A new concise synthesis of (+)-ipomeamarone, (-)-ngaione, and their stereoisomers

Article abstract of DOI:10.1246/cl.140811

A new concise and enantiocontrolled total synthesis of (+)-ipomeamarone (1), a well-known phytoalexin, is described. The key step involved a tetrahydrofuran ring construction from optically active furyl alcohol 5 via the π-allyl palladium complex with a chiral phosphine ligand. This procedure was also applicable to the synthesis of (1)-ngaione (2) and its stereoisomers.

Full text of DOI:10.1246/cl.140811

CL-140811
Received: August 30, 2014 | Accepted: September 27, 2014 | Web Released: October 3, 2014
A New Concise Synthesis of (+)-Ipomeamarone, (¹)-Ngaione, and Their Stereoisomers#
Yoshinosuke Usuki,* Taku Deguchi, and Hideo Iio
Division of Molecular Materials Science, Graduate School of Science, Osaka City University,
3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585
(E-mail: usuki@sci.osaka-cu.ac.jp)
A new concise and enantiocontrolled total synthesis of
(+)-ipomeamarone (1), a well-known phytoalexin, is described.
The key step involved a tetrahydrofuran ring construction from
optically active furyl alcohol 5 via the π-allyl palladium
complex with a chiral phosphine ligand. This procedure was
also applicable to the synthesis of (¹)-ngaione (2) and its
stereoisomers.
oxalyl chloride in the presence of DMF (catalytic amount) led to
acid chloride 7, which was used directly for the Stille coupling
reaction without further purifications.
Metallation of 3-bromofuran7 using n-butyllithium proceed-
ed smoothly to afford 9 by the addition of tributyltin chloride.
The cross-coupling reaction of 9 and acid chloride 7 was carried
out using 5 mol % of [PdCl2(PPh3)2] in benzene to afford 6 in
67% yield.
The Stille coupling product 6 was subjected to enantio-
selective reduction using the CBS catalyst and borane, yielding
furyl alcohol 5 with high enantiomeric excess (>95% ee) in
89% yield (Scheme 3).
(+)-Ipomeamarone (1) (Figure 1) is a well-known furano-
sesquiterpene as one of the first isolated phytoalexins from
mold-damaged sweet potatoes Ipomea batatas by Hiura1 and its
structure was elucidated by Kubota and Matsuura in 1953.2
Absolute stereochemistry of 1 was determined as (2S,5R) by
Nakanishi in 1983.3 Its stereoisomers, (¹)-ngaione (2) and
(+)-epingaione (3), are also known as toxic constituents isolated
from Myoporum deserti.4 These compounds contain the 2,5-
disubstituted tetrahydrofuran skeleton, which was found in many
naturally occurring antibiotics of the monensin type. The unique
structure as well as the significant biological activities for the
toxicological studies led to us to undertake a new enantiose-
lective synthesis of 1. Despite three asymmetric total syntheses
of 1 have been already published,5 we believed a shorter and
concise access was possible. Specifically, our goal was to
develop a synthetic strategy to prepare 1 and its stereoisomers in
a straightforward manner for further biological evaluations.
Herein, we like to report a new concise and enantiocontrolled
total synthesis of (+)-ipomeamarone (1) and its stereoisomers.
Our synthetic strategy of 1, outlined in Scheme 1, involves
THF ring construction from optically active furyl alcohol 5 via
the π-allyl palladium complex with a chiral phosphine ligand.
Furyl alcohol 5 was to be synthesized via the CBS (Corey-
Bakshi-Shibata) reduction of 6, which was obtained by the Stille
coupling of 7 and 9.
Scheme 1. Retrosynthetic analysis of (+)-ipomeamarone (1).
Our total synthesis of 1 commenced with geranyl acetate
(Scheme 2). Selective epoxidation on the terminal double bond
with mCPBA followed by oxidation with HIO4 afforded
aldehyde 11 in 67% yield for 2 steps.6 Jones oxidation of 11
gave acid 8 in 74% yield. Following the treatment of 8 with
Figure 1. Structures of (+)-ipomeamarone (1), (¹)-ngaione (2),
and (¹)-epingaione (3).
Scheme 2. Preparation of furyl ketone 6.
1882 | Chem. Lett. 2014, 43, 1882–1884 | doi:10.1246/cl.140811
© 2014 The Chemical Society of Japan

Table 2. Pd-catalyzed cyclization of 5 with chiral ligands
Chiral phosphine ligand
Entry
4a:4ba
Conv.a/%
Scheme 3. Enantioselective reduction of furyl ketone 6.
(20 mol %)
1
2
3
4
(R)-BINAP
1.2:1
2.1:1
3.7:1
1:4.2
94
98
98
95
(R)-C3TunePhos
(R)-SegPhos
(S)-SegPhos
aDetermined by GC analysis (DB-5 column).12
Figure 2. The differentiation of 1H NMR chemical shift values
between S and R Mosher esters derived from furyl alcohol 5 (¦S-R).
Table 1. Pd-catalyzed cyclization of 5 with achiral ligands
Figure 3. Relative configurations of 4a and 4b.
Entry
Phosphine ligand
4a:4ba
Conv.a/%
1
2
3
4
5
PPh3 (40 mol %)
No reaction
No reaction
1:1.2
®
®
9
9
96
P(o-tolyl)3 (40 mol %)
DPPE (20 mol %)
DPPP (20 mol %)
DPPB (20 mol %)
1:1.3
1:1.7
aDetermined by GC analysis (DB-5 column).12 bdba: dibenzy-
lideneacetone.
The absolute configuration of 5 was confirmed by advanced
Mosher ester analysis (Figure 2),8 which revealed that reduction
using (S)-(¹)-2-methyloxazaborolidine resulted in the formation
of the (R)-alcohol. This result is in agreement with the expected
transition state for the CBS reduction.9
Few examples of stereoselective allylic O-alkylations at
tertiary centers with aliphatic alcohols.10 We anticipated that the
inherent diastereofacial preference of 5 would be to form 4b
(trans) rather than the desired cis-product 4a.11 Initially, we
examined the Pd-catalyzed cyclization of 5 with achiral
phosphine ligands (Table 1).
With monophosphine, the desired reaction would not
proceed at all (Entries 1 and 2), whereas 20 mol % of DPPB
accelerated the desired reaction in 96% conversion (Entry 5).
These results suggested us a C4-bridged diphosphine ligand is
crucial to proceed the cyclization smoothly.
Then we screened a range of chiral catalysts to figure out
that [Pd2(dba)3] with (R)-SegPhos13 enabled us to overcome the
substrate’s diastereofacial bias and favor 4a (Table 2, Entry 3).
Matching-mismatching effects were observed here; (S)-SegPhos
gave substantial (1:4.2) selectivity for the trans-product 4b
(Entry 4).
Scheme 4. Conversion of 4a to (+)-ipomeamarone (1).
4a was subjected to hydroboration with BH3¢THF and the
corresponding alcohol 12 was obtained with 77% (Scheme 4).
Dess-Martin oxidation of alcohol 12 provides the known
aldehyde (2S,5R)-13 in 96% yield, whose analytical and spectral
data were in good agreement with the literature report.5c,14
To complete the synthesis of 1, the previously reported
endgame5c has been slightly modified. The Grignard addition of
isobutylmagnesium bromide to (2S,5R)-13 gave alcohol 14 as a
1:1 mixture of diastereomers quantitatively, which were reoxi-
dized with Dess-Martin periodinane to afford the desired
(+)-ipomeamarone (1) with the correct stereochemistry in 95%
yield. The spectral data of our synthetic (+)-ipomeamarone
agree satisfactorily with those reported.3,15 A new total synthesis
of (+)-ipomeamarone (1) has been thus achieved in 10 steps
with 15.9% overall yield.
Pd-catalyzed cyclization of ent-5, obtained by reduction of 6
with (R)-Me-CBS catalyst, provided ent-4a (with (R)-SegPhos)
and ent-4b (with (S)-SegPhos), respectively (Figure 4). The
same procedure above mentioned is applicable to ent-4a, ent-4b,
and 4b, which were converted to (2R,5S)-13, (2S,5S)-13, and
(2R,5R)-13, respectively.16
The structures of 4a (cis) and 4b (trans) were confirmed
by subsequent NOE experiments (signal enhancements are
indicated by arrows in Figure 3).
Chem. Lett. 2014, 43, 1882–1884 | doi:10.1246/cl.140811
© 2014 The Chemical Society of Japan | 1883

1997, 53, 4353.
12 GC analyses were carried out on a Shimadzu GC-9A
equipped with a DB-5 column (30 M © 0.25 mm i.d., 0.1 ¯m
film thickness). Helium was used as carrier gas and the
following temperature program was employed: initial iso-
thermal period of 5 min at 50 °C, then an increase at
10 °C min¹1 to 200 °C with an isothermal period of 30 min at
200 °C. Retention time: 4a 11.1 min, 4b 11.4 min, 5
19.2 min.
Figure 4. Structures of ent-4a, ent-4b, and the other stereoisomers
13.
13 T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T.
Miura, H. Kumobayashi, Adv. Synth. Catal. 2001, 343, 264.
14 (2S,5R)-13: colorless liquid, [α]D +16.7° (c 1.7, MeOH)
In summary, (+)-ipomeamarone, (¹)-ngaione, and their
stereoisomers have been synthesized from the commercially
available geranyl acetate, involving a Pd-catalyzed cyclization
with (R)- or (S)-SegPhos as a key step to furnish the THF ring
skeleton.
1
[lit5c [α]D +12.48° (c 1.28, MeOH)]; H NMR (400 MHz,
CDCl3): ¤ 9.83 (t, J = 2.7 Hz, 1H), 7.38-7.36 (m, 2H), 6.34
(m, 1H), 4.93 (t, J = 7.1 Hz, 1H), 2.63 (d, J = 2.7 Hz, 2H),
2.30 (m, 1H), 2.05-1.92 (m, 3H), 1.39 (s, 3H); 13C NMR
(100 MHz, CDCl3): ¤ 202.1, 143.4, 139.1, 126.9, 108.6,
87.1, 73.2, 54.9, 37.8, 33.2, 27.2; HRMS(EI) m/z: [M]+
calcd for C11H14O3 194.0943, found 194.0934.
References and Notes
#
This paper is dedicated to the memory of the late emeritus
Professor Takashi Tokoroyama at Osaka City University.
M. Hiura, Report from Gifu Agr. College. 1943, 50, 1.
T. Kubota, T. Matsuura, Nippon Kagaku Zasshi 1953, 74,
248.
15 J. Schneider, J. Lee, K. Yoshihara, K. Mizukawa, K.
Nakanishi, J. Chem. Soc., Chem. Commun. 1984, 372.
16 (2R,5S)-13: colorless liquid, [α]D ¹14.4° (c 1.7, MeOH);
1H NMR (400 MHz, CDCl3): ¤ 9.83 (t, J = 2.7 Hz, 1H),
7.38-7.36 (m, 2H), 6.34 (m, 1H), 4.98 (t, J = 7.1 Hz, 1H),
2.62 (d, J = 2.7 Hz, 2H), 2.30 (m, 1H), 2.05-1.92 (m, 3H),
1.39 (s, 3H); 13C NMR (100 MHz, CDCl3): ¤ 202.1, 143.4,
139.1, 126.9, 108.6, 87.1, 73.2, 54.9, 37.8, 33.2, 27.2;
HRMS(EI) m/z: [M]+ calcd for C11H14O3 194.0943, found
194.0934. (2S,5S)-13: colorless liquid, [α]D ¹13.8° (c 1.1,
1
2
3
4
5
J. A. Schneider, K. Yoshihara, K. Nakanishi, J. Chem. Soc.,
Chem. Commun. 1983, 352.
For a recent example, see: D. Yecheng, Y. Zhen, Y. Yanzhen,
B. Xiulian, Pest Manage. Sci. 2008, 64, 203.
a) H. Nemoto, T. Tanabe, M. Nagamochi, K. Fukumoto,
Heterocycles 1993, 35, 707. b) T. Sugimura, K. Koguro, A.
Tai, Tetrahedron Lett. 1993, 34, 509. c) K. Matsuo, T. Arase,
Chem. Pharm. Bull. 1995, 43, 890.
1
MeOH); H NMR (400 MHz, CDCl3): ¤ 9.86 (t, J = 2.7 Hz,
1H), 7.38 (m, 2H), 6.38 (m, 1H), 4.97 (t, J = 7.1 Hz, 1H),
2.66 (d, J = 2.7 Hz, 2H), 2.27 (m, 1H), 2.02-1.91 (m, 3H),
1.41 (s, 3H); 13C NMR (100 MHz, CDCl3): ¤ 202.1, 143.4,
139.3, 127.1, 108.6, 81.1, 73.9, 54.3, 38.0, 33.3, 28.1;
HRMS(EI) m/z: [M]+ calcd for C11H14O3 194.0943, found
194.0936. (2R,5R)-13: colorless liquid, [α]D +15.5° (c 1.0,
6
7
P. A. Plé, A. Hamon, G. Jones, Tetrahedron 1997, 53, 3395.
Y. Fukuyama, Y. Kawashima, T. Miwa, T. Tokoroyama,
Synthesis 1974, 443.
8
9
I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am.
Chem. Soc. 1991, 113, 4092.
E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc.
1987, 109, 5551.
1
MeOH); H NMR (400 MHz, CDCl3): ¤ 9.86 (t, J = 2.7 Hz,
1H), 7.38 (m, 2H), 6.38 (m, 1H), 4.97 (t, J = 7.1 Hz, 1H),
2.66 (d, J = 2.7 Hz, 2H), 2.27 (m, 1H), 2.02-1.91 (m, 3H),
1.41 (s, 3H); 13C NMR (100 MHz, CDCl3): ¤ 202.1, 143.4,
139.3, 127.1, 108.6, 81.1, 73.9, 54.3, 38.0, 33.3, 28.1;
HRMS(EI) m/z: [M]+ calcd for C11H14O3 194.0943, found
194.0941.
10 a) K. C. Morrison, J. P. Litz, K. P. Scherpelz, P. D. Dossa,
D. A. Vosburg, Org. Lett. 2009, 11, 2217. b) K. K. Wan, J. P.
Litz, D. A. Vosburg, Tetrahedron: Asymmetry 2010, 21,
2425.
11 C. Fournier-Nguefack, P. Lhoste, D. Sinou, Tetrahedron
1884 | Chem. Lett. 2014, 43, 1882–1884 | doi:10.1246/cl.140811
© 2014 The Chemical Society of Japan