Solid-phase development of chiral phosphoramidite ligands for enantioselective conjugate addition reactions

Article abstract of DOI:10.1002/1521-3765(20021018)8:20<4767::AID-CHEM4767>3.0.CO;2-O

The development of a method for the optimization of chiral ligands for the steric steering of enantioselective Cu-catalyzed conjugate additions of Zn-alkyls to enones is described. The method is based on combinatorial principles and solid-phase techniques. It includes the combinatorial synthesis of chiral bispidine-derived ligands embodying a phosphoramidite group on the solid phase and their investigation in immobilized form in the conjugate addition of ZnEt₂ to cyclohexenone as test reaction. The best identified ligands were also synthesized separately and investigated in its soluble form. The results obtained for the polymer-bound ligands correctly mirrored the performance of the soluble ligands. The library embodied members giving ee values varying between 3 and 67%. The "positional scanning" approach proved to be invalid for the study of the ligand system, indicating that this approach in general should be applied with care. Taken together, the method allowed for rapid and efficient optimization of the ligands and led to the development of the first enantioselective, Cu-catalyzed conjugate addition reaction with a polymer-bound ligand.

Full text of DOI:10.1002/1521-3765(20021018)8:20<4767::AID-CHEM4767>3.0.CO;2-O

FULL PAPER
Solid-Phase Development of Chiral Phosphoramidite Ligands for
Enantioselective Conjugate Addition Reactions
Oliver Huttenloch, Eltepu Laxman, and Herbert Waldmann*[a]
Abstract: The development of a meth-
od for the optimization of chiral ligands
for the steric steering of enantioselective
Cu-catalyzed conjugate additions of Zn-
alkyls to enones is described. The meth-
od is based on combinatorial principles
and solid-phase techniques. It includes
the combinatorial synthesis of chiral
bispidine-derived ligands embodying a
phosphoramidite group on the solid
phase and their investigation in immo-
bilized form in the conjugate addition of
ZnEt2 to cyclohexenone as test reaction.
The best identified ligands were also
synthesized separately and investigated
in its soluble form. The results obtained
for the polymer-bound ligands correctly
mirrored the performance of the soluble
ligands. The library embodied members
giving ee values varying between 3 and
67%. The ™positional scanning∫ ap-
proach proved to be invalid for the
study of the ligand system, indicating
that this approach in general should be
applied with care. Taken together, the
method allowed for rapid and efficient
optimization of the ligands and led to
the development of the first enantiose-
lective, Cu-catalyzed conjugate addition
reaction with a polymer-bound ligand.
Keywords: asymmetric catalysis
combinatorial chemistry ¥ conjugate
addition enantioselectivity
solid-phase synthesis
¥
¥
¥
formations by Hoveyda et al.[2] and Jacobsen et al.[3] For solid
phase bound salen ligands such a correlation could not be
determined.[6] While the use of immobilized bis-oxazoline
ligands in Mukaiyama aldol reactions gave results very similar
to the homogeneously catalyzed cycloadditions,[5] in the study
of polymer-bound sulfonamides in combination with dieth-
ylzinc, for this purpose the desired correlation was not given.[7]
The conjugate addition of organometallic reagents to a,b-
unsaturated carbonyl compounds is one of the most important
transformations of organic synthesis. For the enantioselective
steering of this reaction various methods have been devel-
oped,[10] and the Cu-catalyzed addition of dialkylzinc reagents
to a,b-unsaturated enones and related compounds in the
presence of chiral phosphoramidite ligands[10 12] pioneered by
Alexakis et al.[11] and further developed in particular by
Feringa et al.[12] but also by other groups[10] has emerged as a
particularly efficient process. The application of combinato-
rial principles to the development of chiral ligands for Cu-
catalyzed enantioselective conjugate addition processes has
been pursued only in a single case.[13] Gennari et al. employed
solid phase extraction techniques for the generation of soluble
sulfonamide ligands. However, the approach described above,
which has proven so successful for other types of trans-
formations, that is the synthesis of a library of ligands on solid
phase and its use in appropriate screening systems to
ultimately develop soluble chiral ligands, has not been applied
to enantioselectively catalyzed conjugate addition reactions.
Here we describe in full detail[14] the combinatorial syn-
thesis of a library of polymer-bound bispidine-derived phos-
Introduction
The development of enantioselective catalyzed transforma-
tions is among the most important areas of organic synthesis,
and within this field the use of chiral ligands for metal atoms
to direct the steric course of chemical transformations has
proven to be a key methodology. The introduction of new
approaches to accelerate identification and optimization of
such ligands has received particular attention. Very recently,
the application of combinatorial principles to address this
challenge has opened up entirely new opportunities to the
field. In particular, the synthesis of ligand libraries on solid
supports and their application as heterogeneous catalysts in
screening systems has emerged as a powerful technique for
the rapid development of finally soluble ligands for enantio-
9]
selective catalysis.[1
A key demand to be met by this strategy is that the results
obtained with the immobilized ligands should correctly dis-
play the same trends in stereoselection as the corresponding
soluble catalyst systems; ideally they should be (nearly)
identical.[2 8] This demand was partly met in the development
of peptide-derived salicylaldimine ligands for different trans-
[a] Prof. Dr. H. Waldmann, Dr. O. Huttenloch, Dr. E. Laxman
Max-Planck-Institut f¸r molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Universit‰t Dortmund, Fachbereich 3, Organische Chemie
Fax : (‡49)-231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
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H. Waldmann et al.
FULL PAPER
phoramidite ligands and its evaluation in the Cu-catalyzed
enantioselective addition of dialkylzinc reagents to enones.
We demonstrate that the results and trends gleaned from
assaying the polymer-bound ligands provide a sound and
reliable basis for the development of corresponding homoge-
neously soluble ligands.
reagents an unpolar hydroxymethyl polystyrene matrix was
chosen to which the bispidine was attached by esterification.
To determine, if the results to be expected from investigat-
ing such immobilized ligands would be comparable to the
values recorded for soluble ligand 1 phosphoramidites 11 and
12 were synthesized as shown in Schemes 2and 3. Compound
1 has been investigated thoroughly in the conjugate addition
of diethylzinc to cyclohexenone and gave the addition product
with an ee value of 43%.[15, 21]
The hydrogenation-sensitive benzyl group present in oxa-
bispidinone 5 is incompatible with the usual requirements of
solid-phase synthesis and was replaced by an acid-labile Boc
urethane.
N-Dealkylation was achieved by treatment with 1-chloro-
ethylchloroformate and subsequent heating in methanol.[23]
The resulting amine was acylated with di-tert-butylcarbonate
to give intermediate 6 (Scheme 2). The subsequent Wittig
Results and Discussion
We have recently shown that phosphoramidites, such as 1,
embodying a binaphthol unit and a bispidine-derived modu-
lating substituent, can successfully be employed for the steric
steering of Cu-catalyzed enantioselective conjugate addition
reactions.[15] In order to find more efficient catalysts embody-
ing the same underlying structural motifs it was decided to
synthesize a library of ligands 2 (Scheme 1) on a polymeric
support.
O
O
i, ii, iii
iv
O
N
O
N
Boc
Ph
5
6
Z
Y
X
N
O
N
R
O
P
O
P O
O
OMe
O
1
2
Z
O
N
v
Boc
OH
8
O
X
O
Z
Y
N
HO
O
N
R
P O
O
Boc
O
Y
N
PG1
PG2
7
vi
O
N
3
Boc
0.52 mmol g-1
4
Z
9
Scheme 1. Solid-phase optimisation strategy for bispidine phosphorami-
Scheme 2. Synthesis of the model systems 8 and 9: i) ClCOOCH(Cl)CH3,
CH2Cl2, D, 2h; ii) MeOH, D, 2h; iii) Boc 2O, KOH, H2O, dioxane, RT, 12h,
87%; iv) BrPh3P(CH2)4COOH, KOtBu, THF, 08C !RT, 2.5 h, 54%;
v) EEDQ, MeOH, RT, 12h, 82%; vi) DIC, DMAP, CH 2Cl2, 12h, RT,
71%, then Ac2O, pyridine.
dites 1 and 2.
The strategy envisioned to attach the ligands at the
9-position to the solid support. On the one hand, in the
course of the bispidine synthesis the 9-keto intermediate is
18]
formed[16
which opens up various alternatives for attach-
reaction proceeded only with moderate yield which may be
due to the low reactivity of the 9-keto group in bispidinones[14]
observed by us in related cases as well.
ment of a linker group. On the other hand the 9-position is on
the face of the molecule opposite to the catalytically active
metal atom after complexation. It should, therefore, not or
only to a minor extent influence the course of stereoselective
transformations. After unsuccessful attempts to link the
bispidine system as an ester to the solid support,[19] coupling
by a Wittig olefination turned out to be the method of choice
(see below).
It was planned to vary the substitution pattern of the
binaphthyl-phosphoramidite attached to one nitrogen of the
underlying bicycled bispidine system and to vary the nature of
the second heteroatom (O, N, S) as well as the substituent
bound to it, if nitrogen was chosen (Scheme 1).
Carboxylic acid 7 obtained thereby, was then either
converted to methyl ester 8 employing EEDQ as activating
reagent, or it was linked to hydroxymethyl polystyrene under
Steglich conditions to give polymer 9 with a loading of
0.52mmolg À1. Unreacted hydroxy groups were capped by
acylation with acetic anhydride. After removal of the Boc
group from 8 and 9, coupling with (R)-[binaphthyl-2,2'-
diyl]chlorophosphite CIP(BINOL) (10a)[24] yielded phos-
phoramidites 11 and 12 (Scheme 3). Compound 11 was
obtained as mixture of isomers which could not be separated
and was employed as stereodirecting ligand in the conjugate
addition of ZnEt2 to cyclohexenone 13 as such. In this
transformation chiral ketone 14 was obtained with 46% ee at
complete conversion (Scheme 4), that is with slightly higher
stereoselectivity than with parent oxabispidine 1. Thus
For the planning of the asymmetric reactions, the polymeric
carrier should be regarded as part of the solvent system and it
should have properties similar to the solvent employed.[20]
Since toluene is the regular solvent used with dialkylzinc
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Chiral Phosphoramidite Ligands
4767 4780
The polymeric ligand systems synthesized by these different
methods were then subjected to the enantioselective trans-
formations described above. In the course of this investigation
the loading of the resin was varied as well. Initial experiments
employing toluene/CH2Cl2 mixtures (6:1) as solvent were only
poorly reproducible. This finally was traced back to the fact
that in this system both the immobilized ligand and Cu(OTf)2
are insoluble leading to unreproducible catalyst formation.
After substantial experimentation this problem was overcome
by addtion of 3 vol% DMF to the solvent CH2Cl2 to solubilize
Cu(OTf)2 before exposure to the immobilized bispidine
ligand. Treatment of the resin with such a solution (i.e., with
an excess of Cu(OTf)2) resulted in complete and reproducible
loading of the polymer with the Cu salt, excess reagent was
easily washed off. DMF is only a weak ligand for CuII and is
readily replaced by stronger ligands like phosphoramidites.
Investigation of the different polymer catalysts prepared
according to the methods detailed above, gave the results
shown in Scheme 6 and Table 1. Gratifyingly, immobilization
of the ligand and performing the reaction at 08C instead of
À308C (to ensure sufficient swelling of the polymer) resulted
in only a minor drop of the enantioselectivity to 39%. The
method of preparation does not influence the performance of
the catalyst. However, if the catalyst loading becomes too low,
both yield and enantioselectivity decrease (compare entry 2
with entries 1, 3 and 4). Therefore, all further experiments
OR
OR
O
O
i, ii, iii
O
N
O
N
Boc
P O
O
8: R = Me
9: R =
O
O
Cl P
11: R = Me: 41%
12: R =
10a
: 71%
Scheme 3. Synthesis of phosphoramidites 11 and 12: i) TFA, CH2Cl2, 0.5 h,
RT, quant.; ii) Et3N CH2Cl2 (only for 9); iii) 10a, Et3N, toluene, 12h, RT.
O
O
i)
46% ee
Et
13
14
Scheme 4. Conjugate addition of diethylzinc to cyclohexen-2-one with
ligand 11: i) Et2Zn, Cu(OTf)2 (3 mol%), 11 (3.3 mol%), toluene, CH2Cl2,
À308C, 2h, complete conversion.
,introduction of an alkenyl group into the 9-position of the
bicyclic system does not influence the stereoselectivity and
the catalytic activity significantly.
While 11 was synthesized according to the procedure
already established for 1,[15] in the synthesis of the polymer-
bound ligand chlorophosphite 10a was used in excess.
Loading of the resin was determined by gravimetry. Successful
formation of the phosphoramidite is a prerequisite for
catalytic activity and stereoselectivity. Thus, in the presence
of hydroxymethyl polystyrene pretreated with Ac2O or of a
polystyrene resin to which a fully protected bispidine pre-
cursor had been attached, and which subsequently was treated
with chlorophosphite 10a, only very low conversion and no
enantioselectivity was recorded. Finally, formation of the
phosphoramidite was ascertained by treatment of the func-
tionalized resin with TFA in methanol which resulted in
release of 2,2'-dihydroxy-[1,1']binaphthol (see the Experi-
mental Section).
were carried out employing resins with
0.52mmolg À1
a loading of
.
O
O
i
Et
14
13
O
O
O
O
ii, iii
O
N
O
N
P O
O
P O
O
Cu
(OTf)2
Alternatively, the desired polymer-bound phosphoramidite
was formed by treatment of the immobilized N-deprotected
oxabispidine with PCl3 and subsequent reaction of the
intermediary formed dichlorophosphine derivative with diol
15 (Scheme 5).
12
16
Scheme 6. Modified reaction conditions for the conjugate addition with
ligand 12/16: i) Et2Zn, 16 toluene, CH2Cl2, 08C, complete conversion 37
40% ee; ii) 5 equiv Cu(OTf)2, CH2Cl2/3% DMF; iii) washing.
Table 1. Comparison of different solid phase oxa-bispidine ligands 12/16.
Entry[a] Loading/yield[b]
Mode of synthesis[c]
ee (conversion)[d]
O
O
O
1
0.52mmolg À1/71% CIP(BINOL) 10a
39% (complete)
37% (complete)
40% (86%)
i,ii,iii,iv
20.40 mmolg
À1/27% CIP(BINOL) 10a
1.11 mmolgÀ1/76% CIP(BINOL) 10a
O
O
N
3
4
P O
0.52mmolg À1/71% PCl3, BINOL-OH 15 40% (complete)
O
N
O
Boc
HO
HO
[a] Addition of diethylzinc to cylohexen-2-one according to Scheme 7.
[b] Loading/yield of two different resins with a maximum loading of
0.87 mmolgÀ1 and 1.46 mmolgÀ1, respectively. [c] Either with the chloro-
phosphite reagent or with PCl3 and 2,2'-dihydroxy-[1,1']-binaphthyl, see
text. [d] Determined by gas chromatographic analysis using a capillary
column (LipodexE, Macherey&Nagel), in all cases the (R) enantiomer was
formed predominantly.
9
12
15
Scheme 5. Alternative synthesis of phosphoramidite 12: i) TFA, CH2Cl2,
30 min; ii) Et3N, CH2Cl2, 15 min; iii) PCl3, Et3N, THF, 1 h; iv) 15, Et3N,
THF, 12h.
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H. Waldmann et al.
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Synthesis of the library: For the synthesis of a bispidinone-
phosphoramidite library a precursor for attachment to the
solid support was required which carries two orthogonal
protecting groups at the nitrogen atoms. This building block
was generated by double Mannich reaction from 17 yielding
bispidinone 18, subsequent olefination of the ketone to give
olefin 19 and exchange of the N-benzyl group for an Fmoc
urethane (20) (Scheme 7). During hydrogenolytic removal of
OH
OMe
O
O
i
ii
N
N
N
N
Boc
Boc
Ph
Ph
19
22
OMe
OMe
O
O
iii
N
N
N
N
O
H
Boc
R
Boc
O
ii
23
24
i
N
N
N
Scheme 8. Model reactions with bispidine system 23: i) EEDQ, MeOH,
12h, RT, 75%; ii) H 2, Pd/C, EtOH, 12h, RT, 90%; iii) various reactions
and conditions.
Boc
Boc
Ph
17
18
OH
OR
O
O
iii, iv
oxygen, a sulfur or a carbon atom and piperidine system A5
(Figure 1). Compounds A2 A4 were only derivatized as
phosphoramidites. As substituents of the modulating second
nitrogen atom present in A1 initially structural units B1 B28
were chosen (Figure 2). These include aliphatic acyl groups
(B1 B4), the Boc urethane (B5), urea and thiourea groups
(B6, B7), aromatic acyl groups (B8 B14), aromatic substi-
tuted (B15, B16) and simple aliphatic (B17, B18) substituents,
the permethylated amine (B19), sulfonamides (B20 B24)
and phosphorus (B25 B28) substituents.
N
N
N
N
Boc
Fmoc
v
Boc
Ph
19
20: R = H
21: R =
HO
Scheme 7. Synthesis of bispidine 20 and coupling to the solid phase:
i) PhCH2NH2, (HCHO)n, AcOH, MeOH, 658C, 4 h, 81%;
ii) BrPh3P(CH2)4COOH, KOtBu, THF, 08C ! RT, 2.5 h, 68%; iii) H2,
Pd/C, EtOH, 12h, RT, quant.; iv) FmocCl,NaHCO 3, THF, H2O, 12h, RT,
69%; v) DIC, DMAP, CH2Cl2, 12h, RT, 94% (0.61 mmolg À1).
the benzylamine the 9-syn and 9-anti diastereomers are
formed in a 1:1 ratio. Neither at this stage nor after Fmoc
protection could their separation be achieved. Since the
9-substituent does not or only to a minor extent influence the
stereoselection (see above) it appeared justified to employ the
diastereomeric mixture for the library synthesis and evalua-
tion.
Fmoc/Boc-protected bispidine carboxylic acid 20 was
coupled to the solid support in high yield. Resin loading was
determined gravimetrically and by means of UV-spectromet-
ric quantification of the piperidine/fulvene adduct formed in
the course of Fmoc removal.
Library synthesis on the solid support required that reliable
methods for functionalization of the second nitrogen in the
bispidine are available. These were established in solution for
model compound 23 which was obtained from intermediate 19
after esterification and N-debenzylation (Scheme 8). Thus,
methods for acylation, peralkylation, reductive amination,
sulfonation and phosphorylation were established, including
the choice of the right solvent system which should be
homogeneous and allow for good swelling of the resin (see the
Experimental Section for details). These were used for the
analogous reactions on the solid phase.
After the methodical prerequisites had been established,
the synthesis of the desired library was carried out. For this
purpose, three different underlying structural frameworks
were chosen, namely bispidine system A1 embodying a
phosphoramidite and a second nitrogen substituent to mod-
ulate the catalyst properties, hetero-bispidines A2 A4 in
which the modulating substituted nitrogen was replaced by an
Figure 1. (Hetero-)bispidines A1 A4 and piperidine A5 as ligand back-
bones.
O
H
O
O
O
H
O
N
O
N
Me
N
O
S
B1
B2
B3
B4
B5
B6
B7
O
O
O
O
O
O
O
N
O
S
N
Me
N
B8
B9
B10
B11
B12
B13
B14
(Me)2
Me
(dimethylated)
N
B15
B20
B16
B17
B18
B19
O
S
O
O
S
O
O
S
O
O
Me S
O
O
S
O
S
B21
B22
B23
B24
O
PhO P
PhO
O
EtO P
EtO
O
Ph2P
Et2N P
Et2N
B25
B26
B27
B28
Figure 2. Building blocks for the ligand library: nitrogen substituents B1
B28.
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Chiral Phosphoramidite Ligands
4767 4780
The phosphoramidite structure was varied by introduction
of different ortho-substituents into the binaphthyl groups
(C1 C4, Figure 3) which were introduced by means of the
corresponding chlorophosphites (10a d).
frameworks A1 were employed together with the underivated
basic binaphthol phosphoramidite in order to find the best
modulating nitrogen substituents. In the second step, the
structure of the most promising candidates from step one was
varied by introduction of differently substituted binaphthol
units. This round also included hetero-substituted bispidine
cores A2 A4 and piperidine derivative A5.
After completion of the synthesis the ligands were con-
verted to the corresponding polymer-bound copper com-
plexes as described above and investigated in the Cu-
catalyzed conjugate addition of ZnEt2 to cyclohexenone at
08C. After the transformations had reached >95% conver-
sion (2h) the reactions were quenched with 2 n HCl and the
enantiomeric ratio was determined without further separation
procedures by means of gas chromatography, employing a
chiral stationary phase.
R
R = H
C1
R = Me
C2
R = Br
C3
R = Ph
C4
O
O
P
R
Figure 3. Building blocks for the ligand library: BINOL-phosphite groups
C1 C4.
Library synthesis employing bispidine core A1 was carried
out by means of two successive deprotection/N-functionaliza-
tion steps (Scheme 9). Thus, after removal of the Fmoc group
from 21, the nitrogen atom was derivatized by means of the
The results of the first round of investigation are displayed
in Figure 5, see below. It is clearly visible that the nature of the
second nitrogen has a profound influence on the efficiency of
the stereoselection.
O
O
i, ii
O
O
Thus, in the presence of sterically demanding acyl-sub-
stituents such as the isobutyryl (B2, 39% ee) and, in
particular, the pivaloyl group (B3, 44% ee) asymmetric
induction is high. An acetamide (B1, 11% ee), a Boc group
(B5, 2 9%ee), the urea and thiourea groups (B6, B7) (35 and
27%) are less advantageous. Among the aromatic amides,
weakly complexing functional groups such as the thiophene
group (B13, 38% ee) were much better than nitrogen
heterocycles or the unfunctionalized benzamide B8 (23%
ee). Pyridine heterocycles give particularly low ee values
probably due to their ability to from CuII complexes. A similar
trend is visible for B15 (35% ee) and B16 (21% ee)
incorporating an N-benzyl-and a 3-pyridylmethyl group,
respectively. In the presence of aliphatic amines (B17, B18)
the enantioselectivity is low. Permethylation (B19, 2 9%ee)
and generation of an aminophosphine were also less advanta-
geous. Remarkably, toluene sulfonamide B20 (56% ee) and
benzene sulfonamide (B21, 51% ee) gave the highest ee value
as determined in the first screening round; other sulfonamides
(B22 B24, 19 33% ee) were less advantageous. The diphen-
yl phosphoric amide B26 (50% ee) gave the highest ee value
of the phosphorous substituents (B25 B28, 37 41% ee) in
the first screening round.
In order to determine, if the introduction of stereogenic
centres into the N-substituent would give rise to higher
stereoselectivity, the bispidine core (A1) carrying the basic
binaphthol substituent (C1) was combined with N-acetylated
(D1) or N-sulfonylated (D2 D4) amino acids (AA1 AA7)
or dipeptides (AA1/2 AA3) (Figure 4). The synthesis of the
polymer-bound ligands followed the route described above.
However, evaluation of these ligands in the conjugate
addition to cyclohexenone showed that the chiral N-substitu-
ents did not exert a positive effect (Figure 6). Thus, in the
presence of an acetylated or sulfonylated amino acid, the ee
value in most cases remained below the 30% line. For
dipeptide substituents even the 20% value was reached in
only one case.
N
N
N
N
Fmoc
Boc
R¥
O
Boc
21
22
O
iii, iv
R
N
N
R¥
P O
O
R
23
O
R
O
O
O
v, vi, vii
Y
N
P O
O
Y
N
Boc
R
Y = O, S, C
25
24
Scheme 9. Synthesis of solid phase ligands 23 and 25: i) Piperidine;
ii) modification at the N atom; iii) TFA, CH2Cl2, NEt3; iv) ClP(R2BINOL)
Et3N, toluene; v) TFA, CH2Cl2; vi) CH2Cl2, NEt3; vii) ClP(R2BINOL)
Et3N, toluene.
transformations described above to yield intermediates 22.
The Boc group was removed under acidic conditions, the
secondary amine was liberated by treatment with NEt3 and
then the acid-labile phosphoramidites 23 were formed in the
last step. For frameworks A2 A4 embedded in 24 and by
analogy for piperidine derivative A5 the same Boc-depro-
tection/phosphitylation sequence was followed to give poly-
mer-bound ligands 25 (Scheme 9).
Screening of the ligand library: The ligand library was
synthesized and screened for enantioselective catalytic activ-
ity in two rounds of investigation. In the first round only
Based on these results ligands B3, B13, B20 and B26
embodying the most promising N-substituents were subjected
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H. Waldmann et al.
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O
O
N
N
C1
AA(1-7)-AA3-(D1-D4)
(4 -MeO-Bzl)S
Ph
C
O
N
C
O
C
O
N
H
N
C
N
H
H
O
AA3
AA4
AA1
AA2
H3CS
Ph(4-Br)
C
O
N
H
C
O
N
C
O
N
H
H
AA5
AA6
AA7
O
C
O
O
O
O
O
O
S
S
S
CH3
CH3
Ph
Ph(4-CH3)
Figure 5. ee Values determined with ligand combinations A1-B(1 28)-C1.
D1
D2
D3
D4
Figure 4. Amino acid and dipeptide substituted ligands.
to a second round of investigation in which the structure of the
binaphthol system was varied (C1 C4). This second round
also included the bispidine analogues A2 A5. The results of
the corresponding enantioselective conjugate addition reac-
tions are shown in Figure 7.
Several trends are apparent from these reactions. First, for
the pivaloyl amide (A1-B3-C1/C2) raising the steric demand
of the binaphthyl substituent from H to CH3 led to significant
improvement of the enantioselectivity from 44 to 67% ee.
This is the highest value recorded in this study. However, the
selectivity was lower in the presence of a bromo- or phenyl
substituent.
stituted analogue A3 was the least advantageous ligand. In its
presence the polymer turned green, indicating strong com-
plexation of the copper. This is in accordance with the finding
of the pyridine-containing ligand discussed above.
The results shown in Figures 5 7 show that the two
substituents attached to the underlying bispidine core display
cooperative effects. But these effects are not necessarily
additive in each combination within the bispidine system
studied here. A positive influence of a substituent determined
through varying ligand structure at one position while keeping
the other unchanged does not necessarily remain when the
second group is varied.
A similar oberservation is made for the thiophenoylamide,
for which the ee raises from 38% (A1-B13-C1) to 54% (A1-
B13-C2) if a methyl group is
Therefore, the most advantageous modulating N-substitu-
ent identified in the first screening round, that is the 4-tosyl
introduced, but in the presence
of a bromine or a phenyl group
it is lower again (A1-B13-C3/4).
Interestingly, this trend is re-
versed for compounds embody-
ing a toluene sulfonamide (A1-
B20-C1/2) and a diphenyl-phos-
phorylamide (A1-B26-C1/2). In
both cases the ee value was
lower, if a sterically more de-
manding methyl substituent was
introduced into the binaphthol
residue.
In the presence of hetero-
substituted bispidine analogues
A2 A4, and if piperidine build-
ing block A5 was introduced,
the enantioselectivity did not
reach the highest values deter-
mined for the most efficient
combination in the bispidine
system A1. Strikingly, this sub-
Figure 6. ee Values determined with amino acid ligands incorporating substituted amino acids or dipeptides.
4772
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Chem. Eur. J. 2002, 8, No. 2 0

Chiral Phosphoramidite Ligands
4767 4780
X
O
N
N
N
iii
iv
Boc
28
i
N
N
N
N
Boc
H
Boc
27
Ph
O
18 : X = O
26 : X = H2
N
S
Boc
ii
O
29
O
v
O
N
O
N
Boc
Boc
6
30
Scheme 10. Synthesis of Boc-protected (hetero-)bispidines 28, 29 and 30:
i) H2, Pd/C, EtOH, 12h, RT; ii) TosNHNH 2, TosOH, NaCNBH3, DMF,
2h, 100 8C, 43%; iii) Piv2O, DMAP, pyridine, 12h, RT, 71%; iv) TosCl,
DMAP, pyridine 12h, RT, 72% (two steps); v) TosNHNH 2, TosOH,
NaCNBH3, DMF, 2h, 100 8C, 48%.
The Boc group was removed from 28 30 by treatment with
TFA and the liberated amines were then converted into the
desired phosphoramidites employing the method for phos-
phoramidite formation with chlorophosphite 10a and product
isolation developed earlier.[15] However, this procedure was
only practical for ligand 31 which embodies an underivatized
binaphthyl substituent.
If chlorophosphite 10b carrying ortho-methyl-substituted
binaphthol was used in 1.5-fold excess, only traces of the
desired products were isolated. Obviously, the steric demand
of the methyl groups prevent efficient product formation.[27]
Utilization of a large excess of chlorophosphite as in the
generation of the polymer-bound ligand resulted in contam-
ination of the products with the binaphthol after chromato-
graphic separation employing Florisil as the stationary phase.
The synthesis of 30 32 could be achieved by treatment of
the amines obtained from 28 30 with PCl3 first and
subsequent coupling of the resulting dichlorophosphoric acid
amides with ortho-methyl-substituted binaphthol 35 accord-
Figure 7. ee Values determined with ligand combinations Ax-Bx-C(1 4).
group B20 did not emerge as the substituent of choice after
the second round. Rather, the pivaloyl amide B3 which
reached only rank four in the first round turned out to be most
advantageous after appropriate combination with the right
binaphthyl unit. Thus, if we had followed the frequently used
strategy of ™positional scanning∫[2, 25] optimizing each sub-
stituent independently and subsequently carrying only the
best candidate through (instead of several ones as done here),
the most efficient ligand A1-B3-C2 would not have been
identified. This finding is of general relevance to combinato-
rial ligand and catalyst development. It shows that the concept
of ™positional scanning∫ may not be general and should be
applied with care.
Solution-phase validation of the screening results: In order to
validate the screening of the solid phase bound ligands and to
prove the concept of ligand optimization on the solid support,
four soluble ligands were synthesized and the results obtained
in homogeneous solution were compared with the values
determined for the transformations in the presence of the
same ligands immobilized on the solid support. To this end, N-
tosyl-N'-binaphthyl ligand 31 as well as N-pivaloyl- and N-
tosyl-N'-ortho-methylbinaphthyl ligands 32 and 33, and oxa-
N-ortho-methylbinaphthyl bispidine 34 were synthesized as
shown in Schemes 10 and 11.
Boc-/benzyl-protected bispidinone 18 was deoxygenated to
give bispidine 26 by conversion into the tosylhydrazone and
subsequent treatment with NaCNBH3.[25] After hydrogeno-
lytic removal of the N-benzyl protecting group monoprotect-
ed bispidine 26 was obtained, which was converted without
isolation and in high yield into pivalic acid amide 28 and
toluene-sulfonamide 29 (Scheme 10). By analogy Boc-
masked oxa-bispidine 30 was synthesized from ketone 6.
i, ii
O
S
O
S
N
N
N
N
Boc
P
O
O
O
O
29
31
iii, iv
X
N
X
N
Boc
P O
O
OH
OH
X = NPiv 28
NTos 29
O
30
35
X = NPiv 32
30%
12%
3%
NTos
O
33
34
Scheme 11. Synthesis of phosphoramidites 31 34: i) TFA, CH2Cl2,
30 min, RT; ii) ClP(BINOL), 10a, Et3N, toluene, 12h, RT, 51%; iii) TFA,
CH2Cl2, 30 min, RT; iv) PCl3, Et3N, THF, 1 h, 08C, then 35, Et3N, THF,
12h, RT.
Chem. Eur. J. 2002, 8, No. 20
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4773

H. Waldmann et al.
FULL PAPER
Table 2. Comparison of polymer supported ligands with the corresponding soluble ligands.
X
X
X
R
R
R
O
O
N
O
N
N
N
N
P O
O
P O
O
S
P O
O
O
R
R
R
35
36
37
X =
X = H2
R = H
R = Me
Entry[a]
Ligand group
BINOL substitution
H
Heterogenous ee[b] [%] (ligand)
homogenous ee[b] [%] (ligand)
1
2Me
3
4
5
6
oxa- (35)
39 (A2-C1)
43 (1)
45 (
A2-C2)
47 (34)[c]
n.d.
pivaloyl- (36)
H
Me
H
44 (A1-B3-C1)
67 (A1-B3-C2)
56 (A1-B20-C1)
46 (A1-B20-C2)
64 (32)
56 (31)
51 (33)
toluene-4-sulfonyl- (37)
Me
[a] Addition of diethylzinc to cylohexen-2-one according to Scheme 6 using resins with 0.5 0.6 mmolgÀ1 loading or according to Scheme 4 with soluble
ligands at 08C. [b] Determined by gas chromatographic analysis using a capillary column (LipodexE, Macherey&Nagel), in all cases the (R) enantiomer was
formed predominantly. [c] Using 1 mol% ligand.
ing to the alternative procedure for phosphoramidite forma-
tion described above (see Scheme 5). Although yields were
low, phosphoramidites 32 34 were available in sufficient
amounts for further investigation as stereodirecting ligands.
The results obtained in the Cu-catalyzed conjugate addition
of ZnEt2 to cyclohexenone are given in Table 2and compared
with the results observed for the immobilized ligands. In all
cases, the results for the homogeneously catalyzed reactions
very similar to the heterogeneous transformations and also
the trends gleaned from the ligand screening are correctly
mirrored.
Thus, for the oxa-bispidine system (entries 1 and 2) the ee is
slightly higher in both cases if the ortho-methyl substituted
binaphthol is present, and the ee values are very similar.
The pivalic acid amide was also the best ligand in the
homogeneously catalyzed transformations, with a slightly
lower ee value (entry 4).
polymer-bound ligands for enantioselective Cu-catalyzed
conjugate addition reactions.
Our study provides a convincing example for the validity of
the concept that ligand optimization for asymmetric catalysis
by means of combinatorial and solid-phase chemistry is
feasible and efficient. By means of the developed method-
ology a library of 78 ligands was readily synthesized and
screened for performance.
In the screening reported herein, ee values ranging from
3% to 67% were determined; the best ligand showed much
better enantioselectivity than the oxa-bispidine phosphor-
amidite which served as guiding structure for library develop-
ment.
These results open up and indicate the application of our
approach to much broader ligand development both for
conjugate addition reactions and the use of phosphoramidite
ligands in other enantioselective transformations.
Also, the observation that an ortho-methyl group in the
binaphthol substituent leads to a reduction of the enantiose-
lectivity is recorded in the homogeneous case, and once more
the ee values are fairly similar (entries 5 and 6).
Experimental Section
General remarks: Melting points were determined in open capillaries using
a B¸chi 540 apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker AC250, AM400, DRX500, or Varian Mercury400
spectrometer at room temperature. IR spectra were recorded on a Bruker
IFS88 spectrometer. Mass spectra, high-resolution mass spectra (HRMS)
and fast-atom-bombardement mass spectra (FAB) were measured on a
Finnigan MAT MS70 spectrometer. Specific optical rotation values were
determined with a Perkin Elmer polarimeter 341. For gas chromatog-
raphy a Hewlett Packard 5890 SeriesII gas chromatograph with FID
detector and a capillary column FS Lipodex E (Macherey Nagel) was
used.
Conclusion
We have successfully established a method for the combina-
torial development of chiral ligands for Cu-catalyzed enan-
tioselective conjugate addition reactions to enones. An
important feature of this method is that ligand optimization
on the solid phase correctly mirrors the results obtained with
the analogous ligands in homogeneous solution. In addition,
ligand generation on the solid support in this case was much
more advantageous than the synthesis and isolation of the
soluble ligands. Thus, in the case described here the use of the
immobilized ligands appears to be more advantageous. This is
the first case of a development and successful use of chiral
Bispidines with N-acyl groups show splitting of all signals in NMR. This
phenomenon was already described in the literature[28] and is due to the
hindered rotation of the nitrogen substituents.
Solvents were dried by standard methods and used immediately or stored
over molecular sieves. For column chromatography silica gel (40 64 mm,
Baker or Fluka) or Florisil (Fluka) were used. Commercial reagents were
used without further purification except for PCl3 which was distilled. (R)-
1,1'-Binaphthyl-2,2'-diol was purchased from Merck and diethylzinc (1.1m
4774
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Chem. Eur. J. 2002, 8, No. 2 0

Chiral Phosphoramidite Ligands
4767 4780
in toluene) was purchased from Fluka. Pd/C (10%) was donated by
Degussa AG.
Disubstituted 2,2'-dihydroxy-[1,1']-binaphthyls[27, 30] were prepared accord-
7-(tert-Butyloxycarbonyl)-9-(4'-methoxycarbonylbutylidene)-3-oxa-7-aza-
bicyclo[3.3.1]-nonane (8): EEDQ (236 mg, 0.95 mmol) was added to a
solution of carboxylic acid 7 (259 mg, 0.80 mmol) in methanol (8 mL) and
the mixture was stirred at room temperature overnight. After evaporation
of the solvent in vacuo the residue was taken up in ethyl acetate (10 mL)
and extracted with 1n HCl (3 Â 5 mL). The organic layer was dried over
MgSO4 and the solvent was evaporated in vacuo. The residue was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate 5:2to
yield an oil (221 mg, 0.65 mmol, 82%). Rf ˆ 0.38 (cyclohexane/ethyl acetate
5:2); 1H NMR (CDCl3, 400 MHz, mixture of isomers): d ˆ 5.26, 5.25 (t, J ˆ
ing to literature methods.
7-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one (5):[5, 22] A solution of tet-
rahydropyran-4-one (0.92mL, 5.0 mmol), benzylamine (1.11 g, 10.3 mmol)
and acetic acid (0.57 mL, 10.0 mmol) in dry methanol (20 mL) was added
over a period of 1 hto a suspension of coarse-grained paraformaldehyde
(0.66 g, 22.1 mmol) in dry methanol (20 mL) at 658C. Another portion of
paraformaldehyde (0.66 g, 22.1 mmol) was added and the mixture was
stirred for 1 h at 658C. After cooling water (200 mL) and 1n KOH solution
(10 mL) were added, and the aqueous phase was extracted with diethyl
ether (3 Â 100 mL). The combined organic layers were dried over MgSO4
and the solvent was evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (n-hexane/ethyl acetate 2:1) to yield an oil
(1.74 g, 7.52 mmol, 75%) {ref. [22]: 39%}. Rf ˆ 0.37 (n-hexane/ethyl acetate
2:1); 1H NMR (CDCl3, 400 MHz): d ˆ 7.36 7.24 (m, 5H; arom. H), 4.22 (d,
J ˆ 11 Hz, 2H; CH2eqO), 3.89 (dd, J ˆ 11 Hz, J ˆ 3 Hz, CH2axO), 3.57 (s,
2H; CH2Ph), 3.13 (dd, J ˆ 11.5 Hz, J ˆ 3 Hz CH2eqN), 2.95 (dd, J ˆ 11.5 Hz,
J ˆ 6 Hz, CH2axN), 2.53 (br, 2H; CH).
ˆ
7 Hz, 1H (isomers); CH ), 4.48 (t, J ˆ 13 Hz, 1H; CH2eqN), 4.31 (dd, J ˆ
13 Hz, J ˆ 8 Hz, 1H; CH2eqN), 4.13 (t, J ˆ 9 Hz, 1H; CH2eqO), 4.07 (dd, J ˆ
11 Hz, J ˆ 5 Hz, 1H; CH2eqO), 3.70 3.58 (m, 2H; CH2axO), 3.67 (s, 3H;
CH3OCO), 3.08 (t, J ˆ 13 Hz, 1H; CH2axN), 2.98 (m, 1H; CH2axN), 2.53 (m,
1H; CHCH2O), 2.33 (t, J ˆ 7 Hz, 2H; CH2COO), 2.12 2.03 (m, 3H;
ˆ
CHCH2O, CH2CH2COO), 1.71 (dt, J ˆ 8 Hz, 2H; CH2CH ), 1.47 (s, 9H;
(CH3)3C); 13C NMR (CDCl3, 100.6 MHz, mixture of isomers): d ˆ 174.1
ˆ
ˆ
(COOCH3), 155.5, 155.4 (C O urethane), 139.70, 139.67 (C CH), 118.9,
ˆ
118.8 (CH C), 79.5 (C(CH3)3), 74.31, 74.25, 73.5, 73.4 (CH2O), 51.7
ˆ
(CH3OCO), 51.1, 50.4, 50.2, 49.4 (CH2N), 42.4, 42.3, 35.6, 35.5 (CHC ),
ˆ
33.5, 33.4 (CH2COO), 28.7 ((CH3)3C), 26.0 (CH2CH ), 25.4
(CH2CH2COO); IR (KBr): nÄ ˆ 2849 (Bohlmann-band),[29] 1738,
7-(tert-Butyloxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-one
(6):
1694 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 340 (20) [M‡H] , 338
‡
1-Chloroethylchloroformate (306 mL, 2.81 mmol) was added at 08C to a
solution of bispidinone 5 (500 mg, 2.16 mmol) in CH2Cl2 (20 mL). After
slowly warming to room temperature the mixture was refluxed for 2h. All
volatiles were removed in vacuo and the resulting oil was taken up in
methanol (20 mL) and refluxed for 1 h. The solvent was evaporated and the
solid residue was taken up in 1n KOH solution (10 mL) and dioxane
(10 mL). To this mixture was added Boc2O (708 mg, 3.24 mmol) and it was
stirred overnight. The mixture was extracted with diethyl ether (3 Â
30 mL). The combined organic layers were dried over MgSO4 and the
solvent was evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 2:1) to yield a
solid (456 mg, 1.89 mmol, 87%). M.p. 86 878C; Rf ˆ 0.35 (cyclohexane/
ˆ
‡
‡
‡
(15) [M À H] , 240 (100) [M À tBu‡H] , 238 (45) [M À tBu À H] ; HRMS
(FAB, 3-NBA): calcd for C18H30NO5: 340.2124, found: 340.2150.
9-(4'-Methoxycarbonylbutylidene)-3-oxa-7-azabicyclo[3.3.1]nonane-7-[(R)-
binaphthyl-2,2'-diyl]phosphite (11): Trifluoroacetic acid (1 mL) was added
to a solution of Boc-bispidine derivative 8 (108 mg, 0.32mmol) in CH 2Cl2
(1 mL) and the solution was stirred at room temperature for 30 min. After
evaporation of the solvent and additional coevaporation with toluene the
residue was dissolved in toluene (3 mL) and treated with triethylamine
(400 mL, 2.9 mmol). To this solution was added dropwise a solution of (R)-
[binaphthyl-2,2'-diyl]-chlorophosphite 10 (151 mg, 0.43 mmol) in toluene
(1 mL) at room temperature and the mixture was stirred overnight at 808C.
The mixture was filtered and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on Florisil (pre-treated with
triethylamine; cyclohexane/CH2Cl2 2:1, 2% Et 3N) to yield a mixture of
diastereomers as a solid (72mg, 0.13 mmol, 41%). M.p. 105 106 8C;
Rf ˆ 0.9 (CH2Cl2/Et3N 10:1); 1H NMR (CDCl3, 400 MHz, mixture of
diastereomers): d ˆ7.96 (d, J ˆ9 Hz, 1H; arom. H), 7.92 7.87 (m, 3H; arom.
H), 7.56 (dd, J ˆ 9 Hz, J ˆ 3 Hz, 1H; arom. H), 7.44 7.33 (m, 5H; arom. H),
1
ethyl acetate 2:1); H NMR (CDCl3, 400 MHz): d ˆ 4.83 (d, J ˆ 14 Hz, 1H;
CH2eqN), 4.62(d, J ˆ 14 Hz, 1H; CH2eqN), 4.41 (d, J ˆ 11 Hz, 1H; CH2eqO),
4.34 (d, J ˆ 11 Hz, 1H; CH2eqO), 3.93 (d, J ˆ 11 Hz, 1H; CH2axO), 3.88 (d,
J ˆ 11 Hz, 1H; CH2axO), 3.35 (d, J ˆ 14 Hz, 1H; CH2axN), 3.22 (d, J ˆ
14 Hz, 1H; CH2axN), 2.39 (s, 1H; CH), 2.35 (s, 1H; CH), 1.50 (s, 9H;
13
ˆ
(CH3)3C); C NMR (CDCl3, 100.6 MHz): d ˆ 210.9 (CHC O), 155.3
ˆ
(C O urethane), 80.5 (C(CH3)3), 74.2, 74.2 (CH2O), 50.7 (CH2N), 50.6, 50.3
(CH), 49.9 (CH2N), 28.6 ((CH3)3C); IR (KBr): nÄ ˆ 2856 (Bohlmann-
ˆ
7.30 7.22 (m, 2H; arom. H), 5.22, 5.17 (t, J ˆ 3 Hz, 1H (isomers); CH ),
band),[29] 1738, 1671 (C O); MS (EI, 70 eV): m/z (%): 241 (40) [M] , 185
‡
ˆ
4.08 (d, J ˆ 10 Hz, 1H; CH2eqO), 3.99 (t, J ˆ 10 Hz, 1H; CH2eqO), 3.76 3.45
(m, 5H; CH2axO, CH2N(3)), 3.67, 3.64 (s, 3H (isomers); CH3OCO), 3.28
3.19 (m, 1H; CH2N), 2.57 2.51 (m, 1H; CHCH2O), 2.33, 2.30 (t, J ˆ 8 Hz,
2H (isomers); CH2COO), 2.11 2.08 (m, 1H; CHCH2O), 2.05, 1.98 (dt, J ˆ
‡
‡
(35) [M À tBu] , 141 (20) [M À Boc] ; HRMS (EI, 70 eV): calcd for
C12H19NO4: 241.1314, found: 241.1314.
7-(tert-Butyloxycarbonyl)-9-(4'-carboxybutylidene)-3-oxa-7-azabicy-
clo[3.3.1]nonane (7): Potassium-tert-butoxide (837 mg, 7.46 mmol) was
added in portions at 08C to a suspension of (4-carboxybutyl)-triphenyl-
phosphonium bromide (1.65 g, 3.73 mmol) in THF (30 mL). The suspen-
sion was warmed to room temperature and stirred for 30 min. After cooling
to 08C a solution of bispidinone 6 (300 mg, 1.24 mmol) in THF (10 mL) was
added slowly. The mixture was warmed to room temperature slowly and
stirred for 2h. The suspension was poured on sat. NH 4Cl solution (100 mL)
and extracted with chloroform (3 Â 50 mL). The combined organic layers
were dried over MgSO4 and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on silica gel (chloroform/
methanol 1%, then 2%) to yield an oil (293 mg, 0.90 mmol, 72%). Rf ˆ
0.30 (chloroform/methanol 3%); 1H NMR (CDCl3, 400 MHz, mixture of
ˆ
7 Hz, 2H (isomers); CH2CH2COO), 1.74 1.63 (m, 2H; CH2CH );
13C NMR (CDCl3, 100.6 MHz, mixture of diastereomers): d ˆ 174.1
ˆ
(COOCH3), 148.4, 148.3, 147.3, 147.2(arom. C), 138.7 ( C CH), 132.54,
132.47, 132.0, 131.6 (arom. C), 131.4, 131.0, 128.7, 127.5, 127.2, 126.9, 126.8,
125.8, 125.7 (arom. CH), 123.9, 123.5 (arom. C), 121.6, 121.5 (arom. CH),
ˆ
119.9, 119.8 (CH C), 73.7, 73.6, 72.9, 72.8 (CH2O), 52.1 (CH2N), 51.8
ˆ
(CH3OCO), 51.5, 50.8, 50.7 (CH2N), 42.0, 35.3, 35.2 (CHC ), 33.51, 33.49
(CH2COO), 26.0 (CH2CH ), 25.36, 25.32 (CH2CH2COO); 31P NMR
ˆ
(CDCl3, 202.5 MHz): d ˆ 148.5; IR (KBr): nÄ ˆ 2852 (Bohlmann-band),[29]
1736 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 554 (90) [M‡H] , 315 (35)
‡
ˆ
‡
‡
[PBINOL] , 240 (10) [M À PBINOL‡H] ; HRMS (FAB, 3-NBA): m/z
(%): calcd for C33H32NO5P: 554.2096, found: 554.2075.
ˆ
isomers): d ˆ 5.27, 5.26 (t, J ˆ 7 Hz, 1H (isomers); CH ), 4.47 (t, J ˆ 13 Hz,
General procedure for the synthesis of the (3,3'-disubstituted) (R)-
[binaphthyl-2,2'-diyl]-chlorophosphite 10a d:[24] A solution of (3,3'-dis-
ubstituted) 2,2'-dihydroxy-[1,1']-binaphthyl[27, 30] in THF was added over a
period of 30 min to a solution of PCl3 (1.3 equiv) and triethylamine
(2.05 equiv) in THF. The mixture was stirred at room temperature for
90 min. The precipitate was filtered off under argon and the solvent was
evaporated in vacuo. The residue was taken up in diethyl ether and filtered
again under argon. The solvent was evaporated in vacuo. The remaining
voluminous solid was obtained in almost quantitative yield and was used in
coupling procedures with bispidines without further purification.
1H; CH2eqN), 4.30 (t, J ˆ 11 Hz, 1H; CH2eqN), 4.14 (dd, J ˆ 10 Hz, J ˆ 7 Hz,
1H; CH2eqO), 4.07 (dd, J ˆ 10 Hz, J ˆ 4 Hz, 1H; CH2eqO), 3.70 3.58 (m,
2H; CH2axO), 3.09 (m, 1H; CH2axN), 2.99 (m, 1H; CH2axN), 2.54 (m, 1H;
CHCH2O), 2.36 (t, J ˆ 7 Hz, 2H; CH2COOH), 2.12 2.06 (m, 3H;
ˆ
CHCH2O, CH2CH2COOH), 1.71 (dt, J ˆ 7 Hz, 2H; CH2CH ), 1.47 (s,
9H; (CH3)3C); 13C NMR (CDCl3, 100.6 MHz, mixture of isomers): d ˆ
ˆ
ˆ
178.7, 178.6 (COOH), 155.6, 155.55 (C O urethane), 139.6 (C CH), 118.9
ˆ
(CH C), 79.8 (C(CH3)3), 74.3, 74.2, 73.5, 73.4 (CH2O), 51.1, 50.4, 50.1, 49.4
ˆ
(CH2N), 42.3, 42.2, 35.6, 35.4 (CHC ), 33.5 (CH2COOH), 28.7 ((CH3)3C),
ˆ
25.9 (CH2CH ), 25.2 (CH2CH2COOH); IR (KBr): nÄ ˆ 2851 (Bohlmann-
band),[29] 1694 cmÀ1 (C O); MS (FAB, glycerol): m/z (%): 326 (5) [M‡H] ,
Proof of the formation of the phosphoramidites by cleavage from the solid
support: A solution of methanol (0.5 mL), trifluoroacetic acid (0.1 mL) and
CH2Cl2 (2mL) was added to the phosphoramidite resin 12 (53 mg,
‡
ˆ
‡
226 (45) [M À Boc‡H] ; HRMS (FAB, glycerol): calcd for C17H28NO5:
326.1967, found: 326.1951.
Chem. Eur. J. 2002, 8, No. 20
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0820-4775 $ 20.00+.50/0
4775

H. Waldmann et al.
FULL PAPER
0.52mmolg À1, 0.028 mmol) in a syringe reactor. The mixture was shaken
for 1 h. The liquid phase was separated and the resin was washed with
CH2Cl2 (2 Â ). The combined organic layers were evaporated in vacuo
7.21 (m, 5H; arom. H), 5.24 (t, J ˆ 8 Hz, 1H; CH ), 4.29 4.19 (m, 1H; cycl.
NCH2), 4.12 4.02 (m, 1H; cycl. NCH 2), 3.53 3.38 (m, 2H; NCH2Ph),
3.10 2.90 (m, 4H; cycl. NCH2), 2.74 2.67 (m, 1H; CHCH2N), 2.40 2.22
(m, 3H; CHCH2N and cycl. NCH2), 2.33 (t, J ˆ 9 Hz, 2H; CH2COOH),
ˆ
to yield
a colourless solid, 2,2'-dihydroxy-[1,1']-binaphthyl (7.7 mg
(0.027 mmol, 98%). 1H NMR (CDCl3, 400 MHz): d ˆ 7.98 (d, J ˆ 11 Hz,
2H; arom. H), 7.90 (d, J ˆ 11 Hz, 2H; arom. H), 7.40 7.28 (m, 6H; arom.
H), 7.16 (d, J ˆ 10 Hz, 2H; arom. H), 4.83 (brs, 2H; OH).
Addition of diethylzinc to cyclohexen-2-one with soluble ligands, 3-ethyl-
cyclohexanone: The phosphoramidite ligand (0.033 mmol) was added as a
2.09 2.03 (m, 2H; CH2CH ), 1.70 (dt, J ˆ 7 Hz, 2H; CH2CH2COOH), 1.50
ˆ
(s, 9H; (CH3)3C); 13C NMR (CDCl3, 100.6 MHz): d ˆ 178.8 (COOH), 155.3
ˆ
ˆ
(C O urethane), 139.8 (C CH), 138.0 (arom. C), 129.1, 128.4, 127.2 (arom.
ˆ
CH), 119.8 (CH C), 79.5 (C(CH3)3), 62.7 (CH2Ph), 60.0, 59.3 (CH2N(7),
51.0, 50.2, 49.4 (CH2N(3), 40.81 (CHC ), 34.0 (CH2COOH), 33.5 (CHC ),
ˆ
ˆ
ˆ
22.9 ((CH3)3C), 26.3 (CH2CH ), 25.3 (CH2CH2COOH); IR (KBr): nÄ ˆ
solid to
a suspension of copper(ii)trifluoromethanesulfonate (11 mg,
2797 (Bohlmann-band),[29] 1693 cmÀ1 (C O); MS (FAB, glycerol): m/z (%):
ˆ
0.030 mmol) in a mixture of toluene/CH2Cl2 (3.5 mL, 6:1). The mixture
was stirred for 1 h at room temperature and cooled to the indicated
temperature. Then cyclohexen-2-one (96 mL, 1.0 mmol) and diethylzinc
(1.2mL, 1 m solution in toluene, 1.2mmol) were added. The yellow,
heterogeneous reaction mixture was stirred for 2h at the indicated
temperature. Then 1n HCl (5 mL) was added and the mixture was stirred
for 30 min thoroughly. The mixture was extracted with diethyl ether (3 Â
15 mL). The combined organic layers were dried over MgSO4, filtered and
the solvent was evaporated in vacuo with caution. The residue was
chromatographed on silica gel with pentane/diethyl ether and the product
was obtained as a colourless liquid.
‡
‡
‡
415 (85) [M‡H] , 413 (15) [M À H] , 359 (40) [M À tBu‡H] , 357 (20)
‡
‡
[M À tBu À H] , 315 (10) [M À Boc‡H] , 91 (70); HRMS (FAB, glycerol):
calcd for C24H35N2O4: 415.2600, found: 415.2624.
3-(tert-Butyloxycarbonyl)-9-(4'-carboxybutyl)-7-(9''-fluorenylmethyloxy-
carbonyl)-3,7-diazabicyclo[3.3.1]nonane (20): PD/C (10%, 150 mg) was
added to a solution of bispidine derivative 19 (338 mg, 0.815 mmol) in
ethanol (7 mL). The atmosphere was exchanged for hydrogen three times.
The suspension was stirred overnight, filtered over Celite and evaporated
in vacuo. The residual oil was taken up in a suspension of 1n NaHCO3
(5 mL) and THF (2.5 mL) and cooled to 08C. To this suspension was added
dropwise a solution of Fmoc-Cl (316 mg, 1.22 mmol) in THF (2.5 mL).
After warming to room temperature the suspension was stirred overnight.
The pH was lowered to 3 with 1n HCl and the solution was extracted with
chloroform (3 Â 40 mL). The combined organic layers were dried over
MgSO4 and the solvent was evaporated in vacuo. The residue was purified
by flash chromatography on silica gel (n-hexane/ethyl acetate 3:1, 1%
acetic acid) to yield an oil (309 mg, 0.563 mmol, 69%). Rf ˆ 0.32(cyclo-
hexane/ethyl acetate 3:1, 1% acetic acid); 1H NMR (CDCl3, 400 MHz,
mixture of diastereomers): d ˆ 7.75 (d, J ˆ 7 Hz, 2H; Fmoc-CH), 7.63 (d,
J ˆ 7 Hz, 1H; Fmoc-CH), 7.56 (d, J ˆ 7 Hz, 1H; Fmoc-CH), 7.38 (t, J ˆ
7 Hz, 2H; Fmoc-CH), 7.31 (t, J ˆ 7 Hz, 2H; Fmoc-CH), 4.34 3.90 (m, 7H;
Fmoc-CH2, Fmoc-CH, cycl. NCH2eq), 3.28 2.95 (m, 4H; cycl. NCH2ax),
2.36 (t, J ˆ 7 Hz, 2H; CH2COOH), 1.74 1.62(m, 5H; C HCH (3H),
The results with ligand 8 and ligand 32 are given as representative
examples.
a) with ligand 8: Yield: 95%, 46% ee, (R)-enantiomer predominating,
[a]2D0 ˆ ‡10.6 (c ˆ 1.5, CHCl3), {ref. [31]: positive for (R)-enantiomer}.
b) with ligand 32: Yield: 96%, 64% ee, (R)-enantiomer predominating,
[a]2D0 ˆ ‡12.5 (c ˆ 1.0, CHCl3), {ref. [31]: positive for (R)-enantiomer}.
General data: Rf ˆ 0.35 (pentane/diethyl ether 7:1); 1H NMR (CDCl3,
250 MHz): d ˆ 2.48 2.18 (m, 3H), 2.12 1.85 (m, 3H), 1.76 1.55 (m, 2H),
3
1.43 1.26 (m, 3H), 0.91 (t, J ˆ 9 Hz, 3H, CH3); GC (1008C, isothermal):
tR ˆ 16.7 min [(R)-enantiomer], tR ˆ 17.4 min [(S)-enantiomer].
3-(tert-Butyloxycarbonyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonan-9-one
(18): A solution of 1-Boc-piperidin-4-one (2.00 g, 10.0 mmol), benzylamine
(1.11 g, 10.3 mmol) and acetic acid (0.57 mL, 10.0 mmol) in dry methanol
(50 mL) was added dropwise over a period of 1 h at 658C to a suspension of
coarse-grained paraformaldehyde (0.66 g, 22.1 mmol) in dry methanol
(40 mL). Another portion of paraformaldehyde (0.66 g, 22.1 mmol) was
added and the mixture was stirred for 1 h at 658C. After cooling water
(400 mL) and 1n KOH solution (20 mL) was added and the aqueous phase
was extracted with diethyl ether (3 Â 200 mL). The combined organic layers
were dried over MgSO4 and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on silica gel (n-hexane/ethyl
acetate 3:1) to yield an oil (2.63 g, 7.96 mmol, 79%). Rf ˆ 0.35 (n-hexane/
ethyl acetate 3:1); 1H NMR (500 MHz, CDCl3): d ˆ 7.35 7.24 (m, 5H;
arom. H), 4.58 (d, J ˆ 13 Hz, 1H; CH2eqN(3), 4.41 (d, J ˆ 13 Hz, 1H;
CH2eqN(3), 3.54 (d, J ˆ 13 Hz, 1H; NCH2Ph), 3.48 (d, J ˆ 13 Hz, 1H;
NCH2Ph), 3.36 (d, J ˆ 13 Hz, 1H; CH2axN(3)), 3.28 (d, J ˆ 13 Hz, 1H;
CH2axN(3), 3.19 (d, J ˆ 11 Hz, 1H; CH2eqN(7), 3.15 (d, J ˆ 11 Hz, 1H;
CH2eqN(7), 2.72 (d, J ˆ 10 Hz, 1H; CH2axN(7), 2.66 (d, J ˆ 10 Hz, 1H;
CH2CH2COOH),
1.57 1.31
(m,
4H;
CH2(CH2)2COOH,
CH2(CH2)3COOH), 1.45 (s, 9H; (CH3)3C); 13C NMR (CDCl3,
100.6 MHz, mixture of diastereomers): d ˆ 178.6 (COOH), 155.8, 155.3,
ˆ
155.0 (C O urethane), 144.8, 144.2, 141.6, 141.4 (quart., Fmoc), 127.8, 127.7,
127.3, 125.6, 125.3, 120.1 (Fmoc-CH), 79.9 (C(CH3)3), 67.7 (Fmoc-CH2),
50.9, 50.8 (CH2NBoc), 47.5 (Fmoc-CH), 43.3, 42.3 (CH2NFmoc), 38.3
(CHCH2N), 34.1 (CH2COOH), 31.8 (CH2(CH2)4COOH), 30.3
(CH2(CH2)3COOH), 28.6 ((CH3)3C), 26.5 (CH2(CH2)2COOH), 25.0
(CH2CH2COOH); IR (KBr): nÄ ˆ 2866 (Bohlmann-band),[29] 1708 cmÀ1
‡
ˆ
(C O); MS (FAB, glycerol): m/z (%): 547 (3) [M À H] , 493 (10) [M À
‡
tBu‡H] ; HRMS (FAB, glycerol): calcd for C32H41N2O4: 549.2965, found:
549.2978.
Coupling of ligand precursors to the solid phase
a) Boc-oxa-bispidine system 9: A solution of Boc-oxa-bispidine acid 7
(210 mg, 0.645 mmol), N,N'-diisopropylcarbodiimde (133 mL, 0.859 mmol)
and DMAP (10 mg, 0.082mmol) in CH 2Cl2 (8 mL) was added to
hydroxymethylpolystyrene (495 mg, 0.87 mmolgÀ1, 0.431 mmol) in a sy-
ringe reactor. The reactor was shaken overnight, and the resin was washed
with CH2Cl2 (3 Â ) and dried in vacuo. The yield of the anchoring reaction
was determined from the total mass of the resin after the procedure (for
different loadings of the resin, the amount of Boc-oxa-bispidine acid 7 was
increased or lowered accordingly). Yield: 590 mg (71%, equals
0.52mmolg À1).
CH2axN(7), 2.44 (s, 3H; CHCH2N), 2.40 (s, 3H; CHCH2N), 1.54 (s,
13
ˆ
(CH3)3C); C NMR (CDCl3, 125.8 MHz): d ˆ 213.5 (CHC O), 154.7
ˆ
(C O urethan), 137.4 (arom. C), 128.7, 128.3, 127.2 (arom. CH), 80.0
(C(CH3)3), 61.8 (CH2Ph), 59.0, 58.7 (CH2N(7)), 50.5, 49.8 (CH2N(3)), 47.6
[29]
ˆ
(CHC O), 28.6 (CH3)3C); IR (drift): nÄ ˆ 2801 (Bohlmann-band), 1734,
1695 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 331 (65) [M‡H] , 329 (50)
‡
ˆ
‡
‡
‡
[M À H] , 275 (35) [M À tBu‡H] , 273 (55) [M À tBu À H] , 91 (100);
HRMS (FAB, 3-NBA): calcd for C19H27N2O3: 331.2022, found: 331.2035.
3-(tert-Butyloxycarbonyl)-7-benzyl-9-(4'-carboxybutylidene)-3,7-diazabi-
cyclo[3.3.1]-nonane (19): Potassium-tert-butoxide (1.36 g, 12.1 mmol) was
added in portions at 08C to a suspension of (4-carboxybutyl)-triphenyl-
phosphonium bromide (2.68 g, 6.05 mmol) in THF (60 mL). The suspen-
sion was warmed to room temperature and stirred for 30 min. After cooling
to À208C a solution of bispidinone 18 (500 mg, 1.51 mmol) in THF (10 mL)
was added slowly. The mixture was warmed to room temperature slowly
and stirred for 2.5 h. The suspension was poured on sat. NH4Cl solution
(150 mL) and extracted with chloroform (3 Â 50 mL). The combined
organic layers were dried over MgSO4 and the solvent was evaporated in
vacuo. The residue was purified by flash chromatography on silica gel
(chloroform/methanol 20:1) to yield an oil (424 mg, 1.02 mmol, 68%). Rf ˆ
0.23 (chloroform/methanol 20:1); 1H NMR (CDCl3, 400 MHz): d ˆ 7.35
b) Boc-Fmoc-bispidine system 21: A solution of Boc-Fmoc-bispidine
acid 20 (395 mg, 0.720 mmol), N,N'-diisopropylcarbodiimde (143 mL,
0.919 mmol) and DMAP (10 mg, 0.082mmol) in CH 2Cl2 (8 mL) was added
to hydroxymethylpolystyrene (480 mg, 0.87 mmolgÀ1, 0.418 mmol) in a
syringe reactor. The reactor was shaken overnight and the resin was washed
with DMF (2 Â ) and CH2Cl2 (3 Â ) and dried in vacuo. Yield: 690 mg (94%,
equals 0.61 mmolgÀ1).
Loading according to UV absorption of fulvene/piperidine adduct after
cleavage of the Fmoc group: 0.58 mmolgÀ1
.
c) Capping: Capping was performed twice for 10 min with each a mixture
of acetic anhydride, pyridine and CH2Cl2 (1:2:2). The resin was washed with
CH2Cl2 (5 Â ) and dried in vacuo.
4776
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0820-4776 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 2 0

Chiral Phosphoramidite Ligands
4767 4780
Synthesis of phosphoramidite ligands on solid support: The following
general procedures were used as required for the synthesis of the individual
ligand system on solid support.
shaken for 1 h and washed with THF (2 Â ). To the resin was added a
solution of (R)-2,2'-dihydroxy-[1,1']-binaphthyl (46 mg, 0.16 mmol) and
triethylamine (44 mL, 0.32mmol) in THF (2mL). The mixture was shaken
overnight and washed with DMF (2 Â ) and CH2Cl2 (4 Â ) and dried in
vacuo.
a) Cleavage of the Fmoc protecting group: A mixture of DMF and
piperidine (4:1, 2mL) was added to Boc-Fmoc-bispidine resin 21 (55 mg,
0.032mmol) in a syringe reactor, and the mixture was shaken for 15 min.
The resin was washed with CH2Cl2 (3 Â ) and dried in vacuo.
Conjugate addition with polymer-bound ligands: 3-Ethylcyclohexanone: A
solution of copper(ii)-trifluoromethanesulfonate (63 mg, 0.175 mmol) in
CH2Cl2 (3 mL) and DMF (0.1 mL) was added to the phosphoramidite resin
(0.032mmol) in a syringe reactor. The mixture was shaken for 1 h and
washed with a mixture of CH2Cl2/DMF (3:0.1, 1 Â ) and CH2Cl2 (5 Â ).
After drying in vacuo a light brown to deep green resin was obtained.
b) Acylation: To the resin after Fmoc-cleavage (0.032mmol) in a syringe
reactor, was added either [i) acid anhydride (0.16 mmol) and DMAP (2mg,
0.016 mmol) in pyridine/CH2Cl2 (1.5 mL, 1:1) or ii) acid chloride
(0.16 mmol) and DMAP (2mg, 0.016 mmol) in pyridine/CH 2Cl2 (2mL,
1:1) or iii) acid (0.16 mmol, activated with HATU (55 mg, 0.14 mmol) and
iPr2EtN (60 mL, 0.35 mmol) in CH2Cl2 (1.5 mL) for 30 min] and shaken
overnight. The resin was washed with DMF (2 Â ) and CH2Cl2 (4 Â ).
To this resin (0.032mmol) in a round-bottomed flask under argon was
added a mixture of toluene (2.4 mL) and CH2Cl2 (0.4 mL) and the mixture
was stirred slowly for 15 min at 08C.
c) Urea and thiourea groups: To the resin after Fmoc cleavage
To this mixture was added cyclohexen-2-one (77 mL, 0.80 mmol) and
diethylzinc (0.96 mL, 1m solution in toluene, 0.96 mmol). The yellow,
heterogeneous reaction mixture was stirred for 2h at 0 8C. Then 1n HCl
(5 mL) was added and the mixture was stirred for 30 min thoroughly. The
mixture was transferred to a separation funnel and extracted with diethyl
ether (3 Â 10 mL). The combined organic layers were dried over MgSO4,
filtered and examined by gas chromatography.
(0.032mmol) in
a syringe reactor, was added a solution of phenyl
isocyanate (0.16 mmol, 19 mg) and phenyl isothiocyanate (0.16 mmol,
21.6 mg) in CH2Cl2 (2mL). The reaction mixture was shaken for overnight
and washed with DMF (3 Â ) and CH2Cl2 (5 Â ).
d) Reductive amination: To the resin after Fmoc cleavage (0.032mmol) in
a syringe reactor, was added the aldehyde (10 equiv, 0.32mmol) and
NaCNBH3 (0.64 mmol, 40 mg) in a mixture of methanol/CH2Cl2 (2mL,
1.5:1). The mixture was shaken overnight and washed with methanol (2 Â ),
methanol/CH2Cl2 (1:1) and CH2Cl2 (4 Â ).
e) Tosylation, phosphorylation: To the resin after Fmoc cleavage
(0.032mmol) in a syringe reactor, was added either [i) a solution of
toluene-4-sulfonyl chloride (0.16 mmol, 30.5 mg), ii) a solution of chlor-
odiphenylphosphine (0.16 mmol, 30 mL) or iii) a solution of phosphoric
acid diphenylester chloride (0.16 mmol, 33 mL)] and triethylamine
(0.22 mmol, 31 mL) in CH2Cl2 (1.5 mL) (for chlorodiphenylphosphine:
toluene instead of CH2Cl2). The mixture was shaken overnight and washed
with DMF (2 Â ) and CH2Cl2 (4 Â ).
f) Amino acids: After Fmoc cleavage to the resin (0.032mmol) in a syringe
reactor, was added a solution of Fmoc-amino acid (0.16 mmol), HBTU
(0.16 mmol, 60.6 mg), HOBT (0.16 mmol, 21.6 mg) and DIPEA
(0.16 mmol, 20 mg) in CH2Cl2/DMF (2mL, 1:1) and the mixture was
shaken for 3 h. The resin was washed with DMF (3 Â ) and CH2Cl2 (5 Â )
and dried in vacuo.
Below all results obtained with different ligands are presented in tabulated
form. The coding of the different ligands is explained in Figure 1 4 (see
Results and Discussion). Analytical data of the products are given above
(Table 3).
Table 3. Analytical data for the different products.
Compound Con-
version [%]
ee [%] Compound
Con-
version [%]
ee [%]
A1-B1-C1
A1-B2-C1
A1-B3-C1
A1-B4-C1
A1-B5-C1
A1-B6-C1
A1-B7-C1
A1-B8-C1
A1-B9-C1
94
11
39
44
29
21
35
27
23
21
18
11
32
38
31
35
21
12
19
29
56
51
19
27
7
A1-B24-C1
A1-B25-C1
A1-B26-C1
A1-B27-C1
A1-B28-C1
A2-C1
A2-C2
A2-C3
A2-C4
A3-C1
A4-C1
A4-C2
A4-C3
A5-C1
A1-B3-C2
A1-B3-C3
A1-B3-C4
A1-B13-C2
A1-B13-C3
A1-B13-C4
A1-B20-C2
A1-B26-C2
84
33
36
50
38
41
39
45
39
36
18
36
32
30
29
67
quant.
quant.
quant.
quant.
83
81
quant.
74
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
77
quant.
94
quant.
97
The yield was quantitative, as determined by Fmoc-cleavage. The Fmoc
group was again deprotected and the amino acid was treated with i) Ac2O
(0.16 mmol, 16.3 mg) and DMAP (0.016 mmol, 2mg) in pyridine/CH 2Cl2
(2mL, 1:1), ii) methanesulfonyl chloride (0.16 mmol, 18.2mg), iii) benze-
nesulfonyl chloride (0.16 mmol, 28 mg) or iv) toluene-4-sulfonyl chloride
(0.16 mmol, 30.5 mg) and DIPEA (0.32mmol). The reaction mixture was
shaken for overnight and washed with DMF (2 Â ) and CH2Cl2 (4 Â ).
g) Dipeptides: In a syringe reactor, the Fmoc group of the amino acid
derivatives as described above was removed and treated again with another
Fmoc-amino acid (0.16 mmol) as mentioned above. After subsequent Fmoc
removal, the liberated amine was treated with Ac2O, methanesulfonyl
chloride or toluene-4-sulfonyl chloride (0.16 mmol) as described above.
The resin was washed with DMF (3 Â ) and CH2Cl2 (5 Â ).
h) Cleavage of the Boc protecting group: To the resin from steps b) g)
(0.032mmol) or the Boc-oxa-bispidine resin 9 (0.032mmol) in a syringe
reactor, was added a solution of trifluoroacetic acid (1 mL) in CH2Cl2
(1 mL). The mixture was shaken for 30 min and washed with CH2Cl2 (5 Â ).
A solution of triethylamine (0.5 mL) in CH2Cl2 (2mL) was added and the
mixture was shaken for 15 min, washed with CH2Cl2 (5 Â ) and dried in
vacuo to yield the free amine base.
A1-B10-C1 quant.
A1-B11-C1 98
A1-B12-C1 quant.
A1-B13-C1 quant.
A1-B14-C1 quant.
A1-B15-C1 98
A1-B16-C1 97
A1-B17-C1 quant.
A1-B18-C1 quant.
A1-B19-C1 80
A1-B20-C1 quant.
A1-B21-C1 quant.
A1-B22-C1 78
A1-B23-C1 73
C1-AA1-D1 41
C1-AA2-D1 75
C1-AA3-D1 64
C1-AA4-D1 80
C1-AA5-D1 69
C1-AA1-D2 56
C1-AA2-D2 66
C1-AA3-D2 69
C1-AA4-D2 34
C1-AA5-D2 56
C1-AA6-D2 69
C1-AA1-D3 68
C1-AA2-D3 70
C1-AA3-D3 78
C1-AA14-D3 522
quant.
822
1
quant.
quant.
quant.
quant.
quant.
98
38
54
49
38
46
41
C1-AA5-D3
C1-AA6-D3
C1-AA1-D4
C1-AA2-D4
C1-AA3-D4
C1-AA4-D4
C1-AA5-D4
C1-AA7-D4
C1-AA1-AA3-D1 71
C1-AA2-AA3-D1 48
C1-AA1-AA3-D2 7215
C1-AA2-AA3-D2 84
C1-AA1-AA3-D4 83
C1-AA2-AA3-D4 83
65
61
76
63
90
78
65
80
3
20
30
24
34
23
12
29
12
7
11
10
7
6
5
13
15
9
i) Coupling to the phosphoramidite (bispidine and chlorophosphite): The
corresponding solid BINOL-chlorophosphite 10a, 10b, 10c or 10d
(0.16 mmol) was added under argon to the resin in a syringe reactor after
Boc cleavage (0.032mmol). Immediately a solution of triethylamine
(0.32mmol, 44 mL) in toluene (1.5 mL) was added and the mixture was
shaken overnight. The mixture was washed with DMF (2 Â ) and CH2Cl2
(4 Â ) and dried in vacuo.
3
13
31
25
23
14
19
21
j) Coupling to the phosphoramidite (bispidine and PCl3/BINOL):
A
solution of PCl3 (28 mL, 0.32mmol) in THF (1 mL) and a solution of
triethylamine (44 mL, 0.32mmol) in THF (1 mL) was added to the resin
(0.032mmol) in a syringe reactor after Boc cleavage. The mixture was
Chem. Eur. J. 2002, 8, No. 20
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0820-4777 $ 20.00+.50/0
4777

H. Waldmann et al.
FULL PAPER
3-(tert-Butyloxycarbonyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane
(26):
11 Hz, 1H; CH2axN(3), 2.51 (d, J ˆ 11 Hz, 1H; CH2axN(3), 2.42 (s, 3H;
CH3 Tos), 1.91 (brs, 2H; CHCH2N), 1.70 (m, 1H; CH2-bridge), 1.52(s, 9H;
(CH3)3C), 1.46 (m, 1H; CH2-bridge); 13C NMR (CDCl3, 100.6 MHz): d ˆ
Toluene-4-sulfonylhydrazide (584 mg, 3.14 mmol) and toluene-4-sulfonic
acid (64 mg, 0.34 mmol) was added to a suspension of bispidinone 18
(740 mg, 2.24 mmol) in DMF (12 mL). The mixture was heated to 1008C
for 10 min. Then sodium cyanoborohydride (704 mg, 11.2mmol) was added
and the mixture was further heated for 2h to 100 8C. After cooling, toluene
(100 mL) was added and the mixture was washed with water (50 mL), 1n
NaHCO3 solution (50 mL) and water (50 mL) and then dried over MgSO4.
The organic solvent was evaporated in vacuo and the residue was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to
yield a colourless oil (302mg 0.95 mmol, 43%). Rf ˆ 0.42(cyclohexane/
ethyl acetate 4:1). 1H NMR (CDCl3, 400 MHz): d ˆ 7.34 7.18 (m, 5H;
arom. H), 4.16 (d, J ˆ 13 Hz, 1H; CH2eqN(3), 3.99 (d, J ˆ 13 Hz, 1H;
CH2eqN(3), 3.43 (d, J ˆ 14 Hz, 1H; CH2Ph), 3.30 (d, J ˆ 14 Hz, 1H;
CH2Ph), 3.09 (d, J ˆ 13 Hz, 1H; CH2eqN(3), 3.04 (d, J ˆ 13 Hz, 1H;
CH2eqN(3), 2.98 (d, J ˆ 11 Hz, 1H; CH2eqN(7), 2.88 (d, J ˆ 11 Hz, 1H;
CH2eqN(7), 2.21 (d, J ˆ 11 Hz, 1H; CH2axN(7), 2.16 (d, J ˆ 11 Hz, 1H;
CH2axN(7), 1.86 (brs, 1H; CHCH2O), 1.78 (brs, 1H; CHCH2O), 1.68 1.58
(m, 2H; CH2-bridge), 1.59 (s, 9H; (CH3)3C); 13C NMR (CDCl3,
ˆ
155.5 (C O), 143.4, 132.6 (arom. C), 129.6, 128.0 (arom. CH), 79.8
(C(CH3)3), 50.5, 50.4 0 (CH2N(3)), 48.2, 47.3 (CH2N(7)), 30.3 (CH2-bridge),
28.7 ((CH3)3C), 27.9 (CHCH2N), 21.7 (CH3 Tos); IR (drift): nÄ ˆ 2838
(Bohlmann-band[29]), 1698 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 403
ˆ
‡
‡
(5) [M‡Na] , 381 (5) [M‡H] ; HRMS (EI, 70 eV): calcd for C19H29N2O4S:
381.1849, found: 381.1846.
7-(tert-Butyloxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]nonane (30): Toluene-
4-sulfonylhydrazide (259 mg, 1.39 mmol) and toluene-4-sulfonic acid
(28 mg, 0.23 mmol) were added to a solution of bispidinone 6 (240 mg,
0.99 mmol) in DMF (5 mL) and the mixture was heated for 10 min to
1008C. Then sodium cyanoborohydride (313 mg, 4.97 mmol) was added
and the mixture was further heated for 2h to 100 8C. After cooling toluene
(30 mL) was added and the mixture was washed with water (15 mL), 1n
NaHCO3 solution (15 mL) and water (15 mL) and dried over MgSO4. The
organic solvent was evaporated in vacuo and the residue was purified by
flash chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to yield
a colourless solid (108 mg, 0.47 mmol, 48%). M.p. 398C; Rf ˆ 0.34 (cyclo-
hexane/ethyl acetate 4:1); 1H NMR (CDCl3, 400 MHz): d ˆ 4.34 (d, J ˆ
13 Hz, 1H; CH2eqN), 4.19 (d, J ˆ 13 Hz, 1H; CH2eqN), 4.01 (d, J ˆ 11 Hz,
1H; CH2eqO), 3.95 (d, J ˆ 11 Hz, 1H; CH2eqO), 3.73 (d, J ˆ 11 Hz, 1H;
CH2axO), 3.70 (d, J ˆ 11 Hz, 1H; CH2axO), 3.14 (d, J ˆ 13 Hz, 1H; CH2axN),
3.04 (d, J ˆ 13 Hz, 1H; CH2axN), 1.95 1.91 (m, 1H; CHCH2O), 1.82 1.78
(m, 1H; CHCH2O), 1.67 (brs, 1H; CH2-bridge), 1.47 (brs, 1H; CH2-
bridge), 1.47 (s, 9H; (CH3)3C); 13C NMR (CDCl3, 100.6 MHz): d ˆ 155.5
ˆ
100.6 MHz): d ˆ 155.3 (C O), 139.2 (arom. C), 128.8, 128.3, 126.8 (arom.
CH), 78.9 (C(CH3)3), 63.7 (CH2Ph), 59.2, 59.0 (CH2N(7)), 48.6, 47.8
(CH2N(3)), 31.4 (CH2-bridge), 29.2 (CHCH2N), 28.9 ((CH3)3C); IR (KBr):
nÄ ˆ 2795 (Bohlmann-band[29]), 1692cm À1 (C O); MS (FAB, 3-NBA): m/z
ˆ
‡
‡
‡
(%): 317 (45) [M‡H] , 316 (60) [M] , 315 (35) [M À H] , 261 (45) [M À
‡
‡
‡
tBu‡H] , 260 (40) [M À tBu] , 259 (100) [M À tBu À H] , 215 (15) [M À
‡
Boc‡H] ; HRMS (FAB, 3-NBA): calcd for C19H28N2O2: 316.2151, found:
316.2169.
ˆ
(C O urethane), 79.3 (C(CH3)3), 72.3, 72.2 (CH2O), 49.0, 48.0 (CH2N), 31.2
3-(tert-Butyloxycarbonyl)-7-(2',2'-dimethylpropionyl)-3,7-diazabicy-
clo[3.3.1]nonane (28): Pd/C (250 mg, 10%) was added to a suspension of
bispidine 26 (241 mg, 0.76 mmol) in ethanol (5 mL). The atmosphere was
exchanged for hydrogen three times. The mixture was stirred overnight and
the progress of the reaction was checked by TLC. If some starting material
was still remaining further palladium on charcoal (250 mg) was added and
proceeded as above. The mixture was filtered over Celite and the solvent
was evaporated in vacuo. The residue was taken up in pyridine (7 mL) and
treated with DMAP (10 mg, 0.08 mmol) and pivaloyl anhydride (1.55 mL,
7.62mmol). The mixture was stirred overnight at room temperature. The
solvent was evaporated in vacuo and the residue was taken up in CH2Cl2
(30 mL). This mixture was washed once with 1n HCl (15 mL), 1n NaHCO3
(15 mL) and saturated NaCl solution (15 mL) and dried over MgSO4. The
solvent was evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate 2:1) to yield an
colourless oil (169 mg, 0.54 mmol, 71%). Rf ˆ 0.33 (cyclohexane/ethyl
acetate 2:1); 1H NMR (CDCl3, 400 MHz): d ˆ 4.54 (d, J ˆ 13 Hz, 1H;
CH2eqN(3), 4.34 (d, J ˆ 13 Hz, 1H; CH2eqN(3), 4.20 (d, J ˆ 12Hz, 1H;
CH2eqN(7), 4.07 (d, J ˆ 12Hz, 1H; CH 2eqN(7), 3.21 2.96 (m, 4H; CH2N),
1.94 (brs, 2H; CHCH2N), 1.83 1.74 (m, 2H; CH2-bridge), 1.42(s, 9H;
(CH3)3C, Boc), 1.27 (s, 9H; (CH3)3C, Piv); 13C NMR (CDCl3, 100.6 MHz):
(CH2-bridge), 29.7, 29.6 (CHCH2O), 28.7 ((CH3)3C); IR (drift): nÄ ˆ 2863
(Bohlmann-band[29]), 1709 cmÀ1 (C O); MS (EI, 70 eV): m/z (%): 227 (30)
[M] , 171 (50) [M À tBu] , 127 (35) [M À Boc] ; HRMS (EI, 70 eV): calcd
ˆ
‡
‡
‡
for C12H21NO3: 227.1521, found: 227.1523.
3-(Toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-binaphthyl-
2,2'-diyl]-phosphite (31): Trifluoroacetic acid (0.5 mL) was added to a
suspension of Boc-bispidine 29 (70 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) and
the solution was stirred at room temperature for 30 min. After evaporation
of the solvent in vacuo and coevaporation with toluene the residue was
taken up in toluene (2mL) and treated with triethylamine (262 mL,
1.89 mmol). To this mixture was added slowly a solution of chlorophosphite
10 (86 mg, 0.245 mmol) in toluene (3 mL) and the mixture was heated for
5 h at 808C. The precipitate was filtered off and the solvent was evaporated
in vacuo. The residue was purified by flash chromatography over Florisil
(treated with triethylamine) with cyclohexane/CH2Cl2 2:1, 2% triethyl-
amine to yield a colourless solid (50 mg, 0.094 mmol, 51%). Rf ˆ 0.95
(CH2Cl2/Et3N 10:1); m.p. 230 2318C; [a]2D0 ˆ À297 (c ˆ 0.85, CH2Cl2);
1H NMR (CDCl3, 400 MHz): d ˆ 7.97 7.86 (m, 4H; arom., BINOL), 7.76
(d, J ˆ 9 Hz, 1H; arom., BINOL), 7.62(d, J ˆ 8 Hz, 2H; arom., Tos), 7.45
7.20 (m, 9H; arom., BINOL, Tos), 3.74 3.63 (m, 3H; CH2N), 3.37 3.27
(m, 2H; CH2N), 2.61 2.48 (m, 3H; CH2N), 2.43 (s, 3H; CH3), 1.85 (brs,
1H; CHCH2N), 1.68 1.59 (m, 2H; CH2-bridge), 1.51 (brs, 1H; CHCH2N);
13C NMR (CDCl3, 100.6 MHz): d ˆ 150.2, 150.1 (arom. C, BINOL), 143.2,
132.8 (arom. C, Tos), 132.9, 131.6, 130.9, 123.9, 123.6 (arom. C, BINOL),
130.5, 130.0, 128.6, 128.4, 127.4, 127.1, 126.1, 126.0, 124.7, 124.6 (arom. CH,
BINOL), 129.7, 128.0 (arom. CH, Tos), 50.4, 50.0, 49.4, 46.6 (CH2N), 30.7
(CH2-bridge), 27.8, 27.1 (CHCH2N), 21.7 (CH3); 31P NMR (CDCl3,
ˆ
ˆ
d ˆ 177.1 (C O, Piv), 154.9 (C O, Boc), 79.6 (C(CH3)3, Boc), 50.6, 48.8, 47.4
(CH2N), 39.1 (C(CH3)3, Piv), 31.3 (CH2-bridge), 28.9 ((CH3)3C, Boc), 28.6
((CH3)3C, Piv), 28.4, 28.2 (CHCH2N); IR (KBr): nÄ ˆ 2843 (Bohlmann-
band[29]), 1676, 1626 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 333 (7)
ˆ
‡
‡
‡
[M‡Na] , 311 (10) [M‡H] , 255 (100) [M À tBu‡H] , 209 (40) [M À
‡
Boc] ; HRMS (FAB, 3-NBA): calcd for C17H31N2O3: 311.2335, found:
311.2337.
202.5 MHz): d ˆ 147.8; IR (drift): nÄ ˆ 2848 (Bohlmann-band[29]),
7-(tert-Butyloxycarbonyl)-3-(toluene-p-sulfonyl)-diazabicyclo[3.3.1]no-
nane (29): The procedure for the synthesis of pivaloyl-bispidine 28 for the
cleavage of the benzyl group by catalytic hydrogenation was followed. The
residue was taken up in pyridine (7 mL) and treated with DMAP (10 mg,
0.08 mmol) and toluene-4-sulfonylchloride (726 mg, 3.81 mmol). The
mixture was stirred overnight and the solvent was evaporated in vacuo.
The residue was taken up in CH2Cl2 (30 mL) and was washed with 1n HCl
(15 mL), 1n NaHCO3 (15 mL) and sat. NaCl solution (15 mL) and dried
over MgSO4. The solvent was evaporated in vacuo and the crude product
was purified by flash chromatography on silica gel (cyclohexane/ethyl
acetate 2:1) to yield a colourless solid (210 mg, 0.55 mmol, 72%). Rf ˆ 0.32
(cyclohexane/ethyl acetate 2:1); 1H NMR (CDCl3, 400 MHz): d ˆ 7.60 (d,
J ˆ 8 Hz, 2H; arom. Tos), 7.31 (d, J ˆ 8 Hz, 2H; arom. Tos), 4.30 (d, J ˆ
13 Hz, 1H; CH2eqN(7), 4.16 (d, J ˆ 13 Hz, 1H; CH2eqN(7), 3.81 (d, J ˆ
11 Hz, 1H; CH2eqN(3), 3.74 (d, J ˆ 11 Hz, 1H; CH2eqN(3), 3.12(d, J ˆ
13 Hz, 1H; CH2axN(7), 3.01 (d, J ˆ 13 Hz, 1H; CH2axN(7), 2.55 (d, J ˆ
‡
1698 cmÀ1 (C O); MS (FAB, 3-NBA): m/z (%): 595 (20) [M‡H] , 439
ˆ
‡
(15) [M À Tos À H] ; HRMS (FAB, 3-NBA): calcd for C34H32N2O4PS:
595.1821, found: 595.1835.
7-(2',2'-Dimethylpropionyl)-3,7-diazabicyclo[3.3.1]nonane-3-[(R)-(3,3'-di-
methyl)-binaphthyl-2,2'-diyl]phosphite (32): Trifluoroacetic acid (0.5 mL)
was added to a suspension of Boc-bispidine 28 (50.6 mg, 0.163 mmol) in
CH2Cl2 (0.5 mL) and the reaction was stirred at room temperature for
30 min. After evaporation of the solvent in vacuo and coevaporation with
toluene the residue was taken up in 2n KOH solution (5 mL) and extracted
with diethyl ether (3 Â 10 mL). The combined organic layers were dried
over MgSO4 and the solvent was evaporated in vacuo. The crude product
was taken up in THF (1.5 mL) and this solution was added slowly to a
mixture of PCl3 (20 mL, 0.228 mmol) and triethylamine (33 mL, 0.238 mmol)
in THF (1 mL) at 08C. The mixture was stirred for 45 min at 08C. To this
mixture was added dropwise a solution of (R)-(3,3'-dimethyl)binaphthyl-
4778
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0820-4778 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 2 0

Chiral Phosphoramidite Ligands
4767 4780
1H NMR (CDCl3, 400 MHz): d ˆ 7.83, 7.74 (m, 4H; arom. H), 7.39 7.33
(m, 3H; arom. H), 7.27 7.24 (m, 1H; arom. H), 7.21 7.13 (m, 2H; arom.
H), 3.97 (d, J ˆ 11 Hz, 1H; CH2eqO), 3.88 (d, J ˆ 11 Hz, 1H; CH2eqO), 3.79
(d, J ˆ 11 Hz, 1H; CH2axO), 3.73 (d, J ˆ 14 Hz, 1H; CH2N), 3.62(d, J ˆ
11 Hz, 1H; CH2axO), 3.36 (d, J ˆ 13 Hz, 1H; CH2N), 3.32 3.28 (m, 1H;
CH2N), 2.60 (s, 3H; arom. CH3), 2.50 (s, 3H; arom. CH3), 2.46 (d, J ˆ 13 Hz,
CH2N), 1.91 1.87 (m, 1H; CHCH2O), 1.78 1.74 (m, 1H; CHCH2O), 1.64
(s, 1H; CH2-bridge), 1.56 (s, 1H; CH2-bridge); 31P NMR (CDCl3,
2,2'-diol 35 (118 mg, 0.375 mmol) and triethylamine (66 mL, 0.476 mmol) in
THF (2mL) at 0 8C. After warming to room temperature the mixture was
stirred for 1.5 h, filtered and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography on Florisil (treated with
triethylamine) with cyclohexane/CH2Cl2 2:1, 2% triethylamine to yield a
colourless solid (27 mg, 0.049 mmol, 30%). Rf ˆ 0.95 (CH2Cl2/Et3N 10:1);
m.p. 1538C; [a]2D0 ˆ À299 (c ˆ 0.69, CH2Cl2); 1H NMR (CDCl3, 400 MHz):
d ˆ 7.82 7.73 (m, 4H; arom. H), 7.38 7.10 (m, 6H; arom. H), 3.98 3.93
(m, 2H; CH2N), 3.66 3.61 (m, 2H; CH2N), 3.26 3.21 (m, 3H; CH2N),
2.58 (s, 3H; CH3, BINOL), 2.51 (s, 3H; CH3, BINOL), 2.20 (d, J ˆ 12Hz,
1H; CH2N), 1.97 (brs, 1H; CHCH2N), 1.65 1.59 (m, 3H; CH2-bridge,
CHCH2N), 1.32(s, 9H; (CH 3)3C); 13C NMR (CDCl3, 100.6 MHz): d ˆ 176.5
‡
202.5 MHz): d ˆ 145.8; MS (FAB, 3-NBA): m/z (%): 470 (10) [M‡H] ,
‡
‡
469 (8) [M] , 343 (30) [Me2BINOLP] ; HRMS (FAB, 3-NBA): calcd for
C29H29NO3P: 470.1885, found: 470.1877.
ˆ
(C O), 149.1, 148.6, 131.6, 131.5, 131.2, 129.5 (arom. C), 129.6, 129.4, 127.5,
127.4, 127.0, 126.8, 125.1, 125.0, 124.7, 124.5 (arom. CH), 50.0, 49.5, 47.1, 46.3
(CH2N), 38.9 (C(CH3)3), 28.6 ((CH3)3C), 28.2, 28.0 (CHCH2N), 26.9 (CH2-
bridge), 18.0, 17.6 (CH3 BINOL); 31P NMR (CDCl3, 202.5 MHz): d ˆ 145.5;
Acknowledgements
IR (drift): nÄ ˆ 2850 (Bohlmann-band[29]), 1629 cmÀ1 (C O); MS (FAB,
ˆ
This reseach was supported by the Fonds der Chemischen Industrie and the
Alexander von Humboldt-Stiftung.
‡
‡
3-NBA): m/z (%): 553 (90) [M‡H] , 343 (80) [Me2BINOLP] , 209 (65)
‡
[M À Me2BINOLP] ; HRMS (FAB, 3-NBA): calcd for C34H18N2O3P:
553.2620, found: 553.2601.
3-(Toluene-p-sulfonyl)-3,7-diazabicyclo[3.3.1]nonane-7-[(R)-(3,3'-dime-
thyl)binaphthyl-2,2'-diyl]phosphite (33): Trifluoroacetic acid (0.5 mL) was
added to a suspension of Boc-bispidine 29 (60 mg, 0.158 mmol) in CH2Cl2
(0.5 mL) and the mixture was stirred for 30 min. After evaporation of the
solvent in vacuo and coevaporation with toluene the residue was taken up
in 2n KOH solution (5 mL) and extracted with diethyl ether (3 Â 10 mL).
The combined organic layers were dried over MgSO4 and the solvent was
evaporated in vacuo. The crude product was taken up in THF (1.0 mL) and
was slowly added to a mixture of PCl3 (17 mL, 0.197 mmol) and triethyl-
amine (29 mL, 0.208 mmol) in THF (1 mL) at 08C. The mixture was stirred
for 45 min at 08C. To this mixture was added dropwise a solution of (R)-
(3,3'-dimethyl)binaphthyl-2,2'-diol (93 mg, 0.297 mmol) and triethylamine
(45 mL, 0.326 mmol) in THF (1 mL) at 08C. After warming to room
temperature the mixture was stirred for 1.5 h, filtered and the solvent was
evaporated in vacuo. The residue was purified by flash chromatography on
Florisil (treated with triethylamine) with cyclohexane/CH2Cl2 2:1, 2%
triethylamine to yield a colourless solid (11.8 mg, 0.019 mmol, 12%). Rf ˆ
0.95 (CH2Cl2/Et3N 10:1); m.p. 261 2638C; [a]2D0 ˆ À377 (c ˆ 0.37, CH2Cl2);
1H NMR (CDCl3, 400 MHz): d ˆ 7.82 7.74 (m, 4H; arom. H, BINOL), 7.58
(d, J ˆ 8 Hz, 2H; arom. H, Tos), 7.38 7.11 (m, 8H; arom. H, BINOL, Tos),
3.65 (d, J ˆ 11 Hz, 1H; CH2eqN(3), 3.56 (d, J ˆ 11 Hz, 1H; CH2eqN(3), 3.35
(d, J ˆ 13 Hz, 1H; CH2eqN(7), 3.24 (d, J ˆ 13 Hz, 1H; CH2eqN(7), 2.68 (s,
3H; CH3, BINOL), 2.64 2.23 (m, 4H; CH2N), 2.50 (s, 3H; CH3, BINOL)
and 2.42 (s, 3H; CH3, Tos), 1.91 (brs, 1H; CHCH2N), 1.65 1.55 (m, 3H;
CH2-bridge, CHCH2N); 13C NMR (CDCl3, 100.6 MHz): d ˆ 149.4, 149.1
(arom. C, BINOL), 143.2, 132.7 (arom. C, Tos), 131.7, 131.5, 130.9 (arom. C,
BINOL), 129.9 (arom. CH, BINOL), 129.7, 128.0 (arom. CH, Tos), 127.7,
127.6, 127.3, 126.9, 125.2, 125.0, 124.7, 124.6 (arom. CH, BINOL), 49.8, 49.5,
45.7 (CH2N), 27.7 (CHCH2N), 27.1 (CH2-bridge), 27.0 (CHCH2N), 21.7
(CH3, Tos), 18.1, 17.8 (CH3, BINOL); 31P NMR (CDCl3, 202.5 MHz): d ˆ
145.2; IR (drift): nÄ ˆ 2833 (Bohlmann-band[29]); MS (FAB, 3-NBA): m/z
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‡
‡
(%): 623 (15) [M‡H] , 343 (10) [Me2BINOLP] ; HRMS (FAB, 3-NBA):
m/z (%): calcd for C36H36N2O4PS: 623.2133, found: 623.2143.
3-Oxa-7-azabicyclo[3.3.1]nonane-7-[(R)-(3,3'-dimethyl)binaphthyl-2,2'-
diyl]phosphite (34): Trifluoroacetic acid (1 mL) was added to a suspension
of Boc-oxa-bispidine 30 (70 mg, 0.308 mmol) in CH2Cl2 (1 mL) and the
mixture was stirred at room temperature for 30 min. After evaporation of
the solvent in vacuo and coevaporation with toluene the residue was taken
up in 2n KOH solution (5 mL) and extracted with diethyl ether (6 Â
10 mL). The combined organic layers were dried over MgSO4 and the
solvent was evaporated in vacuo. The resulting waxy residue was taken up
in THF (1.5 mL) and was added dropwise to a mixture of PCl3 (27 mL
0.31 mmol) and triethylamin (45 mL, 0.32mmol) in THF (1 mL) at 0 8C.
The mixture was stirred for 45 min at 08C. To this mixture was added
dropwise a solution of (R)-(3,3'-dimethyl)binaphthyl-2,2'-diol (106 mg,
0.34 mmol) and triethylamine (94 mL, 68 mg, 0.68 mmol) in THF (1.5 mL)
at 08C. After warming to room temperature the mixture was stirred for
1.5 h, filtered and the solvent was evaporated in vacuo. The residue was
purified by flash chromatography on Florisil (treated with triethylamine)
with cyclohexane/CH2Cl2 2:1, 2% triethylamine to yield a colourless solid
(4 mg, 0.009 mmol, 3%). Rf ˆ 0.95 (CH2Cl2/Et3N 10:1); m.p. 1678C;
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4, 2427 2430.
Chem. Eur. J. 2002, 8, No. 20
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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4779

H. Waldmann et al.
FULL PAPER
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Received: May 6, 2002 [F4068]
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