Construction of three building blocks for the total synthesis of microsclerodermins

Article abstract of DOI:10.1055/s-1999-2651

Three building blocks 2, 3, and 4 for the total synthesis of microsclerodermins (1) have been efficiently constructed from carboxylic acids 6, 14, and 20, respectively.

Full text of DOI:10.1055/s-1999-2651

LETTER
453
Construction of Three Building Blocks for the Total Synthesis of
Microsclerodermins
Shigekazu Sasaki,a Yasumasa Hamada,*b Takayuki Shioiri*b
aFaculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax +81-52-834-4172, E-mail: shioiri@phar.nagoya-cu.ac.jp
bFaculty of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax: +81-43-290-2987, E-mail: hamada@p.chiba-u.ac.jp
Received 6 January 1999
thesis of a core building block for AMMTD 5.3 We now
wish to report the efficient synthesis of three building
blocks 2-4 for the construction of the whole molecules of
microsclerodermins (1).4
Abstract: Three building blocks 2, 3, and 4 for the total synthesis
of microsclerodermins (1) have been efficiently constructed from
carboxylic acids 6, 14, and 20, respectively.
Key words: microsclerodermin (R)-tryptophan, asymmetric alkyla-
tion, 2-hydroxy-3-pinanone, GABOB
We first started the synthesis of (R)-tryptophan-2-carbox-
ylic acid derivative 2 by use of our own method5,6 involv-
ing the asymmetric alkylation of the chiral Schiff base 11
derived from (-)-2-hydroxy-3-pinanone ((-)-HyPN, 9) and
glycine tert-butyl ester (10), as shown in Scheme 1. The
alkylating agent 8 (mp 218-220 °C) was prepared from in-
dole-2-carboxylic acid (6) by methyl esterification, Man-
nich reaction, followed by quaternization. The Schiff base
11 derived from (-)-HyPN (9) and glycine tert-butyl ester
(10)5 was lithiated with lithium diisopropylamide (LDA)
and then alkylated with the ammonium salt 8 to give the
alkylated Schiff base 12 from which the chiral auxiliary,
(-)-HyPN, was removed by acidic treatment. Reaction of
the resulting amine 13 with di-tert-butyl dicarbonate
(Boc2O) afforded the required (R)-tryptophan-2-carboxy-
lic acid derivative 2, mp 129 °C, [a]D17-7.45 (c 1.2,
Microsclerodermins A and B have been isolated by
Faulkner and co-workers from a deep water sponge of the
genus Microscleroderma.1 They inhibit the growth of
Candida albicans at 2.5 mg/disk. The structures of micro-
sclerodermins A and B (1a and 1b) were determined to be
23-membered cyclic hexapeptides involving four unusual
amino acids, as shown in Figure 1. As a continuation of
our interests in the synthesis of aquatic natural products
having useful biological activities,2 we have been in-
trigued by the synthesis of microsclerodermins because of
their unique structures as well as interesting biological ac-
tivities. We have already revealed a stereoselective syn-
O
NHBoc
O
CO2But
CO2Me
TMSeO2C
N-MeGly
N
2
H
NHBoc
3
H
N
O
CO2H
O
HN
R
H
N
Microsclerodermin A (1a): R = OH
Microsclerodermin B (1b): R = H
N
O
HO
O
HN
O
Me
O
NH
OH
OH
OH
H
N
OMe
N
H
Gly
O
HO
O
OMPM
OTBS
O
BocHN
CO2Tce
CO2Me
NHBoc
4
AMMTD (5)
MeO
Figure 1
Synlett 1999, No. 4, 453–455 ISSN 0936-5214 © Thieme Stuttgart · New York

454
S. Sasaki et al.
LETTER
O
CHCl3), in 60% yield from the Schiff base 11. The enan-
tiomeric excess of 2 proved to be 87% by chiral HPLC,7
and rose to 91% after recrystallization from hexane-ethyl
acetate.
1) CDI, THF
rt, 6 h
HO2C
EtO2C
CO2Bzl
CO2Bzl
2) Mg(O2CCH2CO2Et)2
THF, rt, 12h
NHBoc
14
NHBoc
15
78% in 2 steps
O
1) H2, 5% Pd/C, EtOAc, rt, 2 h
HN
MeI, KHCO3
DMF, 90%
2) ClCO2Et, Et3N, THF, 0°C, 30 min
EtO2C
N
CO2H
N
CO2Me
3) aq. NH3, 0°C, 30 min
86% in 3 steps(16:17=3:1)
H
H
OH
NHBoc
O
6
7
α-OH : 16
β-OH : 17
N+Me3I-
1) Me2NH, HCHO, AcOH
O
2) MeI, THF, reflux
33% in 2 steps
H+ or OH-
HN
HN
N
CO2Me
H
EtO2C
EtO2C
8
OH
NHBoc
NHBoc
OH
OH
16
18
N
CO2But
O
H-Gly-OBut (10)
Scheme 2
BF3•OEt2, benzene
11
ref. 5
(-)-HyPN (9)
1.02, CHCl3)). After catalytic removal of the benzyl func-
tion over Pd/C, reduction of the carbonyl group with sodi-
um borohydride, followed by treatment with 3-(3-
dimethylaminopropyl)-1-ethylcarbodiimide hydrochlo-
ride (EDCI∑HCl) in the presence of N,N-dimethylami-
nopyridine (DMAP) afforded the desired lactone 3 as a
colorless oil,9 [a]D28-0.01 (c 1.74, CHCl3), in 82 % yield
from 19.
OH
N
CO2But
1) LDA, THF, -78°C
2) 8, -78°C to 0°C
overnight
12
MeO2C
N
H
NH2
CO2But
15% citric acid, THF
rt, overnight
N
H
CO2Me
13
O
1) CDI, THF
TMSeO2C
rt, 6 h
HO2C
NHBoc
CO2But
CO2Bzl
NHBoc
CO2Bzl
Boc2O, dioxane
60% in 3 steps
2) CH3CO2TMSe
LDA, THF
NHBoc
14
N
CO2Me
19
2
H
-78°C, 30 min
92%
Scheme 1
O
1) H2, 5% Pd/C, EtOAc, rt, 2 h
O
2) NaBH4, EtOH, 0°C, 15 min
TMSeO2C
For the synthesis of the hydroxypyrrolidinone part of
microsclerodermins (1), we have first synthesized the hy-
droxypyrrolidinone derivative itself as shown in Scheme
2. The aspartic acid derivative 14 as a starting material
was converted to its imidazolide by treatment with N,N’-
carbonyldiimidazole (CDI) followed by the magnesium
enolate of the malonic acid half ester to give the b-keto es-
ter 15. After catalytic removal of the benzyl function over
Pd/C, the resulting acid was converted to the mixed anhy-
dride, which was treated with aqueous ammonia to give a
mixture of the hydroxypyrrolidinones 16 and 17 in a ratio
of 3:1.8 The hemiaminal structure of 16 was found to be
easily dehydrated to give the a,b-unsaturated ester 18 un-
der various acidic as well as basic conditions. Thus we
reasoned that the g-lactone (3) would be a suitable precur-
sor and hydroxypyrrolidinone part could be constructed
after the insertion of 3 to the peptide skeleton of 1.
3) EDCI•HCl, DMAP, CH2Cl2
NHBoc
rt, 4 h, 82% in 3 steps
3
Scheme 3
Finally, the required 4-amino-3-hydroxybutanoic acid
(GABOB) derivative 4 was constructed from methyl
(3R)-3,4-dihydroxybutanoate (21), which was obtained
from dimethyl (R)-malate (20).10 Selective tosylation11 of
the primary alcoholic function of 21, followed by azida-
tion of the resulting monotosylate 22 (mp 81.5-82.5 °C,
[a]D26+6.8 (c 1.1, CHCl3)) furnished the hydroxy azide 23
([a]D25+19.6 (c 1.03, CHCl3)), which was catalytically hy-
drogenated over Pd/C in the presence of Boc2O2 to give
the GABOB derivative 24 ([a]D26+5.37 (c 1.06, CHCl3)).
After replacement of the methyl ester function with the
trichloroethyl (Tce) one, protection of the formed second-
ary alcohol 25 (mp 70.5-71.5 °C, [a]D23+2.08 (c 1.02,
CHCl3)) with tert-butylchlorodimethylsilane (TBSCl) af-
forded the required GABOB derivative 4 as a colorless
oil, [a]D23+8.44 (c 0.98, CHCl3).
Similarly to the synthesis of 16, we synthesized the g-lac-
tone 3 from the aspartic acid derivative 14, as shown in
Scheme 3. The acid 14 was converted to its imidazolide
then reacted with the lithium enolate of trimethylsilylethyl
(TMSe) acetate to give the b-keto ester 19 ([a]D23-20.3 (c
Synlett 1999, No. 4, 453–455 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Construction of Three Building Blocks for the Total Synthesis of Microsclerodermins
455
OH
References and Notes
OH
p-TsCl, Pyridine
ref. 7
CO2Me
CO2Me
HO
CO2Me
(1) Bewley, C. A.; Debitus, C.; Faulkner, D. J. J. Am. Chem. Soc.
1994, 116, 7631-7636.
(2) For a recent example, see Deng, J.; Hamada, Y.; Shioiri, T.
Synthesis 1998, 627-639; Yokokawa, F.; Shioiri, T. J. Org.
Chem. 1998, 63, 8638-8639.
MeO2C
0°C, 20 h, 64%
21
20
OH
OH
NaN3, DMF
TsO
N3
CO2Me
80°C, 3 h, 83%
23
22
(3) Sasaki, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1997,
38, 3013-3016.
OH
H2, 5% Pd/C, Boc2O
EtOAc, rt, 15 h, 87%
1) NaOH, MeOH
(4) A part of this work was presented at First International Peptide
Symposium (Kyoto), November 30-December 5, 1997, Ab-
stracts, p. 162 and at 118th Annual Meeting of Pharmaceutical
Society of Japan (Kyoto), March 31-April 2, 1998, Abstracts,
2, 24.
(5) Oguri, T.; Kawai, N.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1978, 26, 803-808.
(6) Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1995, 51,
12731-12744, and references therein.
(7) HPLC conditions: Daicel Chiralcel OD, flow rate 1.0 mL/min,
hexane-isopropanol=9:1. The reference racemic 2 was prepa-
red analogously from the Schiff base of benzophenone and
glycine tert-butyl ester.
BocHN
CO2Me
2) TceOH, EDCI•HCl
DMAP, CH2Cl2
59% in 2 steps
24
OH
OTBS
TBSCl, imidazole
BocHN
CO2Tce
BocHN
CO2Tce
DMF, rt, 15 h
quant.
4
25
Scheme 4
Scheme 4
(8) The configuration of 16 and 17 was determined by the measu-
rement of NOE in the NMR spectra as followed.
Thus we could complete the efficient synthesis of three
building blocks 2-4 useful for the total synthesis of micro-
sclerodermins (1). Experiments toward this end are ac-
tively being carried out in our laboratories.
O
O
HN
OH
HN
EtO2C
H
EtO2C
H
NHBoc
NHBoc
OH
H
H
H
H
Acknowledgement
24%
31%
1.8%
no NOE
16
17
This work was partly supported by the Grants-in-Aid from the Mi-
nistry of Education, Science, Sports and Culture, Japan. We thank
Mr. K. Yatsui and Miss M. Nakane for their preliminary studies on
the synthesis of the D-tryptophan derivative.
(9) The lactone 3 was obtained as a diastereoisomeric mixture in
preference to the (4S,5R)-isomer, and no separation was at-
tempted at this stage.
(10) (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389-1392.
(b) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake,
T. Tetrahedron 1992, 48, 4067-4086. (c) Cheng, Z.; Hamada,
Y.; Shioiri, T. Synlett 1997, 109-110. (d) Shioiri, T.;
McFarlane, N.; Hamada, Y. Heterocycles 1998, 47, 73-76.
(11) Cf. Bellamy, F. D.; Bondoux, M.; Dodey, P. Tetrahedron Lett.
1990, 31, 7323-7326.
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Synlett 1999, No. 4, 453–455 ISSN 0936-5214 © Thieme Stuttgart · New York