Asymmetric phase-transfer-catalyzed synthesis of five-membered cyclic γ-amino acid precursors

Article abstract of DOI:10.1055/s-0030-1259050

The first example of an intramolecular enantioselective Michael addition of nitronates onto conjugated systems utilizing a chiral phase-transfer catalyst is described. A range of five-membered γ-nitro esters with up to three stereocentres have been prepared and the relative and absolute configurations proven by chemical and crystallographic methods. The products are rapidly obtained and are precursors to five-membered cyclic γ-amino acids

Full text of DOI:10.1055/s-0030-1259050

LETTER
3011
Asymmetric Phase-Transfer-Catalyzed Synthesis of Five-Membered Cyclic
g-Amino Acid Precursors
Five-Membered Cyclic
i
g
-Amin
l
oAcid
l
Precur
a
sors m J. Nodes, Kenneth Shankland, Sundaram Rajkumar, Alexander J. A. Cobb*
School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK
Fax +44(118)3784638; E-mail: a.j.a.cobb@reading.ac.uk
Received 4 October 2010
Me
N
H
Abstract: The first example of an intramolecular enantioselective
Michael addition of nitronates onto conjugated systems utilizing a
chiral phase-transfer catalyst is described. A range of five-mem-
bered g-nitro esters with up to three stereocentres have been pre-
pared and the relative and absolute configurations proven by
chemical and crystallographic methods. The products are rapidly
obtained and are precursors to five-membered cyclic g-amino acids.
Me
CF3
NH
H
S
NO2
*
N
H
CF3
(10 mol%)
NO2
*
OEt
7 d
Key words: organocatalysis, phase transfer, intramolecular,
O
nitronate, Michael addition
O
EtO
1
2
solvent = THF: 61% yield, 30% ee
cf. 90% ee for six-membered system
g-Amino acids represent an important and interesting
class of unnatural biomolecules – their biological activity
is well known and they are used extensively in treatment
of diseases of the central nervous system such as epilepsy,
neuropathic pain, and anxiety. Some g-Amino acids have
also been shown to form interesting unnatural peptides
with well-defined secondary structures known as folda-
mers.1 This exciting area of study has huge potential – not
only in the possibility of gaining a deeper understanding
of biomolecular structure,2 but also in the field of peptido-
mimetics where designed unnatural peptides might mimic
the protein–protein interactions involved in various dis-
ease states.3 In spite of this promise, the development of
foldamers based on g-amino acids has not burgeoned rap-
idly, owing to the difficulty in accessing the appropriate
monomers.
Scheme 1 Attempted synthesis of nitrocyclopentanes using the me-
thodology described in the literature4
ordination. Another detrimental side to this process was
the extended reaction times involved. Therefore, as part of
our efforts to improve this reaction, we decided to turn to
a different mode of catalysis and began to focus on the use
of chiral phase-transfer catalysts to increase reaction
speed and/or enantioselectivity.
Chiral quaternary ammonium salts have been used exten-
sively in the synthesis of unnatural a-amino acids. Most
commonly, they have been used in the alkylation of gly-
cine Schiff bases with reactive electrophiles such as ben-
zyl or allyl halides.5 Michael additions of these same
Schiff bases have also been achieved utilizing Michael
Recently, we demonstrated that the intramolecular
cyclization of nitronates onto conjugated esters using bi-
functional thiourea catalysts was an excellent way of gain-
ing access to six-membered cyclically constrained g-
amino acids.4 However, when we attempted to apply our
methodology to the smaller five-membered ring size, the
reaction slowed down further and both the enantioselec-
tivity and diastereoselectivity suffered dramatically
(Scheme 1).
OH
OH
N
Br
N
Cl
N
N
OMe
4
3
In our original proposed mechanism, we suggested that
the nitronate and the carbonyl of the conjugated ester must
simultaneously coordinate to the thiourea component of
the organocatalyst. This might indeed go some way to-
wards explaining the lack of effective reactivity of the
five-membered systems; that is, the removal of a single
carbon atom must reduce this ability for simultaneous co-
5: R = Ph; X = Br
6: R = 1-anthracenyl; X = Br
7: R = 4-O2NC6H4; X = Br
8: R = 4-FC6H4; X = Br
N
9: R = 2,3,4-F3CC6H2; X = Br
10: R = 2-F3CC6H4; X = Br
11: R = 4-F3CC6H4; X = Br
12: R = 4-MeOC6H5; X = Cl
13: R = 3,5-(F3C)2C6H3; X = Br
14: R = 4-FC6H4; X = BF4
15: R = 4-F3CC6H4; X = BF4
X
R
OH
N
SYNLETT 2010, No. 20, pp 3011–3014
x
x
.x
x
.2
0
1
0
Advanced online publication: 17.11.2010
DOI: 10.1055/s-0030-1259050; Art ID: D26610ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1

3012
W. J. Nodes et al.
LETTER
acceptors such as acrylonitrile6 or various conjugated Using toluene as solvent, we were delighted to find that
ketones7 or esters.8
this screening reaction occurred very rapidly (in general,
TLC showed complete consumption of starting material
after just two hours) to give the trans-cyclized11 product 2
in quantitative yield and moderate enantioselectivity
favoring the 1S,2R isomer.12 Variation of base – which
could be used in substoichiometric amounts – appeared to
have little effect on the enantioselectivity of the reaction
process, with potassium carbonate seeming to give only a
slight improvement on diastereoselectivity. As expected,
the reaction failed to proceed in the absence of either base
or catalyst. Furthermore, lowering the temperature ap-
peared to suppress the reaction altogether. We therefore
proceeded with potassium carbonate as base and exam-
ined a large range of different catalyst structures in an ef-
fort to focus on the improvement of enantioselectivity.
Three varieties of cinchona alkaloid were examined (3, 4,
and 5; entries 6, 7, and 8) – each N-alkylated with a benzyl
group. Each one gave excellent conversion, but the best
balance between enantioselectivity and diastereoselectiv-
ity came from the use of catalyst structure 5, and, as a con-
sequence, we used this framework to investigate the effect
of N-alkylation upon enantio- and diastereocontrol.
The addition of nitronates to conjugated systems using
quaternary ammonium salts has also been demonstrated,
but where these processes have been asymmetric in na-
ture, they have only been intermolecular9 and, although
intramolecular examples exist, to the best of our knowl-
edge, none of these are catalytic enantioselective process-
es.10 Herein, we report our first investigations using
readily accessible cinchona alkaloids in the synthesis of
five-membered cyclic g-amino acids.
We began by focusing on the cyclization of the simplest
substrate 1 (see Table 1) under phase-transfer conditions
and examined the effect of base on reactivity and stereo-
selectivity, initially using the relatively simple and com-
mercially available phase-transfer catalyst 3 (Figure 1).
Table 1 Cyclization of Compound 1
NO2
NO2
phase-transfer catalyst
O
3–15 (10 mol%)
H
*
OEt
base, toluene, r.t., 18 h
quantitative
OEt
O
2
1
A variety of aryl bromides was utilized, each with varying
electronic properties and/or counterions. As might be ex-
pected, it was this variation in N-alkylation that had a
greater effect upon enantioselectivity. In most cases, the
trans system was favored.11 The use of larger counterions
in an attempt to generate a less tightly associated ion pair
did not improve reactivity. In this screen, it was catalyst
11 under the conditions described in entry 14, that gave
the highest enantioselectivity and was therefore the one
we chose to use in a substrate screen. Having identified
this catalyst, a solvent screen was conducted and indeed
toluene was found to be the solvent which gave greatest
enantioselectivity (Table 2).
Entry Catalyst Base
(equiv)
dr (trans/ ee(major, ee(minor,
cis)a,b
4.3:1
4.3:1
3.3:1
4:1
%)c
28
28
29
30
30
28
32
32
20
30
34
18
8
%)c
28
28
32
32
30
32
27
32
20
32
33
18
8
1
2
3
3
KOH (0.5)
NaOH (0.5)
Na2CO3 (0.5)
Cs2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
3
3
4
3
5
3
5:1
6
3
2.7:1
3.5:1
4:1
7
4
We therefore synthesized a range of cyclization precur-
sors including some which would generate three new ste-
reogenic centers (Table 2) and subjected them to catalyst
8
5
9
6
4.3:1
2:3
Table 2 Selected Results from Solvent Optimization
10
11
12
13
14
15
16
17
18
7
NO2
NO2
8
4.6:1
3.8:1
4.3:1
2:3
H
11 (10 mol%)
*
OEt
9
K2CO3 (0.2 equiv)
solvent, r.t.
18 h
O
O
EtO
10
11
12
13
14
15
Entry Solvent
Yield
(%)
dr
ee
ee
50
24
32
36
46
30
24
30
26
32
(trans/cis)a (major, %)b (minor, %)b
4.6:1
3.5:1
2.8:1
2.6:1
1
2
3
4
5
PhMe
CH2Cl2
THF
>99
>99
>99
>99
38
2:3
5:1
5:1
5:1
4:1
50
26
30
4
30
26
30
4
MeCN
H2O
a In all but two cases (entries 10 and 14), the trans system predomi-
nated.
4
4
b Determined by 1H NMR spectroscopy.
c Determined by chiral HPLC.
a Determined by 1H NMR spectroscopy.
b Determined by chiral HPLC.
Synlett 2010, No. 20, 3011–3014 © Thieme Stuttgart · New York

LETTER
Five-Membered Cyclic g-Amino Acid Precursors
3013
Table 3 Substrate Scope (continued)
NO2
H
NO2
R2
R2
11 (10 mol%)
OR1
K2CO3 (0.2 equiv)
toluene, r.t.
18 h
OR1
H
O
O
Product
Yield (%)
dra,b
ee (%)c,d
NO2
H
44
4:1:<1:0
36
H
OBn
O
19
Figure 2 X-ray crystal structure of 2214
NO2
NO2
NO2
H
n-Hex
27
5:2:<1:0
3:2:2:0
6:3:1:0
5:3:2:0
3:2
10
11 (10 mol%), potassium carbonate (20 mol%) in toluene
at room temperature over 18 hours (Table 3).13 The sub-
strate scope showed that the methodology was applicable
to the synthesis of a range of substrates, including the
fluorine-containing analogue 21 and a CBz-protected an-
alogue 22. Interestingly, although the diastereoselectivity
was generally moderate, in all cases it was the trans iso-
mer that was favored and not the cis product as was found
in the screening reaction. In some cases, substitution of
the conjugated ester led to decreased yields.
H
OEt
O
20
H
F
24 (trans)
38 (cis)
83
H
OEt
O
O
21
H
HN
The relative configuration was confirmed by single crys-
tal analysis of the N-CBz-protected product 22 showing
the trans relationship and the configuration of the third
stereogenic center (Figure 2).
OBn
90
10
38
H
OMe
OEt
OEt
O
22
NO2
H
Table 3 Substrate Scope
Ph
73
NO2
NO2
H
H
R2
R2
11 (10 mol%)
OR1
O
K2CO3 (0.2 equiv)
toluene, r.t.
18 h
OR1
H
23
O
O
NO2
H
Product
Yield (%)
dra,b
1:1
ee (%)c,d
50 (cis)
30 (trans)
>99
H
NO2
H
O
2
30 (trans)
28 (cis)
89
a The dr determined by 1H NMR.
H
OBn
b Relative stereochemistry assigned by analogy to compound 22 crys-
tal structure (see Figure 2).
O
16
c The ee determined by chiral HPLC.
NO2
d Absolute stereochemistry assigned as described in ref. 12.
H
61
40
7:3
18
H
Ot-Bu
In conclusion, we have, to the best of our knowledge,
demonstrated the first use of chiral phase-transfer cata-
lysts in the enantioselective, intramolecular reaction of a
nitronate onto a conjugated system, and have generated
useful five-membered systems that are precursors to g-
amino acids. As with other reactions involving chiral am-
monium salts and nitronates, it is assumed that the enantio-
selectivity originates from an association between the
positive charge of the catalyst and the negative charge of
the nitronate. Although the enantioselectivities are rela-
tively low, this work demonstrates that it is possible to
confer some stereoselectivity on this system using phase-
O
17
NO2
H
48 (trans)
34% (cis)
2:1:<1:0
H
OEt
O
18
Synlett 2010, No. 20, 3011–3014 © Thieme Stuttgart · New York

3014
W. J. Nodes et al.
LETTER
(9) (a) Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc.
2004, 126, 11790. (b) Ooi, T.; Takada, S.; Fujioka, S.;
Maruoka, K. Org. Lett. 2005, 7, 5143.
(10) (a) Marsh, G. P.; Parsons, P. J.; McCarthy, C.; Cornique,
X. G. Org. Lett. 2007, 9, 2613. (b) Yasuhara, T.;
Nishimura, K.; Osafune, E.; Muraoka, O.; Kiyoshi, T. Chem.
Pharm. Bull. 2004, 52, 1109.
transfer catalysis – something which had not been previ-
ously achieved. As such, we are currently pursuing im-
proved phase-transfer catalytic systems and conditions to
increase the enantioselectivity of these g-amino acid pre-
cursors which we ultimately intend to utilize in future fol-
damer studies.
(11) Assigned both by comparison to the 1H NMR of a related
compound (see ref. 10a) and by analogous assignment of
the proton signal from the exclusively trans crystals of
compound 22 (as shown by X-ray crystallography).
(12) This was determined by Nef reaction of the product to form
the a-substituted ketone (Scheme 2) and the resulting optical
rotation compared to the literature values, see: Kerr, M. S.;
Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298.
Acknowledgment
We thank the EPSRC (for funding to W.J.N. Grant No : EP/
D070112/1) and the Felix Foundation (for funding to R.S.).
References and Notes
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Guo,
L.; Almeida, A. M.; Zhang, W.; Reidenbach, A. G.; Choi,
S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem. Soc. 2010,
132, 7868. (c) Guo, L.; Chi, Y. G.; Almeida, A. M.; Guzei,
I. A.; Parker, B. K.; Gellman, S. H. J. Am. Chem. Soc. 2009,
131, 16018.
O
NO2
*
H
H
1. NaOEt, EtOH, then
2. HCl–EtOH (1:1)
OEt
OEt
O
O
(2) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
Rev. 2001, 101, 3219. (b) Hill, D. J.; Mio, M. J.; Prince, R.
B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893.
(c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chemistry &
Biodiversity 2004, 1, 1111. (d) Seebach, D.; Gardiner, J.
Acc. Chem. Res. 2008, 41, 1366. (e) Ghosh, A. K.; Bilcer,
G.; Schiltz, G. Synthesis 2001, 2203. (f) List, B.; Castello,
C. Synlett 2001, 1687.
(3) See, for example: (a) Bautista, A. D.; Appelbaum, J. S.;
Craig, C. J.; Michel, J.; Schepartz, A. J. Am. Chem. Soc.
2010, 132, 2904. (b) Horne, W. S.; Boersma, M. D.;
Windsor, M. A.; Gellman, S. H. Angew. Chem. Int. Ed. 2008,
47, 2853. (c) Murray, J. K.; Gellman, S. H. Biopolymers
2007, 88, 657. (d) Sadowsky, J. D.; Fairlie, W. D.; Hadley,
E. B.; Lee, H. S.; Umezawa, N.; Nikolovska-Coleska, Z.;
Wang, S. M.; Huang, D. C. S.; Tomita, Y.; Gellman, S. H.
J. Am. Chem. Soc. 2007, 129, 139.
(4) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J.
A. J. Am. Chem. Soc. 2009, 131, 16016; for an excellent
alternative method, see ref. 1c.
(5) For an excellent review, see : Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656.
(6) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(7) Lygo, B.; Allbutt, B.; Kirton, E. H. M. Tetrahedron Lett.
2005, 46, 4461.
(8) (a) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
9539. (b) Ohshima, T.; Shibuguchi, T.; Fukuta, Y.;
Shibasaki, M. Tetrahedron 2004, 60, 7743.
Scheme 2
(13) Typical Procedure for Organocatalytic Cyclization
Ethyl 2-[(1S,2R)-2-nitrocyclopentyl]acetate (2)
To a solution of (E)-ethyl-7-nitrohept-2-enoate (1, 50.3 mg,
0.25 mmol) in toluene (3 mL) was added phase-transfer
catalyst 11 (10 mol%) and K2CO3 (7 mg, 0.05 mmol). The
resulting solution was stirred for 18 h at 23 °C. After this
time, the solvent was removed under reduced pressure to
give a pale yellow oil that was subjected to flash column
chromatography (SiO2; Et2O–hexane, 1:4). The resulting
colourless oil (50.3 mg, 0.25 mmol, quant.) was analyzed by
chiral HPLC analysis [Chiralcel OD; 0.46 cm ø × 25 cm;
hexane–propan-2-ol (96:4); 1 mL min-1; tR (major diastereo-
mer) = 7.06 min, 7.63 min; tR (minor diastereomer) = 8.03
min, 8.69 min]. [a]D –3.1 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3): 1.24–1.28 (3 H, J = 7.2 Hz, CH3), 1.35–2.37 (6 H,
cyclopent-H), 2.42 (2 H, m, CH2CO2Et), 2.91 (1 H, hex, J =
8.8 Hz, CHCH2CO2Et), 4.14 (2 H, q, J = 7.2 Hz, CH2CH3),
4.81 (1 H, m, CHNO2) [NB: the 1S,2S signal appears as a
multiplet at d = 5.01]. IR: 2979, 1732, 1547, 1373, 1269,
1187, 1028, 913, 734, 648 cm–1. HRMS: m/z calcd for
C9H15NO4Na+: 224.0893; found: 224.0894.
(14) X-ray crystal structural information (CCDC 789178)
available from the Cambridge Crystallographic Data Centre
(CCDC) at http://www.ccdc.cam.ac.uk.
Synlett 2010, No. 20, 3011–3014 © Thieme Stuttgart · New York

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