Enantioselective catalytic conjugate addition of dialkylzinc reagents using copper-phosphoramidite complexes; ligand variation and non-linear effects

Article abstract of DOI:10.1016/S0040-4020(00)00142-3

A variety of new chiral phosphoramidites was synthesised and tested in the copper-catalysed enantioselective conjugate addition of diethylzinc to cyclohexenone and chalcone in order to assess the structural features that are important for stereocontrol. A

Full text of DOI:10.1016/S0040-4020(00)00142-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2865±2878
Enantioselective Catalytic Conjugate Addition of Dialkylzinc
Reagents using Copper±Phosphoramidite Complexes;
Ligand Variation and Non-linear Effects
Â
Leggy A. Arnold, Rosalinde Imbos, Alessandro Mandoli, Andre H. M. de Vries, Robert Naasz
*
and Ben L. Feringa
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
Received 3 November 1999; revised 6 January 2000; accepted 13 January 2000
AbstractÐA variety of new chiral phosphoramidites was synthesised and tested in the copper-catalysed enantioselective conjugate addition
of diethylzinc to cyclohexenone and chalcone in order to assess the structural features that are important for stereocontrol. A sterically
demanding amine moiety is essential to reach high e.e.'s. Enantioselectivities for chalcones up to 89% and for cyclic enones up to 98% were
found. Studies on non-linear effects with the best ligands for both cyclohexenone and chalcone showed clear non-linear effects for both cyclic
and acyclic enones. q 2000 Elsevier Science Ltd. All rights reserved.
Conjugate addition reactions of organometallic reagents to
a,b-unsaturated compounds constitute an important part of
our standard repertoire of synthetic methods for carbon±
carbon formation.1 Although organocuprates and copper-
catalysed 1,4-additions of Grignard- and organolithium
reagents are most frequently employed2,3 a number of
alternatives based on, for example, the use of other metal
catalysts (Ni, Co) or organometallic reagents (R2Zn, R3Al)
has been reported in recent years.4,5
(ii) the ligands associated with it, (iii) the aggregation of
most of these reagents in solution (often solvent dependent),
(iv) the effect on regio- and stereoselectivity by additional
ligands, coordinating solvents and salts, (v) the activation of
the enones by metal ion complexation or via additional
Lewis acid.
Lippard and co-workers10 described the ®rst catalytic conju-
gate addition of n-BuMgBr to 2-cyclohexenone employing
an in situ prepared chiral copper(I) complex derived from
N,N0-dialkylaminotropone-imine in the presence of HMPA
and t-butyldiphenylsilyl chloride leading to e.e.ˆ74%. A
number of copper and zinc catalysed enantioselective conju-
gate additions of Grignard reagents to enones have subse-
quently been reported with e.e's up to 92%.7 Chiral ligands
include aminothiols,11 mercaptophenyloxazolines,12 sugar-
derived thiolates,13 phosphines,14 diamines and amino-
alcohols15 and Taddols.16 Signi®cant enantioselectivities in
catalytic alkyllithium additions to enones have not been
reported until Tanaka and co-workers realised an impressive
e.e. of 99% in the chiral diamino-alkoxycuprate catalysed
addition of MeLi to (E)-2-cyclopentadecenone affording
The potential of conjugate addition reactions in synthesis is
partly due to the large variety of organometallic reagents
and substrates that can be employed and these features have
been a strong impetus in the search for enantioselective
conjugate additions. A number of organocopper reagents
with chiral non-transferable ligands and organocuprates
modi®ed with additional chiral ligands are known today
that provide e.e.'s at the .95% level.2,6±8
Until recently a highly enantioselective catalytic version of
the conjugate addition of organometallic reagents to enones
was lacking9 (Scheme 1). Despite numerous attempts, the
rational design of new chiral catalysts for enantioselective
conjugate addition has met limited success, presumably due
to the fact that several factors that might govern the 1,4-
addition step have to be taken into consideration. Among
these are: (i) the nature of the organometallic reagent (R)nM,
(R)-muscone, although
a high amount of catalyst
(36 mol%) was required to reach these selectivities.17
Keywords: phosphoramidite ligand; copper; enantioselective conjugate
addition; enones; non-linear effect; diethyl zinc; catalytic 1,4-addition.
* Corresponding author. Fax: 131-50-3634296;
Scheme 1.
e-mail: feringa@chem. rug.nl
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00142-3

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L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
Scheme 2.
Ligand accelerated catalysis18 of 1,4-additions of aryl-
lithium reagents, employing chiral diethers, showed
enantioselectivities up to 75%.19
and cyclic enones.32 The introduction of a chiral amine
moiety in 2,20-binaphthol-based phosphoramidite ligands
allowed for the ®rst time catalytic 1,4-addition reactions
of R2Zn reagents to cyclic enones with complete enantio-
control (Scheme 3).33 Employing this new chiral catalyst
e.e.'s .98% were obtained for 6-, 7- and 8-membered
cycloalkenones. Applications of the copper±phosphorami-
dite catalysts include tandem conjugate addition-aldol reac-
tions (e.e. .90%),33 the synthesis of arylnitroalkanes (e.e.'s
up to 92%),34 enantioselective synthesis of cycloalkenones
(e.e. .96%),35 kinetic resolution of diene epoxides (e.e.'s
up to 94%)36 and ring annulations (e.e.'s .96%).37 For
cyclopentenones, Taddol-based phosphoramidites were
introduced leading to e.e.'s of 62%.38 However e.e.'s up
to 72% were found by Pfaltz et al.39 using chiral phosphites
whereas (S)-2,20-binaphthol based bisphosphites resulted in
e.e.'s up to 88.7%.40 A number of related copper catalysed
1,4-additions of dialkylzinc reagents, employing PN41 and
PO42 type chiral ligands, have recently been reported.
Enantioselective carbon±carbon bond formation using
organozinc reagents has become one of the most successful
areas of asymmetric synthesis in recent years.20 Although
dialkylzinc reagents react extremely sluggish with carbonyl
compounds, effective catalysis has been achieved by several
ligands and transition metal complexes. The catalytic effect
can be explained either by alkyl transfer or by changes in
geometry and bond energy of the zinc reagents.21 For
example, dimethylzinc has a linear structure and is not
reactive towards aldehydes or ketones (Scheme 2). Upon
coordination of triazine a tetrahedral con®guration at the
zinc atom and an elongated zinc±carbon bond is found,
resulting in enhanced reactivity of the dialkylzinc reagent.
A number of catalytic 1,4-additions of diethylzinc to enones
employing chiral nickel complexes have been reported.
Based on the work of Luche and Greene,22 an enantio-
selective modi®cation of the nickel catalysed alkyl transfer
from diethylzinc to chalcone was found by Soai and
co-workers.4b,23 A variety of chiral ligands have subse-
quently been used in Ni-catalysed 1,4-additions; these
include chiral (bi)pyridines, aminoalcohols, b-hydroxy-
sulfoximines, proline amides, arene±chromium amino-
alcohols, thiazolidin-4-ones and diamines.24±30
We describe here the synthesis of a variety of phosphor-
amidites and their application as ligands in the copper
catalysed conjugate addition of dialkylzinc reagents to
assess the effect of ligand variation in the asymmetric
catalysis. Highly enantioselective copper±phosphoramidite
catalysed conjugate addition of dialkylzinc reagents to
The following main features emerged from these studies
with different organometallic reagents and a large variety
of ligands: (i) although appreciable e.e's were found the
results did not reveal the key elements to realise complete
stereocontrol and point to a rather complex nature of these
catalytic systems, (ii) most successful catalysts for cyclic
enones do not show signi®cant enantioselectivity for acyclic
enones and vice versa.
Scheme 3.
Alexakis and co-workers reported the ®rst example of
copper catalysed enantioselective conjugate addition
(10 mol% of catalyst, e.e.ˆ32%) of diethylzinc to 2-cyclo-
hexenone employing a trivalent phosphorus ligand .31 Under
the same conditions chalcone gave racemic product. Despite
all these efforts, which represent major advances in the ®eld
of catalytic enantioselective conjugate addition of organo-
metallic reagents, the problem of accomplishing ef®cient
and highly enantioselective catalysis for a wide variety of
enones remained a major challenge.
Recently we have introduced phosphoramidites as chiral
ligands in copper catalysed 1,4-addition of dialkylzinc
reagents and found strong ligand accelerated catalysis and
relatively high e.e. values for the 1,4-adducts of both acyclic
Scheme 4.

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
Table 1. Chiral phosphoramidites based on (S)-2,20-binaphthol
2867
Table 1 (continued)
Entry
Phosphoramidite
Yield(%)
31P NMR
d (ppm)
Entry
Phosphoramidite
Yield(%)
45
31P NMR
d (ppm)
1
2
3a
3b
80
59
148.7
149.8
16
3p
148.9
acyclic enones is reported. Furthermore the results of a
study of non-linear effects in these catalytic reactions are
presented and possible mechanistic implications are
discussed.
3
3c
38
151.7
Synthesis of novel phosphoramidites
4
5
3d
3e
54
65
144.7
145.5
Phosphoramidites [P(NR2)(OR)2] represent a class of
trivalent phosphorus compounds hardly recognised as
ligands for catalytic transformation despite the prominent
role that organophosphorus ligands, especially trivalent
phosphines and phosphites, have played in asymmetric
catalysis.43 Recently achiral phosphoramidites have been
applied as ligands for rhodium catalysed hydroformylation
of 1-octene and styrene.44 The x-value of the applied
phosphoramidites (Rˆaryl, approximately 21)44,45 is lower
than the x-factor of arylphosphites (31) and higher than the
x-value of arylphosphines (13), indicating a moderate
electron withdrawing ability. As the introduction of a
chiral amine moiety in phosphoramidites 3 resulted in a
dramatic increase of the enantioselectivity in our prelimin-
ary catalytic 1,4-additions32,33we examined several novel
phosphoramidites by varying the amine and binaphthol
parts of the ligands.
6
7
3f
32
81
146.5
148.9
3g
8
3h
3i
30
61
43
145.0
144.6
145.0
9
10
3j
Modi®cation of the amine moiety
The N,N-dimethyl substituted ligand 3a (RˆMe) was
obtained by reaction of (S)-2,20-binaphthol and HMPT,46
but due to lack of availability of the analogous phosphor-
triamides another route had to be developed for the modi®ed
phosphoramidites (Scheme 4).
11
3k
45
139.8
Starting from phosphoryl chloride 247 phosphoramidites
3b±3n were synthesised by nucleophilic substitution with
a wide variety of secondary amines. The phosphoramidites
were puri®ed by column chromatography (SiO2, hexane/
CH2Cl2) and were remarkably stable to air and moisture.
The new ligands are compiled in Table 1.
12
13
3l
41
41
145.3
145.3
3m
With diethylamine, dibenzylamine and piperidine the
corresponding amidites 3b,3d and 3e were synthesised in
satisfactory yields, but with the sterically demanding di-i-
propylamine and cis-2,6-dimethylpiperidine the isolated
yield of amidites 3c and 3f was rather low. The yield 3c
was slightly improved by using LDA instead of triethyl-
amine as base. Attempts to increase the steric hindrance at
the amine part of 3 further using 2,2,6,6-tetramethylpiper-
idine were not successful.
14
15
3n
3o
53
46
141.0
147.6
No general trend towards decreased shielding at phosphorus
(down®eld shift) is observed in the 31P NMR spectra of the
ligands with different amine groups. A down®eld shift of the

2868
L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
accomplished by repeated precipitation with hexane.
Compared to the other amidites the phosphorus resonance
is shifted up®eld in this ligand indicating an increased
shielding at phosphorus. The diastereomeric ligands 3l,
3m and 3n were prepared from (S)-2,20-binaphthol 1 and
(S,S)-bis(1-phenylethyl)amine and (R,R)-bis(1-phenylethyl)-
amine and (S)-benzyl(1-phenylethyl)amine, respectively.32
In an attempt to enhance the steric effect on the chiral amine
part of the corresponding bis[(R)-(1-naphthyl)ethyl]amine
derived ligand 3o was prepared via the route outlined in
Scheme 4. Finally the bidentate ligand 3p, corresponding
to monodentate phosphoramidite 3a, was readily obtained
from N,N0-dimethylethylenediamine and phosphoryl
chloride 2 in the presence of Et3N (Scheme 5). The phos-
phorus resonance of bisamidite 3p is nearly the same as
found for the monoamidite 3a indicating the same shielding
at phosphorus in both ligands.
Scheme 5.
phosphorus resonance has been attributed to a decrease of
the s character in the phosphorus lone pair orbital45 probably
induced by an increased phosphorus±nitrogen bond length.
A remarkably high yield of phosphoramidite 3g (81%) was
achieved with (3R,4R)-3,4-diphenylpyrrolidine. Employing
N-methylpiperazine, morpholine and thiomorpholine, an
additional heteroatom was introduced in the amine moiety
of amidites 3. Compared to piperidine substituted phosphor-
amidite 3e no substantial shift of the phosphorus resonance
was observed for 3h±3j, indicating a minor in¯uence of the
heteroatom in the amine part on the phosphorus lone pair.
Modi®cation at the binaphthol moiety
Examination of the molecular structure of the CuI complex
of ligand 3a32 showed that besides the amine part the 3- and
30-positions of the binaphthyl part of the ligand are crucial
for ligand modi®cation. Model studies indicate that substi-
tuents at these positions could affect the binding mode of
alkyl group and enone on the copper in the actual catalyst.
Considerable effort has been devoted to the synthesis of
Using di(2-methoxyphenyl)amine a phosphoramidite was
prepared with oxygen donor groups present at a position
capable offorming a chelated six-membered ring upon bind-
ing of copper to the phosphorus atom. Since ligand 3k was
not stable upon column chromatography isolation was
Scheme 6. Synthesis of 3,30-substituted binaphthols and their conversion to the corresponding phosphoramidites. (a) MeI (excess), K2CO3, acetone (98%) (b)
n-BuLi (2.2 equiv.), TMEDA, diethylether (c) MeI, diethylether (d) bromine, diethylether (e) phenylboronic acid, Pd(PPh3)4 (0.06 equiv.), dimethoxyethane,
NaHCO3, water (f) BBr3, CH2Cl2 (g) HMPT, toluene.

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
2869
3,30-substituted binaphthols as they have shown promising
asymmetric induction in a variety of reactions.39,48 Method-
ology includes the use of Mannich intermediates,49 cross-
couplings of 3,30-dibromo-binapthols50 and ortho-lithiation
of 2,20-bisMOM-substituted binaphthalene.51 The synthesis
of a number of 3,30-disubstituted binaphthols and their
conversion to phosphoramidites is outlined in Scheme 6.
solutions were obtained with these modi®ed ligands. In
order to enhance the solubility of the catalyst complexes
the CuOTf catalysed conjugate addition was investigated
as it is known that dissociation of the tri¯ate counterion in
solution occurs.53 With a catalytic amount (3 mol%) of
phosphoramidite 3a (2.2 equiv. to CuOTf) strong ligand-
acceleration was observed in the conjugate addition of
Et2Zn both to 14 and 16. High yields of adducts 15 (82%)
and 17 (91%) were obtained with e.e.'s slightly higher for
15 (39%) and signi®cantly higher for 17 (65%) compared to
those found for the CuI/3a catalysed reactions.31 Further-
more the addition reactions shown in Scheme 7 appeared to
proceed with the same regio- and enantioselectivities in
CH2Cl2 as in toluene.
Following Crams procedure49 (S)-2,20-binaphthol (1) was
successively methylated to 4a, dilithiated and quenched
with bromine to afford dibromide 6 in 48% yield. The
dilithio-compound was also quenched with methyl iodide
furnishing dimethyl-derivative 5 in 63% yield. For compari-
son, by ortho-lithiation, methyl iodide quenching and
deprotection with MeOH/HCl starting with the MOM
protected analogue of 151 we obtained 8 in 70% overall
yield. For the preparation of 3,30-diphenyl substituted
binaphthol, the dibromo compound 6 was treated with phen-
yl boronic acid under Suzuki cross coupling conditions52 to
furnish 7 in 95% yield. This method resulted in a much
higher yield than via the Grignard cross coupling method.50
With this knowledge the effect of the ligand modi®cation on
the enantioselectivity of the ethyl transfer from diethylzinc
to cyclic (14) and acyclic enones (16) could be examined.
In general a solution of a catalytic amount of (CuOTf)´
benzene (3±5 mol%) and chiral ligand (2.2 equiv. to
copper) in toluene (3±5 ml) were stirred at ambient
temperature for 1 h under Ar, furnishing a clear solution
of the catalyst complex. In case the solution was not clear,
appropriate amounts of CH2Cl2 were added. After addition
of the substrate the mixture was cooled to 2208C, Et2Zn in
toluene was added and stirring continued at 2108C for 16 h.
The conversion was determined by GC analysis and in all
cases regioselectivities for the 1,4-adducts were higher than
90% at .95% conversion. The 1,4-adducts were isolated
and puri®ed by column chromatography (yields .75%)
prior to e.e. determination. Control experiments indicated
that this puri®cation procedure did not effect the e.e. value.
The results are summarised in Table 2.
The 2,20-dimethoxy-3,30-disubstituted derivatives 5±7 were
deprotected quantitatively with BBr3 in CH2Cl2 and the
resulting binaphthols 8±10 converted to the corresponding
phosphoramidites 11±13 with HMPA in toluene (yields
.75%). Phosphoramides 11b and 11c were prepared from
3,30-dimethyl-2,20-dihydroxy-binaphthyl
8
using the
improved synthesis (see Experimental section). The 31P
NMR shifts of 11b (149.2 ppm) and 11c (142.1 ppm) are
in good agreement with those determined for the unsubsti-
tuted amidites 3c and 3i.
Substituted phosphoramidites as ligands in conjugate
additions of diethylzinc
Except for ligand 3h all phosphoramidites showed enantio-
selectivity in the 1,4-addition. In the case of the catalytic
reaction employing 3h, ligand decomposition takes place, as
besides the 1,4-adduct 2,20-binaphthol was isolated. The
following features are emerging when one considers the
various ligand modi®cations:
The effect of the ligand modi®cation was examined in the
enantioselective copper catalysed diethylzinc addition to
two model substrates cyclohexenone 14 and chalcone 16
(Scheme 7). Initially ligands 3b, 3d, 3e, 3i, 3o and 11a
were tested in the CuI catalysed addition of Et2Zn to 14
but the reactions were much slower (2d at 2108C) and the
regioselectivity for the 1,4-adduct 15 lower (ca. 80%)
compared to CuI/3a catalysed reaction.32 Lower isolated
yields and e.e.'s were also found.
² Sterically demanding achiral substituents on the amine
moiety improve the e.e values up to 60 and 83% for 15
and 17, respectively (entries 1±4).
² Ligands with substituents containing heteroatoms in the
amine part retain the ceiling e.e.'s found for 17 (entries
8,9), whereas ligands with aromatic groups at the amine
part furnish 17 with lower e.e.'s (entries 4,6) or showed
to be detrimental for enantioselective ethyl transfer
(entry 10).
This lack of ef®cient catalysis is probably due to solubility
problems with the in situ generated phosphoramidite copper
complexes as contrary to the copper complex of 3a. No clear
Scheme 7.

2870
L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
Table 2. Chiral ligand effect in catalytic 1,4-addition
the amine part of the ligand whereas the effects of variation
in the binaphthol unit are less prominent. A delicate balance
seems to exist between the increase of steric hindrance (a
rather bulky amine is required to achieve high e.e.'s) and the
chirality of the amine moiety.
Entry
Chiral ligand
e.e. of 15 (%) (S)
e.e. of 17 (%) (S)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3f
3g
3h
3I
39
27
60
53
43
47
0
50
65
±
83
53
79
50
±
71
70
13
40a
75a
72a
42a
±
Dialkylzinc Additions to Acyclic Enones
During our studies of the enantioselective conjugated addi-
tion to cyclic enones it was found32 that the catalyst
prepared in situ from Cu(OTf)2 was more active than
using CuOTf and slightly enhanced the enantioselectivity.
The reactions of a number of acyclic enones was examined
with the Cu(OTf)2/phosphoramidite 3c based catalyst. It
should be noted that so far ligand 3c has shown to give
the highest e.e.'s with acyclic enones and the best ligand
3m for cyclohexenone (14) gave only e.eˆ75% in the case
of chalcone (16). Conjugated additions were performed with
2.5 mol% of in situ prepared catalyst (copper/ligand
ratioˆ2) in toluene at 2308C. Under these conditions a
typical aliphatic a,b-unsaturated ketone 3-penten-2-one
(18) did not provide the 1,4-adduct. On the contrary aryl-
substituted enones were converted to the b-substituted
ketones with high chemo-, regio-, and in several cases
excellent enantioselectivities. The results are given in
Table 3.
9
3j
55
10
11
12
13
14
15
16
17
18
19
20
3k
3l
48
75a
.98a
72a
94a
37
3m
3n
3o
3p
11a
11b
11c
12
13
56
59
51
51
52
81
76
23
,20b
35
a Using Cu(OTf)2 at 2258C instead of CuOTf at 2108C.
b No base line separation.
² The introduction of methyl substituents at the 3- and
30-positions of the binaphthol part of the ligand has an
effect only on the enantioselective ethyl addition to
cyclohexenone (e.e. is increased) and chalcone (e.e. is
decreased) when the amine group is small (compare
entry 1 with entry 16). With di-i-propyl or morpholine
based phosphoramidites comparable e.e.'s are observed
as with the unsubstituted analogues (compare entries 17,
18 with entries 3,8).
² Phenyl or bromide substituents at the 3- and 30- positions
of the ligand (entry 19,20) are detrimental for the enan-
tioselectivity in the case of chalcone whereas marginal
effects on the e.e.'s are found for cyclohexenone.
² The introduction of the sterically demanding (R,R)-bis(1-
phenylethyl)amine moiety results in a matched combina-
tion with exceptional high enantioselectivities (.98%)
for 15.33 The mismatched combination derived from
(S,S)-bis(1-phenylethyl)amine and (S)-binaphthol still
affords 75% e.e for 15, a value exceeding those of di-i-
propylamine and dibenzyl amine based ligands. When
the (S)-N-benzyl-1-phenylethyl phosphoramidite is used
the e.e. value for 15 is slightly lower but for 17 a drastic
increase in the enantioselectivity is observed. (compare
entry 13 with entry 11).
Thus diethylzinc addition to chalcone 16 provided 17 in
85% isolated yield and e.eˆ89%. Only a small temperature
effect was observed leading to e.e.'s ranging from 87±90%
(reaction temperatures 210 to 2508C). The presence of an
arylketone moiety seems to be important to reach high e.e's
as the enantioselectivity decreased to 60% when benzylide-
neacetone 19 was employed. Low yields and enantioselec-
tivities were found for heteroaromatic enones 20±23,
presumably due to competitive binding of the copper cata-
lysts to the heteroarene moiety favouring alternative, non-
selective, reaction pathways. The use of p-substituted chal-
cones allows the study of possible electronic effects on the
enantioselectivities in these conjugated additions. Towards
this goal the diethylzinc addition to chalcones 24±30, with
various donor and acceptor substituents at 4- and 40-posi-
tions, was performed under identical conditions (Table 3).
In all cases complete conversion was found and the b-
substituted ketones 37±43 were isolated with high yields
and enantioselectivities (except for nitro-substituted chal-
cone 24). Presumably again the nitro group interferes with
the coordination of the catalyst to the enone moiety although
we recently found that 1,4-additions to nitrocoumarines
proceed with e.e's up to 92%.34 From the results with substi-
tuted chalcones it is evident that the electron donating or
withdrawing properties of the substituents are not of great
importance for the stereoselection. The e.e.'s show only
modest variation ranging from 75 to 89%.
² Surprisingly further increase of the steric hindrance using
3o lead to a drastic decrease of enantioselectivity for 17.
² Employing the bidentate phosphoramidite 3p (ligand/
Cuˆ1.1) in the CuOTf catalysed 1,4-addition to cyclo-
hexenone comparable e.e.'s were found as in the case of
the monodentate ligand 3a (ligand/Cuˆ2.2) (entry 1, 15).
This observation indicates the presence of two monoden-
tate chiral ligands in the catalytically active complex (or
catalyst aggregate).
Non-linear Effects
It is evident from these ®ndings that there is no straightfor-
ward relation between the molecular architecture of the
phosphoramidite ligand, for instance steric requirements,
and the enantioselectivities observed in the conjugate addi-
tion. So far we observed a major in¯uence of the nature of
The study of non-linear effects in asymmetric catalysis has
become an important mechanistic tool20a,54 and the enantio-
meric excess observed in the product can be linear propor-
tional to the enantiomeric excess of the catalyst or shows a

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
Table 3. Catalytic enantioselective 1,4-addition to acyclic enones
2871
Entry
Enone
R1
R2
Product
Yield (%)
e.e.a (%)
1
2
3
4
16
18
19
20
Ph
CH3
Ph
Ph
CH3
CH3
17
31
32
33
85
0
75
40
89
±
60
15
5
6
21
22
34
35
48
30
40
60
7
23
Ph
36
69
29
8
9
24
25
Ph
Ph
37
38
64
85
15
80
10
26
Ph
Ph
39
86
70
11
12
27
28
Ph
40
41
94
65
75
88
13
14
29
30
42
43
80
85
75
89
a Con®gurations or optical rotations of the prevailing enantiomers were not determined.
non-linear relationship which can be either positive (asym-
metric ampli®cation) or negative (asymmetric depletion)
according to Kagan's models.55 The effect of the change
in the enantiomeric composition of the chiral ligand on
the e.e. values of the 1,4-adduct in the copper catalysed
conjugate addition of diethylzinc was examined both for
chalcone and cyclohexenone with the best phosphor-
amidites so far found for acyclic and cyclic enones.
The 1,4-addition of diethylzinc to chalcone catalysed by
Cu(OTf)2 and di-i-propylamine based ligand 3c in toluene
at 2208C provided pure 17 in 85±95% yield. An e.e. of
max. 88% for 17 was found with enantiomerically pure
ligand. The correlation between the % e.e. of ligand 3c
and % e.e. of product 17 is shown in Fig. 1. A clear negative
non-linear correlation is observed.
For the 1,4-addition to cyclohexenone 14 both (S,R,R)-3m
and (R,S,S)-3m were employed and reproducibilities
using these enantiomeric ligands were within 2%, whereas
duplicate experiments were all within 1%. The e.e.max for
Figure 1. Correlation between the enantiomeric excess of the ligand 3c and
the e.e. of 17.
enantiomerically pure ligand 3m is .98%. The relationship

2872
L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
(R,S,S)-3m, respectively. Three complexes can be formed
when non-enantiomerically pure ligand is employed:
M-(R)-3c, (R)-3c; M-(S)-3c, (S)-3c; M-(R)-3c, (S)-3c. The
®rst two complexes will provide enantiomeric adducts
whereas the meso complex M-(R)-3c, (S)-3c generates
racemic product. A negative non-linear relationship points
to a greater reactivity of the heterochiral (meso) catalyst
than the reactivity of the homochiral catalyst. An alternative
explanation might be found in the so called `reservoir effect'
in which aggregation leads to unproductive catalyst
complexes which in¯uences the enantiomeric composition
of the effective catalyst.
Based on the data obtained so far the pathways shown in
Scheme 8 are proposed for the copper phosphoramidite
catalysed 1,4-addition of diethylzinc to enones. Starting
with either the Cu(I)-complex or the Cu(II)-complex
(which is most probably in situ reduced to the corresponding
Cu(I)-complex) and diethylzinc ®rst an ethyl group is trans-
ferred to the copper.21b,57 The enone coordinates to the ethyl
copper species by p-complexation of the ole®nic bond.58
The Lewis acidic Zn(II) centre probably activates the
enone through complexation to the carbonyl group. This
substrate binding and activation could well involve a
(bridged) bimetallic complex. The remaining sites in the
tetrahedral coordination sphere of the copper ion are
occupied by two phosphoramidite ligands providing a
favourable pathway for p-face selective ethyl transfer.
The smaller electronegativity of zinc (1.6) relative to that
of copper (1.9) suggests the generation of the zinc enolate
instead of a copper enolate.59 Via chiral intermediates and
(with the same chiral coordination sphere) 1,4-adduct with
the S-con®guration will be formed for s-trans enones (i.e.
Figure 2. Correlation between the enantiomeric excess of the ligand 3m
and the e.e. of 3-ethyl-cyclohexanone 15 following standard reaction proce-
dures.
between e.e.'s of ligand 3m and product 15 is shown in
Fig. 2. Although less pronounced, as in the previous case,
again a negative non-linear effect is observed.
In all cases the most effective catalyst was made with a
ligand to copper ratio of 2 pointing to an ML2 system.55
The negative non-linear effects for cyclic and acyclic
enones might then be explained by Kagan's model
system55,56 in which fast ligand exchange occurs at the
Cu-centre in a reactive complex bearing two chiral phos-
phoramidite ligands (R)-3c and (S)-3c (or (S, R, R)-3m and
Scheme 8.

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
2873
ethylcyclohexanone 15) and products with the R con®gura-
tion for s-cis enones (i.e. 17). These predictions are in
accordance with the experimental observations for cyclo-
hexenone and chalcone type substrates.
amine and 2.8 mmol n-BuLi) in THF (10 ml). After 16 h at
ambient temperature, the reaction mixture was ®ltered over
celite, concentrated and puri®ed by chromatography (SiO2,
hexane: CH2Cl2) to give the pure amidite.
In depth mechanistic studies are required to substantiate the
proposed pathways and intermediates and to obtain insight
into ligand parameters that govern p-face selection in the
case of cyclic and acyclic enones. The combined results of
these studies will allow us to rationalize the high enantio-
selectivities encountered.
O,O0-(S)-(1,10Dinaphthyl-2,20-diyl)-N,N-diethylphosphor-
1
amidite (3b). [a]D20ˆ15018 (cˆ0.50, CH2Cl2). H NMR
dˆ1.08 (t, Jˆ7.2 Hz, 6H), 2.79±3.21 (m, 4H), 7.18±7.58
(m, 8H), 7.89±8.05 (m, 4H). 13C NMR dˆ14.01, 44.22,
121.97, 122.14, 122.91, 123.98, 124.11, 124.41, 124.65,
126.07, 126.93, 128.20, 129.85, 130.11, 130.65, 131.34,
123.50, 149.17, 149.69. 31P NMR d149.8. HRMS calcd
for C24H22NO2P: 387.139, found 387.139.
Experimental
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N,N-di-i-propyl-
phosphoramidite (3c). [a]2D0ˆ15918 (cˆ0.68, CHCl3). 1H
NMR dˆ1.19 (d, Jˆ6.84 Hz, 6H), 1.24 (d, Jˆ6.84 Hz, 6H),
3.37 (heptet, Jˆ6.84 Hz, 1H), 3.42 (heptet, Jˆ6.84 Hz, 1H),
7.55±7.22 (m, 8H), 7.99±7.89 (m, 4H). 13C NMR dˆ24.27,
24.43, 44.48, 44.74, 121.69, 122.26, 122.32, 123.91, 124.10,
124.45, 125.63, 125.72, 126.96, 128.04, 128.10, 129.18,
130.00, 130.32, 131.16, 132.54, 132.67, 150.03, 150.22,
150.35. 31P NMR dˆ151.7. HRMS calcd for C22H26NO2P:
415.170, found 415.170.
General
Toluene and diethylether were distilled from sodium and
dichloromethane (CH2Cl2) was distilled from P2O5. All
solvents were stored under nitrogen. All secondary amines
were purchased from Aldrich, Fluka or Acros and distilled
before use. The following substances were commercially
available and used without further puri®cation: (S)-
binaphthol (Syncom, Groningen), phenyl boronic acid
(Acros), hexamethylphosphorus triamide (Aldrich),
Cu(OTf)2 (Aldrich) was dried before use, Et2Zn (1.1 M tolu-
ene) (Aldrich). The substituted unsaturated ketones were
commercially available (Lancaster) or synthesised.60 All
reactions were carried out under argon atmosphere using
dried glassware. Chromatography: silica gel Merk Typ
9385 230±400 mesh, TLC: silica gel 60, Merk, 0.25 mm.
Optical rotations were measured on a Perkin±Elmer 241
MC (at RT). Mass spectra (HRMS) were obtained in an
AEI MS-902. HPLC analysis was performed on a Water
480 with a LC spectrophotometer or a Water 600E system
O,O0-(S)-(1,1-Dinaphthyl-2,20-diyl)-N,N-dibenzylphosphor-
amidite (3d). [a]D20ˆ11638 (cˆ0.54, CH2Cl2). H NMR
1
dˆ3.47 (AB system, Jˆ15.0 Hz, 1H), 3.53 (AB system,
Jˆ15.0 Hz, 1H), 4.25 (AB system, Jˆ15.0 Hz, 1H), 4.29
(AB system, Jˆ15.0 Hz, 1H), 7.16±7.51(m, 17H), 7.68±
7.88 (m, 3H), 7.98 (d, Jˆ8.1 Hz, 1H), 8.07 (d, Jˆ8.65 Hz,
1H). 13C NMR dˆ47.90, 48.33, 121.48, 122.16, 122.90,
123.63, 123.85, 124.62, 124.86, 126.10, 126.91, 127.06,
127.35, 128.21, 128.40, 128.84, 130.15, 130.31, 130.64,
131.24, 132.48, 137.83, 149.22, 149.80. 31P NMR
dˆ144.7. HRMS calcd for C34H26NO2P: 511.170, found
511.170.
1
controller with a Waters 991 photodiode array detector. H
NMR, 13C NMR and 31P NMR (CDCl3): d in ppm
(dˆ7.2 ppm) for protons, (dˆ77 ppm) for carbon atoms
and (H3PO4): (dˆ0.0 ppm) for phosphorus atoms.
O,O0-(S)-(1,10-2,20-Diyl)-N-(1-piperidinyl)phosphorami-
1
dite (3e). H NMR dˆ1.36±1.61 (m, 6H), 2.88±3.11 (m,
4H), 7.21±7.56 (m, 8H). 13C NMR dˆ24.88, 26.89, 26.97,
45.10, 45.50, 122.08, 122.18, 122.74, 123.93, 124.08,
124.45, 124.68, 125.97, 126.95, 128.25, 129.75, 130.17,
130.65, 131.33, 132.58, 149.27, 149.90. 31P NMR
dˆ145.5. HRMS calcd for C25H23NO2P: 400.147, found
400.147.
Synthesis of phosphoramidite ligands
Under argon atmosphere: To a cooled solution (2608C) of
PCl3 (270 ml, 3.0 mmol), Et3N (860 ml, 6.0 mmol), and
toluene (5 ml) was added a warm solution (608C) of (S)-
2,20-binaphthol (1) (860 mg, 3.0 mmol) and toluene
(25 ml) in 5 min. After stirring for 2 h the reaction mixture
was warmed up to room temperature and ®ltered under
argon atmosphere. The ®ltrate was treated with Et3N
(410 ml, 2.9 mmol) and 2.9 mmol of the corresponding
secondary amine at 2408C. After 16 h at ambient tempera-
ture, the reaction mixture was ®ltered and puri®ed by
chromatography (SiO2, hexane: CH2Cl2) to give the pure
amidite as a colorless amorphous compound. Stripping
with CH2Cl2 furnished the phosphoramidite as foamy solids
with still some solvent molecules incorporated. Crystallisa-
tion from diethyl ether/CH2Cl2 mixtures gave crystalline
material.
O,O0-(S)-(1,10-2,2 Dinaphthyl-2,20-diyl)N-[1-(2,6-dimethyl)-
piperidinyl]phosphoramidite (3f). [a]2D0ˆ14728 (cˆ0.76,
1
CH2Cl2). H NMR dˆ1.17 (d, Jˆ7.1 Hz, 3H), 1.30 (d,
Jˆ7.1 Hz, 3H), 1.46±1.91 (m, 6H), 3.42±3.52 (m, 1H),
3.86±3.98 (m, 1H), 7.21±7.58 (m, 8H), 7.90±8.01 (m,
4H). 13C NMR dˆ14.43, 23.61, 23.96, 30.99, 31.42,
45.65, 45.81, 46.27, 47.01, 121.89, 122.36, 124.30,
124.62, 125.80, 125.92, 127.09, 128.21, 129.32, 130.15,
130.54, 131.31, 132.65, 132.72, 149.64, 150.02. 31P NMR
dˆ146.5. HRMS calcd for C27H26NO2P: 427.170, found
427.170.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N-[1-((3R,4R)-3,4-
diphenyl)pyrrolidinyl]phosphoramidite (3g). [a]2D0ˆ11648
Improved synthesis for 3c, 3l, 3m, 3n, 3o. The general
procedure as described above was applied to prepare the
phosphoryl chloride (2). This mixture was ®ltered in a
preformed cooled (2408C) solution of (2.8 mmol secondary
1
(cˆ1.35, CH2Cl2). H NMR dˆ3.39±3.62 (m, 6H), 7.16±
7.34 (m, 12 H), 7.43±7.51 (m, 4H), 7.64 (t, Jˆ8.8 Hz, 2H),

2874
L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
7.96±8.08 (m, 4H). 13C NMR dˆ52.27, 52.31, 53.19, 53.40,
121.52, 121.73, 122.83, 123.77, 123.83, 124.48, 124.61,
125.14, 125.92, 125.99, 126.73, 126.83, 128.06, 128.12,
128.17, 128.89, 129.79, 130.11, 130.61, 131.18, 132.46,
132.65, 139.99, 149.55, 149.86, 149.92. 31P NMR
dˆ148.9. HRMS calcd for C36H28NO2P: 537.186, found
537.186.
(m, 18), 4.63 (q, Jˆ7.2 Hz, 2H), 1.85 (d, Jˆ7.2 Hz, 6H). 13
C
NMR dˆ150.2, 149.6, 142.8, 132.8, 131.4, 130.5, 130.5,
130.3, 129.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.2,
127.1, 126.7, 126.0, 124.7, 124.5, 122.4, 52.3, 51.1, 21.8.
31P NMR dˆ145.3. HRMS calcd for C36H30NO2P: 539.201,
found 539.208.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N-benzyl-N0-(S)-1-
phenylethylphosphoramidite (3n). [a]Dˆ11968 (c 0.84,
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N-(1-(N-methyl)pi-
perazidinyl)phosphoramidite (3h). 1H NMR dˆ2.15±
2.26 (m, 7H), 2.91±3.11 (m, 4H), 7.11±7.58 (m, 8H),
7.85±8.05 (m, 4H). 13C NMR dˆ44.31, 44.67, 47.28,
56.54, 56.71, 121.93, 123.06, 123.97, 124.14, 124.86,
125.01, 126.20, 126.82, 128.33, 130.53, 130.81, 131.13,
131.44, 132.34, 132.92, 149.26, 150.01. 31P NMR
dˆ145.0. HRMS calcd for C24H20N2O2P: 414.150, found
414.150.
1
CHCl3). H NMR dˆ8.06±7.10 (m, 22H), 4.15 (m, 1H),
4.11 (d, Jˆ15 Hz, 1H), 3.08 (d, Jˆ15 Hz, 1H), 1.76 (m,
3H). 13C NMR dˆ150.13, 150.09, 149.55, 143.67, 138.58,
132.77, 132.44, 131.37, 130.51, 130.22, 130.09, 128.53,
128.44, 128.27, 128.13, 127.41, 127.33, 127.03, 126.89,
125.99, 124.76, 124.46, 124.10, 122.44, 122.26, 121.64,
57.59, 57.40, 48.27, 23.55, 23.29. 31P NMR dˆ141.0.
HRMS calcd for C35H28N O2P 525.186 found 525.185
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N-(1-morpholinyl)-
phosphoramidite (3i). [a]2D0ˆ13648 (cˆ0.19, CH2Cl2). 1H
NMR dˆ2.93±3.21 (m, 4H), 3.53±3.61 (m, 4H), 7.24±7.60
(m, 8H), 7.92±8.04 (m, 4H). 13C NMR dˆ44.37, 44.73,
67.78, 67.87, 121.90, 122.87, 123.83, 123.95, 124.75,
124.90, 126.20, 126.92, 128.37, 130.09, 130.41, 130.78,
131.42, 132.34, 132.96, 149.32, 149.80. 31P NMR
dˆ144.6. HRMS calcd for C24H20NO3P: 401.118, found
401.118.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N,N0-di-(R,R)-1-
naphthylethylphosphoramidite (3o). [a]Dˆ149.78 (c 0.9,
CHCl3). 1H NMR dˆ8.05±7.21 (m, 24H), 6.73 (t,
Jˆ7.8 Hz, 2H), 5.60 (m, 2H), 1.78 (d, Jˆ6.6, 6H). 13C
NMR dˆ150.42, 150.36, 149.49, 138.27, 133.04, 132.86,
131.46, 130.46, 129.69, 128.33, 128.19, 127.17, 127.14,
126.87, 126.11, 126.09, 125.26, 124.86, 124.78, 124.50,
124.37, 124.28, 124.24, 123.11, 122.73, 122.18, 121.80,
49.60, 49.53, 23.16. 31P NMR (200 MHz) dˆ147.6.
HRMS calcd for C44H34N O2P 639.233, found 639.232.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N-(1-thiomorpholinyl)-
phosphoramidite (3j). [a]2D0ˆ13838 (cˆ0.39, CH2Cl2). 1H
NMR dˆ2.41±2.53 (m, 4H), 3.20±3.38 (m, 4H), 7.22±7.58
(m, 8H), 7.91±8.03 (m, 4H). 13C NMR dˆ42.53, 44.41,
44.77, 122.02, 122.64, 123.86, 123.91, 124.65, 124.89,
126.12, 126.92, 128.31, 130.10, 130.43, 130.77, 131.40,
132.41, 132.83, 149.43, 149.88, 150.04. 31P NMR
dˆ145.0 HRMS calcd for C24H20NO2PS: 417.095, found
417.095.
N,N0-Bis[O,O0-(S)-(1,10-dinaphthyl-2,20-diyl)-N-methyl-
phosphoramidite]ethylenediamine (3p). 1H NMR dˆ2.37
(s, 3H), 2.40 (s, 3H), 3.01±3.19 (m, 2H), 3.29±3.42 (m, 2H),
7.24±7.62 (m, 16H), 7.90±8.04 (m, 8H). 13C NMR
dˆ32.21, 47.09, 47.85, 122.06, 122.26, 122.47, 123.93,
124.05, 124.59, 124.81, 126.09, 126.91, 127.04, 128.27,
128.34, 130.11, 130.30, 130.72, 131.38, 132.56, 132.83,
149.45, 149.98, 150.10. 31P NMR dˆ148.9 HRMS calcd
for C44H34N2O4P: 716.199, found 716.199.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N,N0-di(2-methoxy-
1
phenyl)phosphoramidite (3k). H NMR dˆ3.80 (s, 6H),
Synthesis of 3,30-substituted binaphthols
6.51 (dt, Jˆ7.7 Hz, Jˆ1.3 Hz, 2H), 6.80 (dd, Jˆ8.1 Hz,
Jˆ1.3 Hz, 2H), 6.96 (dt, Jˆ7.7 Hz, Jˆ1.3 Hz, 2H), 7.12±
7.43 (m, 9H), 7.49±7.57 (m, 2H), 7.75 (d, Jˆ8.1 Hz, 1H),
7.93 (t, Jˆ9.4 Hz, 2H). 13C NMR dˆ55.82, 112.24, 120.14,
121.62, 122.13, 124.05, 124.62, 125.38, 125.86, 126.30,
126.74, 127.06, 127.73, 128.73, 128.22, 128.52, 130.05,
130.22, 130.53, 130.62, 131.31, 132.75, 132.97, 155.28.
31P NMR dˆ139.9 HRMS calcd for C34H26NO4PS:
543.160, found 543.160.
3,30-Dimethyl-2,20-dimethoxy-1,10dinaphthyl (5). A solu-
tion of (S)-(4) (0.72 g, 2.29 mmol), prepared according to a
published procedure,49 and TMEDA (1.81 ml, 12.0 mmol)
in 40 ml of diethylether was cooled with ice/water. A 2.0 M
solution of n-BuLi in hexane (4.9 ml, 9.8 mmol) was added
dropwise over a period of 25 min. The mixture was stirred at
08C for 30 min and was then slowly warmed to re¯ux. After
re¯uxing for 20 h the resulting orange suspension was
cooled to 08C and MeI (1.56 ml, 25 mmol) was added drop-
wise over a period of 45 min resulting in a white suspension.
After stirring for 16 h at ambient temperature the white
mixture was poured into 200 ml of aqueous 1 N HCl. The
mixture was extracted with CHCl3 (250 ml) and the organic
layer was washed with saturated solution of NaHCO3
(200 ml), brine (200 ml), dried (Na2SO4) ®ltered and evapo-
rated to give the crude product as a yellow solid (0.94 g).
The crude product was ®ltered over a short column (SiO2,
hexane: EtOAc: CH2Cl2 10:1:1) and recrystallised from
hexane: EtOAc (10:1, 35 ml) to give 5 (0.46 g, 63%) as
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N,N0-di-(S,S)-1-
phenylethylphosphoramidite (3l). [a]Dˆ1202.18 (cˆ0.79,
CHCl3). 1H NMR dˆ8.08±7.78 (m, 4), 7.65±7.24 (m, 18H),
4.47 (q, Jˆ7.2 Hz, 2H), 1.75 (d, Jˆ7.2 Hz, 6H). 13C NMR
dˆ150.45, 150.20, 149.80, 143.13, 132.77, 131.38, 130.47,
129.60, 129.25, 128.33, 128.06, 127.99, 127.79, 127.26,
126.71, 126.05, 125.87, 124.80, 124.36, 122.54, 54.55,
54.34, 23.07, 22.83. 31P NMR dˆ150.4. HRMS calcd for
C36H30NO2P: 539.201, found 539.208.
O,O0-(S)-(1,10-Dinaphthyl-2,20-diyl)-N,N0-di-(R,R)-1-
phenylethylphosphoramidite (3m). [a]Dˆ1456.08 (cˆ
1
colourless crystals. H NMR dˆ2.57 (s, 6H), 3.33 (s, 6H),
1
0.79, CHCl3). H NMR dˆ7.98±8.08 (m, 4H), 7.17±7.74
7.11±7.41 (m, 6H), 7.79±7.86 (m, 4H). 13C NMR dˆ17.23,

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
2875
1
60.07, 124.54, 124.60, 125.29, 125.72, 127.12, 129.56,
130.71, 131.56, 133.11, 155.74.
CH2Cl2). H NMR dˆ1.96 (d, Jˆ9.4 Hz), 7.17±7.52 (m,
12H), 7.70±7.82 (m, 4H), 7.95±8.05 (m, 4H). 13C NMR
dˆ34.01, 34.40, 124.32, 124.73, 124.97, 125.87, 126.63,
126.84, 127.18, 127.93, 127.98, 128.11, 128.21, 128.30,
129.70, 129.83, 129.91, 130.58, 130.75, 130.95, 132.21,
132.39, 134.12, 134.88, 138.03, 147.28. 31P NMR
dˆ147.4 HRMS calcd for C34H26NO2P: 511.170, found
511.170.
3,30-Diphenyl-2,20-dimethoxy-1,10dinaphthyl (7). A mix-
ture of (S)-6 (1.04 g, 2.20 mmol), prepared according to the
published procedure,50 and Pd(PPh3)4 (0.153 g, 0.132
61
mmol) in 10 ml of dimethoxyethane was stirred at room
temperature for 30 min. After addition of PhB(OH)2
(0.59 g, 4.84 mmol) and NaHCO3 (1.1 g in 13 ml of H2O)
the suspension was re¯uxed for 16 h resulting in a colour-
less solution above a brownish gum. After cooling to room
temperature the mixture was washed with brine (25 ml),
dried (Na2SO4) ®ltered, and evaporated to give the crude
product as a foam (1.22 g). The crude product was puri®ed
by column chromatography (SiO2, hexane:toluene 1:1) to
Synthesis of compounds 11b and 11c
These compounds were prepared according to the general
procedure given for compounds 3c, 3l, 3m, 3n, 3o using
3,30-dimethyl-2,20-dihydroxy-1,10;dinaphthyl and the corre-
sponding deprotonated amines.
1
give 7 (0.977 g, 95%) as a colourless powder. H NMR
dˆ3.21 (s, 6H), 7.21±7.53 (m, 12H), 7.80 (d, Jˆ6.8 Hz,
O,O0-(1,10-Dinaphthyl-2,20-diyl-3,30-dimethyl)-N,N0-di-i-
propylphosphoramidite (11b). Yield 37%. [a]2D0ˆ15228
4H), 7.92±8.01 (m, 4H).
1
(cˆ1.00, CH2Cl2). H NMR dˆ1.19 (d, Jˆ4.8 Hz, 12H),
Deprotection of compounds 5, 6, 7
2.58 (s, 3H), 2.60 (s, 3H), 3.32±3.40 (m, 2H), 7.12±7.38
(m, 6H), 7.75±7.82 (m, 4H). 13C NMR dˆ17.25, 18.19,
24.84, 24.91, 45.00, 45.18, 121.93, 123.98, 124.18,
124.44, 124.76, 124.86, 126.85, 127.09, 127.35, 127.45,
129.03, 129.50, 130.28, 130.35, 131.12, 131.70, 149.41,
149.84. 31P NMR dˆ149.2 HRMS calcd for C28H30NO2P:
443.201, found 443.201.
All 3,30-disubstituted-2,20-dimethoxy-1,10-dinaphthyls were
deprotected with BBr3 according to literature procedure49,51
furnishing the corresponding diols 8, 9, 10 in high yields
(.90%). Spectroscopic data (NMR and [a]2D0) of the
compounds 8 and 10 were in good agreement with data in
the literature.49±51
O,O0-(1,10-Dinaphthyl-2,20-diyl-3,30-dimethyl)-N-(1-
morpholinyl)phosphoramidite (11c). Yield 51%. [a]2D0ˆ
14678 (cˆ0.30, CH2Cl2). 1H NMR dˆ2.50 (d,
Jˆ9.4 Hz, 6H), 2.82±3.18 (m, 4H), 3.41±3.64 (m,
4H), 7.14±7.43 (m, 6H), 7.75±7.88 (m, 4H). 31P NMR
dˆ142.1 HRMS calcd for C26H24NO3P: 429.149, found
429.149.
3,30-Dibromo-2,20-dihydroxy-1,10-dinaphthyl (9). [a]2D0ˆ
2898 (cˆ0.58, CH3OH). 1H NMR dˆ5.58 (s, 2H), 7.08 (d,
Jˆ7.6 Hz, 2H), 7.23±7.46 (m, 4H), 7.81 (d, Jˆ7.7 Hz, 2H),
8.23 (s, 2H). 13C NMR (CD3OD/CDCl3) dˆ116.65, 119.26,
128.24, 128.44, 130.94, 133.40, 136.47, 136.84, 152.78.
General procedure for the synthesis of compounds 11a,
12, 13
General procedure for the conjugate addition of
diethylzinc to a,b-unsaturated ketones employing a
chiral catalyst derived from Cu(OTf)2 and a
phosphoramidite
To a mixture of a 3,30-disubstituted-2,20-dihydroxy-1,10-
dinaphthyl (1 mmol) in 5 ml of toluene hexamethyl-
phosphorus triamide (1.5 mmol) was added. The mixture
became clear and after 1 h a white solid precipitated. The
mixture was stirred for 3 h at ambient temperature, 3 ml
diethyl ether was added, and a white solid precipitated.
The solid was collected by ®ltration, washed with diethyl
ether (3 ml), and dried in vacuo to give the pure phosphor-
amidites 11a, 12, 13. Yields .75%.
A solution of Cu(OTf)2 (0.025 mmol) and 0.05 mmol of
phosphoramidite in 5 ml freshly distilled toluene was stirred
under a nitrogen atmosphere at ambient temperature for 1 h.
The substrate was added 1.0 mmol, the mixture was cooled
to 2208C and 1.4 ml of diethylzinc in toluene (1.1 M) was
added. Stirring was continued at 2208C for 16 h. The
conversion was determined by TLC. After complete conver-
sion, the reaction mixture was poured in 25 ml of 1 M HCl
and extracted three times with diethyl ether (60 ml). The
combined organic layers were dried with brine (25 ml)
and Na2SO4, ®ltered and evaporated to yield the crude
1,4-products. After puri®cation by column chromatography
(SiO2 and hexane/diethyl ether), the e.e.'s were determined
by HPLC or GC analyses.
O,O0-(1,10-Dinaphthyl-2,20-diyl-3,30-dimethyl)-N,N0-
dimethylphosphoramidite (11a). [a]2D0ˆ15548 (cˆ0.14,
1
CH2Cl2). H NMR dˆ2.51 (s, 6H), 2.60 (d, Jˆ9.4 Hz,
6H), 7.12±7.43 (m, 6H), 7.73±7.89 (m, 4H). 31P NMR
dˆ145.9. HRMS calcd for C24H22NO2P: 387.139, found
387.139.
O,O0-(1,10-Dinaphthyl-2,20-diyl-3,30-dibromide)-N,N0-
dimethylphosphoramidite (12). [a]2D0ˆ15548 (cˆ0.54,
1
CH2Cl2). H NMR dˆ2.59 (d, Jˆ9.4 Hz, 6H), 7.23±7.31
1,3-Diphenylpentan-1-one (17). e.e. determination by
HPLC analyses; Daicel (Chiralcel OD), 0.25% iPrOH in
hexane, ¯ow rate 1.0 ml/min, UV detector (254 nm); reten-
tion times 16.3 min; 19.0 min. 1H NMR dˆ0.85 (t,
Jˆ7.3 Hz, 3H), 1.60±1.84 (m, 2H), 3.24±3.33 (m, 3H),
7.18±7.33 (m, 5H), 7.41±7.60 (m, 3H), 7.92±7.96 (m,
2H). 13C NMR dˆ12.12 (q), 29.23 (t), 43.00 (d), 45.60
(m, 4H), 7.41±7.49 (m, 2H), 7.84 (d, Jˆ7.7 Hz, 2H), 8.27
(d, Jˆ9.0 Hz, 2H). 31P NMR dˆ148.8 HRMS calcd for
C22H16Br2NO2P: 514.929, found 514.929.
O,O0-(1,10-Dinaphthyl-2,20-diyl-3,30-diphenyl)-N, N0-
dimethylphosphoramidite (13). [a]2D0ˆ14468 (cˆ0.50,

2876
L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
(t), 126.27 (d), 127.65 (d), 128.05 (d), 128.40 (d), 128.52
(d), 132.90 (d), 137.25 (s), 144.67 (s), 199.19 (s).
0.25% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 25.4 min, 27.2 min. 1H NMR
dˆ0.82 (t, Jˆ7.2 Hz, 3H), 1.41±1.58 (m, 2H), 2.21 (s,
3H), 3.18±3.33 (m, 3H), 7.01±7.34 (m, 7H), 7.64 (d,
Jˆ6.8 Hz, 2H). 13C NMR dˆ12.73 (q), 31.45 (t), 41.54
(d), 46.82 (t), 54.25 (q), 112.87 (d), 124.26 (s), 125.42 (d),
127.48 (d), 128.13 (d), 130.75 (d), 137.32 (s), 138.40 (s),
202.76 (s).
1-(2-Furyl)-3(5-methyl-2-furyl)pentan-1-one (33). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),
0.25% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 15.2 min; 18.0 min. 1H NMR
dˆ0.862 (t, Jˆ7.3 Hz, 3H), 1.60±1.74 (m, 2H), 2.21 (s,
3H), 2.93±3.33 (m, 3H), 5.78±5.80 (m, 1H), 5.84±5.88
(m, 1H), 6.49±6.51 (m, 1H), 7.14±7.17 (m, 1H), 7.55±
7.57 (m, 1H). 13C NMR dˆ11.40 (q), 13.25 (q), 26.55
(t), 36.18 (d), 42.36 (t), 105.47 (d), 105.81 (d), 111.97
(d), 117,01 (d), 146.22 (d), 150.30 (s), 155.18 (s),
194.78 (s). HRMS calcd for C13H14O3: 219.556, found
219.556.
1-Phenyl-3-(4-methoxyphenyl)pentan-1-one (39). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),
0.25% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 29.7 min, 34.8 min. 1H NMR
dˆ0.79 (t, Jˆ7.2 Hz, 3H), 1.43±1.63 (m, 2H), 2.16 (s,
3H), 3.21±3.24 (m, 3H), 7.11±7.53 (m, 7H), 7.89 (d,
Jˆ6.8 Hz, 2H). 13C NMR dˆ11.82 (q), 29.10 (t), 42.00
(d), 45.61 (t), 54.97 (q), 113.59 (d), 123.73 (s), 127.84 (d),
127.92 (d), 128.37 (d), 132.75 (d), 138,45 (s), 138.96 (s),
197.68 (s).
1,3-Di(2-thiophene)pentan-1-one (34). e.e. determination
by HPLC analyses; Daicel (Chiralcel OD), 0.25% iPrOH in
hexane, ¯ow rate 1.0 ml/min, UV detector (294 nm); reten-
tion times 18.3 min; 20.1 min. 1H NMR dˆ0.89 (t,
Jˆ7.4 Hz, 3H), 1.60±1.90 (m, 2H), 3.20±3.24 (m, 2H),
3.56±3.67 (m, 1H), 6.83±6.91 (m, 2H), 7.11±7.14 (m,
2H), 7.59±7.68 (m, 2H). 13C NMR dˆ11.18 (q), 30.36 (t),
44.88 (d), 45.17 (t), 122.35 (d), 122.76 (d), 124.53 (d),
125.19 (d), 126.29 (d), 126. 96 (d), 201.18 (s). HRMS
calcd for C13H14OS2: 251.555, found 251.557.
1-(4-Chlorophenyl)-3-phenyl-1-pentanone (40). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),
0.25% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 16.0 min, 17.5 min. 1H NMR
dˆ0.83 (t, Jˆ7.6 Hz, 3H), 1.58±1.83 (m, 2H), 3.17±3.31
(m, 3H), 7.21±7.31 (m, 5H), 7.40 (d, Jˆ7.1 Hz, 2H), 7.84
(d, Jˆ7.2 Hz, 2H). 13C NMR dˆ11.83 (q), 28.98 (t),
42.83 (d), 45.34 (t), 126.24 (d), 127.47 (d), 128.32 (d),
128.69 (d), 129.35 (d), 135.41 (s), 139.98 (s), 144.31 (s),
197.96 (s).
1,4-Di(2-thiophene)-2-ethyl-1,4-butadione (35). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),
10% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 10.1 min, 12.9 min. 1H NMR
dˆ0.962 (t, Jˆ7.5 Hz, 3H), 1.67±1.79 (m, 2H), 3.12±
3.30 (m, 1H), 3.80±3.87 (m, 2H), 7.10±7.16 (m, 2H),
7.61±7.66 (m, 2H), 7.76±7.85 (m, 2H). 13C NMR
dˆ11.16 (q), 28.17 (t), 46.11 (d), 57.93 (d), 122.52 (d),
122.87 (d), 124.61 (d), 124.81 (d), 126.33 (d), 127.29 (d),
139.48 (s), 154.53 (s), 201.53 (s), 202.13 (s) HRMS calcd
for C14H14O2S2: 279.668, found 279.664.
1-Phenyl-4-(4-chlorophenyl)pentan-1-one (41). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),
0.25% iPrOH in hexane, ¯ow rate 1.0 ml/min, UV
1
detector (254 nm); retention times 32.9 min, 37.9 min. H
NMR dˆ0.80 (t, Jˆ7.3 Hz, 3H), 1.56±1.80 (m, 2H),
3.20±3.27 (m, 3H), 7.14±7.59 (m, 7H), 7.89 (d,
Jˆ6.8 Hz, 2H). 13C NMR dˆ11.74 (q), 28.89 (t), 42.10
(d), 45.15 (t), 127.87 (d), 128.38 (d), 128.44 (d),
128.88 (d), 132.80 (s), 132.91 (d), 137.56 (s), 143.02 (s),
198.77 (s).
1-(2-Pyridyl)-3-phenyl-1-pentanone (36). e.e. determina-
tion by HPLC analyses; Daicel (Chiralcel OD), 10% iPrOH
in hexane, ¯ow rate 1.0 ml/min, UV detector (240 nm);
1
retention times 18.2 min, 25.4 min. H NMR dˆ0.81 (t,
1,3-Di-(4-chlorophenyl)pentan-1-one (42). e.e. determina-
tion by HPLC analyses; Daicel (Chiralcel OD), 0.25%
iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(254 nm); retention times 22.3 min, 24.6 min. 1H NMR
dˆ0.79 (t, Jˆ7.1 Hz, 3H), 1.38.1.64 (m, 2H), 3.11±3.31
(m, 3H), 7.42 (d, Jˆ6.8 Hz, 1H), 7.57 (d, Jˆ6.8 Hz, 1H),
7.64 (d, Jˆ6.8 Hz, 1H), 7.79(d, Jˆ6.8 Hz, 1H). 13C NMR
dˆ12.36 (q), 28.14 (t), 1.56 (d), 44.13 (t), 128.33 (d),
128.56 (d), 129.57 (d), 129.88 (d), 134.94 (s), 135.16 (s),
140.40 (s), 143.36 (s), 203.16 (s).
Jˆ7.4 Hz, 3H), 1.60±1.85 (m, 2H), 3.19±3.34 (m, 1H),
3.45±3.69 (m, 2H), 7.10±7.23 (m, 1H), 7.24±7.47 (m,
4H), 7.40±7.47 (ddd, 1H), 7.74±7.82 (dt, 1H), 7.92±7.98
(dt, 1H), 8.65±8.68 (ddd, 1H). 13C NMR dˆ11.79, 29.32,
42.42, 43.98, 121.66, 125.92, 126.84, 127.63, 128.09,
126.68, 144.77, 148.69, 153.45, 200.70.
1-(4-Nitrophenyl)-3-phenyl-1-pentanone (37). e.e. deter-
mination by HPLC analyses; Daicel (Chiralcel OD), 10%
iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(270 nm); retention times 8.7 min, 23.8 min. 1H NMR
dˆ0.876 (t, Jˆ7.4 Hz, 3H), 1.63±1.88 (m, 2H), 3.18±
3.40 (m, 3H), 7.18±7.37 (m, 5H), 8.04 (d, Jˆ6.3 Hz, 2H),
8.32 (d, Jˆ6.3 Hz, 2H). 13C NMR dˆ12.33 (q), 28.16 (t),
41.36 (d), 45.17 (t), 123.16 (d), 125.47 (d), 128.3 (d), 128.73
(d), 129,48 (d), 141.83 (d), 142.41 (d), 148.09 (s), 203.56
(s).
1,3-Di-(4-bromophenyl)pentan-1-one (43). e.e. determi-
nation by HPLC analyses; Daicel (Chiralcel OD), 0.25%
iPrOH in hexane, ¯ow rate 1.0 ml/min, UV detector
(251 nm); retention times 24.8 min, 27.9 min. 1H NMR
dˆ0.80 (t, Jˆ7.3 Hz, 3H), 1.48±1.84 (m, 2H), 3.05±3.13
(m, 3H), 7.23 (d, Jˆ6 Hz, 1H), 7.39 (d, Jˆ6 Hz, 1H), 7.59
(d, Jˆ6 Hz, 1H), 7.74 (d, Jˆ6 Hz, 1H). 13C NMR dˆ11.88
(q), 31.46 (t), 40.18 (d), 43.61 t), 122.01 (s), 122.73 (s),
129.04 (d), 129.94 (d), 131.13 (d), 131.74 (d), 141.20 (s),
142.39 (s), 201.83 s).
1-(4-Methoxyphenyl)-3-phenyl-1-pentanone (38). e.e.
determination by HPLC analyses; Daicel (Chiralcel OD),

L. A. Arnold et al. / Tetrahedron 56 (2000) 2865±2878
2877
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Acknowledgements
Financial support from The Netherlands Organisation for
Scienti®c Research (NWO-CW) and EET is gratefully
acknowledged.
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