Chiral bicyclic phosphoramidites - A new class of ligands for asymmetric catalysis

Article abstract of DOI:10.1002/1521-3765(20010202)7:3<671::AID-CHEM671>3.0.CO;2-M

The development of new ligands for catalytic asymmetric C-C bond formation is of great interest to organic synthesis. We describe here a new class of chiral phosphoramidites that embody one or two binaphthol units attached to an achiral azabicyclic [3.3.1] or [3.3.0] framework. These ligands were easily accessible from (R)-1,1′-binaphthyl-2,2′-dioxaphosphorchloridite (4) and the corresponding heterobicyclic core 1, 2, or 3. They were employed in enantioselective Cu-catalyzed additions of different dialkylzinc reagents to cyclic and acyclic enones. The chiral ketones were obtained with an enantiomeric ratio up to 91:9. The choice of the best ligand proved to be strongly dependent on each substrate. In addition, ligand 6 was found to be the most suitable for Rh-catalyzed hydrogenations of α,β-unsaturated esters, giving rise to dimethyl 2-methylsuccinate and methyl N-acetylalaninate with enantiomer ratios up to 95:5.

Full text of DOI:10.1002/1521-3765(20010202)7:3<671::AID-CHEM671>3.0.CO;2-M

FULL PAPER
Chiral Bicyclic PhosphoramiditesÐ
A New Class of Ligands for Asymmetric Catalysis
Oliver Huttenloch,[a] Jan Spieler,[b] and Herbert Waldmann*[a]
Abstract: The development of new li-
gands for catalytic asymmetric C C
bond formation is of great interest to
organic synthesis. We describe here a
new class of chiral phosphoramidites
that embody one or two binaphthol
units attached to an achiral azabicyclic
[3.3.1] or [3.3.0] framework. These li-
gands were easily accessible from (R)-
1,1'-binaphthyl-2,2'-dioxaphosphor-
chloridite (4) and the corresponding
heterobicyclic core 1, 2, or 3. They were
employed in enantioselective Cu-cata-
lyzed additions of different dialkylzinc
reagents to cyclic and acyclic enones.
The chiral ketones were obtained with
an enantiomeric ratio up to 91:9. The
choice of the best ligand proved to be
strongly dependent on each substrate. In
addition, ligand 6 was found to be the
most suitable for Rh-catalyzed hydro-
genations of a,b-unsaturated esters, giv-
ing rise to dimethyl 2-methylsuccinate
and methyl N-acetylalaninate with
enantiomer ratios up to 95:5.
Keywords: addition
´ asymmetric
catalysis ´ heterocycles ´ hydroge-
nation ´ phosphoramidites
Introduction
Results and Discussion
The development of new methods for the enantioselective
catalysis of widely applicable synthetic transformations like
C C bond formation and reduction reactions is at the heart of
organic synthesis.[1] Of paramount importance to this field is
the accessibility of efficient stereodirecting ligands that are
readily available in both enantiomeric forms. Addressing this
need, recently Feringa et al.[2] introduced chiral phosphor-
amidite ligands for the highly enantioselective copper-cata-
lyzed conjugate addition[3] of dialkylzinc compounds to
enones and a,b-unsaturated nitro compounds.[4] The combi-
nation of an axially chiral binaphthol with a bis(1-phenyl-
ethyl)amine proved to be particularly effective. A second
example for the advantageous use of chiral phosphoramidites,
in this case embodying a chirally modified quinoline back-
bone, was described by Leitner et al.[5] for the Rh-catalyzed
hydrogenation of olefins such as methyl itaconate.
Herein we report on the development of a new class of chiral
phosphoramidite ligands for asymmetric catalysis. These
ligands incorporate an achiral bicyclic backbone, which
determines their underlying structure, and either one or two
amino groups. The heterocycle serves as basic framework to
which phosphoric acid binaphthol esters are attached. The
fine tuning of the heterocycle structure can serve to vary the
spatial arrangement of the stereodirecting binaphthyl groups
and to adapt the ligand structure to the requirements for
highly enantioselective transformations of the varying sub-
strates.
Compounds 1 ± 3 were chosen as heterocyclic backbones.
Bispidine 1[6, 7] and the oxa-analogue 2[8] were synthesized
Me Me
O
N
N
N
N
N
H
H
H
H
H
1
2
3
[a] Prof. Dr. H. Waldmann, Dipl.-Chem. O. Huttenloch
Max-Planck-Institut für molekulare Physiologie
Abteilung Chemische Biologie
according to the convergent synthesis concept recently
forwarded by us for the preparation of chiral amino alcohols
embodying a bispidine framework.[6] Bicyclic diamine 3 was
synthesized according to the literature.[9] C2-symmetric phos-
phoramidites 5 and 6 were prepared with in situ generated
phosphoric acid chloride 4[2a] (Scheme 1) and isolated in pure
form after chromatography on neutral alumina. Synthesis of
ligand 7 required the use of isolated reagent 4[10] at elevated
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Universität Dortmund, Fachbereich 3, Organische Chemie
44221 Dortmund (Germany)
Fax : (‡49)231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[b] Dipl.-Chem. J. Spieler
Institut für Organische Chemie der Universität Karlsruhe (TH)
Richard-Willstätter-Allee 2, 76128 Karlsruhe (Germany)
Chem. Eur. J. 2000, 6, No. 3
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671

H. Waldmann et al.
FULL PAPER
Table 1. Cu-catalyzed enantioselective 1,4-addition of different dialkylzinc
reagents to cyclic enones 8a and 8b.[a]
OH
OH
PCl3, NEt3
toluene, -60°C, 2h
2
Entry
Ligand
Substrate
R
Yield [%][b]
Enantiomer ratio[c]
O
P Cl
O
O
N
1
2
3
4
5[e]
6
5
6
7
5
7
5
8a
8a
8a
8a
8a
8b
Et
Et
Et
Me
Me
Me
96
93
94
91
67
89
78:22
73:27
90:10
91:9[d]
74:26[d]
91:9
toluene
80°C
12h
P
O
O
4
*
7
53%
NEt3
toluene
RT, 2d
1
3
[a] All reactions were carried out in toluene/CH2Cl2 (6/1) at 308C for 3 h
in the presence of Cu(OTf)2 (3 mol%) and ligand (3.3 mol%) unless
otherwise indicated. Dialkylzinc solution was added within 5 min to a
catalyst/substrate mixture. [b] Yield of isolated product after chromatog-
raphy on silica gel. [c] Determined by gas chromatographic analysis using a
capillary column (Lipodex E, Macherey&Nagel), in all cases the R
enantiomer was formed predominantly. [d] Determined by gas chromato-
graphic analysis using a capillary column (Lipodex E, Macherey&Nagel)
using the d-( )-2,3-butandiol acetal of 9b. [e] Reaction temperature 08C.
Me Me
N
N
N
N
P
O
P
O
P
P
O
O
O
O
O
O
*
*
*
*
5
56%
6
58%
Scheme 1. Synthesis of ligands 5 ± 7 with the coupling reagent 4.
Table 2. Cu-catalyzed enantioselective 1,4-addition of different dialkylzinc
reagents to chalcone 10.[a]
temperature and chromatography on magnesium silicate
(Florisil). In line with observations of Feringa et al.,[2a,b]
phosphorus(iii) compounds 5 ± 7 are surprisingly stable to
oxygenation. However, they are acid-labile ruling out chro-
matographic separation on regular silica gel.
Entry
Ligand
R
T [8C]
Yield [%][b]
Enantiomer ratio[c]
In a first set of experiments ligands 5 ± 7 were used in the
Cu-catalyzed conjugate addition of dimethyl- and diethylzinc
to cyclohexenone (8a) and cycloheptenone (8b) (Table 1). To
this end, a solution of the enone and the Cu/ligand complex
was treated with a solution of the dialkylzinc reagent at
308C, and the enantiomer ratio of the addition product was
determined by gas chromatography by employing a chiral
stationary phase. The addition of dimethylzinc to cyclohex-
enone had to be carried out at 08C, at 308C no conversion
was observed.
In the addition of diethylzinc to cyclohexenone, ligand 7
was clearly superior to C2-symmetric bis(phosphoramidite)
ligands 5 and 6 (Table 1, entries 1 ± 3). For 5 and 6 only
moderate stereoselectivity was observed, however, ligand 7
made the addition product 9a available with an enantiomer
ratio of 90:10, a result that is in the preparatively useful range.
In the addition of dimethylzinc to cyclohexenone, however,
C2-symmetric ligand 5 was the best giving rise to the desired
product with a selectivity of 91:9 (Table 1, entries 4 and 5).
The addition of this zinc reagent to cycloheptenone in the
presence of bis(phosphoramidite) 5 proceeded with very
comparable results (Table 1, entry 6).
1[d]
2[d]
3[d]
4[e]
5[e]
6[e]
5
6
7
5
6
7
Et
Et
Et
Bu
Bu
Bu
15
15
15
30
30
30
98
98
97
99
97
97
89:11
79:21
87:13
80:20
80:20
91:9
[a] All reactions were carried out in toluene/CH2Cl2 (4/1) at the indicated
temperature for 3 h in the presence of Cu(OTf)2 (3 mol%) and ligand
(3.3 mol%). [b] Yield of isolated product after chromatography on silica
gel. [c] Determined by HPLC using a Daicel Chiracel OD, in each case the
S enantiomer of 11 was formed predominantly. [d] Diethylzinc solution was
added within 5 min at 158C to a catalyst/chalcone mixture. [e] Chalcone
10 was added within 1 h at the indicated reaction temperature to the
catalyst/dibutylzinc solution.
(Table 2, entries 1 ± 3). If dibutylzinc was employed, ligand 7
delivered the most advantageous results (Table 2, entries 4 ± 6).
From the results detailed in Tables 1 and 2 a clear trend in
favor of one of the three ligands cannot be delineated. Rather,
it appears that the substrates and reagents need a fine tuning
of ligand structure with respect to the precise structure of the
bicyclic framework and the presence of one or two stereo-
directing binaphthol units.
In a second series the addition of zinc reagents to an acyclic
enone, namely chalcone 10 was investigated (Table 2). In the
addition of diethylzinc to chalcone, bispidine-derived bi-
s(phosphoramidite) 5 proved to be the best ligand. However,
for non-C2-symmetric ligand 7 a similar result was recorded
We would like to stress, however, that in the reactions with
both the cyclic and the acyclic enones the zinc reagent attacks
the b-carbon atom of the double bond from the Re face (Re
672
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Chem. Eur. J. 2000, 6, No. 3

Chiral Bicyclic Phosphoramidites
671±675
with respect to the b-carbon atom). This result differs from the
observations made for the phosphoramidite ligands devel-
oped by Feringa et al.,[2e] for which a change in face-selectivity
occurs. We assume that this property is imposed on our ligands
by the presence of the bicyclic backbone. Evidently, the
preorganization of the reactants and the ligand in the
transition state is primarily determined by the steric influence
of the bicyclic framework of the ligands, whereas the
efficiency of the stereoselection is due to fine tuning of ligand
structure. This finding indicates that our original intention
(vide supra) is met by ligands 5 ± 7 and clearly distinguishes
this class of phosphoramidites from the ligands introduced by
Feringa et al.
In order to demonstrate whether the chiral bicyclic
phosphoramidites may also serve as efficient ligands in
different types of reactions, the Rh-catalyzed enantioselective
hydrogenation of a,b-unsaturated esters was investigated. To
this end, dimethyl itaconate and methyl acetamidoacrylate
were hydrogenated (Table 3). For the itaconate 12a C2-
Moreover the same class of ligands could be applied for the
highly enantioselective Rh-catalyzed hydrogenation of a,b-
unsaturated esters. The performance of each ligand is depen-
dent on the type of substrate as well as the metal catalyst
employed.
Experimental Section
General remarks: Melting points were determined in open capillaries by
using a Büchi 535 apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded on a Bruker AC 250, AM 400, or DRX 500 spectrometer at
room temperature. IR spectra were recorded on
a Bruker IFS 88
spectrometer. Mass spectra, high-resolution mass spectra (HRMS), and
fast-atom bombardment mass spectra (FAB) were measured on a Finnigan
MAT MS70 spectrometer. Specific optical rotation values were determined
with a Perkin-Elmer polarimeter 241. High-performance liquid chroma-
tography (HPLC) was performed with
a Merck Hitachi instrument
equipped with a L-3000 diode array detector and for all gas chromatog-
raphy a Hewlett Packard 5890 Series II gas chromatograph was used.
Materials: Solvents were dried by standard methods and used immediately
or stored over molecular sieves. For hydrogenation, solvents were degassed
by freezing in vacuo. For column chromatography silica gel (40 ± 60 mm,
Baker or Fluka), neutral alumina (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, dibutylzinc (1.1m in heptane) and diethylzinc (1.1m in toluene) were
purchased from Fluka and dimethylzinc (2m in toluene) was purchased
from Aldrich. Pd/C (10%) was donated by Degussa-Hüls AG. 3,7-
Diazabicyclo[3. 3.1]nonane (1)[6, 7], 1,5-dimethyl-3,7-diazabicyclo[3. 3.0]oc-
tane (3),[9] and (R)-1,1'-binaphthyl-2,2'-dioxaphosphorchloridite (4)[10] were
prepared according to literature methods.
3-Benzyl-3-aza-7-oxabicyclo[3.3.1]nonane (14):[8] A solution of benzyl-
amine (9.7 mL, 89 mmol), tetrahydropyran-4-one (6) (8.3 mL, 89 mmol),
and acetic acid (5.1 mL, 89 mmol) in MeOH (80 mL) was added over a
period of 1 h to a suspension of paraformaldehyde (5.6 g, 186 mmol), acetic
acid (5.1 mL, 89 mmol) and concentrated HCl (2 mL, 25 mmol) in MeOH
(80 mL) at 658C, and stirred for 6 h. After evaporation of the solvent, water
(200 mL) was added and the pH was adjusted to 10 with 20% KOH. The
aqueous phase was extracted with diethyl ether (4 Â 100 mL) and the
combined organic layers were dried over Na2SO4. Concentration in vacuo
yielded a viscous yellow oil which was used without further purification in
the next step. KOH (30.3 g, 0.54 mol) was added to a solution of the
Mannich product and hydrazine monohydrate (21.9 mL, 0.45 mol) in
diethylene glycol (300 mL). The mixture was stirred for 3 h at 1408C. After
removing the hydrazine and water by distillation at 2008C, cooling the
reaction mixture to room temperature and addition of water (300 mL), the
aqueous phase was extracted with diethyl ether (4 Â 100 mL). The
combined organic layers were dried over Na2SO4 and the solvent was
Table 3. Rh-catalyzed asymmetric hydrogenation of dimethyl itaconate
(12a) and 2-acetamido methyl acrylate (12b).[a]
Entry Ligand Substrate p(H2) [bar] Conversion [%][b] Enantiomer ratio
1
2
3
4
5
6
5
6
7
6
6
6
12a
12a
12a
12a
12b
12b
1.3
1.3
1.3
20
1.3
20
> 99
> 99
5
77:23[c]
95:5[c]
89:11[c]
95:5[c]
90:10
93:7
> 99
98[d]
97[d]
[a] All reactions were carried out in CH2Cl2 at room temperature for 12 h
under the indicated pressure in the presence of [Rh(cod)2]BF4 (1 mol%)
and ligand (1.2 mol%), c(substrate) ˆ 0.05 molL 1. [b] Determined by gas
chromatographic analysis. [c] Determined by gas chromatographic analysis
using a capillary column (Lipodex E, Macherey&Nagel), in all cases the R
enantiomer was formed predominantly. [d] Yield of isolated product after
chromatography on silica gel.
evaporated in vacuo. Distillation under reduced pressure yielded
a
symmetric bicyclic ligand 6 showed the best results yielding
the desired product 13a with an enantiomer ratio of 95:5. In
addition, methyl N-acetylalaninate (13b) was obtained with
useful stereoselectivity. In this case the enantiomer ratio could
be raised substantially by increasing the hydrogen pressure.
colorless oil. Yield: 12.95 g, 59.6 mmol, 67%; b.p. 878C (p ˆ 5 Â
10 1 mbar); 1H NMR (250 MHz, CDCl3): d ˆ 7.42 ± 7.18 (m, 5H; arom.
CH), 3.93 (d, 2J ˆ 10.7 Hz, 2H; OCH2eq), 3.78 (d, 2J ˆ 10.7 Hz, 2H;
OCH2ax), 3.51 (s, 2H; CH2Ph), 2.96 (d, 2J ˆ 11.8 Hz, 2H; NCH2eq), 2.24
(d, 2J ˆ 11.8 Hz, 2H; NCH2ax), 1.84 ± 1.53 (m, 4H; CHCH2, CH2-bridge).
3-Aza-7-oxabicyclo[3.3.1]nonane (2): Pd/C (10%, 4 g) was added to a
solution of 3-benzyl-3-aza-7-oxabicyclo[3.3.1]nonane (14) (12.9 g,
59.4 mmol) and acetic acid (17.4 mL, 0.3 mol) in MeOH (50 mL). The
resulting suspension was stirred at room temperature overnight under an
atmosphere of hydrogen. After filtration through Celite and concentration
in vacuo, water (50 mL) was added. The pH of the aqueous phase was
adjusted to pH 14 with 20% KOH under ice bath cooling and the aqueous
phase was extracted with CH2Cl2 (4 Â 100 mL). After drying the combined
organic layers over Na2SO4 and evaporation of the solvent under reduced
pressure the residue was purified by Kugelrohr distillation. Yield: 6.86 g,
53.9 mmol, 91%; m.p. 648C; 1H NMR (500 MHz, CDCl3): d ˆ 4.03 ± 3.98
(m, 2H; OCH2eq), 3.85 ± 3.82 (m, 2H; OCH2ax), 3.18 ± 3.13 (m, 2H;
NCH2eq), 3.04 ± 2.98 (m, 2H; NCH2ax), 2.76 (brs, 1H; NH), 1.97 ± 1.88 (m,
2H; CH2CH), 1.46 ± 1.44 (m, 2H; CH2-bridge); 13C NMR (125.7 MHz,
Conclusion
We have developed a new set of chiral phosphoramidite
ligands embodying one or two binaphthol units attached to an
achiral azabicyclic [3.3.1] or [3.3.0] framework. These ligands
were successfully employed in enantioselective Cu-catalyzed
conjugate additon reactions of different dialkylzinc reagents
to cyclic and acyclic enones. The Re face selectivity of our
ligands differs from observations made by Feringa et al.[2e]
Chem. Eur. J. 2000, 6, No. 3
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673

H. Waldmann et al.
FULL PAPER
CDCl3): d ˆ 73.29 (OCH2), 51.69 (NCH2), 32.00 (CH2-bridge), 30.11 (CH);
IR (drift): nÄ ˆ 3346 (NH), 2903, 2848 (Bohlmann-band),[11] 1559 (NH),
1456, 1415, 1326, 1264, 1198, and 1100 (OCH2), 853 cm 1; MS (70 eV); m/z
(m, 1H; OCH2CH); 13C NMR (125.8 MHz, CDCl3): d ˆ 150.16, 149.79,
132.80, 132.59, 131.32, 130.70 (arom. C), 130.14, 129.81, 128.32, 128.26,
126.97, 125.96, 125.93, 124.65, 124.46 (arom. CH), 123.89, 123.05 (arom. C),
122.41, 122.32 (arom. CH), 71.41, 71.05 (OCH2), 49.55, 47.18 (NCH2), 30.88
(CH2-bridge), 29.20, 29.07 (OCH2CH); 31P NMR (202.5 MHz, CDCl3) d ˆ
148.41; IR (drift): nÄ ˆ 3059, 2941, 2928, 2842 (Bohlmann-band),[11] 2185,
1921, 1825, 1590, 1504, 1463, 1327, 1233 (PO), 1207 (PO), 1070, 1063, 952,
826, 791, 756 cm 1; HR-FAB (3-NBA) calcd for C27H24N2O4P2: 442.1572,
found: 442.1588.
‡
‡
(%): 127 (72) [M ], 126 (13) [M
H], 106 (11), 96 (11), 94 (11), 83 (13), 82
‡
(26) [M
C2H5O], 70 (13), 69 (11), 68 (23), 67 (23), 57 (16), 44 (100), 43
‡
(53), 42 (29) [C2H4N ], 39 (19); HRMS (70 eV) calcd for C7H13NO:
127.0997, found: 127.0973.
General procedure for the synthesis of the C2-symmetric ligands 5 and 6: A
solution of (R)-1,1'-binaphthyl-2,2'-diol (1.29 g, 4.5 mmol) (4) in hot
toluene (50 mL)[2e] was added over a period of 30 min to a solution of
freshly destilled PCl3 (390 mL, 4.5 mmol) and NEt3 (1.32 mL, 9.5 mmol) in
toluene (8 mL) at 608C. The mixture was stirred for 2 h at 608C and
15 min at room temperature. After cooling to 408C a solution of the
bicyclic amine (1 or 3) (2 mmol) and NEt3 (0.63 mL, 4.5 mmol) in toluene
(2 mL) was added. The suspension was stirred at room temperature for two
days. After filtration through Celite and evaporation of the solvent under
reduced pressure the residue was purified by flash chromatography on
neutral alumina [2% NEt3 in n-hexane/CH2Cl2, 2:1 (v/v)].
General procedure for the addition of dialkylzinc reagents to cyclic enones
(9a, 9b, and 9c) in the presence of chiral ligands: A suspension of Cu(OTf)2
(11 mg, 0.03 mmol) and the phosphoramidite (0.033 mmol) in toluene/
CH2Cl2 ˆ 6:1 (v/v) (3.5 mL) was stirred at room temperature for 1 h. The
suspension was cooled to the indicated temperature and the substrate
(1 mmol) was added. After addition of the dialkylzinc solution (1.2 mmol)
the resulting mixture was stirred at that temperature for 3 h. The solution
was poured onto saturated NH4Cl and extracted with diethyl ether (3 Â
20 mL). The combined organic layers were dried over Na2SO4 and the
solvent was carefully removed in vacuo. The residue was chromatographed
on silica gel to yield the corresponding ketone. The enantiomeric ratio of
9a and 9c was determined by gas chromatography (capillary column:
Machery&Nagel FS Lipodex E (0.25mm  50 m)). For ketone 9b the
corresponding acetal with (d)-( )-2,3-butanediol was used for GC analysis.
3,7-Bis[(R)-1,1'-binaphthyl-2,2'-dioxaphosphepinyl]-3,7-diazabicyclo[3.3.1]-
nonane (5): Yield: 0.85 g, 1.12 mmol, 56%; m.p. 2208C (decomp); [a]D20
ˆ
698.5 (c ˆ 1, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 8.01 (d, 3J ˆ
8.8 Hz, 2H; arom. CH), 7.95 (d, 3J ˆ 8.1 Hz, 2H; arom. CH), 7.89 ± 7.81
(m, 4H; arom. CH), 7.78 (d, 3J ˆ 8.8 Hz, 2H; arom. CH), 7.44 ± 7.33 (m, 8H;
arom. CH), 7.28 ± 7.17 (m, 6H; arom. CH), 3.58 ± 3.51 (m, 2H; NCH2eq),
3.39 (d, 2J ˆ 12.9 Hz, 2H; NCH2eq), 3.15 (d, 2J ˆ 15.7 Hz, 2H; NCH2ax), 2.45
(d, 2J ˆ 12.7 Hz, 2H; NCH2ax), 1.69 ± 1.67 (m, 2H; NCH2CH), 1.35 ± 1.33 (m,
2H; CH2-bridge); 13C NMR (100.6 MHz, CDCl3) d ˆ 150.49, 149.92,
132.94, 132.61, 131.30, 130.73 (arom. C), 130.15, 129.97, 128.32, 128.28,
127.03, 126.90, 126.04, 125.99, 124.71, 124.46 (arom. CH), 123.19, 122.37
(arom. C), 122.17 (arom. CH), 49.54, 49.11, 46.38, 46.11 (NCH2), 32.49
(CH2-bridge), 27.27 (NCH2CH); 31P NMR (202.5 MHz, CDCl3) d ˆ 148.06;
IR (drift): nÄ ˆ 3058, 2927, 2838 (Bohlmann band),[11] 1619, 1590, 1507, 1464,
3-Ethylcyclohexanone (9a) (Table 1, entry 3): Yield: 94%; 79% ee, R
enantiomer predominating; Rf ˆ 0.35 [pentane/diethyl ether, 7:1 (v/v)];
20
[a]D ˆ ‡16.0 (c ˆ 2.0, CHCl3, 79% ee) {ref. [12]: optical rotation positive
for R enantiomer}; 1H NMR (250 MHz, CDCl3): d ˆ 2.48 ± 2.18 (m, 3H),
2.12 ± 1.85 (m, 3H), 1.76 ± 1.55 (m, 2H), 1.43 ± 1.26 (m, 3H), 0.91 (t, 3J ˆ
9 Hz, 3H; CH3); GC (1008C, isothermal): tR ˆ 16.7 min [R enantiomer],
tR ˆ 17.4 min [S enantiomer].
3-Methylcyclohexanone (9b) (Table 1, entry 4): Yield: 91%; 81% ee, R
enantiomer predominating; Rf ˆ 0.40 [pentane/diethyl ether, 7:1 (v/v)];
[a]2D0 ˆ ‡8.5 (c ˆ 2.5, CHCl3, 81% ee) {ref. [13]: [a]D28 ˆ ‡11.7 (CHCl3 for R
1330, 1233 (PO), 1216 (PO), 1148, 1064, 978, 949, 824, 752, 696, 680,
1
617 cm
;
HR-FAB (3-nitrobenzyl alcohol (3-NBA)) calcd for
1
enantiomer)}; H NMR (250 MHz, CDCl3): d ˆ 2.42 ± 2.17 (m, 3H), 2.09 ±
C47H37N2O4P2: 755.2229, found: 755.2203.
1.80 (m, 4H), 1.76 ± 1.57 (m, 1H), 1.42 ± 1.25 (m, 1H), 1.03 (t, 3J ˆ 7 Hz, 3H;
CH3); GC (908C, isothermal, corresponding (d)-( )-2,3-butanediol acetal):
tR ˆ 15.6 min [S diastereomer], tR ˆ 15.9 min [R diastereomer].
1,5-Dimethyl-3,7-bis[(R)-1,1'-binaphthyl-2,2'-dioxaphosphepinyl]-3,7-di-
azabicyclo-[3.3.0]octane (6): Yield: 0.89 g, 1.16 mmol, 58%; m. p. 1688C;
[a]2D0
ˆ
459.6 (c ˆ 1, CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 8.01 (d,
3J ˆ 8.8 Hz, 2H; arom. CH), 7.94 (d, 3J ˆ 8.1 Hz, 2H; arom. CH), 7.82 (d,
3J ˆ 8.1 Hz, 2H; arom. CH), 7.71 (d, 3J ˆ 8.8 Hz, 2H; arom. CH), 7.60 (d,
3J ˆ 8.7 Hz, 2H; arom. CH), 7.46 (d, 3J ˆ 8.5 Hz, 2H; arom. CH), 7.44 ± 7.40
(m, 6H; arom. CH), 7.37 (d, 3J ˆ 8.3 Hz, 2H; arom. CH), 7.32 ± 7.23 (m, 4H;
arom. CH), 3.27 (dd, 2J ˆ 10.6 Hz, 4J ˆ 2.7 Hz, 2H; NCH2), 3.01 (dd, 2J ˆ
10.6 Hz, 4J ˆ 5.2 Hz, 2H; NCH2), 2.97 (dd, 2J ˆ 10.5 Hz, 4J ˆ 3.1 Hz, 2H;
3-Methylcycloheptanone (9c) (Table 1, entry 6): Yield: 89%; 82% ee, R
enantiomer predominating; Rf ˆ 0.32 [pentane/diethyl ether, 10:1 (v/v)];
[a]2D0 ˆ ‡60.9 (c ˆ 1.13, CHCl3, 82% ee) {ref. [14]: [a]2D5 ˆ ‡55.2 (MeOH
1
for R enantiomer)}; H NMR (250 MHz, CDCl3): d ˆ 2.52 ± 2.40 (m, 4H),
1.96 ± 1.82 (m, 4H), 1.70 ± 1.57 (m, 1H), 1.49 ± 1.22 (m, 2H), 1.00 (t, 3J ˆ
9 Hz, 3H; CH3); GC (1008C, isothermal): tR ˆ 17.4 min [S enantiomer],
tR ˆ 18.1 min [R enantiomer].
2
4
NCH2), 2.69 (dd, J ˆ 10.5 Hz, J ˆ 3.7 Hz, 2H; NCH2), 0.87 (s, 6H; CH3);
13C NMR (125.8 MHz, CDCl3): d ˆ 149.88, 149.66, 132.86, 132.58, 131.37,
130.76 (arom. C), 130.29, 129.87, 128.38, 126.99, 126.92, 126.10, 126.08,
124.77, 124.54 (arom. CH), 123.93, 123.83 (arom. C), 122.12, 121.97 (arom.
CH), 57.13, 57.03, 56.90, 56.76 (NCH2), 50.46 (CCH3), 19.07 (CH3); 31P
NMR (202.5 MHz, CDCl3) d ˆ 148.63; IR (drift): nÄ ˆ 3055, 2967, 2870, 2410,
2183, 1904, 1619, 1591, 1507, 1464, 1328, 1232 (PO), 1205 (PO), 1066, 949,
824, 751, 697, 628 cm 1; HR-FAB (3-NBA) calcd. for C48H38N2O4P2:
769.2385, found: 769.2351.
General procedure for the addition of dialkylzinc reagents to acyclic
enones (11a and 11b) in the presence of chiral ligands
Method A: Addition of the zinc reagent to the catalyst/substrate mixture
(Table 2, entries 1 ± 3). A suspension of Cu(OTf)2 (11 mg, 0.03 mmol) and
the phosphoramidite (0.033 mmol) in toluene/CH2Cl2 (4:1; v/v) (4 mL) was
stirred at room temperature for 1 h. The substrate (1 mmol) was added and
the solution was cooled to 158C. After addition of the dialkylzinc
solution (1.5 mmol) the resulting mixture was stirred at that temperature
for 3 h. The suspension was poured onto 2m HCl (20 mL) and extracted
with diethyl ether (3 Â 30 mL). The combined organic layers were dried
over Na2SO4 and the solvent was removed in vacuo. The residue was
chromatographed on silica gel [n-hexane/ethyl acetate, 30:1 (v/v)] to yield
the corresponding 1,3-diphenyl ketone.
3-[(R)-1,1'-Binaphthyl-2,2'-dioxaphosphepinyl]-3-aza-7-oxa-bicyclo[3.3.1]-
nonane (7): A solution of (R)-1,1'-binaphthyl-2,2'-dioxaphosphorchloridite
(4)[10] (0.77 g, 2.2 mmol) in toluene (2 mL) was added at room temperature
to a solution of 3-aza-7-oxabicyclo[3. 3.1]nonane (2) (254 mg, 2 mmol) and
NEt3 (2.8 mL, 20 mmol) in toluene (2 mL). The resulting mixture was
stirred at 808C overnight. After filtration through Celite and evaporation
of the solvent under reduced pressure the residue was purified by flash
chromatography on Florisil deactivated by NEt3 [2% NEt3 in n-hexane/
CH2Cl2, 2:1 (v/v)]. Yield: 0.47 g, 1.06 mmol, 53%; m.p. 2498C (decomp);
Method B: Addition of the substrate to a catalyst/dialkylzinc mixture
(Table 2, entries 4 ± 6). A suspension of Cu(OTf)2 (11 mg, 0.03 mmol) and
the phosphoramidite (0.033 mmol) in toluene/CH2Cl2 (4:1; v/v) (4 mL) was
stirred at room temperature for 1 h. After cooling to 308C the dialkylzinc
solution (1.5 mmol) was added within 5 min. To this mixture was added
over a period of 1 h a solution of the substrate (1 mmol) in toluene/CH2Cl2
(4:1; v/v) (1 mL). The resulting solution was stirred at that temperature for
3 h. The isolation and purification of the product was achieved following
the procedure described above.
[a]2D0
ˆ
503.3 (c ˆ 1, CH2Cl2); 1H NMR (500 MHz, CDCl3): d ˆ 7.96 (d,
3J ˆ 8.8 Hz, 1H; arom. CH), 7.92 ± 7.89 (m, 3H; arom. CH), 7.58 (d, 3J ˆ
8.8 Hz, 1H; arom. CH), 7.45 ± 7.39 (m, 4H; arom. CH), 7.35 (d, 3J ˆ 8.5 Hz,
2
1H; arom. CH), 7.30 ± 7.22 (m, 2H; arom. CH), 3.97 (d, J ˆ 11.1 Hz, 1H;
OCH2eq), 3.87 (d, 2J ˆ 11.1 Hz, 1H; OCH2eq), 3.75 (d, 2J ˆ 11.1 Hz, 1H;
2
OCH2ax), 3.65 (d, J ˆ 11.1 Hz, 1H; OCH2ax), 3.63 ± 3.58 (m, 1H; NCH2eq),
3.41 (d, 2J ˆ 12.7 Hz, 1H; NCH2eq), 3.30 (d, 2J ˆ 13.0 Hz, 1H; NCH2ax),
2.72 ± 2.66 (m, 1H; NCH2ax), 1.87 (d, 2J ˆ 12.4 Hz, 1H; CH2-bridge), 1.76 (d,
2J ˆ 12.4 Hz, 1H; CH2-bridge), 1.64 ± 1.61 (m, 1H; OCH2CH), 1.38 ± 1.35
Enantiomeric ratios were determined by HPLC (column: DAICEL
CHIRACEL OD, 0.2% iPrOH in n-hexane, flow rate 1.0 mLmin 1, UV
detector (255 nm)).
674
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Chem. Eur. J. 2000, 6, No. 3

Chiral Bicyclic Phosphoramidites
671±675
1,3-Diphenylpentan-1-one (11a) (Table 2, entry 1): Yield: 96%; 78% ee, S
enantiomer predominating; Rf ˆ 0.24 [n-hexane/ethyl acetate, 30:1 (v/v)];
[a]2D0 ˆ ‡7.9 (c ˆ 2.5, EtOH, 78% ee) {ref. [15]: [a]2D0 ˆ ‡10.5 (c ˆ 2.5,
EtOH for S enantiomer}; 1H NMR (250 MHz, CDCl3): d ˆ 7.93 ± 7.87 (m,
2H; arom. CH), 7.55 ± 7.50 (m, 1H; arom. CH), 7.45 ± 7.39 (m, 2H; arom.
CH), 7.31 ± 7.15 (m, 5H; arom. CH), 3.28 ± 3.20 (m, 3H; CH2CO and CH-
Ph), 1.83 ± 1.54 (m, 2H; CH2CH3), 0.79 (t, 3J ˆ 7 Hz, CH3); HPLC: tR ˆ
19.7 min [S enantiomer], tR ˆ 24.2 min [R enantiomer].
[1] a) I. Ojima, Catalytic Asymmetric Synthesis, VCH, New York, 1993;
b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994.
[2] a) A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew. Chem. 1996,
108, 2526 ± 2528; Angew. Chem. Int. Ed. Engl. 1996, 35, 2374 ± 2376;
b) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de
Vries, Angew. Chem. 1997, 109, 2733 ± 2736; Angew. Chem. Int. Ed.
Engl. 1997, 36, 2620 ± 2623; c) R. Naasz, L. A. Arnold, M. Pineschi, E.
Keller, B. L. Feringa, J. Am. Chem. Soc. 1999, 121, 1104 ± 1105; d) R.
Imbos, M. H. G. Brilman, M. Pineschi, B. L. Feringa, Org. Lett. 1999,
1, 623 ± 625; e) L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de
Vries, R. Naasz, B. L. Feringa, Tetrahedron 2000, 56, 2865 ± 2878.
[3] Review about CuI-catalyzed Michael additions with phosphorus
ligands: N. Krause, Angew. Chem. 1998, 110, 295 ± 297; Angew. Chem.
Int. Ed. 1998, 37, 283 ± 285.
1,3-Diphenylheptan-1-one (11b) (Table 2, entry 6): Yield: 97%; 81% ee, S
enantiomer predominating; Rf ˆ 0.15 [n-hexane/ethyl acetate, 30:1 (v/v)];
m.p. 578C {ref. [16]: m.p. 588C}; [a]2D0 ˆ ‡14.8 (c ˆ 2.6, CCl4, 81% ee) {ref.
[16]: [a]2D0
ˆ
2.07 (c ˆ 2.598, CCl4 for
R enantiomer with 11% ee};
1H NMR (250 MHz, CDCl3): d ˆ 7.94 ± 7.88 (m, 2H; arom. CH), 7.57 ± 7.39
(m, 3H; arom. CH), 7.34 ± 7.17 (m, 5H; arom. CH), 3.37 ± 3.25 (m, 3H; CH,
CHCH2CO), 1.79 ± 1.60 (m, 2H; CHCH2CH2), 1.35 ± 1.08 (m, 4H;
CH2CH2CH3), 0.86 (d, 3J ˆ 8.6 Hz, 3H; CH3); HPLC: tR ˆ 16.9 min [S
enantiomer], tR ˆ 20.8 min [R enantiomer].
[4] a) N. Sewald, V. Wendisch, Tetrahedron Asymmetry 1998, 9, 1341 ±
1344; b) J. P. G. Versleijen, A. M. van Leusen, B. L. Feringa, Tetrahe-
dron Lett. 1999, 40, 5803 ± 5806.
General procedure for the rhodium-catalyzed hydrogenation of olefins:
Á
[5] G. Francio, F. Faraone, W. Leitner, Angew. Chem. 2000, 112, 1486 ±
After stirring
a solution of the chiral ligand (0.012 mmol) and
1488; Angew. Chem. Int. Ed. 2000, 39, 1428 ± 1430.
[6] J. Spieler, O. Huttenloch, H. Waldmann, Eur. J. Org. Chem. 2000, 5,
391 ± 399.
[7] Syntheses of bispidine 1: a) F. Bohlmann, N. Ottawa, R. Keller,
Liebigs Ann. Chem. 1954, 586, 162 ± 176; b) F. Galinovsky, H. Langer,
Monatsh. Chem. 1955, 86, 449 ± 453; c) H. Stetter, H. Hennig, Chem.
Ber. 1955, 88, 789 ± 795; d) H. Stetter, R. Merten, Chem. Ber. 1957, 90,
868 ± 875; e) P. C. Ruenitz, E. E. Smissman, J. Heterocyclic Chem.
1976, 13, 1111 ± 1113.
[8] 3-Aza-7-oxabicyclo[3.3.1]nonane 2 was prepared in three steps from
tetrahydropyran-4-one and benzylamine (see Experimental Section).
Synthesis of 3-benzyl-3-aza-7-oxabicyclo[3.3.1]nonane: a) G. L. Gar-
rison, K. D. Berlin, B. J. Scherlag, R. Lazzara, E. Patterson, S. Sangiah,
C.-L. Chen, F. Schubot, J. Siripitayananon, M. B. Hossain, D. van der
Helm, J. Org. Chem. 1993, 58, 7670 ± 7678; b) P. Arjunan, K. D. Berlin,
C. L. Barnes, D. van der Helm, J. Org. Chem. 1981, 46, 3196 ± 3204.
[9] P. R. Dave, F. Forohar, T. Axenrod, K. K. Das, L. Qi, C. Watnick, H.
Yazdekhasti, J. Org. Chem. 1996, 61, 8897 ± 8903.
[10] J. Scherer, G. Huttner, M. Büchner, J. Bakos, J. Organomet. Chem.
1996, 520, 45 ± 58.
[11] F. Bohlmann, Chem. Ber. 1958, 91, 2157 ± 2167.
[12] A. K. H. Knöbel, I. H. Escher, A. Pfaltz, Synlett 1997, 1429 ± 1431.
[13] C. Djerassi, J. Burakevich, J. W. Chamberlin, D. Elad, T. Toda, G.
Stork, J. Am. Chem. Soc. 1964, 86, 465 ± 469.
[14] D. A. Lightner, E. L. Docks, Tetrahedron 1979, 35, 713 ± 720.
[15] M. J. Brienne, C. Ouannes, J. Jacques, Bull. Soc. Chim. Fr. 1967, 613 ±
616.
[Rh(cod)2BF4] (4 mg, 0.01 mmol) in degassed CH2Cl2 (2 mL) at room
temperature for 30 min a solution of the respective substrate (1 mmol) in
degassed CH2Cl2 (16 mL) was added. The resulting mixture was stirred at
room temperature for 12 h under an atmosphere of hydrogen (p ˆ 1.3 bar).
In the case of high pressure hydrogenation the mixture was transferred by
syringe into an autoclave previously purged with argon. The solution was
stirred at room temperature for 12 h under an atmosphere of hydrogen
(p ˆ 20 bar). After evaporation of the solvent under reduced pressure the
residue was purified by flash chromatography on silica gel. The enantio-
meric ratio of 13a was determined by gas chromatography (see above),
whereas for 13b the optical rotation value was used.
Dimethyl 2-methylsuccinate (13a) (Table 3, entry 4): Yield: 99%; 90% ee,
R
enantiomer predominating; Rf ˆ 0.26 [n-hexane/ethyl acetate, 10:1
(v/v)]; [a]2D0 ˆ ‡4.2 (c ˆ 2.9, CHCl3, 52% ee) {ref. [17]: [a]2D0 ˆ ‡4.8 (c ˆ
2.3, CHCl3 for R enantiomer}; 1H NMR (250 MHz, CDCl3): d ˆ 3.69 (s, 3H;
OCH3), 3.67 (s, 3H; OCH3), 3.01 ± 2.86 (m, 1H; CH), 2.75 (dd, 2J ˆ 16.5 Hz,
3J ˆ 9.1 Hz, 1H; CH2), 2.41 (dd, 2J ˆ 16.5 Hz, 3J ˆ 6.4 Hz, 1H; CH2), 1.21 (d,
3J ˆ 7.5 Hz, 3H; CHCH3); GC (858C, isothermal): tR ˆ 22.6 min [S enan-
tiomer], tR ˆ 23.5 min [R enantiomer].
Methyl N-acetylalaninate (13b) (Table 3, entry 6): Yield: 97%; 86% ee, R
enantiomer predominating; Rf ˆ 0.23 [n-hexane/ethyl acetate, 4:1 (v/v)];
[a]D20 ˆ ‡7.8 (c ˆ 1, CHCl3, 86% ee) {ref. [18]: [a]2D0
ˆ
9.1 (c ˆ 1, CHCl3 for
S enantiomer}; 1H NMR (250 MHz, CDCl3): d ˆ 6.08 (br s, 1H; NH), 4.67 ±
4.54 (m, 1H; CH), 3.76 (s, 3H; OCH3), 2.02 (s, 3H; C(O)CH3), 1.41 (d, 3J ˆ
6.4 Hz, 3H; CHCH3).
[16] H. Ahlbrecht, H. Sommer, Chem. Ber. 1990, 123, 829 ± 836.
[17] A. Kubo, H. Kubota, M. Takahashi, K. Nunami, J. Org. Chem. 1997,
62, 5830 ± 5837.
[18] M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow, J. Am. Chem.
Soc. 1993, 115, 10125 ± 10138.
Acknowledgement
This research was supported by the Fonds der Chemischen Industrie and by
Degussa-Hüls AG.
Received: September 28, 2000 [F2762]
Chem. Eur. J. 2000, 6, No. 3
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0603-0675 $ 17.50+.50/0
675