Short synthesis of berkeleyamide D and determination of the absolute configuration by the vibrational circular dichroism exciton chirality method

Article abstract of DOI:10.1021/ol500148g

The first synthesis of (±)-berkeleyamide D has been accomplished. The key features of this synthesis include the formation of an α,β-epoxy-γ-lactam via a Darzens reaction and the construction of a spirocyclic ring system by a C-acylation reaction followed by an intramolecular spirocyclization via an epoxide-opening reaction. Following optical resolution by chiral HPLC, the absolute configurations of both enantiomers of berkeleyamide D were determined by the vibrational circular dichroism exciton chirality method.

Full text of DOI:10.1021/ol500148g

Letter
pubs.acs.org/OrgLett
Short Synthesis of Berkeleyamide D and Determination of the
Absolute Configuration by the Vibrational Circular Dichroism Exciton
Chirality Method
Kenta Komori,† Tohru Taniguchi,‡ Shoma Mizutani,† Kenji Monde,‡ Kouji Kuramochi,*,†
and Kazunori Tsubaki†
†Graduate School for Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Shimogamo Hangi-cho, Sakyo-ku, Kyoto
606-8522, Japan
‡Faculty of Advanced Life Science, Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Kita
21 Nishi 11, Sapporo 001-0021, Japan
S
* Supporting Information
ABSTRACT: The first synthesis of ( )-berkeleyamide D has
been accomplished. The key features of this synthesis include
the formation of an α,β-epoxy-γ-lactam via a Darzens reaction
and the construction of a spirocyclic ring system by a C-
acylation reaction followed by an intramolecular spirocycliza-
tion via an epoxide-opening reaction. Following optical
resolution by chiral HPLC, the absolute configurations of
both enantiomers of berkeleyamide D were determined by the
vibrational circular dichroism exciton chirality method.
erkeleyamide D (1) was originally isolated by Stierle et al.1
in 2008 from the acid lake fungus Penicillium rubrum Stoll
(Figure 1) and was shown to inhibit matrix metalloproteinase-3
the S configuration. Recent developments in the vibrational
circular dichroism (VCD) exciton chirality method have made
this a powerful tool for determining absolute configuration.5 In
a similar manner to the exciton chirality method in electronic
circular dichroism (ECD),6 the VCD exciton chirality method
is based on the through-space coupling of two or more IR
chromophores in chiral substrates. The interaction of two IR
chromophores yields a bisignate VCD couplet (a pair of VCD
signals with opposite signs around the absorption regions of the
chromophores) whose sign reflects the absolute configuration
of the molecule. Herein, we report the first synthesis of ( )-1
as well as the determination of the absolute configuration of
(−)-1 and (+)-1 by the VCD exciton chirality method.
Our retrosynthetic analysis of berkeleyamide D (1) is
depicted in Scheme 1. It was envisaged that ( )-1 could be
prepared by the intramolecular epoxide ring-opening reaction
of the enolate derived from β-diketone 4, which could be
prepared by the protection of the hemiaminal in α,β-epoxy-γ-
lactam 5, followed by C-acylation with phenylacetyl chloride.
The α,β-epoxy-γ-lactam 5 could itself be prepared by the
Darzens reaction of α-bromo-β-ketoamide 6a7 with isobutyl-
glyoxal 7.8
B
Figure 1. Structures of berkeleyamide D (1), pseurotin A (2), and
azaspirene (3). Selected carbon atoms have been labeled using the
IUPAC numbering system.
and caspase-1. Although the structure of 1 has been confirmed
by detailed NMR studies, its relative and absolute config-
urations remain undetermined. Several related natural spiro-
heterocyclic γ-lactams have also been reported in the literature
including pseurotin A (2)2 and azaspirene (3).3 The interesting
biological activities and structural complexities of compounds 2
and 3 have attracted considerable interest from synthetic
chemists, which culminated in their total syntheses.4 The
absolute configuration of 2 was determined by X-ray crystallo-
graphic analysis of its 12,13-dibromo derivative.2a,b The
absolute configuration of 3 was determined by Hayashi et
al.4a during their total synthesis of the same compound. The
spirocenters at the C-5 positions in compounds 2 and 3 exist in
The formation of an α,β-epoxy-γ-lactam was initially
investigated using α-bromo-β-ketoamide 6b9 and commercially
available methylglyoxal (40% aqueous solution) as model
substrates (Table 1). The treatment of a mixture of 6b and
methylglyoxal (2.1 equiv) with sodium carbonate (1.0 equiv) in
Received: January 16, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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Letter
Scheme 1. Retrosynthetic Analysis of Berkeleyamide D (1)
Scheme 2. Proposed Mechanism for the Stereoselectivity of
the Key Darzens Reaction
Table 1. Formation of α,β-Epoxy-γ-lactam by the Darzens
a
Reaction Using Model Substrates
Scheme 3. Application of Darzens Reaction for the Synthesis
of Epolactaene (8c) and Its Derivatives 8d−h
a
b
entry
base
solvent
temp (°C)
yield (%)
c
1
2
3
Na2CO3
Na2CO3
Et3N
THF
40
rt
0−69
54
THF/H2O (10:1)
THF/H2O (10:1)
rt
69
a
Reaction conditions: 6b (0.12 mmol), methylglyoxal (0.25 mmol)
1
and base (0.12 mmol) in solvent (3.3 mL). Based on the H NMR
spectrum, product 8b existed as a 7:1 diastereomeric mixture at the γ-
b
c
position in CD3OD. Isolated yield. Poor reproducibility.
THF at 40 °C afforded 8b (Table 1, entry 1), although the
reaction suffered from poor reproducibility, which was
attributed to the poor solubility of sodium carbonate in THF
and the decomposition of product 8b under the reaction
conditions. When the reaction was performed in a 10:1 mixture
of THF and H2O at room temperature, 8b was obtained in 54%
yield with good reproducibility. The use of triethylamine as a
base led to further improvements in the yield of 8b (Table 1,
entry 3). It is noteworthy that trans-epoxide 8b′ was not
observed in any of the reactions described in Table 1 (Scheme
2). The formation of 8b′ would be disfavored by steric
hindrance between the phenyl group in 6b and the methyl
group in methylglyoxal.
This transformation was found to be effective for the
preparation of ( )-epolactaene, which is a microbial metabolite
isolated from Penicillium sp. BM1689-P10 and its derivatives
(Scheme 3).11 The α-bromo-β-ketoamides 6c−h were prepared
by the bromination of the corresponding β-ketoamides
(Supporting Information, Schemes S1−S3). The reaction of
6c with methylglyoxal in the presence of triethylamine in a 10:1
mixture of THF and H2O gave ( )-epolactaene (8c) in 69%
yield (77% yield based on the recovered 6c). The epolactaene
derivatives 8d−h bearing either an aliphatic or aromatic side-
chain were readily prepared by the reaction of the
corresponding α-bromo-β-ketoamides 6d−h with methylglyox-
al.
a
Reaction conditions: 6 (0.15 mmol), methylglyoxal (0.30 mmol) and
triethylamine (0.17 mmol) in solvent (4.5 mL) at room temperature.
Based on the H NMR spectrum, ( )-epolactaene (8c) existed as a
4.7:1 diastereomeric mixture at the γ-position in CD3OD. Although
compounds 8d-f were observed as single diastereomers in CD3OD,
compounds 8g and 8h were observed as 7:1 diastereomeric mixtures.
1
We proceeded to apply our newly developed synthetic
strategy to the synthesis of berkeleyamide D (1) (Scheme 4).
The reaction of α-bromo-β-ketoamide 6a7 with isobutylglyoxal
78 in the presence of triethylamine in 2-propanol gave α,β-
epoxy-γ-lactam 5 in 68% yield. Subsequent treatment of 5 with
10-camphorsulfonic acid (CSA) and triisopropyl orthoformate
in 2-propanol gave 9 as a single diastereomer in 86% yield.12
The treatment of 9 with lithium hexamethyldisilazide
(LHMDS) (2.2 equiv) followed by phenylacetyl chloride (1.0
equiv) gave the spiro lactam 10 in 19% yield, together with the
homodimer 11, which was isolated in 17% yield. The relative
configuration in 10 was determined by NOESY correlations
between H-9 and the methine proton of the isopropyl group at
C-8, between H-9 and the methyl protons of the isopropyl
group, and between 9-OH and the methylene protons at the
isobutyl group (Figure 2). The formation of 10 could
rationalized by the sequential C-acylation of 9, enolization of
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Scheme 4. Synthesis of ( )-Berkeleyamide D (1)
Figure 4. Determination of absolute configurations of (−)-1 and
(+)-1. IR (A) and VCD (B) spectra of (−)-1 (red) and (+)-1 (blue).
The IR and VCD spectra were measured in CDCl3 (3.3 × 10−2 M, l =
100 μm) for 2 and 90 min, respectively. (C) Schematic structures for
(−)-1 and (+)-1.
Figure 2. Selected NOESY correlations in 10. Selected carbon atoms
have been labeled using the IUPAC numbering system.
the resulting 1,3-diketone, and intramolecular spirocyclization
via an epoxide ring-opening reaction (Scheme 1). Although the
inclusion of a variety of different bases and additives was
examined in detail, it was not possible to improve the yield of
10 (Supporting Information, Table S-1). Hydrolysis of 10 with
p-toluenesulfonic acid (TsOH) in THF−H2O gave ( )-1 in
71% yield.13 The 1H and 13C NMR spectra for synthetic ( )-1
were in agreement with those reported for natural 1.1,14
NOESY correlations between H-9 and the methylene protons
of the isobutyl group at C-8 in ( )-1 indicated that there was a
cis relationship between H-9 and the isobutyl group (Figure 3).
lactam at C-6 and the ketone at C-4, respectively (Figure 4A).
The VCD spectra of (−)-1 and (+)-1 exhibited strong bisignate
VCD signals in the CO stretching region (Figure 4B). The
VCD spectrum of (−)-1 showed a positive-negative couplet
going from the lower to higher frequencies, indicating a
clockwise orientation between the two adjacent carbonyl
groups at C-4 and C-6 (Figure 4C). Taken together with the
NOESY correlations, these data indicated that the absolute
configuration of (−)-1 was 5S,8R,9R.15 Thus, natural 1 has the
same absolute configuration for the spirocenter at its C-5
position as the structurally related compounds pseurotin A (2)
and azaspirene (3). The VCD spectrum of (+)-1 showed a
negative−positive couplet going from the lower to higher
frequencies, indicating a counterclockwise orientation between
the two adjacent carbonyl groups. These data therefore
indicated that the absolute configuration of (+)-1 was 5R,8S,9S.
In conclusion, we have developed an efficient method for the
construction of α,β-epoxy-γ-lactams via the Darzens reaction of
α-bromo-β-ketoamides with glyoxals. This method has been
successfully applied to several γ-lactam derivatives, including
( )-epolactaene and the key intermediate for berkeleyamide D.
The key features of our newly developed synthesis of
berkeleyamide D include the construction of the core spiro
ring system by a C-acylation reaction followed by spirocycliza-
tion involving an epoxide ring-opening reaction. After
separation by optical resolution of synthetic ( )-1 using chiral
HPLC, the absolute configurations of (+)-1 and (−)-1 were
determined by the VCD exciton chirality method.
Figure 3. Selected NOESY correlations in ( )-1. Selected carbon
atoms have been labeled using the IUPAC numbering system.
Optical resolution of synthetic ( )-1 by chiral HPLC using a
CHIRALPAK IC column gave both enantiomers of 1, which
possessed almost equal and opposite specific rotation values
[i.e., [α]17 = +84.6 and −85.7, respectively (c 0.25, MeOH)].
D
The specific rotation of natural 1 was reported to be [α]25
=
D
−55.9 (c 0.003, MeOH).1
With both (−)-1 and (+)-1 in hand, we proceeded to
measure their VCD and IR spectra in CDCl3 to determine their
absolute configuration (Figure 4). The IR spectra of (−)-1 and
(+)-1 contained strong absorptions at 1744 and 1686 cm−1,
which were derived from the CO stretching vibrations of the
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Organic Letters
Letter
(12) Because of the steric hindrance, 2-propanol should attack the
iminium ion from the opposite side of the adjacent epoxide.
ASSOCIATED CONTENT
* Supporting Information
Full experimental procedures, characterization data, and NMR
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(13) The 8,9-cis-diol ( )-1 was solely obtained by hydrolysis of
aminal 10. Formation of ( )-1 can be explained by the difference in
thermodynamic stability between 1 and 8-epi-1. Given that the
hemiaminal formation is a reversible process, the thermodynamically
stable product should be obtained. Density functional theory (DFT)
calculations at the B3LYP/6-311+G(d,p) level indicated that the
lowest energy conformation of 1 was more stable than that of 8-epi-1
by 7.2 kcal/mol following zero-point energy corrections.
AUTHOR INFORMATION
Corresponding Author
■
(14) The 1H and 13C NMR spectra of synthetic 1 were in agreement
with those of natural 1, which are provided in the Supporting
*E-mail: kuramoch@kpu.ac.jp.
Notes
1
Information of ref 1. The H NMR assignments for the methine (δ
The authors declare no competing financial interest.
1.95, m) and methylene (δ 1.90, m and 1.61, m) protons of the
isobutyl group in our synthetic 1 were different from those reported in
natural berkeleyamide D (δ 1.92, m for the methine, and δ 1.88, m, 2H
for the methylene); see ref 1. Because a peak at 1.6 ppm appears in the
1H NMR spectrum of natural 1, the signals derived from the
methylene protons of the isobutyl group have been incorrectly
assigned in natural 1.
(15) The absolute configuration of (−)-1 was supported by a
comparison of the experimental and calculated VCD spectra. See the
Supporting Information.
ACKNOWLEDGMENTS
■
This work was supported in part by the Hoansha Foundation
and a grant-in-aid for scientific research (Grant No. 24310151)
from the Ministry of Education, Science, Sports, and Culture of
Japan. This study was carried out using the mass spectrometers
in the Joint Usage/Research Center (JURC) at the Institute for
Chemical Research, Kyoto University.
REFERENCES
■
(1) Stierle, A. A.; Stierle, D. B.; Patacini, B. J. Nat. Prod. 2008, 71,
856−860.
(2) (a) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H.
P. Helv. Chim. Acta 1976, 59, 133−137. (b) Weber, H. P.; Petcher, T.
J.; Bloch, P.; Tamm, C. Helv. Chim. Acta 1976, 59, 137−140.
(c) Bloch, P.; Tamm, C. Helv. Chim. Acta 1981, 64, 304−315.
(3) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.;
Osada, H. Org. Lett. 2002, 4, 2845−2848.
(4) (a) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am.
Chem. Soc. 2002, 124, 12078−12079. (b) Hayashi, Y.; Shoji, M.;
Yamaguchi, S.; Mukaiyama, T.; Yamaguchi, J.; Kakeya, H.; Osada, H.
Org. Lett. 2003, 5, 2287−2290. (c) Aoki, S.; Oi, T.; Shimizu, K.;
Shiraki, R.; Takao, K.; Tadano, K. Heterocycles 2004, 62, 161−166.
(d) Aoki, S.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano, K.
Bull. Chem. Soc. Jpn. 2004, 77, 1703−1716.
(5) (a) Taniguchi, T.; Monde, K. J. Am. Chem. Soc. 2012, 134, 3695−
3698. (b) Asai, T.; Taniguchi, T.; Yamamoto, T.; Monde, K.; Oshima,
Y. Org. Lett. 2013, 15, 4320−4323.
(6) (a) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy−
Exciton Coupling in Organic Stereochemistry; University Science Books:
Mill Valley, CA, 1983. (b) Harada, N.; Nakanishi, K.; Berova, N. In
Comprehensive Chiroptical Spectroscopy; Berova, N., Polavarapu, P. L.,
Nakanishi, K., Woody, R. W., Eds.; Wiley: New York, 2012; Vol. 2, pp
115−166.
(7) Alexander R. P.; Brown, J. A.; Crepy, K. V. L.; Mack, S. R. PCT
Int. Appl. WO 2008047109, Apr 24, 2008.
(8) Girotra, N. N.; Patchett, A. A.; Zimmerman, S. B.; Achimov, D.
L.; Wendler, N. L. J. Med. Chem. 1980, 23, 209−213.
(9) Herschhorn, A.; Lerman, L.; Weitman, M.; Gleenberg, I. O.;
Nudelman, A.; Hizi, A. J. Med. Chem. 2007, 50, 2370−2384.
(10) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Osada, H. J.
Antibiot. 1995, 48, 733−735.
(11) Total synthesis of optically active epolactaene: (a) Hayashi, Y.;
Narasaka, K. Chem. Lett. 1998, 313−314. (b) Hayashi, Y.; Kanayama,
J.; Yamaguchi, J.; Shoji, M. J. Org. Chem. 2002, 67, 9443−9448.
(c) Marumoto, S.; Kogen, H.; Naruto, S. J. Org. Chem. 1998, 63,
2068−2069. (d) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron
1999, 55, 7129−7144. (e) Marumoto, S.; Kogen, H.; Naruto, S.
Tetrahedron 1999, 55, 7145−7156. (f) Kuramochi, K.; Nagata, S.;
Itaya, H.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 7371−
7374. (g) Kuramochi, K.; Nagata, S.; Itaya, H.; Matsubara, Y.; Sunoki,
T.; Uchiro, H.; Takao, K.; Kobayashi, S. Tetrahedron 2003, 59, 9743−
9758. (h) Tan, Z.; Negishi, E. Org. Lett. 2006, 8, 2783−2785.
1389
dx.doi.org/10.1021/ol500148g | Org. Lett. 2014, 16, 1386−1389