The efficient direct synthesis of N,O-acetal compounds as key intermediates of discorhabdin A: Oxidative fragmentation reaction of α-amino acids or β-amino alcohols by using hypervalent iodine(III) reagents

Article abstract of DOI:10.1002/chem.200501635

Hypervalent iodine(III) reagents are readily available, easy to handle, and have a low toxicity and similar reactivities to those of heavy metal reagents, and hence they are used for various oxidative reactions. The oxidative cleavage of alkynes or carbon

Full text of DOI:10.1002/chem.200501635

FULL PAPER
DOI: 10.1002/chem.200501635
The Efficient Direct Synthesis of N,O-Acetal Compounds as Key
Intermediates of Discorhabdin A: Oxidative Fragmentation Reaction of a-
Amino Acids or b-Amino Alcohols by Using Hypervalent Iodine(iii) Rea gents
AHCTREUNG
Yu Harayama, Masako Yoshida, Daigo Kamimura, Yasufumi Wada, and
Yasuyuki Kita*[a]
Abstract: Hypervalent iodine(iii) reagents are readily available, easy to handle,
G
and have a low toxicity and similar reactivities to those of heavy metal reagents,
and hence they are used for various oxidative reactions. The oxidative cleavage of
Keywords: discorhabdin A · hyper-
alkynes or carbonyl compounds by using bis(trifluoroacetoxy)iodo
A
valent
N,O-acetal ·
iodine
reagents
·
·
benzene (C6F5I
A
natural products
thesis of N,O-acetal compounds as key intermediates of discorhabdin A, by the ox-
synthetic methods
idative fragmentation reaction of a-amino acids or b-amino alcohols by using
C6F5I(OCOCF3)2, is described.
A
Introduction
gards to the use of highly toxic reagents, side reactions by
iodine, generality and yield.
N,O-Acetal compounds A are important intermediates as
they are relatively stable, but readily generate unstable N-
imines B, which are attacked by various nucleophiles to pro-
duce functionalized amine and amino acid derivatives C.
a-Amino acids and b-amino alcohols have recently at-
tracted attention because they are easily available and con-
stitute versatile building blocks as well as chiral auxiliaries.
Therefore, the synthesis of N,O-acetal compounds from a-
amino acids or b-amino alcohols facilitates the synthesis of
functionalized natural and unnatural amine or amino acid
derivatives and natural products containing a nitrogen atom
(Scheme 1).[2]
Over the past two decades, hypervalent iodine(iii) re-
G
agents have received significant attention due to their low
toxicity, ready availability, easy handling, and reactivities
similar to those of heavy metal reagents. As a continuation
of our studies on hypervalent iodine chemistry, we have al-
ready reported various oxidative reactions of carbonyl, al-
kynyl, phenol, and phenyl ether derivatives[6] by using
phenyliodine(iii) bis(trifluoroacetate) (PIFA) and PIDA. We
G
have also accomplished the first diastereoselective total syn-
thesis of the marine anticancer alkaloid (+)-discorhabdin
A.[7] The key step in the stereocontrolled total synthesis of
(+)-discorhabdin A involves the diastereoselective oxidative
spirocyclization with PIFA. It has been clarified that the
N,O-acetal compound is an important intermediate in the
synthesis of (+)-discorhabdin A. However, up to this point
we had only converted the b-amino alcohol into the N,O-
acetal intermediate by using highly toxic lead tetraacetate
(Scheme 2).
Several methods have appeared for the synthesis of N,O-
acetal compounds from a-amino acids and b-amino alcohols,
for example, the electrochemical oxidation of a-amino
acids,[3] the oxidation by lead tetraacetate[4] or the oxidative
radical reaction[5] by phenyliodine
(iii) diacetate (PIDA) and
G
iodine. However, these methods are problematic with re-
We recently succeeded in the novel and efficient direct
synthesis of N,O-acetal compounds by the oxidative frag-
mentation reaction of a-amino acids or b-amino alcohols
[a] Y. Harayama, M. Yoshida, D. Kamimura, Y. Wada, Prof. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6, Yamada-oka
Suita, Osaka, 565–0871 (Japan)
with the hypervalent iodine
ACHTREUNG
acetoxy)iodo(iii) pentafluorobenzene (C6F5I
A
ACHTREUNG
and communicated that this reaction could be applied to the
improved synthesis of the N,O-acetal discorhabdin inter-
mediate, which contains functionalized and unstable pyrro-
Fax : (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
Chem. Eur. J. 2006, 12, 4893 – 4899
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4893

hols
(1a–h)
with
C6F5I-
AHCTREUNG
(Table 2). Although the protect-
ing groups on nitrogen were
changed from the carbamates
to Cbz and Bz groups (en-
tries 6–8), most reactions pro-
duced good yields of the N,O-
acetal compounds (2a–h).
Next, we applied this method
to the a-amino acid derivatives
(3a–d) to produce the N,O-
acetal compounds (4a–d) and
Scheme 1. Synthesis and efficient use of N,O-acetals.
examined its application to in-
tramolecular reaction in the absence of MeOH (Table 3).
The formation of 4e (entry 5) is reasonably explained by
supposing that 3e initially produces the iminium intermedi-
ate by treatment with C6F5I(OCOCF3)2 followed by an in-
G
tramolecular cyclization involving the carboxyl group
(Scheme 4).
A plausible reaction mechanism for the formation of N,O-
acetal compounds from b-amino alcohols or a-amino acids
is shown in Scheme 5. It is possible that the reaction pro-
ceeds by a radical pathway, but no signal corresponding to
this was found in our ESR spectroscopic studies. We rather
propose that the reaction proceeds via the five-membered
ring intermediate as proposed in the reaction with lead tet-
raacetate.[9]
Scheme 2. First total synthesis of (+)-discorhabdin A.
loiminoquinone moieties.[8] We now report the details of the
composition of these N,O-acetal compounds and the appli-
cation to the total synthesis of (+)- and (ꢀ)-discorhabdin A
(Scheme 3).
At the end of this reaction, we examined the application
of this methodology to the synthesis of (+)- and (ꢀ)-disco-
rhabdins (Table 4). Almost no reaction of the naphthoqui-
none (5a) occurred when the optimized conditions were
used (entry 1). An explanation for this could be that the
N,O-acetal compound (6a) may be undergoing disintegra-
tion as a result of the acidic reaction conditions. The reac-
tion with NaHCO3 proceeded smoothly (entry 2) to give the
N,O-acetal compound (6a) in almost the same yield as that
when lead tetraacetate was used (entry 3). Similarly, without
NaHCO3 almost no reaction of the b-amino alcohol com-
pound, (+)-5b occurred (entry 4). When NaHCO3 was
added, the N,O-acetal intermediate of (+)-discorhabdin A,
(+)-6b was produced in high yield (entries 5 and 8). The
N,O-acetal compound (ꢀ)-6b was also produced in 93%
yield under the same conditions (entry 9).
Scheme 3. Fragmentation reaction by C6F5I(OCOCF3)2.
A
Results and Discussion
To optimize the reaction conditions, we first examined the
MeO-introduction reaction via the iminium salt with the N-
Fmoc serine methyl ester (1a, Table 1, Fmoc=fluorenylme-
thoxycarbonyl). Almost no reaction occurred when PIDA
The N,O-acetal (ꢀ)-6b was converted to (ꢀ)-dicorhabdin
A by a similar series of reactions as those for (+)-discorhab-
din A, derived from (l)-tyrosine methyl ester (Scheme 6).
and PIFA were used, well-known hypervalent iodine(iii) re-
U
agents, (entries 10 and 11) or when lead tetraacetate or
NaIO4 were used (entries 12–15), while surprisingly, the re-
Conclusion
action proceeded smoothly with C6F5I(OCOCF3)2 to give
A
the desired N,O-acetal compounds (entries 1–7). Specifically,
the reaction employing CH3CN/MeOH 10:1 (slightly diluted
conditions) produced the N,O-acetal compound 2a in good
yield (entry 6).
Similarly, by using these reaction conditions (entry 6,
Table 1), the reactions of other N-protected-b-amino alco-
We have found a mild and efficient fragmentation method
for a-amino acids and b-amino alcohols by using the hyper-
valent iodine
N
N
lead tetraacetate. This method facilitates the synthesis of
functionalized amine or amino acid derivatives. The present
fragmentation method of b-amino alcohols could be success-
4894
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4893 – 4899

Discorhabdin A
FULL PAPER
Table 1. Examination of the reaction conditions with N-Fmoc serine methyl ester.
Experimental Section
1H and 13C NMR spectra were meas-
ured at 300 or 270 MHz with TMS as
the internal standard. IR spectra were
recorded by
a diffuse reflectance
Entry
1[a]
2
3
4
5
6
7
8
Reagent
Solvent
T [8C]
c [M]
t [h]
Yield [%]
measurement of samples dispersed in
KBr powder. Elemental analyses and
HRMS were performed by the Ele-
mental Analysis Section of Osaka Uni-
versity. Merck silica gel 60 for column
chromatography and Merck precoated
TLC plates, silica gel F254, for prepara-
tive TLC were used, respectively.
Materials: N-Fmoc[10] and N-Cbz[11]
amino acids or amino alcohols were
prepared according to the reported
C6F5I
C6F5I
C6F5I
C6F5I
C6F5I
C6F5I
C6F5I
C6F5I
C6F5I
C
CH3CN/MeOH 2:1
CH3CN/MeOH 50:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
AcOEt/MeOH 10:1
AcOEt/MeOH 10:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
CH3CN/MeOH 10:1
AcOEt/MeOH 10:1
CH2Cl2/MeOH 10:1
MeOH
50
50
50
0.1
0.1
0.1
0.1
24
24
24
24
5
5
5
5
5
24
24
24
24
24
24
13[b]
26[b]
41[b]
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
RT
58[b]
0.1
66[b]
0.02
0.02
0.02
0.1
0.02
0.02
0.02
0.02
0.02
0.02
89
41[b]
76
9
43[b]
10
11
12
13
14
15
C6H5I
C6H5I
U
G
trace[b]
trace[b]
trace[b]
trace[b]
trace[b]
trace[b]
ACHTREUNG
procedure. Phenyliodine(iii) bis(tri-
A
Pb
Pb
Pb
ACHTREUNG
fluoroacetate) (PIFA) was prepared
from commercially available phenylio-
dine diacetate (PIDA) and trifluoro-
ACHTREUNG
ACHTREUNG
acid.[12]
penta-
NaIO4
RT!reflux
acetic
Bis(trifluoroacetoxy)iodo(iii)
fluorobenzene (C6F5I(OCOCF3)2) was
A
[a] Without MS 3 ꢁ. [b] Starting materials remained.
H
prepared from pentafluoroiodoben-
zene and nitric acid.[13]
Table 2. Synthesis of N,O-acetals by oxidative fragmentation of b-amino
alcohols with C6F5I(OCOCF3)2.
ACHTREUNG
Entry
Reactant
R1
R2
R3
t [h]
Yield [%]
Scheme 4. Plausible reaction mechanism for the formation of 4e.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-hydroxypropionic
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Cbz
CO2Me
CO2Me
H
CH3
CH
CO2Me
CO2Bn
CO2Me
H
CH3
H
H
H
H
CH3
CH3
5
1
3
0.5
0.5
7
1
2
89
98
90
63
76
80
quant.
47
acid
methyl ester (1a): 1H NMR (270 MHz, CDCl3): d=7.69 (d, J=7.2 Hz,
2H), 7.53 (brs, 2H), 7.33 (t, J=7.2 Hz, 2H), 7.24 (t, J=7.5 Hz, 2H), 5.90
(d, J=7.8 Hz, 1H), 4.41–4.29 (m, 3H), 4.15 (t, J=6.6 Hz, 1H), 3.93 (dd,
J=10.2, 3.0 Hz, 1H), 3.82 (dd, J=9.7, 2.7 Hz, 1H), 3.69 (s, 3H),
2.78 ppm (brs, 1H); 13C NMR (67.8 MHz CDCl3): d=171.06, 156.27,
143.69, 143.56, 141.20, 141.17, 127.65, 126.99, 124.98, 119.89, 67.09, 32.97,
(CH3)2
Cbz
Bz
55.96, 52.63, 46.98 ppm; IR (KBr): n˜ =3350, 2953, 2251, 1693, 1504 cmꢀ1
HRFABMS: calcd for C19H19NO5Na: 364.12 [M+Na]+; found: 364.12.
;
Table 3. Synthesis of N,O-acetals by oxidative fragmentation of a-amino
acids with C6F5I(OCOCF3)2.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-hydroxybutyric acid methyl
ester (1b): 1H NMR (300 MHz, CDCl3): d=7.69 (d, J=7.5 Hz, 2H), 7.54
(d, J=6.9 Hz, 2H), 7.33 (t, J=7.2 Hz, 2H), 7.24 (td, J=7.5, 1.2 Hz, 2H),
5.59 (d, J=9.0 Hz, 1H), 4.36 (d, J=6.9 Hz, 2H), 4.28 (d, J=9.3H, 2H),
4.17 (t, J=6.9 Hz, 1H), 3.70 (s, 3H), 2.01 (brs, 1H), 1.18 ppm (d, J=
6.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d=171.65, 156.71, 143.81,
143.65, 141.28, 127.70, 127.05, 125.06, 119.96, 67.93, 67.18, 59.02, 52.63,
ACHTREUNG
R1
R2
t [h]
Yield [%]
47.12, 19.82 ppm; IR (KBr): n˜ =3433, 2953, 2253, 1713, 1514 cmꢀ1
HRFABMS: calcd for C20H22NO5: 356.15 [M+H]+; found: 356.15.
;
Entry
Reactant
1
2
3
4
5
3a
3b
3c
3d
3e
Fmoc
Fmoc
Fmoc
Cbz
H
CH3
CH2CH2CO2Me
CO2Et
CH2CH2CO2H
1
73
54
55
0.25
0.25
1
(2-Hydroxyethyl)carbamic acid 9H-fluoren-9-yl methyl ester (1c):
1H NMR (300 MHz, CDCl3): d=7.75 (d, J=7.5 Hz, 2H), 7.57 (d, J=
7.5 Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.30 (td, J=7.8, 1.2 Hz, 2H), 5.13
(brs, 1H), 4.42 (d, J=6.6 Hz, 2H), 4.20 (t, J=6.6 Hz, 1H), 3.70 (t, J=
4.5 Hz, 2H), 3.34 ppm (t, J=5.4 Hz, 2H); 13C NMR (75.5 MHz, CDCl3):
d=143.84, 141.31, 127.69, 127.04, 124.99, 119.97, 47.22 ppm; IR (KBr):
n˜ =3477, 3352, 1672, 1537 cmꢀ1; HRFABMS: calcd for C17H17NO3Na:
306.11 [M+Na]+; found: 306.11.
46
Fmoc
0.5
73[b]
[a] The reaction does not proceed at room temperature. [b] Without
MeOH. Product=4e
.
(2-Hydroxy-1-methylethyl)carbamic acid 9H-fluoren-9-yl methyl ester
(1d): 1H NMR (300 MHz, CDCl3): d=7.75 (d, J=7.2 Hz, 2H), 7.58 (d,
J=7.5 Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.30 (td, J=7.5, 1.2 Hz, 2H),
4.83 (brs, 1H), 4.42 (d, J=6.6 Hz, 2H), 4.20 (t, J=6.6 Hz, 1H), 3.81 (brs,
fully applied to an improved synthesis of (+)- and (ꢀ)-disco-
rhabdin A.
Chem. Eur. J. 2006, 12, 4893 – 4899
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4895

Y. Kita et al.
63.79, 58.57, 47.34, 29.19, 19.47,
18.63 ppm; IR (KBr): n˜ =3331, 2961,
1697, 1514 cmꢀ1
; HRFABMS: calcd
for C20H24NO3: 326.18 [M+H]+;
found: 326.18.
2-Benzyloxycarbonylamino-3-hydroxy-
propionic acid methyl ester (1 f):
1H NMR (300 MHz, CDCl3): d=7.26
(s, 5H), 5.77 (d, J=6.2 Hz, 1H), 5.03
(s, 2H), 4.36 (t, J=3.6 Hz, 1H), 3.90
(dd, J=11.1, 3.0 Hz, 1H), 3.81 (dd, J=
11.1, 2.7 Hz, 1H), 3.68 ppm (s, 3H);
13C NMR (75.5 MHz, CDCl3): d=
171.03, 156.24, 135.99, 128.49, 128.20,
128.07, 67.15, 63.11, 56.01, 52.67 ppm;
IR (KBr): n˜ =3364, 2955, 1693,
1504 cmꢀ1
;
HRFABMS: calcd for
C12H16NO5: 254.10 [M+H]+; found:
254.10.
2-Benzyloxycarbonylamino-3-hydroxy-
butyric acid benzyl ester (1g):
1H NMR (270 MHz, CDCl3): d=7.24
(s, 5H), 5.57 (d, J=8.6 Hz, 1H), 5.09
(s, 1H), 5.02 (s, 1H), 4.29–4.24 (m,
1H), 1.94 (brs, 1H), 1.12 ppm (d, J=
6.48 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3): d=170.99, 156.70, 136.09,
135.15, 128.60, 128.49, 128.44, 128.16,
128.00, 68.00, 67.32, 67.16, 59.21,
19.88 ppm; IR (KBr): n˜ =3427, 2978,
Scheme 5. Plausible reaction mechanism for the formation of the N,O-acetals.
Table 4. Synthesis of N,O-acetal compounds by oxidative fragmentation of amino alcohol compounds of disco-
rhabdins with C6F5I(OCOCF3)2.
A
1715, 1520 cmꢀ1
; HRFABMS: calcd
for C19H22NO5: 344.15 [M+H]+;
found: 344.15.
2-Benzoylamino-3-hydroxybutyric acid
methyl ester (1h): Benzoyl chloride
(0.34 mL, 2.95 mmol) and Et3N
(0.82 mL, 5.90 mmol) were added to a
solution of 2-amino-3-hydroxy-butyric
acid methyl ester (500 mg, 2.95 mmol)
in DMF (15 mL) at room temperature.
The reaction mixture was stirred for
10 h, quenched with water and extract-
ed with AcOEt. The combined organic
layers were then washed with brine
and dried over Na2SO4. The product
was isolated by silica-gel column chro-
Entry
Reagent
(equiv)
Solvent
Additive
(equiv)
T
[8C]
t
Yield
[%]
G
U
[h]
1
2
3
4
5
6
7
8
9
5a C6F5I
5a C6F5I
N
RT!reflux 5.0
3
4.0
5.0
50
61
trace
79
26
51
80
matography.
1H NMR
(300 MHz,
5a Pb
A
CDCl3): d=7.77 (d, J=7.2 Hz, 2H),
7.44 (t, J=6.9 Hz, 1H), 7.35 (t, J=
6.9 Hz, 2H), 7.00 (d, J=8.7 Hz, 1H),
4.74 (dd, J=8.7, 2.1 Hz, 1H), 4.41–
4.34 (m, 1H), 3.70 (s, 3H), 1.20 ppm
(+)-5b C6F5I
(+)-5b C6F5I
(+)-5b C6F5I
(+)-5b C6F5I
C
RT!reflux 1.0
1.0
24
1.5
1.5
(+)-5b Pb
A
0
(d,
J=6.3 Hz,
3H);
13C NMR
C
0.75 93
(75.5 MHz, CDCl3): d=171.59, 167.97,
133.58, 131.88, 128.56, 127.18, 68.12,
57.64, 52.62, 19.99 ppm; IR (KBr): n˜ =
3358, 2976, 1745, 1651, 1537 cmꢀ1; HRFABMS: calcd for C12H16NO4:
1H), 3.67–3.64 (m, 1H), 3.54–3.52 (m, 1H), 1.16 ppm (d, J=6.6 Hz, 3H);
13C NMR (75.5 MHz, CDCl3): d=156.55, 143.83, 143.81, 141.27, 127.65,
127.01, 124.93, 119.93, 66.58, 48.89, 47.18, 17.21 ppm; IR (KBr): n˜ =3321,
2945, 1693, 1537 cmꢀ1; HRFABMS: calcd for C18H20NO3: 298.14 [M+H]+;
found: 298.15.
238.11 [M+H]+; found: 238.11.
(9H-Fluoren-9-ylmethoxycarbonylamino)acetic acid (3a): 1H NMR
(270 MHz, CD3OD): d=7.79 (d, J=7.0 Hz, 2H), 7.67 (d, J=7.6 Hz, 2H),
7.38 (t, J=7.3 Hz, 2H), 7.30 (td, J=7.6, 1.4 Hz, 2H), 4.34 (t, J=6.2 Hz,
2H), 4.24 (d, J=6.8 Hz, 1H), 3.83 ppm (s, 2H); 13C NMR (75.5 MHz,
CD3OD): d=173.58, 159.10, 145.23, 142.53, 128.75, 128.13, 126.23, 120.89,
(1-Hydroxy-methyl-2-methylpropyl)carbamic acid 9H-fluoren-9-ylmethyl
ester (1e): 1H NMR (300 MHz, CDCl3): d=7.75 (d, J=7.5 Hz, 2H), 7.58
(d, J=7.5 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.30 (td, J=7.8, 1.2 Hz, 2H),
4.85 (d, J=7.8 Hz, 1H), 4.44 (t, J=6.3 Hz, 2H), 4.21 (t, J=6.6 Hz, 1H),
3.66 (dd, J=9.6, 3.0 Hz, 2H), 3.47–3.45 (m, 1H), 1.87–1.80 (m, 1H), 0.94
(d, J=8.1 Hz, 3H), 0.91 ppm (d, J=7.5 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3): d=143.90, 143.86, 141.34, 127.66, 127.04, 124.97, 119.95, 66.57,
68.15, 43.07 ppm; IR (KBr): n˜ =3319, 3047, 1737, 1697, 1549 cmꢀ1
HRFABMS: calcd for C17H16NO4: 298.11 [M+H]+; found: 298.11.
;
2-(9H-Fluoren-9-ylmethoxycarbonylamino)propionic acid (3b): 1H NMR
(300 MHz, CD3OD): d=7.79 (d, J=7.2 Hz, 2H), 7.67 (t, J=6.9 Hz, 2H),
7.38 (t, J=7.5 Hz, 2H), 7.30 (td, J=7.2, 1.2 Hz, 2H), 4.39–4.14 (m, 4H),
4896
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4893 – 4899

Discorhabdin A
FULL PAPER
Scheme 6. Improved synthesis of (+)- and (ꢀ)-discorhabdin A.
1.39 ppm (d, J=7.2 Hz, 3H); 13C NMR (75.5 MHz, CD3OD): d=176.52,
room temperature. The reaction mixture was refluxed at 958C with stir-
ring for 0.25–7 h. The solution was then quenched with aqueous saturated
NaHCO3 and extracted with AcOEt. The combined organic layers were
washed with brine, dried, and concentrated in vacuo. Purification of the
residue by silica-gel column chromatography gave the corresponding
N,O-acetal compounds.
145.33, 145.17, 142.54, 128.75, 128.15, 128.12, 126.27, 126.21, 120.88, 67.96,
50.81, 17.78 ppm; IR
(KBr): n˜ =3310, 2924, 1693, 1537 cmꢀ1; HRFABMS:
A
calcd for C18H18NO4: 312.12 [M+H]+; found: 312.12.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)pentanedioic acid 5-methyl
ester (3c): 1H NMR (300 MHz, CDCl3): d=7.65 (d, J=7.5 Hz, 2H), 7.47
(d, J=3.3 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H), 7.19 (t, J=7.2 Hz, 2H), 5.65
(brs, 1H), 4.39 (brs, 1H), 4.29 (d, J=6.6 Hz, 2H), 4.10 (t, J=6.6 Hz,
1H), 3.55 (s, 3H), 3.40 (s, 1H), 2.37–2.34 (m, 2H), 2.18–2.16 (m, 1H),
2.00–1.92 ppm (m, 1H); 13C NMR (75.5 MHz, CDCl3): d=173.61, 163.50,
156.31, 143.80, 143.58, 141.20, 127.64, 127.00, 125.03, 119.89, 67.09, 51.81,
47.00, 36.90, 31.79, 30.05, 27.26 ppm; IR (KBr): n˜ =3323, 1951, 1713,
1531 cmꢀ1; HRFABMS: calcd for C21H22NO6: 384.14 [M+H]+; found:
384.15.
[(9H-Fluoren-9-ylmethoxycarbonylamino)]methoxyacetic acid methyl
ester (2a): 1H NMR (300 MHz, CDCl3): d=7.67 (d, J=7.5 Hz, 2H), 7.50
(d, J=6.9 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H), 7.22 (t, J=7.2 Hz, 2H), 5.85
(d, J=9.0 Hz, 1H), 5.27 (d, J=9.6 Hz, 1H), 4.31–4.45 (m, 2H), 4.14 (t,
J=6.6 Hz, 1H), 3.72 (s, 3H), 3.34 ppm (s, 3H); 13C NMR (67.8 MHz,
CDCl3): d=167.69, 155.39, 143.29, 143.16, 141.03, 140.99, 127.46, 126.81,
126.77, 126.76, 126.70, 124.61, 119.75, 119.69, 80.27, 66.92, 55.88, 52.60,
46.71 ppm; IR (KBr): n˜ =3325, 2953, 1715, 1504 cmꢀ1; HRFABMS: calcd
for C19H19NO5Na: 364.12 [M+Na]+; found: 364.12.
2-Benzyloxycarbonylaminomalonic acid monoethyl ester (3d): 1H NMR
(270 MHz, CO
A
Methoxymethylcarbamic acid 9H-fluoren-9-yl methyl ester (2c):
1H NMR (300 MHz, CDCl3): d=7.67 (d, J=7.5 Hz, 2H), 7.50 (d, J=
7.5 Hz, 2H), 7.31 (t, J=7.2 Hz, 2H), 7.22 (t, J=7.2 Hz, 2H), 5.50 (brs,
1H), 4.53 (d, J=7.4 Hz, 2H), 4.37 (d, J=6.9 Hz, 2H), 4.14 (t, J=6.9 Hz,
1H), 3.22 ppm (s, 3H); 13C NMR (75.5 MHz, CDCl3): d=156.37, 143.68,
141.27, 127.69, 127.01, 124.90, 119.95, 73.51, 66.74, 55.54, 53.40,
47.06 ppm; IR (KBr): n˜ =3346, 2943, 1697, 1537 cmꢀ1; HRFABMS: calcd
for C17H17NO3Na: 306.11 [M+Na]+; found: 306.11.
2H), 4.99 (d, J=8.1 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.25 ppm (t, J=
7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d=206.35, 129.17, 128.71,
128.65, 67.18, 62.58, 14.21 ppm; IR (KBr): n˜ =2982, 1732, 1520 cmꢀ1
HRFABMS: calcd for C13H16NO6: 282.10 [M+H]+; found: 282.10.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)pentanedioic
1H NMR (300 MHz, CD3OD): d=7.79 (d, J=7.2 Hz, 2H), 7.69–7.65 (m,
2H), 7.38 (t, J=7.2 Hz, 2H), 7.30 (td, J=7.5, 1.5 Hz, 2H), 4.35 (d, J=
7.8 Hz, 2H), 4.25–4.18 (m, 2H), 2.41 (t, J=7.5 Hz, 2H), 2.24–2.12 (m,
1H), 1.96–1.85 ppm (m, 1H); 13C NMR (75.5 MHz, CD3OD): d=176.39,
175.38, 158.69, 145.32, 145.18, 142.55, 130.11, 128.77, 128.16, 126.27,
120.89, 68.01, 54.63, 32.22, 27.88 ppm; IR (KBr): n˜ =3000, 2253,
1713 cmꢀ1; HRFABMS: calcd for C20H20NO6: 370.13 [M+H]+; found:
370.13.
(1-Methoxy-ethyl)carbamic acid 9H-fluoren-9-ylmethyl ester (2d):
1H NMR (300 MHz, CDCl3): d=7.69 (d, J=7.2 Hz, 2H), 7.52 (d, J=
7.5 Hz, 2H), 7.33 (t, J=7.2 Hz, 2H), 7.23 (t, J=7.5 Hz, 2H), 4.97 (brs,
1H), 4.44 (dd, J=6.9, 10.5 Hz, 1H), 4.32 (dd, J=6.6, 10.5 Hz, 1H), 4.15
(t, J=6.3 Hz, 1H), 3.22 (s, 3H), 1.27 ppm (t, J=2.4 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3): d=155.80, 143.78, 143.68, 141.31, 127.70, 127.04,
127.01, 124.97, 124.89, 124.72, 119.98, 80.00, 66.54, 55.26, 47.17,
General procedure for the oxidative fragmentation reaction of a-amino
acids or b-amino alcohols with C6F5I
21.70 ppm; IR
(KBr): n˜ =3317, 2932, 1713, 1514 cmꢀ1; HRFABMS: calcd
A
for C18H19NO3Na: 320.13 [M+Na]+; found: 320.13.
mosphere, C6F5I(OCOCF3)2 (0.2 mmol) and molecular sieves (3 ꢁ,
850 mgmmolꢀ1) were added to a stirred solution of the amino acid or
amino alcohol (0.1 mmol) in CH3CN (4.5 mL) and CH3OH (0.5 mL) at
(1-Methoxy-2-methylpropyl)carbamic acid 9H-fluoren-9-ylmethyl ester
(2e): 1H NMR (270 MHz, CDCl3): d=7.69 (d, J=7.6 Hz, 2H), 7.52 (d,
Chem. Eur. J. 2006, 12, 4893 – 4899
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4897

Y. Kita et al.
J=7.8 Hz, 2H), 7.32 (t, J=7.3 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 4.85 (d,
J=10.26 Hz, 1H), 4.56–4.33 (m, 3H), 4.15 (t, J=6.48, 1H), 3.21 (s, 3H),
1.77–1.67 (m, 1H), 0.87 (d, J=6.8 Hz, 3H), 0.83 ppm (d, J=6.8 Hz, 3H);
13C NMR (67.8 MHz, CDCl3): d=156.21, 143.69, 143.59, 141.23, 127.60,
126.94, 126.92, 124.86, 124.82, 119.91, 87.73, 66.44, 55.72, 47.34, 33.15,
17.93, 17.26 ppm; IR (KBr): n˜ =3296, 2960, 1693, 1537 cmꢀ1; HRFABMS:
calcd for C20H23NO3Na: 348.16 [M+Na]+; found: 348.16.
Compound (ꢀ)-5b was prepared from (d)-tyrosine methyl ester by a sim-
ilar method to that used for the synthesis of (+)-discorhabdin A from
(l)-tyrosine methyl ester.
5-(Toluene-4-sulfonyl)-3,5,7,8,9,10-hexahydro-2H-1,5,7-triazaacephenan-
thrylen-6-one-8-(hydroxymethyl)-10-spiro-4’-(2’-bromo)cyclohexa-2’,5’-
dien-1’-one ((ꢀ)-5b): 1H NMR (300 MHz, CD3OD): d=8.00 (d, J=
8.4 Hz, 2H), 7.41 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.09 (dd,
J=2.7, 9.6 Hz, 1H), 6.34 (d, J=9.9 Hz, 1H), 3.54–3.80 (m, 5H), 3.11 (m,
1H), 2.81 (m, 2H), 2.34 (s, 3H), 1.91 (t, J=6.9 Hz, 1H), 1.68 ppm (dd,
J=13.5 Hz, 1H); IR (KBr): n˜ =3240, 3465, 1938 cmꢀ1; HRFABMS: calcd
for C26H23BrN3O5S: 568.05 [M+H]+; found: 568.05.
Benzyloxycarbonylaminomethoxyacetic acid methyl ester (2 f): 1H NMR
(300 MHz, CDCl3): d=7.30 (s, 5H), 5.78 (brs, 1H), 5.29 (d, J=9.3 Hz,
1H), 5.08 (s, 2H), 3.74 (s, 3H), 3.39 ppm (s, 3H); 13C NMR (75.5 MHz,
CDCl3): d=167.95, 167.93, 135.70, 128.53, 128.31, 128.13, 80.62, 80.58,
67.34, 67.32, 56.19, 52.86 ppm; IR (KBr): n˜ =3425, 2955, 1730, 1504 cmꢀ1
HRFABMS: calcd for C12H16NO5: 254.10 [M+H]+; found: 254.10.
;
5-(Toluene-4-sulfonyl)-3,5,7,8,9,10-hexahydro-2H-1,5,7-triazaacephenan-
thrylen-6-one-8-methoxy-10-spiro-4’-(2’-bromo)cyclohexa-2’,5’-dien-1’-
one ((ꢀ)-6b): 1H NMR (300 MHz, CO
C
Benzyloxycarbonylaminomethoxyacetic acid benzyl ester (2g): 1H NMR
(300 MHz, CDCl3): d=7.28 (s, 5H), 5.79 (brs, 1H), 5.30 (d, J=9.0 Hz,
1H), 5.14 (s, 2H), 5.07 (s, 2H), 3.37 ppm (s, 3H); 13C NMR (75.5 MHz,
CDCl3): d=136.30, 135.28, 129.27, 129.20, 129.05, 128.98, 128.80, 81.40,
68.49, 68.14, 68.11, 57.08, 57.05 ppm; IR (KBr): n˜ =3323, 2936, 1730,
1514 cmꢀ1; HRFABMS: calcd for C18H20NO5: 330.13 [M+H]+; found:
330.14.
Benzoylaminomethoxyacetic acid methyl ester (2h): 1H NMR (300 MHz,
CDCl3): d=7.79 (dd, J=6.0, 0.9 Hz, 2H), 7.51–7.39 (m, 3H), 7.15 (d, J=
8.7 Hz, 1H), 5.71 (d, J=9.0 Hz, 1H), 3.77 (s, 3H), 3.46 ppm (s, 3H);
13C NMR (75.5 MHz, CDCl3): d=168.56, 167.46, 133.04, 132.30, 128.69,
127.23, 78.64, 56.86, 53.00 ppm; IR (KBr): n˜ =3333, 2953, 1755,
1666 cmꢀ1; HRFABMS: calcd for C11H14NO4: 224.09 [M+H]+; found:
224.09.
(ꢀ)-Discorhabdin A: 1H NMR (300 MHz, CDCl3): d=9.00 (brs, 1H),
7.55 (s, 1H), 6.86 (s, 1H), 5.91 (brs, 1H), 5.33 (brs, 1H), 4.70 (dd, J=7.5,
11.5 Hz, 1H), 4.26 (td, J=6.5, 18.0 Hz, 1H), 3.95 (td, J=8.5, 17.5 Hz,
1H), 2.70–2.89 ppm (m, 6H); 13C NMR (75.5 MHz, (CD3)2SO): d=188.3,
170.0, 157.5, 154.2, 141.4, 124.1, 122.5, 121.1, 118.1, 117.4, 115.2, 61.2,
55.9, 50.3, 50.2, 45.2, 39.0, 17.9 ppm; IR (KBr): n˜ =3345, 1680, 1650, 1605,
1555, 1525, 1475, 1445, 1400, 1385, 1310 cmꢀ1; HRFABMS: calcd for
C18H15BrN3O2S: 416.01 [M+H]+; found: 416.01; [a]D =ꢀ390 (c=0.05 in
MeOH).
The spectral data of methoxymethyl-carbamic acid 9H-fluoren-9-ylmethyl
ester (4a) and (1-methoxyethyl)carbamic acid 9H-fluoren-9-ylmethyl
ester (4b) are in good accordance with those of 2c and d, respectively.
4-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-methoxybutyric
acid
Acknowledgements
methyl ester (4c): 1H NMR (300 MHz, CDCl3): d=7.75 (d, J=7.5 Hz,
2H), 7.57 (d, J=6.9 Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.5 Hz,
2H), 5.10 (d, J=9.6 Hz, 1H), 4.89–4.86 (m, 1H), 4.48 (t, J=7.2 Hz, 1H),
4.40 (t, J=6.3 Hz, 1H), 4.20 (t, J=6.6 Hz, 1H), 3.65 (s, 3H), 3.28 (s, 3H),
2.44–2.35 (m, 2H), 1.98–1.91 ppm (m, 2H); 13C NMR (75.5 MHz,
CDCl3): d=201.98, 173.51, 156.00, 150.47, 143.73, 143.67, 141.33, 127.72,
127.03, 124.90, 119.98, 84.39, 66.61, 55.55, 51.74, 47.20, 30.43, 29.48 ppm;
This research was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Technology,
Japan.
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IR
A
C21H23NO5Na: 392.15 [M+Na]+; found: 392.15.
Benzyloxycarbonylaminomethoxyacetic acid ethyl ester (4d): 1H NMR
(300 MHz, CDCl3): d=7.32–7.23 (m, 5H), 5.80 (d, J=8.4 Hz, 1H), 5.26
(d, J=9.6 Hz, 1H), 5.09 (s, 2H), 4.19 (q, J=6.3 Hz, 2H), 3.39 (s, 3H),
1.25 ppm (t, J=7.2 Hz, 3H); 13C NMR (67.8 MHz, CDCl3): d=167.31,
155.50, 135.63, 128.46, 128.24, 128.06, 80.67, 67.38, 62.23, 56.21,
14.11 ppm; IR (KBr): n˜ =3329, 2939, 1732, 1520 cmꢀ1; HRFABMS: calcd
for C13H18NO5: 268.12 [M+H]+; found: 268.12.
(5-Oxo-tetrahydrofuran-2-yl)carbamic acid 9H-fluoren-9-yl methyl ester
(4e): 1H NMR (270 MHz, CDCl3): d=7.69 (d, J=7.3 Hz, 2H), 7.50 (d,
J=7.3 Hz, 2H), 7.34 (t, J=7.0 Hz, 2H), 7.25 (td, J=7.6, 1.4 Hz, 2H),
5.92 (d, J=5.7 Hz, 1H), 5.5 (d, J=9.7 Hz, 1H), 4.41 (d, J=5.1 Hz, 2H),
4.15 (t, J=6.5 Hz, 1H), 2.66–2.45 (m, 3H), 1.97 ppm (brs, 1H); 13C NMR
(75.5 MHz, CDCl3): d=143.44, 141.28, 127.83, 127.13, 124.91, 120.02,
83.31, 46.90, 28.12 ppm; IR (KBr): n˜ =1715, 1537 cmꢀ1; HRFABMS:
calcd for C19H18NO4: 324.12 [M+H]+; found: 324.12.
General procedure for the oxidative fragmentation reaction of b-amino
alcohol compounds of discorhabdins with C6F5I
A
trogen atmosphere, C6F5I(OCOCF3)2 (0.2 mmol) and molecular sieves
AHCTREUNG
(3 ꢁ, 850 mgmmolꢀ1) were added to a stirred solution of the amino alco-
hol compounds of discorhabdins (0.1 mmol) and NaHCO3 (0.7 mmol) in
CH3CN (4.5 mL) and CH3OH (0.5 mL) at room temperature. The reac-
tion mixture was stirred for 1–5 h. After this time, the solution was con-
centrated in vacuo. Purification of the residue by silica-gel column chro-
matography gave the corresponding N,O-acetal compounds. Spectral data
of compounds, 5a, 6a, (+)-5b, and (+)-6b are in good agreement with
those of the reported data.[7]
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4898
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4893 – 4899

Discorhabdin A
FULL PAPER
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Received: December 29, 2005
Published online: April 10, 2006
Chem. Eur. J. 2006, 12, 4893 – 4899
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4899