Chemoenzymatic synthesis of a novel ligand for rhodium-catalysed asymmetric hydrogenation

Article abstract of DOI:10.1039/a704136e

The hydrogenation of alkenes 7a-g using a chiral rhodium catalyst 6 (based on a bicyclo[3.2.0]heptane framework) takes place to give the phenylalanine derivatives 8a-g with remarkably high stereoselectivity (59-92% ee).

Full text of DOI:10.1039/a704136e

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Chemoenzymatic synthesis of a novel ligand for rhodium-catalysed asymmetric
hydrogenation
Brian Adger,a Ulrich Berens,a Matthew J. Griffiths,b Michael J.Kelly,c Ray McCague,a John A. Miller,c
Christopher F. Palmer,a Stanley M. Roberts,*b Ru¨diger Selke,d Ute Vitiniusb and Guy Wardc
a Chiroscience plc, Cambridge, UK CB4 4WE
b Department of Chemistry, University of Liverpool, Liverpool, UK L69 7ZD
c Department of Chemistry, University of Exeter, Exeter, UK EX4 4QD
d Max Planck-Gesellschaft Zur Fo¨rderung der Wissenschaften e.v., University of Rostock, D-18055 Rostock, Germany
The hydrogenation of alkenes 7a–g using a chiral rhodium
OH
catalyst 6 (based on a bicyclo[3.2.0]heptane framework)
Br
O
takes place to give the phenylalanine derivatives 8a–g with
remarkably high stereoselectivity (59–92% ee).
Br
NAD–H
OH
O
The relatively inflexible, angular shape of the bi-
cyclo[3.2.0]heptane ring system means those substituents on the
concave (endo) face of the molecule are positioned close
together in space. Molecular modelling studies suggested that
the hydroxy groups in bicyclo[3.2.0]heptan-3-endo, 6-endo-
diol would be positioned in such a way that derivitization to
form bis(diarylphosphinyl) groups may provide a novel chiral
ligand for organorhodium-catalysed hydrogenation reactions.1
Optically pure diol 1 may be prepared from (2)-bi-
cyclo[3.2.0]hept-2-en-6-one2 2 by the route described in
Scheme 1. Thus, formation of the bromohydrin3 3,
hydrodebromination (furnishing 4) and stereocontrolled reduc-
tion by delivery of hydride ion from the more exposed exo-face
afforded the diol 1 in 50% overall yield.
NAD–H
Fig. 1 Delivery of hydride to 3
and efficient biocatalytic method utilised a yeast-catalysed
highly enantio- and stereo-selective reduction of racemic ketone
3 (Scheme 2).
It is noteworthy that reduction takes place to give only the
(6S)-bromodiol 5, unlike the corresponding non-enantioselec-
tive bioreduction on the parent compound 2 which gave
(1S,5R,6S)-bicyclo[3.2.0]hept-2-en-6-endo-ol and (1R,5S,6S)-
bicyclo[3.2.0]hept-2-en-6-exo-ol in almost equal quantities.5
Presumably delivery of the hydride ion from the concave face of
(+)-3 is prohibited by unfavourable steric interactions within the
active site of the dehydrogenase (Fig. 1).
The diol (2)-1 was converted into the rhodium complex 6
using standard methodology, and this complex was used to
catalyse the asymmetric hydrogenation of compounds 7a–g to
afford the (R)-phenylalanine derivatives 8a–g in excellent yield
and moderate to good enantiomeric excess (Table 1). Indeed,
H
O
O
O
OH
H
H
H
H
H
H
H
H
i
ii
iii
Br
OH
OH
OH
Table 1 Asymmetric hydrogenation of some enamide esters, 7a–g
2
3
4
1
–
Scheme 1 Reagents and conditions: i, N-Bromosuccinimide, acetone, H2O,
6 h, 80%; ii, Bu3SnH, AIBN, toluene, heat, 82%; iii, NaBH4, MeOH,
278 °C, 76%
CF3SO3
O
PPh2
O
NHCOR2
Ph2P
CO2R1
Rh+(cod)
CO2R1
6
However, since both enantiomers of the diol 1 were required
as intermediates to the chiral ligands it seemed more sensible to
perform a kinetic resolution further along the synthetic
sequence. Kinetic resolution of the racemic alcohols 1 and 4
using lipase-catalysed acylation reactions were unsuccessful.
The bromohydrin (±)-3 was resolved by employing Pseudomo-
nas fluorescens lipase in vinyl acetate4 but a more satisfactory
Ph
NHCOR2
Ph
H
7a–g
8a–g
a R1 = H, R2 = Me
b R1 = R2 = Me
c R1 = H, R2 = Ph
d R1 = Me, R2 = Ph
e R1 = Pri, R2 = Ph
H
f
R1 = But, R2 = Ph
O
O
OH
H
g R1 = Pri, R2 = Me
i
H
H
H
H
H
+
Starting
material
Enantiomeric
excessa (%)
Br
Br
Br
Product
Yield (%)
OH
(±)-3
OH
(+)-5
OH
(+)-3
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
81
73
76
59
61
66
77
> 95
> 95
> 95
> 95
> 95
> 95
> 95
ee >98%
ii
ee >98%
See Scheme 1
(–)-1
(+)-1
7g
8g
Scheme 2 Reagents and conditions: i, Yeast, H2O, 6 h, 100% crude yield;
ii, Bu3SnH, AIBN, toluene, heat, 86%
a Estimation by HPLC using a Chirasil-Val column.
Chem. Commun., 1997
1713

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Table 2 Asymmetric hydrogenation of enamide ester 7a
Footnotes and References
* E-mail: sj11@liverpool.ac.uk
Enantiomeric
† Experimental procedure for the asymmetric hydrogenation of compound
7a. A mixture of complex 6 (8 mg, 0.01 mmol) and a-acetamidocinnamic
acid 7a (205 mg, 1 mmol) was cooled (2 °C) under a nitrogen atmosphere.
Dry, degassed MeOH (5 ml) was added to the mixture, which was stirred
vigorously. The flask was evacuated, filled with hydrogen and stirred for 10
min. A 0.5 ml aliquot was removed from the reaction vessel and treated with
Me3SiCHN2 (2.0 m solution in hexane) in order to convert the acid to the
methyl ester. The solvent was evaporated and the residue was treated with
diethyl ether; filtration and evaporation gave a crude residue (21 mg). The
enantiomeric excess of the product 8a was determined to be 92.5% by chiral
gas chromatography, using a Chirasil-Val-III column.
Volume of
solvent/ml
excess of
product (%)
T/°C
25
12
2
25
25
2
15
15
15
10
5
81
83.5
87.5
88
91.5
92.5
5
1 Review: R. Noyori, Asymmetric Catalysts in Organic Systhesis, Wiley,
New York, 1994, ch. 2; recent publications: G. Zhu, P. Cao, Q. Jiang and
X. Zhang, J. Am. Chem. Soc., 1997, 119, 1799; R. Selke, M. Ohff and
A. Riepe, Tetrahedron, 1996, 52, 15079; M. J. Burk, Y. M. Wang and
J. R. Lee, J. Am. Chem. Soc., 1996, 118, 5142; H.-J. Kreuzfeld,
U. Schmidt, C. Do¨bler and H. W. Krause, Tetrahedron: Asymmetry,
1996, 7, 1011; C. Dobler, H.-J. Kreuzfeld, M. Michalik and
H. W. Krause, Tetrahedron: Asymmetry, 1996, 7, 117; J. Albrechy and
U. Nagel, Angew. Chem., Int. Ed. Engl., 1996, 35, 407.
2 K. Tanaka, O. Kakinoki and F. Toda, Tetrahedron: Asymmetry, 1992, 3,
517.
3 Z. Grudzinski and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1975,
1767.
4 For enzymatic resolution of related bromohydrins, see I. C. Cotterill,
A. G. Sutherland, S. M. Roberts, R. Grobbauer, J. Spreitz and K. Faber,
J. Chem. Soc., Perkin Trans. 1, 1991, 1365; I. C. Cotterill and
S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1992, 2585.
5 R. F. Newton, J. Paton, D. P. Reynolds, S. Young and S. M. Roberts,
J. Chem. Soc., Chem. Commun., 1979, 908; J. Davies, S. M. Roberts,
D. P. Reynolds and R. F. Newton, J. Chem. Soc., Perkin Trans. 1, 1981,
1317; See also G. Fantin, M. Fogagnolo, A. Medici, P. Pedrini,
E. Marotta, M. Monti and R. Righi, Tetrahedron: Asymmetry, 1996, 7,
277.
given the subtlety of the chirality of the bicyclo[3.2.0]heptane
framework, the observed level of enantioselectivity is surpris-
ingly high. The reaction rates were perfectly satisfactory (the
reaction was completed in 2–10 min) using 1 mmol substrate
and 0.01 mmol catalyst in MeOH (15 ml) under an atmosphere
of hydrogen. Using similar conditions, itaconic acid was
reduced to (2S)-methylsuccinate in quantitative yield and 80.5%
ee.
The reaction conditions for the asymmetric reduction of
substrate 7a were investigated further. Lowering the temper-
ature of the reaction and increasing the concentration of the
reactants both proved to be beneficial, with a satisfactory 92.5%
ee for product 8a being obtained at low temperature and high
concentration (Table 2).† The concentration effect may be
explained by the effect on the rate of delivery of hydrogen to the
catalyst, which will be slower in the reactions using small
amounts of solvent. Thus, in the more concentrated solution the
catalyst may experience a lower ‘effective’ hydrogen concen-
tration.6
We thank the BBSRC for a Fellowship (to U. V.) and a CASE
award (to M. J. G.), Chiroscience, and EPSRC and the
University of Exeter for studentships (to J. M. and G. W.) and
Donna Blackmond for enlightening discussions.
6 Y. Sun, R. N. Landau,J. Wang, C. LeBlond and D. G. Blackmond, J. Am.
Chem. Soc., 1996, 118, 1348.
Received in Cambridge, UK, 13th June 1997; 7/04136E
1714
Chem. Commun., 1997