A stereodivergent route to two epimeric 2-pyrrolidinylglycine derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.08.030

A new route to two epimeric 2-pyrrolidinylglycine derivatives is developed, which features Mitsunobu amination of a chiral allyl alcohol and ring-closing metathesis as key steps.

Full text of DOI:10.1016/j.tetlet.2009.08.030

Tetrahedron Letters 50 (2009) 6036–6039
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A stereodivergent route to two epimeric 2-pyrrolidinylglycine derivatives
*
Ayan Bandyopadhyay, Amit K. Pahari, 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 epimeric 2-pyrrolidinylglycine derivatives is developed, which features Mitsunobu
amination of a chiral allyl alcohol and ring-closing metathesis as key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 July 2009
Revised 13 August 2009
Accepted 17 August 2009
Available online 20 August 2009
Keywords:
a-Amino acid
Mitsunobu reaction
Garner’s aldehyde
Ring-closing metathesis
a
,b-Diamino acids belong to an important class of compounds
H
N
of chemical and biological significance.1 Therefore, there is grow-
ing interest in their synthesis.1,2 In particular, diamino acids with
a heterocyclic ring are important as conformationally constrained
amino acids, chiral auxiliaries/building blocks and are present in
several natural products, compounds 1–4 (Fig. 1).3 Moreover, the
synthesis and biological evaluation of heterocycle substituted
OH
HO
O
CO2H
NH2
N
Me3+N
-O2C
O
N
H
2
CO2H
N
H
1
3
non-proteinogenic
We have recently reported the asymmetric synthesis of
a
-amino acids are of current interest.4
R
HN
N
NH
a
,b-dia-
mino acids such as piperidinylglycine5 (5) and azetidinylglycine (6)
derivatives.6 Pyrrolidinylglycine (4) derivatives have also been
synthesised and used as synthetic intermediates/scaffolds.7 Herein,
we report a stereodivergent route to two epimeric 2-pyrrolidinyl-
glycine derivatives in continuation of our interest in the synthesis
of heterocyclic amino acids utilising coded amino acids as chiral
pool.8
HO2C
HO2C
CO2H
NH2
NHBoc
NHBoc
4
5
6
Figure 1. Some
a
,b-diamino acids of importance.
Over the years, Garner’s aldehyde9 (7 and its enantiomer, Fig. 2)
has emerged as a valuable amino acid-derived building block for
the asymmetric synthesis of diverse class of a-amino acids and re-
PG
N
PG
HN
N
X
Y
CHO
Boc
HO2C
lated compounds.10 We anticipated that the dihydropyrrolidinyl-
glycine ring system 10 could possibly be constructed by ring-
closing metathesis of an appropriate N-tethered diene 9 obtainable
from Mitsunobu-type amination of the known chiral allyl alcohol
8a. The epimeric allyl alcohol 8b could then possibly be used to
prepare another stereo-isomer of 10 in an analogous manner.
We thus focused on the preparation of the allyl alcohols 8a–b
(Scheme 1) from the common intermediate 7. Direct vinylation
of Garner’s aldehyde with vinylmagnesium bromide/chloride has
O
O
O
N
N
N
Boc
Boc
Boc
8a, X = H, Y = OH
8b, X = OH, Y = H
7
9
10
Figure 2. Synthetic plan for compound 10.
been reported11 by many workers, including us,8a with varying
degrees of selectivities for isomers 8a–b, depending on the condi-
tions used. However, this has invariably involved tedious separa-
tion of the undesired isomer which is usually formed in
significant amount. We decided to use the three-step procedure
* Corresponding author. Tel.: +91 33 25828750; fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.030

A. Bandyopadhyay et al. / Tetrahedron Letters 50 (2009) 6036–6039
6037
X
X
Y
X Y
Y
CHO
iii
iv
i
O
O
O
O
or ii
NBoc
TMS
NBoc
NBoc
H
NBoc
11, X= H, Y = OH
12, X= OH, Y = H
7
13, X= H, Y = OH
14, X= OH, Y = H
8a, X= H, Y = OH
8b, X= OH, Y = H
Scheme 1. Reagents and conditions: (i) ethynyltrimethylsilane (1.5 equiv), n-BuLi(1.5 equiv), HMPA (2 equiv), THF, ꢀ78 °C, 3 h, 11, 90%; (ii) ethynyltrimethylsilane
(1.5 equiv), n-BuLi (1.5 equiv), ZnBr2 (1.5 equiv), Et2O, ꢀ78 °C to rt, 18 h, 12, 81%; (iii) NH4F, n-Bu4N+HSO4ꢀ, CH2Cl2, rt, 1 h, 13, 86%; 14, 81%; (iv) Lindlar’s catalyst (10 mol %),
H2, MeOH, 0.5–2 h, 8a, 96%; 8b, 99%.
OMs
OMs
OMs
OMs
O
O
O
O
O
NBoc
X
NBoc
X
NBoc
NBoc
19, X = TMS
20, X = H
17, X = TMS
18, X = H
15
16
O
DPPA
Phthalimide
DIAD, Ph3P,
THF, 16 h
N3
N
O
8a 8b
or
NBoc
NBoc
THF, 0 ºC
O
to rt, 12 h
22 (20-28%)
21(~20%)
Scheme 2. Attempted substitutions of compounds 15–20 and 8a–b.
developed by Herold12 for its simplicity and higher level of selec-
tivity in favour of 8a or 8b. Thus, the addition of lithium trimeth-
ylsilylacetelyde to 7, prepared following an improved method,13
proceeded well under the reported conditions to provide a separa-
ble mixture of the anti-propargyl alcohol 11 together with the cor-
responding syn-isomer (anti/syn = 19:1). Deprotection of the
trimethylsilyl group from 11 then led to the acetylene derivative
13 which on partial hydrogenation with Lindlar’s catalyst smoothly
provided the desired allyl alcohol 8a in good overall yield. Simi-
larly, the isomeric alcohol 8b was prepared through compounds
12 and 14.
We then focused on the amination of alcohols 8a–b. To this end,
the corresponding mesylates 15 and 16 (Scheme 2) were prepared
under conventional conditions. However, direct displacement of
the –OMs group in either of 15 or 16 with sodium azide proved
to be difficult under a range of conditions. Similarly, attempted
reaction of each of the mesylates 17–20 separately with azide
ion did not meet our needs and resulted mainly in the formation
of intractable products. Our attempts on direct azidation of the
alcohols 8a–b using diphenylphosphoryl azide (DPPA)14 also
proved to be frustrating. A SN20 displacement leading to 21 in poor
yield was observed. While the SN2- versus SN20-dichotomy of
nucleophilic displacement of allylic alcohols under Mitsunobu con-
ditions is reported,15 success on analogous substrates16 prompted
us to study the direct amination of alcohols 8a and 8b with phthal-
imide/DEAD (or DIAD)/Ph3P combination. However, again only the
transposed product 22 was formed in poor yield in various at-
tempts. Pleasingly, the propargylic alcohol 11 (Scheme 3) under
the same conditions provided the desired product 23a in 43% yield.
The TMS-deprotected acetylenic alcohol 13 reacted slightly better
to provide the corresponding phthalimide 23b. The latter on partial
hydrogenation in the presence of Lindlar’s catalyst provided the
olefin 24 in near quantitative yield. Careful monitoring of the reac-
tion was crucial to avoid further reduction of the alkene during
prolonged reaction times.
Removal of the phthalimido group from the latter using hydra-
zine hydrate proceeded without events and the resulting amine
was protected with Cbz group to provide 25 in an overall yield of
83% over two steps. Similarly, the syn-propargylic alcohol 14 was
converted into the inverted amine derivative 28.
Having access to stereoisomerically pure syn- and anti-allylic
amines 25 and 28, we focused on their conversion to the corre-
NHZ
OH
NPht
NPht
iv
v
iii
i
O
O
O
O
NBoc
NBoc
X
NBoc
NBoc
X
23a, X= TMS
23b X= H
11, X= TMS
13, X= H
24
25
ii
NPht
NPht
NHZ
OH
iii
iv
v
i
O
O
O
O
NBoc
NBoc
NBoc
NBoc
14
26
27
28
Scheme 3. Reagents and conditions: (i) phthalimide (3 equiv), Ph3P (3 equiv), DIAD (3 equiv), toluene, 0 °C to rt, 16 h, 23a, 40%; 23b, 46%; 26, 47%; (ii) NH4F, n-Bu4NþHSO4
ꢀ
CH2Cl2, rt, 1 h, 88%; (iii) Lindlar’s catalyst (10 mol %), H2, MeOH, 0.5–2 h, 24, 99%; 27, 99%; (iv) NH2NH2ꢁH2O, EtOH, rt, 7–12 h; (v) Cbz-Cl, Na2CO3, Et2O–H2O, rt, 3–4 h 25, 91%;
28, 83% over two steps.

6038
A. Bandyopadhyay et al. / Tetrahedron Letters 50 (2009) 6036–6039
ZN
ZN
ZN
ZN
iv
v
HO2C
HO2C
ii
ii
iii
iii
i
i
O
O
O
O
HO
HO
25
28
NBoc
NBoc
NHBoc
NHBoc
29
31
32
33
ZN
ZN
ZN
ZN
iv
v
NBoc
NBoc
NHBoc
NHBoc
34
35
36
37
Scheme 4. Reagents and conditions: (i) allyl bromide, NaH, N,N-DMF, 0 °C to rt, 4 h, 29, 95%; 34, 81%; (ii) Grubbs’ catalyst 30 (5 mol %), CH2Cl2, rt, 6–10 h, 31, 87%; 35, 77%;
(iii) p-TsOH, MeOH, rt, 2–4 h, 32, 94%; 36, 91%; (iv) Dess–Martin periodinane (1.3 equiv), CH2Cl2, rt, 1 h; (v) NaClO2, NaH2PO4, 1-methyl-1-cyclohexene, t-BuOH–H2O, rt, 12 h
33, 90%; 37, 78% over two steps.
7069; (g) Brar, A.; Vankar, Y. D. Tetrahedron Lett. 2006, 47, 9035; (h) Lygo, B.;
Andrews, B. I.; Crossby, J.; Peterson, J. A. Tetrahedron Lett. 2005, 46, 6629; (i)
Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3, 3157; (j) Wanner,
sponding pyrrolidine derivatives by the projected ring-closing
metathesis reaction. Thus, the N-allyl derivatives 29 and 34 were
prepared under conventional conditions (Scheme 4). Ring-closing
metathesis of each of these dienes separately with Grubbs’ catalyst,
benzylidene bistricyclohexyl-phosphinoruthenium(IV) dichlo-
ride17 30, proceeded well under optimised conditions to provide
the pyrrolidine derivatives 31 and 35 in good yields. Acid-catalysed
deprotection of the oxazolidine unit in 31 resulted in the smooth
formation of the amino alcohol 32 which was converted to the cor-
responding carboxylic acid 33 involving sequential oxidation with
Dess–Martin periodinane18 to the corresponding aldehyde fol-
lowed by its Pinnick oxidation19 to the acid in a combined yield
of 90%. Repetition of the same sequence of events on compound
35 led to the isomeric unsaturated pyrrolidinylglycine derivative
37 in good overall yield.20
In summary, we have developed a brief synthesis of two epi-
meric 2-pyrrolidinylglycine derivatives in which one of the stereo-
genic centres of the system comes from the starting material and
the second one is created in a stereodivergent fashion. A Mitsun-
obu-type amination protocol was developed as the key synthetic
step to install the required syn- and anti-diamine relationships.
The methodology developed may prove to be useful for the prepa-
ration of other related 1,2-diamino compounds. The compounds
M. J.; Hauwert, P.; Scoemaker, H. E.; De Gelder, R.; Van Maarseveen, J. H.;
Hiemstra, H. Eur. J. Org. Chem. 2008, 180.
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Thirumalaikumar, M.; Tejero, T.; Kovács, L. Tetrahedron Lett. 2006, 47, 5013; (c)
Foresti, F.; Palmeiri, G.; Petrini, M.; Profeta, R. Org. Biomol. Chem. 2003, 1, 4275;
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7848; (e) Paumier, D.; Garcia, M.; Shipman, M.; Muir, J. C. Synlett 2004, 2212.
8. (a) Chattopadhyay, S. K.; Sarkar, K.; Karmakar, S. Synlett 2005, 2083; (b)
Bandyopadhyay, A.; Pal, B. K.; Chattopadhyay, S. K. Tetrahedron: Asymmetry
2008, 19, 1875; (c) Sarkar, K.; Singha, S.; Chattopadhyay, S. K. Tetrahedron:
Asymmetry 2009, 20, 000. doi:10.1016/j.tetasy.2009.06.021.
9. Garner, P.; Park, J. M. Org. Synth. 1997, 70, 18 (Coll. Vol. 9, p 300).
10. For a review, see: Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1
2001, 2136.
11. (a) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979; (b) Franciotti, M.; Mann,
A.; Taddei, M. Tetrahedron Lett. 1991, 32, 6783; (c) Shimizu, M.; Wakioka, I.;
Fujisawa, T. Tetrahedron Lett. 1997, 38, 6027; (d) Yadav, J. S.; Geetha, V.;
Krishnam Raju, A.; Ganeshwar, D.; Chandrasekhar, S. Tetrahedron Lett. 2003, 44,
2983; (e) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999; (f) Takahat, H.;
Banda, Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60,
8199; (g) Sudhakar, N.; Ravi Kumar, A.; Prabhakar, A.; Jagadeesh, B.;
Venkateswara Rao, B. Tetrahedron Lett. 2005, 46, 325.
12. Herold, P. Helv. Chim. Acta 1988, 53, 2979.
13. McKillop, A.; Taylor, R. J. K.; Watson, R.; Lewis, N. Synthesis 1994, 31.
14. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1977, 18,
1977.
prepared may find application as a
a-amino acid, b-amino acid
and/or ,b-diamino acid in the design and synthesis of modified
a
peptides. Work will be continued in this laboratory along some
of these directions.
15. (a) Berree, F.; Gernigon, N.; Hercouet, A.; Chia, H. L.; Carboni, B. Eur. J. Org.
Chem. 2009, 329; (b) Charette, A. B.; Cote, B. Tetrahedron Lett. 1993, 34, 6833;
(c) Lumin, S.; Yadagiri, P.; Falck, J. R. Tetrahedron Lett. 1989, 29, 4237.
16. Mulzer, J.; Funk, G. Synthesis 1995, 101; For a recent review of Mitsunobu
reaction, see: Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan
Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
Acknowledgements
17. Grubbs, R. H. Tetrahedron 2004, 60, 2117; For a recent review on RCM, see:
Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.;
Roy, B. Tetrahedron 2007, 63, 3919.
We are thankful to DST, Govt. of India (Grant No. SR/S1/OC-51/
2005) for funds and CSIR, New Delhi, for fellowships.
18. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
19. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
20. All new compounds reported here gave satisfactory spectroscopic and/or
References and notes
analytical data. Data for 24: [
a] +28.3 (c 2.0, CHCl3). IR (CHCl3): 1717, 1695,
D
1392, 1366,1220 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.92–7.88 (2H, m, ArH),
.
1. Barret, G. C.. In Amino Acids, Peptides and Proteins; The Chemical Society:
London, 2001; Vol. 32.
2. For some recent reports on a,b-diamino acids, see: (a) Cutting, G. A.; Stainforth,
7.85–7.78 (2H, m, ArH), 6.61–6.52 (1H, m, CH@CH2), 5.47 (1H, d, J = 17.0,
CH@CHtrans), 5.40 (1H, d, J = 11.0, CH@CHcis), 4.87 (1H, t, J = 9.5, CHNPht), 4.73
(1H, dd, J = 4.0, 8.5, CHNBoc), 3.99 (2H, dd, J = 9.6, 14.0, OCH2), 1.73 (3H, s,
CMe), 1.29 (3H, s, CMe), 1.14 (9H, s, CMe3). 13C NMR (75 MHz, CDCl3): d 168.1
(CO–N–CO), 152.7 (CONBoc), 133.9 (ArC), 133.4 (ArCH), 132.8(ArCH), 122.9
(CH@CH2), 121.5 (CH@CH2), 94.3 (O–C–N), 80.1 (OCMe3), 64.7 (OCH2), 57.0
(CHN), 56.8 (CHN), 27.7 (CMe), 27.0 (CMe), 24.3 (CMe3). Mass (TOF MS ES+): m/z
409 (M+Na). Elemental Anal.: C, 65.45; H, 6.94; N, 7.59; C21H26N2O5 requires C,
65.27; H, 6.78; N, 7.25.
N. E.; John, M. P.; KociokKohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129,
10632; (b) Wang, J.; Shi, T.; Deng, G.; Jiang, H.; Liu, H. J. Org. Chem. 2008, 73,
8563; (c) Cheng, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2008, 130, 2170; (d) Hernandez-Toribio, J.; Arrayas, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2008, 130, 16150; (e) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008,
130, 5866; (f) Davies, F. A.; Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833.
3. For a review, see: Viso, A.; de la Pradilla, F.; Garcia, A.; Flores, A. Chem. Rev.
2005, 105, 3167.
Compound 32: IR (CHCl3): 3435, 3346, 2977, 1691, 1499, 1393, 1318 cmꢀ1 1H
.
4. (a) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.; Tang, L. M. J.
NMR (500 MHz, CDCl3): d 7.39–7.35 (5H, m, ArH), 5.81–5.77 (2H, m, CH@CH),
5.18 (2H, s, OCH2Ph), 4.95 (1H, s, NCH), 4.63 (1H, d, J = 8.6, NH), 4.36 (1H, dd,
J = 1.3, 15.5, NCHaCHb), 4.18 (1H, t, J = 6.8, NCH)), 4.05(1H, d, J = 15.3, NCHaCHb),
3.87 (1H, br s, OH), 3.78–3.72 (1H, m, OCHaHb), 3.46–3.39 (1H, m, OCHaHb),
1.42 (9H, s, CMe3). 13C NMR (75 MHz, CDCl3): d 157.2 (NCO), 155.8 (NCO), 136.0
(ArC), 128.5 (ArCH), 128.3(ArCH), 128.0 (CH@CH), 125.7 (CH@CH), 79.3
(OCMe3), 67.7 (OCH2), 65.9 (NCH), 62.7 (NCH), 54.8 (NCH2), 28.2 (CMe3).
Chem. Soc., Perkin Trans.
1 2000, 303; (b) Jirgensons, A.; Marinozzi, M.;
Pelliciarri, R. Tetrahedron 2005, 61, 373; (c) Chakraborty, T. K.; Koley, D.; Ravi,
R.; Kunwar, A. C. Org. Biol. Chem. 2007, 5, 3713; (d) van Esseveldt, B. C. J.; van
Delft, F. L.; de Gelder, R.; Rutjes, F. P. J. T. Org. Lett. 2003, 5, 1717; (e) Bunnage,
M. E.; Davies, S. G.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol. Chem
2004, 2, 2763; (f) Alongi, M.; Minetto, G.; Taddei, M. Tetrahedron Lett. 2005, 46,

A. Bandyopadhyay et al. / Tetrahedron Letters 50 (2009) 6036–6039
6039
Mass (TOF MS ES+): m/z 385 (M+Na).
Compound 33: [
D ꢀ119(c1.4, CHCl3). IR (CHCl3):3327, 2924, 1705, 1499, 1416,
1366 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.39–7.34 (5H, m, ArH), 5.91–5.82 (2H,
m, CH@CH), 5.61 (1H, br s, NH), 5.29 (1H, dd, J = 7.1, 10.8, NCH), 5.12 (2H, s,
OCH2Ph), 4.55–4.46 (1H, m, NCH), 4.27 (1H, d, J = 14.3, NCHaCHb), 4.10 (1H, d,
J = 13.6, NCHaCHb), 1.42 (9H, s, CMe3). 13C NMR (75 MHz, CDCl3): d 173.7 (CO2H),
155.8 (NC@O), 155.0 (NC@O), 136.1 (ArC), 128.4 (ArCH), 128.1 (ArCH), 127.9
(ArCH), 127.5 (CH@CH), 127.0 (CH@CH), 80.0 (OCMe3), 67.4 (OCH2Ph), 67.2
(NCH), 66.9 (NCH), 54.3 (NCH2), 28.2 (CMe3). Mass (TOF MS ES+): m/z 399
(M+ Na).
Compound 36: [
a
]
D +52 (c 2.0, CHCl3). IR (CHCl3): 3422, 1700, 1417, 1366 cmꢀ1
.
a
]
1H NMR (500 MHz, CDCl3): d 7.35–7.28 (5H, m, ArH), 5.79–5.77 (2H, m, CH@CH),
5.60 (1H, d, J = 6.0, NH), 5.11 (2H, s, OCH2Ph), 4.58 (1H, t, J = 6.4, NCH), 4.28 (1H, d,
J = 15.6, NCHaCHb), 4.01 (1H, dd, J = 4.8, 15.6, NCHaCHb), 3.63 (1H, dd, J = 3.2, 12.0,
OCHaHb), 3.56 (br s, 1H, NCH), 3.47 (1H, d, J = 11.6, OCHaHb),1.60 (1H, br s, OH),
1.42 (9H, s, CMe3). 13C NMR (75 MHz, CDCl3): d 156.5 (NC@O), 156.0 (NC@O),
136.2 (ArC), 128.5 (ArCH), 128.1 (ArCH), 127.8 (CH@CH), 126.3 (CH@CH), 79.5
(OCMe3), 67.4 (OCH2Ph), 65.8 (HOCH2), 62.6 (NCH), 55.9 (NCH), 54.1 (NCH2), 28.3
(CMe3). Elemental Anal.: C, 63.14; H, 7.41; N, 7.99; C19H26N2O5 requires C, 62.97;
H, 7.23; N, 7.73. Mass (TOF MS ES+): m/z 385 (M+Na).
.