A highly enantioselective synthesis of cyclic α-amino acids involving a one-pot, single catalyst, tandem hydrogenation-hydroformylation sequence

Article abstract of DOI:10.1039/b200374k

Tandem enantioselective hydrogenation followed by a hydroformylation-cyclisation sequence leading to cyclic α-amino acids with ee's > 95% can be achieved in a single pot, one catalyst system by successive reactions of prochiral dienamide esters with H₂ followed by H₂/CO using Rh(I)DuPHOS.

Full text of DOI:10.1039/b200374k

A highly enantioselective synthesis of cyclic a-amino acids involving a
one-pot, single catalyst, tandem hydrogenation–hydroformylation
sequence†
Euneace Teoh, Eva M. Campi, W. Roy Jackson and Andrea J. Robinson*
Centre for Green Chemistry and School of Chemistry, PO Box 23, Monash University, Victoria 3800,
Australia. E-mail: A.Robinson@sci.monash.edu.au; Fax: 61 03 9905 4597; Tel: 61 03 9905 4553
Received (in Corvallis, OR, USA) 10th January 2002, Accepted 12th March 2002
First published as an Advance Article on the web 5th April 2002
Tandem enantioselective hydrogenation followed by a hy-
droformylation–cyclisation sequence leading to cyclic a-
amino acids with ee’s > 95% can be achieved in a single pot,
one catalyst system by successive reactions of prochiral
dienamide esters with H2 followed by H2/CO using Rh(
DuPHOS.
observed selectivity ( < 2+1 for 4b+5b), however, was con-
siderably lower than expected given that hydroformylation of a
terminal alkene using PPh3 as ligand would be expected to yield
a piperidine+pyrrolidine ratio of ca. 2+1, whereas the bulkier
BIPHEPHOS ligand should bias this ratio to ca. 9+1.12,14 An
I)-
Cyclic amino acids are of increasing biological importance
because of their relationship to naturally occurring biological
molecules, e.g. the izidine alkaloids1 (piperidines), kainic acid
analogues2 (pyrrolidines), and their use in peptidomimetics.3
Recent syntheses of pipecolic acid derivatives have involved
aldol condensation–reductive amination of aspartate b-alde-
hyde,4 intramolecular cyclohydrocarbonylation of unsaturated
amides5 and ruthenium catalysed ring closing metathesis.6 Both
of these latter preparations start with allylglycine which is
available in both enantiomeric forms.7 In spite of these recent
advances, there appears to be a demand for facile routes to this
class of compound as other general syntheses are relatively
limited in scope. In this communication we describe a general
synthesis of either enantiomer of piperidino- and pyrrolidino-
based a-amino acids by a sequence which, in its final form,
involves a single pot, one catalyst reaction sequence. Such
tandem sequences are becoming increasingly important in
organic synthesis and have recently been used for isomerisa-
tion–carbonylation of alkenes.8 Domino reactions employing
hydroformylation–condensation–hydrogenation
sequences
have also recently been reported.9
Rhodium catalysed hydrogenation of the prochiral dienamide
ester 1a under conditions reported by Burk10 gave the
allylglycine derivative 2a in high enantiomeric excess ( > 95%)
and yield (98%) (Scheme 1). Either enantiomer of 2a could be
obtained by the use of (R,R)- or (S,S)-Et-DuPHOS with the
(R,R)-catalyst giving the (R)-enantiomer of 2a.10,11 Excellent
regioselectivity was observed with < 5% of the saturated
product 3a being produced. The unsubstituted analogue 1b was
also hydrogenated under milder conditions to give 2b with
excellent regioselectivity but with a slightly increased amount
of over-reduced material 3b (5–15%). The enantioselectivity
was again > 95% as shown by chiral gas chromatography
(Scheme 1).
Ojima and co-workers have previously reported preparation
of pipecolic acid derivatives from protected allylglycines
closely related to 2b.5 Reactions of 2b using rhodium–
phosphine catalysts with H2/CO under conditions previously
used in our work12 gave very good isolated yields (ca. 70%) of
the cyclic amino acid derivatives 4b and 5b (Table 1, entries 1
and 2) (Scheme 1). The compounds were readily separated and
chiral hplc showed that the enantiomeric excess had not been
compromised. Confirmation that the (R)-configuration was
present in samples of 4b prepared using (R,R)-Et-DuPHOS was
obtained by conversion of 4b to (R)-pipecolic acid hydro-
chloride 6 and comparison of optical rotation values.13
The isolated piperidine 4+pyrrolidine 5 ratio originates from
the regioselectivity exhibited during hydroformylation. The
Scheme 1 (i) 1a: (S,S)-Et-DuPHOS-Rh(
(S,S)-Et-DuPHOS-Rh( ), H2 (30 psi), 3 h, PhH, rt. (ii) H2/CO (1+1), 80–400
psi, 80–100 °C, 20–72 h. [Rh(OAc)2]2, PPh3 or BIPHEPHOS with
substrate+Rh( )+phosphine ratio of 100+1+2.
I
), H2 (90 psi), 2 h, PhH, rt; 1b:
I
I
Table 1 Rhodium catalysed hydroformylation of chiral enamides 2a (R =
Me) and 2b (R = H)a
Product
Catalyst H2/CO
Systemb (psi)
Time Ratio (4 : Yield % ee
Entry
R
T (°C) (h)
5)
(%)c (4/5)g
1
2
3
4
5
6
7
8
H
H
H
H
A
B
B
B
B
A
B
B
400
400
100
80
80 72
80 20
80 20
50+50
73
--/87
88/--
--/87
63+37
71+29
78+22
66+34
67+33
100+0
91+9
66
54d
e
80
80
20
72
—
H
80
75
45
37f
81
99/--
91/98
Me
Me
Me
400
400
400
80 20
80 20
100
72
97/--
a Reaction conditions: Substrate (0.3 mmol) : [Rh(OAc)2]2 : PPh3 or
BIPHEPHOS ratio = 100+1+2 in benzene (5–10 ml) with H2/CO (1+1).
b Catalyst code: A = Rh-PPh3, B = Rh-BIPHEPHOS. c Isolated yield of
cyclic products 4 and 5 after chromatography. d Crude product contained ca.
20% isomerised alkenamide 7. e Crude product contained ca. 50%
isomerised alkenamide 7. f Aldehydes 8a and 9a (ca. 1+1) also obtained. g --
Signifies that enantioselectivity was not assessed.
† Electronic supplementary information (ESI) available: experimental
information. See http://www.rsc.org/suppdata/cc/b2/b200374k/
978
CHEM. COMMUN., 2002, 978–979
This journal is © The Royal Society of Chemistry 2002

explanation for this anomaly became apparent after conducting
the hydroformylation experiments under milder conditions.
Reaction of 2b at 80 °C with 100 psi of H2/CO over 20 h (entry
3) gave a modest yield (54%) of 4b and 5b and ca. 20% of the
sequence involving 1a with Rh-DuPHOS and Rh-PPh3 gave 4a
and 5a in ca. 1+1 ratio in 81% isolated yield (entry 10). The ee
of 4a and 5a were also shown to be 4 95% by chiral hplc.
Next we investigated whether a single catalyst, namely Rh( )-
I
isomerised alkenamide 7. Significantly, Rh(
I)-BIPHEPHOS
DuPHOS, could be employed to facilitate both hydrogenation
and hydroformylation. To our knowledge, the use of Rh-
DuPHOS as a hydroformylation catalyst has not been pre-
viously reported. Reaction of dienamide 1b in the presence of
Rh-DuPHOS alone, initially with H2 at ambient temperature
and then with H2/CO (80 psi) at 80 °C, gave a product
containing significant amounts of the isomerised alkene 7 (entry
11). Reaction using a higher pressure of H2/CO (400 psi) gave
complete conversion to 4b and 5b in ca. equimolar ratio in 91%
isolated yield with excellent enantioselectivity (entry 12). It
appears that the Rh-DuPHOS system is slightly less efficient for
hydroformylation than the Rh-BIPHEPHOS system (compare
entries 5 and 11). A similar diminution in rate was observed for
a reaction of 1a in the presence of Rh-DuPHOS where
hydroformylation under conditions giving complete conversion
using Rh-PPh3 (entry 6, Table 1; entry 10, Table 2) gave
substantial amounts of aldehydes (8a and 9a) (entry 13). A
reaction under more forcing conditions gave complete conver-
sion to the piperidine 4a which was isolated as the sole product
in 58% yield and with 96% ee (entry 14).
These results clearly establish that it is possible to obtain
cyclic a-amino acids in good to very good yields and with
excellent enantioselectivity using a single catalyst in a single
pot via a tandem reaction sequence.
We thank Monash University and the Centre for Green
Chemistry for provision of a postgraduate award (to ET), the
Australian Research Council for its financial support of this
research and Johnson Matthey Pty Ltd for the loan of
rhodium.
catalysed hydroformylation of 7 would favour reaction remote
from the bulky amino acid moiety resulting in pyrrolidine 5b
after cyclisation and dehydration (Scheme 1). This secondary
route to 5b explains the higher than expected amounts of
pyrrolidine in reactions involving 2b. Under lower hydro-
formylation pressure (80 psi) an even greater percentage of 7
(ca. 50%) was observed after 20 h (entry 4) and extended
reaction over 72 h gave significant amounts of 5b (entry 5).
Hydroformylation of the homologue 2a at 80 °C with 400 psi
H2/CO using PPh3 as ligand gave 4a and 5a in a 2+1 ratio (entry
6) whilst a similar reaction using BIPHEPHOS gave a
significant amount of the uncyclised aldehydes 8a and 9a
together with piperidine 4a (entry 7). Increasing the temperature
and reaction time led to complete conversion and isolation of
cyclic compounds 4a and 5a in high yield and in a ratio of
9+1.
A tandem reaction was then investigated which capitalized on
the disparate operating conditions of the two Rh-DuPHOS and
Rh-BIPHEPHOS catalysts. Under mild reaction pressures, only
the Rh-DuPHOS catalyst would be expected to facilitate
hydrogenation of the enamide substrates 1 ensuring the
maintenance of high enantioselectivity. Hence, in the presence
of both Rh-DuPHOS and Rh-BIPHEPHOS, hydrogenation of
1b (rt, 30 psi of H2, 3 h) followed by hydroformylation (80 °C,
80 psi of H2/CO) gave 4b and 5b in a 2+1 ratio and 63% isolated
yield. Importantly, the enantiomeric excess of 4b and 5b was
found to be > 95% (entry 9, Table 2). A similar reaction
Table 2 Rhodium catalysed tandem hydrogenation and hydroformylation of
dienamides 1a (R = Me) and 1b (R (R = H)a
Notes and references
1 H. Takahara, H. Bandoh and T. Momose, Tetrahedron, 1993, 49,
11205.
Product
Catalyst H2/CO
Systemb (psi)
Time Ratio (4 : Yield % ee
T (°C) (h) 5)
2 A. F. Parsons, Tetrahedron, 1996, 52, 4149.
3 S. Hanessian, G. McNaughton-Smith, H.-G. Lombart and W. D. Lubell,
Tetrahedron, 1997, 53, 12789.
4 M. E. Swarbrick, F. Gosselin and W. D. Lubell, J. Org. Chem., 1999, 64,
1993.
5 I. Ojima, M. Tzamarioudaki and M. Eguchi, J. Org. Chem., 1995, 60,
7078.
6 K. C. M. F. Tjen, S. S. Kinderman, H. E. Schoemaker, H. Hiemstra and
F. P. J. T. Rutjes, J. Chem. Soc., Chem. Commun., 2000, 699.
7 F. P. J. T. Rutjes and H. E. Schoemaker, Tetrahedron Lett., 1997, 38,
677.
Entry
R
H
(%)c (4/5)
9
10
11
12
13
14
B + C
Me A + C
80
400
80
80
80
80
80
80
72
20
72
72
20
72
67+33
63
81
—
91
95/95
95/99
56+44
74+26
54+46
83+17
100+0
d
H
H
Me
Me
C
C
C
C
400
400
800
95/99
99/99
96/2
35e
58
f
150
8 R. I. Pugh, E. Drent and P. G. Pringle, J. Chem. Soc., Chem. Commun.,
2001, 1476.
9 B. Breit and S. K. Zahn, Angew. Chem., Int. Ed., 2001, 40, 1910 and
references cited therein.
10 M. J. Burk, J. G. Allen and W. F. Kiesman, J. Am. Chem. Soc., 1998,
120, 657.
11 M. J. Burk, J. E. Feaster, W. A. Nugent and R. L. Harlow, J. Am. Chem.
Soc., 1993, 115, 10125.
12 J. J. Carbo, F. Maseras, C. Bo and P. W. N. M. van Leeuwen, J. Am.
Chem. Soc., 2001, 123, 7630; D. J. Bergmann, E. M. Campi. W. R.
Jackson and A. F. Patti, J. Chem. Soc., Chem. Commun., 1999, 1279; D.
J. Bergmann, E. M. Campi, W. R. Jackson, Q. J. McCubbin and A. F.
Patti, Tetrahedron, 1997, 53, 17449.
13 The found and literature value of [a]D for (S)-6 (+10.0 °C, c = 2, H2O)
were in agreement.
14 A. G. Billig, D. R. Abatjoglou and D. R. Bryant, U.S. Patent 4769498,
1988; G. D. Cuny and S. L. Buchwald, J. Am. Chem. Soc., 1993, 115,
2066.
a Reaction conditions: Substrate (0.3 mmol)
Rh[(OAc)2]2+PPh3 or BIPHEPHOS ratio = 100+1+1+2 in benzene (5–10
ml) with H2 (30 psi, 3 h for 1b and 90 psi, 2 h for 1a) at ambient temperature
:
Rh-Et-DuPHOS+
followed by H2/CO (1+1). b Catalyst code: A
= Rh-PPh3, B = Rh-
BIPHEPHOS, C = Rh-Et-DuPHOS. c Isolated yield of cyclic products 4
and 5 after chromatography. d Crude product contained ca 40% isomerised
alkenamide 7. e Aldehydes 8a and 9a also obtained. f Enantioselectivity was
not assessed.
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