Synthesis and stereochemistry of JBIR-81, a peptide enamide derived from aspergilli

Article abstract of DOI:10.1016/j.tetlet.2018.01.080

The absolute stereochemistry of an aspergilli-derived peptide enamide, JBIR-81, was determined to be 12S, 15S by the first synthesis of (12S,15S)-JBIR-81 and its epimer. The overall yield was 56% over six steps from N-methyl-L-leucine. The (Z)-enamide structure was effectively constructed with use of a copper (I) catalyzed coupling reaction between a vinyl halide and a carboxamide.

Full text of DOI:10.1016/j.tetlet.2018.01.080

Accepted Manuscript
Synthesis and stereochemistry of JBIR-81, a peptide enamide derived from as-
pergilli
Ryo Katsuta, Mami Toyoda, Arata Yajima, Ken Ishigami, Tomoo Nukada
PII:
S0040-4039(18)30125-4
https://doi.org/10.1016/j.tetlet.2018.01.080
TETL 49667
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 December 2017
24 January 2018
26 January 2018
Please cite this article as: Katsuta, R., Toyoda, M., Yajima, A., Ishigami, K., Nukada, T., Synthesis and
stereochemistry of JBIR-81, a peptide enamide derived from aspergilli, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.01.080
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis and stereochemistry of JBIR-81, a
peptide enamide derived from aspergilli
Leave this area blank for abstract info.

Ryo Katsuta, Mami Toyoda, Arata Yajima, Ken Ishigami and Tomoo Nukada

1
Tetrahedron Letters
Synthesis and stereochemistry of JBIR-81, a peptide enamide derived from aspergilli
a,
b
a
a
a
Ryo Katsuta  Mami Toyoda , Arata Yajima , Ken Ishigami and Tomoo Nukada
a
Department of Chemistry for Life Sciences and Agriculture, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan
Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The absolute stereochemistry of an aspergilli-derived peptide enamide, JBIR-81, was
determined to be 12S, 15S by the first synthesis of (12S,15S)-JBIR-81 and its epimer. The
overall yield was 56% over six steps from N-methyl-L-leucine. The (Z)-enamide structure was
effectively constructed with use of a copper (I) catalyzed coupling reaction between a vinyl
halide and a carboxamide.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Enamide
Synthesis
Stereochemistry
Aspergillus
Buchwald coupling
1. Introduction
Enamides are a class of natural products that possess a
covalent bonding between a vinyl group and nitrogen atom of a
carboxamide group. Recently, several peptide enamides were
isolated from various aspergilli. These compounds contain three
amino acid residues, constituted from an acetylated N-terminus,
N-methylated amino acid and dehydrotryptamine (sometimes
substituted) at the C-terminus, which were common to all. Each
of the amino acids differed, as a result of its producing species or
strains, as well as showing remarkable biological activities.
Osada and colleagues isolated a cell cycle inhibiting peptide
1
enamide, terpeptin (1), from Aspergillus terrus 95F-1. This
compound contained a prenyl group on an indol system with two
valine residues (fig. 1). Aspergillamide A (2) is another cell cycle
2
inhibiting compound from A. sp, as well as Miyakamide A (3),
with two phenylalanine residues that show weak cytotoxicity and
3,4
Figure 1. Structures of peptide enamides.
growth inhibition against brine shrimp; compounds 2 and 3 are
isolated with corresponding (E)-enamides. In 2010, Shin-ya and
colleagues isolated JBIRs-81 (4), -82 (5) and 1 from the culture
The goal of this study was to perform a synthetic study of
JBIR-81, regarding the development of an efficient synthetic
route to peptide enamides, and to determine its relative and
absolute stereochemistry.
of A. sp. SpD081030G1f1 derived from Okinawan seaweed5
Sargassum sp., and their planar structures were determined.
Compounds 4 and 5 show protective activity against L-glutamate
toxicity in N18-RE-105 cells, which are thought to be potent free
radical scavenging materials. To date, these structural and
biological features of peptide enamides attracted chemists and
2
. Results and Discussion
6
several total syntheses have been reported. However, no
To determine the stereochemistry of JBIR-81, the synthesis of
two possible diastereomers, namely (12S,15S)- and (12S,15R)-
isomers, was required. According to the research on
previous synthesis combines the following features such as good
selectivity of enamide geometry, stereospecificity of the amino
acid group and a small number of synthetic steps.
miyakamides by Shiomi, Omura and colleagues, geometrical
3
isomerism of the enamide would be considerable. Therefore, we
—
——

Corresponding author. Tel.: +81-3-5477-2542; fax: +81-3-5477-2264; e-mail: r3katsut@nodai.ac.jp

2
Tetrahedron Letters
planned to synthesize this unstable motif in the late stages of
halide 8 in hand, a Cu(I) catalyzed coupling reaction was
13 14
the synthesis via a coupling reaction of a (Z)-vinylhalide and a
peptide amide.
conducted (Table 1). Ma’s coupling conditions, using N,N-
dimethylglycine as a ligand of the Cu(I) species, gave only a
trace amount of coupled product (entry 1). Cesati III’s
conditions, which are also used in the synthesis of a natural
enamide by Cuevas (CuI, N,N’-dimethylethylendiamine,
Cs CO , THF, 70 °C), gave a 39% yield, with severe
2 3
isomerization of the enamide geometry (E/Z = 5/1, entry 2). On
the other hand, when the reaction was carried out using CuI,
Initially, the synthesis of the indolic vinyl bromide was
conducted as illustrated in Scheme 1. An o-nitrobenzenesulfonyl
15
6e
7
(Ns) protected indolcarbaldehyde 6 was converted into the
dibromoolefin 7, according to the synthesis of its p-
toluenesulfonyl derivative by Fujii and Ohno. The regioselective
reduction using tri-n-butyltin hydride produced (Z)-vinyl bromide
8
was performed using commercially available N-methylleucine,
which was converted into the corresponding amide 10 via an
ammonolysis of the ester. The coupling reaction of 10 with N-
acetyl-L-valine (11) was troublesome. All conditions attempted,
using EDC, TBTU, PyBOP, COMU, and HATU with/without
bases and additives, gave dipeptides as a nearly 1:1
8
2 3
N,N’-dimethylethylenediamine, Cs CO in 1,4-dioxane at 90 °C,
in good yield. The synthesis of N-acetylvalyl-N-methylleucine
the reaction yield was remarkably improved, giving 17 (90%);
however, geometrical selectivity was poor (E/Z = 2/1) and
isomerization of the unreacted vinyl bromide was observed (entry
3). Encouraged by this result, the reaction temperature was
9
lowered to 60 °C. As shown in entry 4, isomerization of the
double bond was reduced (Z/E > 20/1) and the product yield was
73%. Furthermore, the isomerization was completely suppressed
10
diastereomeric mixture of the desired 12 and its epimer 13 in
low to moderate yield. However, the use of a Fmoc-protected
valine 14 instead of the acetyl derivative gave 15 in excellent
yield without any epimerization.
by adding a catalytic amount of 2,6-di-tert-butyl-4-methylphenol
16
(BHT) to the reaction (entry 5). Finally, a deprotection of the
tripeptide 17 using thiophenol gave (12S,15S)-JBIR-81 (18) in
excellent yield. The H NMR spectrum of synthetic 18 was
1
A deprotection of the Fmoc protecting group was conducted
observed as a 4:1 mixture of rotational isomers in a DMSO-d
6
17,18
under piperidine/CH
Cl
2 2
conditions; diketopiperadine 16 was
solution.
Exchanging signals were observed between
given in an 84% yield, and the desired free amine was not
corresponding protons of each rotational isomer in a phase
1
1
observed. In response to the results, we thought that the amino
group should be trapped as soon as its generation. The treatment
of 15 with DABCO and excess acetic anhydride gave the N-
sensitive NOESY experiment. The major isomer of 18 showed a
NOESY correlation between N13-Me and 15-H protons, which
indicates a trans-amide configuration in a C12-N13-C14-C15
region (fig. 2).
12
acetyl derivative 12. With the desired dipeptide 12 and vinyl
Scheme 1. Synthesis of (12S,15S)-JBIR-81 (18) and its epimer 19. Reagents, conditions and yields: (a) PPh
to rt, 80%; (b) n-Bu SnH, Pd(PPh , toluene, 0 °C, 82%; (c) SOCl , MeOH, quant.; (d) aq. NH , MeOH, 92%; (e) 11, HATU, i-
Pr NEt, DMF, for 12 22%, for 13 22%; (f) 14, HATU, i-Pr NEt, DMF, 95%.; (g) piperidine, CH Cl , 84%; (h) DABCO, Ac O,
CH Cl , 90%; (i) 8, CuI, MeNHCH CH NHMe, Cs CO , 1,4-diox., 60 °C, sealed tube, 73%, Z/E > 20/1; (j) PhSH, Cs CO , CH CN,
6%; (k) ent-14, HATU, i-Pr NEt, DMF, 98%; (l) DABCO, Ac O, CH Cl , 94%; (m) 8, CuI, MeNHCH CH NHMe, Cs CO , 1,4-
diox., 60 °C, sealed tube, 72%; (n) PhSH, Cs CO , CH CN, 95%.
3 4 2 2
, CBr , CH Cl , –78 °C
3
3
)
4
2
3
2
2
2
2
2
2
2
2
2
2
3
2
3
3
9
2
2
2
2
2
2
2
3
2
3
3

3
Table 1. Reaction conditions, geometrical ratios and yields of the Cu(I) mediated coupling reaction of compounds 12 and 8
a
Entry
Conditions
Ratio E/Z
N/A
Yield (%)
Trace
39
1
2
3
4
5
CuI, Cs
CuI, Cs
CuI, Cs
CuI, Cs
CuI, Cs
2
CO
CO
CO
CO
CO
3
3
3
3
3
, N,N-dimethylglycine, 1,4-dioxane, 80 C
2
, MeNHCH
, MeNHCH
, MeNHCH
, MeNHCH
2
2
2
2
CH
CH
CH
CH
2
2
2
2
NHMe, THF, 70 C
5/1
2
NHMe, 1,4-dioxane, 90 C
NHMe, 1,4-dioxane, 60 C
NHMe, BHT, 1,4-dioxane, 60 C
2/1
90
2
< 1/20
Z only
73
2
70
a
All reactions were carried out in a sealed tube under argon atmosphere.
The minor isomer was identified as a cis-amide by an observed
NOESY correlation between 12-H and 15-H. These rotational
isomerisms were commonly found in peptide enamides such as
synthetic epimers. Further biological research and synthesis of
other peptide enamides are now in progress.
2
3
Acknowledgments
1 2 1
aspergillamide A and miyakamides, A /A and B /B2.
We gratefully acknowledge Dr. K. Shin-ya at The National
Institute of Advanced Industrial Science and Technology (AIST)
for the kind gift of the NMR spectrum of the natural JBIR-81.
Similarly, (12S,15R)-JBIR-81 (19) was synthesized from
compound 10 and N-acetyl-D-valine (ent-14) via a four-step
sequence. The spectroscopic data, including NMR, IR, and MS
19,20
of compound 19, also have good accordance to its structure.
1
3
With two possible epimers of JBIR-81 in hand, the spectral data
of the natural product and synthetic materials were compared.
Table 2. Selected C NMR chemical shifts of the natural and
synthetic JBIR-81 epimers (150 MHz in DMSO-d6)
5
All measured spectral data of 18 were fully identical to those of
1
3
c
 (ppm)
the natural product, while 19’s data were not. Selected C NMR
chemical shifts of the natural product and the major rotarmers of
compounds 18 and 19 are shown in Table 2. In contrast to a good
agreement between the natural product and (12S,15S)-isomer 18,
Synthetic
12S,15S)-isomer 18
a
Position
Natural
b
b
(
(12S,15R)-isomer 19
1
3
there are significant differences between the C chemical shifts
1
1
169.3
54.2
31.2
173.3
54.3
169.2
22.3
30.1
19.0
18.6
36.5
24.7
23.4
21.6
169.2
54.2
31.1
173.2
54.3
169.1
22.3
30.1
19.0
18.5
36.4
24.6
23.3
21.6
169.5
54.2
31.2
173.5
54.6
169.2
22.2
30.2
19.1
18.3
36.5
24.6
23.5
21.3
of the natural compound and (12S,15R)-isomer 19, particularly at
1
12
C15, C21 and C25 (|δnat.–δsynth| = 0.3 ppm). The H NMR signals
1
3-Me
of the minor rotational isomer of synthetic 18 were also found in
the same ratio in a spectrum of the natural product. The same
signs of specific rotations of the natural product and synthetic 18
14
15
17
5
25
D
25
D
(
lit. : [α] –177.7, c 0.1 in MeOH; synthetic: [α] –105, c 0.084
17,21,22
in MeOH)
indicate that the absolute stereochemistry of the
1
1
2
2
2
2
2
2
8
9
0
1
2
3
4
5
natural JBIR-81 is 12S,15S.
a
Numbers of positions are indicated in Fig. 1 or Ref. 5.
Major isomers are listed.
b
References and notes
1
.
a) Kagamizono, T.; Sakai, N.; Arai, K.; Kobinata, K.; Osada, H.
Tetrahedron Lett. 1997, 38, 1223–1226; b) Su, S.; Kakeya, H.;
Osada, H.; Porco, Jr., J. A. Tetrahedron 2003, 59, 8931–8946.
Toske, S. G.; Jensen, P. R.; Kauffman, C. A.; Fenical, W.
Tetrahedron 1998, 54, 13459–13466.
Shiomi, K.; Hatae, K.; Yamaguchi, Y.; Masuma, R.; Tomoda, H.;
Kobayashi, S.; Ōmura, S. J. Antibiot. 2002, 55, 952–961.
Isolation of other aspergilli derived peptide enamides: a) Nakano,
Y.; Sugawara, M. Jpn. Kokai Tokkyo Koho JP 01149776 A, 1986;
b) Adpressa, D. A.; Loesgen, S. Chem. Biodiversity 2016, 13,
2
3
4
.
.
.
Figure 2. Rotational isomers of (12S,15S)-JBIR-81 (18).
3. Conclusions
In summary, the first total synthesis of (12S,15S)-JBIR-81 and
(12S,15R)-isomer was achieved. The overall yield of natural
2
53–259; c) Rank, C.; Klejnstrup, M. L.; Petersen, L. M.;
JBIR-81 was 56% over six steps from N-methyl-L-leucine via a
Cu(I) catalyzed coupling of a vinylbromide and an amide. An
effective and concise synthetic route toward aspergilli derived
peptide enamides was developed. The absolute stereochemistry
of JBIR-81 was determined to be 12S,15S by comparison of
spectral data and specific rotations of the natural product and
Kildgaard, S.; Frisvad, J. C.; Gotfredsen, C. H.; Larsen, T. O.
Metabolites 2012, 2, 39–56.
Izumikawa, M.; Hashimoto, J.; Takagi, M.; Shin-ya, K. J.
Antibiot. 2010, 63, 389–391.
Syntheses of natural enamides: a) Beck, B.; Hess, S.; Dömling, A.
Bioorg. Med. Chem. Lett. 2000, 10, 1701–1705; b) Rivas, L.;
Quintero, L.; Fourrey, J.-L.; Benhida, R. Tetrahedron Lett. 2002,
5
6
.
.

4
Tetrahedron
4
3, 7639–7641; c) see ref. 1b; d) Kuramochi, K.; Osada, Y.;
NMR data of (E)-isomer: 0.84 (3H, d, J = 7.6 Hz), 0.86 (3H, d, J =
7.6 Hz), 0.88 (3H, d, J = 7.6 Hz), 0.90 (3H, d, J = 7.6 Hz), 1.40
(1H, m), 1.59 (1H, ddd, J = 14.5, 10.0, 5.7 Hz), 1.66 (1H, ddd, J =
14.5, 10.1, 4.8 Hz), 1.83 (3H, s), 1.96 (1H, m), 3.12 (3H, s,), 4.47
(1H, t, J = 8.6 Hz), 5.10 (1H, dd, J = 10.1, 5.7 Hz), 6.42 (1H, d, J
= 14.8 Hz), 7.04 (1H, m), 7.10 (1H, m), 7.25 (1H, dd, J = 14.8, 9.8
Hz), 7.36 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 2.4 Hz), 7.60 (1H, d,
J = 7.9 Hz), 8.10, (1H, d, J = 8.6 Hz), 9.95 (1H, d, J = 9.8 Hz),
Kitahara, T. Chem. Lett. 2002, 31, 128–129; e) Murcia, C.; Coello,
L.; Fernández, R.; Martín, M. J.; Reyes, F.; Francesch, A.; Munt,
S.; Cuevas, C. Mar. Drugs 2014, 12, 1116–1130; f) Fong, H. K.
H.; Brunel, J. M.; Longeon, A.; Bourguet-Kondracki, M.-L.;
Barker, D.; Copp, B. R. Org. Biomol. Chem. 2017, 43, 7639–7641.
Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org.
Chem. 2005, 70, 5840–5851.
7
8
.
.
1
3
a) Iwata, A.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem.
6
11.10 (1H, brs); C NMR (150 MHz, DMSO-d , δ) 18.7, 19.1,
2
011, 76, 5506–5512; b) Uenishi, J.; Kawahama, R.; Shiga, Y.;
21.7, 22.3, 23.2, 24.7, 30.2, 31.5, 37.3, 54.2, 54.4, 106.7, 111.7,
112.0, 119.1, 119.4, 119.8, 121.6, 123.6, 125.0, 136.9, 168.2,
169.3, 172.7.
Yonemitsu, O.; Tsuji, J .Tetrahedron Lett. 1996, 37, 6759–6762.
Carprino, L. A. J. Am. Chem. Soc. 1993, 115, 4397–4398.
9
1
.
2
4
0. The stereochemistry of compound 13, synthesized from
compounds 10 and 11, was determined by a comparison of NMR
spectra and specific rotations with those of the established
material, synthesized from compounds 10 and 14 under
epimerization free conditions.
19. Analytical and spectral data of (12S,15R)-JBIR-81 (19): [α]D
=
+49 (c 0.1, MeOH), after evaporation from 0.4% aqueous formic
2
D
4
-1
acid: [α] = +34 (c 0.1, MeOH); IR (KBr, cm ): ν = 3297, 2963,
1
1
744, 732; H NMR (600 MHz, DMSO-d
6
, δ): 0.83 (3H, d, J = 6.5
Hz), 0.84 (3H, d, J = 6.5 Hz), 0.86 (3H, d, J = 6.5 Hz), 0.92 (3H,
d, J = 6.5 Hz), 1.42 (1H, m), 1.55 (1H, ddd, J = 14.1, 10.0, 4.8
Hz), 1.70 (3H s), 1.79 (1H, ddd, J = 14.1, 11.0, 4.1 Hz), 1.95 (1H,
m), 3.01 (3H, s), 4.53 (1H, t, J = 8.3 Hz), 5.20 (1H, dd, J = 11.0,
1
1
1. Wen, S.-J.; Hu, T.-S.; Yao, Z.-J. Tetrahedron 2005, 61, 4931–
4
938.
2. N-Acetyl-N-Fmoc intermediate was not observed in TLC analysis
of the reaction media. This suggests that the de-Fmoc reaction is
followed by acetylation.
4
7
.8 Hz), 5.95 (1H, d, J = 9.6 Hz), 6.59 (1H, dd, J = 10.0, 9.6 Hz),
.03 (1H, t, J = 8.0 Hz), 7.12 1H, dd, J = 8.3, 8.0 Hz), 7.39 (1H, d,
1
1
3. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
J = 8.3 Hz), 7.54 (1H, d, J = 2.4 Hz), 7.59 (1H, d, J = 8.0 Hz),
5
, 3667–3669.
7
.98 (1H, d, J = 8.3 Hz), 8.89 (1H, d, J = 10.0 Hz), 11.2 (1H, brs);
C NMR (150 MHz, DMSO-d , δ): 18.3, 19.1, 21.3, 22.2, 23.5,
6
1
3
4. a) Pan, X.; Ma, D. Org. Lett. 2004, 6, 1809–1812; b) Yang, L.;
Deng, G.; Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X.
Org. Lett. 2007, 9, 1387–1390.
5. Cesati III, R. R.; Dwyer, G.; Jones, R. C.; Hayes, M. P.;
Yalamanchili, P.; Casebier, D. S. Org. Lett. 2007, 9, 5617–5620.
6. Synthesis of compound 17. A mixture of amide 12 (21.2 mg, 74.5
µmol), vinylbromide 8 (36.4 mg, 89.5 µmol), CuI (14.2 mg, 74.5
2
1
4.6, 30.2, 31.2, 36.5, 54.2, 54.6, 103.4, 109.8, 111.6, 118.2,
18.5, 119.2, 121.8, 123.7, 126.8, 135.6, 169.2, 169.5, 173.5;
+
+
1
1
DART-TOFMS m/z calcd. for C24
found to be 427.2699.
35 4 3
H N O [M+H] 427.2704;
2
0. Compound 19 showed a NOESY correlation between the indolic
hydrogen (N1-H) and acetyl protons (18-H). This suggests that the
hydrogen bonding between N1-H and carbonyl oxygen in acetyl
group (C17=O) stabilizes the fifteen-membered cyclic
conformation. This conformation was also supported by the
theoretical calculation performed at EDF2/6-31G* level.
1. The different value of specific rotations between natural and
synthetic compounds was possibly due to an effect of impurities or
corresponding (E)-enamide contained within the sample of the
natural product.
µmol), Cs
dimethylethylenediamine (8.01 µl, 74.5 µmol) and 1,4-dioxane
1.0 ml) in an argon filled sealed tube was heated at 60 °C for 20 h.
2 3
CO (47.2 mg, 145 µmol), N,N’-
(
The reaction mixture was diluted with ethyl acetate (2 ml) and
filtered through a plug of silica gel and washed with ethyl acetate.
Combined filtrate was concentrated in vacuo. The residue was
subjected to a column chromatography over silica gel; elution with
hexanes ethyl acetate (6/1 to 1/1) gave 17 (33.3 mg, 73%) as an
amorphous solid.
2
2
2. In contrast to additions of formic acid affected specific rotations of
2
3
1
7. Analytical and spectral data of (12S,15S)-JBIR-81 (18): [α] = –
1
13
D
compounds 18 and 19, H and C NMR chemical shifts of these
compounds did not affected by formic acid lower than 1% v/v
formic acid concentration. However, extending time of treatment
with formic acid caused isomerization of the enamide geometry in
case of compound 18, while compound 19 was not observed to
isomerize.
2
3 (c 0.1, MeOH), after evaporation from 0.4% aqueous formic
23 -1
acid: [α]D = –105 (c 0.084, MeOH); IR (KBr, cm ): ν = 3310,
2
δ): 0.73 (3H, d, J = 6.8 Hz), 0.80 (3H, d, J = 6.2 Hz), 0.81 (3H, d,
J = 6.2 Hz), 0.89 (3H, d, J = 6.5 Hz), 1.41 (1H, m), 1.58 (1H, ddd,
J = 14.1, 8.9, 5.5 Hz), 1.68 (1H, ddd, J = 14.1, 10.3, 4.8 Hz), 1.80
1
6
961, 1657, 745; H NMR (600 MHz, DMSO-d , major rotarmer,
(
(
3H, s), 1.92 (1H, m), 3.01 (3H, s,), 4.47 (1H, t, J = 8.6 Hz), 5.25
1H, dd, J = 10.3, 5.5 Hz), 5.94 (1H, d, J = 9.6 Hz), 6.62 (1H, dd,
Supplementary Material
J = 10.0, 9.6 Hz), 7.02 (1H, dd, J = 7.2, 6.9 Hz), 7.12 (1H, dd, J =
7
.2, 6.9 Hz), 7.38 (1H, d, J = 7.2 Hz), 7.53-7.58 (2H, m), 8.07, 1
Supplementary material (general procedures and spectroscopic
3
1
13
(1H, d, J = 8.6 Hz), 8.92 (1H, d, J = 10.0 Hz), 11.30 (1H, brs);
C
data of all new compounds, including IR, H and C NMR, and
NMR (150 MHz, DMSO-d
6
, major rotarmer, δ): 18.5, 19.0, 21.6,
1 13
MS, H, C NMR and NOESY spectra of JBIR-81) associated
with this article can be found in the online version. These data
include MOL files and InChiKeys of the most important
compounds described in this article.
2
1
1
4
2.3, 23.3, 24.6, 30.1, 31.1, 36.4, 54.2, 54.3, 103.2, 109.8, 111.6,
18.4, 118.5, 119.2, 121.8, 123.6, 126.7, 135.8, 169.1, 169.2,
+
+
73.2; DART-TOFMS m/z calcd. for C24
27.2704; found to be 427.2688.
35 4 3
H N O [M+H]
1
8. This material also contains a small amount of corresponding (E)-
1
enamide. This (E)-enamide is also shown in the H spectrum of
the natural JBIR-81 at the same geometrical ratio.
The absolute stereochemistry of an aspergilli-
derived peptide enamide, JBIR-81, was determined.
The (Z)-enamide structure was constructed with a
copper (I) catalyzed coupling reaction
Highlights
The concise first synthesis of (12S,15S)-JBIR-81
and its epimer was achieved.