First total synthesis of penmacric acid and its stereoisomer

Article abstract of DOI:10.1016/j.tetlet.2006.11.146

The total synthesis of penmacric acid and its stereoisomer, epipenmacric acid, is reported for the first time starting from trans-4-hydroxy-l-proline. Et₃B-induced diastereoselective radical addition reaction was used to control stereoselectivity at the C3 stereogenic center as a key step.

Full text of DOI:10.1016/j.tetlet.2006.11.146

Tetrahedron Letters 48 (2007) 841–844
First total synthesis of penmacric acid and its stereoisomer
Masafumi Ueda, Ayako Ono, Dai Nakao, Okiko Miyata and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 27 October 2006; revised 18 November 2006; accepted 24 November 2006
Available online 13 December 2006
Abstract—The total synthesis of penmacric acid and its stereoisomer, epipenmacric acid, is reported for the first time starting from
trans-4-hydroxy-L-proline. Et3B-induced diastereoselective radical addition reaction was used to control stereoselectivity at the C3
stereogenic center as a key step.
Ó 2006 Elsevier Ltd. All rights reserved.
Various unusual amino acids have been found in nature
in free zwitterionic form or as constituents of peptides.
Because these amino acids have attracted much atten-
tion from scientists due to their important biological
activities such as antibiotics, neurotoxins, or enzyme
inhibitors,1 many of them are interesting synthetic tar-
gets.2,3 Among them, penmacric acid (1) was isolated
in 1975 independently by Welter et al.4 and Mbadiwe5
from the seeds of the leguminous tree Pentaclethra
macrophylla, which is commonly used for food, dye,
and medicine in West Africa. It has an interesting struc-
ture consisting of glycine and pyroglutamic acid which
are connected via carbon–carbon bond linkage. The
epipenmacric acid, using a stereoselective intermolecular
radical addition to oxime ether as a key step. Although
radical cyclization reactions have been well developed
for the synthesis of biologically important natural and
unnatural compounds,8 the use of the intermolecular
version has not been widely studied so far.9
Our retrosynthetic strategy is based on a Et3B-induced
radical reaction of oxime ether 4 and iodoproline 3 via
an iodine atom-transfer process. We have recently devel-
oped intermolecular alkyl radical additions to various
types of oxime ethers providing a new synthetic
approach to amino acid derivatives.10 We planned to
use iodoproline 3 as a radical precursor bearing a hydr-
oxyl group as a stereochemical auxiliary that would be
expected to confer a high level of stereoinduction in
the radical addition of the pyrrolidine ring onto the
glycine equivalent (Fig. 1).
1
structure was elucidated by H NMR, 13C NMR, CD,
and X-ray studies.6 Despite the unique structural
features, synthetic and biological studies have not been
reported except for only one study reported by Moloney
and co-workers in 2003.7 His group reported an interest-
ing synthetic strategy for penmacric acid using a diaste-
reoselective nucleophilic addition of lactam enolate to
various imines as the key reaction. However, the total
synthesis was not completed yet and suffered from some
inefficient steps including an inversion of the undesired
stereocenter.
We initiated our synthesis with the preparation of the
hydroxylated iodoproline 3 from commercially available
trans-4-hydroxy-L-proline (5) (Scheme 1). After protec-
tion of the amino and carboxyl groups, a Mitsunobu
reaction led to the conversion of the hydroxyl group
to iodide to give 6.11 Elimination of HI using DBU
afforded 3,4-dehydroproline 7 in 71% yield along with
a small amount of the 4,5-dehydro regioisomer.11b 3,4-
Dehydroproline 7 was then epoxidized with mCPBA in
the presence of 4,40-thiobis(6-t-butyl-o-cresol) as a radi-
cal scavenger to give epoxide 8 in a good yield and as a
single stereoisomer.12 Regioselective ring opening of
epoxide 8 with magnesium iodide afforded the expected
3-hydroxy-4-iodoproline 3 in an 87% yield via nucleo-
philic attack of the iodide ion on less hindered carbon
of the epoxy ring.13
To the best of our knowledge, no example of the total
synthesis of penmacric acid has been described in the lit-
erature probably because of the chemical instability of
penmacric acid particularly under strong acidic condi-
tions.6c Herein, we report the first total synthesis of pen-
macric acid (1) and its stereoisomer that we have named
*
Corresponding author. Tel.: +81 78 441 7554; fax: +81 78 441
7556; e-mail: taknaito@kobepharma-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.146

842
M. Ueda et al. / Tetrahedron Letters 48 (2007) 841–844
Table 1. Radical addition to oxime ether 4
OH
NHOBn
H
NH2
H
OH
MeO2C
1'
I
HO2C
3
Et3B
5
CO2H
NOBn
CO2Me
MeO2C
N
CO2Me
O
N
N
Cbz
H
Cbz
Penmacric acid (1)
2
3
4
OH
CO2Me
I
intermolecular radical
addition reaction
NHOBn
CO2Me
H
H
NOBn
MeO2C
1'
1'
OH
OH
MeO2C
BnOHN
N
3
3
Cbz
4
CO2Me
CO2Me
3
N
N
Cbz
Cbz
NOBn
MeO2C
2a
2b
H
Entry
Solvent
T (°C)
Yielda(%)
CO2Me
1
2
3
4b
CH2Cl2
CH2Cl2
Benzene
(CH2Cl)2
25
30
81
68
44
H
N
R
Reflux
Reflux
Reflux
OH
Figure 1. Retrosynthetic strategy toward penmacric acid (1).
a Combined yield of 1:1 mixture of 2a and 2b.
b C3 isomers were also obtained in 22% yield.
HO
I
i-iii
iv
CO2H
the yield and decreased the stereoselectivity (entries 3
and 4).14
CO2Me
N
N
H
Cbz
5
6
OH
CO2Me
O
Reductive cleavage of the N–O bond in the benzyloxy-
amino group and removal of the Cbz group from the
mixture of 2a and 2b gave the free amino groups which
without separation were subsequently protected by the
Boc groups to give 9 (Scheme 2).15,16 Removal of the
hydroxyl group was effectively accomplished by the
Barton–McCombie radical deoxygenation. The corre-
sponding imidazolethiocarbamate 10 was prepared in a
93% yield according to the conventional method and
then reduced with triphenyltin hydride and AIBN to
yield the deoxygenated compound 11 in an 85% yield.
I
vi
v
CO2Me
CO2Me
N
N
N
Cbz
Cbz
Cbz
7
8
3
Scheme 1. Reagents and conditions: (i) CbzCl, NaHCO3, H2O, THF,
rt; (ii) concd H2SO4, MeOH, reflux, 87% (two steps); (iii) MeI, DEAD,
PPh3, THF, rt, 88%; (iv) DBU, toluene, reflux, 71%; (v) mCPBA, 4,40-
thiobis(6-t-butyl-o-cresol), 1,2-dichloroethane, reflux, 59% and (vi)
MgI2, toluene, 0 °C, 87%.
With the radical precursor 3 in hand, we next investi-
gated a radical reaction of 3 with glyoxylic oxime ether
4, which is known to be an excellent radical acceptor as
we previously reported.10 Several conditions for the rad-
ical reaction were screened to optimize the yield and are
summarized in Table 1. When the radical addition reac-
tion of hydroxyl proline 3 to oxime ether 4 was carried
out in CH2Cl2 at room temperature using Et3B as the
radical initiator, two adducts 2a and 2b were obtained
in 30% yield as an inseparable 1:1 mixture of two diaste-
reomers at the C10 position (entry 1). This result showed
that facial selectivity of the pyrrolidine ring is com-
pletely controlled by the hydroxyl group which was
introduced as a stereochemical auxiliary. Another
epimer 2b was expected to be used for the synthesis of
epipenmacric acid in order to establish a divergent
synthesis of penmacric acid and the related compounds.
Although the configuration of 2a and 2b could not be
determined at this stage, it was unambiguously con-
firmed later by the conversion of 2a to the target com-
pound 1. The radical reaction temperature was a key
factor in improving the yield and stereoselectivity, and
the best result was obtained in refluxing CH2Cl2 solution
(entry 2). However, higher temperatures such as in
refluxing benzene or 1,2-dichloroethane did not increase
NHBoc
H
OH
i
MeO2C
ii
2a,b
CO2Me
N
Boc
9a,b
Im
NHBoc
O
H
NHBoc
H
MeO2C
MeO2C
iv
CO2Me
iii
S
CO2Me
N
N
Boc
Boc
10a,b
11a,b
NHBoc
CO2Me
H
H
MeO2C
BocHN
O
CO2Me
O
CO2Me
N
N
Boc
Boc
12a
12b
Scheme 2. Reagents and conditions: (i) H2, Pd(OH)2/C, (Boc)2O,
MeOH, rt, 79%; (ii) TCDI, CH2Cl2, 0 °C, 93%; (iii) Ph3SnH, AIBN,
benzene, reflux, 85% and (iv) RuO2, NaIO4, AcOEt, H2O, 82%.

M. Ueda et al. / Tetrahedron Letters 48 (2007) 841–844
843
3. For selected reviews, see: (a) Phillips, R. S. Tetrahedron:
Asymmetry 2004, 15, 2787; (b) Maruoka, K.; Ooi, T.
Chem. Rev. 2003, 103, 3013; (c) Ohfune, Y. Acc. Chem.
Res. 1992, 25, 360.
4. Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir,
J. Phytochemistry 1975, 14, 1347.
NHBoc
H
NH2
H
HO2C
MeO2C
i
O
CO2Me
O
CO2H
N
N
H
1
Boc
12a
5. Mbadiwe, E. Phytochemistry 1975, 14, 1351.
6. (a) Dupont, P. L.; Dideberg, O.; Welter, A. Acta Cryst.
1975, B31, 1018; (b) Welter, A.; Marlier, M.; Dardenne,
G. Bull. Soc. Chim. Belg. 1975, 84, 243; (c) Welter, A.;
Jadot, J.; Dardenne, G.; Marlier, M.; Casimir, J. Bull. Soc.
Chim. Belg. 1975, 84, 453.
7. Anwer, M.; Bailey, J. H.; Dickinson, L. C.; Edwards, H.
J.; Goswami, R.; Moloney, M. G. Org. Biomol. Chem.
2003, 1, 2364.
CO2Me
H
CO2H
H
H2N
BocHN
ii
O
CO2Me
N
O
CO2H
N
H
Boc
Epipenmacric acid (13)
12b
8. (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1 and 2, For
recent examples, see: (b) Bennasar, M.-L.; Roca, T.;
Ferrando, F. J. Org. Chem. 2006, 71, 1746; (c) Toyota, M.;
Asano, T.; Ihara, M. Org. Lett. 2005, 7, 3929.
Scheme 3. Reagents and conditions: (i) 3 M HCl, AcOEt, rt, 94% and
(ii) 3 M HCl, AcOEt, rt, 52%.
9. For recent examples, see: (a) Szpilman, A. M.; Korshin, E.
E.; Rozenberg, H.; Bachi, M. D. J. Org. Chem. 2005, 70,
3618; (b) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett.
2005, 7, 2587; (c) Yadav, J. S.; Babu, R. S.; Sabitha, G.
Tetrahedron Lett. 2003, 44, 387.
10. For reviews, see: (a) Miyabe, H.; Ueda, M.; Naito, T.
Synlett 2004, 1140; For our recent reports, see: (b)
Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito,
T. J. Org. Chem. 2003, 68, 5618; (c) Ueda, M.; Miyabe, H.;
Nishimura, A.; Sugino, H.; Naito, T. Tetrahedron: Asym-
metry 2003, 14, 2857; (d) Miyabe, H.; Ueda, M.; Nishi-
mura, A.; Naito, T. Tetrahedron 2004, 60, 4227; (e)
McNabb, S. B.; Ueda, M.; Naito, T. Org. Lett. 2004, 6,
1911; (f) Ueda, M.; Miyabe, H.; Sugino, H.; Naito, T. Org.
Biomol. Chem. 2005, 3, 1124; (g) Ueda, M.; Miyabe, H.;
Sugino, H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed.
2005, 44, 6190.
The substituted proline 11 was then oxidized with ruthe-
nium tetraoxide under EtOAc/H2O biphasic conditions
to give the desired lactams 12a and 12b which were
separated at this stage by column chromatography on
silica gel. Finally, deprotection of the two Boc groups
and hydrolysis of two methyl esters with 3 M HCl gave
penmacric acid (1)17 and epipenmacric acid (13)18 in
94% and 52% yields, respectively. The spectral data of
our synthetic sample 1 was identical in all respects with
those of the published data5 (Scheme 3).
In conclusion, the first total and divergent syntheses of
penmacric acid and epipenmacric acid featuring a highly
diastereoselective radical reaction of an iodoproline
derivative with an oxime ether has been accomplished
starting from trans-4-hydroxy-L-proline (5). The advan-
tage of our strategy is centered on the stereoselective
synthesis of unusual and various types of a-substituted
a-amino acids. Therefore, our route can be easily
applied to produce various analogues.
11. (a) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling,
J. D. Angew. Chem., Int. Ed. 2004, 43, 2293; (b)
´
Schumacher, K. K.; Jiang, J.; Joullie, M. M. Tetrahedron:
Asymmetry 1998, 9, 47; (c) Dormoy, J. R. Synthesis 1982,
753.
12. (a) Robinson, J. K.; Lee, V.; Claridge, T. D. W.; Baldwin,
J. E.; Schofield, C. J. Tetrahedron 1998, 54, 981; (b) Kishi,
Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T.
Chem. Commun. 1972, 64.
Acknowledgments
13. Bonini, C.; Righi, G. Tetrahedron 1992, 48, 1531.
14. Procedure for the radical addition reaction (Table 1, entry
3): To a solution of oxime ether 4 (7.8 g, 40 mmol) and
iodide 3 (1.1 g, 2.7 mmol) in CH2Cl2 (5 mL) was added
Et3B (1.0 M in hexane, 6.7 mL, 6.7 mmol) three times
every 1.5 h under N2 atmosphere at reflux. After the
reaction mixture was stirred at the same temperature for
1.5 h, a solution of oxime ether 4 (2.6 g, 13 mmol) in
CH2Cl2 (2 mL) was added. Additionally, Et3B (1.0 M in
hexane, 6.7 mL, 6.7 mmol) was added three times every
1.5 h. After being stirred at the same temperature for 10 h,
the reaction mixture was diluted with satd NaHCO3 and
then extracted with CHCl3. The organic phase was dried
over MgSO4 and concentrated at reduced pressure. The
residue was purified by FCC (hexane:AcOEt (1:1)) to
afford the 1:1 diastereomeric mixture of 2 (1.02 g, 81%) as
a colorless oil.
This work was supported in part by Grant-in-Aid for
Scientific Research on Priority Areas (T.N.) and for
Young Scientists (B) (M.U.) from the Ministry of
Education, Culture, Sports, Science and Technology
of Japan and the Science Research Promotion Fund of
the Japan Private School Promotion Foundation for
research grants. M.U. is grateful for a Fuji Photo Film
Award in Synthetic Organic Chemistry, Japan.
References and notes
1. (a) Chemistry and Biochemistry of the Amino Acids;
Barrett, G. C., Ed.; Champman and Hall: London, 1985;
(b) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl.
1983, 22, 816.
2. (a) Enantioselective Synthesis of b-Amino Acids; Juaristi,
E., Soloshonok, V., Eds.; John Wiley and Sons: Hoboken,
2005; (b) Williams, R. M. Synthesis of Optically Active a-
Amino Acid; Pergamon Press: London, 1989.
15. The radical addition reaction with iodoproline pro-
tected by the Boc group instead of the Cbz group was
not effective due to steric hindrance of the bulky t-Bu
group.
16. Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron Lett.
1988, 29, 2983.

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M. Ueda et al. / Tetrahedron Letters 48 (2007) 841–844
17. Spectral data of 1: hygroscopic white solid. 1H NMR
(CDCl3): d 2.00 (1H, ddd, J = 8.5, 10.0, 13.0 Hz), 2.77
(1H, ddd, J = 8.5, 9.0, 13.0 Hz), 3.11 (1H, dt, J = 6.5,
10.0 Hz), 4.08 (1H, d, J = 7.0 Hz), 4.34 (1H, t,
J = 8.5 Hz); 13C NMR (D2O): d 180.3, 179.3, 174.1,
57.54, 57.46, 44.5, 30.9; HRMS: Calcd for C7H10N2O5
(M+) 202.0589. Found 202.0586; ½aꢀD26 +10.1 (c 0.32, H2O),
18. Spectral data of 13: hygroscopic white solid. 1H
NMR (CDCl3): d 4.19 (1H, t, J = 8.0 Hz), 4.14 (1H,
d, J = 3.0 Hz), 3.41 (1H, td, J = 10.0, 3.5 Hz), 2.60
(1H, ddd, J = 13.5, 10.0, 8.0 Hz), 1.88 (1H, ddd,
J = 13.5, 10.0, 8.0 Hz).; 13C NMR (D2O): d 182.1,
180.0, 175.2, 58.9, 55.6, 45.6, 28.8; HRMS: Calcd for
24
C7H10N2O5 (M+) 202.0589. Found 202.0565; ½aꢀD ꢁ3.74
27
[lit.5 ½aꢀD +11 (c 0.016, H2O)].
(c 0.09, H2O).