Rapid access to cis-cyclobutane γ-amino acids in enantiomerically pure form

Article abstract of DOI:10.1016/j.tetlet.2011.01.013

The (+)-(1R,2S) and (-)-(1S,2R) stereoisomers of 2-(aminomethyl) cyclobutane-1-carboxylic acid have been prepared using a short and efficient strategy, which employs the photochemical [2+2] cycloaddition reaction between ethylene and an unsaturated γ-lactam as the key step.

Full text of DOI:10.1016/j.tetlet.2011.01.013

Tetrahedron Letters 52 (2011) 1253–1255
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid access to cis-cyclobutane
c-amino acids in enantiomerically pure form
Virginie André a, Anne Vidal a, Jean Ollivier a, Sylvie Robin a,b, David J. Aitken a,
⇑
a Université Paris-Sud, ICMMO, 15 rue Georges Clemenceau, 91405 Orsay cedex, France
b Université Paris-Descartes, UFR Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75270 Paris cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The (+)-(1R,2S) and (À)-(1S,2R) stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have
Received 29 November 2010
Revised 20 December 2010
Accepted 5 January 2011
Available online 13 January 2011
been prepared using a short and efficient strategy, which employs the photochemical [2+2] cycloaddition
reaction between ethylene and an unsaturated
c
-lactam as the key step.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclobutanes
c
-Amino acids
Pyrrolinones
Photochemical synthesis
[2+2] Cycloaddition
c-Aminobutyric acid (GABA) plays a key role as a neurotrans-
with unsaturated c
-lactams bearing substituents at ring carbons.12
mitter in the mammalian central nervous system. A wide variety
of derivatives of GABA have therefore been of interest to chemists
and pharmacologists and some structural analogues are of signifi-
cant therapeutic value.1 Independently, in the rapidly developing
While diastereoselectivity in intermolecular [2+2] enone/alkene
photocycloadditions is something of a hit-or-miss affair, notably
with small unhindered alkenes such as ethylene, we reasoned that
the presence of a chiral, non racemic, removable substituent on the
ring nitrogen should in any case facilitate separation of diastereo-
mers and thus provide a very rapid entry to the target structure.
Initial investigations were carried out to identify a convenient
stereogenic nitrogen substituent for the 2-pyrrolinone core. A rep-
resentative structure of each of three substituent types—acyl, oxya-
cyl and alkyl—was selected on the basis of its ready (commercial)
availability (Scheme 1). The N-acyl and N-oxyacyl compounds, 3
and 4, were each derived from 4-trimethylsilyloxy-2-pyrrolidinone
2, which was prepared efficiently from b-hydroxy-GABA according
to a literature procedure.13 Reaction of 2 with the appropriate chiral
acid chloride in basic conditions introduced the N-substituent, and
acidic work-up hydrolysed the silyl ether. Straightforward dehy-
dration using mesyl chloride and triethylamine provided 3 and 4
in 58 and 52% yields, respectively, for the three steps from 2. The
N-alkyl 2-pyrrolinone 5 was prepared in a single step (70% yield)
area of foldamer science,2 oligopeptides containing
c-amino acids
have been shown to adopt well-defined conformations.3–5 Follow-
ing the lead from the related area of oligomers of cyclic b-amino
acids,6 peptides which incorporate cyclic
c-amino acids are now
becoming a focus of attention due to the additional conformational
restrictions which are imposed by the rigidified backbone.
Recently, Gellman observed helical conformations in
-peptides containing cis-cyclohexyl
-amino acids,4 while Smith
reported a parallel sheet structure for trimers of a trans-cyclopro-
pyl
-amino acid.5 Despite recent advances in general synthetic
a/c- and b/
c
c
c
methods,7 access to cyclic
c-amino acids in enantiomerically pure
form remains something of a challenge.8
In order to expand the inventory of readily available backbone-
restricted
c-amino acid building blocks, we sought an efficient
route to the cis-cyclobutane
c-amino acid 1. Only two previous
syntheses of this compound in enantiomerically pure form have
been described; they are lengthy (>8 steps)9 or employ polymer
supported enzymes and reagents leading to only one enantiomer.10
Inspired by recent successes in the synthesis of cis-cyclobutane
b-amino acids,11 we felt that a photochemical approach, schema-
tised in Figure 1, represented an attractive alternative. There is
some precedent for [2+2] photocycloaddition reactions of alkenes
from 2,5-dimethoxy-2,5-dihydrofuran and (S)-a-methylbenzyl-
amine, using a minor adaptation of the literature procedure.14
Each of the 2-pyrrolinones 3–5 was irradiated for 90 min
(400 W lamp, Pyrex filter) in acetone solution while ethylene was
bubbled through the mixture (Scheme 2). In these conditions, the
solvent is probably acting as a photosensitiser; reactions carried
out using non-sensitising solvents (acetonitrile; CH2Cl2) gave much
lower conversions. Results obtained in acetone are summarised in
Table 1. In each case, the desired cyclobutane adducts 6–8 were
formed in good yield, exclusively with a cis-configuration at the
⇑
Corresponding author. Tel.: +33 1 6915 3238; fax: +33 1 6915 6278.
E-mail address: david.aitken@u-psud.fr (D.J. Aitken).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.013

1254
V. André et al. / Tetrahedron Letters 52 (2011) 1253–1255
O
O
COOH
NH2
COOH
NH2
i) 6 M HCl
Δ, 18 h
ii) Dowex-H+
*
*
*
hν
*
*
*
R
N
N
+
Ph
*
48%
(mixture of
diastereomers)
1
(mixture of
enantiomers)
1
8a/b
Figure 1. The photochemical strategy for access to the title compounds.
Scheme 3.
O
HOOC
HO
H2N
HMDS, py
toluene, Δ
5
NH
(ref. 13)
90%
MeO
OMe
70%
CH2
O
H2C
O
hν
TMSO
58%
O
2
i) (S)-α-methyl
benzylamine,
H3O+
i) BuLi, (–)-menthyl
chloroformate
ii) H3O+
i) BuLi, (–)-pino-
N
30%
37%
N
camphoryl chloride
Ph
ii) H3O+
Ph
52%
ii) Na2CO3
8a
iii) MsCl, Et3N
iii) MsCl, Et3N
8b
Na, NH3 (liq),
O
tBuOH
O
O
O
N
O
O
O
N
Ph
N
O
NH
(–)-9
(+)-9
NH
3
5
4
68%
65%
2 steps
Boc2O, DMAP, CH 3CN
O
Scheme 1.
2 steps
O
O
N
O
hν
NBoc
(–)-10
NBoc
(+)-10
(+)-11
CH2
H2C
*
R
*
R
N
acetone
i) LiOH, H2O, THF
ii) H3O+
70%
COOH
NHBoc
86%
20 °C, 90 min
3-5
6-8
COOH
NHBoc
Scheme 2.
(–)-11
Table 1
i) TFA, CH2Cl2
ii) Dowex-H+
>95%
>95%
Photochemical [2+2] cycloaddition reactions of chiral 2-pyrrolinones 3–5 as shown in
Scheme 2
COOH
NH2
COOH
NH2
Entry Substrate Product Yield
(%)
Diastereomer
ratio
Diastereomer
separation
(–)-1
(+)-1
1
2
3
3
4
5
6
7
8
76
71
67
ꢀ50:50
ꢀ50:50
55:45
No
No
Yes
Scheme 4.
Each new derivative 10 was hydrolysed smoothly with lithium
hydroxide to provide the N-Boc -amino acids 11. These N-pro-
tected derivatives are a convenient form for amino acid storage
ring junction. The diastereoselectivity was negligible, as might be
expected with substrates having stereogenic centres which are
not in the immediate vicinity of the reacting enone moiety. A key
observation, though, was that the chromatographic separation of
c
and also a starting point for peptide synthesis. To complete the
synthesis of the free c-amino acids, each derivative 11 was treated
diastereomers of product 8 was very simple (15–40 lm silica gel;
at rt with TFA then eluted through a cation exchange resin (H+
form), using ammonium hydroxide to give the zwitterionic forms
of 1 in near-quantitative yields. All compounds shown in Scheme
4 had spectral and analytical data in complete agreement with
their assigned structure.15–17
petroleum ether/EtOAc gradient 4:1 to 1:1): preparatively, 8a
and 8b were obtained in 30% and 37% yields, respectively. Given
the rapidity of the new access to these enantiomerically pure inter-
mediates, obtained easily on gramme scale (around 10 mmol), we
pursued the synthesis of the target c-amino acid using this route.
In summary, we have established a very rapid photochemical
The two-step transformation of 8a or 8b into the title com-
pounds has been reported,9 and we initially considered a one-step
operation. Indeed, in a test experiment, when a solution of the dia-
stereomeric mixture 8a/8b in 6 M HCl was heated under reflux for
approach for the synthesis of cis-cyclobutane
c-amino acids and
N-protected derivatives in enantiomerically pure form, validated
at present on a several-millimolar scale. Starting from readily
available (commercial) starting materials, this procedure requires
only four synthetic operations and one chromatographic separa-
tion to obtain both enantiomers of the building blocks 11, and con-
stitutes a concise and attractive alternative to the other existing
routes to the title compounds and their derivatives.
18 h, the target c-amino acid was isolated in 48% yield after elution
through cation-exchange resin (Scheme 3). However samples ob-
tained in this way were not of satisfactory purity, and a less drastic
sequence was sought.
The synthesis of each enantiomer of the title compound, and—
importantly—their N-protected derivatives, was best achieved as
shown in Scheme 4. The N-alkyl substituent of each stereoisomer
of 8 was replaced by a Boc group in a two-step operation, via 9,
to introduce the protecting group and to facilitate the ring opening.
References
1. (a) Gajcy, K.; Lochynski, S.; Librowski, T. Curr. Med. Chem. 2010, 17, 2338–2347;
(b) Froelund, B.; Madsen, U. In Textbook of Drug Design and Discovery;

V. André et al. / Tetrahedron Letters 52 (2011) 1253–1255
1255
Krogsgaard-Larsen, P., Stromgaard, K., Madsen, U., Eds., 4th ed.; CRC Press: Boca
Raton, 2010; pp 239–262; (c) Johnston, G. A. R. In GABA in the Nervous System;
Martin, D. L., Olsen, R. W., Eds.; Lippincott, Williams & Wilkins: Philadelphia,
2000; pp 65–80.
10. Baxendale, I. R.; Ernst, M.; Krahnert, W.-R.; Ley, S. V. Synlett 2002, 1641–1644.
11. (a) Fernandes, C.; Gauzy, C.; Yang, Y.; Roy, O.; Pereira, E.; Faure, S.; Aitken, D. J.
Synthesis 2007, 2222–2232; (b) Gauzy, C.; Saby, B.; Pereira, E.; Faure, S.; Aitken,
D. J. Synlett 2006, 1394–1398; (c) Gauzy, C.; Pereira, E.; Faure, S.; Aitken, D. J.
Tetrahedron Lett. 2004, 45, 7095–7097; (d) Aitken, D. J.; Gauzy, C.; Pereira, E.
Tetrahedron Lett. 2002, 43, 6177–6179.
12. (a) Flores, R.; Alibés, R.; Figuerdo, M.; Font, J. Tetrahedron 2009, 65, 6912–6917;
(b) Albrecht, D.; Basler, B.; Bach, T. J. Org. Chem. 2008, 73, 2345–2356; (c)
Wrobel, M. N.; Margaretha, P. Helv. Chim. Acta 2003, 86, 515–521; (d)
Tsujishima, H.; Nakatani, K.; Shimamoto, K.; Shigeri, Y.; Yumoto, N.; Ohfune,
Y. Tetrahedron Lett. 1998, 39, 1193–1196; (e) Meyers, A. I.; Fleming, S. A. J. Am.
Chem. Soc. 1986, 108, 306–307; (f) Reid, S. T.; De Silva, D. Tetrahedron Lett. 1983,
24, 1949–1950.
2. (a) Hecht, S.; Huc, I. Foldamers, Properties, and Applications; Wiley-VCH:
Weinheim, 2007; (b) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366–
1375; (c) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399–1408; (d)
Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3,
252–262; (e) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem.
Rev. 2001, 101, 3893–4011.
3. (a) Chatterjee, S.; Vasudev, P. G.; Raghothama, S.; Ramakrishnan, C.; Shamala,
N.; Balaram, P. J. Am. Chem. Soc. 2009, 131, 5956–5965; (b) Sharma, G. V. M.;
Jadhav, V. B.; Ramakrishna, K. V. S.; Jayaprakash, P.; Narsimulu, K.; Subash, V.;
Kunwar, A. C. J. Am. Chem. Soc. 2006, 128, 14657–14668; (c) Woll, M. G.; Lai, J.
R.; Guzei, I. A.; Taylor, S. J. C.; Smith, M. E. B.; Gellman, S. H. J. Am. Chem. Soc.
2001, 123, 11077–11078; (d) Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B.
Chem. Eur. J. 2002, 8, 573–584; (e) Seebach, D.; Brenner, M.; Rueping, M.;
Schweitzer, B.; Jaun, B. Chem. Commun. 2001, 207–208; (f) Hintermann, T.;
Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998, 81, 938–1002; (g)
Hanessian, S.; Luo, X.; Schaum, R. Tetrahedron Lett. 1999, 40, 4925–4929; (h)
Hanessian, S.; Luo, X.; Schaum, R.; Michnick, S. J. Am. Chem. Soc. 1998, 120,
8569–8570.
4. (a) Guo, L.; Almeida, A. A.; Zhang, W.; Reidenbach, A. G.; Choi, S. H.; Guzei, I. A.;
Gellman, S. H. J. Am. Chem. Soc. 2010, 132, 7868–7869; (b) Guo, L.; Chi, Y.;
Almeida, A. A.; Guzei, I. A.; Parker, B. K.; Gellman, S. H. J. Am. Chem. Soc. 2009,
131, 16018–16020.
5. Qureshi, M. K. N.; Smith, M. D. Chem. Commun. 2006, 5006–5008.
6. Overviews: (a) Sussman, F.; Villaverde, M. C.; Estévez, J. C.; Estévez, R. J. J. Phys
Chem. B 2009, 113, 9669–9680; (b) Fülöp, F.; Martinek, T. A.; Tóth, G. Chem. Soc.
Rev. 2006, 35, 323–334; (c) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
Biodivers. 2004, 1, 1111–1239; (d) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. Rev. 2001, 101, 3219–3232.
13. Tian, Z.; Rasmussen, M.; Wittenberger, S. J. Org. Process Res. Dev. 2002, 6, 416–
418.
14. (a) Alves, J. C. F. J. Braz. Chem. Soc. 2007, 18, 855–859; (b) Poli, G.; Baffoni, S. C.;
Giambastiani, G.; Reginato, G. Tetrahedron 1998, 54, 10403–10418.
15. 8a, 8b, (À)-9 and (+)-9 are known (Ref.9). Our spectral and optical rotation data
for these compounds were consistent with the literature, and were used to
assign the absolute configurations of our compounds.
16. Compound (À)-10: IR (film)
m
(cmÀ1) 2979, 1782, 1744, 1713, 1314; 1H NMR
(CDCl3; 360 MHz) d (ppm) 1.55 (s, 9H), 1.93–2.08 (m, 1H), 2.08–2.21 (m, 1H),
2.28–2.41 (m, 1H), 2.41–2.58 (m, 1H), 2.91 (q, J = 7 Hz, 1H), 3.05–3.15 (m, 1H),
3.62 (d, J = 11 Hz, 1H), 3.79 (dd, J = 11 Hz and 7 Hz, 1H); 13C NMR (CDCl3;
90 MHz) d (ppm) 23.6, 25.7, 27.7, 28.5, 42.3, 52.6, 82.4, 150.3, 177.3; MS (CI-
NH3) m/z 229 [MH+NH3]+, 212 [MH]+; [
had comparable spectral data and [
(film)
(cmÀ1) 3353, 2977, 1704, 1517, 1367, 1170; 1H NMR (CDCl3; 360 MHz)
a
]
D À58 (c 1, CHCl3). Compound (+)-10
a]
D
+60 (c 1, CHCl3). Compound (À)-11: IR
m
d (ppm) 1.47 (s, 9H), 1.73–1.90 (m, 1H), 2.00–2.12 (m, 2H), 2.28–2.39 (m, 1H),
2.80–2.98 (m, 1H), 3.20–3.45 (m, 3H), 4.91 (br s, 1H), 9.70 (br s, 1H); 13C NMR
(CDCl3; 90 MHz) d (ppm) 20.6, 22.3, 27.9, 37.3, 39.7, 42.0, 79.3, 160.2, 178.8;
MS (CI-NH3) m/z 247 [MH+NH3]+, 230 [MH]+; HRMS (ESI): C11H19NNaO4
7. (a) Hanrahan, J. R.; Johnston, G. A. R. In Amino Acids, Peptides and Proteins in
Organic Chemistry; Hughes, A. E., Ed.; Origins and Synthesis of Amino Acids;
Wiley-VCH: Weinheim, 2009; Vol. 1, pp 573–689; (b) Ordóñez, M.; Cativiela, C.
Tetrahedron: Asymmetry 2007, 18, 3–99.
requires m/z 252.1206 [M+Na]+; found 252.1194;
[
a
]
À15 (c 1, CHCl3).
Compound (+)-11: had comparable spectral data and [a] +15 (c 1, CHCl3).
D
D
Compound (+)-1: IR (KBr)
m
(cmÀ1) 3345, 2999, 2931, 2148, 1648, 1578, 1529,
1416; RMN 1H (D2O; 360 MHz) d (ppm) 1.50–1.70 (m, 1H), 2.00–2.10 (m, 3H),
1.70–1.90 (m, 1H), 3.15 (dd, J = 12 Hz and 6 Hz, 1H), 3.29 (dd, J = 12 Hz and
9 Hz, 1H), 3.17–3.30 (m, 1H); 13C NMR (D2O; 90 MHz) d (ppm) 20.9, 22.2, 34.5,
41.5, 42.2, 182.3; HRMS (ESI): C6H12NO2 requires m/z 130.0863 [M+H]+; found
8. Recent enantioselective syntheses of cyclic c-amino acids: (a) Aitken, D. J.; Bull,
S. D.; Davies, I. R.; Drouin, L.; Ollivier, J.; Peed, J. Synlett 2010, 2729–2732; (b)
Eagles, J. B.; Hitchcock, S. R. Tetrahedron: Asymmetry 2010, 21, 519–523; (c)
Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. Tetrahedron 2010, 66, 3599–3607; (d)
Nodes, W. J.; Nutt, D. R.; Chippendale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009,
131, 16016–16017; (e) Prazeres, V. F. V.; Castedo, L.; González-Bello, C. Eur. J.
Org. Chem. 2008, 3991–4003; (f) Rodríguez-Soria, V.; Quintero, L.; Sartillo-
Piscil, F. Tetrahedron 2008, 64, 2750–2754; (g) Aguilera, J.; Gutiérrez-Abad, R.;
Mor, À.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuño, R. M. Tetrahedron: Asymmetry
2008, 19, 2864–2869; (h) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett.
2004, 45, 4277–4280; (i) Hübner, J.; Liebscher, J.; Pätzel, M. Tetrahedron 2002,
58, 10485–10500.
130.0866; [
and [
a
]
+23 (c 1, H2O). Compound (À)-1 had comparable spectral data
D
a
]
D
À24 (c 1, H2O).
17. In our hands, (À)-9 furnished (+)-1 as shown in Scheme 4. The literature (Ref.9)
gives [a]D À24.5 (c 0.5, MeOH) for 1ÁHCl prepared from (À)-9. Samples of 1ÁHCl
prepared from our (+)-1 had [
the literature (Refs.9 and10
dehydrated sample of our (+)-1 (1.5 equiv DCC, CH2Cl2, rt, 90 min) to
a] +5.5 (c 0.5, MeOH). This is inconsistent with
D
)
both in sign and magnitude. We therefore
a
obtain (À)-9 once again and found it to have an ee of >95% by chiral hplc
analysis. We conclude that out collected data are internally coherent and
consistent with complete stereochemical integrity of our samples.
9. Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1999, 55, 261–270.