Practical by ligand design: A new class of monodentate phosphoramidite ligands for rhodium-catalyzed enantioselective hydrogenations

Article abstract of DOI:10.1002/adsc.200606013

A new class of low-cost and easy-to-prepare monodentate phosphoramidite ligands (Cydam-Phos) has been developed from readily accessible and cheap trans-1,2-diaminocyclohexane as starting material through a three-step transformation. This type of ligands exhibited excellent enantioseletivities and high activities in rhodium(I)-catalyzed asymmetric hydrogenations of dehydro-α-amino acid methyl esters 9 (ee: 96.2-99.8%) and acetylenamides 11 (91.8-98.8%). The remarkable substituent effects exhibited by the ligands on the enantioselective control of the catalysis are rationalized on the basis of molecular structure of the catalyst precursor.

Full text of DOI:10.1002/adsc.200606013

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DOI: 10.1002/adsc.200606013
Practical by Ligand Design: A New Class ofMonodentate
Phosphoramidite Ligands for Rhodium-Catalyzed
Enantioselective Hydrogenations
Baoguo Zhao,a Zheng Wang,a and Kuiling Dinga,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: kding@mail.sioc.ac.cn
Received: January 11, 2006; Accepted: April 15, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A new class of low-cost and easy-to-pre- esters 9 (ee: 96.2–99.8%) and acetylenamides 11
pare monodentate phosphoramidite ligands (Cydam- (91.8–98.8%). The remarkable substituent effects ex-
Phos) has been developed from readily accessible hibited by the ligands on the enantioselective control
and cheap trans-1,2-diaminocyclohexane as starting of the catalysis are rationalized on the basis of mo-
material through a three-step transformation. This lecular structure of the catalyst precursor.
type of ligands exhibited excellent enantioseletivities
and high activities in rhodium(I)-catalyzed asymmet- Keywords: asymmetric catalysis; hydrogenation;
ric hydrogenations of dehydro-a-amino acid methyl modular ligands; phosphoramidites; rhodium
Introduction
Although the first catalytic homogeneous enantiose-
lective hydrogenation of olefinic compounds was real-
ized by using chiral monodentate phosphine/Rh com-
plexes,[1] a considerable number of bidentate chiral
phosphine ligands have been developed over the past
three decades since the appearance of Kaganꢀs
DIOP[2a] and Knowlesꢀ DIPAMP[2b,c] in the early
1970s, as well as Noyoriꢀs BINAP shortly thereaf-
ter.[2d] This was probably due to a generally accepted
dogma that monodentate ligands would have too
many degrees of freedom, leading to low enantiose-
lectivity, and that bidentate ligands were a prerequi-
site to reduce the rotational freedom around the
metal-phosphorus bond for efficient asymmetric in-
duction in the catalysis.[3] On the other hand, the pio-
neering works of Ferringa, de Vries, Reetz, Pringle
and others[4] at the beginning of this century brought
about a renaissance for the use of monodentate phos-
phorus ligands (e.g., 1) in asymmetric hydrogenations.
Since then, the development of monodentate phos-
Very recently, we reported a type of modular mono-
phorus ligands, for example, 2 and 3, has been a re- dentate phosphoramidite ligand 3 (DpenPhos) for
search topic of increasing interest due to the facts of Rh(I)-catalyzed asymmetric hydrogenations of a vari-
their easy preparation, good stability, as well as excel- ety of olefin derivatives.[10] Despite the advantages of
lent activity and enantioselectivity in asymmetric cat- excellent enantioselectivities and fine-tuning capabili-
alysis.[5–10]
ty exhibited by this type of ligands, their syntheses
were somewhat tedious. As an effort to develop low-
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Baoguo Zhao et al.
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cost and easy-to-prepare phosphorus ligands which protected intermediate was directly condensed with
can still hold the advantages of DpenPhos, herein we the corresponding acyl chloride without separation.
report our results on the design and synthesis of a The trimethylsilyl groups in the resulting product was
new class of modular monodentate phosphoramidite then removed with KF/TBAB/H2O at room tempera-
ligand 4 (CydamPhos) starting from very cheap and ture, affording the corresponding N,N’-acyl protected
readily accessible trans-1,2-diaminocyclohexane and diphenols 8b–d in high yields. The preparations of di-
salicylaldehyde derivatives, as well as their applica- phenols 8a and 8e–g were more straightforward. Di-
tions in RhI-catalyzed asymmetric hydrogenation of phenol 8a was obtained by direct reaction of 7a with
both a-dehydroamino acid derivatives and a-arylen- acetic anhydride in the presence of K2CO3, and 8e–g
amides.
by the reactions of 7b–d with benzoyl chloride in the
presence of Et3N. Diphenol 8b could be also prepared
in high yield by an analogous procedure as that for
8e–g. Finally, diphenols 8a–g were treated with hexa-
methylphosphorus triamide (HMPT) or hexaethyl-
Results and Discussion
As shown in Scheme 1, the synthesis of monophos- phosphorus triamide in refluxing toluene or xylene to
phorus ligands 4 was quite straightforward. Simple give the desired ligands 4a–i in moderate to good
condensation of (1R,2R)-1,2-diaminocyclohexane (5) yields. These ligands are stable enough to allow ma-
with salicylaldehyde derivatives (6a–d) in hot ethan- nipulation in open air and can be stored under an
ol,[11a] followed by vacuum evaporation of the solvent, argon atmosphere over several months without any
gave the corresponding salen derivatives, which were degradation. It is noteworthy that owing to the facile-
directly submitted to the subsequent intramolecular ness of each step as well as the easy-to-handle nature
reductive coupling using manganese as the reducing of all the related intermediates, ligand 4b could be
agent.[11b] The key diphenol intermediates 7a–d were readily prepared in tens of grams scale without using
obtained in 71–85% overall yields. The hydroxy any chromatographic purification.
groups of 7a were then protected with trimethylsilyl
With ligands 4a–i in hand, we then examined their
chloride (TMSCl) in the presence of Et3N,[11c] and the asymmetric induction ability in Rh(I)-catalyzed enan-
Scheme 1. Synthesis of monodentate ligands 4a–i.
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Ligands for Rhodium-Catalyzed Enantioselective Hydrogenations
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tioselective hydrogenations. In order to optimize the tive 9c and enamide 11a were subsequently investigat-
reaction conditions, ligand 4b was first tested for the ed. As can be seen from Table 1, the substituents R,
Rh(I)-catalyzed enantioselective hydrogenation, and R’ and R’’ in the ligands can exert substantial influen-
the a-dehydroamino acid derivative 9c and a-phenyl- ces on the asymmetric induction of both reactions. In
enamide 11a were taken as representative substrates, particular, the change of R’ groups from N-alkylacyl
respectively. The reactions were carried out at room to N-arylacyl substituents in the ligands can switch
temperature using 1 mol% of Rh(I) catalyst. After a the sense of asymmetric induction from S to R
preliminary examination of the reaction conditions (entry 1 vs. 2; entry 10 vs. 11). On the other hand, the
(See Table S1 in the Supporting Information), it was sterically more demanding 3,5-xylyl is obviously un-
found that dichloromethane was the best choice of favorable to the enantioselective control of the reac-
solvent and a 1:2.1 molar ratio of Rh(I) to 4b was op- tion (entries 2–4 and 11–13). This is different from the
timal for the hydrogenation of both substrates. The substituent effect of R in DepenPhos 3 where more
hydrogenation of a-dehydroamino acid derivative 9c bulky R resulted in better asymmetric induction.[10]
at 20 bar of hydrogen pressure and a-phenylenamide Remarkably, modification of the phosphoramidite N-
11a at 10 bar afforded the highest enantioselectivities substituents R’’ can also lead to a change in enantio-
(99.5% ee and 98.2% ee, respectively).
selectivities, with smaller methyl groups exhibiting
Under the optimized reaction conditions, the im- better ees (entries 1, 2 and 10, 11 vs. entries 5, 6 and
pacts of the R, R’ and R’’ substituents in CydamPhos 14, 15, respectively). The same trend has also been
ligands 4a–i on the enantioselectivities of Rh(I)-cata- observed in the Rh(I)-catalyzed hydrogenations of a-
lyzed hydrogenations of a-dehydroamino acid deriva- dehydroamino acid derivatives and enamides with
Table 1. The impact of R, R’ and R’’ groups in monodenate ligands 4a–i on the enantioselectivity of Rh(I)-catalyzed hydro-
genation of a-dehydroamino acid derivative 9c or enamide 11a.[a]
Entry
R, R’ and R’’ in 4
Substrate
ee [%][b]
Configuration[c]
1
2
3
4
5
6
7
8
R=H, R’=Me, R’’=Me (4a)
R=H, R’=Ph, R’’=Me (4b)
R=H, R’=4-MeC6H4, R’’=Me (4c)
R=H, R’=3,5-Me2C6H3, R’’=Me (4d)
R=H, R’=Me, R’’=Et (4e)
9c
9c
9c
9c
9c
9c
9c
9c
96.0
99.5
96.7
74.6
18.4
94.4
6.5
64.8
22.4
42.3
98.1
95.3
47.8
0
S
R
R
R
R
R
R
S
R=H, R’=Ph, R’’=Et (4f)
R=3-Me, R’=Ph, R’’=Me (4g)
R=4-Me, R’=Ph, R’’=Me (4h)
R=5-Me, R’=Ph, R’’=Me (4i)
R=H, R’=Me, R’’=Me (4a)
R=H, R’=Ph, R’’=Me (4b)
R=H, R’=4-MeC6H4, R’’=Me (4c)
=H, R’=3,5-Me2C6H3, R’’=Me (4d)
R=H, R’=Me, R’’=Et (4e)
9
9c
S
S
10
11
12
13R
14
15
16
17
18
11a
11a
11a
11a
11a
11a
11a
11a
11a
R
R
R
-
R
R
S
R=H, R’=Ph, R’’=Et (4f)
93.6
1.8
34.0
54.9
R=3-Me, R’=Ph, R’’=Me (4g)
R=4-Me, R’=Ph, R’’=Me (4h)
R=5-Me, R’=Ph, R’’=Me (4i)
R
[a]
All of the reactions were carried out at room temperature with a substrate concentration of 0.2M [substrate/cata-
lyst=100:1, Rh(I)/4=2.1)] for 20 h under 20 bar of H2 pressure for 9c or 10 bar for 11a. The conversion of substrate was
determined by 1H NMR to be>99%.
[b]
[c]
Determined by chiral HPLC.
Assigned by comparison of their optical rotations with literature data.[12]
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Baoguo Zhao et al.
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Table 2. Enantioselective hydrogenation of a-dehydroamino
acid 9 and enamide 11 derivatives under the catalysis of
analogous chiral monodentate phosphoramidite li-
gands, such as SIPHOS[7b] and DepenPhos.[10] On the
other hand, the substituent in MonoPhos/Rh(I)-cata-
lyzed reactions showed an opposite effect, where
N,N-diethyl-substituted MonoPhos exhibited a better
enantioselective induction than the N,N-dimethyl ana-
logue.[8j] Although at the present stage the exact
reason for the dramatic substituent effect of the N,N-
substituents (R’’) in these ligands on the enantioselec-
tion of the reaction is still unclear, the fine-tuning of
bite angles (P Rh P) in the catalytically active spe-
cies to match the different substrates may be critical
for both the reactivity and enantioselectivity of the
catalysis. Moreover, the R (Me) group situated at dif-
ferent positions of the phenoxy moieties in the ligands
could also significantly alter the enantioselectivities or
switch the sense of asymmetric induction of the catal-
ysis (entries 7–9 and 16–18). These observations sug-
gested that the stereocontrol capabilities of 4 are
highly sensitive to the subtle changes in the structural
moieties (R, R’ and R’’). These facts along with the
modular nature of this type of ligands suggest that
their asymmetric induction capabilities could be read-
ily tuned by judicious modifications of the R, R’ and
R’’ substituents at the skeleton of the CydamPhos li-
gands, which represents a valuable feature for ligand
optimization. Within the ligand series 4a–i, 4b turns
[Rh
(cod)2]BF4/4b.[a]
A
À
À
Entry R in 9 and 11
ee [%][b] Configuration[c]
1
2
3
4
5
6
7
8
9
10
11
12
H (9a)
CH3 (9b)
C6H5 (9c)
98.8
98.7
99.5
99.7
99.4
99.2
99.3
98.0
97.4
99.5
98.7
99.3
96.2
98.2
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
4-BrC6H4 (9d)
3-BrC6H4 (9e)
2-BrC6H4 (9f)
4-ClC6H4 (9g)
3-ClC6H4 (9h)
4-CH3OC6H4 (9i)
3-CH3OC6H4 (9j)
3-FC6H4 (9k)
4-O2NC6H4 (9l)
2NC6H4 (9m)
3,4-(CH3O)2C6H3 (9n)
132-O
out to be the most enantioselective chiral ligand for 14
15
16
17[d]
18
19
20
21
22
3-AcO-4-CH3OC6H3 (9o) 99.8
2-naphthyl (9p)
C6H5 (9c)
both reactions.
98.4
98.2
98.1
95.0
95.7
98.4
92.2
95.3
91.8
96.8
To investigate the substrate adaptability of the
Rh(I) catalyst composed of ligand 4b, a variety of a-
dehydroamino acid derivatives 9a–p and enamides
11a–h were hydrogenated under the optimized reac-
tion conditions, and the results are summarized in
Table 2. The catalyst Rh(I)/4b is very efficient for the
asymmetric hydrogenation of various a-dehydroami-
no acid derivatives (9a–p), affording the correspond-
C6H5 (11a)
4-ClC6H4 (11b)
4-CH3OC6H4 (11c)
4-CH3C6H4 (11d)
4-FC6H4 (11e)
6H4 (11f)
3-BrC6H4 (11g)
2-naphthyl (11h)
234-BrC
24
ing a-amino acid derivatives (10a–p) with excellent 25
enantioselectivities (96.2–99.8% ee, entries 1–16). The
[a]
All of the reactions were carried out in dichloromethane
at room temperature at a substrate concentration of
0.2M (substrate/catalyst=100:1). The reaction time is 2 h
for substrate 9 and 5 h for 11, respectively. The con-
version of substrate was determined by H NMR to be
>99%.
Determined by chiral HPLC or GC.
Assigned by comparison of their optical rotations with
literature data.[12]
substituent situated at the b-position of the a-dehy-
droamino acid derivatives has little impact on the
enantioselectivity of the reaction. When the hydroge-
nation of a-dehydroamino acid derivative 9c was car-
ried out with reduced catalyst loading (0.1 mol%),
the corresponding a-amino acid derivative could be
obtained in quantitative yield without a significant
1
[b]
[c]
loss of enantioselectivity (entry 17 vs. 3). The catalyst
[d]
Catalyst loading is 0.1 mol% with 20 h of reaction time.
Rh(I)/4b also demonstrated excellent enantioselectivi-
ty in the Rh(I)-catalyzed hydrogenation of a variety
of a-arylenamides 11a–h, affording the corresponding
a-arylamine derivatives 12a–h in 91.8–98.4% ee (en- 4b were obtained by analyzing aliquots taken from re-
tries 18–25). To estimate the catalytic activity of the action mixtures at regular intervals using the
Rh(I) complex with CydamPhos (4) ligand for the 1H NMR technique. All reactions were carried out in
titled reaction, the reaction profiles for the Rh(I)-cat- dichloromethane at room temperature under 15 atm
alyzed hydrogenation of a-dehydroamino acid deriva- of H2 in the presence of 1 mol% catalyst. It was
tive 9c using MonoPhos (1c, where R is methyl), found that the catalyst composed of 4b exhibited a
DpenPhos (3, where R is benzyl and R’ is methyl) or relatively lower catalytic activity than MonoPhos or
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Ligands for Rhodium-Catalyzed Enantioselective Hydrogenations
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À
À
Figure 1. Crystal structure of 4b (top) and [Rh{4b}2
G
been omitted for clarity. Selected interatomic distances [Š], angles, and torsion angles [8] in ligand 4b: P(1) N(2) 1.711(4),
À
À
P(1) O(2) 1.456(3), P(1) O
G
(cod)]+ BF4 : Rh P(1) 2.296(3), Rh P(2) 2.302(3), P(1) N(1)
À
À
1.647(13), P(2) N(2) 1.625(14); P(1) O(1) 1.624(9), P(1) O(2) 1.640(10), P(2) O(3) 1.622(10), P(2) O(4) 1.651(10); P(1)
À
À
À
À
À
Rh P(2) 95.96(11), P(1) Rh P(2) N(2) 27.1(6), P(2) Rh P(1) N(1) 29.6(6).
DpenPhos in this reaction (see Figure S1 in Support- (Figure 1b), which contains two cis-coordinated
ing Information). For the reaction catalyzed by Rh(I)/ monophosphoramidite ligands and adopts a similar
4b, there is clearly an incubation stage for the reac- coordination pattern to those reported for Rh(I) com-
tion within the initial 15 min period, after which the plexes of ligands 2 and 3.[7b,10] One of the N-benzoyl
conversion increased steadily in a nearly linear fash- phenyl rings of each ligand points towards the labile
ion over the following 25 min. Although the exact cod moiety, constituting an integral part of the chiral
reason for the presence of an incubation period is not environment around the Rh(I) center and thus might
clear at present, it is assumed that the catalyst activa- exert a profound influence on the steps of the catalyt-
tion required a period of time for transformation of ic process. The hydrogenation of a-dehydroamino
the catalyst precursor in some way to reach a steady acid derivative 9c with the isolated [Rh{4b}
A
concentration of catalytically active species.[5i]
complex afforded a-amino acid derivative 9c with
The remarkable substituent effects exhibited by 98.8% enantioselectivity, which was essentially same
ligand 4 as discussed above prompted us to investi- as that obtained by using the corresponding in situ
gate the underlying structural reasons. To this end, we prepared catalyst (Table 1, entry 3, 98.5% ee), sug-
succeeded in obtaining single crystals of ligand 4b and gesting that the complex may act as an active catalytic
its Rh(I) complex, both of which were characterized species.[4e,5j,7b,10] This result in combination with the
by X-ray crystallographic analysis. The absolute con- structural features of the Rh complex disclosed above
figuration of ligand 4b was assigned as 2S,3S,5R,6R by might, in part, explain the remarkable remote stereo-
its crystal structure (Figure 1a). The structure of control effect of the substituents R’ at the backbone
Rh(I) complex of ligand 4b was disclosed to be C2 of the ligand in the catalysis.
symmetric with the formula of [Rh{4b}2(cod)]BF4
G
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Baoguo Zhao et al.
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Conclusions
(400 mL) of trans-1R,2R-diaminocyclohexane 5 (21.7 g, 0.19
mol) at room temperature over 1 h. After stirring at reflux
temperature for 12 h, the mixture was cooled to room tem-
perature and the solvent was removed by vacuum evapora-
tion. The oil-like residue was dissolved in a mixture of dry
acetonitrile (1710 mL) and toluene (190 mL). To the solu-
tion was added manganese powder[11b] (325 mesh; 20.9 g,
0.38 mol), and the resulting mixture was cooled to 08C
before trifluoroacetic acid (58.3mL, 0.76 mol) was added
dropwise over a period of 30 min under an Ar atmosphere.
The reaction mixture was stirred vigorously at 208C for 24 h
followed by addition of two additional equivalents of tri-
fluoroacetic acid at 08C. After standing at that temperature
for 2 h, the resulting mixture was filtered and the residue
was washed with petroleum ether (bp 60–908C, 50 mL”2)
to afford a white solid. The solid was dissolved in H2O
(100 mL) and neutralized with saturated NaHCO3 solution
to pH 8. The aqueous solution was extracted with dichloro-
methane (200 mL”3). The combined organic layer was
washed with H2O (100 mL), dried over anhydrous Na2SO4,
and concentrated. The resulting white solid was recrystal-
lized with a mixture of petroleum and ethyl acetate (1:1) to
afford the desired compound (2S,3S,5R,6R)-7a as colorless
needles; yield: 52.3g (85%).
In summary, we have developed a new class of modu-
lar monodentate phosphoramidite ligands, which are
efficient for Rh(I)-catalyzed asymmetric hydrogenation
of a-dehydroamino acid derivatives and a-arylen-
amides. The salient features of this type of ligands, such
as cheap starting material and facile preparation,[13]
structural diversity, as well as remote stereocontrol
capability of backbone substituents, will stimulate
future studies to explore their applications in other
transition metal-catalyzed asymmetric reactions.[9]
Experimental Section
General Remarks
All the experiments which were sensitive to moisture or air
were carried out under an argon atmosphere using standard
Schlenk techniques. NMR spectra were recorded in CDCl3,
CD3OD or DMSO-d6 on a Varian Mercury 300 (1H
300 MHz; 13C 75 MHz, 31P 121 MHz, 19F 282 MHz) spec-
trometer. Chemical shifts are expressed in ppm with an in-
ternal standard: TMS (0 ppm), CDCl3 (7.20 ppm), CD3OD
(3.31 ppm), and DMSO-d6 (2.50 ppm) for 1H and CDCl3
(77.0 ppm) and DMSO-d6 (39.5 ppm) for 13C. 31P NMR
spectra were recorded with 85% H3PO4 as an external ref-
erence. The IR spectra were measured on a Rio-Rad FTS-
185 spectrometer in KBr pellets. EI (70 eV) and ESI mass
spectra were obtained on HP5989 A and Mariner LC-TOF
spectrometers, respectively. HR-MS were determined on an
IonSpect 4.7 TESLA FTMS. Elemental analyses were per-
formed with an Elemental VARIO EL apparatus. Optical
rotations were measured on a Perkin–Elmer 341 automatic
polarimeter. HPLC analyses were carried out on a JASCO
1580 liquid chromatograph with a JASCO CD-1595 detector
and AS-1555 autosampler. GC analyses were measured on
Agilent 6890N network system. trans-1R,2R-Diaminocyclo-
hexane (5) was obtained by optical resolution of a cis/trans-
1,2-diaminocyclohexane (40/60) mixture with l-(+)-tartaric
acid.[11a] 3-Methylsalicylaldehyde, 4-methylsalicylaldehyde
and 5-methylsalicylaldehyde were prepared by following the
literature method.[11d] Dichloromethane was freshly distilled
from calcium hydride and 2-propanol from magnesium fil-
ings, THF, xylene and toluene from sodium benzophenone
ketyl, ethyl acetate and acetonitrile from P2O5.
(2S,3S,5R,6R)-7b, c, d: Following a similar procedure to
that for the preparation of (2S,3S,5R,6R)-7a, (2S,3S,5R,6R)-
7b, c, d were obtained in good yields (80%, 78% and 71%,
respectively).
Preparation of(2 S,3S,5R,6R)-8a
To the mixture of compound (2S,3S,5R,6R)-7a (5.0 g,
15.4 mmol) and anhydrous K2CO3 (11.7 g, 77.2 mmol) in dry
DMF (50 mL), acetic anhydride (6.1 mL, 154 mmol) was
added dropwise at room temperature over 10 min. The reac-
tion mixture was heated to 1208C and stirred at the temper-
ature for 24 h. After removal of the solvent under vacuum,
aqueous NaHCO3 solution (0.5m, 100 mL) was added to the
residue followed by stirring at room temperature to result in
precipitation of a large amount of white solid. The solid was
collected by filtration and washed with water (20 mL”2)
and cooled ethanol (20 mL), respectively, to afford the title
compound (2S,3S,5R,6R)-8a (4.7 g) as a white solid. The fil-
trate was extracted with ethyl acetate (100 mL”3) and the
combined organic layer was washed with water (50 mL”2),
dried over anhydrous Na2SO4, and concentrated under
vacuum. The residue was crystallized from ethyl acetate to
afford additional 1.0 g of (2S,3S,5R,6R)-8a as a white solid;
total yield: 91%.
Ligand Synthesis
The characterization data for the compounds 7a–d, 8a–g and
4a–i can be found in the Supporting Information.
Preparation of(2 S,3S,5R,6R)-8b
Method A: To the solution of compound (2S,3S,5R,6R)-7a
(25 g, 0.077 mol) and NEt3 (48.7 mL, 0.35 mol) in dry tolu-
ene (400 mL), trimethylsilyl chloride (19.6 mL, 0.156 mmol)
was added dropwise at 08C over 20 min. The reaction mix-
ture was heated to reflux and stirred at the temperature for
1 h. After cooling to 08C, benzoyl chloride (18.1 mL, 0.156
Preparation of(2 S,3S,5R,6R)-7a; Typical Procedure
A solution of salicylaldehyde 6a (46.4 g, 0.38 mol) in EtOH
(200 mL) was added dropwise to the ethanol solution
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Ligands for Rhodium-Catalyzed Enantioselective Hydrogenations
mol) was added dropwise to the mixture over 30 min. The
FULL PAPERS
R1=0.0489, wR2=0.1034 on F2 for observed data, Pmax
,
resulting mixture was allowed to warm up to room tempera-
ture and stirred at that temperature overnight. After remov-
al of the solvent under vacuum, to the residue was added
water (150 mL), KF (17.2 g, 0.31 mol) and tetrabutylammo-
nium bromide (0.25 g, 0.77 mmol). The resulting mixture
was stirred at room temperature for 2 h to allow the precipi-
tation of the product. The precipitate formed in the solution
was collected by filtration and washed with water (50 mL”
2) and cooled EtOH (50 mL), respectively. The obtained
white solid was purified by recrystallization from a mixture
of petroleum and ethyl acetate (1:2) to give (2S,3S,5R,6R)-
8b as colorless prisms; yield: 34.9 g (85%).
P
min =0.250, À0.235 ŠÀ3; absolute structure parameter was
À0.3(2). CCDC-277383 contains the supplementary crystal-
lographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the CCDC, Cambridge, CB21EZ, UK; fax: (+44)-
1223–336–033; or e-mail: deposit@ccdec.cam.ac.uk].
Preparation of[{(2 S,3S,5R,6R)-4b}2Rh
A
N
A
solution of Rh(COD)2BF4 (37.0 g, 0.09 mmol) and
N
Method B: To the solution of compound (2S,3S,5R,6R)-7a
(1.0 g, 3.1 mmol) and NEt3 (1.72 mL, 12.3mmol) in dry tolu-
ene (8 mL), benzoyl chloride (1.42 mL, 12.3mmol) was
added dropwise at room temperature over 10 min. The reac-
tion mixture was stirred at 608C overnight. After the remov-
al of toluene under reduced pressure, 20% KOH aqueous
solution (15 mL) and ethanol (15 mL) were added. After
being stirred at room temperature for 6 h, ethanol was re-
moved under vacuum, and the resulting residue was neutral-
ized with 6M HCl aqueous solution to pH 8–9. The resulting
solids were collected by filtration, washed with water
(30 mL”3) and dried under vacuum. The desired compound
(2S,3S,5R,6R)-8b (1.6 g) was obtained in a total yield of
97% as a white solid, which could be used for next step
without further purification.
(2S,3S,5R,6R)-8c and d: Following a similar procedure to
that for the preparation of (2S,3S,5R,6R)-8b (Method A),
(2S,3S,5R,6R)-8c and d were obtained in yields of 98% and
97%, respectively.
(2S,3S,5R,6R)-8e, f, g: Following an analogous procedure
for the preparation of (2S,3S,5R,6R)-8b (Method B),
(2S,3S,5R,6R)-8e, f, g were obtained in yields of 76%, 85%
and 73%, respectively.
(2S,3S,5R,6R)-4b (110.3g, 0.18 mmol) in a mixture of dry di-
chloromethane (5 mL) and toluene (3mL) was stirred at
room temperature for 1 h. The resulting solution was fil-
tered and the filtrate was transferred to a Schlenk tube in
glove box. The Schlenk tube was then sealed with a rubber
plug and allowed to stand at room temperature for a week,
resulting in crystallization of a large amount of single crys-
tals as orange needles. The single crystals were submitted to
X-ray crystallographic analysis, NMR analysis, as well as use
in the catalysis of the hydrogenation of a-dehydroamino
acid derivatives. 1H NMR (300 MHz, CDCl3): d=1.20–1.50
(m, 8H), 1.61–2.02 (m, 10H), 2.10–2.35 (m, 2H), 2.55–2.70
(m, 4H), 2.78 (broad s, 12H), 3.64–3.67 (m, 2H), 4.04–4.12
(m, 2H), 4.52–4.61 (m, 2H), 5.21 (s, 2H), 5.43(s, 2H), 5.67–
5.72 (m, 2H), 6.90–7.08 (m, 8H), 7.12–7.20 (m, 8H), 7.24–
7.40 (m, 10H), 7.43–7.56 (m, 2H), 7.54 (m, 2H), 7.65 (dd,
2H, J=1.5, 7.8 Hz), 7.72 (d, 2H, J=6.9 Hz), 8.02 (d, 2H,
J=8.1 Hz); 31P NMR (121 MHz, CDCl3): d=117.24 (d, J=
235.6 Hz); 19F NMR (282 MHz, CDCl3): d=À153.11.
X-Ray Crystal Structural Data for
[{(2S,3S,5R,6R)-4b}2Rh
N
N
General Procedure for the Preparation of Ligands
4a–i
C92H96BF4N6O8P2Rh, crystal grown from dichloromethane/
toluene, Mr =1665.41, monoclinic, P21, a=9.9434(8), b=
42.996(3), c=10.9801(9) Š; V=4186.7(6) Š3, 1.89<2q<
25.50 degree; 1calc =1.321 gcmÀ3, Z=2, Rint =0.1418. Good-
ness of fit indicator=1.592, final R1=0.1608, wR2=0.3977
on F2 for observed data, Pmax, Pmin =2.690, À2.101 ŠÀ3; ab-
solute structure parameter was 0.00(11). CCDC-277384 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html [or from CCDC, Cambridge,
CB21EZ, UK; fax: (+44)-1223–336–033; or e-mail: deposit@
ccdec.cam.ac.uk].
A solution of 8 (1 mmol) with hexamethylphosphorus tria-
mide (1.1 mmol) in dry toluene (3mL), or with hexaethyl-
phosphorus triamide (1.1 mmol) in dry xylene (3mL) was
heated to reflux and kept stirring at that temperature for
12–24 h under an argon atmosphere until the complete con-
version of 8 (monitored by TLC). After cooling to room
temperature, the reaction mixture was concentrated under
vacuum. The residue was purified either by recrystallization
from the reaction solvent or by flash column chromatogra-
phy on silica gel with hexane/ethyl acetate/triethylamine (1/
0.15/0.1) as eluent to give the corresponding monodentate
phosphoramidite ligands 4 in the yields of 47–85%.
General Procedure for Catalytic Asymmetric
Hydrogenation
X-Ray Crystal Structure Data for (2S,3S,5R,6R)-4b
[Rh(cod)2]BF4 (2.0 mg, 0.005 mmol) and (2S,3S,5R,6R)-4
A
(0.011 mmol) were dissolved in CH2Cl2 (1 mL) under nitro-
gen and the solution was stirred at room temperature for
10 min. The solution of substrate 9 or 11 (0.5 mmol) in
CH2Cl2 (1.5 mL) was added to the above catalyst solution.
The resulting mixture was then transferred to a stainless
C36H36N3O4P,
10.0918(7) Š,
Mr =605.65,
tetragonal,
P43212,
a=
V=
b=10.0918(7) Š,
c=31.024(3) Š;
3159.6(4) Š3; 2.12<2q<28.28 degree; 1calc =1.273gcm À3
,
Z=4, Rint =0.1162. Goodness of fit indicator=0.759, final
Adv. Synth. Catal. 2006, 348, 1049 – 1057
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1055

Baoguo Zhao et al.
FULL PAPERS
steel autoclave under a nitrogen atmosphere, and then
sealed. After purging with hydrogen for 6 times, the final H2
pressure was adjusted to the desired value. After stirring at
room temperature for an appropriate time period, H2 was
released. Removal of the solvent under the reduced pres-
sure afforded the product residue, which was submitted to
1H NMR analysis to assess the conversion of the starting
materials. The crude product was purified by flash column
chromatography and enantiomeric excess of the product was
determined by chiral HPLC or GC.
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Financial support from the NSFC, CAS and the Major Basic
Research Development Program of China (Grant no.
G2000077506) and Committee of Science and Technology of
Shanghai Municipality is gratefully acknowledged
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Adv. Synth. Catal. 2006, 348, 1049 – 1057
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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