The synthesis of spirobitetraline phosphoramidite ligands and their application in rhodium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/adsc.200700109

A racemic 1,1′-spirobitetralin-8,8′-diol (SBITOL) was conveniently synthesized from 3-methoxybenzaldehyde in 26 % yield over 9 steps and resolved via its bis-(S)-camphorsulfonates. The corresponding chiral spirobitetraline monophosphoramidite ligands have

Full text of DOI:10.1002/adsc.200700109

FULL PAPERS
DOI: 10.1002/adsc.200700109
The Synthesis of Spirobitetraline Phosphoramidite Ligands
and their Application in Rhodium-Catalyzed Asymmetric
Hydrogenation
Xiang-Hong Huo,a Jian-Hua Xie,a Qiu-Shi Wang,a and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-organicChemistry, Nankai University
Tianjin 300071, Peopleꢀs Republicof China
Fax : (+86)-22-2350-6177; e-mail: qlzhou@nankai.edu.cn
Received: February 27, 2007; Revised: July 22, 2007
Abstract:
A
racemic 1,1’-spirobitetralin-8,8’-diol complexes were applied in the asymmetric hydroge-
(SBITOL) was conveniently synthesized from 3-me- nation of dehydroamino esters with good to excellent
thoxybenzaldehyde in 26% yield over 9 steps and re- enantioselectivities (up to 99.3% ee).
solved via its bis-(S)-camphorsulfonates. The corre-
sponding chiral spirobitetraline monophosphorami- Keywords: asymmetriactcalysis; hydrogenation;
dite ligands have been prepared and their rhodium monophosphoramidite; rhodium; spirobitetraline
Introduction
of functionalized olefins with good to excellent enan-
tioselectivities. These results show that the enantiose-
lectivities induced by chiral monophosphorus ligands
Asymmetrichydrogenation is one of the most power-
ful tools for the production of optically pure com- are comparable or even superior to those obtained by
pounds and most of the highly efficient catalysts de- chiral bidentate phosphorus ligands.
veloped in recent decades for this transformation are
Besides binaphthyl monophosphorus compounds,
transition metal complexes containing one or more the monophosphorus compounds containing a 1,1’-spi-
chiral phosphorus ligands.[1] The first example of cata- robiindane backbone were another type of efficient li-
lyticasymmetrichydrogenation was reported by
gands in asymmetrichydrogenation. For instance, the
Horner and Knowles who used P-chiral monodentate monodentate spiro phosphoramidite SIPHOS (1) and
phosphane ligands which provided poor enantioselec- phosphonites showed very high enantioselectivities in
tivity.[2] By introducing a C2-symmetricbidentate di-
the Rh-catalyzed asymmetric hydrogenation of func-
phosphine ligand DIOP, which had a chirality on the tionalized olefins such as a- and b-dehydroamino acid
backbone, Kagan significantly improved the enantio- derivatives,[11] a-arylenamides,[12] and unprotected en-
selectivity of asymmetric hydrogenation to a practical- amines.[13] The chiral spiro monophosphoramidite
ly useful level.[3] Since then, the chiral bidentate phos- ligand 2 having a 9,9’-spirobixanthene backbone was
phorus ligands, especially those with a C2-symmetry, reported by Zhang and co-workers and found to be
have predominated in asymmetrichydrogenation re-
efficient for the Rh-catalyzed asymmetric hydrogena-
actions. Enormous numbers of chiral bidentate phos- tions of functionalized olefins.[14] In order to search
phorus ligands such as BINAP,[4] BIPHEMP,[5] for new efficient ligands and to systematically study
DuPhos,[6] PennPhos,[7] and P-Phos[8] have been devel- the effect of the spiro skeleton of ligands on the
oped and demonstrated to be highly enantioselective chiral induction and reactivity of catalysts, we “insert-
in asymmetrichydrogenation. On the contrary, due to
syntheticdiffiuclties and poor stability features, P-
ed” a CH2 group into the five-membered rings of 1,1’-
spirobiindane in ligand 1 to give new spiro monophos-
chiral monodentate phosphane ligands have received phoramidite ligands 3 (Figure 1). We reasoned that
less attention. Recently, the potential of chiral mono- this structural change would increase the rigidity of
dentate phosphorus ligands was re-discovered, and the ligand and might thus influence the enantioselec-
several efficient chiral monophosphorus ligands, tivity of the catalysts in asymmetric hydrogenation.
which have chirality on the backbone, instead of on a Herein, we described the synthesis of spiro phosphor-
phosphorus atom, such as binaphthyl monophos- amidite ligands 3 containing a 1,1’-spirobitetraline
phites[9] and monophosphoamidites,[10] have been de- backbone and their application in Rh-catalyzed asym-
veloped and applied in the asymmetrichydrogenation
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Xiang-Hong Huo et al.
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giving the bromide 5 in 62% yield.[17] The Grignard
reagent generated from the bromide 5 reacted with
methyl formate to provide the alcohol 6 in 85% yield.
The alcohol 6 was then converted to the ketone 7
quantitatively using the Swern oxidation procedure.
Selective bromination of the ketone 7 with NaBr in
the presence of H2O2 yielded the dibromide 8 exclu-
sively. In the ring-closing step, the dibromide 8 was
smoothly cyclized in methanesulfonic acid by the
same procedure which we used in the preparation of
9,9’-spirobifluorene-8,8’-diols,[16a] providing 1,1’-spiro-
bitetraline 9 in 65% yield. After debromination of
compound 9 with BuLi at À788C followed by deme-
thylation with NaSEt in DMF at 160–1708C, the race-
mic1,1 ’-spirobitetralin-8,8’-diol (4) was obtained in
26% overall yield from 3-methoxybenzaldehyde.
Figure 1. Chiral spiro monodentate phosphoramidite ligands.
metrichydrogenation of a-dehydroamino esters in ex-
cellent enantioselectivities.
The X-ray crystal structure of 1,1’-spirobitetralin-
8,8’-diol (4) was measured and compared with that of
1,1’-spirobiindane-7,7’-diol (Figure 2). It was found
that each of the six-membered rings in 1,1’-spirobite-
tralin-8,8’-diol adopt an envelope conformation and
the “insertion” of CH2 groups leads to a crowded and
Results and Discussion
À
À
Synthesis of Sirobitetraline Phosphoramidites
rigid spiro skeleton. The bond angle of C(9) C(8)
C(17) in 1,1’-spirobitetralin-8,8’-diol (111.68) was
À
The 1,1’-spirobitetralin-8,8’-diol (4) was a key inter- smaller than the corresponding bond angle of C(9)
mediate in the preparation of phosphoramidite li- C(8) C(17) in 1,1’-spirobiindane-7,7’-diol (118.88),
À
gands 3. A literature survey revealed that the diol 4 which indicated that the two phenyl rings in the 1,1’-
was an unknown compound.[15] By following the spirobitetralin-8,8’-diol (4) were squeezed closer to
double cyclization strategy for the synthesis of spiro each other. The dihedral angle between the two
diols such as 1,1’-spirobiindane-7,7’-diol and 9,9’-spi- phenyl rings in 1,1’-spirobitetralin-8,8’-diol (85.18) is
robifluorene-1,1’-diol,[16] the spiro diol 4 was prepared larger than that in 1,1’-spirobiindane-7,7’-diol (70.08).
in high yield from 3-methoxyenzaldehyde. The syn- The distance betweeen O(1) and O(2) in 1,1’-spirobi-
thetic route is outlined in Scheme 1. Under classical tetralin-8,8’-diol (4) (3.96 Š) is also larger than that in
Knoevenagel reaction conditions, 3-methoxybenzalde- 1,1’-spirobiindane-7,7’-diol (3.43 Š). These structural
hyde was condensed with malonic acid, followed by properties would make spirobitetraline phosphorami-
reduction with LiAlH4 and bromination with PBr3, dite ligands more sensitive to the sterichindrance of
Scheme 1. Synthesis of 1,1’-spirobitetralin-8,8’-diol (4).
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The Synthesis of Spirobitetraline Phosphoramidite Ligands
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Figure 2. Perspective views of 1,1’-spirobitetralin-8,8’-diol (left) and 1,1’-spirobiindane-7,7’-diol (right).
Scheme 2. Synthesis of the monophosphoramidate ligands (S)-3.
the substrate than spirobiindane phosphoramidite li- the SIPHOS ligands.[11a] The diol (S)-4 was heated
gands in asymmetricreactions. with P(NMe2)3 or P(NEt2)3 in toluene at 1008C for
The racemic spiro diol 4 was resolved via the dia- 4 h to produce the phosphoramidites (S)-3a and (S)-
stereomers of its bis-(S)-camphorsulfonates 3b in 62% and 45% yield, respectively. The phos-
A
ACHTREUNG
(Scheme 2). The racemic diol 4 was converted to the phoramidite (S)-3c was prepared in 67% yield by re-
corresponding diastereomers 11a and 11b by reacting acting (S)-4 with PCl3 in THF at room temperature,
with (1S)-(+)-10-camphorsulfonyl chloride. The dia- followed by treatment with lithium morpholide at
stereomers 11a and 11b were separated in 95% and À788C. The phosphoramidites (R)-3a–c were also
96% yield, respectively, by chromatography on a synthesized from the diol (R)-4.
silica gel column. The optically pure spiro diols (S)-
(+)-4 and (R)-(À)-4 were obtained in good yield
(80%) from the hydrolysis of 11a and 11b in refluxing Asymmetric Hydrogenation of a-Dehydroamino
aqueous NaOH/MeOH. The absolute configuration of Esters
the diol (S)-4 was determined by X-ray diffraction
analysis of a single crystal of its l-menthoxycarboxy- In order to investigate the behavior of spirobitetraline
late (Figure 3).
monophosphoramidite ligands 3 in asymmetriccataly-
The spirobitetraline phosphoramidites (S)-3 were sis, the rhodium-catalyzed hydrogenation of methyl a-
prepared by using the procedure for the synthesis of acetamidocinnamate (12a) was performed. Solvent
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When using coordinating solvents such as MeOH,
acetone and THF, no hydrogenation took place (en-
tries 4 and 5). Considering both the enantioselectivity
of reaction and conversion of substrate a mixture of
CH2Cl2 and toluene (v/v=1/4) was found to be the
best choice of solvent. In this mixed solvent the hy-
drogenation reaction was completed within 36 h and
the product (S)-13a was obtained in 99.6% ee
(entry 9). This result was better than those obtained
by using the ligands SIPHOS (1) (98% ee) and Mono-
Phos (98% ee) under the same reaction conditions.
Increasing hydrogen pressure to 10 atm resulted in a
faster reaction with no obviously diminished enantio-
selectivity (entry 10). Ligands (S)-3b and (S)-3c also
can be used for this transformation albeit with lower
reactivities and enantioselectivities (entries 11 and
12).
Under the optimized reaction conditions, various
dehydroamido acid derivatives 12 can be hydrogenat-
ed with good to excellent enantioselectivities
(Table 2). The superiority of spirotetraline phosphor-
amidite 3a over the SIPHOS in terms of enantioselec-
tivity was observed in the hydrogenation of the sub-
strates having a para-substituent on the phenyl ring
Figure 3. Perspective view of the l-menthoxycarboxylate de-
rivative of (S)-4.
experiments showed that the hydrogenation could be regardless of the electronic properties of the substitu-
carried out in CH2Cl2 under the conditions of 1 ents (entries 2–5). However, in the hydrogenation of
mol% [RhACHTREUNG(COD)2BF4], 2.1 mol% (S)-3a, 1 atm H2 at the substrates having a meta- or ortho-substituent the
room temperature, providing the product (S)-13a with spirotetraline ligand 3a gave lower enantioselectivities
97.5% ee (Table 1, entry 1). Ethyl acetate and toluene than those obtained by SIPHOS (entries 7 and 8).
also could serve as solvent for this hydrogenation, but These results demonstrate that the crowded spirote-
due to the low solubility of 12a in these solvents, the traline phosphoramidite ligands are more sensitive to
hydrogenation could not be completed and only mod- the sterichindranec of the substrate than the spiro-
erate conversions were obtained (entries 2 and 3). biindane phosphoramidite ligands.
Table 1. Asymmetrichydrogenation of methyl a-acetamidocinnamate (12a) catalyzed by the Rh complexes of ligands (S)-3.[a]
Entry
Solvent
Ligand
PH2 [atm]
Time [h]
Yield [%]
% ee[b]
1
2
3
4
5
6
7
8
CH2Cl2
EA
Toluene
MeOH
Acetone
THF
CH2Cl2-Toluene (3/2)
CH2Cl2-Toluene (2/3)
CH2Cl2-Toluene (1/4)
CH2Cl2-Toluene (1/4)
CH2Cl2-Toluene (1/4)
CH2Cl2-Toluene (1/4)
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3b
(S)-3c
1
1
1
1
1
1
1
1
24
36
36
36
36
36
24
36
36
2
100
48
52
97.5
98.3
99.6
ND[d]
ND
NR[c]
NR
NR
100
100
100
100
100
100
ND
97.1
99.2
99.6
99.2
92.0
87.3
9
1
10
11
12
10
10
10
12
15
[a]
Reaction conditions: 0.1 mmol 12a, 0.001 mmol [RhACTHER(UNG COD)2]BF4, 0.0021 mmol (S)-3, CH2Cl2/toluene (1/4, v/v).
Determined by chiral GC (Chirasil-VAL III FSOT).
No reaction.
Not determined.
[b]
[c]
[d]
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The Synthesis of Spirobitetraline Phosphoramidite Ligands
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Table 2. Asymmetrichydrogenation of
a-dehydroamino
Mass spectra were recorded on a LCQ advantage spectrom-
eter with ESI resource. HR-MS were recorded on APEXII
and ZAB-HS spectrometer. GC analyses were performed
using Hewlett Packard Model HP 6890 Series. HPLC analy-
ses were performed using a Hewlett Packard Model HP
1100 Series or Waters 2996 instruments.
esters catalyzed by the Rh complex of ligand 3a.[a]
Entry Ar
Product % ee[b]
Configuration
Synthesis of Racemic 1,1’-Spirobitetralin-8,8’-diol (4)
1
2
3
4
5
6
7
8
9
C6H5
4-MeC6H4
4-MeOC6H4 13c
4-ClC6H4
4-NO2C6H4
3-MeOC6H4 13f
3-NO2C6H4
2-ClC6H4
2-Naphthyl
13a
13b
99.2 (98)
99 (98)
99 (96)
99 (98)
99.3 (99)
97 (97)
98 (99)
92 (97)
98
S
S
S
S
S
S
S
S
S
1,7-Bis(3-methoxyphenyl)heptan-4-ol (6):
A solution of
methyl formate (2.4 g, 0.047 mol) in THF (20 mL) was
added slowly to a stirred solution of 3-(3-methoxyphenyl)-
propylmagnesium bromide in THF (160 mL), which was
prepared from 1-(3-bromopropyl)-3-methoxybenzene (5)[17]
(22.9 g, 0.10 mol) and magnesium (2.6 g, 0.11 mol), at 58C.
After the addition, the ice-water bath was removed, and the
reaction mixture was stirred at room temperature overnight.
The reaction mixture was re-cooled to 08C by an ice-water
bath and aqueous HCl (4M, 120 mL) was carefully added.
The organic layer was extracted with ethyl acetate (3”
100 mL), and washed with brine and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure,
and the residue was purified by chromatography on silica
gel column using ethyl acetate/petroleum ether (1:3) as
eluent to afford 1,7-bis(3-methoxyphenyl) heptan-4-ol (6) as
a colorless oil; yield: 13.0 g (85%); 1H NMR (400 MHz,
CDCl3): d=7.17–7.21 (m, 2H), 6.77 (d, J=7.2 Hz, 2H), 6.72
(s, 4H), 3.79 (s, 6H), 2.59 (t, J=8.0 Hz, 4H), 1.75 (m, 2H),
13d
13e
13g
13h
13i
[a]
Reaction conditions: 0.1 mmol 12, 0.001 mmol [Rh-
(COD)2]BF4, 0.0021 mmol (S)-3a, CH2Cl2/toluene (1/4,
ACHTREUNG
v/v), 10 atm of H2, r.t., 2–3 h, 100% conversion.
Determined by chiral GC (Chirasil-VAL III FSOT). The
numbers in parentheses were obtained using (S)-
SIPHOS.
[b]
Conclusions
A novel class of chiral spiro phosphoramidite ligands 1.63 (m, 2H), 1.48 (m, 4H); 13C NMR (100 MHz, CDCl3):
d=159.8, 144.2, 129.5, 121.1, 114.4, 111.2, 71.9, 55.4, 37.2,
36.1, 27.5; MS (ESI): m/z=327 (M+); anal. calcd. for
C21H28O3: C 76.79, H 8.59; found: C 76.91, H 8.39.
1,7-Bis(3-methoxyphenyl)heptan-4-one (7): Dimethyl sulf-
oxide (3.5 mL, 45 mmol) in CH2Cl2 (5 mL) was added drop-
wise to a stirred solution of oxalyl chloride (4.1 mL,
44 mmol) in CH2Cl2 (120 mL) at À508C. The mixture was
stirred for 15 min, and a solution of 1,7-bis(3-methoxyphen-
yl)- heptan-4-ol (6) (13.0 g, 40 mmol) in CH2Cl2 (20 mL) was
added dropwise during 15 min. The resulting mixture was
based on spirobitetraline backbone has been devel-
oped. The structure study revealed that the spirobite-
traline backbone is crowded and rigid, which resulted
in the enantioselectivity of the spirobitetraline phos-
phoramidite ligands being sensitive to the sterichin-
drance of the substrate in the Rh-catalyzed asymmet-
richydrogenation of a-dehydroamino acid derivatives.
The excellent enantioselective induction of the ligand
3a in this study indicated a high potential for a wide
application of the new spirobitetraline phosphorami- stirred for an additional 30 min below À508C, triethylamine
(21.0 mL, 150 mmol) was added dropwise. After stirring at
À508C for 15 min and at room temperature for 2 h, 50 mL
of water were added, the organiclayer was separated, and
the aqueous layer was extracted with CH2Cl2 (2”50 mL).
The combined organic layer was washed successively with
dilute HCl solution, saturated Na2CO3 and brine, dried over
anhydrous MgSO4. After removal of the solvent, the residue
was purified by chromatography on silica gel column using
ethyl acetate/petroleum ether (1:6) as eluent to afford 1,7-
bis(3-methoxyphenyl)heptan-4-one (7) as a colorless oil;
dite ligands in transition metal-catalyzed asymmetric
catalysis.
Experimental Section
General Remarks
All reactions and manipulations were performed using stan-
dard Schlenk techniques and in an argon-filled glovebox
(VAC DRI-LAB HE 493). THF and toluene were distilled
from sodium benzophenone ketyl. Ethyl acetate and DCM
were distilled from calcium hydride. MeOH was distilled
from Mg. Actone was distilled from P2O5. Hydrogen gas
1
yield: 13.0 g (100%); H NMR (400 MHz, CDCl3): d=7.19
(t, J=8.0 Hz, 2H), 6.75–6.70 (m, 6H), 3.79 (s, 6H), 2.58 (t,
J=7.2 Hz, 4H), 2.38 (t, J=7.2 Hz, 4H), 1.90 (m, 4H);
13C NMR (100 MHz, CDCl3): d=210.6, 159.7, 143.3, 129.3,
120.9, 114.2, 111.2, 55.1, 41.9, 35.1, 25.0; MS (EI): m/z=326
(M+); anal. calcd for C21H26O3 : C 77.27, H 8.03. Found: C
76.98, H 7.93.
1
(99.999%) was purchased from Boc Gas Inc. H, 13C and
31P NMR spectra were recorded on Brucker-300 and Varian-
400 spectrometers. Chemical shifts were reported in ppm
1,7-Bis(2-bromo-5-methoxyphenyl)heptan-4-one (8):
A
downfield from internal Si
A
solution of 20 mL 30% aqueous H2O2 in 60 mL acetic acid
was added dropwise to a stirred solution of 1,7-bis(3-me-
thoxyphenyl)heptan-4-one (7) (11.2 g, 34 mmol) and NaBr
(7.03 g, 34 mmol) in acetic acid (200 mL). The mixture was
respectively. Optical rotations were determined using a
Perkin–Elmer 341 MC polarimeter. Elemental analyses
were performed on Yanaca CDRDER MT-3 instrument.
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stirred at room temperature overnight. The solvent of the
mixture was removed under reduced pressure, and the resi-
due was re-dissolved with water (50 mL) and CH2Cl2
(200 mL). After separation of the organiclayer, the aqueous
layer was extracted with CH2Cl2 (2”70 mL). The combined
organiclayer was washed with dilute HCl, saturated
Na2CO3 and brine, and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure, and the resi-
due was purified by chromatography on silica gel column
using ethyl acetate/petroleum ether (1:7) as eluent to afford
(200 mL) was added and the organiclayer was separated.
The aqueous layer was extracted with additional ethyl ace-
tate (50 mL). The combined organic layer was washed with
dilute HCl, saturated Na2CO3, brine, and dried over anhy-
drous MgSO4. After removal of the solvent, the residue was
purified by chromatography on silica gel column using ethyl
acetate/petroleum ether (1:6) as eluent to afford 1,1’-spirobi-
tetralin-8,8’-diol (4) as a white solid; yield: 3.8 g (76%); mp
132–1338C; 1H NMR (300 MHz, CDCl3): d=7.09 (t, J=
7.5 Hz, 2H), 6.78 (d, J=7.8 Hz, 2H), 6.64 (d, J=7.5 Hz,
2H), 4.84 (s, 2H), 2.90 (m, 4H), 2.16 (m, 2H), 2.04 (m, 2H),
1.90 (m, 4H); 13C NMR (75 MHz, CDCl3): d=153.9, 137.7,
127.5, 127.3, 121.7, 115.1, 37.9, 33.1, 29.7, 18.5; HR-MS (EI):
m/z=280.1461, calcd. for C19H20O2: 280.1463.
1,7-bis(2-bromo-5-methoxyphenyl)heptan-4-one (8) as
a
white solid; yield: 16.5 g (99%); mp 54–568C; 1H NMR
(400 MHz, CDCl3): d=7.39 (d, J=8.8 Hz, 2H), 6.75 (d, J=
2.8 Hz, 2H), 6.64–6.61 (m, 2H), 3.77 (s, 6H), 2.68 (t, J=
8.0 Hz, 4H), 2.46 (t, J=7.2 Hz, 4H), 1.90 (m, 4H);
13C NMR (100 MHz, CDCl3): d=210.3, 158.9, 141.9, 133.3,
116.0, 114.9, 113.3, 55.4, 41.9, 35.4, 23.8; HR-MS (EI): m/z=
482.0096, calcd. for C21H24Br2O3: 482.0092.
A single crystal of 1,1’-spirobitetralin-8,8’-diol (4) was
grown from hexane and analyzed by X-ray diffraction.
Using the same procedure the single crystal of 1,1’-spirobiin-
dane-7,7’-diol was also obtained and analyzed.
5,5’-Dibromo-8,8’-dimethoxy-1,1’-spirobitetraline (9): The
1,7-bis(2-bromo-5-methoxyphenyl)- heptan-4-one (8) (4.0 g,
8.3 mmol) was added to MsOH (30.0 mL) while cooling by
an ice bath. After stirring for 6 h, the solution was quenched
by water. The resulting mixture was extracted with CH2Cl2
(3”100 mL), and the combined organic layer was washed
with dilute HCl, saturated Na2CO3 and brine, and dried
over anhydrous MgSO4. After removal of the solvent, the
residue was purified by recrystallization with ethyl acetate
to afford 5,5’-dibromo-8,8’-dimethoxy-1,1’-spirobitetraline (9)
as a white solid; yield: 2.5 g (65%); mp 212–2148C;
1H NMR (400 MHz, CDCl3): d=7.28 (d, J=8.4 Hz, 2H),
6.46 (d, J=8.4 Hz, 2H), 3.16 (s, 6H), 3.07 (m, 2H), 2.60 (m,
2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.80 (m, 4H); 13C NMR
(100 MHz, CDCl3): d=156.4, 138.7, 138.4, 129.4, 116.7,
112.3, 55.7, 40.4, 33.9, 31.6, 20.0; MS (EI): m/z=466 (M+);
anal. calcd for C21H22Br2O2: C 54.10, H 4.76; mfound: C
53.79, H 5.20.
Resolution of 1,1’-Spirobitetralin-8,8’-diol (4)
(1S)-(+)-10-Camphorsulfonates of 1,1’-spirobitetralin-8,8’-
diols (11a and 11b): (1S)-(+)-10-Camphorsulfonyl chloride
(3.2 g, 12.8 mmol) was added to a stirred solution of rac-4
(1.12 g, 4.0 mmol), NEt3 (4.0 mL) in 40 mL of CH2Cl2 under
nitrogen. After being stirred for 12 h at room temperature,
the mixture was washed with water, dilute HCl and brine,
and dried over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was purified by
chromatography on silica gel column using ethyl acetate/tol-
uene (1:10) as eluent to afford 8,8’-bis[(S)-camphorsulfonyl]-
(S)-1,1’-spirobitetraline (11a) (yield: 1.35 g, 95%) and 8,8’-
bis-[(S)-camphorsulfonyl]-(R)-1,1’-spirobitetraline
(yield: 1.36 g, 96%), respectively.
(11b)
8,8’-Bis-[(1S)-(+)-10-camphorsulfonyl]-(+)-1,1’-spirobite-
traline (11a): White solid; mp 194–1968C; [a]2D0: +39.3 (c
1
8,8’-Dimethoxy-1,1’-spirobitetraline (10): To a stirred solu-
tion of 5,5’-dibromo-8,8’-dimethoxy-1,1’-spirobitetraline (9)
(5.36 g, 11.5 mmol) in dry THF (90 mL) was slowly added n-
BuLi (25.2 mL, 53 mmol, 2.1M in hexane) at À788C within
1 h. The solution was stirred at À788C for additional 1 h,
and the reaction then quenched by slowly adding EtOH
(4.3 mL) at À788C. The solvent was removed under reduced
pressure and the residue was extracted with CH2Cl2. The
combined organic layer was washed with water and brine,
dried over anhydrous MgSO4. After removal of the solvent,
the residue was purified by recrystallization with ethyl ace-
tate to afford 8,8’-dimethoxy-1,1’-spirobitetraline (10) as a
1.4, CH2Cl2); H NMR (300 MHz, CDCl3): d=7.51 (d, J=
8.4 Hz, 2H), 7.11–7.01 (m, 4H), 3.19–3.04 (m, 4H), 2.90–
2.85 (m, 2H), 2.39–2.31 (m, 4H), 2.22–2.17 (m, 2H), 2.10–
2.03 (m, 6H), 1.90–1.84 (m, 6H), 1.57–1.35 (m, 6H), 1.02 (s,
6H), 0.83 (s, 6H); 13C NMR (75 MHz, CDCl3): d=148.6,
140.3, 135.8, 127.0, 126.2, 116.5, 57.8, 47.7, 43.1, 42.4, 39.4,
34.7, 30.7, 26.8, 25.1, 19.8, 19.6, 19.2; HR-MS (EI): m/z=
708.2795, calcd. for C39H48O8S2: 708.2791.
8,8’-Bis-[(1S)-(+)-10-camphorsulfonyl]-(À)-1,1’-spirobite-
traline (11b): White solid; mp 63–658C; [a]2D0: +72.0 (c 2.8,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=
7.2 Hz, 2H), 7.06–7.00 (m, 4H), 3.17–3.06 (m, 2H), 2.97–
2.87 (m, 4H), 2.68–2.55 (m, 2H), 2.25–2.036 (m, 6H), 1.91–
1.76 (m, 4H), 1.55–1.38 (m, 6H), 1.12 (d, J=10.8 Hz, 6H),
0.99 (s, 6H), 0.78 (s, 6H); 13C NMR (100 MHz, CDCl3): d=
140.0, 136.2, 129.2, 128.4, 127.5, 127.4, 126.2, 125.5, 117.4,
117.3, 58.0, 52.2, 48.1, 44.2, 43.7, 43.1, 42.6, 39.7, 34.8, 30.9,
27.7, 27.0, 26.9, 25.1, 21.8, 19.9, 19.7, 19.2; HR-MS (EI):
m/z=708.2786, calcd. for C39H48O8S2: 708.2791.
1
white solid; yield: 3.50 g (99%); mp 143–1458C; H NMR
(300 MHz, CDCl3): d=6.98 (t, J=4.8 Hz, 2H), 6.71 (d, J=
7.5 Hz, 2H), 6.58 (d, J=8.1 Hz, 2H), 3.20 (s, 6H), 2.80 (m,
4H), 2.02 (m, 4H), 1.80 (m, 4H); 13C NMR (75 MHz,
CDCl3): d=157.3, 139.4, 136.5, 125.0, 121.4, 111.0, 55.5, 39.0,
35.0, 31.0, 20.3; HRMS (EI): m/z=308.1776, calcd. for
C21H24O2: 308.1776.
1,1’-Spirobitetralin-8,8’-diol (4): To a suspension of NaH
(5.0 g, 0.21 mol) in 150 mL DMF, EtSH (7.8 mL 0.12 mol)
was added slowly while cooling by an ice bath. The 8,8’-di-
methoxy-1,1’-spirobitetraline (10) (5.5 g, 18 mmol) was
added in one portion, and the mixture was refluxed (160–
1708C) for 12 h. The reaction was quenched by adding
dilute HCl while cooling by an ice bath. Ethyl acetate
Hydrolysis of 11a and 11b: To a solution of NaOH (2.0 g,
50 mmol), H2O (5 mL) and methanol (50 mL) was added
11a or 11b (680 mg, 1.0 mmol) under nitrogen atmosphere,
and the mixture was refluxed for 6 h. The reaction mixture
was cooled and the solvent was evaporated under reduced
pressure. The residue was added 20 mL of water and ex-
tracted with CH2Cl2. The aqueous layer was acidified with 6
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Adv. Synth. Catal. 2007, 349, 2477 – 2484

The Synthesis of Spirobitetraline Phosphoramidite Ligands
FULL PAPERS
N HCl to produce a white precipitate, which was extracted
with CH2Cl2. The combined organic layer was dried over an-
hydrous MgSO4 and was concentrated under reduced pres-
sure. The residue was purified by chromatography on silica
gel column using ethyl acetate/petroleum ether (1:6) as
eluent to yield the corresponding enantiomerically pure
spiro diol.
1H NMR (400 MHz, CDCl3): d=7.08 (t, J=8.0 Hz, 1H),
6.98 (t, J=8.0 Hz, 1H), 6.92–6.86 (m, 3H), 6.64 (d, J=
7.2 Hz, 1H), 2.94–2.91 (m, 4H), 2.57–2.54 (m, 4H), 1.98–
1.84 (m, 4H), 1.83–1.81 (m, 2H), 1.75–1.69 (m, 2H), 0.98 (t,
J=6.8 Hz, 3H); 31P NMR (100 MHz, CDCl3): d=124.2;
13C NMR (100 MHz, CDCl3): d=150.3, 145.9, 141.6, 140.3,
138.1, 137.5, 126.5, 126.0, 125.9, 125.7, 122.7, 122.2, 41.6,
39.1, 37.8, 37.5, 30.0, 29.7, 18.5, 18.4, 15.2; HR-MS (ESI):
m/z=382.1928 (M+H), calcd. for C23H29NO2P: 382.1936
(M+H).
(S)-(À)-O,O’-(1,1’-Spirobitetralin-8,8’-diyl)-P-(1-morpho-
linyl)-phosphoramidate (S)-(À)-3c: To a solution of (S)-(+)-
4 (336 mg, 1.2 mmol), Et3N (0.26 mL, 2.52 mmol) and THF
(20 mL) was added PCl3 (0.12 mL, 1.4 mmol) under nitrogen
atmosphere at 08C and the mixture was stirred for 20 h.
After filtering off the solid under nitrogen, the filtrate was
cooled to À788C and treated with lithium morpholide pre-
pared from morpholine (104 mg, 1.2 mmol) and butyllithium
(2.15M solution in hexane, 0.6 mL, 1.3 mmol) in 15 mL THF
at À308C. The resulting solution was warmed to room tem-
perature and stirred overnight. The solvent was removed
fflnder vacuum and the residue was passed through a silica
gel plug with ethyl acetate/petroleum ether (1:20) as elute to
afford (S)-(À)-3c as a colorless oil and solidified slowly on
standing; yield: 317 mg (67%); [a]2D0: À879 (c 0.1, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=6.92–6.31 (m, 6H), 3.77–
3.61 (m, 4H), 3.02–2.90 (m, 8H), 1.99–1.88 (m, 4H), 1.85–
1.79 (m, 2H), 1.73–1.70 (m, 2H); 31P NMR (125 MHz,
CDCl3): d=116.5; 13C NMR (100 MHz, CDCl3): d=148.9,
126.8, 126.4, 126.3, 125.9, 122.3, 122.0, 68.7, 45.6, 41.6, 37.7,
37.6, 35.2, 29.7, 29.6, 22.9, 18.5; HR-MS (EI): m/z=
395.1650, calcd. for C23H26NO3P: 395.1650.
(+)-1,1’-Spirobitetralin-8,8’-diol (4): White solid; mp 160–
1628C; [a]20: +214 (c 1.0, CH2Cl2).
(À)-1,1’-DSpirobitetralin-8,8’-diol (4): White solid; mp 161–
1638C; [a]2D0: À209 (c 1.0, CH2Cl2).
Determination of the Absolute Configuration of
Spiro Diol 4
The absolute configuration of spiro diol (+)-4 was deter-
mined by X-ray diffraction analysis of the single crystal of l-
menthoxycarboxylate of (+)-4. l-Menthyl chloroformate
(3.5 g, 16 mmol) was added to a stirred solution of (+)-4
(1.12 g, 4.0 mmol), NEt3 (4.0 mL), and DMAP (48 mg,
0.4 mmol) in CH2Cl2 (40 mL) under nitrogen. After being
stirred for 9 h at room temperature, the mixture was washed
with water, dilute HCl and brine. The organicphase was
dried over anhydrous Na2SO4 and concentrated. The residue
was recrystallized with petroleum ether to yield a crystal of
8,8’-bis-(l-menthyloxycarbonyloxy)-(+)-1,1’-spirobitetraline
suitable for X-ray analysis. White solid; mp 154–1568C;
[a]2D0: À43.8 (c 2.0, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d=6.98–6.93 (m, 2H), 6.83–6.75 (m, 4H), 4.29–4.21 (m,
2H), 2.98–2.86 (m, 2H), 2.76–2.70 (m, 2H), 1.99–1.49 (m,
18H), 1.27–1.19 (m, 4H), 0.84–0.73 (m, 16H), 0.69 (d, J=
6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=151.2, 147.9,
138.3, 135.7, 125.1, 124.7, 119.7, 77.4, 46.2, 39.7, 38.2, 34.6,
33.1, 30.3, 29.7, 25.0, 22.2, 21.0, 19.8, 19.0, 15.2; HRMS (EI):
m/z=644.4062, calcd. for C41H56O6: 644.4077.
General Procedure for Asymmetric Hydrogenation of
a-Dehydroamino Esters
The configuration of the spirobitetraline diol moiety in
the crystal of 8,8’-bis(l-menthyloxycarbonyloxy)-(+)-1,1’-
spirobitetraline was determined to be S by X-ray diffraction
analysis.
A solution of [RhACHTRE(UGN cod)2]BF4 (2.0 mg, 0.005 mmol) and
ligand (S)-(À)-3a (3.9 mg, 0.011 mmol) in CH2Cl2 (1.0 mL)
was stirred in a glove-box for 30 min to generate the cata-
lyst. This catalyst solution was added into the solution of
substrate (0.50 mmol) in toluene (4.0 mL). Hydrogenation
was performed in an autoclave with 10 atm of H2 at room
temperature for 3 h. After releasing H2, the reaction mixture
was passed through a short silica gel plug to remove the cat-
alyst. The filtrate was subjected to measurement of the con-
version and the enantiomeric excesses of products by
GC.[11a]
Synthesis of Chiral Spiro Phosphoramidite Ligand 3
(S)-(À)-O,O’-(1,1’-Spirobitetralin-8,8’-diyl)-N,N-dimethyl-
phosphoramidate (S)-(À)-3a: To a stirred solution of (S)-
(+)-4 (224 mg, 0.8 mmol) in 2.0 mL dry toluene was added
PACHTREUNG(NMe2)3 (0.20 mL, 0.9 mmol). The solution was stirred at
1008C for 4 h, and the toluene was removed under reduced
pressure. Flash chromatography on silica gel with ethyl ace-
tate/petroleum ether (1:10) afforded (S)-(À)-3 as a colorless
oil and solidified slowly on standing; yield: 184 mg
(65%); [a]2D0: À349 (c 0.8, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.08 (t, J=8.0 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H),
6.92–6.87 (m, 3H), 6.54 (d, J=8.0 Hz, 1H), 2.94–2.90 (m,
4H), 2.19 (s, 6H), 1.99–1.88 (m, 4H), 1.83–1.79 (m, 2H),
1.73–1.72 (m, 2H); 31P NMR (125 MHz, CDCl3): d=119.5;
13C NMR (100 MHz, CDCl3): d=126.8, 126.4, 126.3, 125.9,
122.3, 122.0, 41.6, 37.7, 37.6, 35.2, 29.7, 29.6, 22.9, 18.5, 15.5;
HR-MS (EI): m/z=353.1546, calcd. for C21H24NO2P:
353.1545.
X-Ray Crystallographic Study
Crystallographic datas (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge CrystallographicData Centre as supplemen-
tary publication No. CCDC-654423 for 1,1’-spirobitetraline-
8,8’-diol, CCDC-654421 for 1,1’-spirobiindane-7,7’-diol and
CCDC-654422 for 8,8’-bis-(l-menthyloxycarbonyloxy)-(+)-
1,1’-spirobitetraline. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax.: (internat.) +44-1223/336-033;
e-mail: deposit@ccdc.cam.ac.uk].
(S)-(À)-O,O’-(1,1’-Spirobitetralin-8,8’-diyl)-N,N-diethyl-
phosphoramidate (S)-3b: The compound (S)-(À)-3b was
prepared in 45% yield from PACHTRE(UNG NEt2)3 by the same proce-
dure as that for (S)-(À)-3a. [a]2D0: À497 (c 0.6, CHCl3);
Adv. Synth. Catal. 2007, 349, 2477 – 2484
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2483

Xiang-Hong Huo et al.
FULL PAPERS
Xiao, P. Cao, X. Zhang, Angew. Chem. 1998, 110, 1203;
Angew. Chem. Int. Ed. 1998, 37, 1100.
Acknowledgements
[8] P-Phos: 2,2’,6,6’-tetramethoxy-4,4’-bis(diphenylphosphi-
no)-3,3’-bipyridine: C.-C. Pai, C.-W. Lin, C.-C. Lin, C.-
C. Chen, A. S. C. Chan, J. Am. Chem. Soc. 2000, 122,
11513.
We thank the National Natural Science Foundation of China,
the Major Basic Research Development Program (Grant
G2000077506), and the Ministry of Education of China for
financial support.
[9] M. T. Reetz, G. Mehler, Angew. Chem. 2000, 112, 4047;
Angew. Chem. Int. Ed. 2000, 39, 3889.
[10] M. van den Berg, A. J. Minnaard, E. P. Schudde, J. va-
n Esch, A. H. M. de Vries, J. G. de Vries, B. L. Feringa,
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[11] a) Y. Fu, J.-H. Xie, A.-G. Hu, H. Zhou, L.-X. Wang,
Q.-L. Zhou, Chem. Commun. 2002, 480; b) Y. Fu, G.-
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2484
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Adv. Synth. Catal. 2007, 349, 2477 – 2484