Application of asymmetric phase-transfer catalysis in the enantioselective synthesis of cis-5-substituted proline esters

Article abstract of DOI:10.1016/j.tet.2010.09.075

A simple, highly stereoselective three-step sequence for the enantioselective synthesis of cis-5-substituted proline esters is described. This sequence features an asymmetric PTC Michael addition, followed by acid catalysed imine exchange and catalytic hydrogenation. Application of this chemistry in the synthesis of the nonpeptide cholecystokinin antagonist (+)-RP-66803 11 is also described.

Full text of DOI:10.1016/j.tet.2010.09.075

Tetrahedron 66 (2010) 8832e8836
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Application of asymmetric phase-transfer catalysis in the enantioselective
synthesis of cis-5-substituted proline esters
,
a
a
a
b
Barry Lygo a , Christopher Beynon , Michael C. McLeod , Claude-Eric Roy , Charles E. Wade
*
a School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2010
Received in revised form 2 September 2010
Accepted 20 September 2010
Available online 24 September 2010
A
simple, highly stereoselective three-step sequence for the enantioselective synthesis of cis-5-
substituted proline esters is described. This sequence features an asymmetric PTC Michael addition,
followed by acid catalysed imine exchange and catalytic hydrogenation. Application of this chemistry in
the synthesis of the nonpeptide cholecystokinin antagonist (þ)-RP-66803 11 is also described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Michael addition
Hydrogenation
Amino acids
Pyrrolidines
1. Introduction
amphibians.3 5-Substituted proline derivatives 4 have also proved
to be of significant interest as modified peptide scaffolds,4 as key
Compounds incorporating the cis-2,5-disubstituted pyrrolidine
fragment 1 have attracted great interest from synthetic organic
chemists and this has resulted in the preparation and character-
isation of a large number of molecules possessing this sub-struc-
tural element (Fig. 1).1 Within this field of study, pyrrolidine 2 and
indolizidine alkaloids 32 have attracted particular attention due to
their occurrence as signalling and protective agents in ants and
fragments in potential pharmaceutical agents,5,6 and as ligands for
asymmetric catalysis.7
Single enantiomers of these structures are commonly prepared
from pyroglutamic acid derivatives,8 but in recent years there has
been increasing interest on the development of alternative
approaches that expand the range of structures, which can be
accessed rapidly from simple starting materials.9
Werecentlydemonstratedthattheuseofmesitolasaco-catalystin
conjunction with the readily-available cinchona alkaloid-derived
phase-transfer catalyst 610 allows for highly enantioselective addition
of glycine imine 5 toawide rangeofMichael acceptors.11 If the Michael
acceptor is an enone, this offers the possibility of preparing enan-
tioenriched pyrrolidines 10 via the three-step sequence outlined in
Scheme 1.12
H
H
H
H
>15,000 compounds
incorporating this sub-structural
element are contained in the
2010 Beilstein Database.1
H
H
N
1
This approach takes advantage of the fact that hydrolysis of the
benzophenone imine moiety in the initial Michael adducts 7 should
lead directly to the pyrroline intermediate 9.13 Subsequent hydro-
genation would then be expected to favour formation of the cis-
5-substituted proline ester 10. Although this sequence appears
straightforward, we envisaged two key issues that might limit
application of this chemistry to the synthesis of highly enantioen-
riched products. Firstly, the pyrroline 9 may be vulnerable to race-
misation during the hydrolysis step, especially if the R-substituent is
a conjugating group. Secondly, competing hydrogenolysis of the
CeNbond maybe an issueduring thehydrogenationstepifR¼aryl.14
H
R
R'
R
R'
N
R
CO2H
N
N
H
H
cis-5-substituted
prolines 4
pyrrolidine alkaloids 2
indolizidine alkaloids 3
Fig. 1. 2,5-Disubstituted pyrrolidines.
* Corresponding author. E-mail address: b.lygo@nottingham.ac.uk (B. Lygo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.075

B. Lygo et al. / Tetrahedron 66 (2010) 8832e8836
8833
With adduct 13 in hand, we next examined the hydrolysis/cyc-
lisation/hydrogenation sequence (Table 2). Conversion to pyrroline
14 was straightforward, and we were able to establish that no loss
of stereochemical integrity occurred under the reaction conditions
shown.16 Prolonged reaction times (days) or the use of stronger
acids (e.g., AcOH) did lead to partial racemisation of the product 14.
O
Ph2C=N
CO2t-Bu
H3O+
R
Ph2C=N
CO2t-Bu
CO2t-Bu
PTC 6, mesitol,
KOH, CH2Cl2
7
5
R
O
H2N
(-H2O)
R
CO2t-Bu
Table 2
N
8
Formation of cis-5-phenyl proline tert-butyl ester 15
9
R
O
Ph2C=N
CO2t-Bu
15% aq. citric acid
Ph
Et
N
hydrogenation
13
N+
H
R
CO2t-Bu
CO2t-Bu
N
14
N
H
THF, RT, 2 h
OBn
Ph
O
Br-
10
6
75%
H2 (1 atm)
RT
Ph
CO2t-Bu
N
H
Scheme 1. Three-step sequence to 5-substituted proline esters.
15
For these reasons, we initially chose to investigate application of this
approach in the synthesis of (þ)-RP-66803 11, a nonpeptide chole-
cystokinin antagonist Fig. 2.5,15
Hydrogenation conditions
Time (h)
Yield 15 (%)
60c
87
dra
eeb
10% Pd/C, MeOH
5% Pt/C, MeOH
5% Pt/C, AcOHd
3
3
4
>20:1
>20:1
>20:1
89
89
73
64
Ph2C=N
CO2t-Bu
CO2t-Bu
By 1H NMR spectroscopy (the minor diastereoisomer could not be detected).
Imine 13 used in this study was 89% ee.
The hydrogenolysis product was also obtained in 30% yield.
Imine 13 was used as the substrate.
a
N
O
b
c
O
Ph
H
N
d
HN
Ph
O
12
O
(+)-RP-66803 11
Hydrogenation of pyrroline esters similar to 14 is typically
performed using Pd/C or PtO2.6,7,9b,14,17 When applied to substrate
14, hydrogenation using 10% Pd/C gave competing hydrogenolysis
(e.g., Table 2 entry 1). Use of PtO2 avoids this problem, but requires
higher pressures of hydrogen in order to achieve a reasonable rate
of reaction. So, in an effort to optimise the hydrogenation we
screened a range of other hydrogenation catalysts (5% Pd/C, 5% Pt/C,
5% Rh/C, 1% Ptþ2% V/C).
Fig. 2. Structures 11 and 12.
2. Results and discussion
The first step of this synthesis required asymmetric conjugate
addition of glycine imine 5 to phenylvinylketone (PVK). Using PTC
6, under our standard conditions (Table 1, entry 1),11 delivered the
desired adduct 13 with high enantiomeric excess, but in relatively
modest yield. Significant quantities of the di-addition product 12
were also produced in this reaction suggesting that the in-
termediate enolate was undergoing a second addition to PVK,
a problem not observed with less reactive enones. Fortunately this
could easily be circumvented simply by adding the PVK slowly over
2 h. This modification lowers the concentration of the PVK in the
reaction mixture and delivers near quantitative yields of the
monoadduct 13 (Table 1, entry 2). We briefly examined the effect of
lowering the catalyst loading (Table 1, entries 3e4), but led to in-
creased reaction times along with a lowering of both chemical yield
and enantioselectivity.
This study established that 5% Pt/C18 gave the highest rate of
hydrogenation, leading to complete reduction of pyrroline 14 within
3 h at atmospheric pressure (Table 2, entry 2). Using these condi-
tions, the desired cis-5-substituted proline ester 15 was obtained as
a single diastereoisomer. We were also able to confirm that no rac-
emisation occurred under these reaction conditions.16 All other
catalysts investigated gave substantially lower rates of reaction. The
use of 5% Pt/C to generate 5-substituted proline derivatives in this
way has rarely been reported,19 but these results suggest that it may
warrant more widespread application. Attempts to promote imine
exchange and hydrogenation in the same pot were partially suc-
cessful (e.g., Table 2, entry 3), but this also led topartial racemisation,
so the two-step sequence was preferred. Synthesis of (þ)-RP-66083
11 was then completed bycouplingof pyrrolidine 15 with the known
glycine derivative 165 (Scheme 2).
Table 1
Enantioselective addition of imine 5 to PVK
O
Ph2C=N
CO2t-Bu
H
N
H
N
Ph
15, HATU, NMM
HO2C
Ph2C=N
CO2t-Bu
(+)-RP-66803 11
13
PTC 6 (10 mol%),
mesitol, KOH,
CH2Cl2, -78 oC
74%
5
O
16
DMF, 0 oC, 20 h
Ph
O
Scheme 2. Completion of the synthesis of (þ)-RP-66803 11.
mol % PTC
Time (h)
Yield (%)
ee (%)
Material prepared in this way had spectroscopic properties in
good agreement with those previously reported,5 and the sign of
optical rotation of the product 11 allowed us to confirm that the
asymmetric PTC Michael addition outlined in Table 1 was selective
for the (S)-enantiomer of the product 13. This is in line with
10
10a
5
1.5
2.5
3.0
63
99
49
51
91
89
92
86
5
11
a
The enone was added over 2 h.

8834
B. Lygo et al. / Tetrahedron 66 (2010) 8832e8836
expectations11 and in agreement with stereochemical models de-
veloped for PTC alkylation reactions involving glycine imine 5 and
catalyst 6.20
Flash chromatography was performed using Merck silica gel
(230e400 mesh) as the stationary phase. Melting points were
determined using
uncorrected.
a Kopfler hot-stage apparatus and are
As outlined earlier, pyrrolidine 15 was chosen as the initial target
in an effort to develop a robust route from glycine imine 5 to proline
ester derivatives 10. It was anticipated that a route that was successful
for this target should also work well for 5-alkyl-substituted proline
esters. In order to confirm this is the case, we have also applied the
same sequence to the synthesis of esters 21 and 22. Ester 21 was se-
lected as a target because it represents the simplest 5-substituted
proline tert-butyl ester,21 and 22 was selected because cis-5-n-butyl
proline esters have been shown to be key intermediates for the syn-
thesis of a range of pyrrolidine22 and indolizidine alkaloids.12,23
The synthesis of both of these target structures proved
straightforward (Scheme 3). In both cases it was not necessary to
employ slow addition of the enone in order to achieve high yields in
the asymmetric PTC Michael addition. This simply reflects the re-
duced reactivity of alkylvinylketones compared with PVK. High
enantiomeric excess was observed for both adducts (17 and 18),
and again we were able to confirm that this was preserved
throughout the three-step sequence to the final product 22.16
Infrared spectra were recorded using either a PerkineElmer FT
1600 or a Nicolet Avatar 360 FT-IR infrared spectrophotometer. 1H
NMR and 13C NMR spectra were recorded on a Bruker AV400 or
DRX500 spectrometer at ambient temperature. Chemical shifts are
quoted relative to residual solvent and J values are given in hertz.
Multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet.
Mass spectra were obtained on a Micromass Autospec or Micro-
mass LCT instruments using electron impact (EI), fast atom bom-
bardment (FAB) or electrospray (ES) ionisation. Specific rotations
were measured using a Jasco DIP370 digital polarimeter at ambient
conditions and are given in units of deg cm2 gꢁ1; c is in g/100 mL of
solvent. HPLC analysis was performed on a HewlettePackard
1100LC machine fitted with a diode array detector. All enantiomeric
excesses were determined via HPLC comparison with racemates
using Chiralcel OD-H or Chiralpak AD columns.
4.1.1. (S)-tert-Butyl 2-(diphenylmethylene)amino-5-oxo-5-phenyl-
pentanoate 13. Potassium hydroxide (19 mg, 0.34 mmol) was
added to a solution of catalyst 6 (11 mg, 0.017 mmol) and mesitol
(2.3 mg, 0.017 mmol) in dichloromethane (1 mL) at 0 ꢀC under an
atmosphere of argon and stirred at this temperature for 30 min.
During this time a colour change from yellow to orange/brown was
observed. The reaction was then cooled to ꢁ78 ꢀC and a solution of
the imine 5 (50 mg, 0.17 mmol) in dichloromethane (1 mL) added.
PVK (34 mg, 0.26 mmol) in dichloromethane (1 mL) was then
added dropwise over 2 h. The reaction mixture was stirred at
ꢁ78 ꢀC for a further 30 min, then filtered through a plug of MgSO4,
warmed to room temperature and concentrated under reduced
pressure. The residue was generally used directly in the next step,
but could also be purified by chromatography on silica gel to give
O
Ph2C=N
R
CO2t-Bu
15% aq. citric acid
5
R
CO2t-Bu
N
PTC 6 (10 mol%),
mesitol, KOH, CH2Cl2
THF, RT, 2 h
19, R = Me, 88%
20, R = n-Bu, 89%
R
O
17, R = Me, 80%, 95% e.e.
18, R = n-Bu, 100%, 96% e.e.
H2 (1 atm)
R
CO2t-Bu
5% Pt/C,
MeOH, RT
N
H
21, R = Me, 100%, >20:1 d.r., 95% e.e.
22, R = n-Bu, 87%, >20:1 d.r., 96% e.e.
the title compound 13 (72 mg, 99%, 89% ee) as a pale yellow oil. Rf
23
Scheme 3. Synthesis of 5-alkyl substituted proline esters.
0.2 (10% EtOAc/petroleum ether); [
a
]
ꢁ15.6 (c 0.70, CHCl3, 89%
D
ee); nmax (film)/cmꢁ1 3006, 2976, 2933, 1731, 1685, 1150; dH
(400 MHz, CDCl3) 7.97e7.94 (2H, m, ArH), 7.67e7.64 (2H, m, ArH),
7.58e7.53 (1H, m, ArH), 7.48e7.30 (8H, m, ArH), 7.17e7.13 (2H, m,
ArH), 4.08 (1H, dd, J 6.5, 5.5, H-2), 3.18e2.99 (2H, m, H2-4),
2.36e2.22 (2H, m, H2-3), 1.46 (9H, s, C(CH3)3); dC (100 MHz, CDCl3)
199.7 (C), 171.1 (C), 170.6 (C), 139.5 (C), 136.9 (C), 136.5 (C), 132.9
(CH),130.3 (CH),128.8 (CH),128.6 (CH),128.6 (CH),128.5 (CH),128.1
(CH), 128.0 (CH), 127.7 (CH), 81.2 (C), 64.8 (CH), 34.7 (CH2), 28.2
(CH2), 28.1 (CH3); m/z (ESIþ) 428 (MHþ, 100%); HMRS (ESIþ) MHþ,
found 428.2207. C28H30NOþ3 requires 428.2220.
This study also led to an important observation regarding the
protocol for the asymmetric Michael addition leading to imine 18.
In our preliminary investigations this compound was only prepared
on 0.17 mmol scale. On scaling up the process, it proved important
to ensure that the temperature of the catalyst/mesitol mixture does
not rise above 0 ꢀC during the reaction with potassium hydroxide.
This precaution results in significantly improved yield and enan-
tiomeric excess compared with that previously reported11 and has
been successfully applied to the preparation of adduct 18 on
0.3e30 mmol scale.
4.1.2. (S)-2-tert-Butoxycarbonyl-5-phenyl-3,4-dihydro-2H-pyrrole
14 (general procedure for hydrolysis/cyclisation). A solution of imine
13 (100 mg, 0.23 mmol) in 15% aqueous citric acid (1 mL) and tet-
rahydrofuran (2 mL) was stirred at room temperature for 2 h then
diluted with dichloromethane (2 mL). The organic layer was
washed with brine (3ꢂ3 mL), dried (MgSO4) and concentrated
under reduced pressure to afford a yellow oil (52 mg). The product
was purified by chromatography on silica gel to afford the title
3. Conclusion
In conclusion, we have been able to develop an efficient, robust
three-step sequence for the stereoselective synthesis of cis-5-
substituted proline esters. The sequence described employs catal-
ysis in all three steps and generates the final products in high
enantio- and diastereo-selectivity.
compound 14 (43 mg, 75%) as a colourless oil. Rf 0.2 (10% EtOAc/
18
petroleum ether); [
a
]
þ88.0 (c 0.70, CHCl3, 89% ee); nmax (film)/
D
4. Experimental
cmꢁ1 2978, 1732, 1154; dH (400 MHz, CDCl3) 7.90e7.88 (2H, m, ArH),
7.47e7.38 (3H, m, ArH), 4.84e4.80 (1H, m, H-2), 3.17e3.08 (1H, m,
Ha-4), 3.02e2.95 (1H, m, Hb-4), 2.37e2.28 (1H, m, Ha-3), 2.21e2.12
(1H, m, Hb-3), 1.50 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 175.8 (C),
172.3 (C), 134.1 (C), 130.8 (CH), 128.5 (CH), 128.1 (CH), 81.1 (C), 75.4
(CH), 35.4 (CH2), 28.1 (CH3), 26.8 (CH2); m/z (ESIþ) 246 (MHþ, 14%),
190 (MHþꢁC4H8, 100); HMRS (ESIþ) MHþ, found 246.1487.
C15H20NOþ2 requires 246.1489. HPLC: column, Chiralcel OD-H;
4.1. General information
All solvents and chemicals were used as provided by the sup-
plier. Reactions were monitored by thin layer chromatography
using Merck silica gel 60 F254 precoated glass TLC plates, visualised
using UV light and then basic potassium permanganate solution.

B. Lygo et al. / Tetrahedron 66 (2010) 8832e8836
8835
mobile phase, hexane/isopropanol (90:10 v/v); flow rate 0.5
mL/min; retention times, 11.3 min (S), 19.8 min (R).
dichloromethane (5 mL) at 0 ꢀC under an atmosphere of argon and
stirred at this temperature for 45 min. During this period it is im-
portant that the reaction temperature does not exceed 0 ꢀC. The
mixture was then cooled to ꢁ78 ꢀC and a pre-cooled solution of the
imine 5 (3.0 mmol) in dichloromethane (4 mL) added dropwise.
The mixture was stirred at ꢁ78 ꢀC for 10 min, then a pre-cooled
solution of the Michael acceptor (4.5 mmol) in dichloromethane
(0.5 mL) was added dropwise. The resulting mixture was stirred at
ꢁ78 ꢀC until complete by TLC, then filtered through a plug of
MgSO4, warmed to room temperature and concentrated under
reduced pressure to afford the crude product. Yields were de-
termined by 1H NMR using veratrole as an internal standard. For
characterisation, an aliquot of the crude product was purified by
chromatography on silica gel.
4.1.3. (2S,5R)-tert-Butyl 5-phenylprolinate 15 (general procedure for
hydrogenation). A mixture of pyrroline 14 (590 mg, 2.4 mmol) and
5% Pt/C (Degussa F105 R/W, 58 mg) in methanol (10 mL) was stirred
at room temperature under 15 psi of hydrogen for 3 h. The reaction
mixture was filtered through Celite and concentrated under re-
duced pressure to afford a green-yellow oil (530 mg). The product
was purified by chromatography on silica gel to afford the title
compound 15 (520 mg, 2.1 mmol, 87%) as a colourless oil. Rf 0.15
25
(20% EtOAc/petroleum ether); [
a]
þ8.4 (c 0.70, CHCl3, 89% ee);
D
nmax (film)/cmꢁ1 3354, 2975, 1726, 1154; dH (400 MHz, CDCl3) 7.45
(2H, d, J 7.5, ArH), 7.34 (2H, dd, J 7.5, 7.5, ArH), 7.28e7.24 (1H, t, J 7.5,
ArH), 4.18 (1H, dd, J 9.0, 6.0, H-2), 3.81 (1H, dd, J 8.5, 5.0, H-5),
2.25e1.64 (4H, m, H2-3þH2-4), 1.50 (9H, s, C(CH3)3); dC (100 MHz,
CDCl3) 174.6 (C), 143.4 (C), 128.5 (CH), 127.1 (CH), 126.8 (CH), 81.1
(C), 63.8 (CH), 61.0 (CH), 34.3 (CH2), 31.0 (CH2), 28.1 (CH3); m/z
(ESIþ) 248 (MHþ, 18%), 192 (MHþC4H8, 100); HMRS (ESIþ) MHþ,
found 248.1639. C15H22NOþ2 requires 248.1651. HPLC: column,
Chiralcel AD; mobile phase, hexane/isopropanol (95:5 v/v); flow
rate 0.75 mL/min; retention times, 11.0 min (S), 16.0 min (R).
4.2.1. (S)-tert-Butyl 2-(diphenylmethylene)amino-5-oxohexanoate,
17. Following the above general procedure, reaction of imine 5
(50 mg, 0.17 mmol) with MVK (72
mL, 0.85 mmol) for 2.5 h provided
the title compound 17 (80%, 95% ee) as a colourless oil. Rf 0.7 (50%
18
Et2O/petroleum ether); [
a]
ꢁ76.9 (c 0.70, CHCl3, 95% ee); nmax
D
(CHCl3)/cmꢁ1 3083, 1717, 1601, 1369, 1153; dH (400 MHz, CDCl3) 7.66
(1H, m, ArH), 7.63 (1H, m, ArH), 7.46 (3H, m, ArH), 7.40e7.38 (2H, m,
ArH), 7.37e7.33 (2H, m, ArH), 7.18e7.16 (1H, m, ArH), 3.97 (1H, dd, J
6.0, 6.0, H-2), 2.60e2.45 (2H, m, H2-4), 2.22 (3H, s, H3-6), 2.16e2.13
(2H, m, H2-3), 1.44 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 208.5 (C),
171.0 (C), 170.6 (C), 139.5 (C), 136.5 (C), 130.4 (CH), 128.8 (CH), 128.7
(CH), 128.5 (CH), 128.1 (CH), 127.7 (CH), 81.2 (C), 64.7 (CH), 39.9
(CH2), 29.9 (CH3), 28.1 (CH3), 27.7 (CH2); m/z (ESIþ) 388 (MNaþ,
13%), 366 (MHþ, 100), 310 (MHþC4H8, 51); HMRS (ESIþ) MHþ, found
366.2062. C19H28NOþ3 requires 366.2068. HPLC: Chiralcel OD-H;
mobile phase, hexane/ethanol (99:1 v/v); flow rate, 0.5 mL/min;
retention times, 15.2 min (R), 17.7 min (S). The 1H NMR spectrum is
in agreement with that previously reported.24
4.1.4. (þ)-RP 66803, 11. HATU (230 mg, 0.60 mmol) was added to
a solution of (3-m-tolylureido)acetic acid 16 (89 mg, 0.43 mmol) in
anhydrous N,N-dimethylformamide (2 mL) at 0 ꢀC. A solution of
proline ester 15 (100 mg, 0.40 mmol) in N,N-dimethylformamide
(2 mL) was then added, followed by N-methylmorpholine (0.19 mL,
0.60 mmol) and the resulting yellow solution stirred at 0 ꢀC for 20 h.
The reaction mixture was diluted with ethyl acetate (20 mL), washed
with water (2ꢂ10 mL), 1 M hydrochloric acid (10 mL), saturated
aqueous sodiumhydrogen carbonate (10 mL) and brine (10 mL), dried
(MgSO4) and concentrated under reduced pressure to afford a yellow
oil (200 mg). The crude product was crystallised from acetonitrile to
afford the title compound 11 (130 mg, 0.30 mmol, 74%) as a colourless
4.2.2. (S)-tert-Butyl 2-(diphenylmethylene)amino-5-oxononanoate, 18.
Following the above general procedure, reaction of imine 5 (878 mg,
2.97 mmol) with hept-1-en-3-one (500 mg, 4.46 mmol) for 8 h pro-
crystalline solid. Mp 153ꢁ155 ꢀC (lit.1 mp 156 ꢀC); [
a]
D
23 þ26.7 (c 1.1,
MeOH, 89% ee) (lit.1 [
a
]D þ36.0 (c 1.0, MeOH)); nmax (film)/cmꢁ1 3356,
2978, 2931, 1736, 1637; dH (400 MHz, DMSO-d6). At ambient tem-
perature a 4:1 mixture of rotamers was observed, 8.66 (1H, s, CON-
HAr), 7.65e7.03 (8H, m, ArH), 6.70 (0.2H, d, J 7.0, CONHArminor), 6.68
(0.8H, d, J 7.0, ArHmajor), 6.27 (0.2H, t J 5.5, CH2NHCOminor), 6.24 (0.8H,
t, J 4.5, CH2NHCOmajor), 5.14 (0.8H, dd, J 8.0, 3.0, H-2major), 4.70 (0.2H,
dd, J 8.0, 4.0, H-2minor), 5.01 (0.2H, t, J 7.0, H-5minor), 4.31 (0.8H, t, J 7.5,
H-5major), 4.03 (0.2H, dd, J 170, 4.5, COCHaHbminor), 3.92 (0.8H, dd, J
14.5, 5.0, COCHaHbmajor), 3.84 (0.2H, dd, J 17.0, 5.5, COCHaHbminor), 3.20
(0.8H, dd, J 14.5, 4.5, COCHaHbmajor), 2.47e1.63 (4H, m, H2-3þH2-4),
2.23 (0.6H, s, ArCH3minor), 2.21 (2.4H, s, ArCH3major), 1.50 (1.8H, s, C
(CH3)3minor),1.47(7.2H, s, C(CH3)3major);dC (100 MHz, DMSO-d6)major
rotamer 171.0 (C), 168.8 (C), 154.7 (C), 142.7 (C), 140.2 (C), 137.7 (C),
128.5 (CH), 128.4 (CH), 127.2 (CH), 126.1 (CH), 121.8 (CH), 118.0 (CH),
114.7 (CH), 80.7 (C), 61.4 (CH), 61.0 (CH), 42.0 (CH2), 33.7 (CH2), 26.8
(CH2), 27.7 (CH3), 21.2 (CH3), minor rotamer 171.2 (C),168.8 (C), 154.9
(C), 143.0 (C), 140.2 (C), 137.7 (C), 128.5 (CH), 127.9 (CH), 126.3 (CH),
125.9 (CH), 121.9 (CH), 118.1 (CH), 114.8 (CH), 81.9 (C), 62.5 (CH), 60.2
(CH), 41.8 (CH2), 33.3 (CH2), 29.6 (CH2), 27.6 (CH3), 21.2 (CH3); m/z
(ESIþ) 897 (M2Naþ, 65%), 875 (M2Hþ, 28), 460 (MNaþ,100), 438 (MHþ,
38); HMRS (ESIþ) MHþ, found 438.2384. C25H32N3Oþ4 requires
438.2384. HPLC: Chiralcel AD; mobile phase, hexane/isopropanol
(90:10 v/v); flow rate 0.75 mL/min; retention times, 20.0 min (2R,5S),
28.3 min (2S,5R). The above 1H NMR spectrum is in agreement with
that previously reported.5
vided the title compound 18 (100%, 96% ee) as a yellow oil. Rf 0.45 (10%
21
EtOAc/petroleum ether); [
a
]
ꢁ53.4 (c 0.70, CHCl3, 96% ee); nmax
D
(CHCl3)/cm‑1 3006, 2962, 2934, 2874, 1726, 1153; dH (400 MHz, CDCl3)
7.63 (2H, d, J 9.0, ArH), 7.48e7.42 (3H, m, ArH), 7.36e7.31 (3H, m, ArH),
7.18e7.15 (2H, m, ArH), 3.95 (1H, dd, J 6.0, 6.0, H-2), 2.59e2.47 (2H, m,
H2-4), 2.41 (2H, t, J 7.5, H2-6), 2.21e2.15 (2H, m, H2-3), 1.58e1.50 (2H,
m, H2-7),1.44 (9H, s, C(CH3)3),1.35e1.25 (2H, m, H2-8), 0.88 (3H, t, J 7.0,
H3-9); dC (100 MHz, CDCl3) 210.7 (C),171.1 (C),170.4 (C),139.5 (C),136.5
(C), 130.3 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.0 (CH), 127.7
(CH), 81.1 (C), 64.8 (CH), 42.6 (CH2), 38.9 (CH2), 28.1 (CH3), 27.8 (CH2),
25.9 (CH2), 22.4 (CH2), 13.9 (CH3); m/z (ESIþ) 408 (MHþ, 100%); HMRS
(ESIþ) MHþ, found 408.2518. C26H34NOþ3 requires 408.2460. HPLC:
Chiralcel OD-H; mobile phase, hexane/isopropanol (99:1 v/v); flow
rate, 0.9 mL/min; retention times, 9.3 min (R), 12.3 min (S).
4.2.3. (S)-2-tert-Butoxycarbonyl-5-methyl-3,4-dihydro-2H-pyrrole,
19. Crude imine 17 (1.2 g, 3.4 mmol) was reacted with 15% aqueous
citric acid following the above procedure to afford the title com-
pound 19 (550 mg, 3.0 mmol, 88%) as a yellow oil. Rf 0.3 (20% EtOAc/
petroleum ether); [
a
]
2D1þ81.8 (c 0.70, CHCl3); nmax (film)/cmꢁ1 2957,
1732, 1648,1368, 1156; dH (400 MHz, CDCl3) 4.57e4.52 (1H, m, H-2),
2.64e2.49 (2H, m, H2-4), 2.20e1.97 (2H, m, H2-3), 2.09 (3H, s, CH3),
1.48 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 178.2 (C), 172.6 (C), 81.0
(C), 75.0 (CH), 39.2 (CH2), 28.1 (CH3), 26.9 (CH2), 19.8 (CH3); m/z
(ESIþ) 367 (M2Hþ, 42%), 184 (MHþ, 100); HMRS (ESIþ) MHþ, found
184.1329. C10H18NOþ2 requires 184.1332.
4.2. General procedure for Michael additions
Potassium hydroxide (5.9 mmol) was added to a pre-cooled
solution of catalyst 6 (0.3 mmol) and mesitol (0.3 mmol) in
4.2.4. (S)-tert-Butyl 2-butyl-1-pyrroline-5-carboxylate, 20. Crude
imine 18 (2.97 mmol) was reacted with 15% aqueous citric acid

8836
B. Lygo et al. / Tetrahedron 66 (2010) 8832e8836
following the above procedure to afford the title compound 20
References and notes
(594 mg, 89%, 96% ee) as a colourless oil. Rf 0.25 (50% Et2O/petroleum
1. CrossFire Beilstein Database: CopyrightÓ 2007, Elsevier Information Systems
GmbH.
22
ether); [
a
]
þ96.6 (c 0.78, EtOH, 96% ee), [lit.3
[a]Dþ90.8 (c 5.1,
D
EtOH)]; dH (400 MHz, CDCl3) 4.60e4.56 (1H, m, H-2), 2.65 (1H, dddd, J
17.5,10.0, 6.0,1.5, Ha-4), 2.50 (1H, dddd, J 17.5,10.0, 6.0,1.5, Hb-4), 2.41
(2H, dt, J 8.0,1.5, 2H-6), 2.15 (1H, dddd, J 13.0,10.0, 9.0, 6.0, Ha-3),1.99
(1H, dddd, J13.0,10.0,6.0, 6.0,Hb-3),1.65e1.58(2H, m, 2H-7),1.49(9H,
s, C(CH3)3), 1.45e1.33 (2H, m, 2H-8), 0.92 (3H, t, J 7.5, CH3); dC
(100 MHz, CDCl3) 181.8 (C), 172.7 (C), 80.9 (C), 74.8 (CH), 37.5 (CH2),
33.5 (CH2), 28.6 (CH2), 28.0 (CH3), 26.7 (CH2), 22.5 (CH2), 13.9 (CH3);
m/z (ESIþ) 473 (M2Naþ, 53%), 451 (M2Hþ, 87%), 226 (MHþ, 100%);
HMRS (ESIþ) MHþ, found 226.1808. C13H24NOþ2 requires 226.1802.
HPLC: Chiracel OD-H; mobile phase, hexane/isopropanol (99:1 v/v);
flow rate 0.7 mL/min; retention times, 10.5 min (S), 16.8 min (R). The
1H NMR spectrum is in agreement with that previously reported.22b
2. Michael, J. P. Nat. Prod. Rep. 2008, 25, 139e165; Daly, J. W.; Spande, T. F.; Gar-
raffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575.
3. Wink, M. In Modern Alkaloids; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-
VCH: Weinheim, 2008; pp 3e23; Aniszewski, T. AlkaloidsdSecrets of Life;
Elsevier: Amsterdam, 2007; Roberts, M. F.; Wink, M. Alkaloids, Biochemistry,
Ecology and Medicinal Applications; Plenum: New York, NY, 1998.
4. Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron
1997, 53, 12789e12854.
5. Manfre, F.; Pulicani, J. P. Tetrahedron: Asymmetry 1994, 5, 235e238 Rhone-
Poulenc Rorer, 1993 WO 9301167-A.
6. Pei, Z.; Li, X.; Longenecker, K.; von Geldern, T. W.; Wiedeman, P. E.; Lubben,
T. H.; Zinker, B. A.; Stewart, K.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.;
Beno, D. W. A.; Long, M.; Wells, H.; Kempf-Grote, A. J.; Madar, D. J.; McDer-
mott, T. S.; Bhagavatula, L.; Fickes, M. G.; Pireh, D.; Solomon, L. R.; Lake, M. R.;
Edalji, R.; Fry, E. H.; Sham, H. L.; Trevillyan, J. M. J. Med. Chem. 2006, 49,
3520e3535; Fournie-Zaluski, M.-C.; Coric, P.; Thery, V.; Gonzales, W.;
Meudal, H.; Turcaud, S.; Michel, J.-B.; Roques, B. P. J. Med. Chem. 1996, 39,
2594e2608.
7. Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287e5290.
8. Panday, S. K.; Prasad, J.; Dikshit, D. K. Tetrahedron: Asymmetry 2009,
20, 1581e1632; Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245e2303.
9. For lead references see: (a) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008,
10, 1409e1412; (b) Llamas, T.; Gomez-Arrayas, R. G.; Carretero, J. C. Org. Lett.
2006, 8, 1795e1798; (c) van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.;
Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791e1795.
10. Lygo, B.; Beaumont, D. J. Chimia 2007, 61, 257e262; Lygo, B.; Andrews, B. I.;
Crosby, J.; Peterson, J. A. Tetrahedron Lett. 2002, 43, 8015e8018; Lygo, B.;
Wainwright, P. G. Tetrahedron 1999, 55, 6289e6300.
4.2.5. (2S,5S)-tert-Butyl 5-methylprolinate, 21. Pyrroline 19 (550 mg,
3.0 mmol) was hydrogenated for 3 h following the procedure
described above to afford the title compound 21 (100%) as a yellow
oil. Rf 0.1 (50% Et2O/petroleum ether); [
a
]
24 ꢁ15.8 (c 0.70, CHCl3, 95%
D
ee), [lit.4
[a]
ꢁ11.8 (c 0.74, CHCl3)]; dH (400 MHz, CDCl3) 3.62 (1H,
D
dd, J 9.0, 5.5, H-2), 3.16e3.10 (1H, m, H-5), 2.11e2.05 (1H, m, Ha-3),
1.91e1.83 (2H, m, Hb-3þHa-4),1.47 (9H, s, C(CH3)3),1.27e1.11 (1H, m,
Hb-4), 1.22 (3H, d, J 6.5, CH3). The 1H NMR spectrum is in agreement
with that previously reported.21
11. Lygo, B.; Beynon, C.; Lumley, C.; McLeod, M. C.; Wade, C. E. Tetrahedron Lett.
4.2.6. (2S, 5S)-tert-Butyl 5-butyl-pyrrolidine-2-carboxylate 22. Pyrro-
line 20 (500 mg, 2.22 mmol) was hydrogenated for 6 h following the
procedure described above to afford the title compound 22 (87%, 96%
2009, 50, 3363e3365.
12. For a closely related sequence involving analogous bis-tert-butylmethyl esters
see Wang, Y.-G.; Kumano, T.; Kano, T.; Maruoka, K. Org. Lett. 2009, 11,
2027e2029.
13. van der Werf, A.; Kellogg, R. M. Tetrahedron Lett. 1991, 32, 3727e3730.
14. Black, D. S.; Edwards, G. L.; Evans, R. H.; Keller, P. A.; Laaman, S. M. Tetrahedron
2000, 56, 1889e1898.
15. For previous synthetic approaches to this target see Refs. 5,9a,c,14 and Ru-
dolph, A. C.; Machauer, R.; Martin, S,F. Tetrahedron Lett. 2004, 45,
4895e4898; Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D.
Org. Lett. 2003, 5, 305e308; Davis, F. A.; Fang, T.; Goswami, R. Org. Lett.
2002, 4, 1599e1602; Haddad, M.; Imogai, H.; Larcheveque, M. J. Org. Chem.
1998, 63, 5680e5683.
16. Enantiomeric excesses were determined via HPLC comparison with racemates
using Chiralcel OD-H or Chiralpak AD columns.
17. Ibrahim, H. H.; Lubell, W. D. J. Org. Chem. 1993, 58, 6438e6441.
18. F105 R/W 5% Pt/C (Degussa) and JM 117 5% Pt/C (Johnson Matthey) gave similar
rates of reaction.
19. Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106, 4539e4547.
20. Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518e525.
21. Mota, A. J.; Chiaroni, A.; Langlois, N. Eur. J. Org. Chem. 2003, 4187e4198.
22. (a) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573e582; (b) Shiosaki, K.;
Rapoport, H. J. Org. Chem. 1985, 50, 1229e1239.
ee) a colourless oil. Rf 0.1 (50% Et2O/petroleum ether); [
a
]
24 ꢁ25.6 (c
D
0.34, EtOH, 96% ee), [lit.5 [
a]D ꢁ18.8 (c 0.8, EtOH)]; dH (100 MHz, CDCl3)
3.63 (1H, dd, J 9.0, 5.5, H-2), 3.04e2.97 (1H, m, H-5), 2.12e2.02 (1H, m,
Ha-3), 1.91e1.83 (3H, m, Hb-3, Ha-4, NH), 1.63e1.55 (1H, m, Ha-6),
1.51e1.45 (1H, m, Hb-6), 1.48 (9H, s, C(CH3)3), 1.44e1.32 (4H, m, 2H-8,
2H-7), 1.27e1.17 (1H, m, Hb-4), 0.92 (3H, br t, J 7.0, CH3); dC (75 MHz,
CDCl3) 174.7 (C), 80.9 (C), 60.7 (CH), 60.4 (CH), 35.6 (CH2), 31.9 (CH2),
30.8 (CH2), 29.6 (CH2), 28.1 (CH3), 22.8 (CH2), 14.1 (CH3); m/z (ESIþ)
455 (M2Hþ, 83%), 228 (MHþ,100%),173 (MHþC4H8, 11%); HMRS (ESIþ)
MHþ, found 228.1974. C13H26NOþ2 requires 228.1958. HPLC: column,
Chiracel AD-H; mobile phase, hexane/ethanol (97:3 v/v); flow rate
0.8 mL/min; retention times, 18.8 min (S), 22.4 min (R). The 1H NMR
spectrum is in agreement with that previously reported.17
23. See for example: Toyooka, N.; Zhou, D.; Nemoto, H.; Tezuka, Y.; Kadota, S.;
Jones, T. H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Synlett 2008, 1894e1896.
24. O’Donnell, M. J.; Delgardo, F.; Dominguez, E.; de Blas, J.; Scott, W. L. Tetrahedron:
Asymmetry 2001, 12, 821e828.
Acknowledgements
Financial support for this work was provided by EPSRC and GSK.