Asymmetric hydrogenation reactions mediated by a new class of bicyclic bisphosphinites

Article abstract of DOI:10.1016/S0957-4166(99)00341-9

The bicyclic alcohol (-)-4 was prepared from (-)-bicyclo[3.2.0]hept-2- en-6-one (-)-1 in 50% yield. The diol (-)-4 was coupled to selected chlorophosphines 6-12 to produce a series of bisphosphinites 13-19 in 89-95% yield. From these bisphosphinites were prepared the rhodium complexes 20-26 which were characterised by ³¹P NMR and used in situ for the asymmetric hydrogenation of α-enamides 27-29. Complexes 21, 23-25 proved to be the superior catalysts for the production of (R)-N-acetylphenylalanine (91, 84, 90 and 87.5% ee) from 27 and (S)-N-acetylalanine methyl ester (70, 72, 68 and 71% ee) from 28.

Full text of DOI:10.1016/S0957-4166(99)00341-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3341–3352
Asymmetric hydrogenation reactions mediated by a new class of
bicyclic bisphosphinites
a
a
a,∗
b
b
Nadine Derrien, Cyril B. Dousson, Stanley M. Roberts, Ulrich Berens, Mark J. Burk and
c
Manuela Ohff
a
Department of Chemistry, Liverpool University, Liverpool L69 7ZD, UK
b
Chirotech Technology Limited, Cambridge Science Park, Cambridge CB4 4WE, UK
c
Institut für Organische Katalyseforschungan der Universität Rostock e.V., Buchbinderstraße 5-6, D-18055 Rostock, Germany
Received 30 June 1999; accepted 9 August 1999
Abstract
The bicyclic alcohol (−)-4 was prepared from (−)-bicyclo[3.2.0]hept-2-en-6-one (−)-1 in 50% yield. The diol
(
−)-4 was coupled to selected chlorophosphines 6–12 to produce a series of bisphosphinites 13–19 in 89–95%
31
yield. From these bisphosphinites were prepared the rhodium complexes 20–26 which were characterised by
P
NMR and used in situ for the asymmetric hydrogenation of α-enamides 27–29. Complexes 21, 23–25 proved to
be the superior catalysts for the production of (R)-N-acetylphenylalanine (91, 84, 90 and 87.5% ee) from 27 and
(
S)-N-acetylalanine methyl ester (70, 72, 68 and 71% ee) from 28. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Wilkinson reported that the complex [Rh(Ph P) Cl] acted as a homogeneous catalyst for the hydroge-
3
3
1
nation of olefins over 30 years ago. Shortly afterwards, Horner published the first attempts to accomplish
asymmetric hydrogenation reactions using Wilkinson-type catalysts. Since that time various chiral
2
bidentate bisphosphine and bisphosphinite ligands have been developed for metal-catalysed asymmetric
3
4
hydrogenation reactions, some of the more popular being Achiwa’s BPPM, Kagan’s DIOP, Knowles’
DiPAMP, Noyori’s BINAP and Burk’s DuPHOS.
5
6
7
The desire for efficient routes to optically active natural and non-natural amino acids focused attention
on the use of chiral bisphosphine- and bisphosphinite-rhodium catalysts for the stereoselective hydroge-
nation of α-(acylamino)acrylates (α-enamides), as outlined in Scheme 1.8
,9
While chiral bisphosphine ligands are still the most commonly-used stereodirecting moieties in such
asymmetric hydrogenations, there is an increasing number of bisphosphinites (Scheme 1) being used
∗
Corresponding author. E-mail: sj11@liverpool.ac.uk
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00341-9

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N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
Scheme 1.
1
0
11
for the same purpose, for example Johnson’s glucophinite, Hayashi’s BDPCP and more recently
12
13,14
15
Zhang’s BICPO, Selke or RajanBabu’s carbohydrate phosphinites,
as well as Chan’s spirOP and
16
DIMOP. One reason for the increasing popularity of bisphosphinite ligands stems from the simple
method of preparation (by reacting diols with chlorophosphines in the presence of a base) and the ready
availability of the necessary starting materials. Thus, the preparation of the requisite chiral diols, which
should be readily available in both enantiomeric forms, has received significant impetus. The hydroxyl
groups must be held in space by a backbone so that, after formation of the bisphosphinite, a metal ion,
for example Rh(I), is tightly chelated between the phosphorus atoms.
2. Results and discussion
We realised that the bicyclo[3.2.0]heptane framework with its relatively inflexible superstructure has
established chemistry available for appending hydroxy substituents at positions which, when modified
to provide phosphinite units, would give the requisite bite-angles for complexation to rhodium(I). In this
article we describe the synthesis of the appropriate bisphosphinites, complexation to the metal and the
stereoselective hydrogenation of α-enamides using these new catalysts.17
2.1. Preparation of chiral phosphinite ligands based on the bicyclo[3.2.0]heptane ring system
18
Bicyclo[3.2.0]hept-2-en-6-one (ꢀ)-1 is readily prepared and may be resolved by preparation of
the bisulfite adduct and formation of diastereomeric salts with (S)-α-phenethylamine (ABAC).1
Treatment of the less water-soluble salt with aqueous hydrochloric acid afforded (−)-1 (Scheme 2).
Bromohydrin formation using N-bromosuccinimide in aqueous acetone furnished the bromohydrin (−)-
9,20
21
22
2
which was hydrodehalogenated giving (−)-3, and reduced with sodium borohydride to give the
diol (−)-4 in 50% overall yield from the ketone (−)-1. It is noteworthy that (−)-4 or (+)-4 may also be
prepared by biotransformations using baker’s yeast17 or lipase-catalysed reactions.
is readily available in both enantiomeric forms.
23,24
In short, the diol
4
Scheme 2. Reagents and conditions: (i) N-bromosuccinimide, H
iii) NaBH , MeOH, −78°C, 2 h (70%)
2
O, 20 h (91%); (ii) nBu
3
SnH, toluene, AIBN, 80°C, 1 h (76%);
(
4
Contemporaneously N,N-diethylphosphoramidous dichloride 525,26 was reacted with the appro-
priate Grignard reagent (RMgX), then dry HCl gas, to produce a series of chlorophosphines 6–12
13,25,27,28
(
Scheme 3).
Coupling of the diol (−)-4 to the chlorophosphines 6–12 in tetrahydrofuran by addition of triethylamine
gave the crude bisphosphinites 13–18 in 89–95% yield. The purity of the bisphosphinites was assessed by

N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
3343
g
Scheme 3. Reagents and conditions: (i) 2 equiv. RMgX, THF, 0°C; (ii) HCl , pentane, 0°C; overall yields 20–56%
31P NMR spectroscopy and by using this method the purities of the crude bisphosphinites were judged to
be 58, 66, 78, 65 and 98%, respectively, and were used in this purity for hydrogenation. The cyclohexyl
compound 19 was difficult to prepare (56% yield) and was produced only in a relatively impure state
31
(
43% pure by P NMR) (in all cases material of higher purity has been obtained for analysis, by filtration
of the crude material through neutral alumina under an atmosphere of an inert gas using diethyl ether as
eluant).
2.2. Formation of the chiral rhodium(I) catalysts and asymmetric hydrogenation of selected alkenes
The bisphosphinites 13–19 (B[3.2.0]DPO) were converted into the rhodium(I) complexes 20–26 using
13,14 31
an established procedure (Eq. 1).
P NMR spectra on complexes 20–26 showed JRhP in the range
175–182 and JPP in the range 0–32 Hz. Each of the catalyst precursors was used, in situ, to promote the
hydrogenation of three substrates, namely α-acetamidocinnamic acid 27, methyl 2-acetamidoacrylate 28
and dimethyl itaconate 29 to give 30, 31 and 32, respectively (Scheme 4).
(1)
Scheme 4.
†
The reactions were conducted in methanol at room temperature under hydrogen (200 psi) and were
complete within 3 h when employing 1 mol% of catalyst and GC/MS monitoring indicated quantitative
conversion of the α-enamide. Previous studies were carried out under atmospheric pressure of hydrogen
and gave a half-life time of 3 min (i.e. reaction is complete after 30 min), showing a good activity of these
catalyst precursors. Each experiment was carried out in triplicate and the results are reported in Table 1.
The compounds 20, 21, 23–25 catalysed the efficient reduction of N-acetylcinnamic acid 27 to give
(R)-N-acetylphenylalanine 30 (ee >80%). The catalysts 21–25 performed less well in the hydrogenation
of methyl 2-acetamidoacylate 28, yielding (S)-N-acetylalanine methyl ester 31 in good (66–72%) but not
excellent enantiomeric excess. None of the catalysts displayed a high degree of control in the asymmetric
†
The hydrogenations were performed in a multiwell bomb rated for high pressure; the lowest pressure which could be read
reliably on the gauge (200 psi) was used.

3344
N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
Table 1
Enantiomeric excess of asymmetric hydrogenation of substrates 27–29
hydrogenation of dimethyl itaconate 29.29 Contrarywise, the bis(dicyclohexyl)phosphinite 26 produced
(S)-N-acetylphenylalanine (55% ee) and (R)-N-acetylalanine methyl ester (26% ee).
It is noteworthy that, for the conversion of N-acetylcinnamic acid 27 into (R)-N-acetyl phenylalanine,
bisphosphinites with electron releasing aryl moieties such as para-fluoro 14, para-methoxy 17 and
-thienyl (18) perform better than the bisphosphinite (15) with an electron-withdrawing substituent
trifluoromethyl) in the para-position. However, the sulfur atom of the thienyl bisphosphinite 18 does
2
(
not interfere, in a manner that has been observed in heterogeneous catalysis. Interestingly, the electron-
donating cyclohexyl groups in compound 26 give rise, not to a higher enantiomeric excess for the
(R)-enantiomer of N-acetylphenylalanine but, instead, this catalyst furnishes the (S)-enantiomer of the
product (albeit in modest enantiomeric excess) due, no doubt, to the different steric environment provided
by the bulky, six-membered saturated rings.
The reduction of α-acetylamidocinnamic acid using the parent catalyst 20 was explored at different
temperatures and different concentrations (Table 2). Conducting the reaction at low temperature in a
concentrated solution led to an improvement in the enantiomeric excess of the product.
Table 2
Asymmetric hydrogenation of 27 using rhodium complex 20a

N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
3345
3. Conclusions
The rhodium(I) complexes 20–26 catalyse the asymmetric hydrogenation of α-acetamidocinnamic
acid to N-acetylphenylalanine, methyl 2-acetamidoacrylate to N-acetylalanine methyl ester and, less
efficiently, dimethyl itaconate to dimethyl 2-methylsuccinate. The relevant ligands 13–19 provide the
chiral framework that leads to the observed asymmetric reduction reactions. The effectiveness of this new
type of catalyst, in this highly competitive field,30 is good but not outstanding. However, the significant
positive points emanating from this research are as follows:
–
–
the bicyclo[3.2.0]heptane framework can provide useful ligands for organometallic catalysts;
bicyclo[3.2.0]heptane-3-endo-6-endo-diol is readily prepared in both enantiomeric forms. When de-
rivatised as a bisphosphinite and complexed to Rh(I), new catalysts for asymmetric hydrogenation
reactions can be readily prepared.
We are investigating the use of the complexes 20–26 as catalysts for other reactions and, at the same
time, we are preparing other types of ligand based on the bicyclo[3.2.0]heptane ring system.
4. Experimental
4.1. General methods
Manipulations of air and moisture sensitive materials were conducted under a nitrogen atmosphere
using standard Schlenk techniques. Tetrahydrofuran (THF), ether, pentane, toluene, methanol and petro-
leum ether, bp 40–60°C (PE), were distilled prior to use. Flash chromatography was performed using
Merck 60 silica gel (40–63 µm). Thin layer chromatography (TLC) was carried out using aluminium
sheets coated with Merck 60 F254 silica gel, R values are quoted with the ratio of the eluant system in
f
v/v and visualisation was achieved using ethanolic p-anisaldehyde followed by heating or by using a UV
1
13
31
19
lamp (254 nm). Melting points are uncorrected. NMR spectra ( H, C, P and F) were recorded using
Bruker AMX400, DRX400, AC300, WM250 and Varian 300 Gemini 2000 spectrometers. The absolute
1
13
value of the coupling constants (J) in hertz and assignments of H and C peaks were determined using
COSY, HETCOR and DEPT135 experiments where necessary. Mass spectra were recorded on Kratos
profile HV3, CIPOS, Fisons TRIO1000 solid probe and VG7070E spectrometers and relative intensity is
quoted. Optical rotations were measured using an Optical Activity LTD AA-1000 polarimeter operating
at 589 nm. Elemental analyses were recorded on a Carlo Erba Strumentazione mod. 1106 CHN analyser.
Enantiomeric excess (ee) was determined by chiral gas chromatography or chiral HPLC and retention
®
times (t ) are quoted in minutes. Chiral GC separations were accomplished using a Lipodex E (25
R
m×0.25 mm×0.2 µm film thickness) column from Macherey–Nagel unless otherwise stated. The carrier
gas was helium. Chiral HPLC separations were carried out on a Chiralpak AD HPLC column (25 cm×4.6
mm) from Daicel. (−)-ABAC was provided by ChiroTech Technology Limited (Cambridge, UK). The
bromide precursors for the chlorophosphine syntheses, cycloocta-1,5-diene (COD), lead(IV) acetate,
palladium(II) acetate, N-bromosuccinimide, trifluoroacetic acid, α-acetamidocinnamic acid, methyl 2-
acetamidoacrylate and dimethyl itaconate, were purchased from Aldrich. n-Tributyltin hydride was
purchased from Avocado. Fluoroboric acid diethyl ether complex (54% in diethyl ether) and sodium
borohydride were purchased from Fluka.

3346
N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
4.2. (1S,5R)-(−)-Bicyclo[3.2.0]hept-2-en-6-one 1
(−)-ABAC (100 g, 321 mmol, 1 equiv.) was dissolved in aqueous hydrochloric acid (592 g, 20% w/w,
10 equiv.) and stirred for 1 h at room temperature. The product (−)-(1) was extracted with diethyl ether
(
3×600 mL) and concentrated carefully under reduced pressure at 10°C to yield (−)-(1) (32 g) as a clear
1
oil (296 mmol, 92%). Bp 57°C, 18 mbar. R (EtOAc:PE, 1:2)=0.74; H NMR (CDCl , 300 MHz) 2.47
f
3
(ddddd, J=17.1, J=9.6, J=2.1, J=1.8, J=1.8, 1H), 2.63–2.67 (m, 1H), 2.69–2.73 (m, 1H), 3.32 (dddd,
J=17.4, J=8.7, J=3.0, J=0.6, 1H), 3.43–3.52 (m, 1H), 3.83–3.91 (m, 1H), 5.77–5.81 (m, 1H), 5.83–5.87
1
3
(
m, 1H); C NMR (75 MHz) 34.83 (CH ), 36.85 (CH), 54.23 (CH ), 61.92 (CH), 132.21, 132.95 (C
2
1
2
2
−
−1
and C ), 211.5 (C ); IR (Nujol) 1790 cm (CO stretch), 2800 cm (CH stretch).
3
6
4.3. (1R,2S,3S,5R)-(−)-2-Bromo-3-hydroxy-bicyclo[3.2.0]heptan-6-one 2
To a solution of (−)-1 (20.01 g, 185.0 mmol) in acetone (371 mL) and water (106 mL) was added
N-bromosuccinimide (42.87 g, 241.0 mmol) in portions. The reaction mixture was stirred at room
temperature for 20 h. Aqueous sodium metabisulfite (80 mL; 10% w/w) was added to the solution until
the initial yellow colour had faded. The acetone was removed under reduced pressure. The residue (white
precipitate in water) was redissolved in EtOAc (500 mL), and washed twice with water (50 mL) and brine
(
50 mL). The organic layer was dried (MgSO ), concentrated under reduced pressure and the residue
4
(
pale yellow solid) purified by crystallisation in EtOAc (53 mL) and PE (100 mL) to give (−)-(2) (34.51 g;
1
3
9
1
3
1%) as white crystals. R (EtOAc:PE, 1:2)=0.44; mp 86°C; H NMR (CDCl , 300 MHz) 2.20 (d, J=2.4,
f
3
3
2
2
3
H, OH, H/D exch.), 2.24 (d, J=14.1, 1H, H4 ), 2.53 (ddd, J=14.1, J=9.6, J=3.9, 1H, H4exo),
.19–3.23 (m, 2H, H7endo and H7exo), 3.56 (ddd, J=14.1, J=7.5, J=7.5, 1H, H ), 3.78–3.85 (m, 1H,
endo
3
3
3
1
1
3
H ), 4.32 (s, 1H, H ), 4.65 (br s, 1H, H ); C NMR (CDCl , 75 MHz) 37.39 (C ), 39.08 (C ), 53.23 (C ),
5
5
2
3
3
4
1
7
81
+
7.43 (C ), 63.44 (C ), 81.99 (C ), 211.50 (C ); MS (CI/NH ) m/z 224.0 (35%, [M Br+NH ] ), 222.0
5
9
2
3
6
3
4
7
+
+
+
(37, [M Br+NH ] ), 142.0 (100, [M+NH −HBr] ), 126.0 (70, [M+NH −BrNH ] ); HRMS (CI/NH )
4
4
4
3
3
+
20
calcd for C H BrO N [M+NH ] : 222.01297; found: 222.01263; [α] −45 (CHCl , c 20.2); anal.
found: C, 41.08; H, 4.43; calcd for C H BrO : C, 41.00; H, 4.42.
7
13
2
4
D
3
7
9
2
4.4. (1R,3R,5R)-(−)-3-Hydroxy-bicyclo[3.2.0]heptan-6-one 3
To a solution of (−)-2 (2.01 g; 9.80 mmol) in dry toluene (15 mL) was added under nitrogen n-
tributyltin hydride (4.28 g, 15 mmol) and AIBN (15 mg, 0.1 mmol). The reaction mixture was heated to
0°C for 1 h, allowed to cool to room temperature and concentrated under reduced pressure providing a
yellow liquid. The tin residues were removed by partitioning between acetonitrile (50 mL) and hexane
8
(
35 mL) and extracting the acetonitrile layer with hexane (4×35 mL). The combined hexane layers were
then back-extracted with acetonitrile (3×30 mL). The combined acetonitrile layers were dried (MgSO ),
4
filtered, evaporated under reduced pressure and the crude product was purified by chromatography on
silica gel with PE:EtOAc (2:1, v/v). The product was crystallised from hexane to yield the title compound
1
(
938 mg; 76%) as white crystals. R (EtOAc:PE, 1:2)=0.21; mp 62°C; H NMR (CDCl , 300 MHz) 1.74
f
3
2
3
3
(
s, 1H, OH, H/D exch.), 1.88 (ddd, J=14.1, J=9.3, J=3.6, 1H, H ), 1.98 (m, 2H, 2H ), 2.20 (d,
4exo
2
2
2
3
3
J=14.1, 1H, H4 ), 2.93 (m, 1H, H ), 3.05 (ddd, J=18.0, J=3.7, J=3.6, 1H, H7endo), 3.22 (ddd,
J=18.0, J=3.7, J=9.6, 1H, H ), 3.62 (m, 1H, H ), 4.56 (br s, 1H, H ); C NMR (75 MHz) 28.54
endo
3
1
2
3
13
7exo
5
3
+
(
1
[
C ), 40.38, 41.16 (C , C ), 53.47 (C ), 63.39 (C ), 75.75 (C ), 214.50 (C ); MS (EI) m/z 126 (4%, [M] ),
1 2 4 7 5 3 6
+
+
08 (76, [M−H O] ), 83 (100); HRMS (EI) calcd for C H O [M] : 126.06808; found: 126.06785;
2 7 10 2
2
0
α] −124 (CHCl , c 20.3).
D
3

N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
3347
4.5. (1R,3R,5R,6S)-(−)-Bicyclo[3.2.0]heptan-3,6-diol 4
To a solution of (−)-3 (19.33 g, 153.0 mmol) in dry methanol (560 mL) at −78°C was added sodium
borohydride (7.52 g; 199.0 mmol) in portions over 5 min. The reaction mixture was stirred for 2 h
and then quenched with saturated aqueous ammonium chloride (20 mL). The mixture was concentrated
under reduced pressure and the yellow liquid obtained was diluted with EtOAc (600 mL) and washed
with water (100 mL) and twice with brine (100 mL). The organic layers were dried (MgSO ) and the
4
solvent concentrated under reduced pressure. The product was purified by silica gel chromatography with
PE:EtOAc (2:3, v/v) and crystallised from hexane to yield diol (−)-4 (13.70 g, 70%) as white crystals. R
f
1
2
3
(
EtOAc:PE, 1:2)=0.21; mp 111°C; H NMR (C D :CS , 1:2, v/v, 400 MHz) 1.59 (ddd, J=14.2, J=8.8,
6 6 2
3
2
3
3
4
J=5.0, 1H, H4exo), 1.63 (m, 2H, H2endo and H2exo), 1.75 (dddd, J=13.4, J=4.8, J=4.8, J=1.3, 1H,
2
2
3
3
H
), 2.03 (d, J=14.2, 1H, H
), 2.35–2.41 (m, 1H, H ), 2.55 (dddd, J=13.4, J=9.2, J=8.8,
1
7endo
4endo
3
4
3
3
3
3
J=1.6, 1H, H7exo), 2.98 (ddd, J=8, J=8, J=8, 1H, H ), 4.13 (m, 1H, H ), 4.31 (ddd, J=3.2, J=3.2,
5
6
3
3
3
13
J=3.2, 1H, H ), 5.02 (d, J=3.6, 1H, OH H/D exch.), 5.14 (d, J=10.4, 1H, OH , H/D exch.);
C
3
3,
6
NMR (C D :CS , 1:2, v/v, 100 MHz) 32.68 (C ), 35.48 (C ), 38.27 (C ), 43.12 (C ), 45.57 (C ), 65.26
6
6
2
1
4
7
2
5
+
+
+
(
1
1
C ), 76.08 (C ); MS (CI/NH ) m/z 146.1 (75%, [M+NH ] ), 129.1 (100, [M+H] ), 128.1 (43, [M] ),
11.0 (40, [M+H−H O] ), 93.0 (17, [M+H−2H O] ); HRMS (CI/NH ) calcd for C H O [M+H] :
2 2 3 7 13 2
6
3
3
4
+
+
+
20
29.09156; found: 129.09144; [α]D −52.4 (CHCl , c 20.0); anal. found: C, 65.28; H, 9.45; calcd for
3
®
C H O : C, 65.60; H, 9.44. Ee >99% by chiral GC (Lipodex E).
7
12
2
4.6. Synthesis of diarylchlorophosphines. General method A
4.6.1. Bis(2-thienyl)chlorophosphine 11
A 3 l three-neck flask fitted under nitrogen with a condenser and a dropping-funnel was charged with
magnesium turnings (42 g, 1.72 mol) in THF (150 mL). To this suspension was added, in portions, a
few drops of a solution of 2-bromothiophene (250 g, 1.53 mol) in THF (200 mL). When the Grignard
reaction had started, the rest of the halide solution was added slowly to maintain a gentle reflux. After the
addition was complete, the reaction was stirred for another 2 h at room temperature. The reaction flask
was cooled to 0°C in an ice bath and 5 (120 g) in THF (100 mL) was added via the dropping-funnel. The
reaction was stirred for 2 h at 0°C and then for 1 h at 40–50°C. After cooling down to room temperature,
pentane (1.2 L) was added to precipitate the magnesium salts. The salts were filtered off, and the solvent
was removed under reduced pressure. To remove the salts completely, the residue was redissolved in
®
pentane and filtered once more through a Celite pad. After removal of the solvent, the solid residue was
dissolved in a Schlenk flask under nitrogen in pentane (600 mL) and the resulting orange solution cooled
to 0°C with an ice bath. Dry HCl gas (excess) was passed through concentrated sulfuric acid and then
bubbled through the reaction solution for 1 h. The salts was filtered off under nitrogen, and the filter cake
was washed with pentane (5×100 mL). After removal of the solvent the crude yellow oil was distilled
1
to give 11 (100 g, 56%) as a pale yellow solid. Bp 144°C, 0.1 mbar; H NMR (CDCl , 400 MHz) 7.19
3
13
(
ddd, J=5.1, J=3.4, J=1.8, 1H), 7.63 (ddd, J=6.4, J=3.4, J=1.0, 1H), 7.78 (dd, J=5.1, J=1.0, 1H);
NMR (CDCl , 100 MHz) 127.67 (d, J =8.7, C ), 133.82 (s, C ), 135.97 (d, J =35.9, C ), 140.19
d, J =46.8, C ); P NMR (CDCl , 162 MHz) 51.1 (s); MS (EI) m/z 234 (16%, [M Cl] ), 232 (40,
M Cl] ), 197 (36, [M−Cl] ), 166 (100, [M−Cl−P] rearr.); HRMS (EI) calcd for C H ClPS [M] :
C
3
2
3
PC
4
5
PC
3
1
31
37
+
(
PC 2 3
35
+
+
+
+
[
8 6 2
231.93372; found: 231.93406.
The diarylchlorophosphines 7–12 were synthesised using the same general method A as for 11.

3348
N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
4.7. Synthesis of the bisphosphinite ligands (B[3.2.0]DPO) 13–19. General method B
To a solution of (−)-4 (300 mg, 2.34 mmol) in dry THF (15 mL) under nitrogen was added triethyl-
amine (0.50 g, 4.91 mmol). This solution was cooled to 0°C in an ice bath and the chlorophosphine (4.91
mmol) was added dropwise. When the addition was complete, the ice bath was removed and stirring was
®
continued at ambient temperature for 15 h. The triethylammonium salt was filtered off through a Celite
pad under nitrogen, and the solvent was removed under reduced pressure to give the crude product, used
at this stage for in situ catalyst preparations. For analytical purposes further purification was carried out.
To remove the remaining salts, chlorophosphine and impurities from this crude, a mixture of dry diethyl
ether:pentane (2:1, v/v) was added to the crude ligand, and this solution was filtered under nitrogen
through a neutral alumina pad. Removal of the solvent gave the bisphosphinite ligand as an oil; most of
the products became solid after a few days. The purity was checked by 3 P NMR.
1
4.7.1. (1R,3R,5R,6S)-3,6-Bis[diphenylphosphinooxy]-bicyclo[3.2.0]heptane 13
This bisphosphinite was synthesised using general method B, and obtained as a white solid (98%
31
13
yield, 40% P NMR purity). C NMR (CDCl , 100 MHz) 30.01 (C ), 33.88 (C ), 37.47 (C ), 40.98
3
1
4
7
(
C ), 45.52 (C ), 70.26 (C ), 85.11 (C ), 128.17, 128.23, 128.85, 128.89, 128.98, 129.01, 129.12, 130.13,
2 5 6 3
IV
1
30.25, 130.34, 130.49, 130.51, 130.68, 130.71, 130.73 (20 CH, Ph), 142.06, 142.25, 142.49 (4 C , Ph);
3
1
+
P NMR (CDCl , 162 MHz) 107.98 (s, 1P), 109.83 (s, 1P); HRMS (EI) calcd for C H F O P [M] :
3
31 26
4
2 2
496.17210; found: 496.17177.
0
4
.7.2. (1R,3R,5R,6S)-3,6-Bis[di(4 -fluorophenyl)phosphinooxy]-bicyclo[3.2.0]heptane 14
This bisphosphinite was synthesised using general method B, and obtained as a white solid (88% yield,
3
1
13
3
9
9% P NMR purity). C NMR (CDCl , 100 MHz) 30.41 (s, C ), 34.02 (d, J =5.6, C ), 37.18 (d,
3 1 PC 4
3
3
3
2
J =6.6, C ), 41.07 (d, J =4.8, C ), 45.65 (d, J =4.9, C ), 70.17 (d, J =16.4, C ), 84.99 (d,
J =17.9, C ), 115.56, 115.59, 115.61 (3 dd, intensity: 1:2:1, J =20.8, J =7.2, 7.4, 7.6, C
C300 and C500 ), 132.29, 132.37, 132.81, 132.91 (4 dd, J =22.9, 22.9, 23.5, 23.5, J =8.1, C 0 0 , C200
and C600), 137.58–138.23 (m, 13 signals, C 0 and C100), 163.61, 163.70, 163.77, 163.80 (4 d, J =247.7,
C4
0 and C400); P NMR (CDCl , 101 MHz) 105.63 (s, 1P), 107.26 (s, 1P); MS (EI) m/z 568 (0.3%,
3
M] ), 458 (13), 316 (16), 239 (37), 238 (43), 237 (100), 219 (33); HRMS (EI) calcd for C H F O P
M] : 568.13446; found: 568.13466.
PC
7
PC
2
PC
5
2
PC
6
2
3
0
, C5
0
,
PC
3
FC
PC
3
3
2
, C6
FC
PC
2
1
1
FC
31
+
[
[
31
26
4
2
2
+
0
4
.7.3. (1R,3R,5R,6S)-3,6-Bis[di(4 -trifluoromethylphenyl)phosphinooxy]-bicyclo[3.2.0]heptane 15
This bisphosphinite was synthesised using general method B, and obtained as a white solid (84%
3
1
13
3
yield, 98% P NMR purity). C NMR (CDCl , 100 MHz) 30.77 (s, C ), 34.19 (d, J =5.8, C ), 37.01
3
1
PC
4
3
3
3
2
(
(
d, J =6.5, C ), 41.25 (d, J =4.9, C ), 45.81 (d, J =5.0, C ), 70.87 (d, J =16.8, C ), 85.75
d, J =17.9, C ), 124.07, 124.08, 124.10, 124.12 (4 q, J =270.6, 4 CF ), 125.41 (m, C
and C500 ), 130.10, 130.24, 130.76, 130.80 (4 d, J =21.6, 21.6, 22.4, 22.2, C
PC
7
PC
2
PC
1
5
PC
6
2
0
, C5
0 , C300
, C200 and C600),
PC
3
FC
3
3
2
0
, C6
0
PC
2
1
1
31.17–132.00 (m, C
0
and C400 ), 146.20, 146.43, 146.66, 146.68 (4 d, J =23.1, 22.9, 23.0, 19.0, C
0
4
PC
1
+
31
and C100); P NMR (CDCl , 101 MHz) 103.21 (s, 1P), 104.59 (s, 1P); MS (EI) m/z 768 (0.3%, [M] ),
3

N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
3349
+
+
4
47 (15, [M−P(Aryl) ] ), 431 (9, [M−OP(Aryl) ] ), 339 (84), 337 (60), 321 (54), 93 (100); HRMS (EI)
2
2
+
calcd for C H F O P [M] : 768.12164; found: 768.12020.
35
26 12
2 2
0 0 0
.7.4. (1R,3R,5R,6S)-3,6-Bis[di(3 ,5 -dimethyl-4 -methoxyphenyl)phosphinooxy]-bicyclo[3.2.0]-
4
heptane 16
This bisphosphinite was synthesised using general method B, and obtained as a white solid (90%
3
1
13
yield, 99% P NMR purity). C NMR (CDCl , 100 MHz) 16.19, 16.21, 16.23 (3 s, intensity: 1:2:1,
3
3
3
3
8
CH ), 29.25 (s, C ), 33.66 (d, J =5.7, C ), 38.30 (d, J =6.8, C ), 40.91 (d, J =4.5, C ), 45.13
3 1 PC 4 PC 7 PC 2
d, J =4.5, C ), 59.58 (bs, 4 OCH ), 69.58 (d, J =15.7, C ), 84.23 (d, J =16.9, C ), 130.64 (bd,
JPC=7.4, C3
3
2
2
(
PC
5
3
PC
6
PC
3
3
2
0
, C5
0 , C300 and C500 ), 130.86, 131.03, 131.25, 131.31 (4 d, J =22.2, 22.0, 22.1, 23.0,
PC
C2
0
, C
0
, C200 and C600 ), 136.91–137.41 (m, C1
0
and C100), 157.89, 157.99, 158.04, 158.05 (4 s, C4
0
and
6
3
1
+
C400 ); P NMR (CDCl , 162 MHz) 105.44 (s, 1P), 107.66 (s, 1P); MS (EI) m/z 728 (6%, [M] ), 453
38), 427 (6, [M−P(Aryl) ] ), 317 (100), 301 (58), 276 (3, [M−Ar−OP(Aryl) ] ); HRMS (EI) calcd for
3
+
+
(
2
2
+
C H O P [M] : 728.33954; found: 728.33997.
43
54
6 2
0
4
.7.5. (1R,3R,5R,6S)-3,6-Bis[di(4 -methoxyphenyl)phosphinooxy]-bicyclo[3.2.0]heptane 17
This bisphosphinite was synthesised using general method B, and obtained as a white solid (84% yield,
3
1
13
3
9
9% P NMR purity). C NMR (CDCl , 100 MHz) 30.24 (s, C ), 34.07 (d, J =4.7, C ), 37.69 (d,
3 1 PC 4
3
3
3
2
J =5.8, C ), 41.15 (d, J =3.3, C ), 45.72 (d, J =3.7, C ), 55.34 (s, 4 OCH ), 69.87 (d, J =15.4,
C ), 84.73 (d, J =17.4, C ), 114.05 ( d , J=7.0, C , C5 , C ,
C200 and C600 ), 133.77–134.32 (m, C1
NMR (CDCl , 101 MHz) 107.45 (s, 1P), 109.68 (s, 1P); MS (EI) m/z 616 (3%, [M] ), 369 (14), 262 (34),
PC
7
PC
2
PC
5
3
PC
2
00 00
0 0 , C300 and C500), 132.10–132.83 (m, C20 0
6
PC
3
3
6
31
0
and C100 ), 160.59, 160.70, 160.78, 160.79 (4 s, C4
0
and C400);
P
+
3
+
2
61 (100), 245 (45); HRMS (EI) calcd for C H O P [M] : 616.21436; found: 616.21316.
35
38
6 2
0
4
.7.6. (1R,3R,5R,6S)-3,6-Bis[di(2 -thienyl)phosphinooxy]-bicyclo[3.2.0]heptane 18
This bisphosphinite was synthesised using general method B, and obtained as a pale yellow paste (92%
3
1
13
3
yield, 98% P NMR purity). C NMR (CDCl , 100 MHz) 30.19 (s, C ), 33.64 (d, J =5.5, C ), 37.51
3
1
PC
4
3
3
3
2
(
d, J =6.7, C ), 41.03 (d, J =4.7, C ), 45.54 (d, J =4.9, C ), 69.59 (d, J =11.9, C ), 84.40 (d,
PC 7 PC 2 PC 5 PC 6
2
3
J =14.7, C ), 127.66, 127.68 (2 d, J =7.8, C
0 and C400), 131.72, 131.87, 132.02, 132.04 (4 s, C50
4
and C500), 133.84, 134.17, 134.25, 134.43 (4 d, J =29.5, 30.1, 31.0, 30.7, C
43.70, 144.00 (4 d, J =33.9, 35.2, 31.7, 35.2, C
P), 88.08 (s, 1P); MS (EI) m/z 520 (0.7%, [M] ), 323 (3.5, [M−P(thienyl) ] ), 297 (61), 280 (15), 215
PC
3
PC
2
0 and C300 ), 146.26, 143.41,
and C200); P NMR (CDCl , 101 MHz) 85.16 (s,
PC
3
1
31
1
1
0
PC
2
3
+
+
2
+
(
45), 213 (76), 197 (100); HRMS (EI) calcd for C H O P S [M] : 519.99780; found: 519.99753.
23
22
2 2 4
4.7.7. (1R,3R,5R,6S)-3,6-Bis[di(cyclohexyl)phosphinooxy]-bicyclo[3.2.0]heptane 19
This bisphosphinite was synthesised using general method B, and obtained as a white solid (56% yield,
3
1
13
4
3% P NMR purity). C NMR (CDCl , 100 MHz) 24.94–27.00 (m), 27.81–28.37 (m), 30.19 (s), 36.56
3
2
2
31
(
(
[
s), 37.24–37.96 (m), 44.01 (s), 59.90 (s), 72.22 (d, J =17.8, C ), 86.72 (d, J =18.3, C ); P NMR
CDCl , 162 MHz) 147.36 (s, 1P), 150.51 (s, 1P); MS (FAB) m/z 437.2 (6%, [M−C H ] ), 307.2 (13,
M−OP(C H ) ] ), 231.1 (44), 215.1 (100).
PC 6 PC 3
+
3
6
11
+
6
11 2

3350
N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
4.8. Preparation of the rhodium complexes 21–26. General method C
To the bisphosphinites 13–19 (2.2 mmol) in a Schlenk flask under nitrogen was added degassed
methanol (20 mL) and [(COD) Rh]BF (4.8 mmol) at room temperature. The mixture was stirred for
2
4
2
h and the solvent was carefully removed under reduced pressure. The residue was then used promptly
for NMR characterisation.
+
−
4
.8.1. [((1R,3R,5R,6S)-3,6-Bis[diphenylphosphinooxy]-bicyclo[3.2.0]heptane)Rh(COD)] BF 20
4
31
P NMR (CDCl , 162 MHz) 109.50 (d, JRhP=178, 1P), 114.80 (d, JRhP=178, 1P).
3
0
+
4
.8.2. [((1R,3R,5R,6S)-3,6-Bis[di(4 -fluorophenyl)phosphinooxy]-bicyclo[3.2.0]heptane)Rh(COD)]
−
BF 21
4
31
P NMR (CDCl , 162 MHz) 105.53 (dd, J =182, J =10.8, 1P), 109.22 (dd, J =182, J =10.8,
3
RhP
PP
RhP
PP
1P).
0
4
.8.3. [((1R,3R,5R,6S)-3,6-Bis[di(4 -trifluoromethylphenyl)phosphinooxy]-bicyclo[3.2.0]heptane)-
+
−
Rh(COD)] BF 22
4
31
P NMR (CDCl , 162 MHz) 96.29 (dd, J =176, J =20.6, 1P), 113.07 (dd, J =176, J =20.6,
3
RhP
PP
RhP
PP
1P).
0
0
0
4
.8.4. [((1R,3R,5R,6S)-3,6-Bis[di(3 ,5 -dimethyl-4 -methoxyphenyl)phosphinooxy]-bicyclo[3.2.0]-
+
−
heptane)Rh(COD)] BF 23
4
31
P NMR (CDCl , 162 MHz) 105.53 (dd, J =182, J =10.8, 1P), 109.22 (dd, J =182, J =10.8,
3
RhP
PP
RhP
PP
1P).
0
4
.8.5. [((1R,3R,5R,6S)-3,6-Bis[di(4 -methoxyphenyl)phosphinooxy]-bicyclo[3.2.0]heptane)
+
−
Rh(COD)] BF 24
4
31
P NMR (CDCl , 162 MHz) 105.94 (dd, J =182, J =9.7, 1P), 110.61 (dd, J =182, J =9.7,
3
RhP
PP
RhP
PP
1P).
.8.6. [((1R,3R,5R,6S)-3,6-Bis[di(2 -thienyl)phosphinooxy]-bicyclo[3.2.0]heptane)Rh(COD)] BF4−
0
+
4
25
31
P NMR (CDCl , 162 MHz) 79.77 (dd, J =175.9, J =39.2, 1P), 93.3 (dd, J =175.9, J =39.2,
3
RhP
PP
RhP
PP
1P).
4
.8.7. [((1R,3R,5R,6S)-3,6-Bis[di(cyclohexyl)phosphinooxy]-bicyclo[3.2.0]heptane)Rh(COD)]+ BF4−
26
31
P NMR (CDCl , 162 MHz) 210.11 (d, JRhP=175.5, 1P), 218.78 (d, JRhP=179.1, 1P).
3

N. Derrien et al. / Tetrahedron: Asymmetry 10 (1999) 3341–3352
3351
4.9. Asymmetric hydrogenation reactions. General method D
To the B[3.2.0]DPO ligand 13–19 (0.01 mmol) was added in a Schlenk flask under nitrogen degassed
methanol (5 mL) and [(COD) Rh]BF (11 µmol). The reaction mixture was stirred at room temperature
2
4
until everything was dissolved. A 50 mL hydrogenation autoclave was charged with 1.0 mmol of
the substrate 27–29 and a magnetic stirrer bar. The autoclave was assembled, flushed five times with
hydrogen (to 200 psi), and the solution of the catalyst formed in situ was added through the solvent port.
Hydrogenation was effected at room temperature (200 psi hydrogen pressure), and was complete after 3
1
h in all cases (reaction monitored either by GC/MS, H NMR or TLC). The enantiomeric excesses (ees)
of the hydrogenated products 30–32 were determined either by chiral HPLC or by chiral GC and are
reported in Tables 1 and 2.
4.9.1. Hydrogenation of α-acetamidocinnamic acid 27
The α-acetamidocinnamic acid was hydrogenated following general method D. The ee was determined
by chiral HPLC (Chiralpak AD). Mobile phase: heptane:i-PrOH:trifluoroacetic acid, 90:10:1, v/v/v. Flow
rate: 1 mL/min, 20 µL injected in IPA. t (min): 10 (R)-enantiomer, 12.5 (S)-enantiomer.
R
4.9.2. Hydrogenation of methyl 2-acetamidoacrylate 28
The methyl 2-acetamidoacrylate was hydrogenated following general method D. The ee was determi-
ned by chiral GC (Chirasil Dex CB column). Injection: 200°C, program: 60°C for 5 min, then 10°C/min,
to 200°C and left for 10 min. Detection: FID 200°C, split 1/100, 1 µL injected in methanol. t : 12.80
R
(S)-enantiomer, 12.95 (R)-enantiomer.
4.9.3. Hydrogenation of dimethyl itaconate 29
The dimethyl itaconate was hydrogenated following general method D. The ee was determined by
chiral GC (Chiraldex G-TA column). Injection: 200°C, program: 80°C for 25 min, split 1/100, 1 µL
injected in methanol. t : 18.80 (S)-enantiomer, 20.10 (R)-enantiomer.
R
Acknowledgements
We thank ChiroTech for a Fellowship (to N.D.) and a studentship (to C.B.D.).
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2
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6
7
8
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8
2
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1
998, 37, 1931–1933, and references cited therein.
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3
1