A biomimetic approach to the synthesis of the core structure of the marine sponge terpene halichonadin G

Article abstract of DOI:10.1002/ejoc.201301206

A pathway for the biosynthesis of halichonadin G involving the unique action of ugiase and isocyanide oxidase is proposed. This hypothesis was tested in a biomimetic approach to the synthesis of the core structural unit of this marine sponge terpene, which relies on a key Ugi coupling reaction and an isocyanide-to-isocyanate oxidative transformation. The results of this effort demonstrate that the biomimetic strategy can be employed to construct the core structure of halichonadin G in an efficient manner. A unique pathway for the biosynthesis of the marine sponge terpene halichonadin G is proposed. On the basis of this proposal, a biomimetic approach involving a Ugi coupling reaction is designed and applied to the efficient construction of the core structure of halichonadin G. Copyright

Full text of DOI:10.1002/ejoc.201301206

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301206
A Biomimetic Approach to the Synthesis of the Core Structure of the Marine
Sponge Terpene Halichonadin G
Kenta Saito,[a] Ayumu Nishimori,[a] Rika Mimura,[a] Keiji Nakano,[a] Hiyoshizo Kotsuki,[a]
Toshiya Masuda,[b] and Yoshiyasu Ichikawa*[a]
Dedicated to Professor Sir Jack Baldwin
Keywords: Biomimetic synthesis / Multicomponent reactions / Natural products / Terpenoids
A pathway for the biosynthesis of halichonadin G involving
and an isocyanide-to-isocyanate oxidative transformation.
the unique action of ugiase and isocyanide oxidase is pro- The results of this effort demonstrate that the biomimetic
posed. This hypothesis was tested in a biomimetic approach
to the synthesis of the core structural unit of this marine
sponge terpene, which relies on a key Ugi coupling reaction
strategy can be employed to construct the core structure of
halichonadin G in an efficient manner.
assembly to construct the central core structure of hal-
ichonadins K and L.[8] The intensity of these recent reports
prompted us to describe the results of our recent investi-
gations aimed at exploring a biomimetic synthesis of
halichonadin G.
Halichonadin G is a marine natural product isolated in
2011 by Kobayashi and his co-workers from the sponge
Halichondria sp. collected at Unten Port on Okinawa Is-
land.[9] The structure of halichonadin G (1), an optically
active amorphous solid, was elucidated by extensive spec-
troscopic analyses as shown in Figure 1.[9] The central core
structure of 1 is iminodiacetic acid (IDA) methyl ester, to
which two common eudesmane sesquiterpenoid units are
appended through amide and urea functionalities.
Introduction
Over the past several decades, we have focused our re-
search efforts on the synthesis of terpene isocyanides iso-
lated from marine organisms.[1] During this research en-
deavor, we proposed a strategy for the synthesis of novel,
marine organism derived terpenes, such as boneratamides
and exigurin,[2] which relies on the use of in vivo Ugi cou-
pling reactions[3] of terpene isocyanides. The boneratamides
were isolated from the marine sponge Axinyssa aplysinoides,
collected in Indonesia, and characterized by Andersen and
co-workers in 2004.[4] Exigurin is a terpene isolated from
the marine sponge Geodia exigna collected off Oshima is-
land, Kagoshima Prefecture, Japan, and its structure was
elucidated by the Ikegami group in 2003.[5]
In 2010, Rodriguez and Aviles isolated the diterpenoid
β-lactam monamphilectine A from a Puerto Rican marine
sponge Hymeniacidon sp. and carried out a semisynthesis
of this substance, which employed a multicomponent Ugi
reaction starting with (–)-8,15-dicyano-11(20)-amphilec-
tene.[6] In 2012, halichonadins K and L were isolated and
characterized by Kobayashi and co-workers.[7] This group
also suggested that the routes for biosynthesis of these hal-
ichonadins involve a reaction of an iminium cation with a
Figure 1. Structures of halichonadin G and its central core struc-
terpene isocyanide.[7] Quickly following Kobayashi’s pro- ture.
posal, Poupon described a biomimetic, three-component
[a] Faculty of Science, Kochi University,
Results and Discussion
Akebono-cho, Kochi 780-8520, Japan
E-mail: ichikawa@kochi-u.ac.jp
In considering the biosynthetic origin of halichonadin G
(1), it is important to recognize that in 2005 Kobayashi de-
scribed the isolation of the terpene isocyanide halichona-
din C (2) from the same marine sponge found at Unten Port
[b] Faculty of Integrated Arts and Sciences, University of
Tokushima,
Tokushima 770-8502, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301206
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Y. Ichikawa et al.
SHORT COMMUNICATION
(Scheme 1).[10] This finding along with chemical intuition However, by switching the protecting group to the more
suggests that halichonadin C (2) is a likely biogenetic pre- robust benzyl group, product 10 (R = CH2Ph) was isolated
cursor of halichonadin G (1). In a route based on this pro- in an improved 67% yield. Removal of the benzyl group in
posal, a hypothetical ugiase might promote a Ugi reaction 10 by using 2,2,2-trichloroethyl chloroformate formed the
of 2 with glycine, formaldehyde, and methanol to generate corresponding 2,2,2-trichloroethoxycarbonyl (Troc) deriva-
terpene–IDA conjugate 3, in which the IDA core is linked tive, albeit in low to variable yields (13–44%). Although
to the terpene unit through an amide bond. In turn, the catalytic hydrogenolytic cleavage of benzyl protecting
action of an isocyanide oxidase on isocyanide 2 would pro- groups is usually sluggish and often requires elevated hydro-
duce isocyanate 4, which through reaction with conjugate 3 gen pressures,[12] hydrogenolysis of 10 by using Pearlman’s
would generate the urea bond in halichonadin G (1). To catalyst proceeded smoothly at atmospheric pressure to fur-
explore the chemical foundation of this proposed biosyn- nish amine 11 in 91% yield. Treatment of 11 with commer-
thetic pathway, we embarked on a study aimed at the syn- cially available cyclohexyl isocyanate then afforded IDA
thesis of an analogue of halichonadin G.
methyl ester 12 (67%), which contains the N-tert-butyl and
N-cyclohexyl groups linked through an amide and urea
bond, respectively.
Scheme 3. Synthesis of the core structure in halichonadin G.
We next turned our attention to the synthesis of the cen-
tral core of halichonadin G, which is linked to the two ter-
pene units (Scheme 4). Starting with known azide 13, pre-
pared from (–)-menthol,[13] menthyl isocyanide 15 was syn-
thesized in 70% overall yield by a sequence involving (1) hy-
drogenation of azide 13 followed by formylation with acetic
formic anhydride and (2) dehydration of resulting for-
mamide 14 with triphosgene and triethylamine. Biomimetic
U-5C-4CR of isocyanide 15 with N-benzylglycine 9b and
paraformaldehyde in methanol proceeded smoothly at
Scheme 1. Plausible biosynthetic pathway of halichonadin G illus-
trating its origin from terpene isocyanide halichonadin C.
Preliminary studies focused on the Ugi five-center four-
component reaction (U-5C-4CR)[11] of tert-butyl isocy
anide, glycine, formaldehyde, and methanol (Scheme 2).
Disappointingly, we did not observe the formation of de-
sired Ugi coupling product 6, and unwanted products 7 and
8 were isolated in 16 and 2% yield, respectively. Major
product 7 most likely arises from 6 through an over-Ugi
reaction.
Scheme 2. Unsuccessful model experiments to mimic the proposed
biosynthesis of halichonadin G.
To circumvent the problem associated with the higher
reactivity of the amine group in 6 than that in glycine, we
carried out the Ugi reaction by employing nitrogen p-meth-
oxybenzyl (PMB) protected glycine derivative 9a
(Scheme 3). Unfortunately, this process generated desired
Ugi product 10 (R = PMB) in a very low yield (Ͻ12%). Scheme 4. Synthesis of a menthyl analogue of halichonadin G.
2
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Core Structure of the Marine Sponge Terpene Halichonadin G
50 °C over 30 min to produce coupling product 16 in 74% in halichonadin G. Moreover, all 13C NMR chemical shifts
yield. Hydrogenolysis of the benzyl group in 16 proceeded for the carbon atoms in the IDA moieties of menthyl analog
uneventfully to furnish secondary amine 17 in 87% yield. 19 and halichonadin G (1) are quite similar (Table 2).
In a parallel route, isocyanate 18 was prepared by oxidation
of isocyanide 15 with pyridine N-oxide (PNP) and a cata-
Conclusions
lytic amount of iodine in the presence of 3 Å molecular si-
eves (MS).[14] Finally, reaction of isocyanate 18 with 17 gave
rise to 19, the menthyl analogue of halichonadin G, in 75%
yield after chromatographic purification.
In the study described above, we successfully tested the
chemical features of our proposed biosynthesis of terpenes
related to halichonadin G. In the biomimetic pathway tar-
geted at menthyl analog 19, the core structure of halichona-
din G was constructed by utilizing a Ugi five-center four-
component reaction and an isocyanide oxidation as the two
key steps. The results of this effort serve to support the pro-
posal that Nature utilizes Ugi-type reactions in biosynthetic
pathways to create molecular diversity in natural products.
Studies targeted at the synthesis of halichonadin G are now
underway in our laboratory.
1
A comparison of the H NMR spectroscopic data in the
IDA moieties of natural halichonadin G (1) and menthyl
analog 19 is shown in Table 1. The 1H NMR chemical shift
and coupling properties of the methylene hydrogen atoms
(2ЈЈ-H and 4ЈЈ-H by using halichonadin G numbering) in
the IDA unit of 19 are quite similar to those of 1. The
chemical shifts of the 6-NH and 6Ј-NH amide hydrogen
atoms in halichonadin G (δ = 4.04 and 7.12 ppm) reside
upfield relative to those in menthyl analogue 19 (δ = 5.22
and 7.89 ppm). This phenomenon is presumably a conse-
quence of the shielding effect of the adjacent alkene moiety
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and 13C
NMR spectra of all relevant compounds.
Table 1. Comparison of selected 1H NMR spectroscopic data[a] for
halichonadin G (1) and model compound 19.
[1] a) Y. Ichikawa, Chem. Lett. 1990, 1347–1350; b) Y. Ichikawa,
Synlett 1991, 715–716; c) Y. Ichikawa, J. Chem. Soc. Perkin
Trans. 1 1992, 2135–2139; d) Y. Ichikawa, M. Yamazaki, M.
Isobe, J. Chem. Soc. Perkin Trans. 1 1993, 2429–2432; e) Y.
Ichikawa, Y. Matsuda, K. Okumura, M. Nakamura, T. Ma-
suda, H. Kotsuki, K. Nakano, Org. Lett. 2011, 13, 2520–2523.
[2] K. Saito, A. Nishimori, H. Kotsuki, K. Nakano, Y. Ichikawa,
Synlett 2013, 24, 757–761.
[3] a) I. Ugi, Angew. Chem. 1982, 94, 826–835; Angew. Chem. Int.
Ed. Engl. 1982, 21, 810–819; b) A. Dömling, I. Ugi, Angew.
Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed. 2000, 39,
3168–3210.
[4] D. E. Williams, B. O. Patrick, A. Tahir, R. Van Soest, M. Rob-
erge, R. J. Andersen, J. Nat. Prod. 2004, 67, 1752–1754.
[5] M. M. Uy, S. Ohta, M. Yanai, E. Ohta, T. Hirata, S. Ikegami,
Tetrahedron 2003, 59, 731–736.
[6] E. Avilés, A. D. Rodríguez, Org. Lett. 2010, 12, 5290–5293.
[7] N. Tanaka, S. Suto, H. Ishiyama, T. Kubota, A. Yamano, M.
Shiro, J. Fromont, J. Kobayashi, Org. Lett. 2012, 14, 3498–
3501.
Position
1
19
δH [ppm] M[b] (J [Hz]) δH [ppm] M[b] (J [Hz])
2ЈЈ
2ЈЈ
4ЈЈ
4.12
3.59
3.92
3.56
7.12
4.04
3.73
d (17.3)
d (17.3)
d (18.1)
d (18.1)
br. d (9.2)
br. d (8.9)
s
4.34[c]
3.94
d (17.9)
d (17.9)
d (16.4)
d (16.4)
br. d (8.6)
br. d (8.6)
s
3.89[c]
3.73
4ЈЈ
6-NH[d]
6Ј-NH[d]
OMe
7.89
5.22
3.76
[8] F. Senejoux, L. Evanno, E. Poupon, Eur. J. Org. Chem. 2013,
[a] Measured in CDCl3. [b] M = multiplicity. [c] Assignments deter-
mined by HMBC experiments. [d] Assignment of these signals may
be interchangeable.
453–455.
[9] S. Suto, N. Tanaka, J. Fromont, J. Kobayashi, Tetrahedron Lett.
2011, 52, 3470–3473.
[10] H. Ishiyama, A. Hashimoto, J. Fromont, Y. Hoshino, Y. Mi-
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[11] a) A. Demharter, W. Hörl, E. Herdtweck, I. Ugi, Angew. Chem.
1996, 108, 185–187; Angew. Chem. Int. Ed. Engl. 1996, 35, 173–
175; b) I. Ugi, A. Demharter, W. Hörl, T. Schmid, Tetrahedron
1996, 52, 11657–11664.
[12] P. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Or-
ganic Synthesis 4th ed., Wiley, Hoboken, 2007.
[13] M. Ito, K. Koyakumaru, T. Ohta, H. Takaya, Synthesis 1995,
376–378.
Table 2. Comparison of selected 13C NMR spectroscopic data[a] for
halichonadin G (1) and model compound 19 and their differences
(Δδ).
Position
δC [ppm]
Δδ[b] [ppm]
1
19
1ЈЈ
2ЈЈ
3ЈЈ
4ЈЈ
5ЈЈ
157.7
51.2
171.8
53.8
157.6
50.8
172.2
54.7
0.1
0.4
–0.4
–1.1
0
[14] a) H. W. Johnson, H. C. Krutzsch, J. Org. Chem. 1967, 32,
1939–1941; b) Y. Ichikawa, T. Nishiyama, M. Isobe, J. Org.
Chem. 2001, 66, 4200–4205.
168.8
168.8
Received: August 9, 2013
[a] Measured in CDCl3. [b] Δδ = δ1 – δ19.
Published Online: ᭿
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Y. Ichikawa et al.
SHORT COMMUNICATION
Biomimetic Synthesis
K. Saito, A. Nishimori, R. Mimura,
K. Nakano, H. Kotsuki, T. Masuda,
Y. Ichikawa* ..................................... 1–4
A Biomimetic Approach to the Synthesis
of the Core Structure of the Marine
Sponge Terpene Halichonadin G
A unique pathway for the biosynthesis of
the marine sponge terpene halichonadin G
is proposed. On the basis of this proposal,
a biomimetic approach involving a Ugi
coupling reaction is designed and applied
to the efficient construction of the core
structure of halichonadin G.
Keywords: Biomimetic synthesis / Multi-
component reactions / Natural products /
Terpenoids
4
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Eur. J. Org. Chem. 0000, 0–0