Straightforward syntheses of furanomycin derivatives and their biological evaluation

Article abstract of DOI:10.1016/S0968-0896(02)00317-6

Several types of furanomycin analogues were synthesized and investigated with respect to their antibacterial activity. Two different synthetic pathways were developed, based on aldol reactions/ring closing metathesis and an ester enolate Claisen rearrangement. Only the natural product and its desmethyl derivative showed antibacterial activity, pointing towards a narrow structure-activity relationship.

Full text of DOI:10.1016/S0968-0896(02)00317-6

Bioorganic & Medicinal Chemistry 10 (2002) 3905–3913
Straightforward Syntheses of Furanomycin Derivatives and
their Biological Evaluation
Uli Kazmaier,a,* Saskia Pahler,a Rainer Endermann,b Dieter Habich,b
Hein-Peter Krollb and Bernd Riedlb
aInstitut fur Organische Chemie, Universitat des Saarlandes, Im Stadtwald, Geb. 23.2, 66123 Saarbrucken, Germany
¨
¨
¨
bBayer AG, Pharma Research, 42096 Wuppertal, Germany
Received 14May 2002; revised 8 July 2002; accepted 18 July 2002
Abstract—Several types of furanomycin analogues were synthesized and investigated with respect to their antibacterial activity.
Two different synthetic pathways were developed, based on aldol reactions/ring closing metathesis and an ester enolate Claisen
rearrangement. Only the natural product and its desmethyl derivative showed antibacterial activity, pointing towards a narrow
structure–activity relationship.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
acetate and one propionate subunit.4 The oxygen atom
is introduced via epoxidation and the furane ring is
formed by an intramolecular epoxide opening.5
In 1967, Katagiri et al. observed that metabolites of the
fungus Streptomyces threomyceticus L-803 inhibit the
growing of Coliphage T2.1 The active compound was
isolated from the fermentation broth and was called fur-
anomycin (1). Subsequent biological studies indicated that
this unusual amino acid suppresses the growing of several
types of micro-organisms such as Echerichia coli, Bacillus
subtilis and several Shigella- and Salmonella strains. The
absolute configuration was determined as aS,2R,5S via
synthesis of furanomycin starting from glucose,2 and by
an X-ray structure of the N-acetyl derivative.3
The antibiotic activity of furanomycin results from an
incorporation of this amino acid into bacterial proteines
instead of isoleucine.6 Therefore their biological activity
is reduced in the presence of isoleucine.1 Investigations
in E. coli indicated that furanomycin hampers the for-
mation of isoleucyl-t-RNA, while other aminoacyl-
t-RNA are not affected.7 Obviously isoleucyl-t-RNA
synthetase accepts 1 as a substrate besides isoleucine,
which explains the incorporation of 1 into peptides and
proteins. This fact is quite surprising, because t-RNA-
synthetases in general show a high substrate specificity.
NMR studies reveal that the conformation of the
enzyme bound furanomycin is very similar to the iso-
leucine analogue, although the structure of these two
amino acids is different.8 The d-methyl group of the Ile
plays a dominant role for substrate recognition and the
differentiation between Ile, Leu and Val. Probably the
5-methyl group of 1 fits into the same binding pocket of
the enzyme. The mechanism of action is highly inter-
esting from a pharmaceutical point of view, and there-
fore several synthetic approaches towards this
antibiotic were developed. Most syntheses are starting
from carbohydrates,9 other approaches are using tar-
taric acid,10 serine,11 or furanes,12 giving rise to 1 in
8–20 steps.
Labeling experiments indicated that furanomycin is
formed via a polyketide pathway starting from two
*Corresponding author. Tel.: +49-681-3023409; fax: +49-681-3022409;
e-mail: u.kazmaier@mx.uni-sb.de
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00317-6

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U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
We were interested to see which structural parameters
are definitely necessary for biological activity and which
ones can be removed or modified. Therefore, our aim
was to develop straightforward protocols towards deri-
vatives without the 5-methyl group (norfuranomycin 2)
which is known to be also biologically active,13 as well
as the corresponding carba analogue (6) and hydro-
genated products. Further derivatives should bear the
methyl group at other positions (3–5), including the
a position. As far as possible, we focused on a diastero-
selective synthesis of the correct a,2 stereorelationship,
without controlling the absolute configuration.
Scheme 1. Retrosynthetic analysis of furanomycin derivatives.
Results and Discussion
An overview over the synthetic steps carried out
towards norfuranomycin and the a-methylated deriva-
tive is given in Scheme 2.
Boc-protected t-butylesters were chosen as starting
materials for an easy simultaneous deprotection at the
end of the synthesis. For the synthesis of norfur-
anomycin 2 the corresponding glycine ester was reacted
in an aldol reaction with crotonaldehyde giving rise to 7
as a 1:1 diastereomeric mixture in 71% yield. The yield
could be increased to 85% by using the titanium eno-
late, while the anti product was formed preferentially
under these conditions (syn/anti 1:2). The subsequent
We decided to use the ring closing metathesis (RCM)
for the construction of the dihydrofurane ring (Scheme
1). The required substrate A for the RCM should be
accessible via O-allylation of b-hydroxyamino acid B,
generated by aldol addition of a suitable protected
amino acid derivative C (PG: protecting group) and an
a,b-unsaturated aldehyde.
Scheme 2. Synthesis of 2,3 and the saturated derivatives 10. Reagents and conditions: (a) 1. 2.5 equiv LDA, THF,ꢀ78 ꢁC; 2. 1.5 equiv TiCl(OiPr)3.
(b) 3 equiv crotonaldehyde, THF,ꢀ78 ꢁC, 3 h. (c) 1.5 equiv Allyl ethyl carbonate, 2.5 mol% (allylPdCl)2, 11 mol% PPh3, 50 ꢁC, 3 d. (d) 2.5 mol%
ꢁ
(Cy3P)2Cl2Ru=CHPh, CH2Cl2, 4 0 C, 16 h. (e) 4M HCl/ dioxane, 16 h. (f) H 2, Pd/C, CH3OH, 12 h. (g) 1. 2.5 equiv LDA, THF,ꢀ78 ꢁC, 2. 3 equiv
crotonal-dehyde, THF,ꢀ78 ꢁC, 3 h. (h) 1.3 equiv KOtBu, 2 equiv allyl bromide, DMF, 0 ꢁC.

U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
3907
Scheme 3. Synthesis of 4 and 5. Reagents and conditions: (a) 1. 2.5 equiv LDA, THF,ꢀ78 ꢁC; 2. 1.5 equiv TiCl(OiPr)3. (b) 3 equiv methacrolein,
ꢁ
THF,ꢀ78 ꢁC, 3 h. (c) 1.3 equiv KOtBu, 2 equiv allyl bromide, DMF, 0 ꢁC. (d) 2.5 mol% (Cy3P)2Cl2Ru=CHPh, CH2Cl2, 4 0 C, 3 d. (e) 4M HCl/
dioxane, 4h. (f) 1. 2.5 equiv LDA, THF, ꢀ78 ꢁC, 2. 3 equiv acrolein, THF,ꢀ78 ꢁC, 3 h. (g) 1.3 equiv KOtBu, 2 equiv methallyl bromide, DMF, 0 ꢁC.
O-allylation was carried out under very mild conditions
using a palladium catalyzed version.14 Ring closing
metathesis using Grubb’s catalyst15 provided 9 in excel-
lent yield as a mixture of diastereomers, which could be
easily separated by flash chromatography. Deprotection
provided the diastereomerically pure norfuranomycins
(2), while subsequent catalytic hydrogenation gave rise to
the saturated derivatives syn- and anti-10. The syn-/anti-
configuration was determined by comparison of the
NMR data of 10 with those of natural norfuranomycin.
The O-allylation worked well, but the yield in the RCM
was even lower as in the previous case. Interestingly, the
cyclization products were formed as a syn/anti mixture
of 2.5:1, while the aldol reaction provided a 1:1 mixture.
Obviously, the syn stereoisomer gave a higher yield in
the RCM. As usual the isomers could be separated at
this stage. A comparable acid sensitivity was found also
with these derivatives 19, and the deprotected amino
acids 5 had to be investigated as crude product.
For the synthesis of cyclopentenylglycine (6), which is
also known as an isoleucine-antagonist,16 we chose
another strategy. Cyclopentenylglycine was obtained by
a modified version of the ester enolate Claisen rearran-
gement, developed in our laboratory17 (Scheme 4).
The a-methylated derivative 3 was obtained by the same
protocol. The diastereomers could be separated on the
aldol stage, and only the syn product 11 was converted
further. In this case, the syn-configuration was deter-
mined by X-ray structure analysis (s. supplementary
material). The palladium catalyzed allylation provided
syn-12 in 52% yield, while an allylation with allyl bro-
mide in the presence of potassium tert-butylate resulted
in a much higher yield. RCM and deprotection gave
syn-3 in high yield.
Coupling of cyclopentenol with Boc-glycine gave rise to
ester 20,18 which was subjected to a chelate Claisen
rearrangement. Deprotonation with LDA occurs first at
the acidic amide functionality, while a second equivalent
base generates the ester enolate. Addition of zinc chloride
results in the formation of a chelated enolate, which shows
an increased stability towards decomposition. Therefore,
the enolates can be warmed up to room temperature,
conditions under which a Claisen rearrangement occurs,
giving rise to protected cyclopentenyl glycine 21 in
excellent yield. In principle, only the Boc-protecting
groups had to be removed to obtain the target amino
acid 6. Unfortunately, in contrast to the furane deriva-
tives, the diastereomers (syn/anti 8:2) could not be
separated at this stage. Therefore, the isomeric mixture of
21 was converted into the corresponding iodolactones19
syn- and anti-22, which could be separated via flash
chromatography. Cleavage of the iodolactones with zinc
in ethanol provided the diastereomerically pure cyclo-
pentenyl glycine derivatives 21, which were deprotected
towards the required amino acids syn- and anti-6. The
hydrogenated product 23 was directly obtained from 21.
The 3- and 4-methylated derivatives 4 and 5 were pre-
pared in analogy to 2 and 3 (Scheme 3). Aldol addition
using 2-methacroleine provided 14 in high yield (syn/
anti 1:1.4). Both allylation protocols were suitable for
the conversion into 15, while allylbromide (88% yield)
was superior to the palladium catalyzed version (70%
yield). In contrast to the unbranched furane rings, the
RCM became problematic with the substituted deriva-
tives. The yield of 46% could not be increased by pro-
longed reaction times (7 days) or higher temperatures
(60 ꢁC). The deprotection of 16 was also problematic.
Under the acidic cleaving conditions decomposition was
observed and we were not able to obtain analytically
pure 4. The crude product was nevertheless subjected to
biological evaluation.
The situation with 5 was comparable. Our first attempt
started from 7, which was allylated with methallylbromide
(86% yield). The yield in the subsequent RCM could
not be increased to more than 6%. Therefore, we deci-
ded to use acroleine in the aldol step, although acroleine
has a much higher tendency to polymerisation. This could
explain the lower yield of 17 (syn/anti 1:1) in the first step.
Biological tests
The growth inhibitory–activity of the furanomycin
derivatives against several microorganisms was eval-
uated (Table 1). Furanomycin was used as a reference.
The results obtained served to see general tendencies in

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U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
Table 1. Growth inhibition of furanomycin derivatives against eubacteria (MIC determination [mg/mL])
Derivative
Structure
Staphylococcus
aureus 133
Staphylococcus
aureus 44
Proteus
vulgaris 1017
Klebsiella
pneumoniae 8085
Escherichia
coli N.
Escherichia
coli A261
1
8
8
>32
>32
2
4
2
3
416
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
4
>32
>32
>32
>32
>32
5
6
7
>32
>32
>32
>32
>32
—
>32
>32
>32
>32
—
>32
>32
—
>32
>32
—
8
9
>32
>32
—
—
—
—
—
—
—
—
—
the structure–activity relationship. Removal of the
methyl group (norfuranomycin) had no significant effect
on the activity versus S. aureus, but versus E. coli.
Obviously, this methyl group is not absolutely necessary
for the biological activity. Variations of the position of
the methyl group abolished activity. Replacing the oxy-
gen in the dihydrofurane ring by carbon also resulted in
inactive derivatives.
THF was distilled from sodium benzophenone, di-
chloromethane and diisopropylamine from calcium
hydride. LDA solutions were prepared from freshly
distilled diisopropylamine and commercially available
n-butyllithium solution (15% in hexane) in THF at
ꢀ20 ꢁC directly before use. The starting materials and
the products were purified by flash chromatography on
silica gel (32–63 mm). Mixtures of ethyl acetate and
hexane were used as eluents. TLC: commercially pre-
coated Polygram# SIL-G/UV 254plates (Macherey-
Nagel). Visualization was accomplished with UV light,
Experimental
iodine, and potassium permanganate solution. 1H and 13
C
All reactions were carried out in oven-dried glassware
(100 ꢁC) under argon. All solvents were dried before use.
NMR: Bruker AC-300 spectrometer. Diastereomeric
ratios were determined by NMR and analytical HPLC

U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
3909
Scheme 4. Synthesis of cyclopentenylglycine and derivatives. Reagents and conditions: (a) 1. 2.5 equiv LDA, 1.2 equiv ZnCl2, THF,ꢀ78 ꢁC ! rt.
(b) 1.5 equiv KI, 1.3 equiv I2, 1.1 equiv NaHCO3, Et2O, H2O, rt. (c) 1.3 equiv Zn, H2O, HOAc, THF, rt. (d) 4M HCl/dioxane, 5 h. (e) H 2, Pd/C,
CH3OH, 6 h.
General procedure for ring closing metatheses (RCM)
using a Knauer Eurosphere column (250 ꢂ 4mm, Si80, 5
mm, flow: 2 mL/min) and a Knauer UV detector.
Grubbs catalyst (0.2 mmol) was added to 10 mmol of
the O-allylated product in 20 mL of dichloromethane.
The dark purple solution was refluxed overnight. The
solvent was evaporated, and the crude product was
purified by flash chromatography.
General procedure for aldol reactions
In a typical experiment a solution of 25 mmol of LDA
in 50 mL of anhydrous THF was added slowly at
ꢀ78 ꢁC under argon to a solution of 10 mmol of
N-protected amino acid ester in 30 mL of THF. In gen-
eral, a pale yellow solution was formed. After 10 min a
solution of 30 mmol of the aldehyde in 45 mL of THF
was added. After 3 h at ꢀ78 ꢁC the reaction was quen-
ched with 1N KHSO4 solution . The mixture was dilu-
ted with diethyl ether and was allowed to warm to rt.
H2O was added and the layers were separated, the aqu-
eous phase was extracted twice with diethyl ether. The
combined organic extracts were washed with brine,
dried over Na2SO4, and the solvent was evaporated.
The crude aldol product was purified by flash chroma-
tography.
General procedure for deprotection
A 4M HCl (5 mL) solution in dioxane was added to 1
mmol of the metathesis product at 0 ꢁC. The mixture
was stirred at this temperature until TLC showed com-
plete removal of the protecting groups. The solvent was
evaporated in vacuum and the crude product was dis-
solved in ethyl acetate. Ether was added to precipitate
the amino acid as its hydrochloride. The precipitate was
separated by centrifugation and dried in vacuum, before
it was used for the biological studies.
Minimal inhibitory concentration (MIC) determination.
MIC values were generated using a microdilution tech-
nique. A vitamin (thiamine, nicotinic acid, biotin) sup-
plemented minimal medium containing 1% glucose and
all amino acids except leucine and isoleucine was used.
MIC was read as the lowest concentration of compound
that completely inhibited bacterial growth.
General procedure for palladium catalyzed O-allylations
Allyl (0.2 mmol) palladium chloride dimer was added to
a solution of 1 mmol triphenylphosphine and 15 mmol
of allyl methyl carbonate in 15 mL of THF. The clear
yellow solution was stirred for 15 min at rt, before 10
mmol of the aldol product was added in 30 mL of THF.
The mixture was warmed to rt overnight. The solvent
was evaporated, and the crude product was purified by
flash chromatography.
tert-Butyl
2-(tert-butyloxycarbonyl)amino-3-hydroxy-
hexenoate (7). Ester 7 was obtained by a slightly mod-
ified version of the general procedure for aldol reaction
(5 mmol scale). 6 mmol of ClTi(OiPr)3 were added to
the lithium enolate, providing a dark red solution of the
corresponding titanium enolate, which was reacted with
crotonaldehyde. The aldol product was obtained after
flash chromatography (hexanes/ethyl acetate, 85:15) as
a colorless oil and a mixture of the diastereomers (syn/
anti 1:2) in 85% yield (1.28 g, 4.2 mmol). 1H NMR
(300 MHz, CDCl3): d=1.41 (s, 9H), 1.44 (s, 9H), 1.67
(d, 3H, J=6.4 Hz), 2.35 (s, 1H), 4.17 (m, 1H), 4.36 (m,
0.3H, syn), 4.41 (m, 0.7H, anti), 5.19 (s, 1H), 5.46 (ddq,
1H, J=15.4, 7.2, 1.5 Hz), 5.70 (dqd, 1H, J=15.3, 6.6,
1.6 Hz). 13C NMR (75 MHz, CDCl3): d=17.7 (q), 28.0,
28.1, 28.2, 28.5 (q), 58.5 (d, syn), 59.1 (d, anti), 73.1 (d,
General procedure for O-allylations using allyl bromide
10 mmol of the aldol product and 20 mmol of the cor-
responding allyl bromide were dissolved in 30 mL DMF
at 0 ꢁC. Subsequently 13 mmol of potassium t-butylat
were added and the yellow solution was warmed to rt
overnight. H2O was added and after separation of the
layers the aqueous layer was extracted three times with
ethyl acetate. The combined organic extracts were
washed twice with H2O, dried over Na2SO4, and the
solvent was evaporated. The crude product was purified
by flash chromatography.

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U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
mmol) as a colorless solid, mp 210–212 ꢁC. H NMR
1
anti), 74.0 (d, syn), 78.9 (s), 82.3 (s, anti), 82.7 (s, syn),
128.4, 128.8 (d), 128.9, 129.5 (d), 156.2 (s), 169.9 (s).
Anal. calcd for C15H27NO5 (301.38): C, 59.78; H, 9.03;
N, 4.65. Found: C, 59.56; H, 8.91; N, 4.62.
(300 MHz, CD3OD): d=4.21 (m, 1H), 4.58 (m, 1H),
4.68 (m, 1H), 5.29 (m, 1H), 5.70 (m, 1H), 6.21 (m, 1H).
13C NMR (75 MHz, CD3OD): d=57.0 (d), 77.4(t), 84.9
(d), 123.8 (d), 133.0 (d), 168.7 (s). Anal. calcd for
C6H10NO3Cl (179.60): C, 40.12; H, 5.61; N, 7.80.
Found: C, 40.07; H, 5.42; N, 7.82.
tert-Butyl
2-(tert-butyloxycarbonyl)amino-3-allyloxy-
hexenoate (8). Allylation product 8 was obtained from
7 (2.5 g, 8.3 mmol) following the general procedure for
palladium catalyzed allylations. The crude product was
purified by flash chromatography (hexanes/ethyl ace-
tate, 98:2) giving rise to 8 as a colorless oil and a mix-
ture of the diastereomers (syn/anti 1:2) in 55% yield
(1.46 g, 4.3 mmol). 1H NMR (300 MHz, CDCl3):
d=1.41 (s, 9H), 1.43 (s, 9H), 1.69 (dd, 3H, J=6.4, 1.2
Hz), 3.72 (dd, 1H, J=12.9, 5.9 Hz), 3.94(ddt, 1H,
J=12.9, 5.9, 1.0 Hz), 4.13–4.21 (m, 2H), 5.13 (dd, 1H,
J=10.3, 1.6 Hz), 5.14(d, 1H, J=15.4Hz), 5.20 (dd, 1H,
J=17.2, 1.6 Hz), 5.36 (d, 0.3H, J=7.8 Hz, syn), 5.39 (d,
0.7H, J=7.8 Hz, anti), 5.70 (dq, 1H,J=15.4, 6.4 Hz),
5.79 (dddd, 1H, J=17.0, 11.3, 11.1, 10.9 Hz). 13C NMR
(75 MHz, CDCl3): d=17.5 (q), 27.8, 28.1 (q), 58.1 (d),
68.9 (d), 79.3 (d), 80.2 (s), 81.4(s), 116.5 (d), 127.1 (d),
130.5 (d), 134.3 (d), 155.8 (s), 169.5 (s). Anal. calcd for
C18H31NO5 (341.45): C, 63.32; H, 9.15; N, 4.10. Found:
C, 63.50; H, 9.09; N, 3.99.
syn-Dihydronorfuranomycin hydrochloride (syn-10).
Amino acid syn-2 (30 mg, 0.17 mmol) was dissolved in
5 mL of methanol before Pd/C (10 mg) was added. The
hydrogenation was carried out in a Parr apparatus at 40
psi H2. After filtration of the catalyst and evaporation
of the solvent syn-10 was obtained as a colorless solid,
mp 216 ꢁC (decomp.). 1H NMR (300 MHz, CD3OD/
D2O): d=1.75 (m, 1H), 1.85–1.91 (m, 3H), 3.73 (dd, 1H,
J=14.5, 7.7 Hz), 3.84 (dd, 1H, J=14.0, 6.2 Hz), 3.92 (d,
1H, J=4.1 Hz), 4.31 (m, 1H). 13C NMR (75 MHz,
CD3OD/D2O): d=26.1, 26.2 (t), 57.4(d), 70.0 (t), 77.6
(d), 172.4(s). HRMS (FAB) calcd for C 6H12NO3
[M++H] 146.1115, found 146.1108.
anti-Dihydronorfuranomycin hydrochloride (anti-10).
Amino acid anti-10 was obtained according to syn-10
in 93% yield as a colorless solid, mp 226 ꢁC. H NMR
1
(300 MHz, D2O): d=1.74–1.90 (m, 3H), 2.03 (m, 1H),
3.52 (d, 1H, J=6.0 Hz) 3.73 (m, 2H), 4.15 (dt, 1H,
J=6.9 Hz). 13C NMR (75 MHz, D2O): d=26.1, 29.3 (t),
58.6 (d), 69.5 (t), 78.1 (d), 173.2 (s). HRMS (FAB) calcd
for C6H12NO3 [M++H] 146.1115, found 146.1098.
tert-Butyl N-(tert-butyloxycarbonyl)-2-(20,50-dihydrofur-
anyl)-glycinate (9). Cyclization product 9 was obtained
from 8 (3.21 g, 9.4mmol) following the general proce-
dure for ring closing metatheses in 94% yield (2.63 g,
8.8 mmol). The diastereomers could be separated by
flash chromatography (hexanes/ethyl acetate, 96:4). syn-
9: colorless oil. 1H NMR (300 MHz, CDCl3): d=1.39 (s,
9H), 1.46 (s, 9H), 4.32 (dd, 1H, J=9.2, 2.2 Hz), 4.56 (m,
1H), 4.65 (m, 1H), 5.06 (d, 1H, J=9.2 Hz), 5.22 (m, 1H),
5.73 (m, 1H), 5.93 (dd, 1H, J=6.2, 1.9 Hz). 13C NMR
(75 MHz, CDCl3): d=27.6, 27.8, 28.0 (q), 57.1 (d), 76.2
(t), 79.3 (s), 81.9 (s), 86.9 (d), 126.2 (d), 128.2 (d), 155.5 (s),
169.2, (s). Anal. calcd for C15H25NO5 (299.37): C, 60.18;
H, 8.42; N, 4.68. Found: C, 60.21; H, 8.28; N, 4.63.
tert-Butyl 2-(tert-butyloxycarbonyl)amino-3-hydroxy-2-
methyl-hexenoate (11). Ester 11 was obtained from 30
mmol (7.36 g) Boc-Ala-OtBu following the general pro-
cedure for aldol reaction as a 1:1 diasteromeric mixture
in 87% yield (8.27 g, 26.2 mmol). The diastereomers
could be separated by flash chromatography (hexanes/
ethyl acetate, 9:1).
syn-11. Colorless solid, mp 103 ꢁC. 1H NMR (300 MHz,
CDCl3): d=1.37 (s, 3H), 1.42, 1.44 (s, 18H), 1.69 (dd,
3H, J=6.6, 1.4Hz), 4.23 (d, 1H, J=7.4Hz), 5.07 (s,
1H), 5.45 (ddd, 1H, J=16.0, 7.4, 1.6 Hz), 5.71 (dd, 1H,
J=15.4, 6.6 Hz). 13C NMR (75 MHz, CDCl3): d=17.6
(q), 20.4(q), 27.7, 28.1 (q), 63.3 (s), 70.6 (d), 79.7 (s),
81.8 (s), 128.1 (d), 129.8 (d), 155.6 (s), 171.5 (s). Anal.
calcd for C16H29NO5 (315.41): C, 60.93; H, 9.27; N,
4.44. Found: C, 60.96; H, 9.31; N, 4.32.
ꢁ
1
anti-9. Colorless solid, mp. 63 C. H NMR (300 MHz,
CDCl3): d=1.31 (s, 18H), 4.38 (dd, 1H, J=9.2, 3.3 Hz),
4.56–4.61 (m, 2H), 5.05 (m 1H), 5.18 (d, 1H, J=8.1 Hz),
5.73 (d, 1H, J=4.4 Hz), 6.00 (d, 1H, J=5.1 Hz). 13C
NMR (75 MHz, CDCl3): d=27.6, 27.7, 28.1 (q), 57.3
(d), 75.8 (t), 79.5 (s), 81.8 (s), 86.5 (d), 125.4(d), 128.8
(d), 155.2 (s), 168.8 (s). HRMS (FAB) calcd for
C15H26NO5 [M++H] 300.1811, found 300.1828.
anti-11. Colorless oil. 1H NMR (300 MHz, CDCl3):
d=1.40, 1.41, 1.43 (s, 18H), 1.51 (s, 3H), 1.66 (dd, 3H,
J=6.5, 0.6 Hz), 4.35 (d, 1H, J=6.7 Hz), 4.89 (s, 1H),
5.37 (ddd, 1H, J=16.0, 6.7, 1.5 Hz), 5.69 (ddd, 1H,
J=16.3, 6.5, 1.0 Hz). 13C NMR (75 MHz, CDCl3):
d=17.5 (q), 20.8 (q), 27.6, 28.0, 28.1, 28.4(q), 60.1 (s),
74.2 (d), 79.9 (s), 82.5 (s), 127.6 (d), 128.4, 128.6 (d),
155.8 (s), 172.1 (s). HRMS (FAB) calcd for C16H30NO5
[M++H] 316.2124, found 316.2145.
syn-Norfuranomycin hydrochloride (syn-2). Deprotection
of syn-9 (300 mg, 1.0 mmol) according to the general
procedure provided syn-2 in 34% yield (62 mg, 0.34
mmol) as a colorless solid, mp 190–200 ꢁC. H NMR
1
(300MHz, CD3OD): d=4.14 (m, 1H), 4.59–4.77 (m, 2H),
5.33 (m, 1H), 5.88 (m, 1H), 6.22 (m, 1H). 13C NMR
(75 MHz, CD3OD): d=62.2 (d), 77.4(t), 85.3 (d), 125.9
(d), 132.8 (d). Anal. calcd for C6H10NO3Cl (179.60): C,
40.12; H, 5.61; N, 7.80. Found: C, 40.33; H, 5.38; N, 7.79.
tert-Butyl syn-2-(tert-butyloxycarbonyl)amino-3-allyloxy-
2-methyl-hexenoate (syn-12). Allylation product syn-12
was obtained from syn-11 (2.86 g, 9.0 mmol) following
the general procedure for O-allylations with allylbromide.
anti-Norfuranomycin hydrochloride (anti-2). Deprotection
of anti-9 (256 mg, 0.8 mmol) according to the general
procedure provided anti-2 in 55% yield (85 mg, 0.47

U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
3911
The crude product was purified by flash chromatography
(hexanes/ethyl acetate, 98:2) giving rise to syn-12 as a col-
orless oil in 82% yield (2.63 g, 7.4mmol). 1H NMR
(300MHz, CDCl3): d=1.42 (s, 18H), 1.43 (s, 3H), 1.72
(dd, 3H, J=6.4, 1.5 Hz), 3.72 (dd, 1H, J=12.8, 6.0 Hz),
3.83 (d, 1H, J=8.8), 3.99 (m, 1H), 5.14(m, 1H), 5.24(m,
1H), 5.25–5.34(m, 2H), 5.69 (dq, 1H, J=15.2, 6.4Hz),
5.82 (m, 1H). 13C NMR (75 MHz, CDCl3): d=17.8 (q),
18.4(q), 27.9, 28.4(q), 63.2 (s), 69.0 (t), 79.2 (s), 81.1 (s),
84.3 (d), 116.8 (t), 125.7 (d), 133.1 (d), 134.5 (d), 155.5 (s),
171.5 (s). Anal. calcd for C19H33NO5 (355.47): C, 64.20;
H, 9.36; N, 3.94. Found: C, 64.17; H, 9.43; N, 3.91.
The crude product was purified by flash chromato-
graphy (hexanes/ethyl acetate, 95:5) giving rise to 15 as
a colorless oil in 88% yield (4.34 g, 12.7 mmol). 1H
NMR (300 MHz, CDCl3): d=1.38, 1.39, 1.42, 1.44 (s,
18H), 1.72 (s, 3H), 3.72 (dd, 1H, J=12.5, 6.2 Hz), 3.82
(d, 0.5H, J=7.0 Hz, anti), 4.00 (dd, 1H, J=12.9, 5.1
Hz), 4.11 (d, 0.5H, J=2.6 Hz, syn), 4.31 (dd, 1H,
J=9.5, 3.3 Hz), 4.95–5.05 (m, 3H), 5.11 (dd, 1H,
J=10.3, 1.8 Hz), 5.20 (dt, 1H, J=17.0, 1.8 Hz), 5.80 (m,
1H). 13C NMR (75 MHz, CDCl3): d=17.8, 18.9 (q),
27.9, 28.0, 28.2 (q), 55.62, 55.65 (d), 70.0, 70.3 (t), 79.3,
79.6 (s), 81.7 (s), 81.9, 83.4(d), 113.6 (t), 114.9, 117.0 (t),
134.2 (d), 140.7 (s), 155.8 (s), 169.7 (s). Anal. calcd for
C18H31NO5 (341.45): C, 63.32; H, 9.15; N, 4.10. Found:
C, 63.16; H, 9.15; N, 4.12.
tert-Butyl
syn-N-(tert-butyloxycarbonyl)-2-(20,50-dihy-
drofuranyl)-alaninate (syn-13). Cyclization product syn-
13 was obtained from syn-12 (2.33 g, 6.0 mmol) follow-
ing the general procedure for ring closing metatheses in
98% yield (1.88 g, 6.0 mmol) after flash chromatography
(hexanes/ethyl acetate, 95:5). Colorless solid, mp 60 ꢁC.
1H NMR (300 MHz, CDCl3): d=1.40, 1.44 (s, 18H), 1.43
(s, 3H), 4.64 (m, 2H), 5.03 (m, 1H), 5.17 (s, 1H), 5.76 (m,
1H), 6.00 (m, 1H). 13C NMR (75 MHz, CDCl3): d=21.0
(q), 27.7, 27.9, 28.3 (q), 63.1 (s), 76.3 (t), 79.1 (s), 81.4(s),
89.8 (d), 125.6 (s), 129.0 (s), 154.8 (s), 171.3 (s). Anal.
calcd for C16H27NO5 (313.39): C, 61.32; H, 8.68; N,
4.47. Found: C, 61.28; H, 8.52; N, 4.46.
tert-Butyl N-(tert-butyloxycarbonyl)-2-(20,50-dihydro-3-
methylfuranyl)-glycinate (16). Cyclization product 16
was obtained from 15 (1.70 g, 5.0 mmol) following the
general procedure for ring closing metatheses in 46%
yield (669 mg, 2.1.mmol). The diastereomers could be
separated by flash chromatography (hexane/ethyl ace-
tate, 98:2).
syn-16. Colorless oil. 1H NMR (300 MHz, CDCl3):
d=1.39, 1.42, 1.43, 1.45 (s, 18H), 1.72 (s, 3H), 3.68 (m,
1H), 3.92 (m, 1H), 4.38 (m, 1H), 4.93 (m, 1H), 5.29 (d, 1H,
J=7.7 Hz), 5.51 (m, 1H). 13C NMR (75 MHz, CDCl3):
d=17.2 (q), 27.7, 27.8, 28.0, 28.1 (q), 55.4(d), 75.6 (t), 79.5
(s), 79.3 (s), 89.1 (s), 129.3 (d), 140.8 (s), 155.0 (s), 168.4 (s).
Anal. calcd for C16H27NO5 (313.39): C, 61.32; H, 8.68; N,
4.48. Found: C, 61.42; H, 8.50; N, 4.33.
syn -ꢀ-Methyl-norfuranomycin hydrochloride (syn-3).
Deprotection of syn-13 (940 mg, 3.0 mmol) according
to the general procedure provided syn-3 in 83% yield
(480 mg, 2.5 mmol) as a colorless solid, mp 175 ꢁC. H
1
NMR (300 MHz, CD3OD): d=1.50 (s, 3H), 4.64 (dddd,
1H, J=13.6, 4.4, 2.6, 1.5 Hz), 4.81 (dddd, 1H, J=13.6,
6.2, 2.6, 1.8 Hz), 5.20 (dddd, 1H, J=8.5, 4.4, 2.2, 1.5
Hz), 5.96 (dtd, 1H, J=6.6, 2.6, 1.5 Hz), 6.32 (ddd, 1H,
J=6.2, 3.4, 1.5 Hz). 13C NMR (75 MHz, CD3OD):
d=18.1 (q), 63.7 (s), 77.5 (t), 89.1 (d), 123.8 (d), 133.6
(d), 172.1 (s). HRMS (FAB) calcd for C7H12NO3
[M++H] 158.0817, found 158.0811.
anti-16. Colorless solid, mp 117 ꢁC. 1H NMR (300 MHz,
CDCl3): d=1.38, 1.41, 1.42, 1.43 (s, 18H), 1.71 (s, 3H),
3.75 (m, 1H), 4.08 (m, 1H), 4.30 (d, 1H, J=9.4Hz), 4.97
(m, 1H), 5.07 (d, 1H, J=9.6 Hz), 5.61 (m, 1H). 13C
NMR (75 MHz, CDCl3): d=18.8 (q), 27.7, 27.8, 28.0
(q), 56.4(d), 79.2 (s), 81.5 (s), 83.6 (d), 75.4(t), 128.5
(d), 140.4 (s), 155.5 (s), 169.5, (s). Anal. calcd for
C16H27NO5 (313.39): C, 61.32; H, 8.68; N, 4.48. Found:
C, 61.17; H, 8.75; N, 4.39.
tert-Butyl 2-(tert-butyloxycarbonyl)amino-3-hydroxy-4-
methyl-hexenoate (14). Ester 14 was obtained by a
slightly modified version of the general procedure for
aldol reactions, starting from Boc-Gly-OtBu (2.32 g, 10.0
mmol). ClTi(OiPr)3 (2.74g, 10.5 mmol) was added to the
lithium enolate, followed by methacrolein (0.5mL, 6.0
mmol) after 10 min. 14 was obtained after flash chroma-
tography (hexanes/ethyl acetate, 85:15) as a colorless oil
and a mixture of diastereomers (syn/anti 1:1.4) in 85%
yield (1.54g, 5.1 mmol). 1H NMR (300MHz, CDCl3):
d=1.39, 1.45 (s, 18H), 1.74 (s, 1.2H syn), 1.76 (s, 1.8H
anti), 2.45 (s, 1H), 4.35 (m, 1H), 4.40 (m, 1H), 4.93 (s, 1H),
5.02 (s, 1H), 5.15 (s, 0.6H, anti), 5.41 (s, 0.4H, syn). 13C
NMR (75 MHz, CDCl3): d=13.9, 18.7 (q), 27.7, 27.8,
28.0, 28.02 (q), 56.3, 57.2 (d), 75.2, 76.2 (d), 79.5, 80.0 (s),
82.1, 82.7 (s), 111.9 (t), 143.3, 143.6 (s), 155.8 (s), 169.1,
170.0 (s). Anal. calcd for C15H27NO5 (301.38): C, 59.78;
H, 9.03; N, 4.65. Found: C, 59.44; H, 9.02; N, 4.78.
syn 3-Methyl-norfuranomycin hydrochloride (syn-4).
Deprotection of syn-16 (125 mg, 0.40 mmol) according
to the general procedure provided syn-4 in 45% yield
(28 mg, 0.18 mmol) as a brownish solid. 1H NMR
(300 MHz, CD3OD): d=1.75 (s, 3H), 4.12 (m, 1H),
4.54–4.71 (m, 2H), 5.29 (m, 1H), 5.88 (m, 1H). 13C
NMR (75 MHz, CD3OD): d=17.4(q), 62.6 (d), 77.4(t),
85.3 (d), 125.9 (d), 139.5 (s). HRMS (FAB) calcd for
C7H12NO3 [M++H] 158.0817, found 158.0831.
anti 3-Methyl-norfuranomycin hydrochloride (anti-4).
Deprotection of anti-16 (125 mg, 0.40 mmol) according
to the general procedure provided anti-4 in 52%
1
yield (33 mg, 0.21 mmol) as a brownish solid. H NMR
(300 MHz, CD3OD): d=1.74(s, 3H), .408 (m, 1H),
4.58–4.75 (m, 2H), 5.18 (m, 1H), 5.93 (m, 1H).
13C NMR (75 MHz, CD3OD): d=18.5 (q), 63.3 (d),
77.6 (t), 81.6 (d), 124.9 (d), 139.1 (s). HRMS (FAB)
calcd for C7H12NO3 [M++H] 158.0817, found
158.0803.
tert-Butyl 2-(tert-butyloxycarbonyl)amino-3-allyloxy-4-
methyl-hexenoate (15). Allylation product 15 was
obtained from 14 (4.37 g, 14.0 mmol) following the
general procedure for O-allylations with allylbromide.

3912
U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
tert-Butyl
2-(tert-butyloxycarbonyl)amino-3-hydroxy-
169.0 (s). Anal. calcd for C16H27NO5 (313.39): C, 61.32;
H, 8.68; N, 4.48. Found: C, 61.52; H, 8.72; N, 4.35.
pentenoate (17). Ester 17 was obtained from 30 mmol
(6.94g) Boc-Gly-OtBu following the general procedure
for aldol reaction as a 1:1 diasteromeric mixture in 65%
yield (5.58 g, 19.4mmol). 1H NMR (300 MHz, CDCl3):
d=1.41, 1.43, 1.45 (s, 18H), 2.48 (s, 1H), 4.24 (m, 0.5H,
syn), 4.41 (m, 0.5H, anti), 4.53 (m, 1H), 5.21 (dd, 2H,
J=10.5, 1.3 Hz), 5.21 (m, 1H), 5.33 (dd, 1H, J=17.2,
1.4Hz), 5.77 (ddd, 0.5H, J=16.2, 11.0, 5.3 Hz, anti),
5.88 (ddd, 0.5H, J=17.2, 10.5, 5.3 Hz, syn). 13C NMR
(75 MHz, CDCl3): d=28.0, 28.8 (q), 58.2 (d, syn), 59.0
(d, anti), 73.1 (d, syn), 74.1 (d, anti), 80.5 (s, syn), 81.0 (s,
anti), 82.6 (s, syn), 82.9 (s, anti), 116.6 (t, syn), 117.0 (t,
anti), 135.5 (d, anti), 136.5 (d, syn), 156.1 (s), 168.8 (s,
anti), 169.8 (s, syn). Anal. calcd for C14H25NO5
(287.36): C, 58.52; H, 8.77; N, 4.87. Found: C, 58.46; H,
8.76; N, 4.85.
syn-4-Methyl-norfuranomycin hydrochloride (syn-5).
Deprotection of syn-18 (125 mg, 0.40 mmol) according
to the general procedure provided syn-5 in 37% yield
(24mg, 0.15 mmol) as a dark yellow solid. 1H NMR
(300 MHz, CD3OD): d=1.73 (s, 3H), 4.15 (m, 1H), 4.51
(m, 2H), 5.26 (m, 1H), 5.42 (m, 1H). 13C NMR
(75 MHz, CD3OD): d=12.4(q), 58.6 (d), 77.7 (t), 85.9
(d), 130.3 (d), 139.4(s). HRMS (FAB) calcd for
C7H12NO3 [M++H] 158.0817, found 158.0831.
anti-4-Methyl-norfuranomycin hydrochloride (anti-5).
Deprotection of anti-18 (125 mg, 0.40 mmol) according
to the general procedure provided anti-8 in 52% yield
(33 mg, 0.21 mmol) as a brown solid. 1H NMR
(300 MHz, CD3OD): d=1.72 (s, 3H), 4.19 (m, 1H),
4.42–4.56 (m, 2H), 5.39 (m, 2H). 13C NMR (75 MHz,
CD3OD): d=12.6 (q), 58.9 (d), 77.5 (t), 85.6 (d), 129.9
(d), 139.1 (s). HRMS (FAB) calcd for C7H12NO3
[M++H] 158.0817, found 158.0805.
tert-Butyl 2-(tert-butyloxycarbonyl)amino-3-methallyloxy-
pentenoate (18). Allylation product 18 was obtained
from 17 (1.00 g, 3.5 mmol) following the general proce-
dure for O-allylations with allylbromide. Methallyl-
bromide (940 mg, 7.0 mmol) was used as the allylation
reagent. The crude product was purified by flash chro-
matography (hexanes/ethyl acetate, 98:2) giving rise to
N-(tert-Butyloxycarbonyl)-2-(cyclopent-2-enyl)glycine (21).
A freshly prepared LDA (25 mmol) solution in 5 mL
THF was added to a stirred mixture of allylic ester 2018
(2.41 g, 10 mmol) and zinc chloride (1.64 g, 11 mmol) in
40 mL dry THF at ꢀ78 ꢁC. The mixture was allowed to
warm up to room temperature overnight. The resulting
clear solution was diluted with ether and hydrolyzed
with 1 N hydrochloric acid. After separation of the
aqueous layer the rearrangement product was extracted
twice with 1 N sodium hydroxide solution. Acidification
of the aqueous layer with KHSO4 and re-extraction
with ether gave the desired n-protected amino acid 21 in
excellent yield (2.27 g, 9.4mmol, 94%) as a pale yellow
wax. The diastereomers were separated via the iodo-
lactones 22. Therefore the iodolactones syn- and anti-22
(367 mg, 1 mmol) were dissolved in a mixture of 5 mL
THF, H2O and HOAc (0.1 mL each) at 0 ꢁC. Zinc
powder (111 mg, 1.7 mmol) was added and the mixture
was allowed to warm up to rt. After stirring for 1 h the
mixture was filtered through a plug of Celite. The solu-
tion was washed twice with 0.1 N NaOH, the aqueous
solution was acidified with 1 N HCl and the amino acids
were extracted with EtOAc.
1
18 as a colorless oil in 87% yield (2.97 g, 8.7 mmol). H
NMR (300 MHz, CDCl3): d=.41, 1.44 (s, 18H), 1.67 (s,
1.5H, syn), 1.68 (s, 1.5H, anti), 3.65 (d, 0.5H, J=12.5
Hz), 3.78 (d, 0.5H, J=12.9 Hz), 3.88 (d, 0.5H, J=12.1
Hz), 3.90 (d, 0.5H, J=12.1 Hz), 4.03 (m, 0.5H, anti),
4.20–4.25 (m, 1H, syn), 4.32 (dd, 0.5H, J=8.8, 4.5 Hz,
anti), 4.77–4.91 (m, 2H), 5.18 (m, 1H), 5.26–5.33 (m,
2H), 5.74(m, 1H).
13C NMR (75 MHz, CDCl3):
d=19.3, 19.4(q), 27.8, 28.1 (q), 57.2, 57.8 (d), 72.3, 72.5
(t), 79.3, 80.3 (s), 79.8 (d), 81.6, 81.8 (s), 111.87, 111.93
(t), 118.8 (t), 134.2, 134.3 (d), 141.5 (s), 155.7 (s), 168.9,
169.3 (s). Anal. calcd for C18H31NO5 (341.45): C, 63.32;
H, 9.15; N, 4.10. Found: C, 63.24; H, 9.19; N, 4.03.
tert-Butyl N-(tert-butyloxycarbonyl)-2-(20,50-dihydro-4-
methylfuranyl)-glycinate (19). Cyclization product 19
was obtained from 18 (2.97 g, 8.7 mmol) following the
general procedure for ring closing metatheses in 28%
yield (759 mg, 2.4mmol). The diastereomers could be
separated by flash chromatography (hexanes/ethyl ace-
tate, 96:6).
syn-19. Colorless oil. 1H NMR (300 MHz, CDCl3):
d=1.45 (s, 18H), 1.72 (s, 3H), 4.25 (dd, 1H, J=9.2, 1.8
Hz), 4.41 (m, 2H), 5.07 (d, 1H, J=9.6 Hz), 5.17 (m,
1H), 5.35 (s, 1H). 13C NMR (75 MHz, CDCl3): d=11.9
(q), 27.6, 27.7, 27.8, 27.9, 28.0, 29.4(q), 57.3 (d), 78.7
(t), 79.2 (s), 81.8 (s), 87.5 (d), 120.2 (d), 138.0 (s), 155.5
(s), 169.4(s). Anal. calcd for C 16H27NO5 (313.39): C,
61.32; H, 8.68; N, 4.48. Found: C, 61.22; H, 8.54; N,
4.45.
syn-ꢁ21. 241 mg (1.0 mmol, 100%) colorless solid, mp
1
104 C. H NMR (300 MHz, CDCl3): d=1.36 (s, 9H),
1.58 (m, 1H), 1.90 (m, 1H), 2.29 (m, 2H), 3.12 (m, 1H),
4.22 (d, 1H, J=5.1 Hz), 5.58 (m, 1H), 5.77 (m, 1H). 13C
NMR (75 MHz, CD3OD): d=24.5 (d), 27.9 (q), 31.7
(d), 48.2 (s), 55.8 (d), 79.6 (s), 130.3 (d), 132.9 (d), 155.6
(s), 173.9 (s).
anti-21. Two hundred mg (0. 83 mmol, 83%) pale yel-
low solid, mp 125 ꢁC. 1H NMR (300 MHz, CDCl3):
d=1.42 (s, 9H), 1.70 (m, 1H), 2.09 (m, 1H), 2.34 (m,
2H), 3.31 (m, 1H), 4.32 (dd, 1H, J=8.8, 4.5 Hz), 4.82
(d, 1H, J=8.5 Hz), 5.53 (dd, 1H, J=5.1, 1.5 Hz), 5.96
(dd, 1H, J=5.5, 2.2 Hz). 13C NMR (75 MHz, CD3OD):
d=26.0 (d), 28.0 (q), 32.2 (d), 47.2 (s), 56.0 (d), 80.0 (s),
127.9 (d), 135.5 (d), 155.9 (s), 176.5 (s). HRMS (FAB)
anti-19. Colorless wax. 1H NMR (300 MHz, CDCl3):
d=1.42 (s, 18H), 1.75 (s, 3H), 4.32 (dd, 1H, J=9.2, 3.3
Hz), 4.44 (s, 2H), 5.06 (m, 1H), 5.21 (d, 1H, J=8.1 Hz),
5.32 (s, 1H). 13C NMR (75 MHz, CDCl3): d=12.0 (q),
27.6, 27.7, 27.8, 28.0, 28.1, 29.4(q), 57.6 (d), 78.3 (t),
79.5 (s), 81.4(s), 87.0 (d), 119.4(d), 138.9 (s), 156.0 (s),

U. Kazmaier et al. / Bioorg. Med. Chem. 10 (2002) 3905–3913
3913
calcd for C12H20NO4 [M++H] 242.1392, found
242.1401.
Cyclopentylglycine hydrochloride (23). Amino acid 23
was obtained from 21 (280 mg, 1.1 mmol) via hydro-
genation and subsequent deprotection as a colorless
solid (185 mg, 1.03 mmol, 93%), mp 200 ꢁC
(decomp).1H NMR (300 MHz, CD3OD): d=1.50 (m,
2H), 1.67 (m, 4H), 1.90 (m, 2H), 2.32 (m, 1H), 3.85 (dd,
1H, J=7.4, 2.9 Hz). 13C NMR (75 MHz, CD3OD):
d=25.8, 26.0 (t), 29.90, 29.92 (t), 43.3 (d), 57.6 (d), 171.6
(s). Anal. calcd for C7H14NO2Cl (179.65): C, 46.80; H,
7.85; N, 7.80. Found: C, 46.86; H, 7.86; N, 7.77.
Iodolactones (22). A solution of KI (200 mg, 1.2 mmol),
I2 (250 mg, 1.0 mmol) and NaHCO3 (70 mg, 0.85 mmol)
were dissolved in 2mL water. Amino acid 21 (190 mg,
0.8 mmol) was added in 2 mL of ether. After stirring
overnight, the mixture was diluted with water and ether
(15 mL each) and the layers were separated. The organic
layer was washed with NaS2O3 solution and the solvent
was removed in vacuum. The diastereomers could be
separated by flash chromatography (hexanes/ethyl ace-
tate, 9:1) giving a overall yield of 89% (250 mg, 0.7 mmol).
Acknowledgements
syn-22. Pale yellow solid, mp 159 ꢁC. 1H NMR
(300 MHz, CDCl3): d=1.44 (s, 9H), 1.85 (d, 1H,
J=15.4Hz), 2.26 (m, 2H), 2.46 (m, 1H), 2.98 (m, 1H),
3.77 (m, 1H), 4.40 (m, 1H), 5.19 (m, 1H), 5.33 (m, 1H).
13C NMR (75 MHz, CD3OD): d=27.9 (d), 28.2 (q),
31.5 (t), 35.0 (t), 44.5 (d), 57.8 (d), 81.0 (s), 91.6 (d),
155.3 (s), 174.8 (s). Anal. calcd for C12H18NO4I
(367.18): C, 39.25; H, 4.94; N, 3.81; I 34.56. Found: C,
39.52; H, 5.13; N, 3.82; I 34.83.
We thank the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie for generous
financial support.
References and Notes
1. Katagiri, K.; Tori, K.; Kimura, Y.; Yoshida, T.; Nagasaki,
T.; Minato, H. J. Med. Chem. 1967, 10, 1149.
2. Joullie, M.; Wang, P. C.; Semple, J. E. J. Am. Chem. Soc.
´
1980, 102, 887.
anti-22. Colorless solid, mp 140 ꢁC. 1H NMR (300 MHz,
CDCl3): d=1.44 (s, 9H), 1.77 (m, 1H), 2.02–2.20 (sh,
3H), 3.56 (m, 1H), 4.46 (m, 1H), 4.56 (m, 1H), 5.06 (m,
1H), 5.14(m, 1H). 13C NMR (75 MHz, CD3OD):
d=22.7 (t), 28.0 (q), 28.3 (d), 34.5 (t), 41.4 (d), 53.2 (d),
80.5 (s), 89.7 (d), 155.0 (s), 174.2 (s). Anal. calcd for
C12H18NO4I (367.18): C, 39.25; H, 4.94; N, 3.81.
Found: C, 39.32; H, 5.04; N, 3.80.
3. Shiro, M.; Nakai, H.; Tori, K.; Nishikawa, J.; Yashimura,
Y.; Katagiri, K. J. Chem. Soc., Chem. Comm. 1980, 375.
4. Parry, R. J.; Bun, H. P. J. Am. Chem. Soc. 1983, 105, 7446.
5. Parry, R. J.; Turakhia, R.; Bun, H. P. J. Am. Chem. Soc.
1988, 110, 4035.
6. Kohno, T.; Kohda, D.; Haruki, M.; Yokoyama, S. J. Bio.
Chem. 1990, 12, 6931.
7. Tanaka, K.; Tomaki, M.; Watanabe, S. Biochim. Biophy-
sica Acta 1969, 159, 244.
syn-Cyclopentenylglycine hydrochloride (syn-6). Depro-
tection of syn-21 (190 mg, 0.80 mmol) according to the
general procedure provided syn-6 in 82% yield (115 mg,
0.65 mmol) as a colorless solid, mp. 180 ꢁC (decomp.).
1H NMR (300 MHz, CD3OD): d=1.78 (m, 1H), 2.11
(m, 1H), 2.43 (m, 2H), 3.40 (m, 1H), 4.08 (d, 1H, J=4.8
Hz), 5.71 (ddd, 1H, J=9.9, 2.2, 1.5 Hz), 6.02 (ddd, 1H,
J=10.3, 2.6, 2.2 Hz). 13C NMR (75 MHz, CD3OD):
d=25.3 (t), 32.9 (t), 56.9 (d), 75.7 (d), 129.2 (t), 136.8 (t),
171.1 (s). Anal. calcd for C7H12NO2Cl (177.63): C, 47.33;
H, 6.81; N, 7.89. Found: C, 47.21; H, 6.78; N, 7.92.
8. Masamune, T.; Ono, M. Chem. Lett. 1975, 625.
9. (a) Robins, M. J.; Parker, J. M. R. Can. J. Chem. 1983,
317. (b) Chen, S.-Y.; Joullie, M. M. J. Org. Chem. 1984, 49,
´
1769. (c) Zhang, J.; Clive, D. L. J. J. Org. Chem. 1999, 64,
1754. (d) Zimmermann, P. J.; Blanarikova, J.; Jager, V.
Angew. Chem. 2000, 112, 936. Angew. Chem. Int. Ed. 2000, 39,
910–912.
10. Kang, S. H.; Lee, S. B. Chem. Comm. 1998, 761.
11. Van Brunt, M. P.; Standaert, R. F. Organic Letters 2000,
5, 705.
12. (a) Masamune, T.; Ono, M. Chem. Lett. 1975, 625. (b)
Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullie
Chem. Soc. 1980, 102, 7505.
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C.; Joullie, M. M. Heterocycles 1981, 16, 1975.
´
, M. M. J. Am.
anti-Cyclopentenylglycine hydrochloride (anti-6). Depro-
tection of anti-21 (190 mg, 0.80 mmol) according to the
general procedure provided anti-6 in 51% yield (71 mg,
0.40 mmol) as a colorless solid, mp. 180 ꢁC (decomp.).
1H NMR (300 MHz, CD3OD): d=1.79 (m, 1H), 2.36 (m,
1H), 2.42 (m, 2H), 3.37 (m, 1H), 3.98 (d, 1H, J=4.8 Hz),
5.63 (ddd, 1H, J=9.9, 2.2, 1.5 Hz), 5.82 (ddd, 1H,
J=10.7, 3.3, 2.2 Hz). 13C NMR (75 MHz, CD3OD):
d=26.8 (t), 32.9 (t), 57.1 (d), 75.7 (d), 128.5 (t), 136.7 (t),
171.1 (s). Anal. calcd for C7H12NO2Cl (177.63): C, 47.33;
H, 6.81; N, 7.89. Found: C, 47.29; H, 6.85; N, 7.87.
´
14. Zumpe, F. L.; Kazmaier, U. Synthesis 1999, 10, 1785.
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5426.
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G. L.; Shive, W. J. Am. Chem. Soc. 1955, 55, 2362.
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3933.