First synthesis of (+)-pteroenone: A defensive metabolite of the abducted antarctic pteropod Clione antarctica

Article abstract of DOI:10.1055/s-2005-862389

(+)-Pteroenone, a defensive metabolite of the abducted antarctic pteropod Clione antarctica, was firstly and efficiently synthesized by employing anti-selective aldol reaction as the key step.

Full text of DOI:10.1055/s-2005-862389

LETTER
635
First Synthesis of (+)-Pteroenone: A Defensive Metabolite of the Abducted
Antarctic Pteropod Clione antarctica
FirstSynthesisof
(
+)-Pteroenon
k
e
o Nakamura,a Hiromasa Kiyota,*a Bill J. Baker,b Shigefumi Kuwaharaa
a
Department of Applied Bioorganic Chemistry, Division of Bioscience & Biotechnology for Future Bioindustry, Graduate School of
Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Fax +81(22)7178783; E-mail: kiyota@biochem.tohoku.ac.jp
b
Department of Chemistry, University of South Florida, 4202 E. Fowler Ave SCA400, Tampa, FL 33620, USA
Fax +1(813)9741733
Received 21 December 2004
This paper is dedicated to Professor Steven V. Ley FRS CBE on the occasion of his 60th birthday.
al. searched for this defensive chemical substance, and
Abstract: (+)-Pteroenone, a defensive metabolite of the abducted
antarctic pteropod Clione antarctica, was firstly and efficiently syn-
thesized by employing anti-selective aldol reaction as the key step.
isolated a compound named pteroenone [(+)-1].2 Here, the
first synthesis of (+)-1 is described.
As shown in Scheme 1, our synthesis of (+)-1 started from
the Evans anti-selective aldol reaction3 of 2 with the
known aldehyde 3,4 giving aldol 4. This aldol 4 was puri-
fied (>99% de) by recrystallization. The absolute con-
figuration was confirmed by converting 4 to the final
compound. The hydroxy group of 4 was protected as TES
ether to give 5. Since substitution of the chiral auxiliary
with propyl group via the Weinreb amide was not effi-
cient,5 the compound 5 was converted to thiol ester 6 with
lithium thioethoxide in quantitative yield.6 Since direct
conversion of thiol ester 6 to ketone 9 failed under a vari-
ety of Fukuyama coupling conditions7 and organocopper
Key words: pteroenone, defensive metabolite, Clione antarctica,
marine natural products, anti-aldol reaction
The pteropod Clione antarctica is a shell-less, pelagic
mollusc, which blooms each austral summer in McMurdo
Sound, Antarctica. There has been known the curious re-
lationship between C. antarctica and an Antarctic hyperi-
id amphipod, Hyperiella dilatata, which is a prey of
several antarctic fishes. Predatory fishes do not eat the
amphipod grasping a pteropod on its dorsum, due to a
feeding deterrent produced by the pteropod.1,2 Yoshida et
O
O
O
O
O
OH
OTES
O
O
a
b
O
N
O
N
O
N
quant.
63%
4 (>99% de)
5
2
3
Bn
Bn
Bn
OTES
OTES
OTES
O
O
OH
c
d
e
EtS
quant.
quant.
83%
6
7
8
OTES
O
OH
O
8
10
f
g
5
6
1
3
96%
93%
9
(+)-pteroenone (1)
Scheme 1 Synthesis of (+)-pteroenone. Reagents and conditions: a) MgCl2 (0.2 equiv), TMSCl (1.5 equiv), Et3N (2 equiv), EtOAc, r.t., 1 d,
recrystallization; b) TESOTf (1.2 equiv), 2,6-lutidine (1.2 equiv), CH2Cl2, –55 °C, 3 h; c) EtSH (3.8 equiv), n-BuLi (2.6 equiv), THF, –78 °C
to 7 °C, 6 h; d) DIBAL (1.01 equiv), CH2Cl2, –80 °C, 20 min; e) n-PrLi (1.1 equiv), Et2O, –80 °C, 30 min; f) IBX (4 equiv), DMSO, r.t., 5 h;
g) HF–TBAF (pH 7, excess), THF–H2O, r.t., 2 h.
SYNLETT 2005, No. 4, pp 0635–0636
0
4.
0
3.
2
0
0
5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862389; Art ID: U35204ST
© Georg Thieme Verlag Stuttgart · New York

636
Y. Nakamura et al.
LETTER
reagents,8 this transformation was achieved in 3 steps:
reduction using DIBAL, alkylation with n-PrLi and IBX
oxidation. Use of n-PrMgBr or n-PrCeCl2 lowered the
yield (<65%). The stereochemistry was retained through
these steps, however, deprotection of the TES group was
troublesome: usual conditions such as HF·pyridine, HF–
MeCN, TBAF, and HOAc–THF–H2O resulted in decom-
position or epimerization. Finally, neutral conditions (pH
6–7) by mixing aqueous HF and TBAF–THF9 gave (+)-1
without epimerization of 5- or 6-position. The purity of
the final compound (+)-1 was 98% ee and 96% de.10 The
overall yield was 47%. The 1H NMR and 13C NMR spec-
tral data and the value of optical rotation were identical
with those reported.2,11
Me
N
O
4
O
a
MeO
HN
37%
O
Bn
11
OH
O
O
37%
Me
N
MeO
10
84%
c
OTES
10%
b
Me
N
MeO
12
38%
d
In conclusion, the first efficient synthesis of a marine
defensive metabolite, (+)-pteroenone was achieved in
high yield using the Evans anti-aldol reaction as the key
step. Synthesis of all four diastereoisomers is under way
and their bioassays will make clear the curious ecological
relationships and generality of this marine repellent.
9
(+)-1
Scheme 2 Other synthetic routes to (+)-1. Reagents and conditions:
a) Me(MeO)NH·HCl (3 equiv), AlCl3 (3 equiv), CH2Cl2, –20 °C to
20 °C; b) n-PrMgBr (3 equiv), THF, 0 °C; c) TESOTf (1.2 equiv),
2,6-lutidine (1.2 equiv), CH2Cl2, –55 °C; d) n-PrLi (3 equiv), THF,
–78 °C.
Acknowledgment
We thank Dr. Yukito Furuya and Mr. Tsutomu Hasaba for technical
assistance. This work was partially supported by grant-in-aid from
Japan Society for the Promotion of Science (no. 14760069), Intelli-
gent Cosmos Foundation and The Naito Foundation.
(6) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31,
2849.
(7) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189. (b) Mori,
Y.; Seki, M. J. Org. Chem. 2003, 68, 1571.
(8) Anderson, R. J.; Henrick, C. A.; Rosenblum, L. D. J. Am.
Chem. Soc. 1974, 96, 3654.
References
(9) Mori, K.; Amaike, M. J. Chem. Soc., Perkin Trans. 1 1994,
2727.
(1) (a) McClintock, J. B.; Janssen, J. Nature 1990, 346, 462.
(b) Bryan, P. J.; Yoshida, W. Y.; McClintock, J. B.; Baker,
B. J. Marine Biology 1995, 122, 271.
(2) Yoshida, W. Y.; Bryan, P. J.; Baker, B. J.; McClintock, J. B.
J. Org. Chem. 1995, 60, 780.
(3) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2002, 124, 392.
(4) (a) Patel, P.; Pattenden, G. Tetrahedron Lett. 1985, 26,
4789. (b) Bartelt, R. J.; Weisleder, D.; Plattner, R. D. J.
Agric. Food Chem. 1990, 38, 2192.
(5) At first, we tried shortcut routes (Scheme 2). The chiral
auxiliary was removed by transamidation to afford Weinreb
amide 10, accompanied by undesired ring-opening
compound 11. A variety of conditions were tried but
formation of 11 could not be suppressed, and all attempts to
convert 11 into 10 or 1 failed. Amide 10 was treated with
excess n-PrMgBr without protecting the hydroxy group to
give the desired compound 1, but only in 10% yield. The
major impurities were retro-aldol reaction products.
Although the hydroxy group was protected, the
(10) Determined by HPLC analysis (98% ee and 96% de):
column, Daicel Chiralcel® OJ (4.6 × 250 mm); solvent,
hexane–i-PrOH (100:1) 0.5 mL/min, 20 °C; detection, 234
nm; tR = 18.9, 19.6 (diastereomers, S = 2%), 22.6
(enantiomer, 1%) and 24.7 [(+)-1, 97%] min. These
retention times of the peaks were identified by the separate
synthesis of other three diastereomers.
(11) Compound (+)-1: colorless oil, [a]D26 +47 (c 0.30, hexane)
{Lit.2, [a]D +48 (c 0.6, hexane)}. 1H NMR (500 MHz, C6D6):
d = 0.82 (3 H, d, J = 7.5 Hz, 5-Me), 0.84 (1 H, t, J = 7.5 Hz,
H-1), 1.58 (3 H, d, J = 7.0 Hz, H-11), 1.62 (2 H, sextet,
J = 7.5 Hz, H-2), 1.65 (3 H, s, 9-Me), 1.67 (1 H, d, J = 3.5
Hz, OH), 1.71 (3 H, s, 7-Me), 2.19 (1 H, td, J = 7.3, 17.5 Hz,
H-3), 2.31 (1 H, td, J = 7.3, 17.5 Hz, H-3), 2.60 (1 H, qd,
J = 7.0, 9.5 Hz, H-5), 4.07 (1 H, dd, J = 2.5, 9.0 Hz, H-6),
5.40 (1 H, q, J = 6.7 Hz, H-10), 5.78 (1 H, s, H-8). All the
signals were fully assigned by HH-COSY, HSQC and
HMBC spectra. In the 1H NMR, signal at d = 2.31 ppm was
misdescribed in ref.2 as 2.21 ppm. 13C NMR (125 MHz in
C6D6): d = 12.5 (7-Me), 13.7 (C-1), 13.9 (C-11), 14.1 (5-
Me), 16.5 (9-Me), 17.0 (C-2), 45.6 (C-3), 48.8 (C-5), 81.3
(C-6), 124.9 (C-10), 132.4 (C-8), 133.2 (C-9), 134.5 (C-7),
213.2 (C-4). HRMS (EI) [M+]: m/z calcd for C14H24O2:
224.1776; found: 224.1779.
corresponding TES ether 12 also gave the ketone 9 in low
yield, accompanied by the over-reacted tertiary alcohol.
Synlett 2005, No. 4, 635–636 © Thieme Stuttgart · New York