A biomimetic approach to terpenes isolated from marine sponges: A Ugi coupling reaction in a hypothetical biosynthesis

Article abstract of DOI:10.1055/s-0032-1318305

A unique pathway for the biosynthesis of marine sponge terpenes is proposed. Based on this proposal, a biomimetic approach using a Ugi coupling reaction has been designed and applied to the efficient construction of the right-side, peptide-like portions of boneratamides and exigurin. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318305

LETTER
▌757
lAetteBr iomimetic Approach to Terpenes Isolated from Marine Sponges:
a Ugi Coupling Reaction in a Hypothetical Biosynthesis
Biomimetic Approach to Marine Sponge Terpenes
Kenta Saito, Ayumu Nishimori, Hiyoshizo Kotsuki, Keiji Nakano, Yoshiyasu Ichikawa*
Faculty of Science, Kochi University, Akebono-cho Kochi 780-8520, Japan
Fax +81(88)8448359; E-mail: ichikawa@kochi-u.ac.jp
Received: 28.12.2012; Accepted after revision: 01.02.2013
Apparently, boneratamides have no isocyano functional-
ity and they are comprised of a terpene unit (left side) link-
ing via an amide bond to a peptide-like moiety (right-
side). The unique structure of the right-side portion of
boneratamides inspired us, because we surmised that
these terpenes might be derived from the terpene isocya-
nide, axisonitrile-33 by a hitherto unrecognized biosyn-
thetic pathway. Our hypothetical biosynthetic pathway of
the right-side portions of boneratamides A–C is presented
retrosynthetically in Scheme 1, which reveals their origin
as a terpene isocyanide and simple precursors. The key
step in the proposed route is a Ugi coupling reaction,4
which shows that boneratamides A–C might be traced
back to three building blocks, including axisonitrile-3 (7),
a carbonyl component, either acetone (8) or acetaldehyde
(9), and glutamic acid (10). In order to explore the plausi-
bility of this biosynthetic hypothesis, we conducted an in-
vestigation of the synthesis of boneratamides A–C using a
biomimetic strategy that is based on the putative Ugi cou-
pling reaction.
Abstract: A unique pathway for the biosynthesis of marine sponge
terpenes is proposed. Based on this proposal, a biomimetic ap-
proach using a Ugi coupling reaction has been designed and applied
to the efficient construction of the right-side, peptide-like portions
of boneratamides and exigurin.
Key words: Ugi reaction, biomimetic synthesis, terpenes, marine
sponges, ugiase
Over the past several decades, our research has focused on
the development of the synthesis of terpene isocyanides
found in marine organisms.1 In recent research endeavors
in this area, our attention has been drawn to the structural-
ly unique group of terpenes, boneratamides A–C (Figure
1).2 Boneratamides A–C were isolated from the marine
sponge Axinyssa aplysinoides by Andersen and co-work-
ers in 2004 and the relative stereochemistry of bonerat-
amide A (1) was determined by X-ray crystallographic
analysis of the corresponding methyl ester 2 (only one en-
antiomer with a C-23S absolute configuration is shown).
The structures of boneratamides B (3) and C (4) were elu-
cidated by extensive NMR spectroscopic studies on the
corresponding methyl esters 5 and 6, which established
that boneratamides B (3) and C (4) are stereoisomers dif-
fering in the relative configuration at either one or both of
the C18 and C23 stereogenic centers.
N
Ugi reaction
C
O
O
axisonitrile-3 (7)
N
N
O
O
H
CO2H
R
O
O
or
H
9
boneratamide A (1: R = Me)
boneratamide B and C (3 and 4: R = H)
8
N
23
N
HO2C
CO2H
NH2
H
CO2R
10
boneratamide A (1): R = H
methyl ester of boneratamide A (2): R = Me
Scheme 1 Retrobiosynthetic analysis of boneratamides illustrating
their terpene isocyanide origin
O
O
During the course of our research efforts in this area, hal-
ichonadins K and L were isolated from marine sponges by
Kobayashi and his co-workers.5 These workers suggested
the possibility that the biogenetic origin of halichonadins
K and L involved reaction of an intermediate iminium cat-
ion with a terpene isocyanide. This publication has
prompted us to disclose our own independently derived
proposal for the biosynthesis of terpenes from marine
sponges and to disclose preliminary synthetic studies, the
first in vitro chemical evidence for the proposed biosyn-
thetic pathway.
N
18
23
N
H
CO2R
H
boneratamide B (3) and C (4): R = H
methyl ester of boneratamide B (5) and C (6): R = Me
Figure 1 Structures of boneratamides A–C and their methyl esters
SYNLETT 2013, 24, 0757–0761
Advanced online publication: 06.03.2013
DOI: 10.1055/s-0032-1318305; Art ID: ST-2012-U1106-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

758
K. Saito et al.
LETTER
A Ugi one-pot multicomponent reaction (MCR) of p- 67% yield.9 Inspection of the 1H NMR and 13C NMR data
methoxyphenyl isocyanide (11),6 acetone (8) and the glu- for boneratamide A methyl ester (2) and γ-lactam 15 sum-
tamic acid derivative 13 was explored as a model for the marized in Table 1 shows that the NMR data of 15 are in
key process involved in the proposed boneratamide ter- good accord with those reported for 2. These observations
pene biosynthesis pathway (Scheme 2). It is well known demonstrate that a simple and remarkably efficient biomi-
that the use of β-amino acids as a bifunctional coupling metic one-pot process led to the formation of the right-
component in the Ugi four-center three-component reac- side portion of boneratamide A (1).
tion (U-4C-3CR) results in β-lactam ring formation.7 Con-
MeO
sequently, we elected to employ γ-amino acid 13 as a
O
substrate, with the expectation that the U-4C-3CR would
MeOH, 50 °C
lead to the construction of a γ-lactam structure corre-
sponding to the right-side portion of boneratamide A.8 Af-
ter some experiments, we were delighted to find that the
Ugi coupling process did indeed generate the right-side
portion of boneratamide A. In fact, reaction of isocyanide
11, acetone (8; 10 equiv) and L-glutamic acid 1-methyl es-
ter (13; 1.5 equiv) in methanol at 50 °C, followed by chro-
matographic purification, furnished γ-lactam 14 in 60%
yield. Furthermore, the sterically hindered tert-butyl iso-
cyanide (12), serving as a model of axisonitrile-3 (7), also
participated in this Ugi reaction producing γ-lactam 15 in
N
C
8
11
HO2C
CO2Me
NH2
or
R
N
C
13
12
O
O
14: R = 4-MeOC6H4 (60%)
15: R = t-Bu (67%)
N
N
H
CO2Me
Scheme 2 One-pot synthesis of the right-side portion of bonerat-
amide A by a Ugi reaction
Table 1 Comparison of NMR Data (C6D6, 500 MHz) for the Methyl Ester of Boneratamide A (2) with γ-Lactam 15
21
O
O
O
20
O
16
N
18
23
N
17
N
N
H
CO2Me
H
CO2Me
γ-lactam 15
25
26
24
methyl ester of boneratamide A (2)
Position
on 2
16
1H NMR
13C NMR
2a
15
2a
15
7.49 (d, J = 10.4 Hz)
7.29 (1 H, br s)
17
172.7
60.9
172.4
60.6
18
20
174.0
30.0
173.9
29.9
21
1.79 (ddd, J = 16.4, 9.5, 1.9 Hz)
2.14 (m)
1.75 (1 H, ddd, J = 16.6, 9.2, 1.7 Hz)
2.04 (1 H, ddd, J = 16.6, 11.4, 9.2 Hz)
1.25 (1 H, m)
21
22
1.30 (m)
24.5
24.6
22
1.42–1.50
1.37–1.44 (1 H, m)
23
3.78 (dd, J = 9.8, 1.5 Hz)
3.72 (1 H, dd, J = 9.7, 1.1 Hz)
57.8
175.5
23.8
57.8
175.8
23.4
24
25
1.66 (s)
1.25 (s)
3.17 (s)
1.56 (3 H, s)
1.12 (3 H, s)
3.11 (3H, s)
26
25.6
25.3
OMe
52.5
52.4
a NMR data of 2 are reproduced from the isolation paper; see ref. 2.
Synlett 2013, 24, 757–761
© Georg Thieme Verlag Stuttgart · New York

LETTER
Biomimetic Approach to Marine Sponge Terpenes
759
A plausible reaction mechanism for the U-4C-3CR form- the isomers of 18 have structures, which are identical to
ing 14 and 15 is shown in Scheme 3. In this pathway, re- the right-side portions of each boneratamide B and C.12
action of acetone (8) with amino acid 13 affords the
MeOH, 50 °C
protonated Schiff base 16, which reacts with the isocya-
O
NH2
+
N
C
+
(37%, 3:1)
nide (11 or 12) to produce O-acylimidate intermediate 17.
Finally, O-to-N acyl migration of 17 gives rise to the final
γ-lactam core in 14 or 15.10
H
HO2C
CO2Me
12
9
19
O
H
N
1) separation
CO2Me
18a or 18b
N
H
OOC
2) toluene, reflux
R
N
C
H
CO2Me
(11 or 12)
H
OMe
+
20
8
13
N
O
Scheme 5 Improved synthesis of 18 using U-5C-4CR
16
O
O
γ-lactam
formation
OMe
O
Formation of 20 in the U-5C–4CR appears to be governed
by the reactivity of the cyclic O-acylimidate intermediate
22 (Scheme 6). Schiff base 21, formed by the reaction of
acetaldehyde (9) with α-amino acid 19, would react with
isocyanide 12 to afford intermediate 22. Since O-to-N
acyl migration of 22 would produce a highly strained α-
lactam, methanol intercepts the O-acylimidate 22 to form
20.
O
N
O
OMe
N
R
N
H
H
R
O
N
14 or 15
17
Scheme 3 A plausible mechanism for the Ugi reaction
Encouraged by these results, we examined a closely relat-
ed process that serves as a model for generating the right-
side portion of boneratamide B (3) and boneratamide C
(4) (Scheme 4). Disappointingly, we observed that Ugi
coupling reaction of tert-butyl isocyanide 12, acetalde-
hyde (9) and γ-amino acid 13 produced an inseparable 1:1
mixture of the γ-lactams 18a and 18b in a low yield
(22%).
COO
N
C
H
12
N
CO2Me
+
9
19
MeOH
21
H
O
MeOH
CO2Me
O
20
NH
MeOH, 50 °C
(22%)
O
NH2
N
+
+
H
22
N
C
H
MeO2C
CO2H
12
9
13
Scheme 6 Mechanism for U-5C-4CR forming 20
O
O
O
O
Synthesis of the despirocyclic boneratamide A analogue
26 was explored (Scheme 7). The known azide 24,13 pre-
pared from (+)-menthol (23), was transformed to the ter-
pene isocyanide 25 in 73% overall yield by employing a
sequence involving: (1) hydrogenation of the azide 24, (2)
reaction of the resulting amine with acetic formic anhy-
dride, and (3) dehydration of the formed formamide with
triphosgene and triethylamine. Ugi reaction of isocyanide
+
N
N
N
N
H
H
CO2Me
CO2Me
H
H
18b
18a
Scheme 4 Model for the synthesis of the right-side portion of
boneratamide B and boneratamide C
In order to find a more efficient method to produce 18a
and 18b in pure forms, our attention turned to a stepwise
synthetic route (Scheme 5) involving a Ugi five-center-
four-component reaction (U-5C–4CR),11 in which α-ami-
no acid 19 serves as a bifunctional starting material. Treat-
ment of tert-butyl isocyanide 12 with acetaldehyde (9)
and L-glutamic acid 5-methyl ester (19) afforded a 3:1
mixture of the diastereomeric amides 20 in 37% yield. To
our delight, a mixture of 20 could be separated and each
isomer was individually subjected to heating in toluene,
furnishing the respective γ-lactams 18a and 18b in pure
form. Although the relative stereochemistries of the dia-
stereomers of 18 and 20 could not be assigned, the NMR
spectroscopic properties of these substances support their
structural assignments and, importantly, they show that
1) H2, Pd/C
AcOCHO
ref. 13
2) triphosgene
Et3N, CH2Cl2
(73%)
OH
N3
N
C
(+)-menthol (23)
24
25
O
O
MeOH, 50 °C
O
8
N
N
H
HO2C
CO2Me
CO2Me
26
NH2
(43%)
13
Scheme 7 Synthesis of 26, a despirocyclic boneratamide A analogue
Synlett 2013, 24, 757–761
© Georg Thieme Verlag Stuttgart · New York

760
K. Saito et al.
LETTER
25, using conditions similar to those described in Scheme In the study described above, we have demonstrated that
2, delivered 26 in 43% yield.
approaches that mimic the newly proposed biosynthetic
pathways can be employed to generate the peptide-type
units in the boneratamides A–C and exigurin. Although
the yields of Ugi reaction in our preliminary results are
only moderate, the concise nature of the multicomponent,
one-pot procedures makes the routes particularly attrac-
tive. In addition, our studies shed some light on the poten-
tially important role played by Ugi reactions in the
biosynthesis of natural products found in marine organ-
isms, which suggests possible involvement of a putative
‘ugiase’ enzyme. The Ugi reaction has been exploited ex-
tensively for combinatorial diversity-oriented synthesis in
the filed of medicinal chemistry, and it is quite surprising
for us to recognize that Nature also employs the Ugi reac-
tion to build up molecular diversity in natural product bio-
synthesis. Further studies on the synthesis of
boneratamides are now under investigation in our labora-
tory.
Parallel to our synthetic studies of boneratamides, we
have surveyed the literatures in order to uncover more ex-
amples of marine natural products that might be biosyn-
thesized via pathways involving Ugi coupling reaction.
This literature browsing found two buried examples, exig-
urin (27) and halichonadin G (28; Figure 2). Exigurin (27)
was isolated by Ikegami group in 2003 from the marine
sponge Geodia exigna.14 In 2011, Kobayashi and his co-
workers isolated halichonadin G (28) from the sponge
Halichondria sp.15 These terpenes share the interesting
amide structural unit 29. We envisioned that the common
structural unit 29 could be synthesized with a similar sce-
nario using U-5C-4CR, which employs a terpene isocya-
nide and a glycine derivative along with formaldehyde.
OMe
OMe
O
O
H
H
N
O
N
O
N
Me
Acknowledgment
H
O
We are grateful for the financial support provided by a Grant-in-Aid
for Scientific Research (C) (23510258) from MEXT.
NH
N
H
Supporting Information for this article is available online at
exigurin (27)
halichonadin G (28)
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
H
MeO
N
References
N
R
terpene
O
O
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(9) A solution of L-glutamic acid 1-methyl ester (13; 430 mg,
2.67 mmol) and acetone (8; 1.30 mL, 17.8 mmol) in MeOH
(25.0 mL) was treated with tert-butyl isocyanide (12; 0.20
mL, 1.78 mmol). After stirring at r.t. for 1.5 h, the solution
terpene
29: R = Me or CONH
Figure 2 Exigurin, halichonadin G and their common amide struc-
tural unit 29
We examined the synthesis of the common structural unit
29 in exigurin (Scheme 8). The model isocyanide 30 was
prepared from (–)-menthol by utilizing a procedure simi-
lar to that described for the preparation of its enantiomer
25 in Scheme 7. One-pot multicomponent Ugi reaction of
isocyanide 30, paraformaldehyde and sarcosine (31) in
methanol led to the formation of the terpene amide 32 in
45% yield. Although low yielding, this potentially biomi-
metic one-step U-5C-4CR approach to construction of the
structural unit 29 found in the marine natural product ex-
igurin is impressive.
OMe
OH
O
N
O
O
31
Me
N
(HCHO)n
H
Me
N
C
NH
MeOH, 50 °C
(45%)
32
30
Scheme 8 Synthesis of an exigurin analogue
Synlett 2013, 24, 757–761
© Georg Thieme Verlag Stuttgart · New York

LETTER
was heated at 50 °C for 24 h, followed by refluxing for 1 h.
Biomimetic Approach to Marine Sponge Terpenes
761
(11) (a) Demharter, A.; Hörl, W.; Herdtweck, E.; Ugi, I. Angew.
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A.; Hörl, W.; Schmid, T. Tetrahedron 1996, 52, 11657.
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The reaction mixture was concentrated under reduced
pressure, and the residue was dissolved in EtOAc and H2O.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts were
dried (Na2SO4) and concentrated to afford the residue, which
was purified by silica gel chromatography to furnish γ-
lactam 15 (337 mg, 67%).
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(15) Suto, S.; Tanaka, N.; Fromont, J.; Kobayashi, J. Tetrahedron
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 757–761

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