Studies toward the synthesis of arteminolide: [5+2] cycloaddition reaction of allenes with oxidopyrylium ions

Article abstract of DOI:10.1016/S0040-4039(00)02324-8

The oxidopyrylium cycloaddition reaction of allenes was investigated. Contrary to other cycloaddition reactions, electron deficient allenes were not reactive at all and electron rich allenes were slightly more reactive than neutral allenes. The intermolecular cycloaddition reaction occurred at the terminal position regardless of substitution patterns. For the intramolecular reaction only the perhydroazulene structure was obtained over other possible products.

Full text of DOI:10.1016/S0040-4039(00)02324-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1695–1698
Studies toward the synthesis of arteminolide: [5+2] cycloaddition
reaction of allenes with oxidopyrylium ions
Hee-Yoon Lee,* Jeong-Hun Sohn and Hyoun Young Kim
Center for Molecular Design and Synthesis, Department of Chemistry and School of Molecular Science (BK21),
Korea Advanced Institute of Science and Technology, Taejon 305-701, South Korea
Received 15 December 2000; accepted 21 December 2000
Abstract—The oxidopyrylium cycloaddition reaction of allenes was investigated. Contrary to other cycloaddition reactions,
electron deficient allenes were not reactive at all and electron rich allenes were slightly more reactive than neutral allenes. The
intermolecular cycloaddition reaction occurred at the terminal position regardless of substitution patterns. For the intramolecular
reaction only the perhydroazulene structure was obtained over other possible products. © 2001 Elsevier Science Ltd. All rights
reserved.
During the course of our studies on the total synthesis
of arteminolide (1), a natural product inhibitor of far-
nesyl transferase,1 we envisioned a biogenetic type syn-
thetic route1,2 using a common intermediate, 2b. The
preparation of 2b could be achieved through an
intramolecular [5+2] cycloaddition reaction of the
allenyl oxidopyrylium ion 3b% as the key step (Fig. 1).
by the electronic bias of allenes in reactivity and
regioselectivity.5 A systematic investigation of the oxi-
dopyrylium cycloaddition reaction of allenes was neces-
sary to evaluate our synthetic strategy.
The intermolecular oxidopyrylium cycloaddition reac-
tion of various allenes was tested to evaluate reactivity
and selectivity of allenes according to the substitution
patterns (Scheme 1). When the oxidopyrylium ion pre-
cursor 43b and an electron rich allene, methoxyallene
(5a),7 were treated with triethylamine in methylene
chloride solution8 cycloadduct 6a was obtained as a
single diastereomer in low yield. Since the major by-
product of the reaction was the dimerization product3b
of the oxidopyrylium ion of 4, methoxyallene was used
as the solvent of the reaction to minimize by-product
formation and to afford a higher yield of 6a. The
cycloaddition reaction of a neutral allene only with
Though [5+2] oxidopyrylium ion cycloaddition reac-
tions with alkenes have been studied for more than 20
years3 and successfully applied to the total synthesis of
natural products,4 the oxidopyrylium cycloaddition
reaction of allenes has not been reported yet. Allenes
are known to be moderately reactive toward cycloaddi-
tion reactions.5a Only electron deficient allenes were
reported to undergo Diels–Alder reactions unless the
reaction was catalysed by transition metals.6 The nitrile
oxide cycloaddition reaction was not strongly affected
OH
O
O
OTBS
-O
O
O
OTBS
O
O
+
O
O
O
OBn
OBn
O
1
3b′
2b
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02324-8

1696
H.-Y. Lee et al. / Tetrahedron Letters 42 (2001) 1695–1698
steric bias, 5b yielded a similar result to the reaction of
5a as a diastereomeric mixture of 6b was obtained. The
structural integrity of 6a and 6b was determined
through H–H COSY and NOE experiments. The oxido-
pyrylium cycloaddition reaction with electron deficient
allenes, 5c9 or 5d10 did not afford any desired products.
The current result shows that the oxidopyrylium
cycloaddition reaction of allenes proceeds preferentially
at the terminal position and the reaction proceeds only
with the sterically less encumbered face to give com-
plete diastereoselectivity. Contrary to substituted
olefins,3b electron deficient allenes are not reactive at all
and electron rich allenes are slightly more reactive than
neutral ones.
With this result in hand, we turned our attention to the
intramolecular cycloaddition reaction. Since it seemed
quite possible that 3a–c could produce 11a–c instead of
2a–c as the reaction could occur at the terminal posi-
tion preferentially, the effect of the length of the tether
on the reaction was investigated. Precursors for the
cycloaddition reaction 3a, 3b and 3c were prepared
from the anion of THP-protected propargyl alcohol 7
in a seven-step sequence (Scheme 2). Addition of 7 to
O
+
NEt3
O
R
R
AcO
O
CH2Cl2
O
5
4
6
Allene
R
Product
Yielda
O CH3
O CH3
5a
5a
6a
6a
25%
46%b
TBSO
5b
6b
10%
BnO
O
OMe
no cycloadduct observed
no cycloadduct observed
5c
5d
Ph
O
S
O
a: yields are isolated and purified yields.
b: methoxyallene was used as the solvent.
Scheme 1.
i) THPOCH2(CH2)nCH2CHO (>90%)
8a-c
HO
Li
THPO
ii) LiAlH4, THF (75-78%)
n
OTHP
7
9a-c
a: n=0
b: n=1
c: n=2
i) NaH, BnBr,
Bu4NI(cat.) ( 93%)
ii) p-TsOH, MeOH
(89-96%)
O
iii) Swern's Oxid. (88%)
Li
O
i)
(76-82%)
TBSO
n
O
n
O
OBn
OBn
AcO
TBSO
ii) VO(acac)2, t-BuOOH, CH2Cl2;
Ac2O, DIPEA, DMAP(cat.) (68-71%)
10a-c
3a-c
Scheme 2.

H.-Y. Lee et al. / Tetrahedron Letters 42 (2001) 1695–1698
1697
O
OTBS
and/or
BnO
OTBS
n
DBU
O
O
BnO
n
O
CH2Cl2
OBn
n+1
AcO
TBSO
3a-c
O
O
11a-c
2a-c
product (yield)
11a (81%)
n
0
1
2
Substrate
3a
3b
3c
2b (45%); diastereoselectivity(α:β=1:2)
no cycloadduct obtained
Scheme 3.
8a–c, followed by LiAlH4 reduction11 afforded allene
9a–c. Protection of the secondary alcohol as the benzyl
ether, followed by deprotection of the primary alcohol
and subsequent oxidation gave allenyl aldehyde 10a–c
in good yield. After the addition of the furfuryl moiety,
selective oxidation of the furan ring with VO(acac)2/t-
BuOOH,12 followed by acetylation of the hydroxy pyra-
nones afforded 3a–c in 68–71% yield.
using 2b as the stereochemistry of benzyl ether in 2b is
not relevant to arteminolide.
Acknowledgements
This work was supported by the Brain Korea 21 Project
2000.
Intramolecular oxidopyrylium-allene cycloaddition of
3a–c with DBU8 produced an interesting result (Scheme
3). As anticipated, the intramolecular cycloaddition
reaction proceeded more efficiently than the intermolec-
ular reaction. In the case of 3a, the cycloadduct 11a was
obtained in 81% yield as a single diastereomer.13 The
cycloaddition reaction of substrates substituted at the
2%-position of the tether have not been reported yet and
it turned out that the diastereoselectivity is as good as
substrates substituted at the 1%-position of the tether.3
The complete diastereoselectivity can be explained
through conformational preference of the benzyl ether
located at the pseudo-equatorial position to avoid
eclipsing interaction with the pyrylium ring. The
cycloaddition reaction of 3b produced 2b, the desired
compound for the total synthesis of arteminolide, in
45% yield as a separable mixture of two diastereomers
(2ba/2bb=2/1). The relative stereochemistry of the two
isomers was determined by 1H NMR coupling con-
stants of the proton at the epimeric center. When 3c
was subjected to the same reaction conditions none of
the possible cycloadduct was produced.
References
1. Lee, S.-H.; Kim, M.-J.; Bok, S. H.; Lee, H.; Kwon, B.-M.
J. Org. Chem. 1998, 63, 7111.
2. Jakupovic, J.; Chen, Z.-L.; Bohlmann, F. Phytochemistry
1987, 26, 2777.
3. (a) Katritzky, A. R.; Dennis, N. Chem. Rev. 1989, 89,
827; (b) Sammes, P. G.; Street, L. J. Gazz. Chim. Ital.
1986, 116, 106; (c) Marshall, K. A.; Mapp, A. K.; Heath-
cock, C. H. J. Org. Chem. 1996, 61, 9135.
4. (a) Wender, P. A.; Jesudason, C. D.; Nakahira, H.;
Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc.
1997, 119, 12976; (b) Wender, P. A.; Lee, H. Y.; Wilhelm,
R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954;
(c) Bauta, W.; Booth, J.; Bos, M. E.; DeLuca, M.;
Diorazio, L.; Donohoe, T.; Magnus, N.; Magnus, P.;
Mendoza, J.; Pye, P.; Tarrant, J.; Thom, S.; Ujjainwalla,
F. Tetrahedron Lett. 1995, 36, 5327.
5. (a) Padwa, A.; Bullock, W. H.; Kline, D. N. J. Org.
Chem. 1989, 54, 2862; (b) Padwa, A.; Kline, D. N.;
Norman, B. H. J. Org. Chem. 1989, 54, 810.
The preferential formation of the five-membered rings
in the intramolecular allenic oxidopyrylium cycloaddi-
tion reaction was quite different from the outcome of
the corresponding intramolecular Diels–Alder reaction
where six-membered ring formations were favored.6a
6. (a) Bull, J. R.; Gordon, R. S.; Hunter, R. Synlett 1989,
599; (b) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am.
Chem. Soc. 1995, 117, 1843.
7. Zimmer, R. Synthesis 1992, 165.
8. General reaction procedure (a) for the intermolecular
reaction: To a 1.0 M solution of 4 with 5 (3 equiv.) in
CH2Cl2, was added Et3N (1.5 equiv.) dropwise at 0°C.
After the reaction was stirred for 20 h at ambient temper-
ature the reaction mixture was diluted with Et2O, washed
subsequently with 0.5N HCl, saturated NaHCO3, and
brine. The product was purified by flash chromatography;
(b) for the intramolecular reaction: DBU (2 equiv.) was
used instead of Et3N and the concentration of the reac-
In summary, the oxidopyrylium cycloaddition reaction
of allenes proceeded preferentially at the terminal posi-
tion and electron-withdrawing groups deactivate allenes
for the cycloaddition reaction. The intramolecular
cycloaddition reaction was sensitive to the length of the
tether. With the desired product 2b in hand, we are
currently pursuing the total synthesis of arteminolide

1698
H.-Y. Lee et al. / Tetrahedron Letters 42 (2001) 1695–1698
tion was 0.02 M. Other reaction conditions were the same
as the intermolecular reaction.
11. Cowie, J. S.; Landor, P. D.; Landor, S. R. J. Chem. Soc.,
Perkin Trans. 1 1973, 720.
9. Lang, R. W.; Hansen, H.-J. Helv. Chim. Acta 1980, 63,
12. Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J.
438.
Org. Chem. 1989, 54, 2085.
10. Denmark, S. E.; Harmata, M. A.; White, K. S. J. Org.
Chem. 1987, 52, 4031.
13. The stereochemistry was assigned with the DIBAL reduc-
tion product of 9a through NOE experiment.
.
.