An efficient synthesis of the piperazinone fragment of pseudotheonamide A1 via a stereoselective intramolecular Michael ring closure

Article abstract of DOI:10.1246/cl.2002.130

The stereoselective intramolecular Michael ring closure of the dipeptide efficiently gives the piperazinone fragment of pseudotheonamide A₁, a serine protease inhibitor from the marine sponge Theonella swinhoei.

Full text of DOI:10.1246/cl.2002.130

130
Chemistry Letters 2002
An Efficient Synthesis of the Piperazinone Fragment of Pseudotheonamide A1
via a Stereoselective Intramolecular Michael Ring Closure
Takayuki Shioiriꢀ and Naoko Irako
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603
(Received November 5, 2001; CL-011105)
The stereoselective intramolecular Michael ring closure of
phosphorylated one 7,7 asshown in Scheme 2. On the other hand,
O-tert-butyldimethylsilyl(TBS)-L-tyrosine (8), prepared from
5,8 resulted in the formation of a mixture of the O-TBS derivative
9 and the O-deprotected one 6. However, the latter waseasily
transformed to the former with TBSCl.
the dipeptide efficiently givesthe piperazinone fragment of
pseudotheonamide A1, a serine protease inhibitor from the marine
sponge Theonella swinhoei.
OR1
Pseudotheonamides have been isolated by Fusetani and co-
workers1 from the marine sponge Theonella swinhoei collected
off Hachijo-jima Island in Japan. They show interesting serine
protease inhibitory activity. Pseudotheonamides A1 (1) and A2
(2) are the principal members of pseudotheonamides, and have a
unique piperazinone ring system. The configuration of 1 at C5 has
proved to be S while that of 2 is R.
OH
OMe
HCl HN
Me
OMe
Me
DEPC, Et3N, DMF
, 1.5 h; rt, 9 h
BocHN
CON
BocHN
CO2H
0
5
6 : R1 = H (57
)
1) TBSCl
imidazole
DMF
2) K2CO3
MeOH
THF, H2O
rt, 4 h
OTBS
7 : R1 = (EtO)2P(O) (35
)
OH
rt, 21 h
OR2
OMe
Me
HCl HN
H
O
HN
5
DEPC, Et3N, DMF
, 1.5 h; rt, 9 h
O
HO
BocHN
CO2H
OMe
NH HN
NH
BocHN
CON
O
0
H
N
Me
9 : R2 = TBS (60
6 : R2 = H (28
8 (quant.)
NH
N
)
HN
TBSCl, imidazole
DMF, rt, 21 h
N
)
O
O
H
O
89
Pseudotheonamide A1 (1)
Scheme 2.
We have been quite interested in the synthesis of structurally
intriguing and biologically active peptidesof aquatic origin, 2 and
we already finished the total synthesis of cyclotheonamide B,3 a
macrocyclic analog of pseudotheonamides. Along this line, we
now selected pseudotheonamide A1 (1) asa synthetic target. We
wish to report here an efficient synthesis of the piperazinone
Reduction of 9 with lithium aluminum hydride gave the
aldehyde 10, which underwent the Wittig olefination with
methoxycarbonylmethylenetriphenylphosphorane to give the
(E)-ꢀ,ꢁ-unsaturated ester 11 as a sole isolable product, as shown
in Scheme 3. Removal of the both Boc and O-TBS functionswith
trimethylsilyl trifluoromethanesulfonate (TMSOTf), followed by
the coupling of the resulting amino compound 12 with Boc-D-
phenylalanine (13) smoothly proceeded to yield the dipeptide 14
whose phenolic O-function was phosphorylated. Although the
phosphoryl group might work as a protective group, it is not
tolerant under alkaline conditionsand itsdeprotection seemed to
be rather difficult at some stages of the synthesis of pseudotheo-
namide A1 (1). Thuswe decided the change of the protective
group, and the group we selected was the 2,6-dichlorobenzyl one.
O-2,6-Dichlorobenzyl(Cl2Bzl)-Boc-L-tyrosine (15) was
converted to the Weinreb amide 16, which wasreduced with
lithium aluminum hydride to give the aldehyde 17. The Wittig
olefination with the phosphorane, acidic treatment of the resulting
ꢀ,ꢁ-unsaturated ester 18, followed by the coupling of the
deprotected amine 19 with Boc-D-phenylalanine (13) efficiently
afforded the ꢀ,ꢁ-unsaturated ester 20 (Scheme 3).
fragment asitsprotected form
3 (R¼2,6-dichlorobenzyl,
Cl2Bzl).4 The key step of our synthesis is the stereoselective
intramolecular Michael ring closure of the dipeptide 4,5 shown in
Scheme 1.
OR
OR
H
O
O
HN
HN
NH OMe
NH2 OMe
O
O
3
4
Scheme 1.
After acidic removal of the Boc group followed by
neutralization, the intramolecular Michael ring closure of the
resulting dipeptide 4 was investigated under several reaction
conditions. So far, the reaction at room temperature in methanol
gave the best result, and the required piperazinone derivative 3
First, conversion of tert-butyloxycarbonyl(BOC)-L-tyrosine
(5) to the corresponding Weinreb amide 6 by use of methoxy
methyl amine and diethyl phosphorocyanidate (DEPC,
(C2H5O)2P(O)CN)6 afforded the desired 6 together with the O-
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
131
OR
OR
1) Me3SiCH2CH2OH
DCC, pyridine, MeCN
rt, 16 h
LiAlH4
Et2O
Ph3P=CHCO2Me
DMSO, rt, 2 h
OMe
Me
rt, 0.5 h
BocHN
9 : R = TBS
16 : R = Cl2Bzl a
CON
BocHN
CHO
2) 4N HCl, rt, 1 h
BocHN
CO2H
H2N
CO2CH2CH2SiMe3
3) 10 aq. NH3
10 : R = TBS (98
)
21
13
17 : R = Cl2Bzl (quant.)
O-Cl2Bzl
OR
OR
TMSOTf, CH2Cl2
0
, 2 h for 11
18
or
BocHN
Me3SiCH2CH2O2C
CO2Me
BocHN
CO2Me
H2N
CO2Me
4N HCl-dioxane
NH
rt, 1 h for 18
12 : R = H
19 : R = Cl2Bzl
11 : R = TBS (60 , E only)
18 : R = Cl2Bzl (80 , E only)
22
OR
Boc-D-Phe-OH (13)
Scheme 5.
DEPC, Et3N
DMF
10 , 2 h; rt, 19 h
BocHN
CONH
CO2Me
Science, Sportsand Culture, Japan for Grants-in-Aid.
14 : R = (EtO)2P(O) (78 in 2 steps)
20 : R = Cl2Bzl (quant. in 2 steps)
Dedicated to Prof. Teruaki Mukaiyama on the occasion of his
75th birthday.
a Prepared from O-2,6-dichlorobenzyl-Boc-L-tyrosine (15).8
Scheme 3.
References and Notes
1
O-Cl2Bzl
Y. Nakao, A. Masuda, S. Matsunaga, and N. Fusetani, J. Am.
Chem. Soc., 121, 2425 (1999).
T. Shioiri and Y. Hamada, Synlett, 2001, 184.
1) 4N HCl
dioxane
2
3
O
MeOH
rt
J. Deng, Y. Hamada, T. Shioiri, S. Matsunaga, and N. Fusetani,
Angew. Chem., Int. Ed. Engl., 33, 1792 (1994); J. Deng, Y.
Hamada, and T. Shioiri, Tetrahedron Lett., 37, 2261 (1996).
N. Irako and T. Shioiri, the 121st Annual Meeting of the
Pharmaceutical Society of Japan, Sapporo, March 2001, Abstr.,
Vol. 2, p 52.
The possibility of the intramolecular Michael addition of the
amino group of phenylalanine to the vinylogoustyroisne
residue was already suggested.1 For a piperazinone synthesis
through the Michael addition, see also D. A. Goff and R. N.
Zuckermann, Tetrahedron Lett., 37, 6247 (1996).
S. Takuma, Y. Hamada, and T. Shioiri, Chem. Pharm, Bull. 30,
3147 (1982) and referencestherein.
HN
20
rt, 63 h
77
NH2 OMe
2) 10 aq. NH3
O
4
5
4
O-Cl2Bzl
O
O-Cl2Bzl
O
H
H
HN
HN
O
6
7
NH OMe
NH OMe
O
The phenolic O-phosphorylation by use of DEPC was already
´
known: A. Guzman and E. Diaz, Synth. Commun., 27, 3035
(1997).
T. Shioiri, T. Imaeda, and Y. Hamada, Heterocycles, 46, 421
(1997).
3
3a
8
9
Scheme 4.
The piperazinone 3 will be more stable than its isomer 3a, from
which the stereochemical assignment of both isomers will be
deduced in addition to spectral evidence. 3: IR vmax (CHCl3)
cmꢁ1: 3378, 2951, 1732, 1667, 1510, 1439, 1240, 1017, 756.
1H-NMR (TMS/CD3OD, 500 MHz) ꢂ 2.26(dd, J ¼ 16:1,
9.1 Hz, 1H), 2.56(dd, J ¼ 6:7, 14.3 Hz, 1H), 2.61(dd, J ¼
16:1, 3.1 Hz, 1H), 2.66(dd, J ¼ 14:0, 9.1 Hz, 1H), 2.81–2.86(m,
2H), 3.19–3.28(m, 1H), 3.34–3.39(m, 2H), 3.43(s, 3H), 5.16(s,
2H), 5.16(s, 2H), 6.89(d, J ¼ 8:5 Hz, 2H), 7.07(d, J ¼ 8:8 Hz,
2H), 7.10–7.34(m, 8H); 3a: IR vmax(neat) cmꢁ1: 3326, 2857,
1732, 1661, 1510, 1439, 1240, 1177, 1017, 765. 1H-NMR
(TMS/CD3OD, 500 MHz) ꢂ 2.41(dd, J ¼ 15:2, 9.8 Hz, 1H),
2.47(dd, J ¼ 15:2, 5.0 Hz, 1H), 2.64(d, J ¼ 7:3 Hz, 2H),
2.81(dd, J ¼ 13:7, 9.8 Hz, 1H), 3.05(dd, J ¼ 13:7, 3.4 Hz,
1H), 3.40–3.44(m, 1H), 3.51(s, 3H), 3.55(dd, J ¼ 9:8, 3.4 Hz,
1H), 3.60(dt, J ¼ 7:3, 3.7 Hz, 1H), 5.18(s, 2H), 6.90(d,
J ¼ 8:8 Hz, 2H), 7.07(d, J ¼ 8:8 Hz, 2H), 7.10–7.80(m, 8H).
wasobtained in 77% yield, 9;10 (Scheme 4). The diastereoisomer
3a, a component of pseudotheonamide A2 (2), wasalso obtained
under some reaction conditions. Addition of triethylamine to
methanol increased this diastereoisomer 3a (3, 46%; 3a, 41%).
Interestingly, the intermolecular Michael addition of the ꢀ,ꢁ-
unsaturated ester 18 with D-phenylalanine trimethylsilylethyl
ester (21), prepared from 13, did not proceed at all under
analogousreaction conditionsto give the Michael adduct 22, as
shown in Scheme 5.
Thus, we could establish a convenient route to the
piperazinone ring component of pseudocyclotheonamide A1 by
use of an intramolecular Michael ring closure as the key step. The
method developed here will offer the general procedure for the
construction of the piperazinone skeleton. The total synthesis of
pseudotheonamide A1 (1) isnow under way.
10 Alkaline hydrolysis of 3 smoothly afforded the corresponding
carboxylic acid.
The authorsare grateful to the Minitsry of Education,