Syntheses of four unusual amino acids, constituents of cyclomarin A

Article abstract of DOI:10.1016/S0040-4039(02)00607-X

The stereoselective syntheses of four unusual amino acids, constituents of cyclomarin A, are described. The protected N-methylhydroxyleucine 2 was synthesized using Evans' asymmetric azide-transfer reaction. The unusual amino acid 3 was prepared via diastereoselective methylation of the L-aspartic acid derived lactone 13. The stereoselective formation of threo-β-methoxyphenylalanine 4 was performed via aldol reaction using Scho?llkopf's chiral glycine enolate. The synthesis of N-reverse prenylated tryptophane 5 was achieved by the AQN ligand-promoted Sharpless regioreversed asymmetric aminohydroxylation protocol.

Full text of DOI:10.1016/S0040-4039(02)00607-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3489–3492
Syntheses of four unusual amino acids, constituents of
cyclomarin A
Hideyuki Sugiyama, Takayuki Shioiri and Fumiaki Yokokawa*
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 15 February 2002; accepted 22 March 2002
Abstract—The stereoselective syntheses of four unusual amino acids, constituents of cyclomarin A, are described. The protected
N-methylhydroxyleucine 2 was synthesized using Evans’ asymmetric azide-transfer reaction. The unusual amino acid 3 was
prepared via diastereoselective methylation of the -aspartic acid derived lactone 13. The stereoselective formation of threo-b-
L
methoxyphenylalanine 4 was performed via aldol reaction using Scho¨llkopf’s chiral glycine enolate. The synthesis of N-reverse
prenylated tryptophane 5 was achieved by the AQN ligand-promoted Sharpless regioreversed asymmetric aminohydroxylation
protocol. © 2002 Elsevier Science Ltd. All rights reserved.
Marine organisms are emerging as a significant new
chemical resource for drug discovery. Many products
having interesting biological activities and structural
features have been isolated from this new source.1
Cyclomarin A (1) is a novel cyclic peptide isolated from
the marine bacterium Streptomyces sp. by Fenical and
co-workers.2 The structure of 1 has been determined
from the X-ray crystallographic analysis of its diacetate
derivative.2c Most importantly, this structure contains
four structurally interesting unusual amino acids, which
have previously never been reported (Fig. 1). Cyclo-
marin A (1) exhibits significant anti-inflammatory prop-
erties in both in vitro and in vivo assays. Furthermore,
1 has been licensed to Phytera Inc. for therapeutic
application, where preclinical trials are currently under-
way.1,2b In continuous studies on the syntheses of bio-
logically active aquatic natural products,3 we have been
interested in the synthesis of cyclomarin A due to its
unique structure as well as important biological activi-
ties. In this paper, we wish to report efficient syntheses
of four unusual amino acid components 2–5 for the
construction of the cyclomarin A molecule (1).
We first started the synthesis of N-methylhydroxy-
leucine precursor (2) using Evans’ asymmetric azide-
transfer reaction,4 as shown in Scheme 1. The half
OH
CO2Et
NHCbz
N
N
O
NHBoc
HO2C
O
H
N
3
O
5
L-N-methylleucine
HO
Me
N
H
O
N
O
N
O
O
Me
HO
L-valine
HN
H
N
OMe
HN
L-alanine
Me
Boc
CO2Me
NHCbz
O
N
O
TBDPSO
CO2Me
MeO
4
2
Cyclomarin A (1)
Figure 1.
Keywords: cyclomarin A; Evans’ asymmetric azide-transfer reaction; Scho¨llkopf’s aldol reaction; Sharpless aminohydroxylation.
* Corresponding author. E-mail: yokokawa@phar.nagoya-cu.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00607-X

3490
H. Sugiyama et al. / Tetrahedron Letters 43 (2002) 3489–3492
O
O
O
O
c
a,b
TBDPSO
TBDPSO
N
TBDPSO
N
CO2Me
O
Ph
6
O
Ph
9
8
O
O
O
Boc
O
N3
NH
f,g,h
d
e
TBDPSO
Boc
N
TBDPSO
N
O
Ph
O
Ph
10
11
Me
O
O
O
N
(EtO)2P
TBDPSO
OMe
N
O
O
7
2
Ph
Scheme 1. (a) DIBAL, ether, −78°C. (b) LiCl, i-Pr2NEt, 7, MeCN, rt, 79% in two steps. (c) H2, 5% Pd/C, EtOAc, 97%. (d)
KHMDS, THF, −78°C; trisyl azide, −78°C, 2 min, AcOH, rt, 82%, single diastereomer. (e) H2, 5% Pd/C, Boc2O, EtOAc, 88%.
(f) aqueous LiOH, 30% aqueous H2O2, THF. (g) NaH, MeI, THF, 0°C to rt. (h) MeI, KHCO3, DMF, 85% in three steps.
reduction of the methyl ester 65 by DIBAL followed by
the Horner–Emmons reaction of the resulting aldehyde
with the phosphonate 76 attached to the chiral auxiliary
under Masamune–Roush conditions7 gave the (E)-
enimide 8 in 79% yield as a single geometric isomer.
After the enimido 8 was hydrogenated to the N-acyl
oxazolidinone 9, the deprotonation of 9 using KHMDS
at −78°C, followed by reaction of the enolate with trisyl
azide according to Evans’ procedure,4 afforded the
azide derivative 10 in 82% yield. The unwanted azide
The threo-b-methoxyphenylalanine 4 was synthesized in
four steps via the aldol reaction using the Scho¨llkopf’s
chiral glycine enolate13 (Scheme 3). Titanium enolate
derived from the bislactim ether 1713b was treated with
benzaldehyde to give the known aldol adduct 1813c as a
single diastereomer. The O-methylation required con-
siderable optimization and was finally accomplished
with Me3O+·BF4
and a Proton sponge® at 4°C to
−14
afford the desired product 19 in 51% yield. Removal of
the chiral auxiliary with aqueous TFA followed by
protection of the resulting amine as a benzyl carbamate
afforded 4 in high yield.
1
diastereomer was not detected by the H NMR analysis
of the crude reaction mixture. Catalytic hydrogenation
over Pd/C in the presence of Boc2O gave the N-Boc
imido 11 in good yield. Subsequent cleavage of the
chiral auxiliary8 and N-methylation using Benoiton’s
procedure,9 followed by methyl esterification provided
the desired product 2 in high yield.
O
CO2Bn
a, b
c
O
BocHN
CO2H
BocHN
Boc-L-Asp(OBzl)-OH (12)
13
The introduction of the b-methyl group of the second
unusual amino acid 3 would be achieved by diastereose-
lective methylation using the lactone 13 having the
O
L
-aspartic acid.10a
f, g
d, e
O
a-chirality which originally existed in
The requisite lactone 1311 was prepared from Boc-
L
-
NH
Asp(OBzl)-OH by reduction of the carboxylic acid via
the mixed anhydride, and then acid-catalyzed lactoniza-
tion. Enolization of 13 with LDA followed by the
treatment with methyl iodide gave a diastereomeric
mixture in a ratio of 10:1, which was readily separated
by silica gel column chromatography to afford 1410b in
67% yield. After the reduction of the lactone to the
lactol, the Wittig homologation to introduce the iso-
propylidene group gave the oxazolidinone 15, which
arose from the attack of the alkoxide on the Boc
carbonyl group. Reinstallation of the Boc group fol-
lowed by the hydrolysis of oxazolidinone afforded the
amino alcohol 16 in high yield. Finally, regeneration of
the carboxyl group without epimerization was achieved
by PDC oxidation of the alcohol12 to give 3 in 88%
yield (Scheme 2).
15
BocHN
O
14
O
h
HO2C
NHBoc
NHBoc
OH
16
3
Scheme 2. (a) ClCO2Et, Et3N, THF, NaBH4, H2O. (b) cat.
TFA, toluene, 52% in two steps. (c) LDA (2.1 equiv.), THF,
−78°C; MeI, 67%. (d) DIBAL, CH2Cl2, −78°C, 87%. (e)
n-BuLi, i-PrP+Ph3P·I−, THF, 85%. (f) Boc2O, DMAP, THF,
96%. (g) 1N aqueous NaOH, THF–MeOH, 90%. (h) PDC,
DMF, rt, 88%.

H. Sugiyama et al. / Tetrahedron Letters 43 (2002) 3489–3492
3491
the 3-formylindole 22. The Sharpless asymmetric di-
hydroxylation (AD)18 of the terminal olefin in the
reverse prenyl group using (DHQD)2PYR as a chiral
ligand16,18b followed by the conversion to the epoxide
via tosylation19 gave the epoxide 25 in 73% yield (three
steps). The enantiomeric excess of 25 was 85%, which
was determined by chiral HPLC.20 The epoxide 25
subjected to the Horner–Emmons reaction with triethyl
phosphonoacetate gave the requisite E-olefin 26 in 83%
yield as a single stereoisomer. The pivotal Sharpless AA
of 26 proceeded as expected to afford the desired
b-hydroxytryptophan fragment 5 in 36% yield (Scheme
4).21
OH OMe
OMe
a (ref 13)
b
N
N
N
N
MeO
OMe
17
18
OMe OMe
OMe
CO2Me
Cbz
c, d
N
N
HN
OMe
4
19
Scheme 3. (a) n-BuLi, THF, −78°C; ClTi(NEt2)3, n-hexane;
PhCHO, 78%. (b) Me3O·BF4, Proton sponge®, CH2Cl2, 4°C,
51% (11% recovered). (c) 1N aqueous TFA, MeCN–THF. (d)
CbzCl, Et3N, THF, 92% in two steps.
In summary, we have accomplished the efficient synthe-
sis of four novel unusual amino acids as appropriate
protected forms, which were useful for the total synthe-
sis of cyclomarin A (1). Experiments toward this end
are actively being carried out in our laboratory.
The remaining unusual amino acid, the N-reverse
prenylated tryptophan 5, has the same configuration as
4. However, the above Scho¨llkopf’s aldol method could
not be used in the synthesis of 5 because the cleavage of
the bislactim ether was not suitable for acid sensitive
b-hydroxytryptophan, which has a vinylogous aminal
structure. Therefore, we employed the AQN ligand-pro-
moted Sharpless asymmetric aminohydroxylation
(AA)15 of the a,b-unsaturated aryl ester for the synthe-
sis of the b-hydroxy tryptophan derivative. Previously,
we reported the efficient synthesis of the unique N-
reverse prenylated indole 2116 from indoline 20, and we
used 21 as a starting material for the synthesis of 5.
Vilsmeier formylation17 of 21 quantitatively afforded
Acknowledgements
This work was financially supported in part by a Grant-
in-Aid from the Uehara Memorial Foundation (to
F.Y.), the Fujisawa Foundation (to F.Y.), and a Grant-
in-Aid from the Ministry of Education, Science, Sports
and Culture, Japan. H.S. is grateful to the Japan Soci-
ety for the Promotion of Science (JSPS) for a postgrad-
uate fellowship.
CHO
ref 16
a
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1
by the H NMR of the corresponding MTPA amide of 5.