Stereoselective synthesis of 2-azetidinylglycine and aminopyrrolidone derivatives from Garner's aldehyde

Article abstract of DOI:10.1016/j.tetasy.2009.04.010

A new route to two hitherto unknown 2-azetidinylglycine derivatives and an aminopyrrolidone derivative has been developed which featured a diastereoselective conjugate addition of benzyl amine to an α,β-unsaturated ester derived from Garner's aldehyde as

Full text of DOI:10.1016/j.tetasy.2009.04.010

Tetrahedron: Asymmetry 20 (2009) 1213–1216
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of 2-azetidinylglycine and aminopyrrolidone
derivatives from Garner’s aldehyde
*
Latibuddin Thander, Kaushik Sarkar, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to two hitherto unknown 2-azetidinylglycine derivatives and an aminopyrrolidone deriva-
tive has been developed which featured a diastereoselective conjugate addition of benzyl amine to an
Received 30 March 2009
Accepted 22 April 2009
Available online 15 May 2009
a,b-unsaturated ester derived from Garner’s aldehyde as the key step.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
bon-nucleophiles13 to compound 7 are known, similar additions of
aliphatic or aromatic amines to compounds of the general struc-
ture 7 have to the best of our knowledge remained unexplored.
This led us to consider the exploration of such a possibility. A vari-
ety of conditions,14 including some excellent asymmetric proto-
cols,15 have been developed over the years for conjugate addition
of amines to enoates. Initial experiments revealed that the addition
of benzylamine to 7 proceeded better under recently reported con-
ditions16 using borax as a catalyst, but only when a mixture of eth-
anol and water (1:1) was used as solvent instead of water as
reported. The b-amino esters 8 and 9 were obtained as an insepa-
rable mixture in a 9:1 ratio (HPLC) and in a combined yield of 82%.
The addition of allylamine under analogous conditions proceeded
smoothly, but the diastereomeric ratio of products 10 and 11
was found to be 67:33. Similarly, the addition of ethylamine solu-
tion (70% in water) also proceeded uneventfully to provide prod-
ucts 12 and 13 in a 71:29 ratio. On the other hand, none of the
aromatic amines such as aniline, p-toluidine or p-anisidine under-
went conjugate addition to 7 under the developed conditions.
The configuration of the major product in each case of the addi-
tion of benzylamine and allylamine was assigned as syn based on
precedence with further support from the following synthetic
work. Thus, the mixture of b-amino esters 8 and 9 on reduction
with LAH led to the formation of the corresponding alcohols 14
and 15 (Scheme 2) which were cleanly separated by column chro-
matography. Hydrogenolytic removal of the N-benzyl group of the
major product 14 led to the formation of the free amine 16 which
was subsequently mono-N-allylated and then N-Cbz-protected to
secure 17. The latter was then converted to the N-tethered diene
18 following a two-step protocol involving the oxidation of the pri-
mary alcohol to the corresponding aldehyde followed by its Wittig
methylenation. The syn-diamine relationship in 18 was unequivo-
cally established by its conversion to the carbocyclic b-lactam
derivative 19 following our earlier report.7 Similarly, a mixture of
b-amino esters 10 and 11 on reduction with LAH provided separa-
ble mixture of the alcohols 20 and 21. The major product 20 was
a,b-Diamino acids belong to an important class of compounds
of relevance in chemistry and biology.1 Therefore, there is contin-
uing interest in their synthesis.2 Of particular interest have been
the derivatives in which one or both of the nitrogen atoms are con-
tained within a heterocyclic ring, for example, compounds 1–4
(Fig. 1). Their importance as constrained amino acids/location in
natural products and their utility as chiral auxiliaries/building
blocks are well documented.3 Moreover, the synthesis and biolog-
ical evaluation of heterocycle-substituted non-proteinogenic
a
-amino acids are a matter of increasing interest.4 For example,
azetidine-2-carboxylic acid and its numerous derivatives have
been studied extensively as mimic of proline and pipecolic acid.5
However, 2-azetidinylglycines of type 5 has not yet received atten-
tion as an a,b-diamino acid of similarity to pyrrolidinyl- and pipe-
ridinylglycines. Herein, we report a concise asymmetric synthesis
of two orthogonally protected 2-azetidinylglycine derivatives in
continuation of our interest in the synthesis of heterocyclic
no acids6 and ,b-diamino acids.7
a-ami-
a
2. Results and discussion
Our synthetic strategy relied on the possibility of the conjugate
addition of a suitable amine to the known8 Garner’s aldehyde9-de-
rived unsaturated ester 7 (Scheme 1), in a diastereoselective man-
ner, as a means for the installation of the required 1,2-diamino
functionality en-route to our projected title compounds. Although
the aza-Michael reaction is a well-known process, reports on sim-
ple diastereoselective conjugate addition of amines to chiral eno-
ates are comparatively less documented.10 Thus, whilst the
conjugate additions of cuprates,11 hydroxylamine12 and other car-
* Corresponding author. Tel.: +91 33 25828750x306; fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.010

1214
L. Thander et al. / Tetrahedron: Asymmetry 20 (2009) 1213–1216
OH
HO
O
NH
CO2H
NH2
NH
NH
N
CO2H
NH2
CO2H
NH2
CO2H
NH2
Me3+N
O
N
-O2C
H
1
2
5
3
4
Figure 1.
NHR
NHR
CO2Et
CO2Et
CHO
NBoc
CO2Et
i
ii
O
O
O
O
+
NBoc
NBoc
NBoc
8
, R = Bn
9
, R = Bn
6
7
10, R = CH2-CH=CH2
12 R = Et
11, R = CH2-CH=CH2
13, R = Et
Scheme 1. Reagents and conditions: (i) triethyl phosphonoacetate, aq K2CO3, Bu4N+Iꢀ, rt, 18 h, 86%; (ii) appropriate amine (5 equiv), borax (0.2 equiv), EtOH–H2O (1:1), rt,
36 h; 8 + 9, 82%; 10 + 11, 79%; 12 + 13, 76%.
then converted to the Cbz-protected amine 17, and thence to diene
18 following a similar sequence of reactions detailed for the con-
version of 16?18. This synthetic work thus established the syn-
configuration of each of the major products 8 and 10 formed in
the respective conjugate addition reactions. Based on these, the
configuration of the major product formed during addition of eth-
ylamine was assigned as 12.
the clean formation of the N-tosylazetidine derivative 22 (Scheme
3) took place in very good yield. The latter under Jones’ oxidation
conditions underwent concomitant opening of the oxazolidine ring
and oxidation of the resulting primary alcohol function to provide
the carboxylic acid 24. Esterification of compound 24 with benzyl
bromide under conventional conditions then led to the orthogo-
nally protected azetidinylglycine derivative 26 in an overall yield
of 49% over three steps. Similarly, the N-nosylazetidine derivative
22 was prepared and converted to compound 27 using a similar se-
quence of reactions.
We then focused on the construction of the azetidine ring
involving N-heterocyclisation of the
c-aminoalcohol moiety in
compound 14. N-Heterocyclisation of a b-aminoalcohol or a
c-ami-
noalcohol through the corresponding N,O-ditosylate leading to the
formation of an aziridine or an azetidine ring is well documented.17
Thus, when a mixture of the b-amino alcohol 16, p-toluenesulfonyl
chloride and powdered KOH17c was refluxed in tetrahydrofuran,
We next considered synthesis of chiral 2-pyrrolidone deriva-
tives from the common intermediate 8 involving an amide bond
formation between the ester carbonyl and the masked
c-amino
function. Thus, the mixture of compounds 8 and 9 was treated with
NH2
ZN
X
Y
ii
iii
iv
v
vi
i
OH
OH
OH
O
O
8
9
O
+
NBoc
NBoc
NBoc
14
16
, X = NHBn, Y = H
, X= H, Y = NHBn
17
15
ZN
H
H
N
BocHN
O
ref 7
O
NBoc
19
18
X
Y
iv
i
OH
O
10 +11
17
18
NBoc
20, X = NHallyl ,Y = H
21, X= H, Y = NHallyl
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, 0 °C to rt, 1 h, 80%; (ii) H2, Pd–C (10%), EtOAc, rt, 12 h, 85%; (iii) allyl bromide, K2CO3, acetone, reflux, 6 h, 39%; (iv) CBzCl,
NaHCO3, EtOAc, rt, 18 h, 94% (v) PCC, MS 4 Å, DCM, rt, 1.5 h, 81%; (vi) MePPh3þBrꢀ, n-BuLi, THF, ꢀ78 °C to rt, 4 h, 78%.

L. Thander et al. / Tetrahedron: Asymmetry 20 (2009) 1213–1216
1215
R
R
R
NH2
N
N
N
iii
i
ii
HO2C
OH
O
BnO2C
O
NBoc
NBoc
NHBoc
NHBoc
24
25
14
, R = Ts, 66%
, R= Ns, 70%
22
23
26
27
, R = Ts, 83%
, R= Ns, 64%
, R = Ts, 90%
, R= Ns, 78%
Scheme 3. Reagents and conditions: (i) TsCl (or NsCl) (2 equiv), KOH, THF, reflux, 5 h; (ii) Jones’ oxidation, acetone, 0 °C to rt, 7 h; (iii) BnBr, Cs2CO3, N,N-DMF, rt, 12 h.
BnHN
NH2Bn
CO2Et
NH2Bn
CO2Et
ii
i
O
O
HO
N
NBoc
8 + 9
H
NH2.TFA
TBDPSO
29 (41%)
28
Scheme 4. Reagents and conditions: (i) 50% TFA in DCM, 0 °C to rt, 1.5 h; (ii) Et3N (5 equiv), TBDPSCl (1.4 equiv), DMAP (cat), DCM, rt, 12 h.
4. (a) Amino Acids Peptides and Proteins; Barret, G. C., Ed.; The Chemical Society:
trifluoroacetic acid to effect simultaneous oxazoliding ring cleav-
age and N-Boc deprotection. The crude TFA-salt 28 (Scheme 4)
London, 2001; Vol. 32, (b) Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. J.; Tang, L. M. J. Chem. Soc., Perkin Trans. 1, 2000, 303.; (c)
when treated with triethylamine in the presence of TBDPS-Cl
underwent ring-closure as well as O-silylation to provide the
substituted aminopyrrolidone derivative 29 in an overall yield of
41% over three steps. The latter was obtained in diastereomerically
pure form after removal of the minor isomer by chromatography.
Various substituted aminopyrrolidone derivatives have interesting
applications and therefore are important synthetic targets.18 The
stereoselective preparation of compound 29 may therefore prove
to be useful.
Hungerford, N. L.; Claridge, T. D. W.; Watterson, M. P.; Aplin, R. T.; Moreno, A.;
Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1 2000, 3666; (d) Bunnage, M. E.;
Davies, S. G.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol. Chem. 2004,
2, 2763; (e) Alongi, M.; Minetto, G.; Taddei, M. Tetrahedron Lett. 2005, 46, 7069;
(f) Lygo, B.; Andrews, B. I.; Crossby, J.; Peterson, J. A. Tetrahedron Lett. 2005, 46,
6629.
5. (a) Sajjadi, Z.; Lubell, W. D. J. Peptide Res. 2005, 65, 298; (b) Baeza, J. L.; Gerona-
Navarro, G.; Perez de Vega, M. J.; Garcia-Lopez, M. T.; Gonzalez-Muniz, R.;
Martin-Martinez, M. Tetrahedron Lett. 2007, 48, 3689.
6. (a) Chattopadhyay, S. K.; Sarkar, K.; Karmakar, S. Synlett 2005, 2083;; (b)
Chattopadhyay, S. K.; Biswas, T.; Biswas, T. Tetrahedron Lett. 2008, 49, 376; (c)
Bandyopadhyay, A.; Pal, B. K.; Chattopadhyay, S. K. Tetrahedron: Asymmetry
2008, 19, 1875.
7. Chattopadhyay, S. K.; Sarkar, K.; Thander, L.; Roy, S. P. Tetrahedron Lett. 2007,
48, 6113.
3. Conclusion
8. Jako, I.; Uiber, P.; Mann, A.; Wermuth, C.-G.; Boulanger, T.; Norberg, B.; Evrard,
G.; Durrant, F. J. Org. Chem. 1991, 56, 5729.
9. (a) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979; (b) McKillop, A.; Taylor, R.
J. K.; Watson, R.; Lewis, N. Synthesis 1994, 31.
10. (a) Dumas, F.; Mezrahb, B.; d’ Anglo, J. J. Org. Chem. 1996, 61, 2293; (b) Xiang,
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Cottrell, I. F.; Moloney, M. G. Tetrahedron Lett. 1997, 33, 5891; (d) Loh, T.-P.;
Wei, L. L. Synlett 1998, 975.
11. (a) Hanessian, S.; Sumi, K. Synthesis 1991, 1083; (b) Hanessian, S.; Demont, E.;
van Otterlo, W. A. L. Tetrahedron Lett. 2000, 41, 4999; (c) Flamant-Robin, C.;
Wang, Q.; Chiaroni, A.; Sasaki, A. N. Tetrahedron Lett. 2002, 58, 10475.
12. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry 1998, 9,
3945.
In short, we have developed a methodology for a diastereoselec-
tive conjugate addition reaction of a suitable alkyl amine to a Gar-
ner’s aldehyde-derived
a,b-unsaturated ester. Although the
stereoselectivity is variable, the sense of stereoselection appears
to be consistent. The developed methodology has been utilised
for the synthesis of two diastereomerically pure19 unknown aze-
tidinylglycine derivatives and a stereodefined aminopyrrolidone
derivative from readily available starting materials and reagents.
The 1,2-diamino compounds prepared may also find other applica-
tions. The azetidinylglycine derivatives thus obtained may find
new application as a new motif in the design and synthesis of pep-
tides with altered structure and function. Work will be continued
in these directions in this laboratory.
13. Raghavan, S.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune, Y. Tetrahedron
Lett. 1993, 34, 5765.
14. For an extensive bibliography, see: Bartoli, G.; Bartolacci, M.; Giuliani, A.;
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15. (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16,
2833; (b) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. E. J. Am. Chem. Soc. 2006,
128, 9329; (c) Reboule, I.; Gil, R.; Collin, J. Eur. J. Org. Chem. 2008, 532.
16. Hussain, S.; Bhardwaj, S. K.; Chaudhuri, M. K.; Kalita, H. Eur. J. Org. Chem. 2007,
374.
17. (a) DeKimpe, N. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Pergamon: New York, 1996; Vol. 1, pp 507–589; (b) Cernerud, M.; Adolfsson,
H.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, 2655; (c) Ghorai, M. K.; Das, K.;
Kumar, A. Tetrahedron Lett. 2007, 48, 2471.
18. (a) Langlois, N.; Calvez, O.; Radom, M.-O. Tetrahedron Lett. 1997, 38, 8037; (b)
Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.; Courtney, S. Org.
Lett. 2002, 4, 1026; (c) Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.;
Roberts, P. M.; Smith, A. D.; Rodriguez-Solla, H.; Thomas, J. E.; Toms, S. M. Org.
Biomol. Chem. 2007, 5, 1961.
Acknowledgement
We are thankful to DST, New Delhi, for funds (Grant No. SR/S1/
OC-51/2005).
References
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J. E.; Adlington, R. M.; Mellor, L. C. Tetrahedron 1994, 50, 5049; (c) Deng, J.;
Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1996, 37, 2261; (d) Dumez, E.; Szeki, A.;
Jackson, R. F. W. Synlett 2001, 1214; (e) Englund, E. A.; Gopi, H. N.; Appealla, D.
H. Org. Lett. 2004, 6, 213; (f) Merino, P.; Pádár, P.; Delso, I.; Thirumalaikumar,
M.; Tejero, T.; Kovács, L. Tetrahedron Lett. 2006, 47, 5013.
3. (a) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485; (b) Chang, H.-C.; Lee, T.-H.;
Chuang, L.-Y.; Yen, M.-H.; Hung, W.-C. Cancer Lett. 1999, 145, 1; (c) Hanessian,
S. Heterocycles 2000, 52, 1231; (d) Foresti, F.; Palmeiri, G.; Petrini, M.; Profeta, R.
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Muir, J. C. Synlett 2004, 2212.
19. All new compounds reported here gave satisfactory spectroscopic and/or
analytical data. Data for 26: Mp 60 °C. [
a]D = +9 (c 1.51, MeOH). IR (KBr): 3443,
1751, 1724, 1496, 1348, 1160 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.64 (2H, d,
.
J = 8.1), 7.45ꢀ7.37 (5H, m), 7.29 (2H, d, J = 8.1), 5.65 (1H, d, J = 9.6), 5.27 (2H,
ABq, J = 12.5), 4.55 (1H, t, J = 7.4), 4.38 (1H, d, J = 9.6), 3.68–3.64 (1H, m), 3.43
(1H, q, J = 8.4), 2.44 (3H, s), 2.21–2.15 (1H, m), 1.91–1.89 (1H, m), 1.45 (9H, s).
13C NMR (75 MHz, CDCl3): d 169.5, 156.4, 144.3, 135.2, 130.6, 129.7, 128.6,
128.5, 128.3, 126.8, 80.2, 67.7, 63.3, 56.2, 47.8, 28.2, 21.5, 18.1 HRMS (TOF MS
ES+): obsd 497.1729 (M+Na); calcd 497.1722.
Compound 27: Mp 116 °C [a]D = ꢀ13.3 (c 1.50, CHCl3). IR (KBr): 3402, 1745,

1216
1697, 1529, 1499, 1348, 1162 cmꢀ1
L. Thander et al. / Tetrahedron: Asymmetry 20 (2009) 1213–1216
1H NMR (300 MHz, CDCl3): d 8.30 (2H, d, 772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.64–7.60 (4H, m), 7.45–7.37 (6H,
.
.
J = 8.7), 7.91 (2H, d, J = 8.7), 7.42 (5H, m), 5.52 (1H, d, J = 9.6), 5.25 (2H, ABq,
J = 12.1), 4.64 (1H, t, J = 7.8), 4.44 (1H, d, J = 9.9), 3.74 (1H, m), 3.51 (1H, q, J = 8.3),
2.25 (1H, m), 2.01 (1H, m), 1.46 (9H, s). 13C NMR (75 MHz, CDCl3): d 169.4, 156.3,
150.5, 135.0, 129.7, 128.7, 128.67, 128.65, 128.62, 124.3, 80.6, 68.0, 64.0, 56.0,
48.3, 28.2, 18.3. HRMS (TOF MS ES+): obsd 528.1411 (M+Na); calcd 528.1417.
m), 7.30–7.24 (6H, m), 5.71 (1H, s), 3.75–3.65 (3H, m), 3.63–3.57 (2H, m),
3.26–3.25 (1H, m), 2.63 (1H, dd, J = 7.8, 17.1), 2.20 (1H, dd, J = 5.1, 17.1), 1.04
(9H, s). 13C NMR (75 MHz, CDCl3): d 176.1 (s), 139.3 (s), 135.5 (d), 135.4 (d),
132.7 (s), 130.0 (d), 129.9 (d), 128.5 (d), 128.0 (d), 127.8 (d), 127.2 (d), 65.9
(t), 62.1 (d), 55.6 (d), 51.5 (t), 37.9 (t), 26.7 (q), 19.1(s). MS (TOF MS ES+):
481 (M+Na).
Compound 29: [a]D = ꢀ2 (c 4.25, MeOH). IR (CHCl3): 3360, 1735, 1410, 1059,