Facile synthesis of unsaturated pyroglutaminol derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.06.096

A novel approach to the synthesis of unsaturated pyroglutaminol derivatives was developed. Condensation of a protected serine derivative with Meldrum's acid followed by decarboxylative cyclization afforded a tetramic acid, which was then converted to a hy

Full text of DOI:10.1016/j.tetlet.2009.06.096

Tetrahedron Letters 50 (2009) 5053–5055
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of unsaturated pyroglutaminol derivatives
*
Makoto Oba , Chihiro Ito, Takahiro Hayashi, Kozaburo Nishiyama
Department of Materials Chemistry, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of unsaturated pyroglutaminol derivatives was developed. Condensa-
tion of a protected serine derivative with Meldrum’s acid followed by decarboxylative cyclization affor-
ded a tetramic acid, which was then converted to a hydroxylactam using sodium borohydride. Iodine
displacement of the hydroxyl group induced spontaneous elimination to afford unsaturated pyroglutami-
nol derivatives in good yields.
Received 27 May 2009
Accepted 19 June 2009
Available online 23 June 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Unsaturated pyroglutaminol
Chiral template
Serine
Meldrum’s acid
Iodination
Unsaturated pyroglutaminol derivatives 1 and their bicyclic
analogues 2 (Fig. 1) are recognized as versatile chiral building
blocks for the synthesis of optically active compounds. Their versa-
tility comes about because the olefin functionality can be easily
modified in a stereospecific manner by conjugate addition, dihydr-
oxylation, cyclopropanation, epoxidation, cycloaddition, and so
on.1–3 We have often used the unsaturated pyroglutaminols 1 as
chiral templates for the stereoselective synthesis of stable iso-
tope-labeled amino acids.4
and Meldrum’s acid was originally reported by Jouin and co-work-
ers in conjunction with statine synthesis.8 The procedure was
modified by Ma and co-workers, who used N,N0-dicyclohexylcarbo-
diimide (DCC) instead of currently commercially unavailable iso-
propenyl chloroformate as a carboxyl activating agent.9
Following Ma’s method, we carried out the DCC-promoted con-
densation of N-Boc-
presence of 4-dimethylaminopyridine (DMAP) to give compound
6a. An -form of protected serine was used as a source of chirality
L-Ser(Bn)-OH (5a) with Meldrum’s acid in the
L
Recently, we and Herdeis et al. independently reported the
synthesis of unsaturated pyroglutamate derivatives 35 and 4,6 in
which the carboxyl function is protectedas 5-methyl-2,7,8-trioxabi-
cyclo[3.2.1]octane (ABO ester) or 4-methyl-2,6,7-trioxabicyclo
[2.2.2]octane (OBO ester), respectively. These orthopyroglutamates
serve as versatile chiral templates for the synthesis of a variety of
nonproteinogenic amino acids.
for economical reasons. Decarboxylative cyclization of 6a in reflux-
ing ethyl acetate for 0.5 h produced tetramic acid 7a, which upon
reduction with sodium borohydride, afforded hydroxypyrogluta-
minol 8a as a single diastereomer in 53% yield based on 5a. Com-
pounds 6a and 7a seemed to be relatively unstable and were
used immediately in the next step without further purification.
As shown in Table 1, other protected L-serine derivatives 5b–d
In general, chiral unsaturated
c
-lactams as shown in Figure 1 are
were similarly converted to the corresponding hydroxypyroglu-
prepared from optically active glutamic acid via a multistep process
which involves the use of a highly toxic organoselenium reagent to
introduce the olefin functionality (Scheme 1, route A). Some alterna-
tive routes, such as a ring-closing olefin metathesis, to the unsatu-
rated pyroglutaminols can be seen in the literature (route B).3c,7
However, these methods are only rarely used. We herein describe
a novel approach to the synthesis of unsaturated pyroglutaminol
derivatives 1, which is based on a formal dehydration of hydroxypy-
roglutaminol derived from serine and Meldrum’s acid (route C).
The synthetic course of hydroxypyroglutaminol derivatives 8 is
outlined in Table 1. Preparation of 8 starting from protected serine
OR2
O
O
N
R1
N
O
R3
1
2
O
Me
O
Me
O
O
R4 R4
=
O
N
O
O
Boc
(ABO)
(OBO)
3
4
* Corresponding author. Tel.: +81 55 968 1111; fax: +81 55 968 1155.
E-mail address: makoto@wing.ncc.u-tokai.ac.jp (M. Oba).
Figure 1. Unsaturated c-lactam derivatives.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.096

5054
M. Oba et al. / Tetrahedron Letters 50 (2009) 5053–5055
PhSe
OR2
glutamic acid
route A
O
N
R1
OR2
OR2
route B
O
O
N
R1
N
R1
OH
OR2
O
O
1
route C
serine
+
O
O
N
O
R1
Meldrum's acid
Scheme 1. Synthetic route to unsaturated pyroglutaminol derivatives 1.
Table 1
Preparation of hydroxypyroglutaminol 8a–d
O
O
OH
CO2H
OR2
Meldrum's acid, DCC, DMAP
CH2Cl2, rt, on
R1
OR2
O
N
NHR1
O
H
5a-d
6a-d
O
OH
NaBH4
OR2
AcOEt
reflux, 0.5 h
OR2
O
O
N
N
R1
CH2Cl2, rt, on
R1
7a-d
8a-d
Entry
R1
R2
8, Yielda (%)
1
2
3
4
Boc
Boc
Fmoc
Cbz
Bn
(a)
53
55
62
52
Figure 2. Molecular structures of model compounds I0 and III0 for mesylate I and
iodide III, optimized at the B3LYP/6-31G(d,p) and B3LYP/6-31G(d,p)+LANL2DZdp(I)
levels of theory, respectively.
TBDMS
tert-Bu
Bn
(b)
(c)
(d)
a
Isolated yield based on the starting protected amino acid.
groups. If typical anti-elimination occurs, loss of either of two dif-
ferent anti-periplanar hydrogen atoms, H3S or H5, leads to the
desired product 1a (path A) or its regioisomer II (path B), respec-
tively. The kinetic intermediate II immediately isomerizes to ther-
taminols 8b–d in acceptable overall yields over three steps.
Although Jouin8a and Joullié10 reported that DCC is not a suitable
reagent for the initial condensation step, the DCC–DMAP carboxyl
activation system worked well in our case.
modynamically more stable 1a as
a racemate. The energy
Preparation of unsaturated pyroglutaminol derivatives 1 is
expected to be accomplished by elimination of the hydroxyl group
of 8 via the corresponding sulfonate. When a solution of 8a in pyr-
idine was treated with methanesulfonyl chloride, the mesylate I so
formed underwent spontaneous elimination to afford the desired
olefin 1a in 57% yield (Scheme 2). However, its specific rotation,
difference between 1a and II is calculated to be 2.38 kcal/mol at
the B3LYP/6-31G(d,p) level of theory. We assume that competition
between paths A and B accounts for the observed racemization.
We next investigated the preparation of unsaturated pyroglu-
taminols 1 via a halogenation–dehydrohalogenation sequence.
Considering the leaving aptitude of the halogen atoms, we adopted
iodination conditions (Table 2). In general, iodination of alcohols
proceeds through inversion of the configuration. The structure of
model iodide III’ optimized at the B3LYP/6-31G(d,p)+LANL2DZd-
p(I)12 level of theory is shown in Figure 2. In this case, there is only
one anti-periplanar hydrogen, H3R, with respect to the iodine atom.
Therefore, its elimination is expected to produce 1 exclusively
without affecting the chiral center.
½
a 2D6
+80 (c 1.00, CHCl3), is much smaller than that of the optically
ꢀ
pure sample (½a 2D4
ꢀ
+141 (c 1.03, CHCl3)), indicating that partial
racemization took place during elimination. Changing the sulfony-
lating agent to p-toluenesulfonyl chloride or trifluoromethanesul-
fonic anhydride did not improve the outcome.
Figure 2 shows an optimized11 structure of model mesylate I0,
where the tert-butyl and benzyl groups of I are replaced by methyl
Iodination of 8a was performed using the I2–Ph3P complex in
the presence of imidazole.13 The reaction was accompanied by
spontaneous elimination of hydrogen iodide to give 1a in 83% yield
(entry 3). For the sake of simple workup, similar treatment of 8a on
polymer-supported triphenylphosphine (ps-Ph3P)14 was carried
out and found to be effective in giving 1a in 80% yield (entry 4).
However, iodination of 8a under the standard Mitsunobu condi-
tions resulted in unsatisfactory yields (entries 1 and 2). A combina-
tion of iodine, ps-Ph3P, and imidazole in refluxing CH2Cl2 works
well with other hydroxypyroglutaminol derivatives 8b–d, giving
the corresponding unsaturated pyroglutaminols 1b–d in good
yields (entries 5, 6, and 7).
OH
OBn
OMs
MeSO2Cl (MsCl)
OBn
O
O
N
N
pyridine, 50 oC, on
Boc
Boc
8a
I
path A
path B
OBn
OBn
O
O
N
N
Boc
Boc
To determine whether the synthesis of the olefin 1a proceeded
with complete retention of chiral integrity, 1a was converted to
II
1a
Scheme 2. Conversion of 8a to 1a using a sulfonylation–elimination procedure.
D-glutamic acid (11). As shown in Scheme 3, 1a was hydrogenated

M. Oba et al. / Tetrahedron Letters 50 (2009) 5053–5055
5055
Table 2
serine and Meldrum’s acid, with NaBH4 followed by iodination of
the hydroxyl group directly affords the unsaturated pyroglutami-
nol derivatives in good yields over four steps without affecting
chiral integrity.
Preparation of unsaturated pyroglutaminol 1a–d via a halogenation–dehydrohalo-
genation sequence
OH
OR2
I
iodination conditions
reflux, on
OR2
O
O
N
N
R1
References and notes
R1
1. Books and reviews: (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis.
Construction of Chiral Molecule Using Amino Acids; John Wiley: New York, 1987;
(b) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825–1872; (c) Nájera, C.;
Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245–2303.
2. Pioneering works: (a) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511–
3513; (b) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org. Chem.
1991, 56, 4167–4176; (c) Hamada, Y.; Kawai, A.; Kohno, Y.; Hara, O.; Shioiri, T. J.
Am. Chem. Soc. 1989, 111, 1524–1525; (d) Hanessian, S.; Ratovelomanana, V.
Synlett 1990, 501–503; (e) Baldwin, J. E.; Moloney, M. G.; Shim, S. B. Tetrahedron
Lett. 1991, 32, 1379–1380.
8a-d
III
OR2
elimination
O
N
R1
1a-d
Entry
R1
R2
Conditions
Yielda (%)
3. Recent examples: (a) Flemer, S.; Wurthmann, A.; Mamai, A.; Madalengoitia, J. S.
J. Org. Chem. 2008, 73, 7593–7602; (b) Einsiedel, J.; Lanig, H.; Waibel, R.;
Gmeiner, P. J. Org. Chem. 2007, 72, 9102–9113; (c) Spiess, S.; Berthold, C.;
Weihofen, R.; Helmchen, G. Org. Biomol. Chem. 2007, 5, 2357–2360; (d) Alvarez
de Cienfuegos, L.; Langlois, N. Tetrahedron: Asymmetry 2006, 17, 1863–1866; (e)
Milne, C.; Powell, A.; Jim, J.; Al Nakeeb, M.; Smith, C. P.; Micklefield, J. J. Am.
Chem. Soc. 2006, 128, 11250–11259; (f) Hanessian, S.; Gauchet, C.; Charron, G.;
Marin, J.; Nakache, P. J. Org. Chem. 2006, 71, 2760–2778.
1
2
3
4
5
6
7
Boc
Boc
Boc
Boc
Boc
Fmoc
Cbz
Bn
Bn
Bn
Bn
TBDMS
tert-Bu
Bn
(a)
(a)
(a)
(a)
(b)
(c)
(d)
MeI, Ph3P, DEAD, THF
MeI, Ph3P, DMAD, THF
I2, Ph3P, imidazole, CH2Cl2
I2, ps-Ph3P, imidazole, CH2Cl2
I2, ps-Ph3P, imidazole, CH2Cl2
I2, ps-Ph3P, imidazole, CH2Cl2
I2, ps-Ph3P, imidazole, CH2Cl2
36
61
83
80
90
78
81
4. (a) Oba, M.; Kobayashi, M.; Oikawa, F.; Nishiyama, K.; Kainosho, M. J. Org. Chem.
2001, 66, 5919–5922; (b) Oba, M.; Miyakawa, A.; Shionoya, M.; Nishiyama, K. J.
Labelled Compd. Radiopharm. 2001, 44, 141–147; (c) Oba, M.; Miyakawa, A.;
Nishiyama, K.; Terauchi, T.; Kainosho, M. J. Org. Chem. 1999, 64, 9275–9278.
5. (a) Oba, M.; Nishiyama, N.; Nishiyama, K. Chem. Commun. 2003, 776–777; (b)
Oba, M.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2005, 61, 8456–8464; (c)
Oba, M.; Saegusa, T.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2009, 65, 128–
133.
a
Isolated yield.
H2, 10% Pd/C
OH
1a
O
N
Boc
AcOEt
96%
6. Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217–229.
7. Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65–66.
9
8. (a) Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans. 1 1987, 1177–1182;
(b) Galeotti, N.; Poncet, J.; Chiche, L.; Jouin, P. J. Org. Chem. 1993, 58, 5370–5376.
9. (a) Ma, D.; Ma, J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996, 7, 2365–2370;
(b) He, G.; Wang, J.; Ma, D. Org. Lett. 2007, 9, 1367–1369.
10. Jiang, J.; Li, W.-R.; Przeslawski, R. M.; Joullié, M. M. Tetrahedron Lett. 1993, 34,
6705–6708.
RuCl3, NaIO4
acetone-H2O
O
CO2H
N
Boc
10
11. All calculations were performed using the GAUSSIAN 03 program package: Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega,
N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz,
J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. GAUSSIAN 03,
Revision D.02; Gaussian: Wallingford, CT, 2004.
1) 1M HCl, reflux, 3 h
HO2C
CO2H
NH2
11
2) propylene oxide,
EtOH, reflux, 1 h
59% (3 steps)
Scheme 3. Conversion of 1a to
D
-glutamic acid (11).
in the presence of 10% palladium on carbon and the liberated
hydroxymethyl group of pyroglutaminol 9 was oxidized with
RuO4 prepared in situ from RuCl3 and NaIO4.15 The obtained crude
pyroglutamic acid 10 was hydrolyzed in refluxing 1 M HCl for 3 h
to give glutamic acid hydrochloride which upon treatment with
12. Geometry of III0 was fully optimized at the B3LYP level of theory using the 6-
31G(d) basis set in combination with the LANL2DZdp effective core potential
basis set for iodine atom. This combination is denoted as 6-
31G(d)+LANL2DZdp(I). The basis set for I was obtained from use of the Basis
Set Exchange software and the EMSL Basis Set Library: (a) Feller, D. J. Comput.
Chem. 1996, 17, 1571–1586; (b) Schuchardt, K. L.; Didier, B. T.; Elsethagen, T.;
Sun, L.; Gurumoorthi, V.; Chase, J.; Li, J.; Windus, T. L. J. Chem. Inf. Model. 2007,
47, 1045–1052.
propylene oxide in refluxing ethanol gave free
D-glutamic acid
(11) in 59% yield over three steps. As expected, the enantiomeric
purity of 11 was found to be >99% by HPLC analysis using a chiral
stationary column (MCIGEL CRS10W).
In conclusion, we developed a novel and concise approach to
the synthesis of unsaturated pyroglutaminol derivatives, versatile
chiral building blocks for the synthesis of optically active com-
pounds. Reduction of tetramic acid, obtained from the protected
13. Haynes, R. K.; Holden, M. Aust. J. Chem. 1982, 35, 517–524.
14. Anilkumar, G.; Nambu, H.; Kita, Y. Org. Process Res. Dev. 2002, 6, 190–191.
15. Haines, A. H. Methods for the Oxidation of Organic Compounds; Academic Press:
London, 1988.