Synthesis and conformational analysis of a novel ansadipeptide

Article abstract of DOI:10.1055/s-2002-34378

A novel ansapeptide 6 was synthesized from tyrosine (5) and Bic 3b as the amino acid components and oxalic acid as the connecting link. The conformational properties of 6 were calculated by molecular mechanics.

Full text of DOI:10.1055/s-2002-34378

PAPER
2091
Synthesis and Conformational Analysis of a Novel Ansadipeptide
Synthesis
o
and Conform
h
ationa
l
A
na
l
a
ysis of
a
N
n
A
nsadip
n
eptide Mulzer,* Oliver Langer
Institut für Organische Chemie, Universität Wien, Währinger Strasse 38, 1090 Wien, Austria
Fax +43(1)427752189; E-mail: johann.mulzer@univie.ac.at
Received 13 June 2002
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday.
OH
O
Abstract: A novel ansapeptide 6 was synthesized from tyrosine (5)
O
and Bic 3b as the amino acid components and oxalic acid as the con-
necting link. The conformational properties of 6 were calculated by
molecular mechanics.
O
H
H
O
N
N
H
HO
N
HO2C
N
Key words: ansa compounds, peptidomimetics -amino acids,
conformation analysis, molecular mechanics
H
N
NHAc
O
O
H
O
HO
1
2
Naturally occurring ansapeptides such as tripeptide K-131
(1) or S2052 (2) (Figure 1) show high in-vivo stability,
high permeability through cell membrane and, as a conse-
quence, enhanced bioavailability compared to their nor-
mal peptide analogs.3
Figure 1
core provides a rigid template for a variety of different
alignments of carboxyl, amino and side chain functional-
ities, which are located in two cis-fused cyclopentane
rings. Ring A houses the -amino acid moiety at C2 and
C3, whereas the 8-position in ring B may be functional-
ized with a ketone, a ketal or a secondary hydroxyl func-
tion (Scheme 1).
For instance, the tyrosine ansapeptide 2 is a water-soluble
inhibitor of the enzyme matrix-metalloproeinase (MPP).
MPP plays a key role in the development of cancer and
arthitis.4 Apart from biological activity the molecular con-
straints dictated by the ansa structure may be expected to
induce some interesting conformational properties. On
this background we designed a novel ansadipeptide con-
taining the aromatic -aminoacid L-tyrosine and the -
aminoacid, Bic 3a, a novel cispentacin5analog. The Bic-
Our plan was first to synthesize dipeptide 5 by coupling
Fmoc-tyr(t-Bu)-OH (4) and the Bic-derivative 3b
(Scheme 1). Later, the ansa-bridge could be closed via a
suitable spacer linking both hydroxyl functions. To make
R1
R2
8
B
1
H
H
A
CO2R
2
3
Y
3a R, R1 = H; R2 = OH; Y = NH2
3b R = Me; R1, R2 = -O-(CH2)3O-; Y = NH2
tBuO
O
O
anti
OH
O
OH
O
Fmoc
N
H
HO
4
O
3b
CO2Me
MeO2C
CH2
NHFmoc
peptide coupling
NH
HN
Fmoc
N
H
O
O
5
6
Scheme 1
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,2091,2095,ftx,en;C02302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2092
J. Mulzer, O. Langer
PAPER
O
O
O
O
O
O
O
O
d
b
H
H
CO2Me
MeO2C
MeO2C
O
NH
10
X
Y
O
N
H
9: Y = N3
3b: Y = NH2
7: X = OH
8: X = ONs
c
a
O
O
OH
O
O
HO
e, f
H
H
g
H
H
CO2Me
CO2Me
NH
CH2
FmocHN
NH
O
FmocHN
11
O
6
Scheme 2 Synthesis of 6; Reagents and Conditions: (a) Et3N, CH2Cl2, 4-NO2-C6H4-SO2Cl, 0 °C, 3 h, 95%; (b) NaN3, DMF, r.t., 8 h, 95%;
(c) H2, Pd/C, r.t., 2 d, 82%; (d) Fmoc- S-tyrosine(t-Bu)-OH, 1.5 equiv TBTU, 1.5 equiv NNM, then 3b in DMF, 91%; (e) TFA H2O Et3SiH
(18:1:1), 4.5 h, r.t.; (f) SiO2, H2O, MeOH, 1 h, r.t., 72% over two steps; (g) oxalylchloride (4 equiv), NNM (10 equiv), CH2Cl2, 2 h, r.t., 38%
O
O
the ring small and, hence, conformationally rigid, we de-
cided to use oxalic acid as the spacer component. In this
way, the ansa-depsipeptide 6 was our synthetic goal. The
synthesis is shown in Scheme 2.
O
O
H
H
Readily available -hydroxy ester 76 was converted into
nosylate 8, which was subjected to a clean SN2-substitu-
tion with azide to give 9. Reduction of the azide with H2
and Pd/C furnished the amino ester 3b, which was cou-
pled with tyrosine 5 via TBTU activation to give dipeptide
10. Removal of tertiary butyl ether and the acetonide fol-
lowed by reduction of the ketone so formed was achieved
in one operation with a mixture of TFA and Et3SiH to gen-
erate endo alcohol 11 stereoselectively. Cyclization with
oxalylchloride and NNM was performed under high dilu-
CO2Me
CH2
NH
AcHN
O
12
Figure 2
apart, so that intra-annular repulsions are relatively small
and some open space is left between the two rings. The
methyl ester carbonyl serves as an acceptor for two NH-
hydrogen bridges: one from the peptidic and one from the
exocyclic NH, which may contribute to rigidify the con-
formation in this section of the molecule. As a conse-
quence an open turn structure is generated for the
dipeptide section both ends of which point towards the
spectator in the projection of Figure 3. The dipeptide is
appropriately substituted to be incorporated as a
peptidomimetic8 into the backbone of biologically rele-
6
tion conditions (6 10 M in CH2Cl2) to form ansa-pep-
tide 6 in 38% yield.
Conformational Analysis via Force Field Calculation
As the Fmoc-protecting group can be assumed to be with-
out an influence on the conformation of the ansa ring sys-
tem, the much simpler acetyl derivative 12 (Figure 2) was
used for the molecular dynamics calculation (Tinker7
v3.8, MM3-force field, 400000 MD-steps at 0.2 fs, 800 K,
saving every 40 fs). 2000 conformers were obtained, min-
imized (MM3-force field, GRMS-cutoff-criterion 0.001
kcal/mol/Å) and sorted according to increasing MM3-po-
tential energy. The structure of the global individual min-
imum is shown in Figure 3.
It can be seen that the oxalate moiety acts as a spacer to
keep the benzenoid and the bicyclononane ring systems
Figure 3 Two representations of the structure of the individual glo-
bal minimum of ansapeptide 12
Synthesis 2002, No. 14, 2091–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis and Conformational Analysis of a Novel Ansadipeptide
2093
MS (EI, 70 eV, 130 °C): m/z (%) = 469 (17.4), 410 (2.1), 368 (5.5),
267 (84.8), 207 (30.7), 181 (31.8), 128 (70.8), 93 (40.6), 69 (90.4),
41 (100).
vant peptides and may generate interesting agonistic or
antagonistic properties in comparison to the native com-
pound.9 Studies in connection with GnRH-analogs10are
underway in our laboratory.
Anal. Calcd for C21H27NO9S: C, 53.72; H, 5.80; N, 2.98. Found: C,
53.98; H, 5.38; N, 3.04.
Reaction progress was monitored by analytical thin-layer chroma-
tography (TLC) using silica gel 60 F254 aluminium foils. Visualiza-
tion was accomplished by UV illumination (254 nm), 0.2%
ninhydrin in EtOH, or anisaldehyde/H2SO4 in EtOH (1:2:98). Flash
chromatography was performed using 40–63 m silica gel packing
unless otherwise noted with EtOAc and hexane as eluents. 1H NMR
and 13C NMR spectra were recorded at 400 and 250 and 100 and
62.5 MHz, respectively. Chemical shifts ( ) are reported as parts per
million from an internal tetramethylsilane (TMS) standard in the
solvent indicated or by using the respective residual signal at 25 °C
unless otherwise noted. Coupling constants were determined from
1H NMR, the symbol is used to denote pseudo coupling. Elemen-
tal analyses were performed by the ‘Mikroanalytisches Laboratori-
um, Institut für Physikalische Chemie der Universität Wien’. ESI
spectra were recorded at the ‘Institut für Organische Chemie der
Universität Frankfurt am Main’ and at the ‘Institut für Analytische
Chemie der Universität Wien’.
Methyl-(1R,2S,3R,5S)-7,7-(2 ,2 -dimethyltrimethylenedioxy)-3-
azidobicyclo[3.3.0]octan-2-oate (9)
To a suspension of nosylate 8 (109.2 g, 0.23 mol) in DMF (150 mL)
was added NaN3 (37.7 g, 0.58 mol) at r.t. in portions during 5 min.
The dark red suspension was stirred at r.t. for 8 h during which it
turned yellow with a colorless precipitate. Another NaN3 (7.5 g,
0.12 mol) was added and the suspension was allowed to stir until
complete consumption of starting material according to TLC analy-
sis. H2O (30 mL) was added, the resulting soln was extracted with
hexanes (3 60 mL), combined organic layers dried over MgSO4,
and concentrated to an amber residue. Chromatography on silica gel
(20% EtOAc hexanes) afforded a viscous oil, which was dissolved
in a small amount of hexanes and cooled in a freezer to –30 °C.
Crystallization was initiated by carefully warming the bottom of the
flask in a warm water bath. Following this procedure azide 9 (68.1
g, 95%) was obtained as a slightly yellowish solid.
[ ]D20 –62.1 (c = 3.3, CHCl3).
All reactions using air- or H2O-sensitive reagents were conducted
under an Ar atmosphere with anhyd solvents. Solvents were puri-
fied as follows: EtOAc and hexanes were fractionally distilled,
CH2Cl2 was distilled and filtered through alumina B (activity grade
super I), DMF was distilled from CaH2. Et3N and N-methyl mor-
pholine were refluxed for several hours over CaH2 and then slowly
distilled. All other reagents were purchased from commercial sup-
pliers and used without further purification.
IR (thin film): 2954s, 2865m, 2110vs, 1740vs 1436m, 1330m,
1264m, 1106vs, 1019m, 881m, 739m, 610vs, 513m cm–1.
1H NMR (250 MHz, CDCl3): = 4.29 ( td, J = 3.8, 0.8 Hz, 1 H),
3.75 (s, 3 H), 3.47 (s, 4 H), 2.98 ( quint.d, J = 9.3, 3.5, Hz, 1 H),
2.91 (dd, J = 8.9, 4.3 Hz, 1 H), 2.81 ( quint.d, J = 9.2, 4.1 Hz, 1 H),
2.18 (ddd, J = 13.4, 8.4, 1.5 Hz, 1 H), 2.10–1.90 (m, 3 H), 1.74 (ddd,
J = 13.5, 8.9, 4.5 Hz, 1 H), 0.98 (s, 3 H), 0.96 (s, 3 H).
13C NMR (62.5 MHz, CDCl3): = 172.6, 110.2, 72.9, 71.9, 67.0,
56.0, 52.0, 40.7, 39.8, 39.1, 38.5, 38.1, 30.5, 22.9.
Methyl-(1R,2S,3S,5S)-7,7-(2 ,2 -dimethyltrimethylenedioxy)-3-
(4-nitrobenzyl-sulfonyloxy)-bicyclo[3.3.0]octan-2-oate (8)
To a soln of -hydroxy ester 7 (56.9 g, 0.20 mol) in CH2Cl2 (500
mL) at 0 °C was added Et3N (57.0 g, 0.56 mmol, 2.8 equiv). The
soln was allowed to stir for 5 min, then 4-nitrobenzenesulfonyl
chloride (62.1 g, 0.28 mol, 1.4 equiv) was added in small portions
during 10 min. The dark reddish brown soln was allowed to stir for
3 h at 0 °C, until complete consumption of starting material (moni-
tored by TLC analysis). A mixture of hexanes EtOAc, (300 mL,
1:1) was added and the resulting suspension was filtered through a
plug of silica gel. The plug was washed with hexanes EtOAc (100
mL). The solvent was removed to two thirds under reduced pres-
sure, and the resulting suspension was again filtered. The filtrate
was concentrated to a brown oil, dissolved in warm tert-butyl meth-
yl ether (750 mL) and warm hexanes (500 mL) was added. The
product was allowed to crystallize overnight and fine yellow nee-
dles (83.3 g) were obtained. A second crystallization from the moth-
er liquor afforded another 5.4 g of product, a total of 88.7 g (95%).
MS (EI, 70 eV, 60 °C): m/z (%) = 309 (0.8), 281 (2.3), 267 (18.2),
238 (8.6), 213 (8.2), 195 (2.5), 180 (20.5), 168 (17.0), 155 (16.5),
128 (34.4), 94 (21.3), 79 (20.2), 69 (89.3), 56 (25.8).
Anal. Calcd for C15H23N3O4: C, 58.24; H, 7.49; N, 13.58. Found: C,
58.46; H, 7.35; N, 13.72.
Methyl-(1R,2S,3R,5S)-7,7-(2 ,2 -dimethyltrimethylenedioxy)-3-
amino-bicyclo[3.3.0]octan-2-oate (3b)
To a soln of azide 9 (30.9 g, 0.10 mol) in EtOAc (900 mL) was add-
ed Pd/C (10%, 350 mg) and H2 was allowed to bubble through the
soln in a weak stream for two days. The soln was filtered through a
plug of celite, concentrated under vacuum, co-evaporated with tol-
uene (1 × 100 mL, then 1 × 50 mL), then dissolved in Et2O (500
mL), and cooled to 0 °C. A soln of HCl in Et2O (110 mL, 1 M) was
added, and the resulting hydrochloride was filtered. The solid was
dissolved and partitioned between a soln of Et3N (10 g) in Et2O (250
mL). The phases were separated, the aq phase was again extracted
with Et2O (2 100 mL). Pooled organic phases were dried
(MgSO4) and concentrated to a yellowish oil which solidified after
several hours to an almost colorless solid 3b (23.2 g, 82%).
[ ]D20 –11.6 (c = 2.2, CHCl3).
IR (thin film): 3107w, 2955s, 2868m, 1736vs, 1608w, 1534vs,
1436m, 1372s, 1351vs, 1313s, 1188vs, 1116vs, 1094vs, 1014m,
964s, 919s, 738vs, 685m, 619vs, 557m, 512w, 466w cm–1.
1H NMR (400 MHz, CDCl3): = 8.37 (ddd, J = 9.2, 2.2, 2.2 Hz, 2
H), 8.08 (ddd, J = 9.1, 2.2, 2.2 Hz, 2 H), 4.96 (ddd, J = 9.4, 9.4, 6.7
Hz, 1 H), 2.92 ( t, J = 8.8 Hz, 1 H), 3.57 (s, 3 H), 3.48 (s, 2 H), 3.43
(s, 2 H), 2.60–2.45 (m, 2 H), 2.41–2.32 (m, 1 H), 2.12–2.05 (m, 1
H), 2.05–1.97 (m, 2 H), 1.93–1.86 (m, 1 H), 1.84–1.75 (m, 1 H),
0.96 (s, 3 H), 0.94 (s, 3 H).
IR (thin film): 3383w, 2952vs, 2865s, 1730s, 1617br, 1473m,
1435s, 1203s, 1170s, 1115vs, 1020s, 907m, 882m, 610vs, 511m
cm–1.
1H NMR (250 MHz, CDCl3): = 3.68 (mc, 1 H), 3.66 (s, 3 H), 3.42
(s, 4 H), 2.89 (mc, 1 H), 2.77 (ddd, J = 16.4, 8.2, 2.7 Hz, 1 H), 2.70
(dd, J = 7.7, 5.1, 1 H), 2.13 (ddd, J = 18.9, 9.0, 1.4, 1 H), 2.07 (ddd,
J = 18.7, 8.9, 1.3, 1 H), 1.89–1.55 (m, 4 H), 1.17 (s, 2 H), 0.93 (s, 3
H), 0.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): = 173.1, 150.7, 142.4, 129.4, 124.3,
109.4, 84.4, 72.5, 71.7, 55.0, 52.1, 42.0, 39.7, 38.5, 38.3, 36.0, 30.1,
22.5.
13C NMR (62.5 MHz, CDCl3): = 174.2, 109.7, 72.1, 71.8, 56.8,
55.9, 51.4, 41.8, 41.1, 39.9, 38.8, 37.8, 30.0, 22.5.
Synthesis 2002, No. 14, 2091–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

2094
J. Mulzer, O. Langer
PAPER
MS (EI, 70 eV, 60 °C): m/z (%) = 283 (13.2), 268 (8.6), 251 (7.0),
240 (3.2), 213 (15.3), 207 (24.4), 196 (54.5), 179 (84.3), 166 (19.5),
152 (58.9), 139 (21.3), 128 (32.3), 96 (30.6), 81 (18.7), 69 (100.0),
56 (53.4).
13C NMR (MeOH-d4, J-mod, 62.5 MHz): = 175.2q, 173.7q,
161.0q, 158.0q, 157.3q, 145.2q, 142.5q, 131.3t, 129.1q, 128.7t,
128.2t, 126.1t, 120.9t, 116.2t, 75.3t, 68.0, 58.0, 55.7, 54.7, 52.2,
49.8, 48.3, 44.3, 42.7, 41.9, 39.7, 39.6, 38.6.
Anal. Calcd for C15H25NO4: C, 63.58; H, 8.89; N, 4.94. Found: C,
63.52; H, 8.68; N, 4.83.
Anal. Calcd for C34H36N2O7: C, 69.85; H, 6.21; N, 4.79. Found: C,
69.72; H, 6.43; N, 4.63.
Methyl-(1S,2R,3aS,6aR)-2-[(2S)-3-(4-tert-butoxyphenyl)-2-
{[(9H-fluoren-9-yl-methoxy)-carbonyl]-amino}-propanoyl)-
amino]-5,5-(2 ,2 -dimethyl-trimethylenedioxy)-octahydro-1-
pentalenoate (10)
Methyl-(6R,8S,9R,10S,11R,14S)-14-{[(9H-Fluoren-9-yl-meth-
oxy)-carbonyl]-amino}-3,4,13-trioxo-2,5-dioxa-12-aza-tetracy-
clo[14.2.2.16,9.18,11]-docosa1(18),16,19-trien-10-oate (6)
Compound 11 (70 mg, 0.12 mmol) in CH2Cl2 (100 mL) was treated
dropwise with oxalylchloride (63 mg, 0.50 mmol) in CH2Cl2 (50
mL) and NNM (125 mg, 1.25 mmol) in CH2Cl2 (50 mL) from two
separate syringe pumps over 2 h at 22 °C. The mixture was concen-
trated under reduced pressure and the residue was purified by chro-
matography (Et2O–hexane–MeOH, 4:1:0.05) on sephadex LH-20
(MeOH) to give 6 (26.7 mg, 38%) as an amorphous colorless solid;
Rf 0.36 (Et2O–hexane–MeOH, 4:1:0.05).
To a soln of O-(benzotriazol-1-yl)-N,N,N ,N -tetramethyluranium
tetrafluoroborate (TBTU) (0.96 g, 3.00 mmol, 1.5 equiv) and NNM
(0.61 g, 6.00 mmol, 3.0 equiv) and Fmoc-Tyr(t-Bu)-OH (4) (1.15 g,
2.50 mmol, 1.25 equiv) in DMF (10 mL) was added dropwise ami-
no ester 3b (0.57 g, 2.00 mmol) in DMF (5 mL). The mixture was
stirred at 22 °C for 1 h, cooled to 0 °C and treated with sat. aq
NH4Cl (20 mL). The mixture was partitioned between CH2Cl2 (100
mL) and brine (50 mL) and the aq phase was again extracted with
CH2Cl2 (100 mL). The combined organic extracts were concentrat-
ed under reduced pressure and then purified twice by flash chroma-
tography (Et2O–hexane, 1:1, then 2:1) to furnish 10 (1.33 g, 91%)
as a colorless foam; Rf 0.57 (Et2O–hexane, 1:1).
[ ]D20 –10.6 (c = 2, CHCl3).
IR (Si, Film): 3331br, 2950m, 1718s, 1654s, 1616w, 1516s, 1450s,
1232br, 1106w, 817w cm–1.
1H NMR (MeOH-d4, 250 MHz): = 7.78 (d, J = 7.1 Hz, 2 H), 7.59
(d, J = 7.1 Hz, 2 H), 7.38 (dd, J = 7.2, 7.2 Hz, 2 H), 7.30 (mc, 2 H),
7.04 (d, J = 7.8 Hz, 2 H), 6.70 (d, J = 8.2 Hz, 2 H), 4.52 (q, J = 5.9
Hz, 1 H), 4.40–4.05 (m, 5 H), 3.55 (s, 3 H), 3.00 (t, J = 5.9 Hz, 1 H),
2.91 (mc, 1 H), 2.84–2.69 (m, 2 H), 2.54 (mc, 1 H), 2.04 (mc, 2 H),
1.86 (mc, 1 H), 1.70 (mc, 1 H), 1.50–1.25 (m, 2 H).
[ ]D20 –10.6 (c = 2, CHCl3).
IR (Si, Film): 3320br, 3021m, 2955m, 1782vs, 1718vs, 1655vs,
1515w, 1516vs, 1350m, 1221vs, 1167vs, 1106m, 1033w, 972w,
866w, 828w cm–1.
1H NMR (CDCl3, 250 MHz): = 7.75 (d, J = 7.4 Hz, 2 H), 7.57 (d,
J = 7.6 Hz, 2 H), 7.39 (dd, J = 7.0, 7.0 Hz, 2 H), 7.30 (ddd, J = 7.4,
7.4, 1.2 Hz, 2 H), 7.15–7.02 (m, 2 H), 6.91 (d, J = 8.3 Hz, 2 H), 6.13
(br. d, J = 6.9 Hz, 1 H), 5.50–5.35 (m, 1 H), 4.52 (quint., J = 6.7 Hz,
1 H), 4.38 (d, J = 7.1 Hz, 2 H), 4.32–4.22 (m, 1 H), 4.20 (t, J = 6.9
Hz, 1 H), 3.57 (s, 3 H), 3.45 (s, 2 H), 3.43 (s, 2 H), 3.13–2.84 (m, 2
H), 2.79 (t, J = 5.7 Hz, 1 H), 2.71 (mc, 1 H), 2.59–2.40 (m, 1 H),
2.24–2.04 (m, 2 H), 1.90–1.52 (m, 4 H), 1.32 (s, 9 H), 0.95 (s, 3 H),
0.94 (s, 3 H).
13C NMR (MeOH-d4, J-mod, 62.5 MHz): = 175.3q, 173.8q,
158.0q, 157.3q, 145.2q, 142.6q, 131.3t, 129.2q, 128.8t, 128.2t,
126.2t, 126.1t, 120.9t, 116.2t, 75.4t, 68.0s, 58.0, 55.7, 54.7, 52.2,
48.4, 44.3, 42.7, 41.9, 39.7, 39.6, 38.7, 38.6.
MS (EI, 70 eV, 20 °C): m/z (%) = 530, 486, 429 (M dibenzoful-
ven
OCH3), 414 (M – fluorenylmethoxycarbonyl), 397, 345
(11.6), 282, 255 (47.5; Bic-Oxalat), 223 (51.5; Bic), 136 [100.0;
H2N–CH–CH2(C6H4OH)], 107 (11.2).
13C NMR (CDCl3, 62.5 MHz): = 173.9q, 170.1q, 155.7q, 154.5q,
143.82q, 143.78q, 141.3q, 131.2q, 129.7t, 127.7t, 127.1t, 125.0t,
124.3t, 120.0t, 109.0q, 78.3, 72.1, 72.0, 67.1, 65.8, 56.6, 52.8, 52.4,
51.8, 47.1, 42.8, 39.8, 39.1, 38.5, 37.2, 30.0s, 28.8p, 22.5p.
MS (FAB, 7 kV, 3 mA): m/z = 585.3 (M - oxalate), 412.3, 179.1.
Anal. Calcd for C36H34N2O9: C, 67.70; H, 5.37; N, 4.39. Found: C,
67.52; H, 5.68; N, 4.33.
MS (FAB, 20 kV, 2 A, glycerol-matrix): m/z = 725.5 (M), 277.2,
179.1 (dibenzo-fulven + H).
Acknowledgement
We thank Schering AG (Berlin) for providing compound 7, and the
‘Fonds der Chemischen Industrie’ and the Graduiertenkolleg ‘Che-
mische und biologische Synthese von Wirkstoffen’ of the Universi-
ty of Frankfurt/Main for granting scholarships to O.L.
Anal. Calcd for C43H52N2O8: C, 71.25; H, 7.23; N, 3.86. Found: C,
70.85; H, 7.60; N, 4.01.
Methyl-(1S,2R,3aS,5R,6aR)-2-{[(2S)-2-{[(9H-Fluoren-9-yl-me-
thoxy)-carbonyl]-amino}-3-(4-hydroxy-phenyl)propanoyl]-
amino}-5-hydroxyoctahydro-1-pentalenoate (11)
References
Compound 10 (362 mg, 0.50 mmol) was stirred for 4.5 h at 22 °C in
a mixture of TFA (9 mL), H2O (0.5 mL) and Et3SiH (0.5 mL). The
mixture was concentrated under reduced pressure and diluted with
EtOH (20 mL). Silica gel (1 g) was added and the mixture was
stirred at 22 °C for 1 h, filtered and evaporated under reduced pres-
sure. Chromatography (Et2O–hexane–MeOH, 4:1:0.05) furnished
diol 11 (212 mg, 72%) as a colorless amorphous solid; Rf 0.43
(Et2O–hexane–MeOH, 4:1:0.05).
(1) (a) Kase, M.; Kaneko, M.; Yamada, K. J. Antibiot. 1987, 40,
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[ ]D20 –11.0 (c = 2, CHCl3).
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(5) Cispentacin = 2-aminocyclopentanecarboxylic acid (2-
ACPC), for a related approach using trans-4-hydroxy-
proline as a template see: Arasappan, A.; Chen, K. X.;
1H NMR (MeOH-d4, 250 MHz): = 7.76 (d, J = 7.6, 2 H), 7.58 (d,
J = 7.1, 2 H), 7.37 (t, J = 7.4, 2 H), 7.28 (dddd, J = 7.4, 7.4, 3.3, 1.2,
2 H), 7.04 (d, J = 8.0, 2 H), 6.70 (d, J = 8.5, 2 H), 4.52 (q, J = 6.0,
1 H), 4.29 (mc, 3 H), 4.13 (mc, 2 H), 3.54 (s, 3 H), 3.35 (s, 2 H), 2.99
(t, J = 6.1, 1 H), 2.91 (m, 1 H), 2.83–2.66 (m, 2 H), 2.52 (mc, 1 H),
2.02 (mc, 2 H), 1.86 (mc, 1 H), 1.69 (mc, 1 H), 1.40 (mc, 1 H), 1.33
(mc, 1 H).
Synthesis 2002, No. 14, 2091–2095 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis and Conformational Analysis of a Novel Ansadipeptide
2095
Njoroge, F. G.; Parekh, T. N.; Girijavallabhan, V. J. Org.
Chem. 2002, 67, 3923.
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(8) See for example: (a) Hanessian, S.; McNaughton-Smith, G.;
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(9) See for example: (a) Baures, P. W.; Ojala, W. H.; Gleason,
W. B.; Johnson, R. L. J. Pept. Res. 1997, 50, 1. (b) Nagai,
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(10) Kutscher, B.; Bernd, M.; Beckers, T.; Polymeropulos, E. E.;
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Angew. Chem. 1997, 109, 2240.
Synthesis 2002, No. 14, 2091–2095 ISSN 0039-7881 © Thieme Stuttgart · New York