One-pot tandem enantioselective hydrogenation-hydroformylation synthesis of cyclic α-amino acids

Article abstract of DOI:10.1039/b209087m

Five- and six-membered cyclic amino acids can be prepared in good yield with high ee (> 95%) via tandem rhodium-DuPHOS catalysed asymmetric hydrogenation followed by a rhodium-catalysed hydroformylation-cyclisation sequence in a single pot. The synthesis can be achieved using Rh-DuPHOS as the sole catalyst.

Full text of DOI:10.1039/b209087m

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One-pot tandem enantioselective hydrogenation–hydroformylation
synthesis of cyclic a-amino acids
Euneace Teoh, Eva M. Campi, W. Roy Jackson and Andrea J. Robinson*
Centre for Green Chemistry and School of Chemistry, Monash University, PO Box 23,
Victoria 3800, Australia. E-mail: A.Robinson@sci.monash.edu.au; Fax: +61 03 9905 4597;
Tel: +61 03 9905 4553
Received (in New Haven, CT, USA) 6th September 2002, Accepted 18th October 2002
First published as an Advance Article on the web 3rd January 2003
Five- and six-membered cyclic amino acids can be prepared in good yield with high ee ( > 95%) via tandem
rhodium-DuPHOS catalysed asymmetric hydrogenation followed by a rhodium-catalysed hydroformylation–
cyclisation sequence in a single pot. The synthesis can be achieved using Rh-DuPHOS as the sole catalyst.
Introduction
There is a growing trend in the pharmaceutical and fine chemi-
cals industries towards replacing classical organic synthesis
with cleaner catalytic alternatives. Attention to E factor,1 the
amount of waste generated per kilo of product,2 has driven
chemists to reduce or eliminate the use and generation of toxic
and hazardous reagents and solvents. Tandem reaction
sequences employing catalytic processes therefore offer a
remarkable opportunity to conduct organic synthesis in a
highly efficient manner. Furthermore, reaction sequences
which possess high atom economy3 and simultaneously incor-
porate stereochemistry into the framework of the desired tar-
get would be considered even more efficient.4 In this context,
we have recently developed an enantioselective synthesis of
cyclic a-amino acids via domino catalytic asymmetric hydroge-
nation–hydroformylation protocol.5 Cyclic amino acids are of
increasing biological importance because of their relationship
to naturally occurring biological molecules, e.g. the izidine
alkaloids6 (piperidines) and kainic acid7 (pyrrolidines), and
their use in peptidomimetics.8 The sequential transformation
described herein allows the formation of a new C–C single
bond and heterocycle formation with concomitant generation
of a stereogenic centre. Other highly efficient domino reactions
have also recently been reported and include hydroformy-
lation–Knoevenagel–hydrogenation,9 hydroformylation–Wit-
tig,10 isomerization–hydroformylation,11 hydroformylation–
conjugate addition12 and isomerisation–carbonylation13
sequences.
Scheme 1
out using the unsaturated aldehydes 2a–2c (Scheme 1). The
use of tetramethylguanidine (TMG) as base at low tempera-
ture in THF has been described by Burk et al. and the dien-
amide esters 1a–1c were obtained in acceptable yields (1a, 55%;
1b, 87%; 1c, 38%) using this method.14
Asymmetric hydrogenations
The DuPHOS ligand developed by the DuPont company has
been shown to give complexes with rhodium which give excel-
lent enantioselectivities when used as catalysts in hydrogena-
tion of prochiral substrates.19 Recently Burk et al. have
demonstrated that high regio- and enantioselectivities can be
achieved in the hydrogenation of prochiral dienamide esters.14
In this paper, the dienamide esters 1 were hydrogenated in
either methanol or benzene with Rh-Et-DuPHOS using short
reaction times (Scheme 2). Full conversions and high enantio-
selectivity (ee) were achieved in methanol ( > 80% ee) and ben-
zene ( > 95% ee) (Table 1). As the substrates were more soluble
In this paper, we describe an enantioselective tandem hydro-
genation–hydroformylation–cyclisation sequence leading to
cyclic a-amino acid derivatives.
Results and discussion
Synthesis of hydrogenation precursors
The hydrogenation precursors, the dienamide esters 1, were
readily accessible by reaction of unsaturated aldehydes 2 with
the phosphonate 314,15 (Scheme 1). The Cbz-protected phos-
phonate 415 was prepared in 81% yield and converted quanti-
tatively into the N-acetyl-protected phosphonate 3.15 An
alternative route to 3 from methyl N-acetyl-2-methoxyglyci-
nate16,17 gave the phosphonate in a poor yield (30%). Hor-
ner–Emmons olefination18 of the phosphonate 3 was carried
Scheme 2
DOI: 10.1039/b209087m
New J. Chem., 2003, 27, 387–394
387
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Table
1
Rh-catalysed asymmetric hydrogenation of dienamide
Table 2 Rh-catalysed hydroformylation of hydrogenated enamides
esters 1a
5a; R ¼ Me and 5b; R ¼ Ha
Pressure/ Time/
psi
Ratiob Yield
Product 5:6
(%)c eed
%
Catalyst CO/
system
Time/ Product Yield
h
ratio 9:10 (%)b
%
Entry Substrate
R
n
h
Entry
R
H2/psi T/ꢀC
eec 9/10
1
2
3
4
5
6
1a
1a
1b
1b
1b
1c
Me
Me
H
0
0
0
0
0
2
90
90
30
30
30
30
2
2
3
3
3
2
5a
5a
5b
5b
5b
5c
94:6
99
98
88
90
90
90
95
7
8
Me
Me
Me
Me
H
A
B
B
A
A
B
B
B
B
400
400
400
400
400
400
100
80
80
80
20
20
72
20
72
20
20
20
72
67:33
100:0
91:9
45
91/98
—
95:5
95:5
95:5
95:5
92:8
95e
95
37d
81
9
100
80
97/98
—
H
76f
95e
98
10
11
12
13
14
15
80:20
50:50
63:37
71:29
78:22
66:34
47e
73
H
80
80
—/87
88/—
—/87
—
H
H
66
54f
H
80
80
a
All reactions were performed in benzene using Rh-(R,R)-Et-DuPHOS with
g
H
substrate:catalyst ratio ¼ 100:1 at ambient temperature, 100% conversion was
H
80
80
75
99/99
b
observed in all cases. For specific conditions, refer to experimental. % Over-
reduction was estimated by 1H NMR. Isolated yield of 5 + 6 after passage
Reaction
conditions:
substrate:[Rh(OAc)2]2:PPh3
or
BIPHEPHOS
c
a
d
through a short plug of silica. % ee of 5 was assessed by chiral capillary GC
ratio ¼ 100:1:2 in benzene (5–10 mL), A ¼ Rh-PPh3 and B ¼ Rh-BIPHE-
e
column (CP-Chirasil Val). Reaction using Rh-(S,S)-Et-DuPHOS giving (S)-
b
PHOS. For specific conditions, refer to experimental. Isolated yield of cyclic
f
5. Reaction carried out in methanol.
c
products 9 and 10 after chromatography. % ee was assessed by chiral HPLC
column (DAICEL Chiralcel1 OD); — Signifies that enantiomeric excess (ee)
d
e
was not assessed. Aldehydes 7a and 8a (ca. 1:1) also obtained. Initial isola-
f
tion of amidals 11 and 12. Crude product contained ca. 20% isomerised alk-
in benzene and the % ee was found to be higher, subsequent
reactions were carried out in benzene. An increase in pressure,
reaction duration and catalyst loading increased the amount of
over-reduction.14 For unsubstituted dienamide esters 1b and 1c
(entries 3 to 6), a low pressure (30 psi of H2) and short reaction
time (2–3 h) were used to give < 8% of the over-reduced by-
product 6 with 100% conversion of starting material 1. In con-
trast for the substituted substrate 1a (entries 1 and 2), higher
pressure (90 psi of H2) was needed for the hydrogenation to
go to completion in 2 h. In all cases, the products were isolated
in high yields. Enantiomeric excess was assessed by chiral
capillary GC.
g
enamide 13. Crude product contained ca. 50% isomerised alkenamide 13.
ligand gave 9a and 10a in a 2:1 ratio (entry 7), whilst under
the same conditions, use of the BIPHEPHOS ligand led to
incomplete cyclisation and isolation of aldehydes 7a and 8a
(entry 8). Reaction using BIPHEPHOS at the same pressure
but with increased temperature and reaction time gave com-
plete conversion with a higher ratio of piperidine 9a to pyrro-
lidine 10a (9:1 ratio) (entry 9) consistent with the bulky ligand
directing the initial hydroformylation to the less hindered car-
bon of the alkene. In one reaction using PPh3 as ligand, the
initial product contained the amidals 11 and 12 which dehy-
drated on standing in CDCl3 to give the enamides 9a and
10a (entry 10). Similar amidals have been isolated by Ojima
and coworkers.20,22
Hydroformylation of 5b, containing a terminal alkene, sur-
prisingly gave a lower than expected piperidine 9b:pyrrolidine
10b ratio in all cases. Reaction of 5b using the PPh3 ligand gave
a 1:1 ratio of the cyclic amino acid derivatives 9b and 10b
(entry 11), in contrast to the ca. 2:1 ratio obtained with 5a.
Reaction using BIPHEPHOS gave 9b and 10b in a ratio of
2:1, again lower than the ratio of > 9:1 usually obtained for
hydroformylation of terminal alkenes with this ligand23 (entry
12). A reaction using 100 psi CO/H2 and the BIPHEPHOS
ligand led to formation of the isomerised alkenamide 13 in
ca. 20% yield (entry 13). This isomer would preferentially be
hydroformylated and cyclised to give pyrrolidine 10b, which
explains the unexpected higher ratio of pyrrolidine 10b in the
reactions. A reaction at even lower pressure (80 psi) gave ca.
50% of the isomerised alkenamide 13 (entry 14). Extending
the reaction time under these conditions gave the cyclic pro-
ducts 9b and 10b in 75% yield (entry 15).
Hydroformylation
Preparation of pyrrolidine and piperidine derivatives. Hetero-
cyclic compounds can be obtained in good yields by a hydro-
formylation–cyclisation reaction sequence from unsaturated
amines and amides.20,21 Ojima et al. have applied this metho-
dology to the preparation of pipecolic acid derivatives by
hydroformylation of enamides related to 1b.22 High regioselec-
tivity was obtained when the bulky phosphite BIPHEPHOS23
was used as a ligand. The methodology has now been applied
to reactions of the chiral enamides 5, leading predominantly to
the cyclic amido esters 9 and 10 presumably via the aldehydes 7
and 8 as shown in Scheme 3. The reactions were carried out
using Rh/PPh3 or Rh/BIPHEPHOS under 400 psi of CO/
H2 (1:1) and gave the piperidine 9 and pyrrolidine 10 deriva-
tives. The 5- and 6-membered ring compounds were readily
separated by chromatography and chiral HPLC showed that
the enantiomeric excess (ee) of these compounds was preserved
(Table 2). Hydroformylation of enamide 5a using the PPh3
This result is very unexpected in that, although alkene iso-
merisation by related rhodium compounds is well established,
the terminal alkene normally hydroformylates faster than inter-
nal alkenes. Thus, such a phenomenon is consistent with the
recently reported high yields of straight chain aldehydes from
hydroformylation of internal alkenes using a Rh-NAPHOS
catalyst.24 Similarly, a tandem isomerisation–carbonylation
sequence gave linear esters from a Pd-catalysed carbonylation
of internal alkenes.13 One possible explanation for this result
is that chelation of rhodium to the amido carbonyl leads to
preferential hydroformylation of the internal double bond as
is the case for the preceding hydrogenation reaction.19,25
One-pot tandem reactions. The possibility of carrying out the
hydrogenation–hydroformylation sequence in a single pot was
examined (Scheme 4). Hydrogenation of the dienamides 1a
and 1b was carried out in a vessel containing both the Rh-
DuPHOS and either Rh-BIPHEPHOS or Rh-PPh3 catalysts.
Scheme 3
388
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Scheme 4
After the low pressure hydrogenation was complete, the gas
was vented and replaced by a 1:1 CO/H2 gas mixture and
the temperature raised to 80 ꢀC. Good to very good yields of
the heterocycles 9 and 10 were obtained (Table 3, entries 16
and 17). Excellent enantioselectivity ( > 95% ee) of 9 and 10
was maintained, showing that there was no significant compe-
tition by Rh-BIPHEPHOS or Rh-PPh3 in the hydrogenation
step catalysed by Rh-DuPHOS. Reaction of the terminal
alkene 1b gave some isomerised alkene 13 (25%) in addition
to the heterocycles 9b and 10b (Table 3, entry 17).
Scheme 5
The possibility of using Rh-DuPHOS as a catalyst for both
reactions was investigated. This catalyst has not been used pre-
viously for hydroformylation reactions. Reactions of diena-
mide substrates 1a and 1b using Rh-Et-DuPHOS, initially
under hydrogenation conditions and then under hydroformy-
lation conditions, gave the expected cyclic products 9 and 10
in reasonable yields (Table 3). Again, the enantiomeric excess
(ee) was found to be excellent ( > 98%). Comparison of the
results reported in entries 9 (Table 2) and 19 (Table 3) suggests
that Rh-DuPHOS appears to be a slightly less efficient catalyst
than Rh-BIPHEPHOS as it needed more forcing conditions to
give complete conversion of dienamide 1a to cyclic products 9a
and 10a. Comparison of entries 7 (Table 2) and 18/19 (Table
3) shows that Rh-DuPHOS is also less efficient than the Rh-
PPh3 system. A similar scenario was observed in reaction of
dienamide 1b, as it too required higher pressure to achieve
100% completion and 91% isolated yield of 9b and 10b (com-
pare entries 15 (Table 2) and 20/21 (Table 3)).
hydroformylated using the Rh-PPh3 and Rh-BIPHEPHOS
systems and gave the aldehydes 14 and 15 (entries 22 and
23). No cyclic material was observed.
A one-pot tandem reaction was carried out using a higher
pressure and temperature for a longer period of time with
the mixed Rh-DuPHOS and Rh-BIPHEPHOS catalysts (Table
4, entry 24). The major product was the saturated compound
6c. Chromatography gave a mixture of the two heterocycles
17 and 18 in ca. 1:1 ratio and ca. 24% yield. No 8-membered
ring compound 16 was detected. Formation of 18 means that
some of the aldehyde 19 has been generated via initial alkene
isomerisation.
A one-pot reaction using only Rh-DuPHOS as catalyst
under the same conditions again gave predominantly the satu-
rated compound 6c (Table 4, entry 25). Chromatography led
to the isolation of the 6-ring compound 18 in 12% yield. The
difficulty associated with the formation of 7- and 8-membered
rings accounts for the low yields of heterocycles but the forma-
tion of large amounts of hydrogenated rather than hydrofor-
mylated material is hard to understand.
Attempted preparation of 7- and 8-membered cyclic amino
acid derivatives. Attempts were made to extend the method
to the preparation of larger ring cyclic amido esters from a
longer chain hydrogenation precursor (Scheme 5) and the
results are summarised in Table 4. The enamide ester 5c was
Preparation of a cyclic a-amino acid. The piperidine 9b pre-
pared using (R,R)-Et-DuPHOS-Rh was converted into the
pipecolic acid hydrochloride 21 (Scheme 6)and its optical
Table 3 One-pot tandem reaction of dienamide esters 1a; R ¼ Me
and 1b; R ¼ Ha
Table 4 Attempted synthesis of 7- and 8-membered cyclic amino
acidsa
Catalyst CO/
T/
Time/ Product
Yield % eec
Entry
R
system
H2/psi ꢀC
h
ratio 9:10 (%)b
9/10
Catalyst CO/H2/ T/ Time/ Product ratiob
Yield
(%)c
16
17
18
19
20
21
Me A + C
B + C
400
80
80 20
80 72
80 20
150 72
80 72
80 72
56:44
67:33
83:17
100:0
74:26
54:46
81
95/99
95/95
99/99
96/—
—
Entry Substrate system
psi
ꢀC
h
17:18
H
60d
35e
d
e
Me
Me
H
C
C
C
C
400
800
80
22
23
24
25
5c
5c
1c
1c
A
400
400
800
800
80
80
20
20
—
—
12
24
58
f
B
B + C
C
150 72
150 72
50:50f
0:100g
H
400
91
95/99
a
a
Reaction conditions: substrate:Rh-Et-DuPHOS:[Rh(OAc)2]2:PPh3 or BIPHE-
PHOS ratio ¼ 100:1:1:2 in benzene (5–10 mL) with H2 (90 psi, 2 h for 1a and 30
psi, 3 h for 1b) at ambient temperature followed by CO/H2 (1:1 ratio), A ¼ Rh-
PPh3 , B ¼ Rh-BIPHEPHOS and C ¼ Rh-Et-DuPHOS. b Isolated yield of cyc-
lic products 9 and 10 after chromatography. c % ee was assessed by chiral HPLC
column (DAICEL Chiralcel1 OD); — Signifies that enantioselectivity was not
Reaction conditions: substrate:Rh-Et-DuPHOS:[Rh(OAc)2]2:PPh3 or BIPHE-
PHOS ratio ¼ 100:1:1:2 in benzene (5–10 mL) with 30 psi of H2 for 2 h at
ambient temperature followed by CO/H2 (1:1 ratio), A ¼ Rh-PPh3 , B ¼ Rh-
b
BIPHEPHOS and C ¼ Rh-Et-DuPHOS. — Signifies that no cyclic products
c
were observed. Isolated yield of cyclic products 17 and 18 after chromatogra-
phy. d Aldehydes 14 and 15 were obtained in 1:1 ratio (63% yield). e Aldehydes
d
e
f
14 and 15 present in 1:1 ratio; not isolated. Crude product contained ca. 74%
assessed. Isomerised alkene 13 also isolated (25% yield). Aldehydes 7a and
f
8a also obtained (ca. 15%). Crude product contained ca. 40% isomerised alk-
g
over-reduced by-product 6c. Crude product contained ca. 67% over-reduced
enamide 13.
by-product 6c.
New J. Chem., 2003, 27, 387–394
389

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Chemicals. [Rh(OAc)2]2 and BIPHEPHOS22 were prepared
by Eva M. Campi. PPh3 was obtained from Aldrich. H2 and
1:1 molar mixture of CO/H2 were obtained from BOC gases.
Synthesis of hydrogenation precursors
Scheme 6
Methyl 2-benzyloxycarbonylamino-2-(dimethoxyphosphinyl)-
acetate 4. The Cbz-protected phosphonate 4 was prepared as
described by Schmidt15 from methyl N-benzyloxycarbonyl-2-
methoxyglycinate16,17 (23.0 g, 90.81 mmol) as a white solid,
rotation, [a]D +10ꢀ was almost identical to a literature [a]D
+10.8ꢀ for the (R)-enantiomer.26 Thus the initial enantioselec-
tive hydrogenation using Rh-(R,R)-Et-DuPHOS was highly
selective for the (R)-configuration of the product in agreement
with previous findings.19,27
1
(24.33 g, 81%); mp 77–78 ꢀC (lit.15 80 ꢀC). H NMR: d [minor
rotamer in brackets] 3.77–3.83 (m, 9H, COOCH3 ,
2 ꢁ CH3OP), 4.93 (dd, 1H, J ¼ 22.4, 9.3 Hz, [5.12, bd, J
ꢃ8.2 Hz], H2), 5.13 (d, 1H, J ¼ 12.2 Hz) and 5.15 (d, 1H,
J ¼ 12.1 Hz, CH2O), 5.77 (bd, 1H, J ꢃ8.2 Hz, [6.21, bs],
NH), 7.32–7.40 (m, 5H, ArH). 13C NMR: d [minor rotamer
in brackets] 52.4 (d, J ¼ 148.0 Hz, [73.9, s], C2), 53.7 [53.5]
(COOCH3), 54.4 (d, J ¼ 6.9 Hz, CH3OP), 54.5 (d, J ¼ 6.6
Hz, CH3OP), 67.9 [67.7] (CH2O), 128.4, 128.5, 128.8 (ArCH),
136.0 (C10), 155.8 [155.9] (CONH), 167.3 [170.0] (C1). 31P
NMR: d 19.62 (s). MS (ESI+, MeOH): m/z 354.1 (M + Na)+.
Conclusion
High yields of 5- and 6-membered ring a-amino acid deriva-
tives, viz. the piperidines 9 and pyrrolidines 10, can be obtained
with high ee using one or two catalysts in a one-pot reaction.
The reaction involves a tandem hydrogenation, hydroformyla-
tion, cyclisation sequence. It has been demonstrated that Rh-
DuPHOS can act as an efficient catalyst for hydroformylation
as well as hydrogenation reactions.
Reactions of glycine derivatives 1a and 1b, substituted with
1,3-dienes, gave surprisingly high ratios of products arising
from branched as opposed to linear aldehydes. Similarly, reac-
tions of the homologous 1,5-diene derivative 1c gave the 6- and
7-membered ring heterocycles 18 and 17, suggesting that iso-
merisation competes with hydroformylation and that forma-
tion of internal aldehydes is favoured, possibly because of
intramolecular chelation of the rhodium catalyst to the oxygen
of the acetamido carbonyl group.
Methyl 2-acetylamino-2-(dimethoxyphosphinyl)acetate 3. The
N-acetyl phosphonate 3 was prepared as described by Schmidt
et al.15 from the phosphonate 4 (10.0 g, 30.18 mmol) as a white
solid (8.06 g, 100%); mp 90–92 ꢀC (lit.15 88–89 ꢀC). 1H NMR: d
2.06 (s, 3H, COCH3), 3.79–3.81 (m, 9H, COOCH3 ,
2 ꢁ CH3OP), 5.24 (dd, 1H, J ¼ 22.3, 8.5 Hz, H2), 6.74 (d,
1H, J ¼ 8.6 Hz, NH). 13C NMR: d 23.3 (COCH3), 49.3 (d,
J ¼ 147.2 Hz, C2), 53.7 (COOCH3), 54.3 (d, J ¼ 6.6 Hz,
CH3OP), 54.6 (d, J ¼ 6.3 Hz, CH3OP), 167.3 (d, J ¼ 2.0 Hz,
C1), 169.7 (d, J ¼ 5.7 Hz, CONH). MS (ESI+, MeOH): m/z
262.0 (M + Na)+.
An alternative route to the phosphonate 3 involved reaction
of methyl N-acetyl-2-methoxyglycinate16,17 (1.01 g, 6.27 mmol)
with phosphorus(III) chloride (0.55 mL, 6.27 mmol) and tri-
methyl phosphite (0.74 mL, 6.27 mmol) at 70 ꢀC as described
for the preparation of the Cbz-protected phosphonate 415 to
give 3 as a white solid (0.43 g, 30%).
Experimental
1H NMR and 13C NMR spectra were recorded at 300 MHz
and 75 MHz respectively with a Varian Mercury 300 Q Spec-
trometer in CDCl3 and referenced to Me4Si unless otherwise
stated. 31P NMR spectra were recorded at 121.5 MHz on a
Bruker AM-300 spectrometer in deuterated solvents with
85% phosphoric acid (H3PO4) as the external standard. EI
mass spectra were recorded on a Hewlett Packard Trio-1 spec-
trometer operating at 200 ꢀC/70 eV. ESI mass spectra were
recorded on a Micromass Platform spectrometer. HRMS were
recorded on a Bruker BioApex 47e Fourier transform mass
spectrometer.
4-Pentenal 2c. Following the method described by Swern
et a1.,28,29 reaction of 4-penten-1-ol (1.0 mL, 9.70 mmol) with
dimethyl sulfoxide (1.52 mL, 21.34 mmol), oxalyl chloride
(0.93 mL, 10.67 mmol) and triethylamine (6.76 mL, 48.50
mmol) gave an oil (1.30 g). The 1H and 13C NMR spectra indi-
cated that the crude oil was a mixture of 4-pentenal 2c and
starting material (d 3.62, t, CH2) in an ratio of ꢃ1:0.2.
(approximate yield for 2c was 83%). The crude product was
used in the preparation of (2Z)-methyl 2-acetamidohepta-2,6-
Analytical gas chromatography (GC) was carried out using
a Chrompack CP-Chirasil Val chiral column (column: 0.25
mm ꢁ 50 m, 50 CP2/XE-60-S-VAL-S-A-PEA) using helium
as the carrier gas and follows the temperature program: initial
column temperature was 100 ꢀC for 1 min, then heated to
280 ꢀC for 9 min at 5 ꢀC minꢂ1. High performance liquid chro-
matography (HPLC) was carried out on a Varian LC Model
5000 instrument with a Varian UV-50 detector and using a
DAICEL Chiralcel1 OD column. The solvent system used
was 10% isopropanol:90% hexane with a flow rate of 1.0 mL
minꢂ1. A solution (10 mL) of the purified compound in HPLC
grade isopropanol was used for injection. Optical rotations
1
dienoate 1c. H NMR: d 2.13 (q, 2H, J ¼ 7.0 Hz, H3), 2.39
(td, 2H, J ¼ 7.0, 1.4 Hz, H2), 4.94–5.10 (m, 2H, H5), 5.82
(ddt, 1H, J ¼ 17.1, 10.2, 6.3 Hz, H4), 9.78 (t, 1H, J ¼ 1.5
Hz, H1). 13C NMR: d 26.2 (C3), 42.8 (C2), 115.5 (C5), 136.4
(C4), 201.7 (C1). The spectral data were consistent with litera-
ture data.30
(2Z,4E)-Methyl 2-acetamidohexa-2,4-dienoate 1a. Tetra-
methylguanidine (0.61 mL, 4.89 mmol) was added to a
solution of methyl 2-acetylamino-2-(dimethoxyphosphinyl)
acetate 3 (0.88 g, 3.68 mmol) in distilled THF (15 mL) at
ꢂ78 ꢀC following the method described by Burk.14 After 15
min, crotonaldehyde 2a (0.40 mL, 4.42 mmol) was added
and the mixture was stirred for 2 h at ꢂ78 ꢀC. The mixture
was warmed to 25 ꢀC using a warm water bath and stirred at
this temperature for a further 2 h. The mixture was diluted
with CH2Cl2 (20 mL), washed with 1 M HCl (2 ꢁ 10 mL), 1
M CuSO4(2 ꢁ 10 mL), saturated NaHCO3 (2 ꢁ 10 mL) and 1
M NaCl (10 mL). The organic layer was dried with MgSO4
and concentrated under reduced pressure to give an oil (0.90
g). Purification by flash chromatography on silica gel using
20
[a]D were measured using a Perkin Elmer Model 141 Polari-
meter. Melting points were determined using a Gallenkamp
melting point apparatus and are uncorrected. Microanalysis
were carried out by Chemical and Microanalytical Services
Pty. Ltd., Melbourne (CMAS).
Materials
[(COD)Rh-((2R,5R)-Et-DuPHOS)]OTf
((2S,5S)-Et-DuPHOS)]OTf were used as supplied from Strem
and
[(COD)Rh-
390
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1
ethyl acetate and light petroleum (2:1) gave the dienoate 1a as
a white solid (0.37 g, 55%), (Rf 0.21), mp 88–90 ꢀC (lit.14 89–
90.1 ꢀC). 1H NMR: d 1.88 (d, 3H, J ¼ 5.2 Hz, H6), 2.16 (s,
3H, COCH3), 3.17 (s, 3H, COOCH3), 6.16–6.20 (m, 2H, H4,
H5), 6.90 (bs, 1H, NH), 7.08 (d, 1H, J ¼ 10.1 Hz, H3). 13C
NMR: d 19.3 (C6), 23.6 (COCH3), 52.6 (COOCH3), 121.6
(C2), 126.9, 134.5, 139.7 (C3, C4, C5), 165.7, 169.2 (C1,
CONH).MS (ESI+, MeOH): m/z 206.0 (M + Na)+.
1142, 968 cmꢂ1. H NMR: d 1.67 (ddt, 3H, J ¼ 6.4, 1.7, 1.1
Hz, H6), 2.03 (s, 3H, COCH3), 2.43–2.51 (m, 2H, H3), 3.75
(s, 3H, COOCH3), 4.63 (dt, 1H, J ¼ 7.8, 5.6 Hz, H2), 5.28
(m, 1H, H5), 5.55 (dqt, 1H, J ¼ 15.1, 6.4, 1.2 Hz, H4), 5.98
(bs, 1H, NH). 13C NMR: d 18.3 (C6), 23.4 (COCH3), 35.6
(C3), 52.3, 52.6 (C2, COOCH3), 124.6, 130.1 (C4, C5), 169.8,
172.6 (C1, CONH). MS (ESI+, MeOH): m/z 207.9
22
(M + Na)+. [a]D ꢂ55ꢀ (c 1.18, CHCl3) containing 6% of 6a
(lit.14 [a]D ꢂ57.2ꢀ (c 1.18, CHCl3) containing < 2% of 6a).
20
(2Z)-Methyl 2-acetamidopenta-2,4-dienoate 1b. Using the
method described above, tetramethylguanidine (1.90 mL,
14.90 mmol) and hydroquinone (5 mg) were added to a solu-
tion of the phosphonate 3 (3.0 g, 11.23 mmol) in distilled
THF (35 mL) at ꢂ78 ꢀC. After 15 min, acrolein 2b (0.90 mL,
13.47 mmol) was added, the mixture stirred at ꢂ78 ꢀC for 2
h then at 25 ꢀC for 2 h and worked up to give an oil (2.81
g). Purification by flash chromatography on silica gel using
ethyl acetate and light petroleum (1:1) gave the (2Z)-dienoate
1b as a white solid (1.65 g, 87%), (Rf 0.2); mp 61–63 ꢀC. IR
(KBr): 3277, 3011, 2955, 1733, 1655, 1594, 1518, 1438, 1113,
(2R)-Methyl 2-acetamidopent-4-enoate 5b. Hydrogenation of
(2Z)-methyl 2-acetamidopenta-2,4-dienoate 1b (40 mg, 0.24
mmol) in benzene was carried out at 30 psi for 3 h using
Rh-(R,R)-Et-DuPHOS. Purification by passing through a
short plug of silica with ethyl acetate gave an oil (36 mg,
88%). The 1H NMR spectrum indicated the (2R)-pent-4-en-
oate 5b and the fully saturated compound, (2R)-methyl 2-acet-
amidopentanoate 6b [d 0.93 (t, J ¼ 7.3 Hz, CH3), 1.25–1.44
(m, CH2)] in a 95:5 ratio respectively. A solution of the oil
in dichloromethane (2 mL) was injected into the GC chiral
column to give two peaks: (R), t1 ¼ 18.2 min; (S), t2 ¼ 18.6
min; ee 95% (R). IR (neat): 3278, 1744, 1657, 1546, 1438,
1
1016, 994, 950, 768 cmꢂ1. H NMR: d 2.14 (s, 3H, COCH3),
3.79 (s, 3H, COOCH3), 5.47 (d, 1H, J ¼ 10.1 Hz, H5(E)),
5.59 (d, 1H, J ¼ 16.9 Hz, H5(Z)), 6.39–6.52 (m, 1H, H4),
7.03 (d, 1H, J ¼ 11.3 Hz, H3), 7.12 (bs, 1H, NH). 13C
NMR: d 23.8 (COCH3), 52.8 (COOCH3), 132.1, 132.9 (C3,
C4), 123.7 (C2), 125.2 (C5), 165.6, 168.8 (C1, CONH). Calc.
for C8H11NO3 : C, 56.78; H, 6.54; N, 8.28. Found: C, 56.66;
H, 6.67; N, 8.29%.
1375, 1151 cmꢂ1 1H NMR: d 2.00 (s, 3H, COCH3), 2.42–
.
2.61 (m, 2H, H3), 3.72 (s, 3H, COOCH3), 4.66 (m, 1H,
H2), 5.09 (d, 1H, J ¼ 16.2 Hz, H5(Z)), 5.10 (d, 1H, J ¼ 11.1
Hz, H5(E)), 5.65 (m, 1H, H4), 6.14 (bs, 1H, NH). 13C
NMR: d 23.4 (COCH3), 51.8, 52.5 (C2, COOCH3), 119.2
(C5), 132.2 (C4), 169.7, 172.2 (C1, CONH). HRMS (ESI+,
MeOH): calc. for (C8H13NO3 + Na)+ m/z 194.0793, found
22
194.0785 (M + Na)+. [a]D ꢂ43ꢀ (c 0.047, CH3Cl) containing
(2Z)-Methyl 2-acetamidohepta-2,6-dienoate 1c. Reaction of
tetramethylguanidine (0.31 mL, 3.95 mmol) and the phospho-
nate 3 (0.71 g, 2.97 mmol) in distilled THF (10 mL) with 4-pen-
tenal 2c (0.69 mL, 3.57 mmol) as described above gave an oil
(0.47 g). Purification by flash chromatography on silica gel
using ethyl acetate and light petroleum (1:1) gave the (2Z)-
dienoate 1c as a white solid (0.22 g, 38%), (Rf 0.24); mp
44–45 ꢀC (lit.15 44 ꢀC). 1H NMR: d 2.10 (s, 3H, COCH3),
2.16–2.29 (m, 4H, H4, H5), 3.75 (s, 3H, COOCH3), 4.97–
5.08 (m, 2H, H7), 5.79 (ddt, 1H, J ¼ 17.1, 10.4, 6.4 Hz, H6),
6.64 (t, 1H, J ¼ 6.6 Hz, H3), 7.90 (bs, 1H, NH). 13C NMR:
d 23.2 (COCH3), 28.0 (C4), 32.3 (C5), 52.3 (COOCH3), 115.5
(C7), 125.9 (C2), 137.0 (C3), 138.0 (C6), 165.0, 169.2 (C1,
CONH). MS (ESI+, MeOH): m/z 220.1 (M + Na)+.
5% of 6b.
(2R)-Methyl 2-acetamidohept-6-enoate 5c. Hydrogenation of
(2Z)-methyl 2-acetamidohepta-2,6-dienoate 1c (40 mg, 0.20
mmol) in benzene was carried out at 30 psi for 2 h using
Rh-(R,R)-Et-DuPHOS. Purification by passing through a
short plug of silica with ethyl acetate gave an oil (36 mg,
1
90%). The H NMR spectrum indicated the (2R)-hept-6-eno-
ate 5c and the fully saturated compound, (2R)-methyl 2-acet-
amidoheptanoate 6c [(d 0.88 (t, J ¼ 6.6 Hz, CH3)] in a 92:8
ratio respectively. A solution of the oil in dichloromethane
(2 mL) was injected into the GC chiral column to give two
peaks: (R), t1 ¼ 25.9 min; (S), t2 ¼ 26.1 min; ee 98% (R). IR
(neat): 3286, 2954, 1745, 1658, 1547, 1436, 1374, 1264, 1210
Asymmetric hydrogenations
1
cmꢂ1. H NMR: d 1.26–1.53 (m, 2H, H4), 1.58–1.91 (m, 2H,
H3), 2.03 (s, 3H, COCH3), 2.06–2.10 (m, 2H, H5), 3.75 (s,
3H, COOCH3), 4.61 (td, 1H, J ¼ 7.7, 5.5 Hz, H2), 4.95–5.05
(m, 2H, H7), 5.75 (ddt, 1H, J ¼ 17.0, 10.4, 6.5 Hz, H6),
6.30 (bs, 1H, NH). 13C NMR: d 23.5 (COCH3), 24.8 (C4),
32.2 (C3), 33.5 (C5), 52.4, 52.7 (C2, COOCH3), 115.3 (C7),
138.0 (C6), 170.1, 173.3 (C1, CONH). HRMS (EI, MeOH):
calc. for (C10H17NO3–COCH3) m/z 156.1024, found
In a dry box, the substrate, catalyst (substrate:catalyst ¼
100:1) and deoxygenated methanol or benzene were added into
a Fischer–Porter tube. Three vacuum/nitrogen cycles were
used to purge the gas line of any oxygen, followed by three
vacuum/nitrogen cycles and three vacuum/hydrogen cycles
of the vessel before the vessel was pressurized to the stated
pressure with hydrogen. The vessel was left stirring at ambient
temperature for the reported period of time. For liquid sub-
strates, a freeze–pump–thaw cycle was applied, the solution
was transferred into a dry box and loaded into a Fischer–
Porter tube.
22
156.1024 (M–COCH3). [a]D ꢂ60ꢀ (c 0.15, CH3Cl) containing
8% of 6c.
Hydroformylations
(2R,4E)-Methyl 2-acetamidohex-4-enoate 5a. (2Z,4E)-
Methyl 2-acetamidohexa-2,4-dienoate 1a (0.42 g, 2.18 mmol)
and [(COD)Rh-(R,R)-Et-DuPHOS]OTf were dissolved in ben-
zene (10 mL). The vessel was charged with hydrogen (90 psi)
and the mixture stirred for 2 h. The hydrogen was vented
and the mixture was concentrated to give an oil (0.42 g). Pur-
ification by passing through a short silica plug with ethyl acet-
ate gave an oil (0.40 g, 99%). The 1H NMR spectrum of the oil
indicated the (2R,4E)-hex-4-enoate 5a and the fully saturated
compound, (2R,4E)-methyl 2-acetamidohexanoate 6a [d 0.89
(m, CH3), 1.22–1.39 (m, CH2)] in a 94:6 ratio respectively.
IR (neat) 3284, 2954, 1747, 1658, 1547, 1437, 1375, 1217,
Reactions with CO/H2 were carried out in a 100 mL Parr
stainless steel autoclave fitted with a glass liner and magnetic
stirrer bead.21,31 After the reagents and substrate had been
added under nitrogen into the autoclave, the vessel was
flushed three times with 100 psi of CO/H2 (1:1 molar ratio)
and then pressurized to the stated pressure of the same gases.
The autoclave was inserted to the heating block where its tem-
perature was controlled by a thermocouple and the reaction
was stirred with a magnetic stirrer under the heating block.
The vessel was left stirring at the reported temperature for
the reported period of time. At the end of the reaction, the
vessel was left to cool to ambient temperature. The gases were
New J. Chem., 2003, 27, 387–394
391

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(2R)-N-acetyl-4-ethyl-4,5-didehydroprolinate 10a in 17% yield
respectively.
released slowly and the contents were treated and analyzed as
reported.
Similar reactions were carried out by varying ligand, pres-
sure, temperature and reaction time. The results are sum-
marised in Table 2.
Reaction of (2R,4E)-methyl 2-acetamidohex-4-enoate 5a.
(2R)-Methyl N-acetyl-5-methyl-5,6-didehydropipecolate 9a
and (2R)-methyl N-acetyl-4-ethyl-4,5-didehydroprolinate 10a.
(2R,4E)-Methyl 2-acetamidohex-4-enoate 5a (40 mg, 0.22
mmol), rhodium(II) acetate dimer (1.0 mg, 2.2 mmol) and
BIPHEPHOS (3.5 mg, 4.4 mmol) were dissolved in deoxyge-
nated benzene (5 mL). The autoclave was pressurized to 400
psi of CO/H2 (1:1 molar ratio) and heated to 100 ꢀC. After
72 h, the autoclave was cooled to ambient temperature and
the solvent was removed under reduced pressure to give an
brown oil (50 mg). The 1H and 13C NMR spectra of the crude
oil showed the pipecolate 9a and the prolinate 10a in a 91:9
ratio respectively. The compounds were separated by chroma-
tography on silica gel using ethyl acetate and light petroleum
(3:1 ratio).
Reaction of (2S)-methyl 2-acetamidopent-4-enoate 5b. (2S)-
Methyl N-acetyl-5,6-didehydropipecolate 9b and (2S)-methyl
N-acetyl-4-methyl-4,5-didehydroprolinate 10b. The (2S)-pent-
4-enoate 5b (74 mg, 0.43 mmol), rhodium(II) acetate dimer
(1.9 mg, 4.3 mmol) and BIPHEPHOS (6.8 mg, 8.6 mmol) in
deoxygenated benzene (10 mL) were reacted with CO/H2 (80
psi) at 80 ꢀC for 72 h to give a brown oil (80 mg). The 1H
NMR spectrum indicated the pipecolate 9b and the prolinate
10b were present in a 66:34 ratio respectively. The two com-
pounds were separated using column chromatography (3:1 of
ethyl acetate:light petroleum).
(2S)-Methyl N-acetyl-5,6-didehydropipecolate 9b was iso-
lated as clear oil (38 mg, 48%), (Rf 0.5). HPLC: (S), t1 ¼ 9.3
min (R), t2 ¼ 26.5 min; ee 99% (S). IR (neat): 3468, 1744,
(2R)-Methyl N-acetyl-5-methyl-5,6-didehydropipecolate 9a
was isolated as clear oil (30 mg, 70%), (Rf 0.51). HPLC: (S),
t1 ¼ 7.9 min; (R), t2 ¼ 10.5 min; ee 97% (R). IR (neat):
1
1674, 1645, 1417, 1383, 1347, 1208, 1045 cmꢂ1. H NMR: d
1
1744, 1654, 1404, 1205, 1174 cmꢂ1. H NMR: d [minor rota-
[minor rotamer in brackets] 1.80–2.12 (m, 3H, H3, H4a),
2.23 (s, 3H, [2.13, s], COCH3), 2.35–2.41 (m, 1H, H4b), 3.73
(s, 3H, [3.75, s], COOCH3), 4.97 (m, 1H, [5.00–5.10, m], H5),
5.24 (m, 1H, [4.65–4.66, m], H2), 6.63 (d, 1H, J 8.6 Hz, H6).
13C NMR: d [minor rotamer in brackets] 18.9 [18.6] (C3),
21.5 (COCH3), 23.3 [23.9] (C4), 51.7 [55.7] (C2), 52.3 [52.6]
(COOCH3), 107.1 [107.0] (C5), 125.1 [123.2] (C6), 168.5,
171.0 (C1, CONH). Calc. for C9H13NO3 : C, 58.99; H, 7.16;
mer in brackets] 1.70 (s, 3H, [1.74, s], CH3C5), 1.80–2.00 (m,
3H, H3, H4a), 2.22 (s, 3H, [2.11, s], COCH3), 2.37 (m, 1H,
H4b), 3.71 (s, 3H, [3.76, s], COOCH3), 5.23 (m, 1H, [4.60,
bs], H2), 6.40 (s, 1H, [7.04, s], H6). 13C NMR: d [minor rota-
mer in brackets] 21.4 [21.2] (CH3C5), 21.75 [21.85] (COCH3),
23.7 [24.2] (C3), 24.7 [24.3] (C4), 51.3 [53.1] (C2), 52.7 [55.4]
(COOCH3), 116.1 [116.7] (C5), 120.1 [118.4] (C6), 168.2,
171.3 (C1, CONH). Calc. for C10H14NO3 : C, 60.88; H, 7.67;
20
N, 7.65. Found: C, 59.01; H, 7.12; N, 7.60%. [a]D ꢂ64ꢀ
20
N, 7.10. Found: C, 60.74; H, 7.69; N, 6.96%. [a]D +138ꢀ
(c 0.016, CH3Cl).
(c 0.034, CH3Cl).
(2S)-Methyl N-acetyl-4-methyl-4,5-didehydroprolinate 10b
was isolated as a colourless oil (21 mg, 27%), (Rf 0.3). HPLC:
(S), t1 ¼ 12.2 min; (R), t2 ¼ 26.2 min; ee 99% (S). IR (neat):
(2R)-Methyl N-acetyl-4-ethyl-4,5-didehydroprolinate (10a)
was obtained as clear oil (5 mg, 11%), (Rf 0.34). HPLC: (S),
t1 ¼ 11.0 min; (R), t2 ¼ 18.7 min; ee 98% (R). IR (neat):
3296, 1746, 1654, 1542, 1375, 1208 cmꢂ1 1H NMR: d 1.74
.
1
2858, 1750, 1647, 1438, 1208 cmꢂ1. H NMR: d 1.08 (t, 3H,
(s, 3H, CH3C4), 2.14 (s, 3H, COCH3), 2.50 (m, 1H, H3a),
2.94 (m, 1H, H3b), 3.76 (s, 3H, COOCH3), 4.82 (dd, 1H,
J ¼ 11.7, 5.1 Hz, H2), 6.22 (q, 1H, J ¼ 1.8 Hz, H5). 13C
NMR: d 13.8 (CH3C4), 21.9 (COCH3), 38.3 (C3), 52.8
(COOCH3), 58.5 (C2), 120.2 (C4), 124.3 (C5), 165.9, 171.9
(C1, CONH). HRMS (ESI+, MeOH): calc. for (C9H13NO3 +
Na)+ m/z 206.0793, found, 206.0787 (M + Na)+.
J ¼ 7.5 Hz, CH3CH2), 2.03–213 (m, 2H, CH3CH2), 2.15 (s,
3H, COCH3), 2.52 (dd, 1H, J ¼ 16.8, 5.1 Hz, H3a), 2.96
(dd, 1H, J ¼ 16.7, 11.7 Hz, H3b), 3.76 (s, 3H, COOCH3),
4.82 (dd, 1H, J ¼ 11.7, 5.2 Hz, H2), 6.19–6.21 (m, 1H, H5).
13C NMR: d 12.5 (CH3CH2), 21.8 (C3), 21.9 (COCH3), 36.7
(CH3CH2), 52.7, 58.7 (C2, COOCH3), 122.9 (C5), 126.4
(C4), 166.0, 171.9 (C1, CONH). HRMS (EI, MeOH): calc.
Reaction of 5b (40 mg, 0.23 mmol) using BIPHEPHOS at
80 ꢀC, 80 psi for 20 h gave a crude oil containing ca. 50% of
the pent-3-enoate 13 and the cyclic compounds 9b and 10b
in a ratio of 78:22. (2S,3E)-Methyl 2-acetamidopent-3-enoate
13 was isolated as a clear oil, (Rf 0.4). IR (neat): 3283, 1746,
20
for C10H15NO3 m/z 197.1052, found 197.1046 (M). [a]D
+114ꢀ (c 0.028, CH3Cl).
A similar reaction using BIPHEPHOS at 80 ꢀC, 400 psi gave
a mixture of the aldehydes 7a and 8a (ratio ca. 1:1) and the
pipecolate 9a. 1H NMR: d for 7a, 9.61 (d, J ¼ 1.5 Hz,
CHO); for 8a, 9.76 (d, J ¼ 1.5 Hz, CHO). The pipecolate 9a
was isolated in 37% yield.
1
1655, 1542, 1375 cmꢂ1. H NMR: d 1.70 (ddd, 3H, J ¼ 6.5,
1.7, 1.2 Hz, H5), 2.03 (s, 3H, COCH3), 3.75 (s, 3H, COOCH3),
5.03 (m, 1H, H2), 5.46 (ddq, 1H, J ¼ 15.3, 6.4, 1.7 Hz, H4),
5.77 (m, 1H, H3), 6.16 (bs, 1H, NH). 13C NMR: d 18.2 (C5),
23.5 (COCH3), 53.0, 54.5 (C2, COOCH3), 125.2, 130.3 (C3,
C4), 169.6, 171.8 (C1, CONH). HRMS (ESI+, MeOH): calc.
for (C8H13NO3 + H)+ m/z 172.0974, found, 172.0964
(M + H)+.
A reaction of the hex-4-enoate 5a (50 mg, 0.27 mmol), rho-
dium(II) acetate dimer (1.2 mg, 2.7 mmol) and triphenylpho-
sphine (1.4 mg, 5.4 mmol) at 80 ꢀC with 400 psi of CO/H2
for 20 h gave a brown oil (64 mg). The 1H and 13C NMR
spectra of the crude oil showed (2R)-methyl N-acetyl-5-
methyl-6-hydroxypipecolate 11 and (2R)-methyl N-acetyl-4-
ethyl-5-hydroxyprolinate 12 in 4:1 ratio. The compounds were
separated using column chromatography (ethyl acetate).
(2R)-methyl N-acetyl-5-methyl-6-hydroxypipecolate 11: 1H
NMR. d 1.07 (d, 3H, J ¼ 9.0 Hz, CH3–C5), 1.31–1.79 (m,
5H, H3, 4 5), 2.22 (s, 3H, COCH3), 3.71 (s, 3H, COOCH3),
4.39 (t, 1H, J ¼ 8.9 Hz, H2), 5.05 (m, 1H, H6).
Similar reactions were carried out by varying ligand, pres-
sure, temperature and reaction time. The results are sum-
marised in Table 2.
Reaction of (2R)-methyl 2-acetamidohept-6-enoate 5c. (2R)-
Methyl 2-acetamido-7-formylheptanoate 14 and (2R)-methyl 2-
acetamido-6-formylheptanoate 15. The (2R)-hept-4-enoate 5c
(70 mg, 0.36 mmol), rhodium(II) acetate dimer (1.6 mg, 3.6
mmol) and triphenylphosphine (1.9 mg, 7.2 mmol) in deoxyge-
nated benzene (10 mL) were reacted with CO/H2 (400 psi) at
(2R)-methyl N-acetyl-4-ethyl-5-hydroxyprolinate 12: 1H
NMR. d 1.08 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 1.31–1.73 (m,
3H, CH3CH2 , H4), 2.15 (s, 3H, COCH3), 2.37–2.47 (m, 2H,
H3), 3.76 (s, 3H, COOCH3), 4.44–4.53 (m, 1H, H2), 5.29 (m,
1H, H5).
1
80 ꢀC for 20 h to give a brown oil (80 mg). The H and 13C
The CDCl3 solutions of 11 and 12 on storing for
several hours underwent dehydration to give (2R)-methyl N-
acetyl-5-methyl-5,6-didehydropipecolate 9a in 30% yield and
NMR spectra indicated the two aldehydes 14 and 15 were pre-
sent in a 50:50 ratio. The aldehydes were partially separated
using radial chromatography (ethyl acetate:light petroleum,
392
New J. Chem., 2003, 27, 387–394

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1:1) to give a sample of 14 and a sample of 15 containing 20%
of the isomer 14.
67:33 ratio respectively as well as the isomerised alkene 13
(ca. 25%). The compounds were separated as described pre-
viously. The (2S)-pipecolate 9b was isolated as a clear oil (17
mg, 39%). HPLC showed the ee as 97% (S). The (2S)-prolinate
10b was obtained as a colourless oil (9 mg, 21%). HPLC
showed the ee as 99% (S).
The (2R)-heptanoate 14 was isolated as a yellow oil (28 mg,
34%), (Rf 0.86). IR (neat): 3296, 2938, 1744, 1657, 1542, 1438,
1
1438, 1375, 1211, 1167 cmꢂ1. H NMR: d [minor rotamer in
brackets] 1.20–1.37 (m, 4H, H4, H5), 1.55–1.69 (m, 2H, H6),
1.77–1.83 (m, 2H, H3), 2.00 (s, 3H, [2.02, s], COCH3), 2.41
(td, 2H, J ¼ 7.2, 1.7 Hz, H7), 3.75 (s, 3H, [3.72, s], COOCH3),
4.62 (m, 1H, H2), 6.14 (bs, 1H, NH), 9.73 (t, 1H, J ¼ 1.7 Hz,
[9.75, m], CHO). 13C NMR: d 24.5 (COCH3), 22.1 (C6), 25.3
(C4), 29.0 (C5), 32.6 (C3), 44.0 (C7), 52.3, 52.7 (C2,
COOCH3), 170.0, 173.2 (C1, CONH), 202.6 (CHO). HRMS
(EI, MeOH): calc. for (C11H19NO4–COCH3) m/z 186.1130,
found, 186.1133 (M–COCH3).
Reaction of (2Z)-methyl 2-acetamidohepta-2,6-dienoate 1c.
(2S)-Methyl
N-acetyl-6-methyl-6,7-didehydroazepan-1-yl-2-
carboxylate 17 and (2S)-methyl N-acetyl-5-ethyl-5,6-didehydro-
pipecolate 18. The (2Z)-hepta-2,6-dienoate 1c (40 mg, 0.20
mmol), [(COD)Rh-(S,S)-Et-DuPHOS]OTf, rhodium(II) acet-
ate dimer (1.1 mg, 2.5 mmol) and BIPHEPHOS (3.9 mg, 5.0
mmol) in deoxygenated benzene (10 mL) were reacted with
hydrogen at 30 psi for 2 h. The hydrogen was vented and the
autoclave was pressurized to 800 psi of CO/H2 and heated to
The (2R)-heptanoate 15 was obtained as a yellow oil (24 mg,
29%), (Rf 0.95) containing 20% of 14. IR (neat): 1740, 1656,
1
1545, 1438, 1375, 1212, 1178 cmꢂ1. H NMR: d (1:1 mixture
1
150 ꢀC for 72 h. After work up, the H NMR spectrum of the
of two diastereoisomers) 1.10 (d, 3H, J ¼ 7.0 Hz, H7), 1.23–
1.46 (m, 3H, H4, H5a), 1.58–1.90 (m, 3H, H3, H5b), 2.03 (s,
3H, COCH3), 2.24–2.38 (m, 1H, H6), 3.75 (s, 3H, COOCH3),
4.63 (m, 1H, H2), 6.21 (d, 1H, J ¼ 7.8 Hz, NH), 9.60 (m, 1H,
CHO).y 13C NMR: d (1:1 mixture of two diastereoisomers)
13.8 (C7), 23.0 (C4), 30.2 (C5), 32.9 (C3), 46.5 (C6), 52.2,
52.8 (C2, COOCH3), 170.1, 173.2 (C1, CONH), 204.9
(CHO). HRMS (EI, MeOH): calc. for (C11H19NO4–COCH3)
m/z 186.1130, found, 186.1133 (M–COCH3). A similar reac-
tion was carried out using 5c (37 mg), rhodium(II) acetate
dimer (0.9 mg, 8.4 mmol) and BIPHEPHOS (3.0 mg, 3.8 mmol)
also gave a 1:1 mixture of the aldehydes 14 and 15.
crude oil (40 mg) showed three compounds, (2S)-methyl
N-acetyl-6-methyl-6,7-didehydroazepan-1-yl-2-carboxylate 17,
(2S)-methyl N-acetyl-5-ethyl-5,6-didehydropipecolate 18 and
(2S)-methyl 2-acetamidoheptanoate 6c in a 13:13:74 ratio
respectively. Purification using radial chromatography (ethyl
acetate:light petroleum ¼ 1:1) gave a sample of the cyclic pro-
ducts 17 and 18 in a ca. 1:1 ratio as a yellow oil (10 mg, 24%),
(Rf 0.33). HRMS (ESI+, MeOH): calc. for (C11H17NO3 + Na)+
m/z 234.1106, found, 234.1097 (M + Na)+.
(2S)-Methyl 2-acetamido-6-methyl-6,7-didehydroazepan-1-
yl-2-carboxylate 17, 1H NMR: d 1.6–2.2 (m, 6H, H3, H4,
H5), 1.74 (d, 3H, J ¼ 1.3 Hz, CH3), 2.09 (s, 3H, COCH3),
3.70 (s, 3H, COOCH3), 5.14 (dd, 1H, J ¼ 7.4, 5.2 Hz, H2),
6.10 (s, 1H, H7).
One-pot tandem hydrogenation and hydroformylation reactions
(2S)-Methyl N-acetyl-5-ethyl-5,6-didehydropipecolate 18,1H
NMR: d 1.03 (t, 3H, J ¼ 7.4 Hz, CH3CH2), 1.78–1.90 (m, 1H,
H3), 1.93–2.09 (m, 4H, H4, CH3CH2), 2.23 (s, 3H, COCH3);
2.33–2.40 (m, 1H, H3); 3.71 (s, 3H, COOCH3); 5.20 (m, 1H,
H2); 6.39 (bs, 1H, H6).
Reactions were carried out in a 100 mL Parr autoclave (see
previous conditions used for hydroformylation reactions).
Two catalyst system
(2S)-Methyl 2-acetamidoheptanoate 6c, (Rf 0.44) was iso-
lated as a yellow oil. IR (neat) 3311, 1738, 1656 cmꢂ1 1H
.
The ratio of substrate:Rh-DuPHOS:[Rh(OAc)2]2:BIPHE-
PHOS or PPh3 was 100:1:1:2; CO/H2 (1:1 molar mixture).
NMR: d 0.88 (t, 3H, J ¼ 6.6 Hz, H7), 1.21–1.41 (m, 6H),
1.59–1.71 (m, 1H), 1.78–1.97 (m, 1H), 2.03 (s, 3H, COCH3),
3.75 (s, 3H, COOCH3), 4.61 (m, 1H, H2), 6.19 (bd, 1H, J
7.2 Hz, NH). 13C NMR: d 14.3 (C7), 22.8 (C4), 23.6 (COCH3),
25.2 (C5), 31.7, 32.9 (C3, C6), 52.5, 52.7, C2, COOCH3), 169.9,
173.4 (C1, CONH). MS (ESI+, MeOH): m/z 224.3 (M + Na)+.
Reaction of (2Z,4E)-methyl 2-acetamidohexa-2,4-dienoate
1a. The (2Z,4E)-hexa-2,4-dienoate 1a (50 mg, 0.27 mmol),
[(COD)Rh-(S,S)-Et-DuPHOS]OTf, rhodium(II) acetate dimer
(1.2 mg, 2.7 mmol) and triphenylphosphine (1.4 mg, 5.4 mmol)
were dissolved in deoxygenated benzene (10 mL) as described
previously. The autoclave was charged with hydrogen (90 psi)
and the mixture was stirred for 2 h. The hydrogen was vented
and the autoclave was pressurized to 400 psi of CO/H2 and
One catalyst system
The ratio of substrate:Rh-DuPHOS was 100:1; CO/H2 (1:1
molar mixture).
1
heated to 80 ꢀC for 20 h to give a brown oil (50 mg). The H
NMR spectrum of the crude oil showed two compounds, the
pipecolate 9a and the prolinate 10a in a 56:44 ratio respec-
tively. The compounds were separated as described previously.
The (2S)-pipecolate 9a was isolated as a clear oil (27 mg, 51%).
HPLC showed the ee as 95% (S). The (2S)-prolinate 10a was
obtained as a clear oil (16 mg, 30%). HPLC showed the ee
as 99% (S).
Reaction of (2Z,4E)-methyl 2-acetamidohexa-2,4-dienoate
1a. The (2Z,4E)-hexa-2,4-dienoate 1a (40 mg, 0.22 mmol)
and [(COD)Rh-(S,S)-Et-DuPHOS]OTf in deoxygenated ben-
zene (10 mL) were reacted with hydrogen at 90 psi for 2 h.
The hydrogen was vented and the autoclave was pressurized
to 800 psi of CO/H2 and heated to 150 ꢀC for 72 h. After work
1
up, the H NMR spectrum of the crude oil (40 mg) showed
only the pipecolate 9a. Purification using chromatography
(ethyl acetate:light petroleum ¼ 3:1) gave the (2S)-pipecolate
9a as a clear oil (25 mg, 58%). HPLC showed the ee as 96% (S).
A similar reaction was carried out at 400 psi, 80 ꢀC for 20 h
gave a mixture of 9a and 10a (ratio 83:17) as well as ca. 15% of
the aldehydes 7a and 8a (1H NMR: d 9.76).
Reaction of (2Z)-methyl 2-acetamidopenta-2,4-dienoate 1b. A
solution of the (2Z)-penta-2,4-dienoate 1b (40 mg, 0.24 mmol),
[(COD)Rh-(S,S)-Et-DuPHOS]OTf, rhodium(II) acetate dimer
(1.0 mg, 2.4 mmol) and BIPHEPHOS (3.4 mg, 5.4 mmol) in
deoxygenated benzene (10 mL) was reacted with hydrogen at
30 psi for 3 h. The hydrogen was vented and the autoclave
was pressurized to 80 psi of CO/H2 and heated to 80 ꢀC for
1
Reaction of (2Z)-methyl 2-acetamidopenta-2,4-dienoate 1b.
The (2Z)-penta-2,4-dienoate 1b (50 mg, 0.30 mmol) and
[(COD)Rh-(S,S)-Et-DuPHOS]OTf in deoxygenated benzene
(10 mL) were reacted with hydrogen at 30 psi for 3 h. The
hydrogen was vented and the autoclave was pressurized to
400 psi of CO/H2 and heated to 80 ꢀC for 72 h. After work
72 h. After work up, the H NMR spectrum of the crude oil
(40 mg) showed the pipecolate 9b and the prolinate 10b in a
y At 400 MHz using a Bruker-DRX spectrometer, all chemical shifts
were the same except for the CHO peaks at d 9.59 (d, 1H, J ¼ 1.9
Hz) and 9.60 (d, 1H, J ¼ 1.8 Hz). CHO.
New J. Chem., 2003, 27, 387–394
393

View Article Online
up, the 1H NMR spectrum of the crude oil (40 mg) showed the
pipecolate 9b and the prolinate 10b in a 54:46 ratio respec-
tively. The compounds were separated as described previously.
The (2S)-pipecolate 9b was isolated as a clear oil (22 mg, 40%).
HPLC showed the ee as 94% (S). The (2S)-prolinate 10b was
isolated as an oil (28 mg, 51%). HPLC showed the ee as
99% (S).
A similar reaction was carried out at 80 psi, 80 ꢀC for 72 h
gave 9b and 10b in a 74:26 ratio respectively as well as ca.
40% of the isomerised alkene 13. The spectral data were con-
sistent with those described above.
found, 152.0680 (M + Na)+. [a]D +10ꢀ (c 0.002, H2O)
20
20
(lit.26 for (2R)-21, [a]D +10.8ꢀ (c 2, H2O)).
Acknowledgements
We thank Monash University and the Centre for Green Chem-
istry for provision of a postgraduate award (to E. T.), the Aus-
tralian Research Council for its financial support to research
and Johnson Matthey Pty Ltd for a loan of rhodium.
Reaction of (2Z)-methyl 2-acetamidohepta-2,6-dienoate 1c.
The (2Z)-hepta-2,6-dienoate 1c (40 mg, 0.20 mmol) and
[(COD)Rh-(S,S)-Et-DuPHOS]OTf in deoxygenated benzene
(10 mL) were reacted with hydrogen at 30 psi for 2 h. The
hydrogen was vented and the autoclave was pressurized to
800 psi of CO/H2 and heated to 150 ꢀC for 72 h. After work
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1
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394
New J. Chem., 2003, 27, 387–394