Total synthesis of exigurin: The Ugi reaction in a hypothetical biosynthesis of natural products

Article abstract of DOI:10.1039/c9ob02249j

The first total synthesis of a marine natural product, exigurin, has been accomplished in 13 steps starting from (+)-menthone. The key intermediate (-)-10-epi-axisonitrile-3 was prepared by stereoselective intramolecular cyclopropanation followed by a cyclopropane ring opening reaction by the azide anion. The bioinspired Ugi reaction of (-)-10-epi-axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and amino acid units were linked through an amide bond.

Full text of DOI:10.1039/c9ob02249j

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DOI: 10.1039/C9OB02249J
ARTICLE
Total Synthesis of Exigurin: Ugi Reaction in a Hypothetical
Biosynthesis of Natural Products
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Seijiro Hosokawa,*a Keisuke Nakanishi,a Yutaro Udagawa,a Mitsutoshi Maeda,b Seiya Sato,b Keiji
Nakano,b Toshiya Masudac and Yoshiyasu Ichikawa*b
The first total synthesis of a marine natural product exigurin has been accomplished in 13 steps starting from (+)-
menthone.
The key intermediate (–)-10-epi-axisonitrile-3 was prepared using stereoselective intramolecular
cyclopropanation followed by cyclopropane ring opening reaction by azide anion. A bioinspired Ugi reaction of (–)-10-epi-
axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and
amino acid units are linked through an amide bond.
Introduction
O
The marine world is characterized by countless numbers of
unique organisms that produce an extraordinary abundance of
structurally and functionally diverse secondary metabolites.1
Consequently, marine organisms have continued to serve as
sources for a wide variety of biologically active natural
products, which are generated by unique biosynthetic
pathways that are not present in land organisms.2 With this
ocean’s blessing in mind, we have focused on two marine
natural products, exigurin (1) and boneratamide A (2) (Fig. 1).
Exigurin (1) was isolated in 2003 by Ohta and Ikegami from the
marine sponge Geodia exigua collected in Oshima island.3 In
the following year, Anderson and co-workers isolated
O
Me
N
O
N
N
H
N
H
CO2H
CO2Me
exigurin (
1)
boneratamide A (2)
Figure 1 Structures of exigurin and boneratamide A
We were captivated by the unusual structures of exigurin (1)
and boneratamide A (2), both of which contain terpene and
amino acid units connected through an amide linkage. Of
particularly interest is the fact that these terpene-amino acid
conjugates possess a common imino-diacetic acid structural
motif. This type of structural motif is found in products of the
Ugi reaction,5 which has found widespread use in both
boneratamide
A (2) from the marine sponge Axinyssa
aplysinoides collected in Indonesia.4
diversity and target-oriented organic synthesis.6
This
relationship led us to propose that exigurin and boneratamide
A might be constructed in the marine sponges through
hitherto unrecognized biosynthetic pathway that utilizes Ugi
reactions (Scheme 1).7 Specifically, exigurin (1) might originate
from four building blocks including (–)-10-epi-axisonitrile-3
(3),8 and the simple substances formaldehyde, sarcosine and
methanol. Similarly, Ugi reaction between axisonitrile-3 (4),9
acetone and glutamic acid could be the key step in the
biosynthesis of boneratamide A (2). Although Rodriguez used
the Ugi reaction to transform 8,15-diisocyano-11(20)-
amphilectene to monamphilectine A,10 the possibility that a
Ugi type pathway is involved in the biosynthesis of exigurin
and boneratamide A has been overlooked by the scientific
community.11
a. Department of Applied Chemistry, Faculty of Advanced Science and Engineering,
Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan, E-mail:
seijiro@waseda.jp
b. Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan, E-mail:
ichikawa@kochi-u.ac.jp
c. Graduate School of Human Life Science, Osaka City University, Osaka 558−8585,
Japan.
†Electronic supplementary information (ESI) available. CCDC 1943181 and
1943176. For ESI and crystallographic data in CIF or other electronic format, see
DOI: 10.1039/x0xx00000x
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carbocation
formation
DOI: 10.1039/C9OB02249J
fragmentation
10
Me
HCHO
MeOH
N
H
CO2H
OH
10
exigurin (1)
Ugi reaction
N
C
II
(–)-10-epi-cubebol (
I)
(–)-10-epi-axisonitrile-3 (3)
Ritter reaction
H2OC
CO2H
NH2
O
N
C
H
C
N
boneratamides A (2)
(–)-10-epi-axisonitrile-3 (3)
III
N
C
Ugi reaction
1) carbocation formation
2) fragmentation
axisonitrile-3 (4)
Scheme 1 Presumed biosyntheses of exigurin and boneratamide A from marine
terpene isocyanides
3) Ritter reaction
N
OH
C
In order to assess the feasibility of the hypothesis described
above and to generate sufficient quantities for biological
studies, we designed a research project aimed at the total
synthesis of exigurin (1) and boneratamide A (2). The initial
stage of this project focused on the synthesis of (–)-10-epi-
axisonitrile-3 (3) and axisonitrile-3 (4), which would serve as
substrates in the hypothetical Ugi reactions. The recent report
on the synthesis of exiguamide, a precursor of (–)-10-epi-
axisonitrile-3 (3), by Watanabe and Takikawa12 prompted us to
present the results of the preliminary phase of our
investigation, which resulted in the synthesis of (–)-10-epi-
axisonitrile-3 (3), a key intermediate for axisonitrile-3 (4) and
total synthesis of exigurin (1).
axisonitrile-3 (4)
(+)-cubebol (IV
)
H
H2O
OH
OH
(–)-cubebol (
V
)
axenol (VI)
Scheme 2 Hypothetical biosynthesis of (–)-10-epi-axisonitrile-3 and axisonitrile-3
Guided by the hypothetical biosynthesis shown in Scheme 2,
we formulated
a retrosynthetic analysis of (–)-10-epi-
Results and discussion
axisonitrile-3 (3) and axisonitrile-3 (4) (Scheme 3). When we
could take advantage for introducing a nitrogen substituent
using the Ritter reaction for the synthesis of (–)-10-epi-
axisonitrile-3 (3), we could utilize cyclopropyl ketone I as a
precursor to generate carbocation for the Ritter reaction.
Our plan for the synthesis of (–)-10-epi-axisonitrile-3 (3) and
axisonitrile-3 (4) was guided by a consideration of the
hypothetical biosynthetic routes depicted in Scheme 2. In the
case of (–)-10-epi-axisonitrile-3 (3), ionization of (–)-10-epi-
cubebol (I) would form the cyclopropylcarbinyl cation II, which
upon cyclopropane ring opening would produce homoallylic
carbocation III. Cyanide promoted Ritter reaction of III would
then generate the (–)-10-epi-axisonitrile-3 (3).13a,b A similar
reaction sequence applied to (+)-cubebol (IV) would generate
axisonitrile-3 (4). These hypothetical biosynthetic pathways
are supported by the report of De Rosa and his co-workers,
who isolated (–)-cubebol (V) and axenol (VI) from the marine
alga Taonia atomaria and proposed that they are
biosynthetically related via solvolytic conversion of V to VI.13c
Moreover, cyclopropyl ketone
I would be derived by
intramolecular cyclopropanation of -diazoketone II, which
would be produced from a simple terpene building block (+)-
menthone (5). Similarly, retrosynthetic analysis of axisonitrile-
3 (4) may lead to cyclopropyl ketone III and -diazoketone IV
which would be derived from a common starting material, (+)-
menthone (5).
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The analysis of the previous works led us to selecVitewthAreticle-Oknelitnoe
DOI: 10.1039/C9OB02249J
sulfones 6 and 7 as key intermediates for the synthesis of (–)-
10-epi-axisonitrile-3 and axisonitrile-3 (Figure 2). We expected
that bulky phenyl sulfonyl group would be placed on the
cyclohexene ring in a transition state of cyclopropanation,
which would cause enhanced steric interaction between
phenyl sulfonyl group and isopropyl group. As a result, the
intramolecular cyclopropanation reaction would occur on the
more sterically accessible cyclohexene face anti to the
isopropyl group. Furthermore, a higher selectivity of 6 for
cyclopropanation than that of 7 would be expected, because
the phenyl sulfonyl group in 6 would be strongly influenced by
the pseudo-axial methyl group on C(10) in the transition state
for cyclopropanation. In addition to introducing steric bulk, we
expected that the phenyl sulfonyl group would facilitate diazo
group transfer to the -methylene positions of 6 and 7. With
these analyses in mind, we focused attention on the synthesis
Scheme 3 Retrosynthetic analysis of (–)-10-epi-axisonitrile-3 and axisonitrile-3
Given the retrosynthesis outlined in Scheme 3, one challenging
aspect of an approach to the synthesis of (–)-10-epi-
axisonitrile-3 (3) and axisonitrile-3 (4) is stereocontrol in the
intramolecular cyclopropanation reactions of -diazoketones II
and IV (Scheme 3).14 A literature survey revealed that a
similar intramolecular cyclopropanation used by Yoshikoshi in
the synthesis of (–)-cubebol (I  II and III, Scheme 4)15
produced an approximately 1:1 mixture of cyclopropanation
products. Likewise, Piers reported cyclopropanation of -
diazoketone IV in the synthesis of -cubebene.16 In this case,
the diastereo-facial selectivity in cyclopropanation was poor in
favour of undesired diastereomer VI. In analysing these
previous observations, we reasoned that the observed low
degrees of stereoselectivity might be a consequence of the
fact that -diazoketones I and IV both possess sterically small
hydrogen atoms at their -positions. We surmised that
introduction of a more sterically bulky substituent at the
diazoketone -position could increase steric repulsive
interactions between diazoketone moiety and isopropyl group
in the transition state of cyclopropanation, leading to
improved facial selectivity.
of -keto sulfones
6 and 7 and their diazo transfer-
intramolecular cyclopropanation sequences.
R
H
10
H
CH3
PhO2S
6
O
H
CH3
PhO2S
H
R
R = CH2CH2COCH2SO2Ph
7
O
Figure 2 Candidates for intramolecular cyclopropanation precursors
Cu powder
cyclohexane
+
refluxed
N2
(46:54)
O
O
O
The synthesis of -keto sulfone 6 and its intramolecular
cyclopropanation for the synthesis of (–)-10-epi-axisonitrile-3
are outlined in Scheme 5. Following the procedure reported
by Hodgson,17 allyl alcohol 10 was prepared from (+)-
menthone (5). Accordingly, formylation of 5 with methyl
formate and sodium methoxide, accompanied by
epimerization of the isopropyl group-substituted stereogenic
center, produced an inseparable 93:7 mixture of
hydroxymethylene ketones 8 and 9. Reduction of this mixture
with lithium aluminum hydride (LAH) in ether followed by
chromatographic separation afforded allyl alcohols 10 and 11
in respective 44% and 4% yields from (+)-menthone (5). This
LAH reduction presumably occurred via a sequence involving
(i) hydride addition to deprotonated exocyclic olefin, (ii) -
H
H
H
I
II
III
CuSO4
cyclohexane
+
refluxed
N2
(37:63)
O
O
O
H
H
H
IV
VI
V
Scheme 4 Previous works of related intramolecular cyclopropanation
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elimination of aluminum-complexed oxygen from the formed
ketone enolate, and (iii) reduction of the resulting enone.18
Johnson-Claisen rearrangement of 10 was effected by heating
with triethyl orthoacetate in toluene in the presence of o-
nitrophenol to furnish -unsaturated ester 12 in 71% yield.19
Treatment of methyl phenyl sulfone with n-butyllithium
generated (phenylsulfonyl)methyl lithium, which reacted with
ester 12 to afford -keto sulfone 6 in excellent yield.20
Subsequent diazo transfer was accomplished by treatment of 6
with p-acetamidobenzenesulfonyl azide (p-ABSA) and
triethylamine to provide the cyclopropanation substrate 13 in
84% yield.21 Pleasingly, heating a toluene solution of -diazo-
-keto sulfone 13 in the presence of copper (II) N-(tert-
butyl)salicylaldimine (14)22 at 80 °C resulted in formation of
cyclopropyl ketone 15 as a single diastereomer in 75% yield.
View Article Online
DOI: 10.1039/C9OB02249J
Figure 3 X-ray crystallographic analysis of 15
Preparation of the cyclopropyl ketone intermediate required
for the synthesis of axisonitrile-3 started with kinetic
formylation of (+)-menthone (5) previously reported by
Hodgson17a,23 (Scheme 6). Deprotonation of 5 with lithium
diisopropyl amide (LDA) in THF at –78 °C, followed by
treatment with 2,2,2-trifluoroethyl formate produced
hydroxymethylene ketone 9, which was then reduced with
LAH to afford allyl alcohol 11. Although the yield of this two
step sequence was low especially when performed on a large-
scale (15%), the process produced 11 without altering the
configuration of the isopropyl group-substituted stereogenic
center. Following the same sequence of reactions depicted in
Scheme 5, allyl alcohol 11 was transformed into -diazo--
ketosulfone 17. Intramolecular cyclopropanation of 17 using
catalyst 14 was carried out under conditions similar to those
employed to convert 13 into 15. Disappointingly, this
cyclopropanation produced a mixture of multiple substances
from which the desired product 19 was obtained in only 17%
yield. In an effort to improve yields of cyclopropanation
process, we attempted to optimize the copper catalyst by
replacement of alkyl groups on the imines and introduction of
substituents on the para-position in benzene rings.24 After
considerable experimentation, we found that the catalyst 18
(R1 = CH3, R2 = F) gave the most promising results. In the
event, cyclopropanation of 17 using the catalyst 18 afforded
Scheme 5 Preparation of cyclopropyl ketone intermediate in the synthesis of (–)-10-
epi-axisonitrile-3
The structure of cyclopropyl ketone 15 was established by
using X-ray crystallographic method (Figure 3). Analysis of the
crystal structure shows that the right-hand cyclohexane ring in
15 exists in a boat conformation, which avoids an unfavorable
axial orientation of C(10) methyl group in
conformation.
a
chair cyclopropyl ketone 19 in 47% yield. The structure of 19 was
unambiguously determined by X-ray crystallographic analysis.
Pleasingly, the intramolecular cyclopropanation of 17 occurred
from the opposite side to the isopropyl group to install the
desired stereochemistry.
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DOI: 10.1039/C9OB02249J
During our studies of the Ritter reaction, a preliminary report
of the synthesis of exiguamide (21) was reported by Watanabe
and his coworkers (Scheme 8).28 To our surprise, Watanabe’s
group used cyclopropyl ketone 15 as an intermediate in their
synthetic route. Moreover, Watanabe’s initial plan for the
synthesis of exiguamide was based on cyclopropane ring
opening process using Ritter reaction. As in our approach, this
process proved to be unsuccessful. This led Watanabe to
implement a revised synthetic plan employing azide anion
promoted cyclopropane ring opening.29 Owing to our
observations and the lack of success encountered by
Watanabe, we decided to abandon the Ritter reaction
approach and to use cyclopropane ring opening reaction of 15
with azide anion.
N3
NHCHO
NaN3
SO2Ph
O
SO2Ph
O
steps
15
20
exiguamide (21
)
Scheme 8 A preliminary report for the synthesis of exiguamide by Watanabe group
The route for our synthesis of (–)-10-epi-axisonitrile-3 (3) via
exiguamide (21) starting from cyclopropyl ketone 15 is given in
Scheme 9.
Initial attempts of the doubly activated
Scheme
6 Preparation of cyclopropyl ketone intermediate for the synthesis of
cyclopropane ring opening reaction of 15 with azide anion
(NaN3) in a variety of solvents (HMPA, DMPU or DMF) under
thermal conditions (around 100 °C) gave none of the desired
product.30 However, we found that when conditions described
by Melnikov (NaN3, Et3N･HCl, DMF, 100 °C) were utilized, 15
was transformed to ring opened adduct 20 albeit in only 30%
yield.31 Encouraged by this result, we screened Lewis acid
additives and found that reaction of 15 in the presence of
magnesium perchlorate in DMF at 100 °C produced 20 in 28%
axisonitrile-3
In a study that paralleled the synthesis of cyclopropyl ketone
intermediates 15 and 19, we investigated the feasibility of the
key Ritter reaction in the hypothetical biosynthetic routes
depicted in Scheme 2. For this purpose, we chose (+)-cubebol
(I) and (+)--cubebene (II) as substrates (Scheme 7), because
they are ideal for testing the hypothesis of De Rosa.
Moreover, (+)-cubebol (I) and (+)--cubebene (II) can be
readily prepared from D-carvone using routes reported by
Fehr25 and Fürstner.26 Disappointingly, we observed that Ritter
reactions of both (+)-cubebol (I) and (+)--cubebene (II) with
acetonitrile produced complex product mixtures,27 and not
even trace amounts of the Ritter reaction products.
yield.32
Further improvement using a combination of
magnesium perchlorate and phase transfer catalyst (n-Bu4N･
HSO4) in DMF at 100 °C increased the yield of 20 up to 66%.
Introduction of the methyl group and double bond to 20 was
achieved in two steps involving triflation of ketosulfone 20
with triflic anhydride and sodium hydride, followed by
palladium-catalyzed Suzuki-Miyaura coupling of the resulting
vinyl triflate 22 employing trimethylboroxine.33
These
processes formed 23 in 88% yield over two steps. Treatment
of 23 with samarium diiodide in the presence of HMPA and
ethanol caused removal of sulfonyl group and concurrent azide
reduction to afford amine 24.34 Formylation of amine 24 with
acetic formic anhydride provided exiguamide (21) in 34% yield
over two steps. Finally, dehydration of 21 with triphosgene in
the presence of triethylamine gave rise to (–)-10-epi-
axisonitrile-3 (3) in 88% yield.35
H
complex
product
mixtures
or
CH3CN
OH
(+)-
-cubebene (II)
(+)-cubebol (I)
Scheme 7 Unsuccessful Ritter reaction
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material ([]D25 = +24.3, c = 0.69, CHCl3) differedViienw sAirgticnle fOrnolimne
that of natural exigurin ([]D = −32, c = 0.03, CHCl3). Ohta and
Ikegami reported that (–)-10-epi-axisonitrile-3 and exigurin
h
P
O2
S
24
DOI: 10.1039/C9OB02249J
O
NaN3
n-Bu4NHSO4
Mg(ClO4)2
NaH, Tf2O
were isolated from the same sponge and that natural (–)-10-
DME
(92%)
DMF, 100 °C
(66%)
O
25
N3
epi-axisonitrile-3 has a negative specific rotation ([]D
=
SO2Ph
−43.5, c = 0.64, CHCl3), which is identical to that observed for
23
15
20
our synthetic substance ([]D = −37.8, c = 0.75, CHCl3).
h
P
h
P
O2
O2
Considering the plausible biosynthesis of exigurin, the absolute
configuration of natural and synthetic (–)-10-epi-axisonitrile-3
should be the same with that of natural exigurin. In addition,
the reported characterization of natural exigurin was carried
out using only microgram quantities (400 g of exigurin from
wet sponge in 0.0003% isolated yield). Thus, we speculate
that the discrepancy between the specific rotation of synthetic
and natural exigurin is a consequence of inaccuracies in
measuring specific rotations with exceptionally small sample
quantities.
S
S
OTf
Me3B3O3
Pd(PPh3)4
SmI2, HMPA
EtOH, THF
(50%)
K2CO3, dioxane
(96%)
N3
22
N3
23
triphosgene
Et3N
AcOCHO
Cl2
CH2
AcOEt
(68%)
NH2
NCHO
H
N
(88%)
C
24
21
3
Scheme 9 Synthesis of exiguamide and (–)-10-epi-axisonitrile-3
Conclusions
In summary, we developed stereoselective intramolecular
cyclopropanation for the preparation of key cyclopropyl
ketone intermediates 15 and 19 for the synthesis of (–)-10-epi-
axisonitrile-3 (3) and axisonitrile-3 (4) starting with a common
starting material (+)-menthone (5). Further manipulation of
cyclopropyl ketone intermediate 15 led to the successful
synthesis of (–)-10-epi-axisonitrile-3 (3). Bioinspired U-5C-4CR
employing (–)-10-epi-axisonitrile-3 (3), formaldehyde and
sarcosine in methanol showed remarkable efficiency to
assemble multicomponents in a one-pot process to establish
the first total synthesis of exigurin (1) in 13 steps from (+)-
menthone (5). The results of the current study shed light on a
long-standing mystery relating to the biosynthetic origin of
exigurin.37 It is now apparent that the Ugi type reaction is not
confined to the realm of organic synthesis and that
conjugation of terpenes with amino acids by the Ugi reaction is
one of the Nature’s strategies to expand the diversity of
natural products. Further studies on the synthesis of
boneratamide A are under way in our laboratory.
With (–)-10-epi-axisonitrile-3 (3) in hand, the stage was now
set to carry out bioinspired Ugi five-centre four-component
reaction (U-5C-4CR) leading to exigurin (1) (Scheme 10).36 In
the event, a solution of sarcosine and formaldehyde in
methanol at 50 °C was treated with (–)-10-epi-axisonitrile-3
(3). After stirring the reaction mixture at 50 °C for 20 minutes,
exigurin (1) was isolated in 53% yield after chromatographic
purification. The probable reaction mechanism of the U-5C-
4CR started with condensation of sarcosine with formaldehyde
to form the corresponding iminium ion 25. After addition of (–
)-10-epi-axisonitrile-3 (3) to 25, cyclic O-acyl-imide 26 would
form. Nucleophilic attack of methanol (fourth component)
occurs at the carboxylic carbon (fifth reacting centre) in 26.
Subsequent six-membered ring opening reaction would lead to
the formation of exigurin (1). Although the yield was modest,
the multiple step sequence of U-5C-4CR took place in one-pot
under mild reaction conditions to furnish exigurin (1).
Me
Me
N
3
N
H
CO2H
Experimental
For full experimental procedures, spectroscopic and analytical
data for all new compounds including copies of NMR spectra,
see the ESI.
MeOH
HCHO
N
C
HO
25
O
3
Me
N
O
Me
N
U-5C-4CR
(53%)
O
N
O
N
H
Conflicts of interest
There are no conflicts to declare.
CO2Me
MeOH
exigurin (
1)
26
Scheme 10 Total synthesis of exigurin through the U-5C-4CR
The 1H and 13C NMR spectra recorded on synthetic exigurin (1)
were in full agreement with those reported for the natural
product.35 However, the specific rotation of the synthetic
Acknowledgements
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16 E. Piers, R. W. Britton and W. D. Waal, Can. J. VCiehweAmrti.c,le1O9n7lin1e,
We are most grateful to Professor Shinji Ohta (Hiroshima
University) for kindly providing us with NMR spectra data of
exiguamide (21), (–)-10-epi-axisonitrile-3 (3) and exigurin (1).
The Materials Characterization Central Laboratory at Waseda
University is gratefully acknowledged for X-ray analysis. We
acknowledge the financial support provided by a Grant-in-Aid
for Scientific Research (C) (16K01916) from MEXT.
49, 12-19.
DOI: 10.1039/C9OB02249J
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18 A. S. Dreiding and J. A. Hartman, J. Am. Chem. Soc., 1953, 75,
939-943.
19 (a) W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J.
Brocksom, T.-T. Li, D. J. Faulkner and M. R. Petersen, J. Am.
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27 For the Ritter reaction using acetonitrile in the syntheses of
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28 H. Watanabe, Abstracts of Papers: 26th Banyu Sendai
Symposium, Sendai, Japan, June 6, 2015.
29 Personal communications from Professor Hidenori
Watanabe. From our unsuccessful experiments of Ritter
reaction in Scheme 7, we believe that hypothesis of the
formation of carbocation II and ensuing Ritter reaction in
Scheme 2 is questionable. Both cubebol and cubebene are
likely to be thermodynamically stable and sink products to
the bottom of biosynthesis.
30 (a) S. Danishefsky and G. Rovnyak, J. Org. Chem., 1975, 40,
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Notes and references
1
(a) J. W. Blunt and M. H. G. Munro, Dictionary of Marine
Natural Products. With CD-ROM, Chapman & Hall/CRC, 2007;
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Keyzers and M. R. Prinsep, Nat. Prod. Rep., 2018, 35, 8-53.
Marine organisms employ an unusual organic reaction in
2
their biosynthesis.
One of the striking examples is
halichonadin H biosynthesis in which the Passerini-type
reaction is employed. See the references: (a) Y. Ichikawa, T.
Yamasaki, K. Nakanishi, Y. Udagawa, S. Hosokawa and T.
Masuda, Synthesis, 2019, 51, 2305-2310; (b) S. Suto, N.
Tanaka, J. Fromont and J. Kobayashi, Tetrahedron Lett.,
2011, 52, 3470-3473.
M. M. Uy, S. Ohta, M. Yanai, E. Ohta, T. Hirata and S.
Ikegami, Tetrahedron, 2003, 59, 731-736.
D. E. Williams, B. O. Patrick, A. Tahir, R. Van Soest, M.
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1754.
3
4
5
6
7
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R. Mimura, A. Kitamori, A. Matsukawa, A. Ikeda, T. Masuda,
H. Kotsuki and K. Nakano, Heterocycles, 2016, 92, 1040-1053.
(–)-10-Epi-axisonitrile-3 (3) is a typical marine terpene
isocyanide, previously isolated from the nudibranch Phylliella
pustulosa. See the reference: T. Okino, E. Yoshimura, H.
Hirota and N. Fusetani, Tetrahedron, 1996, 52, 9447-9454.
For the first report of isolation and structural elucidation of
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8
9
10 E. Avilés and A. D. Rodríguez, Org. Lett., 2010, 12, 5290-
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11 For other natural products presumably derived from the Ugi
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12 S. Konishi, Y. Mitani, N. Mori, H. Takikawa and H. Watanabe,
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13 (a) M. J. Garson, J. Chem. Soc., Chem. Commun., 1986, 35-36;
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35 The 1H and 13C NMR spectra recorded on synthetic
exiguamide (22), (–)-10-epi-axisonitrile-3 (3) and exigurin (1)
are in full agreement with those reported for the natural
products. See the ESI for details.
36 (a) A. Demharter, W. Hörl, E. Herdtweck and I. Ugi, Angew.
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37 M. J. Garson and J. S. Simpson, Nat. Prod. Rep., 2004, 21,
164-179.
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Contents entry text: Bioinspired U-5C-4CR employing (–)-10-
epi-axisonitrile-3 established the first total synthesis of
exigurin in 13 steps from (+)-menthone.
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