Biomimetic Approaches Employing the Ugi Five-Center Four-Component Reaction for Synthesis of the Right-Hand Portion of Halichonadin Q and the Central Part of Halichonadin M

Article abstract of DOI:10.1055/s-0034-1380438

One-pot syntheses of models of the right-hand portion and the central part of the respective structures of halichonadins Q and M, using the Ugi five-center four-component reaction (U-5C-4CR), were executed. The biomimetic strategy employed in these routes demonstrates the feasibility of pathways we have proposed for the biosynthesis of marine organisms.

Full text of DOI:10.1055/s-0034-1380438

SYNTHESIS
0
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8
1
1
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7
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1
0
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©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 3043–3048
3043
paper
Synthesis
R. Mimura et al.
Paper
Biomimetic Approaches Employing the Ugi Five-Center Four-
Component Reaction for Synthesis of the Right-Hand Portion of
Halichonadin Q and the Central Part of Halichonadin M
Rika Mimuraa
Ayumi Kitamoria
Akifumi Ikedaa
Toshiya Masudab
Keiji Nakanoa
OMe
O
O
NH2
HO
aq HCHO
N
HN
O
MeOH
N
H
N
C
Hiyoshizo Kotsukia
O
Yoshiyasu Ichikawa*a
O
COOH
N
N
O
a
Faculty of Science, Kochi University, Akebono-cho Kochi
H
N
H
780-8520, Japan
ichikawa@kochi-u.ac.jp
Faculty of Integrated Arts and Sciences, University of
Tokushima, Tokushima 770-8502, Japan
aq HCHO
MeOH
OMe
b
Received: 07.04.2015
Accepted after revision 11.05.2015
Published online: 09.07.2015
DOI: 10.1055/s-0034-1380438; Art ID: ss-2015-f0232-op
O
O
H
N
O
N
O
N
R
N
H
H
Abstract One-pot syntheses of models of the right-hand portion and
the central part of the respective structures of halichonadins Q and M,
using the Ugi five-center four-component reaction (U-5C-4CR), were
executed. The biomimetic strategy employed in these routes demon-
strates the feasibility of pathways we have proposed for the biosynthe-
sis of marine organisms.
OMe
OMe
R = terpene
halichonadin Q (1)
right-hand structure of 1
MeO
Key words Ugi reaction, multicomponent reaction, biomimetic syn-
thesis, terpenes, isocyanides
MeO
H
R
O
O
HN
O
HN
N
O
N
O
In long-term investigations, our efforts have been di-
O
R
H
N
H
rected towards the synthesis of terpene isocyanides origi-
N
H
1
nating from marine organisms. During the course of these
studies, we put forth the biosynthetic hypothesis that a
R = terpene
central structure of 2
2
number of terpenes, such as exigurin, boneratamides and
halichonadin M (2)
3
halichonadin G, are generated in vivo through Ugi coupling
4
Figure 1 Structures of halichonadins Q and M and their core motifs
reaction sequences starting with terpene isocyanides. In
this context, a recent report by Kobayashi and his co-work-
ers at Hokkaido University captured our attention. The
Kobayashi group isolated a number of terpenes, including
halichonadins M–Q, from the light-brown marine sponge
Halichondria sp. collected at Unten Port in Okinawa island.5
Of specific interest were the halichonadins Q (1) and M (2)
6
from a marine sponge found at Unten Port. We surmised
that hypothetical action of a ugiase-type enzyme might cat-
alyze a coupling reaction of 3 with L-proline, formaldehyde
and methanol to produce the terpene–amino acid conju-
gate, halichonadin Q (1). A similar ugiase-catalyzed cou-
pling reaction of 3 with glycine, formaldehyde and metha-
nol would give rise to the IDA methyl ester 4. This hypo-
thetical intermediate 4 would further react with a second
mole of halichonadin C and formaldehyde to generate hali-
chonadin M (2). Considering this hypothetical biosynthetic
speculation as a blueprint, we designed biomimetic-based
processes for the synthesis of the structural motifs found in
halichonadins Q and M.
(Figure 1), terpenes that have a common structure in which
eudesmane-type sesquiterpenes and amino acid moieties
are uniquely connected to form an imino-diacetic acid (IDA)
methyl ester structural motif.
Consideration of plausible biosynthetic pathways led us
to suggest that the biosynthetic route for construction of
halichonadins Q and M, shown in Scheme 1, involves the in-
termediacy of the terpene isocyanide halichonadin C (3).
Notably, isocyanide 3 was isolated by the Kobayashi group
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044
Synthesis
R. Mimura et al.
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9
, L-proline, aqueous formaldehyde and methanol at 50 °C
HN
for two hours led to formation of methyl ester 10a in 60%
yield. In this case, less than 0.2% of the acid 10b was formed.
The results in this experiment using a model terpene isocy-
anide 9 showed that a biomimetic, one-pot process should
be applicable to the synthesis of the right-hand portion of
halichonadin Q in a simple and remarkably efficient man-
ner.8
H
HCHO
MeOH
N
C
O
OH
OH
halichonadin Q (1)
ugiase
halichonadin C (3)
ugiase
HCHO, MeOH, H2N
O
O
H
N
COOH
N
aq HCHO,
H
O
OMe
HCHO
halichonadin C (3)
H
N
O
MeOH, 50 °C
(60%)
N
N
N
O
C
H
H
halichonadin M (2)
OR
ugiase
4
9
1
1
0a R = Me
0b R = H
MeI, KHCO3
DMF (< 0.2%)
Scheme 1 Plausible biosynthetic pathway for the generation of hali-
chonadins Q and M illustrating their origin from the terpene isocyanide,
halichonadin C
Scheme 3 The U-5C-4CR using terpene-isocyanide, L-proline and
aqueous formaldehyde in methanol
As a simple model system to test the biomimetic strate-
gy for synthesis of halichonadin Q, the Ugi five-center four-
component reaction (U-5C-4CR) of tert-butyl isocyanide
We next turned our attention to modelling the biomi-
metic process that could be employed to generate the cen-
tral part of halichonadin M (2) (Scheme 4). The hydrochlo-
ride salt of N-allyl-protected glycine 12, formed by acid-
7
(
5) was explored (Scheme 2). We found that stirring a solu-
9
tion of tert-butyl isocyanide (5), L-proline, aqueous formal-
dehyde in methanol at 50 °C for five hours led to formation
of chromatographically pure IDA methyl ester 7 in 66%
yield. In addition, the aqueous phase obtained during an ex-
traction step in the work-up was concentrated to afford the
highly polar product 8, which was treated with methyl io-
dide and potassium bicarbonate in N,N-dimethylformamide
to afford an additional methyl ester 7 (6%, combined yield
catalyzed hydrolysis of the corresponding ester 11, was
subjected directly to the U-5C-4CR with tert-butyl isocya-
nide (5), paraformaldehyde, triethylamine and methanol.
This reaction generated the desired adduct 13 in 79% yield.
Palladium-catalyzed deprotection of allylamine 13 using
N,N′-dimethylbarbituric acid as an allyl group scavenger
gave the corresponding amine 14,10 which is a structural
model of the hypothetical intermediate 4 in the proposed
biosynthetic pathway to halichonadin M (Scheme 1). Disap-
pointingly, reaction of amine 14 with tert-butyl isocyanide
(5) and aqueous formaldehyde in methanol gave a complex
mixture of products.11 After some unsuccessful experi-
ments, an alternative approach using the U-5C-4CR was se-
cured. To our delight, the free acid 15, produced from 14 by
treatment with 3 M HCl, did undergo the U-5C-4CR with
tert-butyl isocyanide and aqueous formaldehyde in metha-
nol to form 16 (54% overall from 14), a substance contain-
ing the central structure of halichonadin M.
In further studies aimed at exploring the biomimetic
synthesis of halichonadin M, the U-5C-4CR using the ter-
pene isocyanide 9 was investigated (Scheme 5). This pro-
cess, employing conditions similar to those described in
Scheme 4, proceeded uneventfully to furnish the desired
adduct 17 in 76% yield. While palladium-catalyzed removal
of the allyl group in 17 to form 18a occurred smoothly, sep-
aration of the by-product, triphenylphosphine oxide,
proved to be problematic owing to its TLC behavior being
similar to that of the product 18a. After some experiments,
it was found that triphenylphosphine oxide was removed
by washing an aqueous reaction mixture obtained after hy-
drolysis of the ester 18a with dichloromethane. The corre-
72%). The mechanism for formation of 7 and 8 likely in-
volves the intermediacy of O-acylimidate 6, which is inter-
cepted by either methanol or water.
N
COOH
N
aq HCHO,
H
N
C
N
O
O
MeOH, 50 °C
5
••
6
MeOH or H2O
N
O
O
N
N
+
N
H
H
O
OMe
O
OH
7
(66%)
8
MeI, KHCO3, DMF
(6%)
Scheme 2 A model synthesis of halichonadin Q using tert-butyl isocya-
nide
We also explored the U-5C-4CR of terpene isocyanide 9,
which was prepared from (–)-menthol by using our previ-
3
ously described method (Scheme 3). Stirring a mixture of
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045
Synthesis
R. Mimura et al.
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prepare 14 using tert-butyl isocyanide (5), glycine and
paraformaldehyde in methanol. Unexpectedly, mono-Ugi
product 14 was not formed, but over-Ugi reaction product
16 was isolated in low yield (16%). Since this previously un-
wanted product 16 turned out to be a desirable product
possessing the central structural motif found in halichona-
din M, we attempted to improve this process as a new ap-
proach to the biomimetic synthesis of halichonadin M.
Since the carboxylic acid 15 underwent smooth U-5C-4CR
(Scheme 4), we conjectured that the over-Ugi product 16
most likely arose from carboxylic acid 21, which was
formed by reaction of water in methanol with O-acyl imi-
date intermediate 20. Based on these considerations, a one-
pot approach for the preparation of the central structure of
halichonadin M using aqueous formaldehyde was examined
(Scheme 7).
N
C
5
O
OEt
O
N
OH
Cl
3
M HCl
0 °C
(HCHO)n, Et3N
8
MeOH, 50 °C
(79%)
N
H
(83%)
H
H
1
1
12
O
N
OMe
O
N
OMe
N,N'-dimethylbarbituric acid
Pd(OAc)2, Ph3P
3 M HCl
0 °C
H
H
8
N
EtOH
83%)
H
N
(
1
3
O
1
4
O
O
OH
O
N
OMe
N
C
5
H
aq HCHO
H
H
N
Cl
N
H
MeOH, 50 °C
54%, 2 steps)
H
N
N
O
(
1
5
O
N
OMe
1
6
O
O
N
C
H
Scheme 4 A model synthesis of the central structure of halichonadin
O
OH
N
5
M employing the U-5C-4CR
H
N
(HCHO)n, MeOH
O
H2N
sponding hydrochloride salt of 18b underwent the U-5C-
CR with the terpene isocyanide 9 to give rise to 19, the
16 (16%)
O
4
central structural motif of halichonadin M with two ter-
pene units, in 54% overall yield from 17.
H
N
RO
H
N
H
O
N
O
N
OH
N
O
O
O
MeO
O
Cl
20
14 R = Me
21 R = H
•
•
H
H
2
H O
12
N
HN
C
(
HCHO)n, Et3N
MeOH, 50 °C
Scheme 6 Unsuccessful experiment to obtain the mono-Ugi product
N
O
9
(
76%)
17
As anticipated, the U-5C-4CR using terpene isocyanide
9
, glycine and aqueous formaldehyde in methanol at 50 °C
for 60 minutes produced the menthyl analogue of hali-
chonadin M 19 in 32% yield after chromatographic purifica-
tion.12 While the yield is low, the experimentally simple
one-pot process enables concise assembly of multiple com-
ponents. It should be noted that the stepwise synthesis of
19 shown in Scheme 5 required the four-step operations
from terpene isocyanide 9 in an overall 41% yield.
RO
N,N'-dimethylbarbituric acid
Pd(OAc)2, Ph3P, EtOH
3
M HCl
0 °C
O
HN
8
N
H
O
1
1
8a R = Me
8b R = H
O
N
MeO
O
C
aq HCHO,
9
N
HN
O
MeOH, 50 °C
N
(
54%, 3 steps)
H
O
MeO
NH2
19
HO
O
HN
Scheme 5 Synthesis of the central structure of halichonadin M starting
aq HCHO
from a terpene isocyanide
N
O
N
MeOH, 50 °C
C
O
(32%)
In order to develop a more concise approach to the cen-
tral structure of halichonadin M, we reconsidered our un-
successful experiment previously experienced in an earlier
study focusing on the synthesis of the core structure of hal-
N
H
9
19
Scheme 7 A one-pot synthesis of the menthyl analogue of halichona-
3
ichonadin G (Scheme 6). In this effort, we initially hoped to
din M
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046
Synthesis
R. Mimura et al.
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1
In the investigation described above, we developed con-
cise biomimetic approaches to the syntheses of the respec-
tive right-hand portion and central part of halichonadins Q
and M using the U-5C-4CR. The biomimetic syntheses pre-
sented here clearly demonstrate the feasibility of our pro-
posed biosynthesis, wherein the marine organisms employ
the Ugi reaction to create natural product structural diver-
sity. While the Ugi reaction has been exploited extensively
in combinatorial diversity-oriented syntheses in the field of
medicinal chemistry, there are few reports that the Ugi re-
H NMR (CDCl , 400 MHz): δ = 1.35 (s, 9 H), 1.78–2.00 (m, 3 H), 2.17
3
(qd, J = 13.0, 8.8 Hz, 1 H), 2.53 (q, J = 8.8 Hz, 1 H), 3.08 (d, J = 16.8 Hz, 1
H), 3.13–3.20 (m, 1 H), 3.25 (d, J = 16.8 Hz, 1 H), 3.38 (dd, J = 8.8, 4.8
Hz, 1 H), 3.71 (s, 3 H), 7.36 (br s, 1 H).
1
H NMR (C D N, 500 MHz): δ = 1.42 (s, 9 H), 1.52–1.76 (m, 2 H), 1.78–
5
5
1
.90 (m, 1 H), 2.00 (qd, J = 13.0, 8.8 Hz, 1 H), 2.43 (m, 1 H), 3.03–3.11
(
(
1
m, 1 H), 3.29 (d, J = 16.0 Hz, 1 H), 3.44 (d, J = 16.0 Hz, 1 H), 3.40–3.48
m, 1 H), 3.61 (s, 3 H), 7.69 (br s, 1 H).
3
C NMR (CDCl , 125 MHz): δ = 24.1, 28.5, 29.8, 50.1, 51.7, 54.5, 59.4,
3
6
5.7, 169.8, 174.6.
13
C NMR (C D N, 125 MHz): δ = 24.6, 28.8, 30.2, 50.3, 51.75, 54.80,
13
5
5
action is employed in biosynthetic pathways. Our studies
might shed light on an important role of the Ugi reaction in
Nature to expand the diversity of secondary metabolites.
5
9.8, 66.0, 170.0, 175.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H23N O : 243.1709; found:
2
2
3
43.1703.
(
S)-Methyl 1-{2-[(1S,2S,5R)-2-Isopropyl-5-methylcyclohexylami-
Melting points were recorded on a micro melting point apparatus and
are not corrected. Optical rotations were measured at the sodium D
no]-2-oxoethyl}pyrrolidine-2-carboxylate (10a)
To a solution of L-proline (557 mg, 4.84 mmol) in MeOH (32.0 mL) at
r.t. was added aqueous formaldehyde (37%, 0.90 mL, 12.1 mmol). Af-
ter stirring at 50 °C for 20 min, isocyanide 9 (400 mg, 2.42 mmol) was
added. The reaction mixture was stirred at 50 °C for 2 h, and then
concentrated under reduced pressure. The resultant residue was
line with a 100 mm path length cell, and are reported as follows:
T
[
α]D , concentration (g/100 mL), and solvent. Infrared spectra are re-
–1
1
ported in wavenumbers (cm ). H NMR data are reported in ppm
with CHCl (7.26 ppm) and pyridine (7.19 ppm) as internal standards.
3
13
C NMR chemical shifts are reported in ppm relative to CDCl3 (77.0
ppm) and C D N (123.5 ppm) as internal standards. High-resolution
treated with H O, and the aqueous layer was extracted with EtOAc.
The combined organic layer was washed with brine, and dried
2
5
5
mass spectra (HRMS) are reported in m/z. Moisture- or oxygen-sensi-
(Na SO ). Concentration under reduced pressure provided a residue
2 4
tive reactions were run under an argon atmosphere. CH Cl was dried
2
2
which was purified by silica gel chromatography (EtOAc–hexane, 2:1)
to afford methyl ester 10a (589 mg, 60%) as a pale yellow oil.
over molecular sieves 3 Å. Pyridine and Et N were stocked over anhy-
3
drous KOH. All other commercially available reagents were used as re-
ceived.
The aqueous layer was treated using conditions similar to those used
for 8, affording a second portion of methyl ester 10a (0.7 mg, < 0.2%).
[
α]D21 +5.10 (c 1.00, MeOH).
IR (NaCl): 3340, 2950, 2921, 1740, 1675, 1520, 1203, 754 cm–1
H NMR (CDCl , 500 MHz): δ = 0.86 (d, J = 7.0 Hz, 3 H), 0.90 (t, J = 6.0
Hz, 6 H), 0.92–0.97 (m, 2 H), 1.00–1.15 (m, 2 H), 1.28 (m, 1 H), 1.46–
1.58 (m, 1 H), 1.77 (br d, J = 13.0 Hz, 1 H), 1.83–1.93 (m, 4 H), 1.97 (m,
1 H), 2.18 (qd, J = 14.0, 13.0 Hz, 1 H), 2.51 (dd, J = 17.0, 9.0 Hz, 1 H),
3.11 (quin, J = 5.0 Hz, 1 H), 3.14 (d, J = 17.0 Hz, 1 H), 3.39 (d, J = 17.0
Hz, 1 H), 3.45 (dd, J = 10.0, 5.0 Hz, 1 H), 3.70 (s, 3 H), 4.29 (dd, J = 9.0,
3.0 Hz, 1 H), 7.76 (br d, J = 9.0 Hz, 1 H).
(S)-Methyl 1-[2-(tert-Butylamino)-2-oxoethyl]pyrrolidine-2-car-
boxylate (7)
.
To a solution of L-proline (450 mg, 3.91 mmol) in MeOH (14.0 mL) at
r.t. was added aqueous formaldehyde (37%, 0.73 mL, 9.77 mmol). Af-
ter stirring at 50 °C for 15 min, tert-butyl isocyanide (5) (0.23 mL,
1
3
1.95 mmol) was added. The solution was stirred at 50 °C for 5 h, and
concentrated under reduced pressure. The resulting residue was
treated with H O (ca. 6.0 mL), and the aqueous layer was extracted
with EtOAc (× 3). The combined organic layer was washed with brine
and dried (Na SO ). Concentration under reduced pressure provided
2
2
4
1
H NMR (C D N, 500 MHz): δ = 0.78–1.10 (m, 13 H), 1.26 (qd, J = 10.0,
5
5
the crude residue, which was subjected to silica gel chromatography
EtOAc–hexane, 2:1) to afford methyl ester 7 (314 mg, 66%) as a color-
3.0 Hz, 1 H), 1.38–1.50 (m, 1 H), 1.58–1.80 (m, 4 H), 1.88 (m, 1 H),
(
1.98–2.10 (m, 2 H), 2.41 (q, J = 8.5 Hz, 1 H), 3.08–3.15 (m, 1 H), 3.29 (d,
less oil.
J = 16.5 Hz, 1 H), 3.51 (dd, J = 9.5, 6.0 Hz, 1 H), 3.61 (s, 3 H), 3.62 (d, J =
16.5 Hz, 1 H), 4.57 (dd, J = 9.0, 3.0 Hz, 1 H), 8.02 (br d, J = 9.0 Hz, 1 H).
The aqueous layer was concentrated under reduced pressure. The re-
sulting crude amino acid 8 was dissolved in EtOH, and the solvent was
removed azeotropically on a rotary evaporator. This procedure was
repeated twice more, and then the residue was dried in a desiccator
over P O under vacuum (ca. 20 mmHg) overnight. The crude amino
13
C NMR (CDCl , 125 MHz): δ = 20.6, 21.1. 22.2, 24.4, 25.4, 26.4, 29.8
3
(2C), 34.8, 40.0, 45.6, 46.2, 51.8, 54.7, 58.6, 65.6, 169.9, 174.5.
13
C NMR (C D N, 125 MHz): δ = 20.9, 21.3, 22.6, 24.8, 25.8, 26.8, 30.1,
5
5
2
5
30.2, 35.2, 40.7, 45.8, 46.6, 51.9, 54.9, 59.2, 65.8, 169.9, 175.0.
acid 8 (468 mg) was suspended in toluene, and the solvent was re-
moved azeotropically (× 2), giving a residue that was dissolved in
HRMS (ESI): m/z [M + H]+ calcd for C18H33N O : 325.2491; found:
2
3
DMF (2.0 mL). To this solution was added KHCO (431 mg, 3.98 mmol)
325.2476.
3
and MeI (0.25 mL, 3.98 mmol). After being stirred at r.t. for 2.5 h, the
reaction mixture was diluted with H O. The aqueous layer was ex-
2
Methyl 2-(Allyl{2-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylami-
no]- 2-oxoethyl}amino)acetate (17)
tracted with Et O, and the combined organic layer was washed with
2
H O and brine. After drying over anhydrous Na SO , concentration
2
2
4
To a solution of N-allylglycine hydrochloride (12) (550 mg, 3.63
under reduced pressure gave the crude residue, which was subjected
to silica gel chromatography (EtOAc–hexane, 2:1) to furnish a second
portion of methyl ester 7 (10 mg, 6%; combined yield 72%).
mmol) in MeOH (22.5 mL) was added Et N (1.0 mL, 7.26 mmol) and
3
paraformaldehyde (436 mg, 14.52 mmol). After stirring at 50 °C for 1
h, a solution of terpene isocyanide 9 (401 mg, 2.42 mmol) in MeOH
(1.5 mL) was added. The reaction mixture was stirred at 50 °C for 30
min, and then concentrated under reduced pressure. The resulting
[
α]D23 –26.6 (c 1.00, CHCl3).
IR (NaCl): 3326, 2967, 2874, 1740, 1677, 1523, 1205 cm–1
.
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3
047
Synthesis
R. Mimura et al.
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residue was dissolved in EtOAc and H O. The separated aqueous layer
sure to afford a residue (311 mg), which was subjected to silica gel
chromatography (EtOAc–hexane, 1:1) to furnish 19 (94 mg, 32% cal-
culated based on isocyanide 9) as a white solid.
2
was extracted with EtOAc, and the combined organic extract was
washed with brine and dried (Na SO ). Concentration under reduced
2
4
pressure afforded a residue (751 mg), which was subjected to silica
gel chromatography (EtOAc–hexane, 1:2) to furnish the Ugi coupling
product 17 (599 mg, 76%) as a yellow oil.
Mp 137–138 °C; [α]D18 +37.7 (c 1.00, CHCl3).
IR (KBr): 3300, 2949, 2871, 1746, 1654, 1541, 1457, 1201 cm–1
1H NMR (500 MHz, CDCl
): δ = 0.87 (d, J = 6.5 Hz, 6 H), 0.88 (d, J = 6.5
Hz, 6 H), 0.89 (d, J = 7.0 Hz, 6 H), 0.84–1.16 (m, 8 H), 1.25 (m, 2 H),
.44 (m, 2 H), 1.76 (br d, J = 12.5 Hz, 2 H), 1.79–1.88 (m, 4 H), 3.35 (s, 4
.
α]D20 +23.8 (c 1.00, CHCl3).
3
[
IR (NaCl): 3352, 2950, 2922, 1746, 1678, 1515, 1457, 1203 cm–1
.
1
1
H NMR (500 MHz, CDCl ): δ = 0.87 (d, J = 7.5 Hz, 3 H), 0.88 (d, J = 7.0
H), 3.45 (s, 2 H), 3.75 (s, 3 H), 4.38 (m, 2 H), 6.90 (br d, J = 9.0 Hz, 2 H).
3
Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H), 0.84–1.14 (m, 4 H), 1.28 (m, 1 H),
1
H NMR (500 MHz, C D N): δ = 0.80 (d, J = 6.5 Hz, 6 H), 0.87 (d, J = 6.5
5
5
1
3
.45 (m, 1 H), 1.77 (br d, J = 13.5 Hz, 1 H), 1.80–1.89 (m, 2 H), 3.18–
.24 (m, 4 H), 3.37 (s, 2 H), 3.71 (s, 3 H), 4.33 (m, 1 H), 5.20 (d, J = 10.0
Hz, 6 H), 0.99 (d, J = 6.5 Hz, 6 H), 0.78–1.11 (m, 8 H), 1.46 (q, J = 13.0
Hz, 2 H), 1.52–1.61 (m, 2 H), 1.64–1.78 (m, 4 H), 1.99 (br d, J = 13.0 Hz,
2
1
13
Hz, 1 H), 5.23 (d, J = 16.5 Hz, 1 H), 5.78 (ddt, J = 6.3, 10.0, 16.5 Hz, 1 H),
H), 3.51 (s, 3 H), 3.80 (br s, 4 H), 3.82 (d, J = 17.7 Hz, 1 H), 3.85 (d, J =
7.7 Hz, 1 H), 4.71 (m, 2 H), 8.28 (br d, J = 9.0 Hz, 2 H).
7.66 (d, J = 7.5 Hz, 1 H).
13
C NMR (125 MHz, CDCl ): δ = 20.6, 20.9, 22.2, 25.2, 26.7, 29.5, 34.7,
3
C NMR (125 MHz, CDCl ): δ = 20.6, 21.0, 22.2, 25.1, 26.7, 29.5, 34.7,
3
0.2, 46.0, 46.2, 51.8, 55.6, 59.1, 168.9, 171.6.
40.1, 45.5, 46.2, 51.6, 55.0, 57.7, 58.3, 118.8, 133.8, 169.4, 171.1.
4
13
HRMS (ESI): m/z [M + H]+ calcd for C18H32N O : 325.2491; found:
2
3
C NMR (125 MHz, C D N): δ = 21.1, 21.3, 22.7, 25.3, 26.8, 29.8, 35.3,
5 5
1.1, 46.2, 46.7, 51.4, 55.7, 58.8, 170.3, 172.1.
325.2478.
4
HRMS (ESI): m/z [M + H]+ calcd for C27H50N O : 480.3801; found:
3
4
Methyl 2-(Bis{2-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexylami-
no]- 2-oxoethyl}amino)acetate (19)
480.3807.
To a solution of 17 (250 mg, 0.77 mmol) in EtOH (7.70 mL) was added
N,N′-dimethylbarbituric acid (156 mg, 1.00 mmol) and Ph P (61 mg,
3
Supporting Information
0.23 mmol). After degassing the solution, Pd(OAc)2 (13 mg, 0.058
mmol) was added under an argon atmosphere. The reaction mixture
was stirred at r.t. for 1.5 h, and concentrated under reduced pressure.
The resulting residue was subjected to silica gel chromatography
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380438.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
(EtOAc–hexane, 1:1) to afford a mixture of 18a and triphenylphos-
phine oxide (222 mg) as a brown oil.
References
A solution of the mixture containing 18a (222 mg) dissolved in 3 M
(
1) (a) Ichikawa, Y. Chem. Lett. 1990, 1347. (b) Ichikawa, Y. Synlett
HCl (2.0 mL) was stirred at 80 °C for 10 h, and washed with CH Cl .
2
2
1991, 715. (c) Ichikawa, Y. J. Chem. Soc., Perkin Trans. 1 1992,
The separated aqueous layer was concentrated in vacuo giving a solid
that was dissolved in toluene (ca. 5 mL). The solvent was removed
azeotropically on a rotary evaporator. After repeating this procedure
2
135. (d) Ichikawa, Y.; Yamazaki, M.; Isobe, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 2429. (e) Ichikawa, Y.; Matsuda, Y.;
Okumura, K.; Nakamura, M.; Masuda, T.; Kotsuki, H.; Nakano, K.
Org. Lett. 2011, 13, 2520.
(× 4), the crude white solid obtained was dried under vacuum for 30
min to yield the crude hydrochloride salt of 18b as a white solid (155
mg).
(
(
(
(
2) Saito, K.; Nishimori, A.; Kotsuki, H.; Nakano, K.; Ichikawa, Y.
Synlett 2013, 24, 757.
To a solution of the crude hydrochloride salt of 18b (155 mg) in MeOH
3) Saito, K.; Nishimori, A.; Mimura, R.; Nakano, K.; Kotsuki, H.;
Masuda, T.; Ichikawa, Y. Eur. J. Org. Chem. 2013, 2013, 7041.
4) (a) Ugi, I.; Steinbrückner, C. Chem. Ber. 1961, 94, 2802.
(7.0 mL) was added aqueous formaldehyde (37%, 0.29 mL, 3.85
mmol). After stirring at 50 °C for 30 min, a solution of terpene isocya-
nide 9 (159 mg, 0.96 mmol) in MeOH (0.7 mL) was added. The reac-
tion mixture was stirred at 50 °C for 30 min, and then concentrated
under reduced pressure. The resulting residue was dissolved in EtOAc
(b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
5) Tanaka, N.; Suto, S.; Asai, M.; Kusama, T.; Takahashi-Nakaguchi,
A.; Gonoi, T.; Fromont, J.; Kobayash, J. i. Heterocycles 2015, 90,
1
and H O, and the separated aqueous layer was extracted with EtOAc.
2
73.
6) Suto, S.; Tanaka, N.; Fromont, J.; Kobayash, J. i. Tetrahedron Lett.
011, 52, 3470.
The combined organic extract was washed with brine, dried (Na SO )
2
4
(
(
and concentrated to afford the residue (284 mg), which was purified
by silica gel chromatography (EtOAc–hexane, 1:1) to afford 19 (199
mg, 54%, 3 steps from 17).
2
7) (a) Demharter, A.; Hörl, W.; Herdtweck, E.; Ugi, I. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 173. (b) Ugi, I.; Demharter, A.; Hörl, W.;
Schmid, T. Tetrahedron 1996, 52, 11657.
One-Pot Synthesis of the Halichonadin M Analogue 19
8) For comparison of the 1H and 13C NMR data sets of the IDA
(
A solution of glycine (136 mg, 1.82 mmol) and aqueous formaldehyde
methyl ester moiety in natural halichonadin Q (1) with those in
the tert-butyl and menthyl analogues 7 and 10a, see the Sup-
porting Information.
(37%, 0.45 mL, 6.05 mmol) in MeOH (5.0 mL) was stirred at 50 °C for 1
h. To this solution was added a solution of isocyanide 9 (200 mg, 1.21
mmol) in MeOH (1.0 mL). After stirring at 50 °C for 1 h, the reaction
mixture was concentrated under reduced pressure to afford a residue,
(9) Speziale, A. J.; Jaworski, E. G. J. Org. Chem. 1960, 25, 728.
(10) Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109.
which was dissolved in EtOAc and H O. The separated aqueous layer
2
was extracted with EtOAc. The combined organic extract was washed
with brine and dried (Na SO ) and concentrated under reduced pres-
(11) Although we observed the formation of 16 by TLC, a serious
problem in separating a by-product having an R value similar to
2
4
f
that of 16 hampered further optimization of this process.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3043–3048

3
048
Synthesis
R. Mimura et al.
Paper
(
12) See the Supporting Information for the comparison of the 1H
(13) (a) Avilés, E.; Rodríguez, A. D. Org. Lett. 2010, 12, 5290.
(b) Tanaka, N.; Suto, S.; Ishiyama, H.; Kubota, T.; Yamano, A.;
Shiro, M.; Fromont, J.; Kobayashi, J. Org. Lett. 2012, 14, 3498.
13
and C NMR data sets of the IDA methyl ester moiety in hali-
chonadin M (2) with those in 16 and 19.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3043–3048