enones, in particular chal-
cones, have been reported, employing several chiral
ligands including diamines, pyridine methanols, proline
amides, and amino alcohols.
16
A notable accomplishment
is the 90% enantiomeric excess (ee) reached by Soai in
the conjugate addition of Et
2
Zn to acyclic enones using a
nickel-ephedrine-based catalyst.
16e
Trivalent phosphorus
compounds represent another class of ligands that have
been used for a considerable time in stoichiometric
conjugate additions.
17
The first application in a catalytic
addition of Et
2
Zn to cyclohexenone, which resulted in 32%
ee, was reported by Alexakis.
18
Detailed studies by Bolm
19
and our group
20
revealed that, like the asymmetric copper-
catalyzed conjugate addition of Grignard reagents,
8
these
carbon-carbon bond formations are highly sensitive to a
large number of factors that govern catalyst activity and
enantioselectivity. In addition to the structures of the
enones and the ligands, these are inter alia the nature of
the solvent, Ni-ligand ratio, counterions, temperature,
and addition rate.
A very important feature is the apparent lack of one
unique and highly reactive catalyst. The dependence of
the stereocontrol on the concentration of the catalyst as
well as the conversion and the presence of nonlinear
effects points to equilibria between several (diastereo-
meric) catalytically active species.
Copper Phosphoramidite Catalysts in
Conjugate Addition
The numerous studies, including our own, on asymmetric
1,4-addition of organometallic reagents mentioned above
did not clearly show us the key elements for the realization
of complete stereocontrol. Apparently, modest enantio-
selectivities are rather easily achieved with structurally
diverse chiral ligands.
We realized that several competing catalytically active
complexes, including achiral ones, might be present.
Therefore, the key question in our design of an enanti-
oselective catalytic system was that of how to achieve very
efficient ligand-accelerated catalysis.
21
This concept in-
volves the presence of a chiral ligand that leads to a highly
reactive catalyst, strongly favoring an enantioselective
pathway over any nonselective pathway.
Since relatively hard (amino alcohols) as well as soft
(thiols, phosphines) chiral ligands result in active catalysts
for 1,4-additions, we anticipated that the catalytic activity
might be enhanced by fine-tuning the electronic proper-
ties of trivalent phosphorus ligands. Toward this goal we
have introduced phosphoramidites,
22
which have electron
donor-acceptor properties typically between those of
arylphosphines and arylphosphites.
In contrast to the large number of phosphines and
phosphites frequently employed as ligands in asymmetric
catalysis, phosphoramidites have not been used, presum-
ably because of the sensitivity toward hydrolysis attributed
to this class of compounds.
We discovered that chiral phosphoramidites 1 based
on 2,2-binaphthol are, however, not only remarkably
stable but also excellent ligands for Cu-catalyzed 1,4-
addition of R
2
Zn to cyclic and acyclic enones, as shown
in Scheme 4.
23
Detailed examination of the Et
2
Zn addition to model
substrates chalcone and cyclohexenone employing 1-3
mol % of catalyst, prepared in situ from CuI or CuOTf and
phosphoramidite 2, revealed the following features: (1)
Scheme 2
Scheme 3
Scheme 4
Phosphoramidite Ligands in Conjugate Additions
Feringa
VOL. 33, NO. 6, 2000 /
ACCOUNTS OF CHEMICAL RESEARCH
347

Excellent chemo- and regioselectivities (>95%) for the 1,4-
adducts. (2) Relatively short reaction times, as complete
conversions are reached in less than 3 h, even at -35 °C.
(3) Significant enantioselectivities for both cyclic and
acyclic enones using the same catalyst. This was an
exciting observation, as the latter feature is notably absent
with almost all other catalysts for asymmetric 1,4-addition
of organometallic reagents.
Of all the 1,4-additions to enones we had been studying
so far, the copper-phosphoramidite catalyst turned out
to be by far the best in providing a clean and fast
formation of β-alkylated ketones. We were delighted to
find that the high catalytic activity was the result of a
strong ligand accelerating effect.
Important improvements, including better solubility of
the catalyst and slightly enhanced ee values, were found
when Cu(OTf)
2
was used for the in situ preparation of the
catalyst instead of CuI or CuOTf. Apparently, in situ
reduction to the corresponding Cu(I) complex takes place.
For application in synthesis, the easy handling of Cu(OTf)
2
compared to CuOTf is probably most significant.
Once we had realized our first major goalsefficient
ligand-accelerated catalysisswe focused on reaching high
enantioselectivity by ligand modification. Structural varia-
tions of the phosphoramidites can be easily explored by
a modular variation of the amine and binaphthol moieties.
The X-ray structure of the CuI complex of phosphor-
amidite 2 guided us, as it shows that the obvious positions
for ligand modification are the amine moiety and the 3,3-
positions of the binaphthyl part of the ligand. Substituents
at these positions will point toward an alkyl moiety or an
enone bound to copper (vide infra) (Figure 1).
The most significant improvements of the ligands with
respect to the enantioselectivity in the catalytic 1,4-
addition are observed when sterically demanding substit-
uents are introduced at nitrogen. When the diisopropyl-
amine derived ligand 3 is employed, ee’s of 60% and 90%
for cyclohexenone and chalcone, respectively, are reached
(Scheme 4).
A breakthrough was achieved when the nonchiral
amine moiety in the (S)-2,2-binaphthol-based phos-
phoramidite ligand was replaced by a second chiral
structural unit, that is, the sterically demanding (R,R)-bis-
(1-phenylethyl)amine, resulting in phosphoramidite 4.A
matched combination results in a highly selective catalyst
for the addition of diorganozinc reagents to cyclohexenone
(Scheme 5).
10
Even when only 0.5 mol % catalyst (Cu-to-ligand ratio
1:2) is employed, excellent yields and ee values exceeding
98% are obtained, and recently turnover numbers greater
than 3000 were realized.
24
The scope and efficiency of this
novel monodentate ligand 4 is remarkable, as is illustrated
in Table 1 for cyclic enones.
When the new chiral copper phosphoramidite catalyst
is used, enantioselectivities up to 90% for acyclic enones
(chalcones)
25
and >98% for cyclic enones (cyclohex-
enones)
10
are now routinely obtained.
26
Catalytic Cycle
A proposed pathway for the catalytic 1,4-addition, based
on mechanistic studies in organocuprate and zincate
chemistry
6,11
and the results obtained by us so far,
10,23,25
FIGURE 1. X-ray structure of the CuI complex of ligand 2.
Scheme 5
Table 1. Enantioselective 1,4-Addition of R
2
Zn
Compounds to Cyclic Enones Catalyzed by Cu(OTf)
2
/4
RR
1
n yield (%) ee (%)
C
2
H
5
H194 >98
C
2
H
5
H 0 75 10
C
2
H
5
H295 >98
C
2
H
5
H 3 95 97
C
2
H
5
CH
3
174 >98
C
2
H
5
C
6
H
5
193 >98
CH
3
H172 >98
CH
3
CH
3
168 >98
C
7
H
15
H 1 95 95
i-C
3
H
7
H 1 95 94
(CH
2
)C
6
H
5
H 1 53 95
(CH
2
)
5
OAc H 1 77 95
(CH
2
)
3
CH(OC
2
H
5
)
2
H 1 91 97
Phosphoramidite Ligands in Conjugate Additions
Feringa
348
ACCOUNTS OF CHEMICAL RESEARCH
/ VOL. 33, NO. 6, 2000

is shown in Scheme 6. Starting either with a Cu(I)-
phosphoramidite complex or preferably the Cu(OTf)
2
-
phosphoramidite complex, transfer of an alkyl fragment
from R
2
Zn to the copper center takes place. Complexation
of the alkylzinc fragment to the enone carbonyl and
formation of the π-complex of the copper alkyl species
with the enone results in complex 5. Due to the high levels
of stereocontrol reached in this catalytic cycle, 5 might
well be formulated as a bimetallic complex, leading to a
fixed conformation of the enone. Subsequent alkyl transfer
generates zinc enolate 6, which upon protonation affords
the β-substituted cycloalkanone 7, or alternatively 6 may
be trapped in tandem protocols (vide infra).
The optimum ligand-to-copper ratio of 2, the nearly
identical selectivities with mono- and bidentate phos-
phoramidites (except for cyclopentenones),
23,25b
and the
observation of nonlinear effects
25a
strongly point to the
presence of two ligands in the active catalyst.
Cyclic Enones
The scope of the novel catalytic 1,4-addition includes
cyclic enones with different ring sizes and substituent
patterns leading to 3-substituted cyclohexanones, cyclo-
heptanones, and cyclooctanones with ee’s exceeding 97%
(Figure 2).
10,27
Suprisingly, the enantioselectivity is not
affected in the case of 4,4-disubstituted cyclohexenones
(e.g., dialkyl, diphenyl), whereas for 5,5-disubstituted
cyclohexenones a slight depletion of ee is observed,
presumably due to unfavorable 1,3-diaxial interactions.
The catalytic 1,4-addition of a variety of functionalized
dialkylzinc reagents proceeds with comparable enantio-
selectivities (Scheme 7, Table 1). Starting with the corre-
sponding alkenes, the R
2
Zn reagents are readily prepared
by hydroboration and subsequent zinc exchange accord-
ing to the procedure of Knochel
28
or via the corresponding
Grignard reagent. It is particularly noteworthy that the
catalyst tolerates ester and acetal functionalities.
In sharp contrast with the uniformly high enantio-
selectivity obtained when the ring size of the enone is
increased, the very low selectivity (10% ee with ligand 4)
that is found in the 1,4-addition of diethylzinc to cyclo-
pentenone is remarkable. Employing a binaphthol-based
phosphite ligand, Pfaltz was able to raise the ee to 72% in
this addition.
29
We followed two approaches involving
ligand modifications that led to significant improvements
in the case of cyclopentenone. The first approach involves
a Taddol-based phosphoramidite (8) in the presence of
molecular sieves,
32
whereas the second is based on bis-
phosphoramidite ligand 9, leading to 83% ee.
25b
However, raising enantioselectivities to the >95% level
in catalytic routes to the (synthetically important) cyclo-
pentanone building blocks is a still major challenge.
Conjugate Additions to Cyclohexadienones
Chiral synthons derived from 4,4-disubstituted cyclohexa-
dienones are highly attractive due to their multifunctional
nature. Conjugate addition to symmetric dienones results
in desymmetrization of the prochiral dienone moiety
30
(Scheme 8a). When the two substituents are equal, as is
the case with benzoquinone monoacetals 10, side selec-
tivesRe versus Si facesaddition of the organometallic
reagent will afford a single stereocenter. Enantioselectivi-
ties ranging from 85% to 99% were found, depending on
the size of the acetal moiety and the nature of the R
2
Zn
reagents. For example, 4,4-dimethoxy-5-methylcyclohex-
enone (16) is readily obtained in 76% isolated yield with
a rewarding 99% ee (Figure 3).
An intriguing question was posed to us in the case of
cyclohexadienones with two different substituents, i.e., an
alkoxy group and an alkyl group, at the 4-position (Scheme
FIGURE 2. Cycloalkanones obtained by enantioselective catalytic
1,4-addition using R
2
Zn and catalyst Cu
II
(OTf)
2
/4. Substituents R are
given in Table 1.
Scheme 6
Scheme 7
Phosphoramidite Ligands in Conjugate Additions
Feringa
VOL. 33, NO. 6, 2000 /
ACCOUNTS OF CHEMICAL RESEARCH
349

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Frequently Asked Questions (14)
Q1. What are the contributions mentioned in the paper "Phosphoramidites: marvellous ligands in catalytic asymmetric conjugate addition" ?

Applications in catalytic routes to cycloalkanones as well as tandem and annulation procedures with excellent enantioselectivities are discussed. 

11The ability of organozinc reagents to undergo transmetalation permits their conversion in more reactive organometallic reagents RMLn, which has been demonstrated with Ni,12 Cu,13 Pd,14 and Ti.15 Alkyl transfer from diorganozinc reagents to enones can also be effected by nickel catalysts. 

Trivalent phosphorus compounds represent another class of ligands that have been used for a considerable time in stoichiometric conjugate additions. 

Among the most widely used methods for the construction of carbon-carbon bonds are conjugate addition reactions of carbon nucleophiles to R,â-unsaturated compounds.3 

The finding that the copper-phosphoramidite catalyst tolerated functionalized dialkylzinc reagents constitutes the foundation for novel catalytic enantioselective annulation methods. 

The Hajos-Parrish asymmetric versionof the Robinson annulation is one of the most prominent protocols in the construction of carbocyclic compounds (Scheme 10a), frequenty used in the synthesis of steroids and terpenes. 

Due to the high levels of stereocontrol reached in this catalytic cycle, 5 might well be formulated as a bimetallic complex, leading to a fixed conformation of the enone. 

In contrast to the large number of phosphines and phosphites frequently employed as ligands in asymmetric catalysis, phosphoramidites have not been used, presumably because of the sensitivity toward hydrolysis attributed to this class of compounds. 

The first catalytic regio- and enantioselective threecomponent coupling of organozinc reagents was, indeed, achieved, affording trans-2,3-disubstituted cyclohexanones with ee’s exceeding 90% in all cases examined (Scheme 9).10 

Enantioselective versions of these alkyltransfer reactions to acyclic enones, in particular chalcones, have been reported, employing several chiral ligands including diamines, pyridine methanols, proline amides, and amino alcohols.16 A notable accomplishment is the 90% enantiomeric excess (ee) reached by Soai in the conjugate addition of Et2Zn to acyclic enones using a nickel-ephedrine-based catalyst. 

The optimum ligand-to-copper ratio of 2, the nearly identical selectivities with mono- and bidentate phosphoramidites (except for cyclopentenones),23,25b and the observation of nonlinear effects25a strongly point to the presence of two ligands in the active catalyst. 

The X-ray structure of the CuI complex of phosphoramidite 2 guided us, as it shows that the obvious positions for ligand modification are the amine moiety and the 3,3′- positions of the binaphthyl part of the ligand. 

The tandem addition (1.2 mol % catalyst) of Me2Zn and propanal to cyclohexenone, providing diketone 20 (after oxidation) in 81% yield with 97% ee, is an illustrative example. 

Structural variations of the phosphoramidites can be easily explored by a modular variation of the amine and binaphthol moieties.