Enantioselective Synthesis of Cephalimysins B and C

Article abstract of DOI:10.1021/acs.orglett.6b03373

The first synthesis of cephalimysins B and C is reported. The route features a Ni(II)-diamine-catalyzed enantioselective conjugate addition of a densely substituted 3(2H)-furanone and an efficient dihydroxylation-lactonization sequence as key steps in the assembly of the spirocyclic core. The fully synthetic strategy is amenable to analog preparation.

Full text of DOI:10.1021/acs.orglett.6b03373

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Cephalimysins B and C
David Chalupa,† Petra Vojackova,† Jirí Partl,†,§ Drazen Pavlovic,†,‡,∥ Marek Necas,†
́
̌
́
̌
̌
́
̌
,†,‡
̌
and Jakub Svenda*
†Department of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
‡International Clinical Research Center, St. Anne’s University Hospital, Brno, 656 91, Czech Republic
S
* Supporting Information
ABSTRACT: The first synthesis of cephalimysins B and C is reported. The route features a Ni(II)−diamine-catalyzed
enantioselective conjugate addition of a densely substituted 3(2H)-furanone and an efficient dihydroxylation−lactonization
sequence as key steps in the assembly of the spirocyclic core. The fully synthetic strategy is amenable to analog preparation.
ephalimysins B (1) and C (2) are secondary metabolites
isolated from Aspergillus sp.1 that belong to a small family
of natural products named pseurotins (Figure 1). All members
FD-838 (4).8 A similar disconnection was targeted by Tadano
and colleagues in their synthesis of pseurotin A and azaspirene.9
Enolate chemistry of a substituted γ-lactam featured also in the
recent short synthesis of ( )-berkeleyamide D by Kuramochi
and co-workers.10 A distinct and concise strategy was disclosed
by Rovis and colleagues, who utilized an enantioselective
Stetter reaction to prepare three diastereomers of cephalimysin
A.11
C
In most of these previous strategies, assembly of the γ-lactam
preceded construction of the furanone ring.12 Here, we describe
a complementary approach that explores the chemical reactivity
of a densely substituted 3(2H)-furanone intermediate. Key
elements of our plan steered toward the synthesis of
cephalimysin C (2) are summarized in Scheme 1. Spirocyclic
γ-lactone 5 was recognized as a plausible precursor of the target
γ-lactam. The lactone (5) can be disconnected into the
furanone and the alkynyl ketone fragments (6 and 7,
respectively). In the forward (synthetic) direction, a conjugate
addition reaction between 6 and 7 followed by a dihydrox-
ylation−lactonization sequence would form the γ-lactone
Figure 1. Stereoisomeric structures of cephalimysins B (1), C (2), D
(3), and FD-838 (4).
of the family share a densely substituted spirocyclic 3(2H)-
furanone−γ-lactam core2 but vary in terms of stereochemistry
and appendage diversity. This relatively underexplored scaffold
is understood to be a product of hybrid polyketide−
nonribosomal peptide synthase biosynthetic machinery3 and
has been linked to a spectrum of biological effects. Examples
include inhibition of angiogenesis,4 inhibition of IgE
production,5 cytotoxicity toward certain cancer cell lines,6 or
antibacterial and antifungal activity.7
Scheme 1. Retrosynthetic Analysis of Cephalimysin C (2)
Target-directed syntheses of several pseurotins were reported
in the literature. Hayashi and co-workers used an aldol reaction
approach to couple a functionalized γ-lactam with different
aldehydes to access pseurotin A, azaspirene, synerazole, and
Received: November 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
intermediate (5). Incorporation of an activated (trifluoroethyl)
ester within the furanone was expected to facilitate the
lactonization step.
furfural (9) to form adduct ( )-10 (85% yield, dr ≥95:5;
relative stereochemistry not determined).16
Acidic workup (acetic acid) was employed to prevent
undesired post-aldol lactonization (δ-lactone formation) that
was observed under basic conditions. Oxidation of the aldol
adduct [( )-10] with 2-iodoxybenzoic acid in acetonitrile17
(1.5 equiv, 80 °C) proceeded smoothly, and the α-diazo 1,3-
dicarbonyl [( )-11] was isolated in 85% yield after simple
filtration. Brief exposure of ( )-11 to catalytic quantities (0.25
mol %) of rhodium(II) acetate dimer as a suspension in
preheated toluene (80 °C, 20 min) led to the clean formation
In realizing the plan outlined above, we had to address
uncertainties in the preparation and handling of the furanone
fragment (6). Although 2-alkoxycarbonyl 3(2H)-furanones of
similar substitution pattern are known,13 they can suffer from
limited stability that includes facile air oxidation.14 We pursued
rhodium(II)-catalyzed cyclization of diazo carbonyls13e,15 as a
mild method for construction of the furanone fragment, and the
optimized sequence is shown in Scheme 2.
1
of furanone 6 (≥95% conversion by H NMR analysis). To
assess its chemical stability, we analyzed the solution of 6 in
Scheme 2. Preparation of the Furanone Fragment (6)
1
CDCl3 by H NMR and found that the cyclization product
gradually decomposed on the order of hours (see Supporting
Information (SI) for the time-course experiment).
The spiro carbon atom of cephalimysins B (1) and C (2) was
established in the planned conjugate addition (Scheme 3).
Reaction between freshly prepared furanone 6 and alkynyl
ketone 7 was initially examined in the presence of N,N-
diisopropylethylamine (0.2 equiv) in acetonitrile. Under these
conditions, a racemic C-alkenylation product (enone ( )-12)
formed selectively as the Z-isomer (Z:E ≥95:5) in 62% isolated
yield (two steps from ( )-11). The product was stereochemi-
cally stable when kept neat but underwent slow Z → E
isomerization in CDCl3 solution.18
To achieve clean dihydroxylation of the electron-poor enone
[( )-12], we used a citric acid modified Upjohn protocol
described by Sharpless and co-workers.19 Under these
conditions, the in situ lactonization of intermediate diols led
to a mixture of two diastereomeric γ-lactones [( )-5:( )-13 =
7:1, 90% combined yield]. The use of an activated ester was
Titanium enolate generated from readily available α-diazo
trifluoroethyl ester 8 (titanium(IV) chloride, −78 °C) under-
went an aldol reaction with commercially available 5-ethyl-
Scheme 3. Synthesis of Racemic Cephalimysins B [( )-1] and C [( )-2]
B
DOI: 10.1021/acs.orglett.6b03373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
required for the spontaneous lactonization, where the
trifluoroethyl ester was superior due to the straightforward
product isolation (no chromatography required).20 The relative
stereochemistry of the separable γ-lactones was assigned by
comparative analysis with the 14-desmethyl analogs, for which
we had determined X-ray crystal structures (Scheme 3,
bottom). In an attempt to access a complementary stereo-
chemistry found in cephalimysin D (3) and FD-838 (4), we
also studied dihydroxylation of the E-isomer of enone ( )-12
(see SI). The major γ-lactone obtained in this experiment
converged, later in the synthesis, with the Z-isomer-derived
major lactone ( )-5, indicating that the osmium reagent
approached preferentially from the same π-face regardless of
the enone stereochemistry.
Trimethylsilylation of the 7:1 mixture of ( )-5 and ( )-13
with excess N,O-bis(trimethylsilyl)acetamide, followed by
treatment with 7 M ammonia solution in methanol at 0 °C,
provided primary amide ( )-14 (single diastereomer, 37% yield
over two steps).21 Oxidation of the revealed secondary alcohol
using Dess−Martin periodinane22 gave a 1,2-diketone (13C
NMR analysis), which underwent an intramolecular cyclization
to hydroxy spirolactam ( )-15 upon cleavage of the
trimethylsilyl ether (ammonium fluoride in methanol). Because
( )-15 displayed limited stability during silica-gel chromatog-
raphy, the crude material was processed forward. Introduction
of the methoxy group was accomplished under mild conditions
using a novel procedure. Treatment of ( )-15 with a gold(I)
triflimide−triphenylphosphine complex (10 mol %) in
methanol (23 °C, 1 h) gave racemic cephalimysin C [( )-2]
in a 3:1 mixture with cephalimysin B [( )-1] in a combined
yield of 35% over three steps.23 Spectral data for ( )-1 and
( )-2 were in full agreement with the literature,1 and the
structures were cemented further by an X-ray crystal structure
of 14-desmethylcephalimysin C (Scheme 3, bottom) prepared
by the same route.
the product.25 Examined cinchona alkaloids, and their thiourea
or squaric acid derivatives, also catalyzed the reaction but with
significantly diminished enantioselectivities (≤35% ee). To our
knowledge, the Ni(II)−diamine catalyst was not described in
conjugate additions with alkynones or enones previously.
The six-step sequence described in Scheme 3 converted
enone (R)-12 (96% ee) to cephalimysin C (2, 96% ee; see SI).
An analogous sequence starting from the enantiomeric enone
[(S)-12, 94% ee] gave ent-cephalimysin C (ent-2, 90% ee; see
SI). Importantly, the (S)-enone also provided cephalimysin B
(1; see SI), an observation consistent with the reported
opposite configuration of the spiro carbon atom of cepha-
limysins B (1) and C (2).1
There are only a few reports in which systematic structural
modifications (primarily semisynthesis and precursor-directed
biosynthesis derived) were examined in the context of
biological activity of pseurotins.5,26 The concise and modular
route to cephalimysins B (1) and C (2) described herein has an
exciting potential in this area. By a simple variation of the
furanone or the alkynyl ketone components, we were able to
rapidly access numerous spirocyclic analogs with a selection
depicted in Figure 2.
The natural products cephalimysins B (1) and C (2) were
previously assigned opposite configuration at the spiro carbon.1
To control the absolute stereochemistry at this position, we
examined several chiral amine-containing catalysts in the
conjugate addition process described above. Promising levels
of enantioselectivity were observed with the Ni(II)−diamine
complex described by Evans and Seidel (Scheme 4).24 The
optimized reaction conditions (10 mol % of (S,S)-16, toluene−
dichloromethane, −40 °C, 120 h) afforded the addition
product [(R)-12] in 96% ee (79% over two steps, Z/E =
5:1). For reproducible results, it was essential to reach high
conversion, otherwise a background reaction occurred during
the purification process and eroded the enantiomeric purity of
Figure 2. Selection of spirocyclic analogs prepared.
In summary, we have completed the first synthesis of
cephalimysins B (1) and C (2), which proceeded in 12 steps
from 3-oxopentanoic acid. Our strategy made use of Ni(II)−
diamine-catalyzed enantioselective conjugate addition of a
reactive 3(2H)-furanone intermediate and featured an efficient
dihydroxylation−lactonization sequence. The work lends
support to the previously assigned structures of the natural
products cephalimysins B (1) and C (2). Importantly, our
route is amenable to analog synthesis and is envisioned to aid
the mapping of the biological activity of molecules featuring the
underexplored spirocyclic scaffold of pseurotins.
Scheme 4. Enantioselective Conjugate Addition of Furanone
6
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03373.
Detailed experimental procedures and spectroscopic data
for all new compounds (PDF)
Crystallographic data (CIF, CIF, CIF)
C
DOI: 10.1021/acs.orglett.6b03373
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Aoki, S.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano,
K. Heterocycles 2004, 62, 161−166. (b) Aoki, S.; Oi, T.; Shimizu, K.;
Shiraki, R.; Takao, K.; Tadano, K. Bull. Chem. Soc. Jpn. 2004, 77,
1703−1716.
(10) (a) Komori, K.; Taniguchi, T.; Mizutani, S.; Monde, K.;
Kuramochi, K.; Tsubaki, K. Org. Lett. 2014, 16, 1386−1389.
(b) Mizutani, S.; Komori, K.; Kai, C.; Kuramochi, K.; Tsubaki, K.
Tetrahedron 2016, 72, 6640−6645.
(11) Lathrop, S. P.; Rovis, T. Chem. Sci. 2013, 4, 1668−1673.
(12) For the synthetic studies toward pseurotins, see: (a) Dolder, M.;
Shao, X.; Tamm, C. Helv. Chim. Acta 1990, 73, 63−68. (b) Shao, X.;
Dolder, M.; Tamm, C. Helv. Chim. Acta 1990, 73, 483−491. (c) Su, Z.;
Tamm, C. Helv. Chim. Acta 1995, 78, 1278−1290. (d) Su, Z.; Tamm,
C. Tetrahedron 1995, 51, 11177−11182. (e) Mitchell, J. M.; Finney, N.
S. Org. Biomol. Chem. 2005, 3, 4274−4281. (f) Orellana, A.; Rovis, T.
Chem. Commun. 2008, 730−732.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: svenda@chemi.muni.cz.
ORCID
̌
Jakub Svenda: 0000-0001-9232-3218
Present Addresses
§Synthon, Blansko, 678 01, Czech Republic.
∥Department of Pharmaceutical and Medicinal Chemistry,
Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Notes
The authors declare no competing financial interest.
(13) (a) Lutz, T. G.; Clevette, D. J.; Hoveyda, H. R.; Karunaratne, V.;
Nordin, A.; Sjoeberg, S.; Winter, M.; Orvig, C. Can. J. Chem. 1994, 72,
1362−1369. (b) Yamamoto, M. J. Chem. Soc., Perkin Trans. 1 1976,
1688−1691. (c) Wasserman, H. H.; Lee, G. M. Tetrahedron Lett. 1994,
35, 9783−9786. (d) Kraus, G. A.; Wei, J. J. Nat. Prod. 2004, 67, 1039−
1040. (e) Du, C.; Li, L.; Li, Y.; Xie, Z. Angew. Chem., Int. Ed. 2009, 48,
7853−7856.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support provided by the
Marie Curie Career Integration Grant (322001), the Bader
Philanthropies grant (15329), and the ICRC-ERA-Human-
Bridge project (GA316345). The X-ray diffraction and Bio-
SAXS core facility supported by the CIISB research infra-
structure (LM2015043 funded by MEYS CR) is acknowledged
for the crystallographic analysis. We thank Dr. Kamil Paruch
(Masaryk University) for his support.
(14) (a) Takei, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1970, 43,
3607−3608. (b) Truong, P.; Xu, X.; Doyle, M. P. Tetrahedron Lett.
2011, 52, 2093−2096.
(15) (a) Bien, S.; Gillon, A. Tetrahedron Lett. 1974, 15, 3073−3074.
(b) Bien, S.; Gillon, A.; Kohen, S. J. Chem. Soc., Perkin Trans. 1 1976,
489−492. (c) Doyle, M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q. J.
Org. Chem. 1991, 56, 820−829.
REFERENCES
■
(1) Yamada, T.; Kitada, H.; Kajimoto, T.; Numata, A.; Tanaka, R. J.
Org. Chem. 2010, 75, 4146−4153.
(2) For the X-ray crystal structure of 12,13-dibromopseurotin A, see:
Weber, H. P.; Petcher, T. J.; Bloch, P.; Tamm, C. Helv. Chim. Acta
1976, 59, 137−140.
(16) Calter, M. A.; Zhu, C. J. Org. Chem. 1999, 64, 1415−1419.
(17) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001−3003.
1
(18) The Z to E ratio was determined by H NMR in d6-acetone,
where the isomerization process was found to be negligible.
(19) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. Adv. Synth. Catal. 2002, 344, 421−433.
(20) Dihydroxylation−lactonization sequence examined with a
phenyl ester analog involved problematic separation of in situ liberated
phenol.
(3) (a) Maiya, S.; Grundmann, A.; Li, X.; Li, S. M.; Turner, G.
ChemBioChem 2007, 8, 1736−1743. (b) Wiemann, P.; Guo, C. J.;
Palmer, J. M.; Sekonyela, R.; Wang, C. C. C.; Keller, N. P. Proc. Natl.
Acad. Sci. U. S. A. 2013, 110, 17065−17070. (c) Tsunematsu, Y.;
Fukutomi, M.; Saruwatari, T.; Noguchi, H.; Hotta, K.; Tang, Y.;
Watanabe, K. Angew. Chem., Int. Ed. 2014, 53, 8475−8479.
(d) Yamamoto, T.; Tsunematsu, Y.; Hara, K.; Suzuki, T.; Kishimoto,
S.; Kawagishi, H.; Noguchi, H.; Hashimoto, H.; Tang, Y.; Hotta, K.;
Watanabe, K. Angew. Chem., Int. Ed. 2016, 55, 6207−6210. (e)
Review: Boettger, D.; Hertweck, C. ChemBioChem 2013, 14, 28−42.
(4) (a) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.;
Osada, H. Org. Lett. 2002, 4, 2845−2848. (b) Asami, Y.; Kakeya, H.;
Komi, Y.; Kojima, S.; Nishikawa, K.; Beebe, K.; Neckers, L.; Osada, H.
Cancer Sci. 2008, 99, 1853−1858. (c) Emoto, M.; Yano, K.; Choijamts,
B.; Sakai, S.; Hirasawa, S.; Wakamori, S.; Aizawa, M.; Nabeshima, K.;
Tachibana, K.; Kanomata, N. Anticancer Res. 2015, 35, 2739−2746.
(5) Ishikawa, M.; Ninomiya, T.; Akabane, H.; Kushida, N.; Tsujiuchi,
G.; Ohyama, M.; Gomi, S.; Shito, K.; Murata, T. Bioorg. Med. Chem.
Lett. 2009, 19, 1457−1460.
(21) Examined alternative protective groups and sources of ammonia
did not improve the yield of the primary amide.
(22) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156.
(23) The procedure described by Hayashi and colleagues (ref 8b)
using acetyl chloride in methanol gave the same (3:1) mixture of
cephalimysins C and B but required a longer reaction time and
resulted in diminished yields of the products.
(24) (a) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958−
9959. (b) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007,
129, 11583−11592.
(25) As found in a control experiment, silica gel effectively catalyzed
nonenantioselective, though highly Z-selective (Z:E = 11:1), 1,4-
addition between furanone 6 and alkynyl ketone 7.
(26) Igarashi, Y.; Yabuta, Y.; Sekine, A.; Fujii, K.; Harada, K. I.;
Oikawa, T.; Sato, M.; Furumai, T.; Oki, T. J. Antibiot. 2004, 57, 748−
754.
(6) (a) Yamada, T.; Imai, E.; Nakatuji, K.; Numata, A.; Tanaka, R.
Tetrahedron Lett. 2007, 48, 6294−6296. (b) Ge, H. M.; Yu, Z. G.;
Zhang, J.; Wu, J. H.; Tan, R. X. J. Nat. Prod. 2009, 72, 753−755.
(7) (a) Ando, O.; Satake, H.; Nakajima, M.; Sato, A.; Nakamura, T.;
Kinoshita, T.; Furuya, K.; Haneishi, T. J. Antibiot. 1991, 44, 382−389.
(b) Zhang, M.; Wang, W. L.; Fang, Y. C.; Zhu, T. J.; Gu, Q. Q.; Zhu,
W. M. J. Nat. Prod. 2008, 71, 985−989.
(8) (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) Hayashi, Y.; Shoji, M.; Mukaiyama,
T.; Gotoh, H.; Yamaguchi, S.; Nakata, M.; Kakeya, H.; Osada, H. J.
Org. Chem. 2005, 70, 5643−5654. (d) Hayashi, Y.; Sankar, K.;
Ishikawa, H.; Nozawa, Y.; Mizoue, K.; Kakeya, H. Bioorg. Med. Chem.
Lett. 2009, 19, 3863−3865.
D
DOI: 10.1021/acs.orglett.6b03373
Org. Lett. XXXX, XXX, XXX−XXX