The first total synthesis of a macrocyclic anti-protozoan, LL-Z1640-2

Article abstract of DOI:10.1246/cl.2001.172

Anti-protozoan, LL-Z1640-2 has been stereoselectively synthesized from D-ribose through Sonogashira coupling, Tsuji hydrogenolysis, and Mukaiyama lactonization.

Full text of DOI:10.1246/cl.2001.172

172
Chemistry Letters 2001
The First Total Synthesis of a Macrocyclic Anti-protozoan, LL-Z1640-2
Kuniaki Tatsuta,* Satoko Takano, Toshimitsu Sato, and Satoshi Nakano
Department of Applied Chemistry, School of Science and Engineering, Waseda University,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555
(Received December 1, 2000; CL-001088)
Anti-protozoan, LL-Z1640-2 has been stereoselectively
synthesized from D-ribose through Sonogashira coupling, Tsuji
hydrogenolysis, and Mukaiyama lactonization.
A macrocyclic nonaketide, LL-Z1640-2 (1) was isolated as
an anti-protozoan from fungi, and the structure was determined
by X-ray studies to be a zearalenone-like macrocyclic com-
pound (Figure 1).1 Recently, LL-Z1640-2 (1) was also found to
inhibit the JNK/p38 pathways in signal-specific manner.2
give 1011 as a single product with a trace of its diastereomer.
Without determination of the configuration, 10 was used for the
following reactions, because the hydroxy group would be
removed in a later step (5→13). After removal of the TMS
group, the resulting 7 was coupled with the iodobenzene 6,
which was prepared according to Hegedus’ procedures,5 in the
presence of Pd(OAc)2, CuI and Ph3P to afford 11.12 This was
protected to the ethoxycarbonate 12 which, upon reduction with
Lindlar catalyst, gave the Z-olefin 5. Hydrogenolysis of 5 pro-
ceeded smoothly under Tsuji’s conditions9 to give the desired
E-olefin 13. After de-O-acylation of 13, the produced primary
alcohol was oxidized to the aldehyde, which was treated with
CBr4 and Ph3P to give the dibromo-olefin 14. Exposure of 14
with n-BuLi produced the intermediary lithiated acetylide,
which reacted with the optically active (S)-propylene oxide 15
to afford the alcohol 16. This was also hydrogenated over
Lindlar catalyst to the Z-olefin 17. Saponification of 17 to the
hydroxy acid 4 was followed by cyclization under Mukaiyama
conditions8 to afford the lactone 18. After removal of all O-
MOM groups, oxidation of the resulting allyl alcohol was
examined under various conditions. Only Dess–Martin reagent
and DDQ effected selective oxidation of the allyl alcohol to
give the α,β-unsaturated ketone 1 in 62% and 20% yields,
respectively. This ketone was identical in all respects with the
natural product 1,13 completing the total synthesis.
It is well-known that the synthesis of simple zearalenone
analogs such as 2 and 3 is effected by various methodologies,
for example: 1) Wittig reaction with poly-substituted benzalde-
hydes; 2) Dieckmann or aldol-type reaction;3 3) reaction of
phenylsulfonyl- or thiomethylbenzenes with alkyl iodides;4 4)
reaction of trialkylstannyl olefins with iodobenzenes;5,6 5) ring-
forming olefin methathesis.7 However, the more complex and
labile structure 1 can limit the scope of the above-mentioned
methods. The total synthesis of LL-Z1640-2 (1) has not been
accomplished by these earlier routes.
Herein, we describe the first total synthesis of LL-Z1640-2
(1) from a carbohydrate by a straightforward strategy.
Retrosynthetically, we envisioned the Mukaiyama cycliza-
tion8 of the hydroxy acid 4 to be a means potentially well suited
to the assembly of the lactone 1 (Scheme 1). Access to this
advanced intermediate was to be gained by Tsuji hydrogenoly-
sis9 of 5 followed by reaction with the optically active epoxide
15. The key compound 5 would be prepared through
Sonogashira coupling10 of 6 with 7, the latter of which could be
derived from D-ribose (8).
This work was financially supported by Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
Science, Sport and Culture.
D-Ribose (8) was converted into the properly protected
ribopyranose 9 in 3 steps (Scheme 2). Reaction of 9 with the
lithiated acetylide was followed by selective pivaloylation to
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
173
1H NMR δ 1.21 (9H, s), 3.41 (3H, s), 3.42 (3H, s), 3.46 (3H, s), 3.51
(3H, s), 3.79 (3H, s), 3.89 (1H, dd, J = 8.0 and 2.0), 3.91 (3H, s), 3.99
(1H, dd, J = 8.0 and 2.0), 4.14 (1H, dd, J = 11.0 and 8.0), 4.17 (1H,
ddd, J = 8.0, 2.0, and 2.0), 4.38 (1H, dd, J = 11.0 and 2.0), 4.74 (1H, d,
J = 8.0), 4.75 (1H, d, J = 8.0), 4.77 (2H, s), 4.80 (1H, d, J = 8.0), 4.81
(1H, d, J = 8.0), 4.82 (1H, d, J = 2.0), 5.15 (2H, s), 6.66 (1H, d, J =
2.5), 6.71 (1H, d, J = 2.5), 12: 1H NMR δ 1.21 (9H, s), 1.32 (3H, dd, J
= 7.0 and 7.0), 4.05 (1H, dd, J = 6.0 and 4.0), 4.14 (2H, m), 4.20 (1H,
dd, J = 12.0 and 6.0), 4.23 (1H, q, J = 7.0), 4.24 (1H, q, J = 7.0), 4.42
(1H, dd, J = 12.0 and 3.0), 5.79 (1H, d, J = 4.0), 6.67 (1H, d, J = 2.5),
6.72 (1H, d, J = 2.5), 13: [α]D +19˚ (c 0.62, MeOH); 1H NMR δ 1.22
(9H, s), 2.56 (2H, m), 3.88 (1H, m), 3.94 (1H, m), 3.96 (1H, m), 4.16
(1H, dd, J = 12.0 and 6.0), 4.47 (1H, dd, J = 12.0 and 3.0), 6.26 (1H,
dt, J = 16.0 and 6.5), 6.46 (1H, d, J=16.0), 6.61 (1H, d, J = 2.0), 6.69
(1H, d, J = 2.0), 14: [α]D –15° (c 0.69, MeOH); 1H NMR δ 2.59 (2H,
m), 3.84 (1H,m), 3.85 (1H, m), 4.51 (1H, dd, J = 9.0 and 4.0), 6.29
(1H, dt, J = 16.0 and 7.0), 6.47 (1H, d, J = 16.0), 6.55 (1H, d, J = 9.0),
6.60 (1H, d, J = 2.5), 6.70 (1H, d, J = 2.5), 16: [α]D –77˚ (c 0.71,
MeOH); 1H NMR δ 1.24 (3H, d, J = 6.0), 2.34 (1H, ddd, J = 16.0, 7.0,
and 2.0), 2.45 (1H, ddd, J = 16.0, 4.0, and 2.0), 2.56 (1H, dddd, J =
15.0, 8.0, 8.0, and 1.0), 2.68 (1H, dddd, J = 15.0, 7.0, 4.0, and 1.0),
3.89 (1H, m), 3.94 (1H, ddd, J = 7.0, 6.0, and 4.0), 3.98 (1H, ddd, J =
8.0, 6.0, and 4.0), 4.64 (1H, m), 6.28 (1H, ddd, J = 18.0, 8.0, and 7.0),
6.46 (1H, ddd, J=18.0, 1.0, and 1.0), 6.60 (1H, d, J = 2.5), 6.70 (1H, d,
J = 2.5), 17: 1H NMR δ 5.54 (1H, dd, J = 11.0 and 9.0), 5.84 (1H, dt, J
= 11.0 and 8.0), 6.30 (1H, dt, J = 16.0 and 7.0), 6.45 (1H, d, J = 16.0),
18: [α]D +22° (c 0.88, MeOH), 1H NMR δ 1.39 (3H, d, J = 6.0), 2.31
(1H, br s), 2.39 (1H, dddd, J = 16.0, 8.0, 4.5, and 1.0), 2.71 (1H, m),
3.04 (1H, br s), 3.36 (3H, br s), 3.37 (3H, s), 3.39 (3H, s), 3.45 (3H, s),
3.79 (3H, s), 3.85 (1H, m), 3.97 (1H, br s), 4.53 (1H, d, J = 6.0), 4.54
(1H, d, J = 6.0), 4.64 (1H, d, J = 5.5), 4.65 (1H, d, J = 5.5), 4.71 (1H,
d, J = 6.0), 4.75 (1H, d, J = 6.0), 4.77 (1H, d, J = 6.0), 5.11 (1H, d, J =
6.0), 5.17 (1H, d, J = 6.0), 5.42 (1H, br s), 5.57 (1H, dd, J=10.0 and
10.0), 5.85 (1H, br s), 6.12 (1H, br s), 6.51 (1H, d, J=2.0), 6.57 (1H, d,
J = 2.0), 6.60 (1H, br s).
References and Notes
1
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11 Selected data for key compounds: Optical rotations (22 ˚C) and 1H
NMR spectra (J in Hz; 400 and 500 MHz) were measured in MeOH
and CDCl3. 1: mp 166–168 °C; [α]D –73° (c 0.33, MeOH) [lit.,1 mp
1
172 °C; [α]D –75° (MeOH)]; H NMR δ 1.47 (3H, d, J = 6.0), 2.14
(1H, ddd, J = 16.0, 10.5, and 3.0), 2.21 (1H, m) 2.42 (1H, br d, J =
9.0), 2.51 (1H, dddd, J=17.0, 3.0, 2.0, and 2.0), 3.58 (1H, ddd, J =
17.0, 12.0, and 12.0), 3.75 (1H, d, J = 5.5), 3.81 (3H, s), 3.99 (1H, br
s), 4.51 (1H, m), 5.25 (1H, ddq, J = 12.0, 6.0, and 2.0), 5.99 (1H,
ddd, J = 16.0, 10.5, and 4.0), 6.21 (1H, ddd, J = 12.0, 12.0, and 2.0),
6.33 (1H, dd, J = 12.0 and 3.0), 6.38 (1H, d, J = 3.0), 6.40 (1H, d, J
1
= 3.0), 6.88 (1H, dd, J = 16.0 and 2.0), 12.15 (1H, s), 5: H NMR δ
1.20 (9H, s), 1.38, (3H, t, J = 7.0), 3.84 (1H, m), 4.00 (2H, m), 4.16
(3H, m), 4.35 (1H, dd, J = 12.5 and 3.0), 5.76 (1H, dd, J = 10.0 and
5.0), 5.81 (1H, dd, J = 11.5 and 10.0), 6.65 (1H, d, J = 2.0), 6.75
1
(1H, d, J = 11.5), 6.91 (1H, d, J = 2.0), 6: H-NMR δ 3.56 (3H, s),
3.78 (3H, s), 3.92 (3H, s), 5.14 (3H, s), 6.70 (1H, d, J = 1.5), 6.98
(1H, d, J = 1.5), 7: 1H NMR δ 1.22 (9H, s), 2.49 (1H, d, J = 2.0),
3.86 (1H, dd, J = 8.5 and 2.0), 3.94 (1H, dd, J = 8.5 and 2.0),
4.10–4.16 (2H, m), 4.34 (1H, dd, J = 10.0 and 2.0), 4.63 (1H, dd, J =
2.0 and 2.0), 4.64 (1H, s), 10: H NMR δ 0.01 (9H, s), 1.05 (9H, s),
3.68 (1H, dd, J = 8.0 and 1.0), 3.79 (1H, dd, J=8.0 and 2.0),
3.94–4.00 (2H, m), 4.16 (1H, d, J = 8.0), 4.43 (1H, d, J = 1.0), 11:
12 S. Takano, T. Sugihara, K. Samizu, M. Akiyama, and K. Ogasawara,
Chem. Lett., 1989, 1781.
13 An authentic sample of natural LL-Z1640-2 was kindly provided by
Dr. Y. Iino, Ajinomoto Co., Inc.
1